Search results for: signaling pathway

Authors: Jason Gica, Yi-Hsieng Samuel Wu, Deng-Jye Yang, Yi-Chen Chen

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Mycotoxins, harmful secondary metabolites produced by certain fungi species, pose significant risks to animals and humans worldwide. Their stable properties lead to contamination during grain harvesting, transportation, and storage, as well as in processed food products. The prevalence of mycotoxin contamination has attracted significant attention due to its adverse impact on food safety and global trade. The secondary contamination pathway from animal products has been identified as an important route of exposure, posing health risks for livestock and humans consuming contaminated products. Pork, one of the highly consumed meat products in Taiwan according to the National Food Consumption Database, plays a critical role in the nation's diet and economy. Given its substantial consumption, pork processing products are a significant component of the food supply chain and a potential source of mycotoxin contamination. This study is paramount for formulating effective regulations and strategies to mitigate mycotoxin-related risks in the food supply chain. By establishing a reliable analytical method, this research contributes to safeguarding public health and enhancing the quality of pork processing products. The findings will serve as valuable guidance for policymakers, food industries, and consumers to ensure a safer food supply chain in the face of emerging mycotoxin challenges. An innovative and efficient analytical approach is proposed using Ultra-High Performance Liquid Chromatography coupled with Temperature Control Fluorescence Detector Light (UHPLC-TCFLD) to determine multiple mycotoxins in pork meat samples due to its exceptional capacity to detect multiple mycotoxins at the lowest levels of concentration, making it highly sensitive and reliable for comprehensive mycotoxin analysis. Additionally, its ability to simultaneously detect multiple mycotoxins in a single run significantly reduces the time and resources required for analysis, making it a cost-effective solution for monitoring mycotoxin contamination in pork processing products. The research aims to optimize the efficient mycotoxin QuEChERs extraction method and rigorously validate its accuracy and precision. The results will provide crucial insights into mycotoxin levels in pork processing products.

Keywords: multiple-mycotoxin analysis, pork processing products, QuEChERs, UHPLC-TCFLD, validation

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Authors: Hirseland Andreas, Kerschbaumer Lukas

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In the case of Germany, there are about one million long-term unemployed – a figure that did not vary much during the past years. These long-term unemployed did not benefit from the prospering labor market while most short-term unemployed did. Instead, they are continuously dependent on welfare and sometimes precarious short-term employment, experiencing work poverty. Long-term unemployment thus turns into a main obstacle to become employed again, especially if it is accompanied by other impediments such as low-level education (school/vocational), poor health (especially chronical illness), advanced age (older than fifty), immigrant status, motherhood or engagement in care for other relatives. As can be shown by this current research project, in these cases the chance to regain employment decreases to near nil. Almost two-thirds of all welfare recipients have multiple impediments which hinder a successful transition from welfare back to sustainable and sufficient employment. Prospective employers are unlikely to hire long-term unemployed with additional impediments because they evaluate potential employees on their negative signaling (e.g. low-level education) and the implicit assumption of unproductiveness (e.g. poor health, age). Some findings of the panel survey “Labor market and social security” (PASS) carried out by the Institute of Employment Research (the research institute of the German Federal Labor Agency) spread a ray of hope, showing that unlikely does not necessarily mean impossible. The presentation reports on current research on these very scarce “success stories” of unlikely transitions from long-term unemployment to work and how these cases were able to perform this switch against all odds. The study is based on a mixed-method design. Within the panel survey (~15,000 respondents in ~10,000 households), only 66 cases of such unlikely transitions were observed. These cases have been explored by qualitative inquiry – in depth-interviews and qualitative network techniques. There is strong evidence that sustainable transitions are influenced by certain biographical resources like habits of network use, a set of informal skills and particularly a resilient way of dealing with obstacles, combined with contextual factors rather than by job-placement procedures promoted by Job-Centers according to activation rules or by following formal paths of application. On the employer’s side small and medium-sized enterprises are often found to give job opportunities to a wider variety of applicants, often based on a slow but steadily increasing relationship leading to employment. According to these results it is possible to show and discuss some limitations of (German) activation policies targeting the labor market and their impact on welfare dependency and long-term unemployment. Based on these findings, indications for more supportive small-scale measures in the field of labor-market policies are suggested to help long-term unemployed with multiple impediments to overcome their situation (e.g. organizing small-scale-structures and low-threshold services to encounter possible employers on a more informal basis like “meet and greet”).

Keywords: against-all-odds, mixed-methods, Welfare State, long-term unemployment

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Authors: Ewelina Wisnik, Zsolt Regdon, Kinga Chmielewska, Laszlo Virag, Agnieszka Robaszkiewicz

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Apart from protecting genome, PARP1 has been documented to regulate many intracellular processes inter alia gene transcription by physically interacting with chromatin bound proteins and by their ADP-ribosylation. Our recent findings indicate that expression of PARP1 decreases during the differentiation of human CD34+ hematopoietic stem cells to monocytes as a consequence of differentiation-associated cell growth arrest and formation of E2F4-RBL2-HDAC1-SWI/SNF repressive complex at the promoter of this gene. Since the RBL2 complexes repress genes in a E2F-dependent manner and are widespread in the genome in G0 arrested cells, we asked (a) if RBL2 directly contributes to defining monocyte phenotype and function by targeting gene promoters and (b) if RBL2 controls gene transcription indirectly by repressing PARP1. For identification of genes controlled by RBL2 and/or PARP1,we used primer libraries for surface receptors and TLR signaling mediators, genes were silenced by siRNA or shRNA, analysis of gene promoter occupation by selected proteins was carried out by ChIP-qPCR, while statistical analysis in GraphPad Prism 5 and STATISTICA, ChIP-Seq data were analysed in Galaxy 2.5.0.0. On the list of 28 genes regulated by RBL2, we identified only four solely repressed by RBL2-E2F4-HDAC1-BRM complex. Surprisingly, 24 out of 28 emerged genes controlled by RBL2 were co-regulated by PARP1 in six different manners. In one mode of RBL2/PARP1 co-operation, represented by MAP2K6 and MAPK3, PARP1 was found to associate with gene promoters upon RBL2 silencing, which was previously shown to restore PARP1 expression in monocytes. PARP1 effect on gene transcription was observed only in the presence of active EP300, which acetylated gene promoters and activated transcription. Further analysis revealed that PARP1 binding to MA2K6 and MAPK3 promoters enabled recruitment of EP300 in monocytes, while in proliferating cancer cell lines, which actively transcribe PARP1, this protein maintained EP300 at the promoters of MA2K6 and MAPK3. Genome-wide analysis revealed a similar distribution of PARP1 and EP300 around transcription start sites and the co-occupancy of some gene promoters by PARP1 and EP300 in cancer cells. Here, we described a new RBL2/PARP1/EP300 axis which controls gene transcription regardless of the cell type. In this model cell, cycle-dependent transcription of PARP1 regulates expression of some genes repressed by RBL2 upon cell cycle limitation. Thus, RBL2 may indirectly regulate transcription of some genes by controlling the expression of EP300-recruiting PARP1. Acknowledgement: This work was financed by Polish National Science Centre grants nr DEC-2013/11/D/NZ2/00033 and DEC-2015/19/N/NZ2/01735. L.V. is funded by the National Research, Development and Innovation Office grants GINOP-2.3.2-15-2016-00020 TUMORDNS, GINOP-2.3.2-15-2016-00048-STAYALIVE and OTKA K112336. AR is supported by Polish Ministry of Science and Higher Education 776/STYP/11/2016.

Keywords: retinoblastoma transcriptional co-repressor like 2 (RBL2), poly(ADP-ribose) polymerase 1 (PARP1), E1A binding protein p300 (EP300), monocytes

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Authors: Rashmi Shukla, Yamini Bhusan Tripathi

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Diabetic nephropathy (DN) is characterized as diabetic kidney disease which involves many pathways e.g. hyperactivated protein kinase c (PKC), polyol pathway, excess production of advanced glycation end product (AGEs) & free radical accumulation etc. All of them results to hypoxia followed by apoptosis of podocytes, glomerulosclerosis, extracellular matrix (ECM) accumulation and fibrosis resulting to irreversible changes in kidney. This is continuously rising worldwide and there are not enough specific drugs, to retard its progress. Due to increasing side effects of allopathic drugs, interest in herbal remedies is growing. Earlier, we have reported that PTY-2 (a phytomedicine, derived from Pueraria tuberosa Linn.) inhibits the accumulation of extracellular matrix (ECM) through activation of MMP-9. Present study exhibited the therapeutic potential of Pueraria tuberosa in the prevention of podocytes apoptosis and modulation of nephrin expression in streptozotocin (STZ) induced DN rats. DN rats were produced by maintaining persistent hyperglycemia for 8 weeks by intra-peritoneal injection of 55 mg/kg streptozotocin (STZ). These rats were randomly divided in 2 groups, i.e. DN control, and DN+ water extract of Pueraria tuberosa (PTW). One group of age-matched normal rats served as non-diabetic control (group-1), The STZ induced DN rats (group-2) and DN+PTW treated rats (group-3). The PTW was orally administered (0.3g/kg) daily to group-2 rats and drug vector (1 ml of 10% tween 20) in control rats. The treatments were continued for 20 days and blood and urine samples were collected. Rats were then sacrificed to investigate the expression Bcl2, Bax and nephroprotective protein i.e. nephrin in kidney glomerulus. The effect of PTW was evaluated, we have found that the PTW significantly(p < .001) reversed the raised serum urea, serum creatinine, urine protein and improved the creatinine clearance in STZ induce diabetic nephropathy in rats and also significantly(p < .001) prevented the rise in urine albumin excretion. The Western blot analysis of kidney tissue homogenate showed increased expression of Bcl2 in PTW treated rats. The RT-PCR showed the increased expression and accumulation of nephrin mRNA. The confocal photomicrographs also supported the reduction of Bax and a simultaneous increase in Bcl2 and nephrin in glomerular podocytes. Hence, our finding suggests that the nephroprotective role of PTW is mediated via restoration of nephrin thus prevents the podocytes apoptosis and ameliorates diabetic nephropathy. The clinical trial of PTW would prove to be a potential food supplement/ drug of alternative medicine for patients with diabetic nephropathy in early stage.

