Search results for: gene frequency
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 5344

Search results for: gene frequency

3814 Tuberculosis : Still a Nightmare for Third World Countries

Authors: Muhammad Younas, Zimal Naveed

Abstract:

Introduction : TB is caused by the bacillus Mycobacterium tuberculosis, which is spread when people who are sick with TB expel bacteria into the air (e.g. by coughing). The 30 high TB burden countries accounted for 87% of all estimated incident cases worldwide, and eight of these countries accounted for more than two thirds of the global total: India (27%), Indonesia (10%), China (7.1%), the Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%) and the Democratic Republic of the Congo (3.0%). Objective : To analyze prevalence of tuberculosis among the people who presented at THQ hospital Bhalwal between April 2024 to June 2024. Method : Total of 9200 patients presented in the OPD of THQ hospital Bhalwal were included in the study. These presumed cases underwent diagnostic testing by sputum for AFB, Gene expert and chest x rays. The data was then classified based Pulmonary and Extra-pulmonary TB disease and further classified on the basis of bacteriology positive and clinically diagnosed TB. The registered TB cases were then classified in 8 age groups in years and according to the gender. All the registered TB cases were then tested for HIV to observe the relation between Tuberculosis and HIV. Results : The total of 9200 patients presented to OPD during the period of 3 months between April 2024 to June 2024. Total registered cases of Tuberculosis were 161 (comprising 153 new cases and 8 cases after treatment failure). Out of the new cases 83 were males and 70 female cases were identified. The majority of males that were identified lies between age 55-64 and 65 and above while the majority of females that were diagnosed lies in the age group of 5-14 and 15-24. All the registered cases were then tested for HIV but none of them were found to be positive. Conclusion : According to World Health Organisation Global Tuberculosis Report, the incidence of Tubeculosis per 100000 people was 258, equivalent to 0.258 %. However, the study reveals an exceptionally high frequency of TB cases. The prevalence of Tuberculosis per 100000 people was found to be 1750 which is equivalent to 1.75 %. The study revealed that larger proportion of the population is currently affected by TB compared to the global average incidence reported by the WHO. The findings of the study indicates that the prevalence of tuberculosis (TB) among females is most common in the younger population, specifically between the ages of 5 to 24, and particularly within the peak fertility age group of 15 to 24 years. The health of women in their peak fertility years is crucial for maternal and child health outcomes. This highlights the need for targeted public health interventions in this area to manage and reduce the burden of TB.

Keywords: AGE, AFB, female, male

Procedia PDF Downloads 17
3813 Effect of Salinity and Heavy Metal Toxicity on Gene Expression, and Morphological Characteristics in Stevia rebaudiana Plants

Authors: Umara Nissar Rafiqi, Irum Gul, Nazima Nasrullah, Monica Saifi, Malik Z. Abdin

Abstract:

