Search results for: genetic code

Authors: Simone Raimondi De Souza, Glaucia Maria Moraes De Oliveira, Ronir Raggio Luiz, Glorimar Rosa

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Introduction: Obesity is among the main risk factors for cardiovascular disease (CVD). Genesis is multifactorial, including genetic, hormonal and environmental factors disorders, among which inadequate feeding pattern, for which nutritional counseling strategies have proven effective. The consumption of beta-glucans (soluble fibers that reportedly promote satiety) present in oat bran can be an effective strategy for preventing and treating obesity. Other benefits have been observed with oat bran consumption, such as reduction of hypercholesterolemia and hyperglycemia, two other risk factors for CVD. Objectives: To analyze the effect of oat bran consumption associated with nutritional counseling in reducing body mass index (BMI), blood cholesterol, glucose profile, waist and neck circumference in obese individuals, and to evaluate the change in eating pattern. Methods: clinical trial, randomized, double-blind, placebo-controlled, lasting 90 days with adults of both genders, with BMI ≥30kg/m2. The study was approved by the Ethics in Research involving human beings in a public institute of cardiology, in Rio de Janeiro, Brazil. Individuals were invited to participate and accepted formally by signing the Terms of Consent. Participants were randomized into oat bran group (gOB) or placebo group (gPCB) and received, respectively: morning prepared consisting of 40g oat bran, 30g of skimmed milk powder and 1g sweetener sucralose; refined flour 40g rice, 30g of milk powder and 1g sweetener sucralose. The Ten Steps to Healthy Eating, of Brazilian Ministry of Health were used to support the nutritional counseling. Variables analyzed: gender; age; BMI, waist circumference (WC) neck circumference (NC); systolic blood pressure (SBP); diastolic blood pressure (DBP); food consumption, total cholesterol (TC), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), non-HDL cholesterol (nHDLc), triglycerides (TG), fasting glucose (FG), fasting insulin (FI) and HOMA-IR. Dietary intake was assessed by 24-hour dietary recall. The Diet Quality Index revised for the Brazilian population (IQD-R) assessed quality of feeding pattern. Statistical analyzes were performed using SPSS version 21, considering statistically significant p-value less than 0.05. Results: A total of 38 participants were included, age = 50 ± 7,6years, 63% women. 19 subjects were placed in gOB and 19 in gPCB. After intervention, statistically significant reductions were observed in the following parameters: in gOB: IQD-R, TC, LDL-c, nHDL-c, FI, SBP, DBP, BMI, WC, NC; in gPCB: IQD-R, LDL-c, SBP, DBP, BMI, WC, NC. No statistically significant differences were observed in the results between groups. Conclusion: Our results reinforce nutritional counseling as important strategy for prevention and treatment of obesity and suggest that inclusion of oat bran in daily diet can bring additional benefits controlling risk factors for CVD. More studies are needed to establish all benefits of oat bran to human health as well as the ideal daily dose for consumption.

Keywords: oat bran, cardiovascular disease, nutritional counseling, obesity

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Authors: Nisha Sharma, Mili Kaur, Ashutosh Halder, Seema Kaushal, Manoj Kumar, Manish Jain

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Purpose: To investigate microRNAs (miRNA) as an epigenomic etiological factor in idiopathic non-obstructive azoospermia (NOA). In order to achieve the same, an association was seen between occupational exposure to radiation, thermal, and chemical factors and idiopathic cases of non-obstructive azoospermia, and later, testicular differential miRNA expression profiling was done in exposure group NOA cases. Method: It is a prospective study in which 200 apparent idiopathic male factor infertility cases, who have been advised to undergo testicular fine needle aspiration (FNA) evaluation, are recruited. A detailed occupational history was taken to understand the possible type of exposure due to the nature and duration of work. A total of 26 patients were excluded upon XY-FISH and Yq microdeletion tests due to the presence of genetic causes of infertility, 6 hypospermatogeneis (HS), six Sertoli cell-only syndrome (SCOS), and six normospermatogeneis patients testicular FNA samples were used for RNA isolation followed by small RNA sequencing and nCounter miRNA expression analysis. Differential miRNA expression profile of HS and SCOS patients was done. A web-based tool, miRNet, was used to predict the interacting compounds or chemicals using the shortlisted miRNAs with high fold change. The major limitation encountered in this study was the insufficient quantity of testicular FNA sample used for total RNA isolation, which resulted in a low yield and RNA integrity number (RIN) value. Therefore, the number of RNA samples admissible for differential miRNA expression analysis was very small in comparison to the total number of patients recruited. Results: Differential expression analysis revealed 69 down-regulated and 40 up-regulated miRNAs in HS and 66 down-regulated and 33 up-regulated miRNAs in SCOS in comparison to normospermatogenesis controls. The miRNA interaction analysis using the miRNet tool showed that the differential expression profiles of HS and SCOS patients were associated with arsenic trioxide, bisphenol-A, calcium sulphate, lithium, and cadmium. These compounds are reproductive toxins and might be responsible for miRNA-mediated epigenetic deregulation leading to NOA. The association between occupational risk factor exposure and the non-exposure group of NOA patients was not statistically significant, with ꭓ2 (3, N= 178) = 6.70, p= 0.082. The association between individual exposure groups (radiation, thermal, and chemical) and various sub-types of NOA is also not significant, with ꭓ2 (9, N= 178) = 15.06, p= 0.089. Functional analysis of HS and SCOS patients' miRNA profiles revealed some important miR-family members in terms of male fertility. The miR-181 family plays a role in the differentiation of spermatogonia and spermatocytes, as well as the transcriptional regulation of haploid germ cells. The miR-34 family is expressed in spermatocytes and round spermatids and is involved in the regulation of SSCs differentiation. Conclusion: The reproductive toxins might adopt the miRNA-mediated mechanism of disease development in idiopathic cases of NOA. Chemical compound induced; miRNA-mediated epigenetic deregulation can give a future perspective on the etiopathogenesis of the disease.

Keywords: microRNA, non-obstructive azoospermia (NOA), occupational exposure, hypospermatogenesis (HS), Sertoli cell only syndrome (SCOS)

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Authors: Kamyar Tolouei, Ehsan Moosavi

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In open-pit mines, the long-term production scheduling optimization problem (LTPSOP) is a complicated problem that contains constraints, large datasets, and uncertainties. Uncertainty in the output is caused by several geological, economic, or technical factors. Due to its dimensions and NP-hard nature, it is usually difficult to find an ideal solution to the LTPSOP. The optimal schedule generally restricts the ore, metal, and waste tonnages, average grades, and cash flows of each period. Past decades have witnessed important measurements of long-term production scheduling and optimal algorithms since researchers have become highly cognizant of the issue. In fact, it is not possible to consider LTPSOP as a well-solved problem. Traditional production scheduling methods in open-pit mines apply an estimated orebody model to produce optimal schedules. The smoothing result of some geostatistical estimation procedures causes most of the mine schedules and production predictions to be unrealistic and imperfect. With the expansion of simulation procedures, the risks from grade uncertainty in ore reserves can be evaluated and organized through a set of equally probable orebody realizations. In this paper, to synthesize grade uncertainty into the strategic mine schedule, a stochastic integer programming framework is presented to LTPSOP. The objective function of the model is to maximize the net present value and minimize the risk of deviation from the production targets considering grade uncertainty simultaneously while satisfying all technical constraints and operational requirements. Instead of applying one estimated orebody model as input to optimize the production schedule, a set of equally probable orebody realizations are applied to synthesize grade uncertainty in the strategic mine schedule and to produce a more profitable and risk-based production schedule. A mixture of metaheuristic procedures and mathematical methods paves the way to achieve an appropriate solution. This paper introduced a hybrid model between the augmented Lagrangian relaxation (ALR) method and the metaheuristic algorithm, the Harris Hawks optimization (HHO), to solve the LTPSOP under grade uncertainty conditions. In this study, the HHO is experienced to update Lagrange coefficients. Besides, a machine learning method called Random Forest is applied to estimate gold grade in a mineral deposit. The Monte Carlo method is used as the simulation method with 20 realizations. The results specify that the progressive versions have been considerably developed in comparison with the traditional methods. The outcomes were also compared with the ALR-genetic algorithm and ALR-sub-gradient. To indicate the applicability of the model, a case study on an open-pit gold mining operation is implemented. The framework displays the capability to minimize risk and improvement in the expected net present value and financial profitability for LTPSOP. The framework could control geological risk more effectively than the traditional procedure considering grade uncertainty in the hybrid model framework.

Keywords: grade uncertainty, metaheuristic algorithms, open-pit mine, production scheduling optimization

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Authors: Kimberley Adamek

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According to the Council on Tall Buildings, there has been a rapid increase in the construction of tall or “megatall” buildings over the past two decades. Simultaneously, the New England Journal of Medicine has reported that there has been a steady increase in climate related natural disasters since the 1970s; the eastern expansion of the USA's infamous Tornado Alley being just one of many current issues. In the future, this could mean that tall buildings, which already guide high speed winds down to pedestrian levels would have to withstand stronger forces and protect pedestrians in more extreme ways. Although many projects are required to be verified within wind tunnels and a handful of cities such as San Francisco have included wind testing within building code standards, there are still many examples where wind is only considered for basic loading. This typically results in and an increase of structural expense and unwanted mitigation strategies that are proposed late within a project. When building cities, architects rarely consider how each building alters the invisible patterns of wind and how these alterations effect other areas in different ways later on. It is not until these forces move, overpower and even destroy cities that people take notice. For example, towers have caused winds to blow objects into people (Walkie-Talkie Tower, Leeds, England), cause building parts to vibrate and produce loud humming noises (Beetham Tower, Manchester), caused wind tunnels in streets as well as many other issues. Alternatively, there exist towers which have used their form to naturally draw in air and ventilate entire facilities in order to eliminate the needs for costly HVAC systems (The Met, Thailand) and used their form to increase wind speeds to generate electricity (Bahrain Tower, Dubai). Wind and weather exist and effect all parts of the world in ways such as: Science, health, war, infrastructure, catastrophes, tourism, shopping, media and materials. Working in partnership with a leading wind engineering company RWDI, a series of tests, images and animations documenting discovered interactions of different building forms with wind will be collected to emphasize the possibilities for wind use to architects. A site within San Francisco (due to its increasing tower development, consistently wind conditions and existing strict wind comfort criteria) will host a final design. Iterations of this design will be tested within the wind tunnel and computational fluid dynamic systems which will expose, utilize and manipulate wind flows to create new forms, technologies and experiences. Ultimately, this thesis aims to question the amount which the environment is allowed to permeate building enclosures, uncover new programmatic possibilities for wind in buildings, and push the boundaries of working with the wind to ensure the development and safety of future cities. This investigation will improve and expand upon the traditional understanding of wind in order to give architects, wind engineers as well as the general public the ability to broaden their scope in order to productively utilize this living phenomenon that everyone constantly feels but cannot see.