Keywords: Pueraria tuberosa, diabetic nephropathy, anti-apoptosis, nephrin

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Authors: Anna Ghosh, Dominic Shields, Ceri McIntosh, Stephen Crank

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A 29-year-old male was a referral to the maxillofacial unit following a referral from his general dental practitioner via a routine pathway regarding a large periapical lesion on the LR4 with root resorption. The patient was asymptomatic, the LR4 vital and unrestored, and this was an incidental finding at a routine check-up. The patient's past medical history was unremarkable. Examination revealed no extra or intra-oral pathology and non-mobile teeth. No focal neurology was detected. An orthopantogram demonstrated a well-defined unilocular corticated radiolucency associated with the LR4. The root appeared shortened with the radiolucency between the root and a radio-opacity, possibly representing the displacement of the apical tip of the tooth. It was recommended that the referring general practitioner should proceed with orthograde root canal therapy, after which time exploration, enucleation, and retrograde root filling of the LR4 would be carried out by a maxillofacial unit. The patient was reviewed six months later where, due to the COVID-19 pandemic, the patient had been unable to access general dental services for the root canal treatment. He was still entirely asymptomatic. A one-year review was planned in the hope this would allow time for the orthograde root canal therapy to be completed. At this review, the orthograde root canal therapy had still not been completed. Interestingly, a repeat orthopantogram revealed a significant reduction in size with good bony infill and a significant reduction in the size of the lesion. Due to the ongoing delays with primary care dental therapy, the patient was subsequently internally referred to the restorative dentistry department for care. The patient was seen again by oral and maxillo-facial surgery in mid-2022 where he still reports this tooth as asymptomatic with no focal neurology. The patient's history was fully reviewed, and noted that 15 years previously, the patient underwent open reduction and internal fixation of a left angle of mandible fracture. Temporary IMF involving IMF screws and fixation wires were employed to maintain occlusion during plating and subsequently removed post-operatively. It is proposed that the radiolucency was, as a result of the IMF screw placement, penetrating the LR4 root resulting in resorption of the tooth root and development of a radiolucency. This case highlights the importance of careful screw size and physical site location, and placement of IMF screws, as there can be permeant damage to a patient’s dentition.

Keywords: facial trauma, inter-maxillary fixation, mandibular radiolucency, oral and maxillo-facial surgery

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Authors: Huan Peng, Chenye Zeng, Zhao Wang

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is a leading cause of dementia syndromes and has become a huge burden on society and families. The main pathological features of AD involve excessive deposition of β-amyloid (Aβ) and Tau proteins in the brain, resulting in loss of neurons, expansion of neuroinflammation, and cognitive dysfunction in patients. Researchers have found effective drugs to clear the brain of error-accumulating proteins or to slow the loss of neurons, but their direct administration has key bottlenecks such as single-drug limitation, rapid blood clearance rate, impenetrable blood-brain barrier (BBB), and poor ability to target tissues and cells. Therefore, we are committed to seeking a suitable and efficient delivery system. Inspired by the possibility that exosomes may be involved in the secretion and transport mechanism of many signaling molecules or proteins in the brain, exosomes have attracted extensive attention as natural nanoscale drug carriers. We selected exosomes derived from bone marrow mesenchymal stem cells (MSC-EXO) with low immunogenicity and exosomes derived from hippocampal neurons (HT22-EXO) that may have excellent homing ability to overcome the deficiencies of oral or injectable pathways and bypass the BBB through nasal administration and evaluated their delivery ability and effect on AD. First, MSC-EXO and HT22 cells were isolated and cultured, and MSCs were identified by microimaging and flow cytometry. Then MSC-EXO and HT22-EXO were obtained by gradient centrifugation and qEV SEC separation column, and a series of physicochemical characterization were performed by transmission electron microscope, western blot, nanoparticle tracking analysis and dynamic light scattering. Next, exosomes labeled with lipophilic fluorescent dye were administered to WT mice and APP/PS1 mice to obtain fluorescence images of various organs at different times. Finally, APP/PS1 mice were administered intranasally with two exosomes 20 times over 40 days and 20 μL each time. Behavioral analysis and pathological section analysis of the hippocampus were performed after the experiment. The results showed that MSC-EXO and HT22-EXO were successfully isolated and characterized, and they had good biocompatibility. MSC-EXO showed excellent brain enrichment in APP/PS1 mice after intranasal administration, could improve the neuronal damage and reduce inflammation levels in the hippocampus of APP/PS1 mice, and the improvement effect was significantly better than HT22-EXO. However, intranasal administration of the two exosomes did not cause depression and anxious-like phenotypes in APP/PS1 mice, nor significantly improved the short-term or spatial learning and memory ability of APP/PS1 mice, and had no significant effect on the content of Aβ plaques in the hippocampus, which also meant that MSC-EXO could use their own advantages in combination with other drugs to clear Aβ plaques. The possibility of realizing highly effective non-invasive synergistic treatment for AD provides new strategies and ideas for clinical research.

Keywords: Alzheimer’s disease, exosomes derived from mesenchymal stem cell, intranasal administration, therapy-carrier dual roles

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Authors: Ahlam Ali, Katrina Lappin, Jaine Blayney, Ken Mills

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Leukaemia is the most frequently (30%) occurring type of paediatric cancer. Of these, approximately 80% are acute lymphoblastic leukaemia (ALL) with acute myeloid leukaemia (AML) cases making up the remaining 20% alongside other leukaemias. Unfortunately, children with AML do not have promising prognosis with only 60% surviving 5 years or longer. It has been highlighted recently the need for age-specific therapies for AML patients, with paediatric AML cases having a different mutational landscape compared with AML diagnosed in adult patients. Drug Repurposing is a recognized strategy in drug discovery and development where an already approved drug is used for diseases other than originally indicated. We aim to identify novel combination therapies with the promise of providing alternative more effective and less toxic induction therapy options. Our in-silico analysis highlighted ‘cell death and survival’ as an aberrant, potentially targetable pathway in paediatric AML patients. On this basis, 83 apoptotic inducing compounds were screened. A preliminary single agent screen was also performed to eliminate potentially toxic chemicals, then drugs were constructed into a pooled library with 10 drugs per well over 160 wells, with 45 possible pairs and 120 triples in each well. Seven cell lines were used during this study to represent the clonality of AML in paediatric patients (Kasumi-1, CMK, CMS, MV11-14, PL21, THP1, MOLM-13). Cytotoxicity was assessed up to 72 hours using CellTox™ Green reagent. Fluorescence readings were normalized to a DMSO control. Z-Score was assigned to each well based on the mean and standard deviation of all the data. Combinations with a Z-Score <2 were eliminated and the remaining wells were taken forward for further analysis. A well was considered ‘successful’ if each drug individually demonstrated a Z-Score <2, while the combination exhibited a Z-Score >2. Each of the ten compounds in one well (155) had minimal or no effect as single agents on cell viability however, a combination of two or more of the compounds resulted in a substantial increase in cell death, therefore the ten compounds were de-convoluted to identify a possible synergistic pair/triple combinations. The screen identified two possible ‘novel’ drug pairing, with BCL2 inhibitor ABT-737, combined with either a CDK inhibitor Purvalanol A, or AKT/ PI3K inhibitor LY294002. (ABT-737- 100 nM+ Purvalanol A- 1 µM) (ABT-737- 100 nM+ LY294002- 2 µM). Three possible triple combinations were identified (LY2409881+Akti-1/2+Purvalanol A, SU9516+Akti-1/2+Purvalanol A, and ABT-737+LY2409881+Purvalanol A), which will be taken forward for examining their efficacy at varying concentrations and dosing schedules, across multiple paediatric AML cell lines for optimisation of maximum synergy. We believe that our combination screening approach has potential for future use with a larger cohort of drugs including FDA approved compounds and patient material.