Background: Stevia rebaudiana, a member of Asteraceae family is an important medicinal plant and produces a commercially used non-caloric natural sweetener, which is also an alternate herbal cure for diabetes. Steviol glycosides are the main sweetening compounds present in these plants. Secondary metabolites are crucial to the adaption of plants to the environment and its overcoming stress conditions. In agricultural procedures, the abiotic stresses like salinity, high metal toxicity and drought, in particular, are responsible for the majority of the reduction that differentiates yield potential from harvestable yield. Salt stress and heavy metal toxicity lead to increased production of reactive oxygen species (ROS). To avoid oxidative damage due to ROS and osmotic stress, plants have a system of anti-oxidant enzymes along with several stress induced enzymes. This helps in scavenging the ROS and relieve the osmotic stress in different cell compartments. However, whether stress induced toxicity modulates the activity of these enzymes in Stevia rebaudiana is poorly understood. Aim: The present study focussed on the effect of salinity, heavy metal toxicity (lead and mercury) on physiological traits and transcriptional profiling of Stevia rebaudiana. Method: Stevia rebaudiana plants were collected from the Central Institute of Medicinal and Aromatic plants (CIMAP), Patnagar, India and maintained under controlled conditions in a greenhouse at Hamdard University, Delhi, India. The plants were subjected to different concentrations of salt (0, 25, 50 and 75 mM respectively) and heavy metals, lead and mercury (0, 100, 200 and 300 µM respectively). The physiological traits such as shoot length, root numbers, leaf growth were evaluated. The samples were collected at different developmental stages and analysed for transcription profiling by RT-PCR. Transcriptional studies in stevia rebaudiana involves important antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), cytochrome P450 monooxygenase (CYP) and stress induced aquaporin (AQU), auxin repressed protein (ARP-1), Ndhc gene. The data was analysed using GraphPad Prism and expressed as mean ± SD. Result: Low salinity and lower metal toxicity did not affect the fresh weight of the plant. However, this was substantially decreased by 55% at high salinity and heavy metal treatment. With increasing salinity and heavy metal toxicity, the values of all studied physiological traits were significantly decreased. Chlorosis in treated plants was also observed which could be due to changes in Fe:Zn ratio. At low concentrations (upto 25 mM) of NaCl and heavy metals, we did not observe any significant difference in the gene expressions of treated plants compared to control plants. Interestingly, at high salt concentration and high metal toxicity, a significant increase in the expression profile of stress induced genes was observed in treated plants compared to control (p < 0.005). Conclusion: Stevia rebaudiana is tolerant to lower salt and heavy metal concentration. This study also suggests that with the increase in concentrations of salt and heavy metals, harvest yield of S. rebaudiana was hampered.

Keywords: Stevia rebaudiana, natural sweetener, salinity, heavy metal toxicity

Procedia PDF Downloads 191
3812 Study of Linear Generator for Vibration Energy Harvesting of Frequency more than 50Hz

Authors: Seong-Jin Cho, Jin Ho Kim

Abstract:

Energy harvesting is the technology which gathers and converts external energies such as light, vibration and heat which are disposed into reusable electrical energy and uses such electrical energy. The vibration energy harvesting is very interesting technology because it produces very high density of energy and unaffected by the climate. Vibration energy can be harvested by the electrostatic, electromagnetic and piezoelectric systems. The electrostatic system has low energy conversion efficiency, and the piezoelectric system is expensive and needs the frequent maintenance because it is made of piezoelectric ceramic. On the other hand, the electromagnetic system has a long life time and high harvesting efficiency, and it is relatively cheap. The electromagnetic harvesting system includes the linear generator and the rotary-type generator. The rotary-type generators require the additional mechanical conversion device if it uses linear motion of vibration. But, the linear generator uses directly linear motion of vibration without a mechanical conversion device, and it has uncomplicated structure and light weight compared with the rotary-type generator. Therefore, the linear electromagnetic generator can be useful in using vibration energy harvesting. The pole transformer systems need electricity sensor system for sending voltage and power information to administrator. Therefore, the battery is essential, and its regular maintenance of replacement is required. In case of the transformer of high location in mountainous areas, the person can’t easily access it resulting in high maintenance cost. To overcome these problems, we designed and developed the linear electromagnetic generator which can replace battery in electricity sensor system for sending voltage and power information of the pole transformer. And, it uses vibration energy of frequency more than 50 Hz by the pole transformer. In order to analyze the electromagnetic characteristics of small linear electric generator, a commercial electromagnetic finite element analysis program "MAXWELL" was used. Then, through the actual production and experiment of linear generator, we confirmed output power of linear generator.

Keywords: energy harvesting, frequency, linear generator, experiment

Procedia PDF Downloads 255
3811 Design and Development of the Force Plate for the Study of Driving-Point Biodynamic Responses

Authors: Vikas Kumar, V. H. Saran, Arpit Mathur, Avik Kathuria

Abstract:

The evaluation of biodynamic responses of the human body to whole body vibration exposure is necessary to quantify the exposure effects. A force plate model has been designed with the help of CAD software, which was investigated by performing the modal, stress and strain analysis using finite element approach in the software. The results of the modal, stress and strain analysis were under the limits for measurements of biodynamic responses to whole body vibration. The physical model of the force plate was manufactured and fixed to the vibration simulator and further used in the experimentation for the evaluation of apparent mass responses of the ten recruited subjects standing in an erect posture exposed to vertical whole body vibration. The platform was excited with sinusoidal vibration at vibration magnitude: 1.0 and 1.5 m/s2 rms at different frequency of 2, 3, 4, 5, 6, 8, 10, 12.5, 16 and 20 Hz. The results of magnitude of normalised apparent mass have shown the trend observed in the many past studies. The peak in the normalised apparent mass has been observed at 4 & 5 Hz frequency of vertical whole body vibration. The nonlinearity with respect to vibration magnitude has been also observed in the normalised apparent mass responses.