Keywords: wind engineering, climate, visualization, architectural aerodynamics

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Authors: Sharma Aseem, Dhurat Rachita, Pawar Varsha, Khalse Manisha

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Introduction: Androgenetic alopecia (AGA) is a prevalent condition characterized by progressive hair thinning driven by genetic and androgen-related factors. The current FDA-approved treatments include oral finasteride and topical minoxidil, though many patients seek combination therapies to enhance results. This study aims to evaluate the effectiveness of a combination therapy involving Minoxidil, Finasteride, and Capixyl™ based on feedback from dermatologists. Methodology: A survey, validated by experts, was distributed to 29 leading dermatologists across India (in Tier 1 and 2 cities). The survey examined real-world clinical experiences, focusing on patient outcomes and the overall effectiveness of the mentioned formulation. Results: Among the surveyed dermatologists, 41.4% identified women aged 35-40 as the most frequently diagnosed with female pattern hair loss. The combination therapy with Minoxidil, Finasteride, and Capixyl™ was utilized by 34.5% of dermatologists for over 60 patients per month. The majority highlighted the benefits of this combination therapy, which acts via multiple mechanisms, such as vasodilation and dihydrotestosterone (DHT) receptor blockade, resulting in improved hair regrowth. Additionally, patients demonstrated better clinical outcomes, enhanced compliance, and fewer side effects. Demographically, younger patients, particularly those with AGA for less than 10 years, responded more positively to the treatment. Early intervention led to quicker and more significant results. Overall satisfaction among dermatologists was high, with 86.2% expressing positive feedback on the therapy. In terms of treatment outcomes, 51.7% of dermatologists observed visible results within 4-6 months, while 34.5% noticed a significant reduction in hair fall within 8-12 weeks. Improvements in scalp health were reported by 48.3%, and 51.7% saw an increased hair density within 3-4 months. Despite mild side effects such as scalp irritation, dryness, flaking, and occasional issues like folliculitis, headaches, itching, and redness, patient satisfaction remained high. Dermatologists reported that 93.1% of patients experienced faster and better hair regrowth with Capixyl™ compared to Minoxidil alone. Suggestions for improving the formulation included incorporating peptides like Saw Palmetto and enhancing product packaging to better meet patient needs. Discussion: The combination of Minoxidil, Finasteride, and Capixyl™ yielded positive clinical outcomes, especially in improving hair density, scalp health, and overall patient satisfaction. Dermatologists found that Capixyl™ peptides enhanced the therapeutic effect, promoting hair regrowth and improving compliance. While side effects were generally mild, there were suggestions to further improve the formulation by adding additional peptides like Saw Palmetto. Conclusion: The combination of Minoxidil and Finasteride fortified with Capixyl™ presents a promising therapeutic option for managing AGA. Dermatologists reported significant improvements in hair density, scalp health, and patient satisfaction. With its favorable efficacy and manageable side effects, this formulation proves to be a valuable addition to the treatment landscape for AGA.

Keywords: androgenetic alopecia, combination therapy, minoxidil, finasteride, capixyl

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Authors: Arup Dutta, Badrul Alam, Sayed M. Wazed, Taslima Newaz, Srobonti Dutta

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Background: In today's world, with modern science and contemporary technology, a lot of diseases may be quickly identified and ruled out, but children's fever of unknown origin (FUO) still presents diagnostic difficulties in clinical settings. Any fever that reaches 38 °C and lasts for more than seven days without a known cause is now classified as a fever of unknown origin (FUO). Despite tremendous progress in the medical sector, fever of unknown origin, or FOU, persists as a major health issue and a major contributor to morbidity and mortality, particularly in children, and its spectrum is sometimes unpredictable. The etiology is influenced by geographic location, age, socioeconomic level, frequency of antibiotic resistance, and genetic vulnerability. Since there are currently no known diagnostic algorithms, doctors are forced to evaluate each patient one at a time with extreme caution. A persistent fever poses difficulties for both the patient and the doctor. This prospective observational study was carried out in a Bangladeshi tertiary care hospital from June 2018 to May 2019 with the goal of identifying the epidemiological patterns of fever of unknown origin in pediatric patients. Methods: It was a hospital-based prospective observational study carried out on 106 children (between 2 months and 12 years) with prolonged fever of >38.0 °C lasting for more than 7 days without a clear source. Children with additional chronic diseases or known immunodeficiency problems were not allowed. Clinical practices that helped determine the definitive etiology were assessed. Initial testing included a complete blood count, a routine urine examination, PBF, a chest X-ray, CRP measurement, blood cultures, serology, and additional pertinent investigations. The analysis focused mostly on the etiological results. The standard program SPSS 21 was used to analyze all of the study data. Findings: A total of 106 patients identified as having FUO were assessed, with over half (57.5%) being female and the majority (40.6%) falling within the 1 to 3-year age range. The study categorized the etiological outcomes into five groups: infections, malignancies, connective tissue conditions, miscellaneous, and undiagnosed. In the group that was being studied, infections were found to be the main cause in 44.3% of cases. Undiagnosed cases came in at 31.1%, cancers at 10.4%, other causes at 8.5%, and connective tissue disorders at 4.7%. Hepato-splenomegaly was seen in people with enteric fever, malaria, acute lymphoid leukemia, lymphoma, and hepatic abscesses, either by itself or in combination with other conditions. About 53% of people who were not diagnosed also had hepato-splenomegaly at the same time. Conclusion: Infections are the primary cause of PUO (pyrexia of unknown origin) in children, with undiagnosed cases being the second most common cause. An incremental approach is beneficial in the process of diagnosing a condition. Non-invasive examinations are used to diagnose infections and connective tissue disorders, while invasive investigations are used to diagnose cancer and other ailments. According to this study, the prevalence of undiagnosed diseases is still remarkable, so extensive historical analysis and physical examinations are necessary in order to provide a precise diagnosis.

Keywords: children, diagnostic challenges, fever of unknown origin, pediatric fever, undiagnosed diseases

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Authors: Mariam Khaled, Noha Farag, Ghada Mohamed Abdel Salam, Khaled Abu-Aisha, Mohamed El-Azizi

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Gastric and colorectal cancers are among the most frequent causes of cancer-associated mortalities in Africa. They have been considered as a global public health concern, as nearly one million new cases are reported per year. IL-1β is a pro-inflammatory cytokine-produced by activated macrophages and monocytes- and a member of the IL-1 family. The inactive IL-1β precursor is cleaved and activated by caspase-1 enzyme, which itself is activated by the assembly of intracellular structures defined as NLRP3 (Nod Like receptor P3) inflammasomes. Activated IL-1β stimulates the Interleukin-1 receptor type-1 (IL-1R1), which is responsible for the initiation of a signal transduction pathway leading to cell proliferation. It has been proven that the IL-1β gene is a highly polymorphic gene in which single nucleotide polymorphisms (SNPs) may affect its expression. It has been previously reported that SNPs including base transitions between C and T at positions, -511 (C-T; dbSNP: rs16944) and -31 (C-T; dbSNP: rs1143627), from the transcriptional start site, contribute to the pathogenesis of gastric and colorectal cancers by affecting IL-1β levels. Altered production of IL-1β due to such polymorphisms is suspected to stimulate an amplified inflammatory response and promote Epithelial Mesenchymal Transition leading to malignancy. Allele frequency distribution of the IL-1β-31 and -511 SNPs, in different populations, and their correlation to the incidence of gastric and colorectal cancers, has been intriguing to researchers worldwide. The current study aims to investigate allele distributions of the IL-1β SNPs among gastric and colorectal cancers Egyptian patients. In order to achieve to that, 89 Biopsy and surgical specimens from the antrum and corpus mucosa of chronic gastritis subjects and gastric and colorectal carcinoma patients was collected for DNA extraction followed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The amplified PCR products of IL-1β-31C > T and IL-1β-511T > C were digested by incubation with the restriction endonuclease enzymes ALu1 and Ava1. Statistical analysis was carried out to determine the allele frequency distribution in the three studied groups. Also, the effect of the IL-1β -31 and -511 SNPs on nuclear factor binding was analyzed using Fluorescence Electrophoretic Mobility Shift Assay (EMSA), preceded by nuclear factor extraction from gastric and colorectal tissue samples and LPS stimulated monocytes. The results of this study showed that a significantly higher percentage of Egyptian gastric cancer patients have a homozygous CC genotype at the IL-1β-31 position and a heterozygous TC genotype at the IL-1β-511 position. Moreover, a significantly higher percentage of the colorectal cancer patients have a homozygous CC genotype at the IL-1β-31 and -511 positions as compared to the control group. In addition, the EMSA results showed that IL-1β-31C/T and IL-1β-511T/C SNPs do not affect nuclear factor binding. Results of this study suggest that the IL-1β-31 C/T and IL-1β-511 T/C may be correlated to the incidence of gastric cancer in Egyptian patients; however, similar findings couldn’t be proven in the colorectal cancer patients group for the IL-1β-511 T/C SNP. This is the first study to investigate IL-1β -31 and -511 SNPs in the Egyptian population.