Keywords: AML, drug repurposing, ABT-737, apoptosis

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Authors: José Maria, Vânia Laranjo, Luís Abrunhosa, António Inês

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The occurrence of mycotoxigenic moulds such as Aspergillus, Penicillium and Fusarium in food and feed has an important impact on public health, by the appearance of acute and chronic mycotoxicoses in humans and animals, which is more severe in the developing countries due to lack of food security, poverty and malnutrition. This mould contamination also constitutes a major economic problem due the lost of crop production. A great variety of filamentous fungi is able to produce highly toxic secondary metabolites known as mycotoxins. Most of the mycotoxins are carcinogenic, mutagenic, neurotoxic and immunosuppressive, being ochratoxin A (OTA) one of the most important. OTA is toxic to animals and humans, mainly due to its nephrotoxic properties. Several approaches have been developed for decontamination of mycotoxins in foods, such as, prevention of contamination, biodegradation of mycotoxins-containing food and feed with microorganisms or enzymes and inhibition or absorption of mycotoxin content of consumed food into the digestive tract. Some group of Gram-positive bacteria named lactic acid bacteria (LAB) are able to release some molecules that can influence the mould growth, improving the shelf life of many fermented products and reducing health risks due to exposure to mycotoxins. Some LAB are capable of mycotoxin detoxification. Recently our group was the first to describe the ability of LAB strains to biodegrade OTA, more specifically, Pediococcus parvulus strains isolated from Douro wines. The pathway of this biodegradation was identified previously in other microorganisms. OTA can be degraded through the hydrolysis of the amide bond that links the L-β-phenylalanine molecule to the ochratoxin alpha (OTα) a non toxic compound. It is known that some peptidases from different origins can mediate the hydrolysis reaction like, carboxypeptidase A an enzyme from the bovine pancreas, a commercial lipase and several commercial proteases. So, we wanted to have a better understanding of this OTA degradation process when LAB are involved and identify which molecules where present in this process. For achieving our aim we used some bioinformatics tools (BLAST, CLUSTALX2, CLC Sequence Viewer 7, Finch TV). We also designed specific primers and realized gene specific PCR. The template DNA used came from LAB strains samples of our previous work, and other DNA LAB strains isolated from elderberry fruit, silage, milk and sausages. Through the employment of bioinformatics tools it was possible to identify several proteins belonging to the carboxypeptidase family that participate in the process of OTA degradation, such as serine type D-Ala-D-Ala carboxypeptidase and membrane carboxypeptidase. In conclusions, this work has identified carboxypeptidase proteins being one of the molecules present in the OTA degradation process when LAB are involved.

Keywords: carboxypeptidase, lactic acid bacteria, mycotoxins, ochratoxin a.

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Authors: Olubisi Friday Oluduro

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The Paris Agreement 2015, the result of negotiations under the United Nations Framework Convention on Climate Change (UNFCCC), after Kyoto Protocol expiration, sets a long-term goal of limiting the increase in the global average temperature to well below 2 degrees Celsius above pre-industrial levels, and of pursuing efforts to limiting this temperature increase to 1.5 degrees Celsius. An advancement on the erstwhile Kyoto Protocol which sets commitments to only a limited number of Parties to reduce their greenhouse gas (GHGs) emissions, it includes the goal to increase the ability to adapt to the adverse impacts of climate change and to make finance flows consistent with a pathway towards low GHGs emissions. For it achieve these goals, the Agreement requires all Parties to undertake efforts towards reaching global peaking of GHG emissions as soon as possible and towards achieving a balance between anthropogenic emissions by sources and removals by sinks in the second half of the twenty-first century. In addition to climate change mitigation, the Agreement aims at enhancing adaptive capacity, strengthening resilience and reducing the vulnerability to climate change in different parts of the world. It acknowledges the importance of addressing loss and damage associated with the adverse of climate change. The Agreement also contains comprehensive provisions on support to be provided to developing countries, which includes finance, technology transfer and capacity building. To ensure that such supports and actions are transparent, the Agreement contains a number reporting provisions, requiring parties to choose the efforts and measures that mostly suit them (Nationally Determined Contributions), providing for a mechanism of assessing progress and increasing global ambition over time by a regular global stocktake. Despite the somewhat global look of the Agreement, it has been fraught with manifold limitations threatening its very existential capability to produce any meaningful result. Considering these obvious limitations some of which were the very cause of the failure of its predecessor—the Kyoto Protocol—such as the non-participation of the United States, non-payment of funds into the various coffers for appropriate strategic purposes, among others. These have left the developing countries largely threatened eve the more, being more vulnerable than the developed countries, which are really responsible for the climate change scourge. The paper seeks to examine the mitigation and adaptation measures under the Paris Agreement 2015, appraise the present situation since the Agreement was concluded and ascertain whether the developing countries have been better or worse off since the Agreement was concluded, and examine why and how, while projecting a way forward in the present circumstance. It would conclude with recommendations towards ameliorating the situation.

Keywords: mitigation, adaptation, climate change, Paris agreement 2015, framework

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Authors: Ruth Green, Samantha Milton, Rinal Desai

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Background/Aims: Eye pain/swelling/redness is a common presentation to Barnet General Hospital (a district general hospital), pediatric emergency department, and is managed by both the pediatric and emergency teams. The management of each child differs dramatically depending on the healthcare professional who reviews them. There also appears to be confusion in diagnosis between periorbital cellulitis, pre-septal cellulitis, and orbital cellulitis. Pre septal cellulitis refers to an inflammation of the eyelids and soft tissue anterior to the orbital septum. In contrast, orbital cellulitis is a serious, rapidly progressive infection of soft tissues located posterior to the orbital septum. Pre-septal cellulitis is more prevalent and less serious than orbital cellulitis, although it may be part of a continuous spectrum if untreated. Pre-septal cellulitis should there be diagnosed and treated urgently to prevent spread to the septum. For the purpose of the audit, the term periorbital cellulitis has been used as an umbrella term for all spectrums of this infection. The audit aimed to look at, how as a whole, the department is diagnosing and managing orbital and pre-septal cellulitis. Gold Standard: Patients of the same age and diagnosis should be treated with the same medication, advice, and follow-up. Method: Data was collected retrospectively from pediatric patients ( < 18years) who attended the emergency department from June 2019 to February 2020 who had been coded as pre-septal cellulitis, periorbital cellulitis, orbital cellulitis, or eye pain/swelling/redness. Demographics, signs and symptoms, management, and follow-up were recorded for all patients with any of the diagnoses of pre-septal, periorbital, or orbital cellulitis. A Microsoft Excel spreadsheet was used to record the anonymised data. Results: There were vast discrepancies in the diagnosis, management, and follow-up of patients with periorbital cellulitis. Conclusion/Discussion: The audit concluded there is no uniform approach to managing periorbital cellulitis in Barnet General Hospital Paediatric Emergency Department. Healthcare professionals misdiagnosed conjunctivitis as periorbital cellulitis, and adequate steps did not appear to be documented on excluding red flag signs and symptoms of patients presenting. There was no consistency in follow-up, with some patients having timely phone reviews or clinical reviews for mild symptoms. Advice given by the staff was appropriate, and patients did return when symptoms got worse and were treated accordingly. Plan: Given the inconsistency, a gold standard care pathway or local easily accessible clinical guideline can be developed to help with the diagnosis and management of periorbital cellulitis. Along with this, a teaching session can be carried out for the staff of the pediatric team and emergency department to disseminate the teaching. Following the introduction of a guideline and teaching sessions, patients notes can be re-reviewed to check improvement in patient care.

Keywords: periorbital cellulitis, preseptal cellulitis, orbital cellulitis, erythematous eyelid

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Authors: Tatjana Stefanovic Stanojevic, Milica Tosic Radev, Aleksandra Bogdanovic

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Depression is considered to be a leading cause of death and disability in the female population, and that is the reason why understanding the dynamics of the onset of depressive symptomatology is important. A review of the literature indicates the relationship between depressive symptoms and insecure attachment patterns, but very few studies have examined the mechanism underlying this relation. The aim of the study was to examine the pathway from the preoccupied attachment pattern to depressive symptomatology, as well as to test the mediation effect of mentalization, social anxiety and rumination in this relationship using a serial mediation model. The research was carried out on a geographical cluster sample from the general population of Serbia included within the project ‘Indicators and models of family and work roles harmonization’ funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia. This research was carried out on a subsample of 791 working-age female adults from 37 urban and rural locations distributed through 20 administrative districts of Serbia. The respondents filled in a battery of instruments, including Relationship Questionnaire - Clinical Version (RQ - CV), The Mentalization Scale (MentS), Scale of Social Anxiety (SA), Patient Ruminative Thought Style Questionnaire (RTSQ), Health Questionnaire (PHQ-9). The results confirm our assumption that the total indirect effect of the preoccupied attachment pattern to depressive symptoms is significant across all mediators separately. More importantly, this effect is still present in a model with a sequential mediator relationship, where social anxiety, rumination, and mentalization were perceived as serial mediators of a relationship between preoccupied attachment and depressive symptoms (estimated indirect effect=0.004, boot-strapped 95% CI=0.002 to 0.007). Our findings suggest that there is a significant specific indirect effect of the preoccupied attachment pattern to depressive symptoms, occurring through mentalization, social anxiety and rumination, indicating that preoccupied attachment cause decrease of a self related mentalization, which in turn causes increasing of social anxiety and rumination, concluding in depressive symptoms as a final consequence. The finding that the path from the preoccupied attachment pattern to depressive symptoms is typical in women is understandable from the perspective of both evolutionary and culturally conditioned gender differences. The practical implications of the study are reflected in the recommendations for the prevention and forehand psychotherapy response among preoccupied women with depressive symptomatology. Treatment of this specific group of depressed patients should be focused on strengthening mentalization, learning to accept and to understand herself better, reducing anxiety in situations where mistakes are visible to others, and replacing the rumination strategy with more constructive coping strategies.