Keywords: whole body vibration, apparent mass, modeling, force plate

Procedia PDF Downloads 406
3810 A Study of the Trade-off Energy Consumption-Performance-Schedulability for DVFS Multicore Systems

Authors: Jalil Boudjadar

Abstract:

Dynamic Voltage and Frequency Scaling (DVFS) multicore platforms are promising execution platforms that enable high computational performance, less energy consumption and flexibility in scheduling the system processes. However, the resulting interleaving and memory interference together with per-core frequency tuning make real-time guarantees hard to be delivered. Besides, energy consumption represents a strong constraint for the deployment of such systems on energy-limited settings. Identifying the system configurations that would achieve a high performance and consume less energy while guaranteeing the system schedulability is a complex task in the design of modern embedded systems. This work studies the trade-off between energy consumption, cores utilization and memory bottleneck and their impact on the schedulability of DVFS multicore time-critical systems with a hierarchy of shared memories. We build a model-based framework using Parametrized Timed Automata of UPPAAL to analyze the mutual impact of performance, energy consumption and schedulability of DVFS multicore systems, and demonstrate the trade-off on an actual case study.

Keywords: time-critical systems, multicore systems, schedulability analysis, energy consumption, performance analysis

Procedia PDF Downloads 103
3809 Design of an Acoustic System for Small-Scale Power Plants

Authors: Mohammadreza Judaki, Hosein Mohammadnezhad Shourkaei

Abstract:

Usually, noise generated by industrial units, is a pollution and disturbs people and causes problems for human health and sometimes these units will be closed because they cannot eliminate this pollution. Small-scale power plants usually are built close to residential areas, and noise generated by these power plants is an important factor in choosing their location and their design. Materials used to reduce noise are studied by measuring their absorption and reflection index numerically and experimentally. We can use MIKI model (Yasushi Miki, 1990) to simulate absorption index by using software like Ansys or Soundflow and compare calculation results with experimental simulation data. We consider high frequency sounds of power plant engines octave band diagram because dB value of high frequency noise is more noticeable for human ears. To prove this, in this study we first will study calculating octave band of engines exhausts and then we will study acoustic behavior of materials that we will use in high frequencies and this will give us our optimum noise reduction plan.

Keywords: acoustic materials, eliminating engine noise, octave level diagram, power plant noise

Procedia PDF Downloads 138
3808 Gear Fault Diagnosis Based on Optimal Morlet Wavelet Filter and Autocorrelation Enhancement

Authors: Mohamed El Morsy, Gabriela Achtenová

Abstract:

Condition monitoring is used to increase machinery availability and machinery performance, whilst reducing consequential damage, increasing machine life, reducing spare parts inventories, and reducing breakdown maintenance. An efficient condition monitoring system provides early warning of faults by predicting them at an early stage. When a localized fault occurs in gears, the vibration signals always exhibit non-stationary behavior. The periodic impulsive feature of the vibration signal appears in the time domain and the corresponding gear mesh frequency (GMF) emerges in the frequency domain. However, one limitation of frequency-domain analysis is its inability to handle non-stationary waveform signals, which are very common when machinery faults occur. Particularly at the early stage of gear failure, the GMF contains very little energy and is often overwhelmed by noise and higher-level macro-structural vibrations. An effective signal processing method would be necessary to remove such corrupting noise and interference. In this paper, a new hybrid method based on optimal Morlet wavelet filter and autocorrelation enhancement is presented. First, to eliminate the frequency associated with interferential vibrations, the vibration signal is filtered with a band-pass filter determined by a Morlet wavelet whose parameters are selected or optimized based on maximum Kurtosis. Then, to further reduce the residual in-band noise and highlight the periodic impulsive feature, an autocorrelation enhancement algorithm is applied to the filtered signal. The test stand is equipped with three dynamometers; the input dynamometer serves as the internal combustion engine, the output dynamometers induce a load on the output joint shaft flanges. The pitting defect is manufactured on the tooth side of a gear of the fifth speed on the secondary shaft. The gearbox used for experimental measurements is of the type most commonly used in modern small to mid-sized passenger cars with transversely mounted powertrain and front wheel drive: a five-speed gearbox with final drive gear and front wheel differential. The results obtained from practical experiments prove that the proposed method is very effective for gear fault diagnosis.