Keywords: colorectal cancer, Egyptian patients, gastric cancer, interleukin-1β, single nucleotide polymorphisms

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Authors: Sachin Mulmi Shrestha, Xin Fang, Hui Ye, Lihua Ren, Qinghua Ji, Ruihua Shi

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Background: Esophageal squamous cell carcinoma (ESCC) is a tumor arising from esophageal epithelial cells and is one of the major disease subtype in Asian countries, including China. Esophageal cancer is the 7th highest incidence based on the 2020 data of GLOBOCAN. The pathogenesis of cancer is still not well understood as many molecular and genetic basis of esophageal carcinogenesis has yet to be clearly elucidated. Circular RNAs are RNA molecules that are formed by back-splicing covalently joined 3′- and 5′-endsrather than canonical splicing, and recent data suggest circular RNAs could sponge miRNAs and are enriched with functional miRNA binding sites. Hence, we studied the mechanism of circular RNA, its biological function, and the relationship between microRNA in the carcinogenesis of ESCC. Methods: 4 pairs of normal and esophageal cancer tissues were collected in Zhongda hospital, affiliated to Southeast University, and high-throughput RNA sequencing was done. The result revealed that circ_0032746 was upregulated, and thus we selected circ_0032746 for further study. The backsplice junction of circRNA was validated by sanger sequence, and stability was determined by RNASE R assay. The binding site of circRNA and microRNA was predicted by circinteractome,mirandaand RNAhybrid database. Furthermore, circRNA was silenced by siRNA and then by lentivirus. The regulatory axis of circ0032746/miR4270 was validated by shRNA, mimic, and inhibitor transfection. Then, in vitro experiments were performed to assess the role of circ0032746 on proliferation (CCK-8 assay and colon formation assay), migration and invasion (Transewell assay), and apoptosis of ESCC. Results: The upregulated circ0032746 was validated in 9 pairs of tissues and 5 types of cell lines by qPCR, which showed high expression and was statistically significant (P<0.005) ). Upregulated circ0032746 was silenced by shRNA, which showed significant knockdown in KYSE 30 and TE-1 cell lines expression compared to control. Nuclear and cytoplasmic mRNA fraction experiment displayed the cytoplasmic location of circ0032746. The sponging of miR4270 was validated by co-transfection of sh-circ0032746 and mimic or inhibitor. Transfection with mimic showed the decreased expression of circ_0032746, whereas inhibitor inhibited the result. In vitro experiments showed that silencing of circ_0032746 inhibited the proliferation, migration, and invasion compared to the negative control group. The apoptosis was seen higher in a knockdown group than in the control group. Furthermore, 11 common mircoRNA target mRNAs were predicted by Targetscan, MirTarbase, and miRanda database, which may further play role in the pathogenesis. Conclusion: Our results showed that novel circ_0032746 is upregulated in ESCC and plays role in itsoncogenicity. Silencing of circ_0032746 inhibits the proliferation and migration of ESCC whereas increases the apoptosis of cancer cells. Hence, circ0032746 acts as an oncogene in ESCC by sponging with miR4270 and could be a potential biomarker in the diagnosis of ESCC in the future.

Keywords: circRNA, esophageal squamous cell carcinoma, microRNA, upregulated

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Authors: Meiling Yu, Nadia Rouatbi, Khuloud T. Al-Jamal

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Background: Treatment of neurological disorders with modern medical and surgical approaches remains difficult. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. The treatment of brain diseases with gene therapy requires the gene-editing tool to be delivered efficiently to the central nervous system. In this study, we explored the efficiency of different delivery routes, namely intravenous (i.v.), intra-cranial (i.c.), and intra-nasal (i.n.), to deliver stable nucleic acid-lipid particles (SNALPs) containing gene-editing tools namely Cas9 mRNA and sgRNA encoding for GFP as a reporter protein. We hypothesise that SNALPs can reach the brain and perform gene-editing to different extents depending on the administration route. Intranasal administration (i.n.) offers an attractive and non-invasive way to access the brain circumventing the blood–brain barrier. Successful delivery of gene-editing tools to the brain offers a great opportunity for therapeutic target validation and nucleic acids therapeutics delivery to improve treatment options for a range of neurodegenerative diseases. In this study, we utilised Rosa26-Cas9 knock-in mice, expressing GFP, to study brain distribution and gene-editing efficiency of SNALPs after i.v.; i.c. and i.n. routes of administration. Methods: Single guide RNA (sgRNA) against GFP has been designed and validated by in vitro nuclease assay. SNALPs were formulated and characterised using dynamic light scattering. The encapsulation efficiency of nucleic acids (NA) was measured by RiboGreen™ assay. SNALPs were incubated in serum to assess their ability to protect NA from degradation. Rosa26-Cas9 knock-in mice were i.v., i.n., or i.c. administered with SNALPs to test in vivo gene-editing (GFP knockout) efficiency. SNALPs were given as three doses of 0.64 mg/kg sgGFP following i.v. and i.n. or a single dose of 0.25 mg/kg sgGFP following i.c.. knockout efficiency was assessed after seven days using Sanger Sequencing and Inference of CRISPR Edits (ICE) analysis. In vivo, the biodistribution of DiR labelled SNALPs (SNALPs-DiR) was assessed at 24h post-administration using IVIS Lumina Series III. Results: Serum-stable SNALPs produced were 130-140 nm in diameter with ~90% nucleic acid loading efficiency. SNALPs could reach and stay in the brain for up to 24h following i.v.; i.n. and i.c. administration. Decreasing GFP expression (around 50% after i.v. and i.c. and 20% following i.n.) was confirmed by optical imaging. Despite the small number of mice used, ICE analysis confirmed GFP knockout in mice brains. Additional studies are currently taking place to increase mice numbers. Conclusion: Results confirmed efficient gene knockout achieved by SNALPs in Rosa26-Cas9 knock-in mice expressing GFP following different routes of administrations in the following order i.v.= i.c.> i.n. Each of the administration routes has its pros and cons. The next stages of the project involve assessing gene-editing efficiency in wild-type mice and replacing GFP as a model target with therapeutic target genes implicated in Motor Neuron Disease pathology.

Keywords: CRISPR, nanoparticles, brain diseases, administration routes

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Authors: Maria Amelia V. C. Araujo, Billy J. Araujo, Brian Greenwood

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The flow over a backward-facing step is characterized by the presence of flow separation, recirculation and reattachment, for a simple geometry. This type of fluid behaviour takes place in many practical engineering applications, hence the reason for being investigated. Historically, fluid flows over a backward-facing step have been examined in many experiments using a variety of measuring techniques such as laser Doppler velocimetry (LDV), hot-wire anemometry, particle image velocimetry or hot-film sensors. However, some of these techniques cannot conveniently be used in separated flows or are too complicated and expensive. In this work, the applicability of the acoustic Doppler velocimetry (ADV) technique is investigated to such type of flows, at various Reynolds numbers corresponding to different flow regimes. The use of this measuring technique in separated flows is very difficult to find in literature. Besides, most of the situations where the Reynolds number effect is evaluated in separated flows are in numerical modelling. The ADV technique has the advantage in providing nearly non-invasive measurements, which is important in resolving turbulence. The ADV Nortek Vectrino+ was used to characterize the flow, in a recirculating laboratory flume, at various Reynolds Numbers (Reh = 3738, 5452, 7908 and 17388) based on the step height (h), in order to capture different flow regimes, and the results compared to those obtained using other measuring techniques. To compare results with other researchers, the step height, expansion ratio and the positions upstream and downstream the step were reproduced. The post-processing of the AVD records was performed using a customized numerical code, which implements several filtering techniques. Subsequently, the Vectrino noise level was evaluated by computing the power spectral density for the stream-wise horizontal velocity component. The normalized mean stream-wise velocity profiles, skin-friction coefficients and reattachment lengths were obtained for each Reh. Turbulent kinetic energy, Reynolds shear stresses and normal Reynolds stresses were determined for Reh = 7908. An uncertainty analysis was carried out, for the measured variables, using the moving block bootstrap technique. Low noise levels were obtained after implementing the post-processing techniques, showing their effectiveness. Besides, the errors obtained in the uncertainty analysis were relatively low, in general. For Reh = 7908, the normalized mean stream-wise velocity and turbulence profiles were compared directly with those acquired by other researchers using the LDV technique and a good agreement was found. The ADV technique proved to be able to characterize the flow properly over a backward-facing step, although additional caution should be taken for measurements very close to the bottom. The ADV measurements showed reliable results regarding: a) the stream-wise velocity profiles; b) the turbulent shear stress; c) the reattachment length; d) the identification of the transition from transitional to turbulent flows. Despite being a relatively inexpensive technique, acoustic Doppler velocimetry can be used with confidence in separated flows and thus very useful for numerical model validation. However, it is very important to perform adequate post-processing of the acquired data, to obtain low noise levels, thus decreasing the uncertainty.

Keywords: ADV, experimental data, multiple Reynolds number, post-processing

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Authors: Faheema Khan

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To investigate the ability of sensitive and tolerant genotype of Glycine max to adapt to a saline environment in a field, we examined the growth performance, water relation and activities of antioxidant enzymes in relation to photosynthetic rate, chlorophyll a fluorescence, photosynthetic pigment concentration, protein and proline in plants exposed to salt stress. Ten soybean genotypes (Pusa-20, Pusa-40, Pusa-37, Pusa-16, Pusa-24, Pusa-22, BRAGG, PK-416, PK-1042, and DS-9712) were selected and grown hydroponically. After 3 days of proper germination, the seedlings were transferred to Hoagland’s solution (Hoagland and Arnon 1950). The growth chamber was maintained at a photosynthetic photon flux density of 430 μmol m−2 s−1, 14 h of light, 10 h of dark and a relative humidity of 60%. The nutrient solution was bubbled with sterile air and changed on alternate days. Ten-day-old seedlings were given seven levels of salt in the form of NaCl viz., T1 = 0 mM NaCl, T2=25 mM NaCl, T3=50 mM NaCl, T4=75 mM NaCl, T5=100 mM NaCl, T6=125 mM NaCl, T7=150 mM NaCl. The investigation showed that genotype Pusa-24, PK-416 and Pusa-20 appeared to be the most salt-sensitive. genotypes as inferred from their significantly reduced length, fresh weight and dry weight in response to the NaCl exposure. Pusa-37 appeared to be the most tolerant genotype since no significant effect of NaCl treatment on growth was found. We observed a greater decline in the photosynthetic variables like photosynthetic rate, chlorophyll fluorescence and chlorophyll content, in salt-sensitive (Pusa-24) genotype than in salt-tolerant Pusa-37 under high salinity. Numerous primers were verified on ten soybean genotypes obtained from Operon technologies among which 30 RAPD primers shown high polymorphism and genetic variation. The Jaccard’s similarity coefficient values for each pairwise comparison between cultivars were calculated and similarity coefficient matrix was constructed. The closer varieties in the cluster behaved similar in their response to salinity tolerance. Intra-clustering within the two clusters precisely grouped the 10 genotypes in sub-cluster as expected from their physiological findings.Salt tolerant genotype Pusa-37, was further analysed by 2-Dimensional gel electrophoresis to analyse the differential expression of proteins at high salt stress. In the Present study, 173 protein spots were identified. Of these, 40 proteins responsive to salinity were either up- or down-regulated in Pusa-37. Proteomic analysis in salt-tolerant genotype (Pusa-37) led to the detection of proteins involved in a variety of biological processes, such as protein synthesis (12 %), redox regulation (19 %), primary and secondary metabolism (25 %), or disease- and defence-related processes (32 %). In conclusion, the soybean plants in our study responded to salt stress by changing their protein expression pattern. The photosynthetic, biochemical and molecular study showed that there is variability in salt tolerance behaviour in soybean genotypes. Pusa-24 is the salt-sensitive and Pusa-37 is the salt-tolerant genotype. Moreover this study gives new insights into the salt-stress response in soybean and demonstrates the power of genomic and proteomic approach in plant biology studies which finally could help us in identifying the possible regulatory switches (gene/s) controlling the salt tolerant genotype of the crop plants and their possible role in defence mechanism.