Keywords: preoccupied attachment, depression, serial mediation model, mentalization, rumination

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Authors: Babak Forouraghi

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A genetic circuit is a collection of interacting genes and proteins that enable individual cells to implement and perform vital biological functions such as cell division, growth, death, and signaling. In cell engineering, synthetic gene circuits are engineered networks of genes specifically designed to implement functionalities that are not evolved by nature. These engineered networks enable scientists to tackle complex problems such as engineering cells to produce therapeutics within the patient's body, altering T cells to target cancer-related antigens for treatment, improving antibody production using engineered cells, tissue engineering, and production of genetically modified plants and livestock. Construction of computational models to realize genetic circuits is an especially challenging task since it requires the discovery of flow of genetic information in complex biological systems. Building synthetic biological models is also a time-consuming process with relatively low prediction accuracy for highly complex genetic circuits. The primary goal of this study was to investigate the utility of a pre-trained bidirectional encoder transformer that can accurately predict gene expressions in genetic circuit designs. The main reason behind using transformers is their innate ability (attention mechanism) to take account of the semantic context present in long DNA chains that are heavily dependent on spatial representation of their constituent genes. Previous approaches to gene circuit design, such as CNN and RNN architectures, are unable to capture semantic dependencies in long contexts as required in most real-world applications of synthetic biology. For instance, RNN models (LSTM, GRU), although able to learn long-term dependencies, greatly suffer from vanishing gradient and low-efficiency problem when they sequentially process past states and compresses contextual information into a bottleneck with long input sequences. In other words, these architectures are not equipped with the necessary attention mechanisms to follow a long chain of genes with thousands of tokens. To address the above-mentioned limitations of previous approaches, a transformer model was built in this work as a variation to the existing DNA Bidirectional Encoder Representations from Transformers (DNABERT) model. It is shown that the proposed transformer is capable of capturing contextual information from long input sequences with attention mechanism. In a previous work on genetic circuit design, the traditional approaches to classification and regression, such as Random Forrest, Support Vector Machine, and Artificial Neural Networks, were able to achieve reasonably high R2 accuracy levels of 0.95 to 0.97. However, the transformer model utilized in this work with its attention-based mechanism, was able to achieve a perfect accuracy level of 100%. Further, it is demonstrated that the efficiency of the transformer-based gene expression classifier is not dependent on presence of large amounts of training examples, which may be difficult to compile in many real-world gene circuit designs.

Keywords: transformers, generative ai, gene expression design, classification

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Authors: Felicia Orah Rein Moshe

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Soil erosion has become a priority global concern, impairing water quality and degrading ecosystem services. In Mediterranean climates, following a long dry period, the onset of rain occurs when agricultural soils are often bare and most vulnerable to erosion. Early storms transport sediments and sediment-bound pollutants into streams, along with dissolved chemicals. This results in loss of valuable topsoil, water quality degradation, and potentially expensive dredged-material disposal costs. Information on the provenance of fine sediment and priority sources of adsorbed pollutants represents a critical need for developing effective control strategies aimed at source reduction. Modifying sediment traps designed for marine systems, this study tested a cost-effective method to collect suspended sediments on a catchment scale to characterize stream water quality during first-flush storm events in a flashy Eastern Mediterranean coastal perennial stream. This study investigated the Kishon Basin, deploying sediment traps in 23 locations, including 4 in the mainstream and one downstream in each of 19 tributaries, enabling the characterization of sediment as a vehicle for transporting chemicals. Further, it enabled direct comparison of sediment-bound pollutants transported during the first-flush winter storms of 2020 from each of 19 tributaries, allowing subsequent ecotoxicity ranking. Sediment samples were successfully captured in 22 locations. Pesticides, pharmaceuticals, nutrients, and metal concentrations were quantified, identifying a total of 50 pesticides, 15 pharmaceuticals, and 22 metals, with 16 pesticides and 3 pharmaceuticals found in all 23 locations, demonstrating the importance of this transport pathway. Heavy metals were detected in only one tributary, identifying an important watershed pollution source with immediate potential influence on long-term dredging costs. Simultaneous sediment sampling at first flush storms enabled clear identification of priority tributaries and their chemical contributions, advancing a new national watershed monitoring approach, facilitating strategic plan development based on source reduction, and advancing the goal of improving the farm-stream interface, conserving soil resources, and protecting water quality.

Keywords: adsorbed pollution, dredged material, heavy metals, suspended sediment, water quality monitoring

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Authors: A. Newman-Tancredi, R. Depoortère, P. Gruca, E. Litwa, M. Lason, M. Papp

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The N-methyl-D-aspartic acid (NMDA) receptor antagonist, ketamine, can elicit rapid-acting antidepressant (RAAD) effects in treatment-resistant patients, but it requires parenteral co-administration with a classical antidepressant under medical supervision. In addition, ketamine can also produce serious side effects that limit its long-term use, and there is much interest in identifying RAADs based on ketamine’s mechanism of action but with safer profiles. Ketamine elicits GABAergic interneuron inhibition, glutamatergic neuron stimulation, and, notably, activation of serotonin 5-HT1A receptors in the prefrontal cortex (PFC). Direct activation of the latter receptor subpopulation with selective ‘biased agonists’ may therefore be a promising strategy to identify novel RAADs and, consistent with this hypothesis, the prototypical cortical biased agonist, NLX-101, exhibited robust RAAD-like activity in the chronic mild stress model of depression (CMS). The present study compared the effects of a novel, selective 5-HT1A receptor-biased agonist, NLX-204, with those of ketamine and NLX-101. Materials and methods: CMS procedure was conducted on Wistar rats; drugs were administered either intraperitoneally (i.p.) or by bilateral intracortical microinjection. Ketamine: 10 mg/kg i.p. or 10 µg/side in PFC; NLX-204 and NLX-101: 0.08 and 0.16 mg/kg i.p. or 16 µg/side in PFC. In addition, interaction studies were carried out with systemic NLX-204 or NLX-101 (each at 0.16 mg/kg i.p.) in combination with intracortical WAY-100635 (selective 5-HT1A receptor antagonist; 2 µg/side) or muscimol (GABA-A receptor agonist, 12.5 ng/side). Anhedonia was assessed by CMS-induced decrease in sucrose solution consumption; anxiety-like behavior was assessed using the Elevated Plus Maze (EPM), and cognitive impairment was assessed by the Novel Object Recognition (NOR) test. Results: A single administration of NLX-204 was sufficient to reverse the CMS-induced deficit in sucrose consumption, similarly to ketamine and NLX-101. NLX-204 also reduced CMS-induced anxiety in the EPM and abolished CMS-induced NOR deficits. These effects were maintained (EPM and NOR) or enhanced (sucrose consumption) over a subsequent 2-week period of treatment. The anti-anhedonic response of the drugs was also maintained for several weeks Following treatment discontinuation, suggesting that they had sustained effects on neuronal networks. A single PFC administration of NLX-204 reversed deficient sucrose consumption, similarly to ketamine and NLX-101. Moreover, the anti-anhedonic activities of systemic NLX-204 and NLX 101 were abolished by coadministration with intracortical WAY-100635 or muscimol. Conclusions: (i) The antidepressant-like activity of NLX-204 in the rat CMS model was as rapid as that of ketamine or NLX-101, supporting targeting cortical 5-HT1A receptors with selective, biased agonists to achieve RAAD effects. (ii)The anti-anhedonic activity of systemic NLX-204 was mimicked by local administration of the compound in the PFC, confirming the involvement of cortical circuits in its RAAD-like effects. (iii) Notably, the effects of systemic NLX-204 and NLX-101 were abolished by PFC administration of muscimol, indicating that they act by (indirectly) eliciting a reduction in cortical GABAergic neurotransmission. This is consistent with ketamine’s mechanism of action and suggests that there are converging NMDA and 5-HT1A receptor signaling cascades in PFC underlying the RAAD-like activities of ketamine and NLX-204. Acknowledgements: The study was financially supported by NCN grant no. 2019/35/B/NZ7/00787.