Keywords: wavelet analysis, pitted gear, autocorrelation, gear fault diagnosis

Procedia PDF Downloads 383
3807 High-Frequency Acoustic Microscopy Imaging of Pellet/Cladding Interface in Nuclear Fuel Rods

Authors: H. Saikouk, D. Laux, Emmanuel Le Clézio, B. Lacroix, K. Audic, R. Largenton, E. Federici, G. Despaux

Abstract:

Pressurized Water Reactor (PWR) fuel rods are made of ceramic pellets (e.g. UO2 or (U,Pu) O2) assembled in a zirconium cladding tube. By design, an initial gap exists between these two elements. During irradiation, they both undergo transformations leading progressively to the closure of this gap. A local and non destructive examination of the pellet/cladding interface could constitute a useful help to identify the zones where the two materials are in contact, particularly at high burnups when a strong chemical bonding occurs under nominal operating conditions in PWR fuel rods. The evolution of the pellet/cladding bonding during irradiation is also an area of interest. In this context, the Institute of Electronic and Systems (IES- UMR CNRS 5214), in collaboration with the Alternative Energies and Atomic Energy Commission (CEA), is developing a high frequency acoustic microscope adapted to the control and imaging of the pellet/cladding interface with high resolution. Because the geometrical, chemical and mechanical nature of the contact interface is neither axially nor radially homogeneous, 2D images of this interface need to be acquired via this ultrasonic system with a highly performing processing signal and by means of controlled displacement of the sample rod along both its axis and its circumference. Modeling the multi-layer system (water, cladding, fuel etc.) is necessary in this present study and aims to take into account all the parameters that have an influence on the resolution of the acquired images. The first prototype of this microscope and the first results of the visualization of the inner face of the cladding will be presented in a poster in order to highlight the potentials of the system, whose final objective is to be introduced in the existing bench MEGAFOX dedicated to the non-destructive examination of irradiated fuel rods at LECA-STAR facility in CEA-Cadarache.

Keywords: high-frequency acoustic microscopy, multi-layer model, non-destructive testing, nuclear fuel rod, pellet/cladding interface, signal processing

Procedia PDF Downloads 181
3806 Characterizing Nasal Microbiota in COVID-19 Patients: Insights from Nanopore Technology and Comparative Analysis

Authors: David Pinzauti, Simon De Jaegher, Maria D'Aguano, Manuele Biazzo

Abstract:

The COVID-19 pandemic has left an indelible mark on global health, leading to a pressing need for understanding the intricate interactions between the virus and the human microbiome. This study focuses on characterizing the nasal microbiota of patients affected by COVID-19, with a specific emphasis on the comparison with unaffected individuals, to shed light on the crucial role of the microbiome in the development of this viral disease. To achieve this objective, Nanopore technology was employed to analyze the bacterial 16s rRNA full-length gene present in nasal swabs collected in Malta between January 2021 and August 2022. A comprehensive dataset consisting of 268 samples (126 SARS-negative samples and 142 SARS-positive samples) was subjected to a comparative analysis using an in-house, custom pipeline. The findings from this study revealed that individuals affected by COVID-19 possess a nasal microbiota that is significantly less diverse, as evidenced by lower α diversity, and is characterized by distinct microbial communities compared to unaffected individuals. The beta diversity analyses were carried out at different taxonomic resolutions. At the phylum level, Bacteroidota was found to be more prevalent in SARS-negative samples, suggesting a potential decrease during the course of viral infection. At the species level, the identification of several specific biomarkers further underscores the critical role of the nasal microbiota in COVID-19 pathogenesis. Notably, species such as Finegoldia magna, Moraxella catarrhalis, and others exhibited relative abundance in SARS-positive samples, potentially serving as significant indicators of the disease. This study presents valuable insights into the relationship between COVID-19 and the nasal microbiota. The identification of distinct microbial communities and potential biomarkers associated with the disease offers promising avenues for further research and therapeutic interventions aimed at enhancing public health outcomes in the context of COVID-19.