Keywords: glycine max, salt stress, RAPD, genomic and proteomic variability

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Authors: Massimiliano Biagini, Marco Spinsanti, Gabriella De Angelis, Sara Tomei, Ilaria Ferlenghi, Maria Scarselli, Alessia Biolchi, Alessandro Muzzi, Brunella Brunelli, Silvana Savino, Marzia M. Giuliani, Isabel Delany, Paolo Costantino, Rino Rappuoli, Vega Masignani, Nathalie Norais

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The gram-negative bacterium Neisseria meningitidis serogroup B (MenB) is an exclusively human pathogen representing the major cause of meningitides and severe sepsis in infants and children but also in young adults. This pathogen is usually present in the 30% of healthy population that act as a reservoir, spreading it through saliva and respiratory fluids during coughing, sneezing, kissing. Among surface-exposed protein components of this diplococcus, factor H binding protein is a lipoprotein proved to be a protective antigen used as a component of the recently licensed Bexsero vaccine. fHbp is a highly variable meningococcal protein: to reflect its remarkable sequence variability, it has been classified in three variants (or two subfamilies), and with poor cross-protection among the different variants. Furthermore, the level of fHbp expression varies significantly among strains, and this has also been considered an important factor for predicting MenB strain susceptibility to anti-fHbp antisera. Different methods have been used to assess fHbp expression on meningococcal strains, however, all these methods use anti-fHbp antibodies, and for this reason, the results are affected by the different affinity that antibodies can have to different antigenic variants. To overcome the limitations of an antibody-based quantification, we developed a quantitative Mass Spectrometry (MS) approach. Selected Reaction Monitoring (SRM) recently emerged as a powerful MS tool for detecting and quantifying proteins in complex mixtures. SRM is based on the targeted detection of ProteoTypicPeptides (PTPs), which are unique signatures of a protein that can be easily detected and quantified by MS. This approach, proven to be highly sensitive, quantitatively accurate and highly reproducible, was used to quantify the absolute amount of fHbp antigen in total extracts derived from 105 clinical isolates, evenly distributed among the three main variant groups and selected to be representative of the fHbp circulating subvariants around the world. We extended the study at the genetic level investigating the correlation between the differential level of expression and polymorphisms present within the genes and their promoter sequences. The implications of fHbp expression on the susceptibility of the strain to killing by anti-fHbp antisera are also presented. To date this is the first comprehensive fHbp expression profiling in a large panel of Neisseria meningitidis clinical isolates driven by an antibody-independent MS-based methodology, opening the door to new applications in vaccine coverage prediction and reinforcing the molecular understanding of released vaccines.

Keywords: quantitative mass spectrometry, Neisseria meningitidis, vaccines, bexsero, molecular epidemiology

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Authors: Changhan Ouyang, Zhonglin Xie

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In response to proatherosclerotic factors such as oxidized lipids, or to therapeutic interventions such as angioplasty, stents, or bypass surgery, vascular smooth muscle cells (VSMCs) migrate from the media to the intima, resulting in intimal hyperplasia, restenosis, graft failure, or atherosclerosis. These proatherosclerotic factors also activate autophagy in VSMCs. However, the functional role of autophagy in vascular health and disease remains poorly understood. In the present study, we determined the role of autophagy in the regulation of VSMC migration. Autophagy activity in cultured human aortic smooth muscle cells (HASMCs) and mouse carotid arteries was measured by Western blot analysis of microtubule-associated protein 1 light chain 3 B (LC3B) and P62. The VSMC migration was determined by scratch wound assay and transwell migration assay. Ex vivo smooth muscle cell migration was determined using aortic ring assay. The in vivo SMC migration was examined by staining the carotid artery sections with smooth muscle alpha actin (alpha SMA) after carotid artery ligation. To examine the relationship between autophagy and neointimal hyperplasia, C57BL/6J mice were subjected to carotid artery ligation. Seven days after injury, protein levels of Atg5, Atg7, Beclin1, and LC3B drastically increased and remained higher in the injured arteries three weeks after the injury. In parallel with the activation of autophagy, vascular injury-induced neointimal hyperplasia as estimated by increased intima/media ratio. The en face staining of carotid artery showed that vascular injury enhanced alpha SMA staining in the intimal cells as compared with the sham operation. Treatment of HASMCs with platelet-derived growth factor (PDGF), one of the major factors for vascular remodeling in response to vascular injury, increased Atg7 and LC3 II protein levels and enhanced autophagosome formation. In addition, aortic ring assay demonstrated that PDGF treated aortic rings displayed an increase in neovessel formation compared with control rings. Whole mount staining for CD31 and alpha SMA in PDGF treated neovessels revealed that the neovessel structures were stained by alpha SMA but not CD31. In contrast, pharmacological and genetic suppression of autophagy inhibits VSMC migration. Especially, gene silencing of Atg7 inhibited VSMC migration induced by PDGF. Furthermore, three weeks after ligation, markedly decreased neointimal formation was found in mice treated with chloroquine, an inhibitor of autophagy. Quantitative morphometric analysis of the injured vessels revealed a marked reduction in the intima/media ratio in the mice treated with chloroquine. Conclusion: Autophagy activation increases VSMC migration while autophagy suppression inhibits VSMC migration. These findings suggest that autophagy suppression may be an important therapeutic strategy for atherosclerosis and intimal hyperplasia.

Keywords: autophagy, vascular smooth muscle cell, migration, neointimal formation

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Authors: Alena Nesterenko, Svetlana Petrikova

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Research evaluation is one of the most important elements of self-regulation and development of researchers as it is impartial and independent process of assessment. The method of expert evaluations as a scientific instrument solving complicated non-formalized problems is firstly a scientifically sound way to conduct the assessment which maximum effectiveness of work at every step and secondly the usage of quantitative methods for evaluation, assessment of expert opinion and collective processing of the results. These two features distinguish the method of expert evaluations from long-known expertise widespread in many areas of knowledge. Different typical problems require different types of expert evaluations methods. Several issues which arise with these methods are experts’ selection, management of assessment procedure, proceeding of the results and remuneration for the experts. To address these issues an on-line system was created with the primary purpose of development of a versatile application for many workgroups with matching approaches to scientific work management. Online documentation assessment and statistics system allows: - To realize within one platform independent activities of different workgroups (e.g. expert officers, managers). - To establish different workspaces for corresponding workgroups where custom users database can be created according to particular needs. - To form for each workgroup required output documents. - To configure information gathering for each workgroup (forms of assessment, tests, inventories). - To create and operate personal databases of remote users. - To set up automatic notification through e-mail. The next stage is development of quantitative and qualitative criteria to form a database of experts. The inventory was made so that the experts may not only submit their personal data, place of work and scientific degree but also keywords according to their expertise, academic interests, ORCID, Researcher ID, SPIN-code RSCI, Scopus AuthorID, knowledge of languages, primary scientific publications. For each project, competition assessments are processed in accordance to ordering party demands in forms of apprised inventories, commentaries (50-250 characters) and overall review (1500 characters) in which expert states the absence of conflict of interest. Evaluation is conducted as follows: as applications are added to database expert officer selects experts, generally, two persons per application. Experts are selected according to the keywords; this method proved to be good unlike the OECD classifier. The last stage: the choice of the experts is approved by the supervisor, the e-mails are sent to the experts with invitation to assess the project. An expert supervisor is controlling experts writing reports for all formalities to be in place (time-frame, propriety, correspondence). If the difference in assessment exceeds four points, the third evaluation is appointed. As the expert finishes work on his expert opinion, system shows contract marked ‘new’, managers commence with the contract and the expert gets e-mail that the contract is formed and ready to be signed. All formalities are concluded and the expert gets remuneration for his work. The specificity of interaction of the examination officer with other experts will be presented in the report.

Keywords: expertise, management of research evaluation, method of expert evaluations, research evaluation

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Authors: Anubhav Kumar Dwivedi, Arshad Khan, S. N. Tripathi, Manish Joshi, Gaurav Mishra, Dinesh Nath, Naveen Tiwari, B. K. Sapra

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In a nuclear reactor accident scenario, a large number of fission products may release to the piping system of the primary heat transport. The released fission products, mostly in the form of the aerosol, get deposited on the inner surface of the piping system mainly due to gravitational settling and thermophoretic deposition. The removal processes in the complex piping system are controlled to a large extent by the thermal-hydraulic conditions like temperature, pressure, and flow rates. These parameters generally vary with time and therefore must be carefully monitored to predict the aerosol behavior in the piping system. The removal process of aerosol depends on the size of particles that determines how many particles get deposit or travel across the bends and reach to the other end of the piping system. The released aerosol gets deposited onto the inner surface of the piping system by various mechanisms like gravitational settling, Brownian diffusion, thermophoretic deposition, and by other deposition mechanisms. To quantify the correct estimate of deposition, the identification and understanding of the aforementioned deposition mechanisms are of great importance. These mechanisms are significantly affected by different flow and thermodynamic conditions. Thermophoresis also plays a significant role in particle deposition. In the present study, a series of experiments were performed in the piping system of the National Aerosol Test Facility (NATF), BARC using metal aerosols (zinc) in dry environments to study the spatial distribution of particles mass and number concentration, and their depletion due to various removal mechanisms in the piping system. The experiments were performed at two different carrier gas flow rates. The commercial CFD software FLUENT is used to determine the distribution of temperature, velocity, pressure, and turbulence quantities in the piping system. In addition to the in-built models for turbulence, heat transfer and flow in the commercial CFD code (FLUENT), a new sub-model PBM (population balance model) is used to describe the coagulation process and to compute the number concentration along with the size distribution at different sections of the piping. In the sub-model coagulation kernels are incorporated through user-defined function (UDF). The experimental results are compared with the CFD modeled results. It is found that most of the Zn particles (more than 35 %) deposit near the inlet of the plenum chamber and a low deposition is obtained in piping sections. The MMAD decreases along the length of the test assembly, which shows that large particles get deposited or removed in the course of flow, and only fine particles travel to the end of the piping system. The effect of a bend is also observed, and it is found that the relative loss in mass concentration at bends is more in case of a high flow rate. The simulation results show that the thermophoresis and depositional effects are more dominating for the small and larger sizes as compared to the intermediate particles size. Both SEM and XRD analysis of the collected samples show the samples are highly agglomerated non-spherical and composed mainly of ZnO. The coupled model framed in this work could be used as an important tool for predicting size distribution and concentration of some other aerosol released during a reactor accident scenario.