Keywords: depression, ketamine, serotonin, 5-HT1A receptor, chronic mild stress

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Authors: Kathrina Aseanne Acapulco-Gomez, Shayne Julieane Morales, Tzar Francis Verame

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Mean platelet volume (MPV) is the most accurate measure of the size of platelets and is routinely measured by most automated hematological analyzers. Several studies have shown associations between MPV and cardiovascular risks and outcomes. Although its measurement may provide useful data, MPV remains to be a diagnostic tool that is yet to be included in routine clinical decision making. The aim of this systematic review and meta-analysis is to determine summary estimates of the diagnostic accuracy of mean platelet volume for the diagnosis of myocardial infarction among adult patients with angina and/or its equivalents in terms of sensitivity, specificity, diagnostic odds ratio, and likelihood ratios, and to determine the difference of the mean MPV values between those with MI and those in the non-MI controls. The primary search was done through search in electronic databases PubMed, Cochrane Review CENTRAL, HERDIN (Health Research and Development Information Network), Google Scholar, Philippine Journal of Pathology, and Philippine College of Physicians Philippine Journal of Internal Medicine. The reference list of original reports was also searched. Cross-sectional, cohort, and case-control articles studying the diagnostic performance of mean platelet volume in the diagnosis of acute myocardial infarction in adult patients were included in the study. Studies were included if: (1) CBC was taken upon presentation to the ER or upon admission (within 24 hours of symptom onset); (2) myocardial infarction was diagnosed with serum markers, ECG, or according to accepted guidelines by the Cardiology societies (American Heart Association (AHA), American College of Cardiology (ACC), European Society of Cardiology (ESC); and, (3) if outcomes were measured as significant difference AND/OR sensitivity and specificity. The authors independently screened for inclusion of all the identified potential studies as a result of the search. Eligible studies were appraised using well-defined criteria. Any disagreement between the reviewers was resolved through discussion and consensus. The overall mean MPV value of those with MI (9.702 fl; 95% CI 9.07 – 10.33) was higher than in those of the non-MI control group (8.85 fl; 95% CI 8.23 – 9.46). Interpretation of the calculated t-value of 2.0827 showed that there was a significant difference in the mean MPV values of those with MI and those of the non-MI controls. The summary sensitivity (Se) and specificity (Sp) for MPV were 0.66 (95% CI; 0.59 - 0.73) and 0.60 (95% CI; 0.43 – 0.75), respectively. The pooled diagnostic odds ratio (DOR) was 2.92 (95% CI; 1.90 – 4.50). The positive likelihood ratio of MPV in the diagnosis of myocardial infarction was 1.65 (95% CI; 1.20 – 22.27), and the negative likelihood ratio was 0.56 (95% CI; 0.50 – 0.64). The intended role for MPV in the diagnostic pathway of myocardial infarction would perhaps be best as a triage tool. With a DOR of 2.92, MPV values can discriminate between those who have MI and those without. For a patient with angina presenting with elevated MPV values, it is 1.65 times more likely that he has MI. Thus, it is implied that the decision to treat a patient with angina or its equivalents as a case of MI could be supported by an elevated MPV value.

Keywords: mean platelet volume, MPV, myocardial infarction, angina, chest pain

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Authors: Babak Forouraghi

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A genetic circuit is a collection of interacting genes and proteins that enable individual cells to implement and perform vital biological functions such as cell division, growth, death, and signaling. In cell engineering, synthetic gene circuits are engineered networks of genes specifically designed to implement functionalities that are not evolved by nature. These engineered networks enable scientists to tackle complex problems such as engineering cells to produce therapeutics within the patient's body, altering T cells to target cancer-related antigens for treatment, improving antibody production using engineered cells, tissue engineering, and production of genetically modified plants and livestock. Construction of computational models to realize genetic circuits is an especially challenging task since it requires the discovery of the flow of genetic information in complex biological systems. Building synthetic biological models is also a time-consuming process with relatively low prediction accuracy for highly complex genetic circuits. The primary goal of this study was to investigate the utility of a pre-trained bidirectional encoder transformer that can accurately predict gene expressions in genetic circuit designs. The main reason behind using transformers is their innate ability (attention mechanism) to take account of the semantic context present in long DNA chains that are heavily dependent on the spatial representation of their constituent genes. Previous approaches to gene circuit design, such as CNN and RNN architectures, are unable to capture semantic dependencies in long contexts, as required in most real-world applications of synthetic biology. For instance, RNN models (LSTM, GRU), although able to learn long-term dependencies, greatly suffer from vanishing gradient and low-efficiency problem when they sequentially process past states and compresses contextual information into a bottleneck with long input sequences. In other words, these architectures are not equipped with the necessary attention mechanisms to follow a long chain of genes with thousands of tokens. To address the above-mentioned limitations, a transformer model was built in this work as a variation to the existing DNA Bidirectional Encoder Representations from Transformers (DNABERT) model. It is shown that the proposed transformer is capable of capturing contextual information from long input sequences with an attention mechanism. In previous works on genetic circuit design, the traditional approaches to classification and regression, such as Random Forrest, Support Vector Machine, and Artificial Neural Networks, were able to achieve reasonably high R2 accuracy levels of 0.95 to 0.97. However, the transformer model utilized in this work, with its attention-based mechanism, was able to achieve a perfect accuracy level of 100%. Further, it is demonstrated that the efficiency of the transformer-based gene expression classifier is not dependent on the presence of large amounts of training examples, which may be difficult to compile in many real-world gene circuit designs.

Keywords: machine learning, classification and regression, gene circuit design, bidirectional transformers

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Authors: Caroline Mendes, Mary McNamara, Orla Howe

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Drug delivery systems are proposed for use in cancer treatment to specifically target cancer cells and deliver a therapeutic dose without affecting normal cells. For that purpose, the use of folate receptors (FR) can be considered a key strategy, since they are commonly over-expressed in cancer cells. In this study, cyclodextrins (CD) have being used as vehicles to target FR and deliver the chemotherapeutic drug, methotrexate (MTX). CDs have the ability to form inclusion complexes, in which molecules of suitable dimensions are included within their cavities. Here, β-CD has been modified using folic acid so as to specifically target the FR. Thus, this drug delivery system consists of β-CD, folic acid and MTX (CDEnFA:MTX). Cellular uptake of folic acid is mediated with high affinity by folate receptors while the cellular uptake of antifolates, such as MTX, is mediated with high affinity by the reduced folate carriers (RFCs). This study addresses the gene (mRNA) and protein expression levels of FRs and RFCs in the cancer cell lines CaCo-2, SKOV-3, HeLa, MCF-7, A549 and the normal cell line BEAS-2B, quantified by real-time polymerase chain reaction (real-time PCR) and flow cytometry, respectively. From that, four cell lines with different levels of FRs, were chosen for cytotoxicity assays of MTX and CDEnFA:MTX using the MTT assay. Real-time PCR and flow cytometry data demonstrated that all cell lines ubiquitously express moderate levels of RFC. These experiments have also shown that levels of FR protein in CaCo-2 cells are high, while levels in SKOV-3, HeLa and MCF-7 cells are moderate. A549 and BEAS-2B cells express low levels of FR protein. FRs are highly expressed in all the cancer cell lines analysed when compared to the normal cell line BEAS-2B. The cell lines CaCo-2, MCF-7, A549 and BEAS-2B were used in the cell viability assays. 48 hours treatment with the free drug and the complex resulted in IC50 values of 93.9 µM ± 15.2 and 56.0 µM ± 4.0 for CaCo-2 for free MTX and CDEnFA:MTX respectively, 118.2 µM ± 16.8 and 97.8 µM ± 12.3 for MCF-7, 36.4 µM ± 6.9 and 75.0 µM ± 10.5 for A549 and 132.6 µM ± 16.1 and 288.1 µM ± 26.3 for BEAS-2B. These results demonstrate that free MTX is more toxic towards cell lines expressing low levels of FR, such as the BEAS-2B. More importantly, these results demonstrate that the inclusion complex CDEnFA:MTX showed greater cytotoxicity than the free drug towards the high FR expressing CaCo-2 cells, indicating that it has potential to target this receptor, enhancing the specificity and the efficiency of the drug. The use of cell imaging by confocal microscopy has allowed visualisation of FR targeting in cancer cells, as well as the identification of the interlisation pathway of the drug. Hence, the cellular uptake and internalisation process of this drug delivery system is being addressed.

Keywords: cancer treatment, cyclodextrins, drug delivery, folate receptors, reduced folate carriers

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Authors: Esther Acha, Jose Cambra, De Chen

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Hydrogen is considered an important energy vector for the 21st century. Nowadays there are some difficulties for hydrogen economy implantation, and one of them is the high purity required for hydrogen. This energy vector is still being mainly produced from fuels, from wich hydrogen is produced as a component of a mixture containing other gases, such as CO, CO2 and H2O. A forthcoming sustainable pathway for hydrogen is steam-reforming of bio-oils derived from biomass, e.g. via fast pyrolysis. Bio-oils are a mixture of acids, alcohols, aldehydes, esters, ketones, sugars phenols, guaiacols, syringols, furans, multi-functional compounds and also up to a 30 wt% of water. The sorption enhanced steam reforming (SESR) process is attracting a great deal of attention due to the fact that it combines both hydrogen production and CO2 separation. In the SESR process, carbon dioxide is captured by an in situ sorbent, which shifts the reversible reforming and water gas shift reactions to the product side, beyond their conventional thermodynamic limits, giving rise to a higher hydrogen production and lower cost. The hydrogen containing mixture has been obtained from the SESR of bio-oil type compounds. Different types of catalysts have been tested. All of them contain Ni at around a 30 wt %. Two samples have been prepared with the wet impregnation technique over conventional (gamma alumina) and non-conventional (olivine) supports. And a third catalysts has been prepared over a hydrotalcite-like material (HT). The employed sorbent is a commercial dolomite. The activity tests were performed in a bench-scale plant (PID Eng&Tech), using a stainless steel fixed bed reactor. The catalysts were reduced in situ in the reactor, before the activity tests. The effluent stream was cooled down, thus condensed liquid was collected and weighed, and the gas phase was analysed online by a microGC. The hydrogen yield, and process behavior was analysed without the sorbent (the traditional SR where a second purification step will be needed but that operates in steady state) and the SESR (where the purification step could be avoided but that operates in batch state). The influence of the support type and preparation method will be observed in the produced hydrogen yield. Additionally, the stability of the catalysts is critical, due to the fact that in SESR process sorption-desorption steps are required. The produced hydrogen yield and hydrogen purity has to be high and also stable, even after several sorption-desorption cycles. The prepared catalysts were characterized employing different techniques to determine the physicochemical properties of the fresh-reduced and used (after the activity tests) materials. The characterization results, together with the activity results show the influence of the catalysts preparation method, calcination temperature, or can even explain the observed yield and conversion.