Keywords: COVID-19, nasal microbiota, nanopore technology, 16s rRNA gene, biomarkers

Procedia PDF Downloads 62
3805 Dynamic Investigation of Brake Squeal Problem in The Presence of Kinematic Nonlinearities

Authors: Shahroz Khan, Osman Taha Şen

Abstract:

In automotive brake systems, brake noise has been a major problem, and brake squeal is one of the critical ones which is an instability issue. The brake squeal produces an audible sound at high frequency that is irritating to the human ear. To study this critical problem, first a nonlinear mathematical model with three degree of freedom is developed. This model consists of a point mass that simulates the brake pad and a sliding surface that simulates the brake rotor. The model exposes kinematic and clearance nonlinearities, but no friction nonlinearity. In the formulation, the friction coefficient is assumed to be constant and the friction force does not change direction. The nonlinear governing equations of the model are first obtained, and numerical solutions are sought for different cases. Second, a computational model for the squeal problem is developed with a commercial software, and computational solutions are obtained with two different types of contact cases (solid-to-solid and sphere-to-plane). This model consists of three rigid bodies and several elastic elements that simulate the key characteristics of a brake system. The response obtained from this model is compared with numerical solutions in time and frequency domain.

Keywords: contact force, nonlinearities, brake squeal, vehicle brake

Procedia PDF Downloads 242
3804 A Novel Approach to Asynchronous State Machine Modeling on Multisim for Avoiding Function Hazards

Authors: Parisi L., Hamili D., Azlan N.

Abstract:

The aim of this study was to design and simulate a particular type of Asynchronous State Machine (ASM), namely a ‘traffic light controller’ (TLC), operated at a frequency of 0.5 Hz. The design task involved two main stages: firstly, designing a 4-bit binary counter using J-K flip flops as the timing signal and subsequently, attaining the digital logic by deploying ASM design process. The TLC was designed such that it showed a sequence of three different colours, i.e. red, yellow and green, corresponding to set thresholds by deploying the least number of AND, OR and NOT gates possible. The software Multisim was deployed to design such circuit and simulate it for circuit troubleshooting in order for it to display the output sequence of the three different colours on the traffic light in the correct order. A clock signal, an asynchronous 4-bit binary counter that was designed through the use of J-K flip flops along with an ASM were used to complete this sequence, which was programmed to be repeated indefinitely. Eventually, the circuit was debugged and optimized, thus displaying the correct waveforms of the three outputs through the logic analyzer. However, hazards occurred when the frequency was increased to 10 MHz. This was attributed to delays in the feedback being too high.

Keywords: asynchronous state machine, traffic light controller, circuit design, digital electronics

Procedia PDF Downloads 423
3803 Radio Frequency Identification (Rfid) Cost-Effective, Location-Based System for Managing Construction Materials

Authors: Mourad Bakouka, Abdelaziz Rabehi

Abstract:

Companies need to have logistics and transportation in place that can adapt to the changing nature of construction sites. This ensures they can react quickly when needed. A study was conducted to develop a way to locate and track materials on construction sites. The system is an RFID/GPS integration that's required to pull off this feat. The study also reports how the platform has been used in construction. They found many advantages to using it, including reductions in both time and costs as well as improved management of materials orders. . For example, the time in which a project could start up was shortened from two weeks to three days with just a single digital order. As of now, the technology is still limited in its widespread adoption due largely to overall lack of awareness and difficulty connecting to it. However, as more and more companies embrace it in construction, the technology is expected to become ubiquitous. The developed platform provides contractors and construction managers with real-time information about the status of materials and work, allowing them to better manage the workflow in a project. The study sheds new light on this subject, which is essential to know. This work is becoming increasingly aware of the use of smart tools in constructing buildings.