Keywords: aerosol, CFD, deposition, coagulation

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Authors: Abiodun Amusan, Olugbenga Akinola, Kazeem Akano, María Hernández-Castañeda, Jenna Dick, Akintunde Sowunmi, Geoffrey Hart, Grace Gbotosho

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Introduction: Artemisinin-based Combination Therapy (ACTs) is the cornerstone malaria treatment option in most malaria-endemic countries. Unfortunately, the malaria control effort is constantly being threatened by resistance of Plasmodium falciparum to ACTs. The recent evidence of artemisinin resistance in East Africa and its possibility of spreading to other African regions portends an imminent health catastrophe. This study aimed at evaluating the occurrence, prevalence, and influence of artemisinin-resistance markers on treatment outcomes in Ibadan before and after post-adoption of artemisinin combination therapy (ACTs) in Nigeria in 2005. Method: The study involved day zero dry blood spot (DBS) obtained from malaria patients during retrospective (2000-2005) and prospective (2021) studies. A cohort in the prospective study received oral dihydroartemisinin-piperaquine and underwent a 42-day follow-up to observe treatment outcomes. Genomic DNA was extracted from the DBS samples using a QIAamp blood extraction kit. Fragments of P. falciparum kelch13 (Pfkelch13), P. falciparum coronin (Pfcoronin), P. falciparum multidrug resistance 2 (PfMDR2), and P. falciparum chloroquine resistance transporter (PfCRT) genes were amplified and sequenced on a sanger sequencing platform to identify artemisinin resistance-associated mutations. Mutations were identified by aligning sequenced data with reference sequences obtained from the National Center for Biotechnology Information. Data were analyzed using descriptive statistics and student t-tests. Results: Mean parasite clearance time (PCT) and fever clearance time (FCT) were 2.1 ± 0.6 days (95% CI: 1.97-2.24) and 1.3 ± 0.7 days (95% CI: 1.1-1.6) respectively. Four mutations, K189T [34/53(64.2%)], R255K [2/53(3.8%)], K189N [1/53(1.9%)] and N217H [1/53(1.9%)] were identified within the N-terminal (Coiled-coil containing) domain of Pfkelch13. No artemisinin resistance-associated mutation usually found within the β-propeller domain of the Pfkelch13 gene was found in these analyzed samples. However, K189T and R255K mutations showed a significant correlation with longer parasite clearance time in the patients (P<0.002). The observed Pfkelch13 gene changes did not influence the baseline mean parasitemia (P = 0.44). P76S [17/100 (17%)] and V62M [1/100 (1%)] changes were identified in the Pfcoronin gene fragment without any influence on the parasitological parameters. No change was observed in the PfMDR2 gene, while no artemisinin resistance-associated mutation was found in the PfCRT gene. Furthermore, a sample each in the retrospective study contained the Pfkelch13 K189T and Pfcoronin P76S mutations. Conclusion: The study revealed absence of genetic-based evidence of artemisinin resistance in the study population at the time of study. The high frequency of K189T Pfkelch13 mutation and its correlation with increased parasite clearance time in this study may depict geographical variation of resistance mediators and imminent artemisinin resistance, respectively. The study also revealed an inherent potential of parasites to harbour drug-resistant genotypes before the introduction of ACTs in Nigeria.

Keywords: artemisinin resistance, plasmodium falciparum, Pfkelch13 mutations, Pfcoronin

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Authors: Wen-Yang Hu, Ranli Lu, Mark Maienschein-Cline, Danping Hu, Larisa Nonn, Toshi Shioda, Gail S. Prins

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Background: Genetic mutations are highly associated with increased prostate cancer risk. In addition to whole genome sequencing, somatic mutations can be identified by aligning transcriptome sequences to the human genome. Here we analyzed bulk RNAseq and single cell RNAseq data of human prostate cancer cells and their matched non-cancer cells in benign regions from 4 individual patients. Methods: Sequencing raw reads were aligned to the reference genome hg38 using STAR. Variants were annotated using Annovar with respect to overlap gene annotation information, effect on gene and protein sequence, and SIFT annotation of nonsynonymous variant effect. We determined cancer-specific novel alleles by comparing variant calls in cancer cells to matched benign cells from the same individual by selecting unique alleles that were only detected in the cancer samples. Results: In bulk RNAseq data from 3 patients, the most common variants were the noncoding mutations at UTR3/UTR5, and the major variant types were single-nucleotide polymorphisms (SNP) including frameshift mutations. C>T transversion is the most frequently presented substitution of SNP. A total of 222 genes carrying unique exonic or UTR variants were revealed in cancer cells across 3 patients but not in benign cells. Among them, transcriptome levels of 7 genes (CITED2, YOD1, MCM4, HNRNPA2B1, KIF20B, DPYSL2, NR4A1) were significantly up or down regulated in cancer stem cells. Out of the 222 commonly mutated genes in cancer, 19 have nonsynonymous variants and 11 are damaged genes with variants including SIFT, frameshifts, stop gain/loss, and insertions/deletions (indels). Two damaged genes, activating transcription factor 6 (ATF6) and histone demethylase KDM3A are of particular interest; the former is a survival factor for certain cancer cells while the later positively activates androgen receptor target genes in prostate cancer. Further, single cell RNAseq data of cancer cells and their matched non-cancer benign cells from both primary 2D and 3D tumoroid cultures were analyzed. Similar to the bulk RNAseq data, single cell RNAseq in cancer demonstrated that the exonic mutations are less common than noncoding variants, with SNPs including frameshift mutations the most frequently presented types in cancer. Compared to cancer stem cell enriched-3D tumoroids, 2D cancer cells carried 3-times higher variants, 8-times more coding mutations and 10-times more nonsynonymous SNP. Finally, in both 2D primary and 3D tumoroid cultures, cancer stem cells exhibited fewer coding mutations and noncoding SNP or insertions/deletions than non-stem cancer cells. Summary: Our study demonstrates the usefulness of bulk and single cell RNAseaq data in identifying somatic mutations in prostate cancer, providing an alternative method in screening candidate genes for prostate cancer diagnosis and potential therapeutic targets. Cancer stem cells carry fewer somatic mutations than non-stem cancer cells due to their inherited immortal stand DNA from parental stem cells that explains their long-lived characteristics.

Keywords: prostate cancer, stem cell, genomic mutation, RNAseq

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Authors: Noury Bakrim

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When dealing with motivation/arbitrariness, forming form (Forma Formans) and morphodynamics are to be grasped as relevant implications of enunciation/enactment, schematization within the specificity of language as sound/meaning articulation. Thus, the fact that a language is a form does not contradict stasis/dynamic enunciation (reflexivity vs double articulation). Moreover, some languages exemplify the role of the forming form, uttering, and schematization (roots in Semitic languages, the Chinese case). Beyond the evolutionary biosemiotic process (form/substance bifurcation, the split between realization/representation), non-isomorphism/asymmetry between linguistic form/norm and linguistic realization (phonetics for instance) opens up a new horizon problematizing the role of Brain – sensorimotor contribution in the continuous forming form. Therefore, we hypothesize biotization as both process/trace co-constructing motivation/forming form. Henceforth, referring to our findings concerning distribution and motivation patterns within Berber written texts (pulse based obstruents and nasal-lateral levels in poetry) and oral storytelling (consonant intensity clustering in quantitative and semantic/prosodic motivation), we understand consonant clustering, motivation and schematization as a complex phenomenon partaking in patterns of oral/written iconic prosody and reflexive metalinguistic representation opening the stable form. We focus our inquiry on both Amazigh and English clusters (/spl/, /spr/) and iconic consonant iteration in [gnunnuy] (to roll/tumble), [smummuy] (to moan sadly or crankily). For instance, the syllabic structures of /splaeʃ/ and /splaet/ imply an anamorphic representation of the state of the world: splash, impact on aquatic surfaces/splat impact on the ground. The pair has stridency and distribution as distinctive features which specify its phonetic realization (and a part of its meaning) /ʃ/ is [+ strident] and /t/ is [+ distributed] on the vocal tract. Schematization is then a process relating both physiology/code as an arthron vocal/bodily, vocal/practical shaping of the motor-articulatory system, leading to syntactic/semantic thematization (agent/patient roles in /spl/, /sm/ and other clusters or the tense uvular /qq/ at the initial position in Berber). Furthermore, the productivity of serial syllable sequencing in Berber points out different expressivity forms. We postulate two Components of motivated formalization: i) the process of memory paradigmatization relating to sequence modeling under sensorimotor/verbal specific categories (production/perception), ii) the process of phonotactic selection - prosodic unconscious/subconscious distribution by virtue of iconicity. Basing on multiple tests including a questionnaire, phonotactic/visual recognition and oral/written reproduction, we aim at patterning/conceptualizing consonant schematization and motivation among EFL and Amazigh (Berber) learners and speakers integrating biolinguistic hypotheses.

Keywords: consonant motivation and prosody, language and order of life, anamorphic representation, represented representation, biotization, sensori-motor and brain representation, form, formalization and schematization

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Authors: Caspar Goeke, Holger Finger, Dorena Diekamp, Peter König

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Online-based research has recently gained increasing attention from various fields of research in the cognitive sciences. Technological advances in the form of online crowdsourcing (Amazon Mechanical Turk), open data repositories (Open Science Framework), and online analysis (Ipython notebook) offer rich possibilities to improve, validate, and speed up research. However, until today there is no cross-platform integration of these subsystems. Furthermore, implementation of online studies still suffers from the complex implementation (server infrastructure, database programming, security considerations etc.). Here we propose and test a new JavaScript framework that enables researchers to conduct any kind of behavioral research in the browser without the need to program a single line of code. In particular our framework offers the possibility to manipulate and combine the experimental stimuli via a graphical editor, directly in the browser. Moreover, we included an action-event system that can be used to handle user interactions, interactively change stimuli properties or store participants’ responses. Besides traditional recordings such as reaction time, mouse and keyboard presses, the tool offers webcam based eye and face-tracking. On top of these features our framework also takes care about the participant recruitment, via crowdsourcing platforms such as Amazon Mechanical Turk. Furthermore, the build in functionality of google translate will ensure automatic text translations of the experimental content. Thereby, thousands of participants from different cultures and nationalities can be recruited literally within hours. Finally, the recorded data can be visualized and cleaned online, and then exported into the desired formats (csv, xls, sav, mat) for statistical analysis. Alternatively, the data can also be analyzed online within our framework using the integrated Ipython notebook. The framework was designed such that studies can be used interchangeably between researchers. This will support not only the idea of open data repositories but also constitutes the possibility to share and reuse the experimental designs and analyses such that the validity of the paradigms will be improved. Particularly, sharing and integrating the experimental designs and analysis will lead to an increased consistency of experimental paradigms. To demonstrate the functionality of the framework we present the results of a pilot study in the field of spatial navigation that was conducted using the framework. Specifically, we recruited over 2000 subjects with various cultural backgrounds and consequently analyzed performance difference in dependence on the factors culture, gender and age. Overall, our results demonstrate a strong influence of cultural factors in spatial cognition. Such an influence has not yet been reported before and would not have been possible to show without the massive amount of data collected via our framework. In fact, these findings shed new lights on cultural differences in spatial navigation. As a consequence we conclude that our new framework constitutes a wide range of advantages for online research and a methodological innovation, by which new insights can be revealed on the basis of massive data collection.