Keywords: CO2 sorbent, enhanced steam reforming, hydrogen

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Authors: A. Onur Kutlu, H. Tolga Bolukbasi

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Since the 1990s, governments, international organizations and scholars have drawn increasing attention to the significance of women in the labour force. While advanced industrial countries in North Western Europe and North America have managed to increase female labour force participation (FLFP) in the early post world war two period, emerging economies of the 1970s have only been able to increase FLFP only a decade later. Among these areas, Southern Europe features a wave of remarkable bounce backs in FLFP. However, despite striking similarities between the features in Southern Europe and those in Turkey, Turkey has not been able to pull women into the labour force. Despite a host of institutional similarities, Turkey has failed to reach to the level of her Southern European neighbours. This paper addresses the puzzle why Turkey lag behind in FLFP in comparison to her Southern European neighbours. There are signs showing that FLFP is currently reaching a critical threshold at a time when structural factors may allow a trend. It is not known, however, the constellation of conditions which may bring rising FLFP in Turkey. In order to gain analytical leverage from similar transitions in countries that share similar labour market and welfare state regime characteristics, this paper identifies the conditions in Southern Europe that brought rising FLFP to be able to explore the prospects for Turkey. Second, this paper takes these variables in the fuzzy set Qualitative Comparative Analysis (fsQCA) as conditions which can potentially explain the outcome of rising FLFP in Portugal, Spain, Italy, Greece and Turkey. The purpose here is to identify any causal pathway there may exist that lead to rising FLFP in Southern Europe. In order to do so, this study analyses two time periods in all cases, which represent different periods for different countries. The first period is identified on the basis of low FLFP and the second period on the basis of the transition to significantly higher FLFP. Third, the conditions are treated following the standard procedures in fsQCA, which provide equifinal: two distinct paths to higher levels of FLFP in Southern Europe, each of which may potentially increase FLFP in Turkey. Based on this analysis, this paper proposes that there exist two distinct paths leading to higher levels of FLFP in Southern Europe. Among these paths, salience of left parties emerges as a sufficient condition. In cases where this condition was not present, a second path combining enlarging service sector employment, increased tertiary education among women and increased childcare enrolment rates led to increasing FLFP.

Keywords: female labour force participation, fsQCA, Southern Europe, Turkey

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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: Shilpee Jain, Sachin Latiyan, Kaushik Suneet

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Unlike traditional robots, medical microbots are not only smaller in size, but they also possess various unique properties, for example, biocompatibility, stability in the biological fluids, navigation opposite to the bloodstream, wireless control over locomotion, etc. The idea behind their usage in the medical field was to build a minimally invasive method for addressing the post-operative complications, including longer recovery time, infection eruption and pain. Herein, the present study demonstrates the fabrication of dual nature magneto-conducting Fe3O4 magnetic nanoparticles (MNPs) and SU8 derived carbon-based Janus microbots for the efficient intracellular delivery of biomolecules. The low aspect ratio with feature size 2-5 μm microbots were fabricated by using a photolithography technique. These microbots were pyrolyzed at 900°C, which converts SU8 into amorphous carbon. The pyrolyzed microbots have dual properties, i.e., the half part is magneto-conducting and another half is only conducting for sufficing the therapeutic payloads efficiently with the application of external electric/magnetic field stimulations. For the efficient intracellular delivery of the microbots, the size and aspect ratio plays a significant role. However, on a smaller scale, the proper control over movement is difficult to achieve. The dual nature of Janus microbots allowed to control its maneuverability in the complex fluids using external electric as well as the magnetic field. Interestingly, Janus microbots move faster with the application of an external electric field (44 µm/s) as compared to the magnetic field (18 µm/s) application. Furthermore, these Janus microbots exhibit auto-fluorescence behavior that will help to track their pathway during navigation. Typically, the use of MNPs in the microdevices enhances the tendency to agglomerate. However, the incorporation of Fe₃O₄ MNPs in the pyrolyzed carbon reduces the chances of agglomeration of the microbots. The biocompatibility of the medical microbots, which is the essential property of any biosystems, was determined in vitro using HeLa cells. The microbots were found to compatible with HeLa cells. Additionally, the intracellular uptake of microbots was higher in the presence of an external electric field as compared to without electric field stimulation. In summary, the cytocompatible Janus microbots were fabricated successfully. They are stable in the biological fluids, wireless controllable navigation with the help of a few Guess external magnetic fields, their movement can be tracked because of autofluorescence behavior, they are less susceptible to agglomeration and higher cellular uptake could be achieved with the application of the external electric field. Thus, these carriers could offer a versatile platform to suffice the therapeutic payloads under wireless actuation.

Keywords: amorphous carbon, electric/magnetic stimulations, Janus microbots, magnetic nanoparticles, minimally invasive procedures

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Authors: Geday Elias, Montaigne Etienne, Padilla Martine, Tollossa Degefa

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Smallholder farmers’ participation in agricultural value chain identified as a pathway to get out of poverty trap in Ethiopia. The smallholder dairy activities have a huge potential in poverty reduction through enhancing income, achieving food and nutritional security in the country. However, much less is known about the effects of smallholder’s participation in milk value chain on household food security and nutrition. This paper therefore, aims at evaluating the effects of smallholders’ participation in milk value chain on household food security taking in to account the four pillars of food security measurements (availability, access, utilization and stability). Using a semi-structured interview, a cross sectional farm household data collected from a randomly selected sample of 333 households (170 in Amhara and 163 in Oromia regions).Binary logit and propensity score matching( PSM) models are employed to examine the mechanisms through which smallholder’s participation in the milk value chain affects household food security where crop production, per capita calorie intakes, diet diversity score, and food insecurity access scale are used to measure food availability, access, utilization and stability respectively. Our findings reveal from 333 households, only 34.5% of smallholder farmers are participated in the milk value chain. Limited access to inputs and services, limited access to inputs markets and high transaction costs are key constraints for smallholders’ limited access to the milk value chain. To estimate the true average participation effects of milk value chain for participated households, the outcome variables (food security) of farm households who participated in milk value chain are compared with the outcome variables if the farm households had not participated. The PSM analysis reveals smallholder’s participation in milk value chain has a significant positive effect on household income, food security and nutrition. Smallholder farmers who are participated in milk chain are better by 15 quintals crops production and 73 percent of per capita calorie intakes in food availability and access respectively than smallholder farmers who are not participated in the market. Similarly, the participated households are better in dietary quality by 112 percents than non-participated households. Finally, smallholders’ who are participated in milk value chain are better in reducing household vulnerability to food insecurity by an average of 130 percent than non participated households. The results also shows income earned from milk value chain participation contributed to reduce capital’s constraints of the participated households’ by higher farm income and total household income by 5164 ETB and 14265 ETB respectively. This study therefore, confirms the potential role of smallholders’ participation in food value chain to get out of poverty trap through improving rural household income, food security and nutrition. Therefore, identified the determinants of smallholder participation in milk value chain and the participation effects on food security in the study areas are worth considering as a positive knock for policymakers and development agents to tackle the poverty trap in the study area in particular and in the country in general.

Keywords: effects, food security and nutrition, milk, participation, smallholders, value chain

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Authors: David A. Ullisch, Yantree D. Sankar-Thomas, Stefan Wilke, Thomas Selge, Matthias Pump, Thomas Leibold, Kai Schütte, Gilbert Gorr

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Plants have been considered as a source of natural substances for ages. Secondary metabolites from plants are utilized especially in medical applications but are more and more interesting as cosmetical ingredients and in the field of nutraceuticals. However, supply of compounds from natural harvest can be limited by numerous factors i.e. endangered species, low product content, climate impacts and cost intensive extraction. Especially in the pharmaceutical industry the ability to provide sufficient amounts of product and high quality are additional requirements which in some cases are difficult to fulfill by plant harvest. Whereas in many cases the complexity of secondary metabolites precludes chemical synthesis on a reasonable commercial basis, plant cells contain the biosynthetic pathway – a natural chemical factory – for a given compound. A promising approach for the sustainable production of natural products can be plant cell fermentation (PCF®). A thoroughly accomplished development process comprises the identification of a high producing cell line, optimization of growth and production conditions, the development of a robust and reliable production process and its scale-up. In order to address persistent, long lasting production, development of cryopreservation protocols and generation of working cell banks is another important requirement to be considered. So far the most prominent example using a PCF® process is the production of the anticancer compound paclitaxel. To demonstrate the power of plant suspension cultures here we present three case studies: 1) For more than 17 years Phyton produces paclitaxel at industrial scale i.e. up to 75,000 L in scale. With 60 g/kg dw this fully controlled process which is applied according to GMP results in outstanding high yields. 2) Thapsigargin is another anticancer compound which is currently isolated from seeds of Thapsia garganica. Thapsigargin is a powerful cytotoxin – a SERCA inhibitor – and the precursor for the derivative ADT, the key ingredient of the investigational prodrug Mipsagargin (G-202) which is in several clinical trials. Phyton successfully generated plant cell lines capable to express this compound. Here we present data about the screening for high producing cell lines. 3) The third case study covers ingenol-3-mebutate. This compound is found in the milky sap of the intact plants of the Euphorbiacae family at very low concentrations. Ingenol-3-mebutate is used in Picato® which is approved against actinic keratosis. Generation of cell lines expressing significant amounts of ingenol-3-mebutate is another example underlining the strength of plant cell culture. The authors gratefully acknowledge Inspyr Therapeutics for funding.