Keywords: cultural differences, crowdsourcing, JavaScript framework, methodological innovation, online data collection, online study, spatial cognition

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Authors: Mei Chen, Yingping Hou, Michelle Hao, Soheil Aghamohammadzadeh, Esteban Terzo, Roger Clark, Vijay Modur

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Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genetic skin condition characterized by skin tearing and unremitting blistering upon minimal trauma. Repeated blistering, fibrosis, and scarring lead to aggressive squamous cell carcinoma later in life. RDEB is caused by mutations in the COL7A1 gene encoding collagen type VII (C7), the major component of anchoring fibrils mediating epidermis-dermis adherence. Nonsense mutations in the COL7A1 gene of a subset of RDEB patients leads to premature termination codons (PTC). Similarly, most Junctional Epidermolysis Bullosa (JEB) cases are caused by nonsense mutations in the LAMB3 gene encoding the β3 subunit of laminin 332. Currently, there is an unmet need for the treatment of RDEB and JEB. Zikani Therapeutics has discovered an array of macrocyclic compounds with ring structures similar to macrolide antibiotics that can facilitate readthrough activity of nonsense mutations in the COL7A1 and LAMB3 genes by acting as Ribosome Modulating Agents (RMAs). The medicinal chemistry synthetic advancements of these macrocyclic compounds have allowed targeting the human ribosome while preserving the structural elements responsible for the safety and pharmacokinetic profile of clinically used macrolide antibiotics. Methods: C7 expression was used as a measure of readthrough activity by immunoblot assays in two primary human fibroblasts from RDEB patients (R578X/R578X and R163X/R1683X-COL7A1). Similarly, immunoblot assays in C325X/c.629-12T > A-LAMB3 keratinocytes were used to measure readthrough activity for JEB. The relative readthrough activity of each compound was measured relative to Gentamicin. An imaging-based fibroblast migration assay was used as an assessment of C7 functionality in RDEB-fibroblasts over 16-20 hrs. The incubation period for the above experiments was 48 hrs for RDEB fibroblasts and 72 hours for JEB keratinocytes. Results: 9 RMAs demonstrated increased protein expression in both patient RDEB fibroblasts. The highest readthrough activity at tested concentrations without cytotoxicities increased protein expression up to 179% of Gentamicin (400 µg/ml), with favored readthrough activity in R163X/R1683X-COL7A1 fibroblasts. Concurrent with protein expression, fibroblast hypermotility phenotype observed in RDEB was rescued by reducing motility by ~35% to WT levels (the same level as 690 µM Gentamicin treated cells). Laminin β3 expression was also shown to be increased by 6 RMAs in keratinocytes to 33-83% of (400 µg/ml) Gentamicin. Conclusions: To date, 9 RMAs have been identified that enhance the expression of functional C7 in a mutation-dependent manner in two different RDEB patient fibroblast backgrounds (R578X/R578X and R163X/R1683X-COL7A1). A further 6 RMAs have been identified that enhance the readthrough of C325X-LAMB3 in JEB patient keratinocytes. Based on the clinical trial conducted by us with topical gentamycin in 2017, Zikani’s RMAs achieve clinically significant levels of read-through for the treatment of recessive dystrophic and Junctional Epidermolysis Bullosa.

Keywords: epidermolysis bullosa, nonsense mutation, readthrough, ribosome modulation

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Authors: Christine Wiesenthal

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This paper asks how to read a particularly vexed and complicated life writing text. For over half a century, the wartime journals of Ruth Andreas Friedrich (1901-1977) circulated as among a handful of more or less authoritative and “authentic” first-hand accounts of German resistance under Hitler. A professional journalist, Andreas Friedrich is remembered today largely through her publications at the war’s end, which appeared in English as Berlin Underground (published by Henry Holt in 1947), just before their publication in Germany as Der Schattenmann “The Shadow Man” (also in 1947). A British edition by the now obscure Latimer House Limited (London) followed in 1948; it is based closely on but is not identical to, the Henry Holt American edition, which in turn differs significantly from its German counterpart. Both Berlin Underground and Der Schattenmann figure Andreas-Friedrich as a key figure in an anti-fascist cell that operated in Berlin under the code name “Uncle Emil,” and provide a riveting account of political terror, opportunism, and dissent under the Nazi regime. Recent scholars have, however, begun to raise fascinating and controversial questions about Andreas-Friedrich’s own writing/reconstruction process in compiling the journals and about her highly selective curatorial role and claims. The apparent absence of any surviving original manuscript for Andreas-Friedrich’s journals amplifies the questions around them. Crucially, so too does the role of the translator of the English editions of Berlin Underground, the enigmatic June Barrows Mussey, a subject that has thus far gone virtually unnoticed and which this paper will focus on. Mussey, a prolific American translator, simultaneously cultivated a career as a professional magician, publishing a number of books on that subject under the alias Henry Hay. While the record indicates that Mussey attempted to compartmentalize his professional life, research into the publishing and translation history of Berlin Underground suggests that the two roles converge in the fact of the translator’s invisibility, by effacing the traces of his own hand and leaving unmarked his own significant textual interventions, Mussey, in effect, edited, abridged, and altered Andreas Friedrich’s journals for the second time. In fact, it could be said that while the fictitious “Uncle Emil” is positioned as “the shadow man” of the German edition, Mussey himself also emerges as precisely that in the English rendering of the journals. The implications of Mussey’s translation of Andreas Friedrich’s journals are one of the most important un-examined gaps in the shadowy publishing history of Berlin Underground, a history full of “tricks” (Mussey’s words) and illusions of transparency. Based largely on archival research of unpublished materials and methods of close reading and comparative analysis, this study will seek to convey some preliminary insights and exploratory work and frame questions toward what is ultimately envisioned as an experimental project in poetic historiography. As this work is still in the early stages, it would be especially welcome to have the opportunity provided by this conference to connect with a community of life writing colleagues who might help think through some of the challenges and possibilities that lie ahead.

Keywords: women’s wartime diaries, translation studies, auto/biographical theory, politics of life writing

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Authors: Joanna Marie A. Paulino-Morente, Vaneza Valentina L. Penolio, Grace Sabado

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Ovarian cancer is extremely hard to diagnose in its early stages, and those afflicted at the time of diagnosis are typically asymptomatic and in the late stages of the disease, with metastasis to other organs. Ovarian cancers often occur sporadically, with only 5% associated with hereditary mutations. Mutations in the BRCA1 and BRCA2 tumor suppressor genes have been found to be responsible for the majority of hereditary ovarian cancers. One type of ovarian tumor is Malignant Mixed Mullerian Tumor (MMMT), which is a very rare and aggressive type, accounting for only 1% of all ovarian cancers. Reported is a case of a 43-year-old G3P3 (3003), who came into our institution due to a 2-month history of difficulty of breathing. Family history reveals that her eldest and younger sisters both died of ovarian malignancy, with her younger sister having a histopathology report of endometrioid ovarian carcinoma, left ovary stage IIIb. She still has 2 asymptomatic sisters. Physical examination pointed to pleural effusion of right lung, and presence of bilateral ovarian new growth, which had a Sassone score of 13. Admitting Diagnosis was G3P3 (3003), Ovarian New Growth, bilateral, Malignant; Pleural effusion secondary to malignancy. BRCA was requested to establish a hereditary mutation; however, the patient had no funds. Once the patient was stabilized, TAHBSO with surgical staging was performed. Intraoperatively, the pelvic cavity was occupied by firm, irregularly shaped ovaries, with a colorectal metastasis. Microscopic sections from both ovaries and the colorectal metastasis had pleomorphic tumor cells lined by cuboidal to columnar epithelium exhibiting glandular complexity, displaying nuclear atypia and increased nuclear-cytoplasmic ratio, which are infiltrating the stroma, consistent with the features of Malignant Mixed Mullerian Tumor, since MMMT is composed histologically of malignant epithelial and sarcomatous elements. In conclusion, discussed is the clinic-pathological feature of a patient with primary ovarian Malignant Mixed Mullerian Tumor, a rare malignancy comprising only 1% of all ovarian neoplasms. Also, by understanding the hereditary ovarian cancer syndromes and its relation to this patient, it cannot be overemphasized that a comprehensive family history is really fundamental for early diagnosis. The familial association of the disease, given that the patient has two sisters who were diagnosed with an advanced stage of ovarian cancer and succumbed to the disease at a much earlier age than what is reported in the general population, points to a possible hereditary syndrome which occurs in only 5% of ovarian neoplasms. In a low-resource setting, being in a third world country, the following will be recommended for monitoring and/or screening women who are at high risk for developing ovarian cancer, such as the remaining sisters of the patient: 1) Physical examination focusing on the breast, abdomen, and rectal area every 6 months. 2) Transvaginal sonography every 6 months. 3) Mammography annually. 4) CA125 for postmenopausal women. 5) Genetic testing for BRCA1 and BRCA2 will be reserved for those who are financially capable.