Keywords: Ingenol-3-mebutate, plant cell culture, sustainability, thapsigargin

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Authors: M. J. Eichner, Y. S. Sarhan

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Overall study purpose has been the evaluation of ‘Vertical Villages’ as a new sustainable building typology, reducing significantly negative impacts of rapid urbanization processes in third world capital cities. Commonly in fast-growing cities, housing and job supply, educational and recreational opportunities, as well as public transportation infrastructure, are not accommodating rapid population growth, exposing people to high noise and emission polluted living environments with low-quality neighborhoods and a lack of recreational areas. Like many others, Egypt’s capital city Cairo, according to the UN facing annual population growth rates of up to 428.000 people, is struggling to address the general deterioration of urban living conditions. New settlements typologies and urban reconstruction approach hardly follow sustainable urbanization principles or socio-ecologic urbanization models with severe effects not only for inhabitants but also for the local environment and global climate. The authors prove that ‘Vertical Village’ buildings can offer a sustainable solution for increasing urban density with at the same time improving the living quality and urban environment significantly. Inserting them within high-density urban fabrics the ecologic and socio-cultural conditions of low-quality neighborhoods can be transformed towards districts, considering all needs of sustainable and social urban life. This study analyzes existing building typologies in Cairo’s «low quality - high density» districts Ard el Lewa, Dokki and Mohandesen according to benchmarks for sustainable residential buildings, identifying major problems and deficits. In 3 case study design projects, the sustainable transformation potential through ‘Vertical Village’ buildings are laid out and comparative studies show the improvement of the urban microclimate, safety, social diversity, sense of community, aesthetics, privacy, efficiency, healthiness and accessibility. The main result of the paper is that the disadvantages of density and overpopulation in developing countries can be converted with ‘Vertical Village’ buildings into advantages, achieving attractive and environmentally friendly living environments with multiple synergies. The paper is documenting based on scientific criteria that mixed-use vertical building structures, designed according to sustainable principles of low rise housing, can serve as an alternative to convert «low quality - high density» districts in megacities, opening a pathway for governments to achieve sustainable urban transformation goals. Neglected informal urban districts, home to millions of the poorer population groups, can be converted into healthier living and working environments.

Keywords: sustainable, architecture, urbanization, urban transformation, vertical village

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Authors: Dian Mayasari, Yosi Bayu Murti, Sylvia Utami Tunjung Pratiwi, Sudarsono

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Melastoma malabathricum L. is an Indo-Pacific herb that has been traditionally used to treat several ailments such as wounds, dysentery, diarrhea, toothache, and diabetes. This plant is common across tropical Indo-Pacific archipelagos and is tolerant of a range of soils, from low-lying areas subject to saltwater inundation to the salt-free conditions of mountain slopes. How the soil and environmental variation influences secondary metabolite production in the herb, and an understanding of the plant’s utility as traditional medicine, remain largely unknown and unexplored. The objective of this study is to evaluate the variability of the metabolic profiles of M. malabathricum L. across its geographic distribution. By employing high-performance liquid chromatography-diode array detector (HPLC-DAD), a highly established, simple, sensitive, and reliable method was employed for establishing the chemical fingerprints of 72 samples of M. malabathricum L. leaves from various geographical locations in Indonesia. Specimens collected from six terrestrial and archipelago regions of Indonesia were analyzed by HPLC to generate chromatogram peak profiles that could be compared across each region. Data corresponding to the common peak areas of HPLC chromatographic fingerprint were analyzed by hierarchical component analysis (HCA) and principal component analysis (PCA) to extract information on the most significant variables contributing to characterization and classification of analyzed samples data. Principal component values were identified as PC1 and PC2 with 41.14% and 19.32%, respectively. Based on variety and origin, the high-performance liquid chromatography method validated the chemical fingerprint results used to screen the in vitro antioxidant activity of M. malabathricum L. The result shows that the developed method has potential values for the quality of similar M. malabathrium L. samples. These findings provide a pathway for the development and utilization of references for the identification of M. malabathricum L. Our results indicate the importance of considering geographic distribution during field-collection efforts as they demonstrate regional metabolic variation in secondary metabolites of M. malabathricum L., as illustrated by HPLC chromatogram peaks and their antioxidant activities. The results also confirm the utility of this simple approach to a rapid evaluation of metabolic variation between plants and their potential ethnobotanical properties, potentially due to the environments from whence they were collected. This information will facilitate the optimization of growth conditions to suit particular medicinal qualities.

Keywords: fingerprint, high performance liquid chromatography, Melastoma malabathricum l., metabolic profiles, principal component analysis

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Authors: Sally Abu Sabaa, Lindsey Gutt

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In an attempt to use education as a way of raising a socially responsible and engaged global citizen, the YU-Bridge program, the largest and fastest pathway program of its kind in North America, has embarked on the journey of integrating general themes from the UN’s sustainable developmental goals (SDGs) in its English for Academic Purposes (EAP) curriculum. The purpose of this initiative was to redefine the general philosophy of education in the middle of a pandemic and align with York University’s University Academic Plan that was released in summer 2020 framed around the SDGs. The YUB program attracts international students from all over the world but mainly from China, and its goal is to enable students to achieve the minimum language requirement to join their undergraduate courses at York University. However, along with measuring outcomes, objectives, and the students’ GPA, instructors and academics are always seeking innovation of the YUB curriculum to adapt to the ever growing challenges of academics in the university context, in order to focus more on subject matter that students will be exposed to in their undergraduate studies. However, with the sudden change that has happened globally with the advance of the COVID-19 pandemic, and other natural disasters like the increase in forest fires and floods, rethinking the philosophy and goal of education was a must. Accordingly, the SDGs became the solid pillars upon which we, academics and administrators of the program, could build a new curriculum and shift our perspective from simply ESL education to education with moral and ethical goals. The preliminary implementation of this initiative was supported by an institutional-wide consultation with EAP instructors who have diverse experiences, disciplines, and interests. Along with brainstorming sessions and mini-pilot projects preceding the integration of the SDGs in the YUB-EAP curriculum, those meetings led to creating a general outline of a curriculum and an assessment framework that has the SDGs at its core with the medium of ESL used for language instruction. Accordingly, a community of knowledge exchange was spontaneously created and facilitated by instructors. This has led to knowledge, resources, and teaching pedagogies being shared and examined further. In addition, experiences and reactions of students are being shared, leading to constructive discussions about opportunities and challenges with the integration of the SDGs. The discussions have branched out to discussions about cultural and political barriers along with a thirst for knowledge and engagement, which has resulted in increased engagement not only on the part of the students but the instructors as well. Later in the program, two surveys will be conducted: one for the students and one for the instructors to measure the level of engagement of each in this initiative as well as to elicit suggestions for further development. This paper will describe this fundamental step into using ESL methodology as a mode of disseminating essential ethical and socially correct knowledge for all learners in the 21st Century, the students’ reactions, and the teachers’ involvement and reflections.