Keywords: BRCA, hereditary breast-ovarian cancer syndrome, malignant mixed mullerian tumor, ovarian cancer

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Authors: Sarwan Dhir, Suma Basak, Dipika Parajulee

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Alfalfa is renowned for its nutritional and biopharmaceutical value as a perennial forage legume. However, establishing a rapid plant regeneration protocol using somatic embryogenesis and efficient transformation frequency are the crucial prerequisites for gene editing in alfalfa. This study was undertaken to establish and improve the protocol for somatic embryogenesis and subsequent plant regeneration. The experiments were conducted in response to natural sensitivity using various antibiotics such as cefotaxime, carbenicillin, gentamycin, hygromycin, and kanamycin. Using 3-week-old leaf tissue, somatic embryogenesis was initiated on Gamborg’s B5 basal (B5H) medium supplemented with 3% maltose, 0.9µM Kinetin, and 4.5µM 2,4-D. Embryogenic callus (EC) obtained from the B5H medium exhibited a high rate of somatic embryo formation (97.9%) after 3 weeks when the cultures were placed in the dark. Different developmental stages of somatic embryos and cotyledonary stages were then transferred to Murashige and Skoog’s (MS) basal medium under light, resulting in a 94% regeneration rate of plantlets. Our results indicate that leaf segments can grow (tolerate) up to 450 mg/L of cefotaxime and 400 mg/L of carbenicillin in the culture medium. However, the survival threshold for hygromycin at 12.5 mg/L, kanamycin at 250 mg/L, gentamycin at 50 mg/L, and timentin (300 mg/L). The experiment to improve the protocol for achieving efficient transient gene expression in alfalfa through genetic transformation with the Agrobacterium tumefaciens pCAMBIA1304 vector was also conducted. The vector contains two reporter genes such as β-glucuronidase (GUS) and green fluorescent protein (GFP), along with a selectable hygromycin B phosphotransferase gene (HPT), all driven under the CaMV 35s promoter. Various transformation parameters were optimized using 3-week-old in vitro-grown plantlets. The different parameters such as types of explant, leaf ages, preculture days, segment sizes, wounding types, bacterial concentrations, infection periods, co-cultivation periods, different concentrations of acetosyringone, silver nitrate, and calcium chloride were optimized for transient gene expression. The transient gene expression was confirmed via histochemical GUS and GFP visualization under fluorescent microscopy. The data were analyzed based on the semi-quantitative observation of the percentage and number of blue GUS spots on different days of agro-infection. The highest percentage of GUS positivity (76.2%) was observed in 3-week-old leaf segments wounded using a scalpel blade of 11 size- after 3 days of post-incubation at a bacterial concentration of 0.6, with 2 days of preculture, 30 min of bacterial-leaf segment co-cultivation, with the addition of 150 µM acetosyringone, 4 mM calcium chloride, and 75 µM silver nitrate. Our results suggest that various factors influence T-DNA delivery in the Agrobacterium-mediated transformation of alfalfa. The stable gene expression in the putative transgenic tissue was confirmed using PCR amplification of both marker genes, indicating that gene expression in explants was not solely due to Agrobacterium, but also from transformed cells. The improved protocol could be used for generating transgenic alfalfa plants using genome editing techniques such as CRISPR/Cas9.

Keywords: Medicago sativa l. (Alfalfa), agrobacterium tumefaciens, β-glucuronidase, green fluorescent protein, transient gene

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Authors: Majed Al Otaibi, Melissa Lessard-Beaudoin, Amel Loudghi, Raphael Chouinard-Watkins, Melanie Plourde, Frederic Calon, C. Alexandre Castellano, Stephen Cunnane, Helene Payette, Pierrette Gaudreau, Denis Gris, Rona K. Graham

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Introduction: Alzheimer disease (AD) is a chronic disorder that affects millions of individuals worldwide. Symptoms include memory dysfunction, and also alterations in attention, planning, language and overall cognitive function. Olfactory dysfunction is a common symptom of several neurological disorders including AD. Studying the mechanisms underlying the olfactory dysfunction may therefore lead to the discovery of potential biomarkers and/or treatments for neurodegenerative diseases. Objectives: To determine if olfactory dysfunction predicts future cognitive impairment in the aging population and to characterize the olfactory system in a murine model expressing a genetic factor of AD. Method: For the human study, quantitative olfactory tests (UPSIT and OMT) have been done on 93 subjects (aged 80 to 94 years) from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge) cohort accepting to participate in the ORCA secondary study. The telephone Modified Mini Mental State examination (t-MMSE) was used to assess cognition levels, and an olfactory self-report was also collected. In a separate cohort, olfactory cortical volume was calculated using MRI results from healthy old adults (n=25) and patients with AD (n=18) using the AAL single-subject atlas and performed with the PNEURO tool (PMOD 3.7). For the murine study, we are using Western blotting, RT-PCR and immunohistochemistry. Result: Human Study: Based on the self-report, 81% of the participants claimed to not suffer from any problem with olfaction. However, based on the UPSIT, 94% of those subjects showed a poor olfactory performance and different forms of microsmia. Moreover, the results confirm that olfactory function declines with age. We also detected a significant decrease in olfactory cortical volume in AD individuals compared to controls. Murine study: Preliminary data demonstrate there is a significant decrease in expression levels of the proform of caspase-3 and the caspase substrate STK3, in the olfactory bulb of mice expressing human APOE4 compared with controls. In addition, there is a significant decrease in the expression level of the caspase-9 proform and caspase-8 active fragment. Analysis of the mature neuron marker, NeuN, shows decreased expression levels of both isoforms. The data also suggest that Iba-1 immunostaining is increased in the olfactory bulb of APOE4 mice compared to wild type mice. Conclusions: The activation of caspase-3 may be the cause of the decreased levels of STK3 through caspase cleavage and may play role in the inflammation observed. In the clinical study, our results suggest that seniors are unaware of their olfactory function status and therefore it is not sufficient to measure olfaction using the self-report in the elderly. Studying olfactory function and cognitive performance in the aging population will help to discover biomarkers in the early stage of the AD.

Keywords: Alzheimer's disease, APOE4, cognition, caspase, brain atrophy, neurodegenerative, olfactory dysfunction

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Authors: Lorenzo Casagrande, Antonio Bonati, Ferdinando Auricchio, Antonio Occhiuzzi

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This paper summarizes the results of a survey on smart non-structural element dynamic dissipation when installed in modern high-rise mega-frame prototypes. An innovative glazed curtain wall was designed using Shape Memory Alloy (SMA) joints in order to increase the energy dissipation and enhance the seismic/wind response of the structures. The studied buildings consisted of thirty- and sixty-storey planar frames, extracted from reference three-dimensional steel Moment Resisting Frame (MRF) with outriggers and belt trusses. The internal core was composed of a CBF system, whilst outriggers were placed every fifteen stories to limit second order effects and inter-storey drifts. These structural systems were designed in accordance with European rules and numerical FE models were developed with an open-source code, able to account for geometric and material nonlinearities. With regard to the characterization of non-structural building components, full-scale crescendo tests were performed on aluminium/glass curtain wall units at the laboratory of the Construction Technologies Institute (ITC) of the Italian National Research Council (CNR), deriving force-displacement curves. Three-dimensional brick-based inelastic FE models were calibrated according to experimental results, simulating the fac¸ade response. Since recent seismic events and extreme dynamic wind loads have generated the large occurrence of non-structural components failure, which causes sensitive economic losses and represents a hazard for pedestrians safety, a more dissipative glazed curtain wall was studied. Taking advantage of the mechanical properties of SMA, advanced smart joints were designed with the aim to enhance both the dynamic performance of the single non-structural unit and the global behavior. Thus, three-dimensional brick-based plastic FE models were produced, based on the innovated non-structural system, simulating the evolution of mechanical degradation in aluminium-to-glass and SMA-to-glass connections when high deformations occurred. Consequently, equivalent nonlinear links were calibrated to reproduce the behavior of both tested and smart designed units, and implemented on the thirty- and sixty-storey structural planar frame FE models. Nonlinear time history analyses (NLTHAs) were performed to quantify the potential of the new system, when considered in the lateral resisting frame system (LRFS) of modern high-rise MRFs. Sensitivity to the structure height was explored comparing the responses of the two prototypes. Trends in global and local performance were discussed to show that, if accurately designed, advanced materials in non-structural elements provide new sources of energy dissipation.

Keywords: advanced technologies, glazed curtain walls, non-structural elements, seismic-action reduction, shape memory alloy

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Authors: Tatiana Butkova, Nikolai Kibrik, Kristina Malsagova, Alexander Izotov, Alexander Stepanov, Anna Kaysheva

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Relevance. The genetic risk of developing schizophrenia is determined by two factors: single nucleotide polymorphisms and gene copy number variations. The search for serological markers for early diagnosis of schizophrenia is driven by the fact that the first five years of the disease are accompanied by significant biological, psychological, and social changes. It is during this period that pathological processes are most amenable to correction. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) that are hypothesized to potentially influence the onset and development of the endogenous process. Materials and Methods It was analyzed 73 single nucleotide polymorphism variants. The study included 48 patients undergoing inpatient treatment at "Psychiatric Clinical Hospital No. 1" in Moscow, comprising 23 females and 25 males. Inclusion criteria: - Patients aged 18 and above. - Diagnosis according to ICD-10: F20.0, F20.2, F20.8, F21.8, F25.1, F25.2. - Voluntary informed consent from patients. Exclusion criteria included: - The presence of concurrent somatic or neurological pathology, neuroinfections, epilepsy, organic central nervous system damage of any etiology, and regular use of medication. - Substance abuse and alcohol dependence. - Women who were pregnant or breastfeeding. Clinical and psychopathological assessment was complemented by psychometric evaluation using the PANSS scale at the beginning and end of treatment. The duration of observation during therapy was 4-6 weeks. Total DNA extraction was performed using QIAamp DNA. Blood samples were processed on Illumina HiScan and genotyped for 652,297 markers on the Infinium Global Chips Screening Array-24v2.0 using the IMPUTE2 program with parameters Ne=20,000 and k=90. Additional filtration was performed based on INFO>0.5 and genotype probability>0.5. Quality control of the obtained DNA was conducted using agarose gel electrophoresis, with each tested sample having a volume of 100 µL. Results. It was observed that several SNPs exhibited gender dependence. We identified groups of single nucleotide polymorphisms with a membership of 80% or more in either the female or male gender. These SNPs included rs2661319, rs2842030, rs4606, rs11868035, rs518147, rs5993883, and rs6269.Another noteworthy finding was the limited combination of SNPs sufficient to manifest clinical symptoms leading to hospitalization. Among all 48 patients, each of whom was analyzed for deviations in 73 SNPs, it was discovered that the combination of involved SNPs in the manifestation of pronounced clinical symptoms of schizophrenia was 19±3 out of 73 possible. In study, the frequency of occurrence of single nucleotide polymorphisms also varied. The most frequently observed SNPs were rs4849127 (in 90% of cases), rs1150226 (86%), rs1414334 (75%), rs10170310 (73%), rs2857657, and rs4436578 (71%). Conclusion. Thus, the results of this study provide additional evidence that these genes may be associated with the development of schizophrenia spectrum disorders. However, it's impossible cannot rule out the hypothesis that these polymorphisms may be in linkage disequilibrium with other functionally significant polymorphisms that may actually be involved in schizophrenia spectrum disorders. It has been shown that missense SNPs by themselves are likely not causative of the disease but are in strong linkage disequilibrium with non-functional SNPs that may indeed contribute to disease predisposition.