Keywords: EAP, curriculum, education, global citizen

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Authors: Chang-Hui Shen, Paulina Konarzewska

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Cell homeostasis is regulated by vacuolar activity and it has been shown that lipid composition of the vacuole plays an important role in vacuolar function. The major phosphoinositide species present in the vacuolar membrane include phosphatidylinositol 3,5-biphosphate (PI(3,5)P₂) which is generated from PI(3)P controlled by Fab1p. Deletion of FAB1 gene reduce the synthesis of PI(3,5)P₂ and thus result in enlarged or fragmented vacuoles, with neutral vacuolar pH due to reduced vacuolar H⁺-ATPase activity. These mutants also exhibited poor growth at high extracellular pH and in the presence of CaCl₂. Conversely, VPS34 regulates the synthesis of PI(3)P from phosphatidylinositol (PI), and the lack of Vps34p results in the reduction of vacuolar activity. Although the cellular observations are clear, it is still unknown about the molecular mechanism between the phospholipid biosynthesis pathway and vacuolar activity. Since both VPS34 and FAB1 are important in vacuolar activity, we hypothesize that the molecular mechanism of vacuolar function might be regulated by the transcriptional regulators of phospholipid biosynthesis. In this study, we study the role of the major phospholipid biosynthesis transcription factor, INO2, in the regulation of vacuolar activity. We first performed qRT-PCR to examine the effect of Ino2p on the expression of VPS34 and FAB1. Our results showed that VPS34 was upregulated in the presence of inositol for both WT and ino2Δ cells. However, FAB1 was only upregulated significantly in ino2Δ cells. This indicated that Ino2p might be the negative regulator for FAB1 expression. Next, growth sensitivity experiment showed that WT, vma3Δ, and ino2Δ grew well in growth medium buffered to pH 5.5 containing 10 mM CaCl₂. As cells were switched to growth medium buffered to pH 7 containing CaCl₂ WT, ino2Δ and opi1Δ showed growth reduction, whereas vma3Δ was completely nonviable. As the concentration of CaCl₂ was increased to 60 mM, ino2Δ cells showed moderate growth reduction compared to WT. This result suggests that ino2Δ cells have better vacuolar activity. Microscopic analysis and vacuolar acidification were employed to further elucidate the importance of INO2 in vacuolar homeostasis. Analysis of vacuolar morphology indicated that WT and vma3Δ cells displayed vacuoles that occupied a small area of the cell when grown in media buffered to pH 5.5. Whereas, ino2Δ displayed fragmented vacuoles. On the other hand, all strains grown in media buffered to pH 7, exhibited enlarged vacuoles that occupied most of the cell’s surface. This indicated that the presence of INO2 may play negative effect in vacuolar morphology when cells are grown in media buffered to pH 5.5. Furthermore, vacuolar acidification assay showed that only vma3Δ cells displayed notably less acidic vacuoles as cells were grown in media buffered to pH 5.5 and pH 7. Whereas, ino2Δ cells displayed more acidic pH compared to WT at pH7. Taken together, our results demonstrated the molecular mechanism of the vacuolar activity regulated by the phospholipid biosynthesis transcription factors Ino2p. Ino2p negatively regulates vacuolar activity through the expression of FAB1.

Keywords: vacuole, phospholipid, homeostasis, Ino2p, FAB1

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Authors: João Costa, Francisco Albuquerque, Ricardo J. Santos, Madalena M. Dias, José Carlos B. Lopes, Marcelo Costa

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Nowadays, it is well recognized that carbon dioxide emissions, together with other greenhouse gases, are responsible for the dramatic climate changes that have been occurring over the past decades. Gas hydrates are currently seen as a promising and disruptive set of materials that can be used as a basis for developing new technologies for CO₂ capture and storage. Its potential as a clean and safe pathway for CCS is tremendous since it requires only water and gas to be mixed under favorable temperatures and mild high pressures. However, the hydrates formation process is highly exothermic; it releases about 2 MJ per kilogram of CO₂, and it only occurs in a narrow window of operational temperatures (0 - 10 °C) and pressures (15 to 40 bar). Efficient continuous hydrate production at a specific temperature range necessitates high heat transfer rates in mixing processes. Past technologies often struggled to meet this requirement, resulting in low productivity or extended mixing/contact times due to inadequate heat transfer rates, which consistently posed a limitation. Consequently, there is a need for more effective continuous hydrate production technologies in industrial applications. In this work, a network mixing continuous production technology has been shown to be viable for producing CO₂ hydrates. The structured mixer used throughout this work consists of a network of unit cells comprising mixing chambers interconnected by transport channels. These mixing features result in enhanced heat and mass transfer rates and high interfacial surface area. The mixer capacity emerges from the fact that, under proper hydrodynamic conditions, the flow inside the mixing chambers becomes fully chaotic and self-sustained oscillatory flow, inducing intense local laminar mixing. The device presents specific heat transfer rates ranging from 107 to 108 W⋅m⁻³⋅K⁻¹. A laboratory scale pilot installation was built using a device capable of continuously capturing 1 kg⋅h⁻¹ of CO₂, in an aqueous slurry of up to 20% in mass. The strong mixing intensity has proven to be sufficient to enhance dissolution and initiate hydrate crystallization without the need for external seeding mechanisms and to achieve, at the device outlet, conversions of 99% in CO₂. CO₂ dissolution experiments revealed that the overall liquid mass transfer coefficient is orders of magnitude larger than in similar devices with the same purpose, ranging from 1 000 to 12 000 h⁻¹. The present technology has shown itself to be capable of continuously producing CO₂ hydrates. Furthermore, the modular characteristics of the technology, where scalability is straightforward, underline the potential development of a modular hydrate-based CO₂ capture process for large-scale applications.

Keywords: network, mixing, hydrates, continuous process, carbon dioxide

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Authors: Amruta D. S. Pathare, Indira Hinduja, Kusum Zaveri

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Implantation failure (IF) even after the good-quality embryo transfer (ET) in the physiologically normal endometrium is the main obstacle in in vitro fertilization (IVF). Various microarray studies have been performed worldwide to elucidate the genes requisite for endometrial receptivity. These studies have included the population based on different phases of menstrual cycle during natural cycle and stimulated cycle in normal fertile women. Additionally, the literature is also available in recurrent implantation failure patients versus oocyte donors in natural cycle. However, for the first time, we aim to study the genomics of endometrial receptivity in IF patients under controlled ovarian stimulation (COS) during which ET is generally practised in IVF. Endometrial gene expression profiling in IF patients (n=10) and oocyte donors (n=8) were compared during window of implantation under COS by whole genome microarray (using Illumina platform). Enrichment analysis of microarray data was performed to determine dys-regulated biological functions and pathways using Database for Annotation, Visualization and Integrated Discovery, v6.8 (DAVID). The enrichment mapping was performed with the help of Cytoscape software. Microarray results were validated by real-time PCR. Localization of genes related to immune response (Progestagen-Associated Endometrial Protein (PAEP), Leukaemia Inhibitory Factor (LIF), Interleukin-6 Signal Transducer (IL6ST) was detected by immunohistochemistry. The study revealed 418 genes downregulated and 519 genes upregulated in IF patients compared to healthy fertile controls. The gene ontology, pathway analysis and enrichment mapping revealed significant downregulation in activation and regulation of immune and inflammation response in IF patients under COS. The lower expression of Progestagen Associated Endometrial Protein (PAEP), Leukemia Inhibitory Factor (LIF) and Interleukin 6 Signal Transducer (IL6ST) in cases compared to controls by real time and immunohistochemistry suggests the functional importance of these genes. The study was proved useful to uncover the probable reason of implantation failure being imbalance of immune and inflammatory regulation in our group of subjects. Based on the present study findings, a panel of significant dysregulated genes related to immune and inflammatory pathways needs to be further substantiated in larger cohort in natural as well as stimulated cycle. Upon which these genes could be screened in IF patients during window of implantation (WOI) before going for embryo transfer or any other immunological treatment. This would help to estimate the regulation of specific immune response during WOI in a patient. The appropriate treatment of either activation of immune response or suppression of immune response can be then attempted in IF patients to enhance the receptivity of endometrium.

Keywords: endometrial receptivity, immune and inflammatory response, gene expression microarray, window of implantation

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Authors: Gehan ElAkabawy

Abstract:

Background: Diabetes mellitus causes severe deteriorations of almost all the organs and systems of the body, as well as significant damage to the oral cavity. The oral changes are mainly related to salivary glands dysfunction characterized by hyposalivation and xerostomia, which significantly reduce diabetic patients’ quality of life. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that the trophic support mediated by dental pulp stem cells can rescue the functional and structural alterations of damaged salivary glands. However, potential differentiation and paracrine effects of human dental pulp stem cells in diabetic-induced parotid gland damage have not been previously investigated. Our study aimed to investigate the therapeutic effects of intravenous transplantation of human dental pulp stem cells (hDPSCs) on parotid gland injury in a rat model of streptozotocin (STZ)-induced type 1 diabetes. Methods: Thirty Sprague-Dawley male rats were randomly categorised into three groups: control, diabetic (STZ), and transplanted (STZ+hDPSCs). hDPSCs or vehicle was injected into the tail vein 7 days after STZ injection. The fasting blood glucose levels were monitored weekly. A glucose tolerance test was performed, and the parotid gland weight, salivary flow rate, oxidative stress indices, parotid gland histology, and caspase-3, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen (PCNA) expression in parotid tissues were assessed 28 days post-transplantation. Results: Transplantation of hDPSCs downregulated blood glucose, improved the salivary flow rate, and reduced oxidative stress. The cells migrated to, survived, and differentiated into acinar, ductal, and myoepithelial cells in the STZ-injured parotid gland. Moreover, they downregulated the expression of caspase-3 and upregulated the expression of VEGF and PCNA, likely exerting pro-angiogenetic and antiapoptotic effects and promoting endogenous regeneration. In addition, the transplanted cells enhanced the parotid nitric oxide (NO) -tetrahydrobiopterin (BH4) pathway. Conclusions: Our results show that hDPSCs can migrate to and survive within the STZ-injured parotid gland, where they prevent its functional and morphological damage by restoring normal glucose levels, differentiating into parotid cell populations, and stimulating paracrine-mediated regeneration. Thus, hDPSCs may have therapeutic potential in the treatment of diabetes-induced parotid gland injury.

Keywords: dental pulp stem cells, diabetes, streptozotocin, parotid gland

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