Keywords: gene polymorphisms, genotyping, single nucleotide polymorphisms, schizophrenia.

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Authors: Peggy M. Randon, Lisa Randon

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Introduction: The post-COVID-19 era has presented unique challenges for addressing complex mental health issues, particularly due to exacerbated stress, increased social isolation, and disrupted continuity of care. This article outlines relevant health disparities and policy implications within the context of the United States while maintaining international relevance. Methods: A comprehensive literature review (including studies, reports, and policy documents) was conducted to examine concerns related to childhood-onset schizophrenia and the impact on patients and their families. Qualitative and quantitative data were synthesized to provide insights into the complex etiology of schizophrenia, the effects of the pandemic, and the challenges faced by socioeconomically disadvantaged populations. Case studies were employed to illustrate real-world examples and areas requiring policy reform. Results: Early intervention in childhood is crucial for preventing or mitigating the long-term impact of complex psychotic disorders, particularly schizophrenia. A comprehensive understanding of the genetic, environmental, and physiological factors contributing to the development of schizophrenia is essential. The COVID-19 pandemic worsened symptoms and disrupted treatment for many adolescent patients with schizophrenia, emphasizing the need for adaptive interventions and the utilization of virtual platforms. Health disparities, including stigma, financial constraints, and language or cultural barriers, further limit access to care, especially for socioeconomically disadvantaged populations. Policy implications: Current US health policies inadequately support patients with schizophrenia. The limited availability of longitudinal care, insufficient resources for families, and stigmatization represent ongoing policy challenges. Addressing these issues necessitates increased research funding, improved access to affordable treatment plans, and cultural competency training for healthcare providers. Public awareness campaigns are crucial to promote knowledge, awareness, and acceptance of mental health disorders. Conclusion: The unique challenges faced by children and families in the US affected by schizophrenia and other psychotic disorders have yet to be adequately addressed on institutional and systemic levels. The relevance of findings to an international audience is emphasized by examining the complex factors contributing to the onset of psychotic disorders and their global policy implications. The broad impact of the COVID-19 pandemic on mental health underscores the need for adaptive interventions and global responses. Addressing policy challenges, improving access to care, and reducing the stigma associated with mental health disorders are crucial steps toward enhancing the lives of adolescents and young adults with schizophrenia and their family members. The implementation of virtual platforms can help overcome barriers and ensure equitable access to support and resources for all patients, enabling them to lead healthy and fulfilling lives.

Keywords: childhood, schizophrenia, policy, United, States, health, disparities

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Authors: Natalia Hordynska, Magdalena Szechynska-Hebda, Miroslaw Sobczak, Elzbieta Rozanska, Joanna Troczynska, Zofia Banaszak, Maria Wedzony

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Albinism is a common problem encountered in wheat and triticale breeding programs, which require in vitro culture steps e.g. generation of doubled haploids via androgenesis process. Genetic factor is a major determinant of albinism, however, environmental conditions such as temperature and media composition influence the frequency of albino plant formation. Cold incubation of wheat and triticale spikes induced a switch from gametophytic to sporophytic development. Further, androgenic structures formed from anthers of the genotypes susceptible to androgenesis or treated with cold stress, had a pool of structurally primitive plastids, with small starch granules or swollen thylakoids. High temperature was a factor inducing andro-genesis of wheat and triticale, but at the same time, it was a factor favoring the formation of albino plants. In genotypes susceptible to albinism or after heat stress conditions, cells formed from anthers were vacuolated, and plastids were eliminated. Partial or complete loss of chlorophyll pigments and incomplete differentiation of chloroplast membranes result in formation of tissues or whole plant unable to perform photosynthesis. Indeed, susceptibility to the andro-genesis process was associated with an increase of total concentration of photosynthetic pigments in anthers, spikes and regenerated plants. The proper balance of the synthesis of various pigments, was the starting point for their proper incorporation into photosynthetic membranes. In contrast, genotypes resistant to the androgenesis process and those treated with heat, contained 100 times lower content of photosynthetic pigments. In particular, the synthesis of violaxanthin, zeaxanthin, lutein and chlorophyll b was limited. Furthermore, deregulation of starch and lipids synthesis, which led to the formation of very complex starch granules and an increased number of oleosomes, respectively, correlated with the reduction of the efficiency of androgenesis. The content of other sugars varied depending on the genotype and the type of stress. The highest content of various sugars was found for genotypes susceptible to andro-genesis, and highly reduced for genotypes resistant to androgenesis. The most important sugars seem to be glucose and fructose. They are involved in sugar sensing and signaling pathways, which affect the expression of various genes and regulate plant development. Sucrose, on the other hand, seems to have minor effect at each stage of the androgenesis. The sugar metabolism was related to metabolic activity of microspores. The genotypes susceptible to androgenesis process had much faster mitochondrium- and chloroplast-dependent energy conversion and higher heat production by tissues. Thus, the effectiveness of metabolic processes, their balance and the flexibility under the stress was a factor determining the direction of microspore development, and in the later stages of the androgenesis process, a factor supporting the induction of androgenic structures, chloroplast formation and the regeneration of green plants. The work was financed by Ministry of Agriculture and Rural Development within Program: ‘Biological Progress in Plant Production’, project no HOR.hn.802.15.2018.

Keywords: androgenesis, chloroplast, metabolism, temperature stress

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Authors: Adriana Haulica

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Powered by Machine Learning, Precise medicine is tailored by now to use genetic and molecular profiling, with the aim of optimizing the therapeutic benefits for cohorts of patients. As the majority of Machine Language algorithms come from heuristics, the outputs have contextual validity. This is not very restrictive in the sense that medicine itself is not an exact science. Meanwhile, the progress made in Molecular Biology, Bioinformatics, Computational Biology, and Precise Medicine, correlated with the huge amount of human biology data and the increase in computational power, opens new healthcare challenges. A more accurate diagnosis is needed along with real-time treatments by processing as much as possible from the available information. The purpose of this paper is to present a deeper vision for the future of Artificial Intelligence in Precise medicine. In fact, actual Machine Learning algorithms use standard mathematical knowledge, mostly Euclidian metrics and standard computation rules. The loss of information arising from the classical methods prevents obtaining 100% evidence on the diagnosis process. To overcome these problems, we introduce MEDICOMPILLS, a new architectural concept tool of information processing in Precise medicine that delivers diagnosis and therapy advice. This tool processes poly-field digital resources: global knowledge related to biomedicine in a direct or indirect manner but also technical databases, Natural Language Processing algorithms, and strong class optimization functions. As the name suggests, the heart of this tool is a compiler. The approach is completely new, tailored for omics and clinical data. Firstly, the intrinsic biological intuition is different from the well-known “a needle in a haystack” approach usually used when Machine Learning algorithms have to process differential genomic or molecular data to find biomarkers. Also, even if the input is seized from various types of data, the working engine inside the MEDICOMPILLS does not search for patterns as an integrative tool. This approach deciphers the biological meaning of input data up to the metabolic and physiologic mechanisms, based on a compiler with grammars issued from bio-algebra-inspired mathematics. It translates input data into bio-semantic units with the help of contextual information iteratively until Bio-Logical operations can be performed on the base of the “common denominator “rule. The rigorousness of MEDICOMPILLS comes from the structure of the contextual information on functions, built to be analogous to mathematical “proofs”. The major impact of this architecture is expressed by the high accuracy of the diagnosis. Detected as a multiple conditions diagnostic, constituted by some main diseases along with unhealthy biological states, this format is highly suitable for therapy proposal and disease prevention. The use of MEDICOMPILLS architecture is highly beneficial for the healthcare industry. The expectation is to generate a strategic trend in Precise medicine, making medicine more like an exact science and reducing the considerable risk of errors in diagnostics and therapies. The tool can be used by pharmaceutical laboratories for the discovery of new cures. It will also contribute to better design of clinical trials and speed them up.

Keywords: bio-semantic units, multiple conditions diagnosis, NLP, omics

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Authors: A. Coetzee, C. F. Kelly, E. Even-Zahav

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Dominant approaches to livestock production are harmful to the environment, human health and animal welfare, yet global meat consumption is rising. Sustainable alternative production approaches are therefore urgently required, and ‘free range’ is the main alternative for chicken meat offered in South Africa (and globally). Although the South African Poultry Association provides non-binding guidelines, there is a lack of formal definition and regulation of free range chicken production, meaning it is unclear what this alternative entails and if it is consistently practised (a trend observed globally). The objective of this exploratory qualitative case study is therefore to investigate who and what determines free range chicken. The case study, conducted from a social constructivist worldview, uses semi-structured interviews, photographs and document analysis to collect data. Interviews are conducted with those involved with bringing free range chicken to the market - farmers, chefs, retailers, and regulators. Data is analysed using thematic analysis to establish dominant patterns in the data. The five major themes identified (based on prevalence in data and on achieving the research objective) are: 1) free range means a bird reared with good animal welfare in mind, 2) free range means quality meat, 3) free range means a profitable business, 4) free range is determined by decision makers or by access to markets, and 5) free range is coupled with concerns about the lack of regulation. Unpacking the findings in the context of the literature reveals who and what determines free range. The research uncovers wide-ranging interpretations of ‘free range’, driven by the absence of formal regulation for free range chicken practices and the lack of independent private certification. This means that the term ‘free range’ is socially constructed, thus varied and complex. The case study also shows that whether chicken meat is free range is generally determined by those who have access to markets. Large retailers claim adherence to the internationally recognised Five Freedoms, also include in the South African Poultry Association Code of Good Practice, which others in the sector say are too broad to be meaningful. Producers describe animal welfare concerns as the main driver for how they practice/view free range production, yet these interpretations vary. An additional driver is a focus on human health, which participants achieve mainly through the use of antibiotic-free feed, resulting in what participants regard as higher quality meat. The participants are also strongly driven by business imperatives, with most stating that free range chicken should carry a higher price than conventionally-reared chicken due to increased production costs. Recommendations from this study focus on, inter alia, a need to understand consumers’ perspectives on free range chicken, given that those in the sector claim they are responding to consumer demand, and conducting environmental research such as life cycle assessment studies to establish the true (environmental) sustainability of free range production. At present, it seems the sector mostly responds to social sustainability: human health and animal welfare.

Keywords: chicken meat production, free range, socially constructed, sustainability

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