Keywords: materials management, internet of things (IoT), radio frequency identification (RFID), construction site, supply chain management

Procedia PDF Downloads 75
3802 Phase Control in Population Inversion Using Chirped Laser

Authors: Avijit Datta

Abstract:

We have presented a phase control scheme in population transfer using chirped laser fields. A chirped pulse can do population transfer from one level to another level via adiabatic rapid passage accessible by one photon dipole transition. We propose to use a pair of phase-locked chirped pulses of the same frequency w(t) instead of a singly chirped-pulse frequency w(t). Simultaneous action of phase controlled interference in addition to rapid adiabatic passages due to chirped pulses lead to phase control over this population transfer dynamics. We have demonstrated the proposed phase control scheme over the population distribution from the initial level X(v=0,j=0) to C(v=2,j=1) level of hydrogen molecule using a pair of phase-locked and similarly chirped laser pulses. We have extended this two-level system to three-level 1+1 ladder system of hydrogen molecule from X level to final J(v=2,j=2) level via C intermediate level using two pairs of laser pulses having frequencies w(t) and w'(t) respectively and obtained laudable control over the population distribution among three levels. We also have presented some results of interference effects of w₁(t) and its third harmonics w₃(t).

Keywords: phase control, population transfer, chirped laser pulses, rapid adiabatic passage, laser-molecule interaction

Procedia PDF Downloads 355
3801 Analysis of Vocal Pathologies Through Subglottic Pressure Measurement

Authors: Perla Elizabeth Jimarez Rocha, Carolina Daniela Tejeda Franco, Arturo Minor Martínez, Annel Gomez Coello

Abstract:

One of the biggest problems in developing new therapies for the management and treatment of voice disorders is the difficulty of objectively evaluating the results of each treatment. A system was proposed that captures and records voice signals, in addition to analyzing the vocal quality (fundamental frequency, zero crossings, energy, and amplitude spectrum), as well as the subglottic pressure (cm H2O) during the sustained phonation of the vowel / a /; a recording system is implemented, as well as an interactive system that records information on subglottic pressure. In Mexico City, a control group of 31 patients with phoniatric pathology is proposed; non-invasive tests were performed for these most common vocal pathologies (Nodules, Polyps, Irritative Laryngitis, Ventricular Dysphonia, Laryngeal Cancer, Dysphonia, and Dysphagia). The most common pathology was irritative laryngitis (32%), followed by vocal fold paralysis (unilateral and bilateral,19.4 %). We take into consideration men and women in the pathological groups due to the physiological difference. They were separated in gender by the difference in the morphology of the respiratory tract.

Keywords: amplitude spectrum, energy, fundamental frequency, subglottic pressure, zero crossings

Procedia PDF Downloads 117
3800 Polyphenol-Rich Aronia Melanocarpa Juice Consumption and Line-1 Dna Methylation in a Cohort at Cardiovascular Risk

Authors: Ljiljana Stojković, Manja Zec, Maja Zivkovic, Maja Bundalo, Marija Glibetić, Dragan Alavantić, Aleksandra Stankovic

Abstract:

Cardiovascular disease (CVD) is associated with alterations in DNA methylation, the latter modulated by dietary polyphenols. The present pilot study (part of the original clinical study registered as NCT02800967 at www.clinicaltrials.gov) aimed to investigate the impact of 4-week daily consumption of polyphenol-rich Aronia melanocarpa juice on Long Interspersed Nucleotide Element-1 (LINE-1) methylation in peripheral blood leukocytes, in subjects (n=34, age of 41.1±6.6 years) at moderate CVD risk, including an increased body mass index, central obesity, high normal blood pressure and/or dyslipidemia. The goal was also to examine whether factors known to affect DNA methylation, such as folate intake levels, MTHFR C677T gene variant, as well as the anthropometric and metabolic parameters, modulated the LINE-1 methylation levels upon consumption of polyphenol-rich Aronia juice. The experimental analysis of LINE-1 methylation was done by the MethyLight method. MTHFR C677T genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Folate intake was assessed by processing the data from the food frequency questionnaire and repeated 24-hour dietary recalls. Serum lipid profile was determined by using Roche Diagnostics kits. The statistical analyses were performed using the Statistica software package. In women, after vs. before the treatment period, a significant decrease in LINE-1 methylation levels was observed (97.54±1.50% vs. 98.39±0.86%, respectively; P=0.01). The change (after vs. before treatment) in LINE-1 methylation correlated directly with MTHFR 677T allele presence, average daily folate intake and the change in serum low-density lipoprotein cholesterol, while inversely with the change in serum triacylglycerols (R=0.72, R2=0.52, adjusted R2=0.36, P=0.03). The current results imply potential cardioprotective effects of habitual polyphenol-rich Aronia juice consumption achieved through the modifications of DNA methylation pattern in subjects at CVD risk, which should be further confirmed. Hence, the precision nutrition-driven modulations of DNA methylation may become targets for new approaches in the prevention and treatment of CVD.

Keywords: Aronia melanocarpa, cardiovascular risk, LINE-1, methylation, peripheral blood leukocytes, polyphenol

Procedia PDF Downloads 190
3799 Ultrasound Therapy: Amplitude Modulation Technique for Tissue Ablation by Acoustic Cavitation

Authors: Fares A. Mayia, Mahmoud A. Yamany, Mushabbab A. Asiri

Abstract:

In recent years, non-invasive Focused Ultrasound (FU) has been utilized for generating bubbles (cavities) to ablate target tissue by mechanical fractionation. Intensities >10 kW/cm² are required to generate the inertial cavities. The generation, rapid growth, and collapse of these inertial cavities cause tissue fractionation and the process is called Histotripsy. The ability to fractionate tissue from outside the body has many clinical applications including the destruction of the tumor mass. The process of tissue fractionation leaves a void at the treated site, where all the affected tissue is liquefied to particles at sub-micron size. The liquefied tissue will eventually be absorbed by the body. Histotripsy is a promising non-invasive treatment modality. This paper presents a technique for generating inertial cavities at lower intensities (< 1 kW/cm²). The technique (patent pending) is based on amplitude modulation (AM), whereby a low frequency signal modulates the amplitude of a higher frequency FU wave. Cavitation threshold is lower at low frequencies; the intensity required to generate cavitation in water at 10 kHz is two orders of magnitude lower than the intensity at 1 MHz. The Amplitude Modulation technique can operate in both continuous wave (CW) and pulse wave (PW) modes, and the percentage modulation (modulation index) can be varied from 0 % (thermal effect) to 100 % (cavitation effect), thus allowing a range of ablating effects from Hyperthermia to Histotripsy. Furthermore, changing the frequency of the modulating signal allows controlling the size of the generated cavities. Results from in vitro work demonstrate the efficacy of the new technique in fractionating soft tissue and solid calcium carbonate (Chalk) material. The technique, when combined with MR or Ultrasound imaging, will present a precise treatment modality for ablating diseased tissue without affecting the surrounding healthy tissue.

Keywords: focused ultrasound therapy, histotripsy, inertial cavitation, mechanical tissue ablation

Procedia PDF Downloads 314
3798 Isolation and Identification of Salmonella spp and Salmonella enteritidis, from Distributed Chicken Samples in the Tehran Province using Culture and PCR Techniques

Authors: Seyedeh Banafsheh Bagheri Marzouni, Sona Rostampour Yasouri

Abstract:

Salmonella is one of the most important common pathogens between humans and animals worldwide. Globally, the prevalence of the disease in humans is due to the consumption of food contaminated with animal-derived Salmonella. These foods include eggs, red meat, chicken, and milk. Contamination of chicken and its products with Salmonella may occur at any stage of the chicken processing chain. Salmonella infection is usually not fatal. However, its occurrence is considered dangerous in some individuals, such as infants, children, the elderly, pregnant women, or individuals with weakened immune systems. If Salmonella infection enters the bloodstream, the possibility of contamination of tissues throughout the body will arise. Therefore, determining the potential risk of Salmonella at various stages is essential from the perspective of consumers and public health. The aim of this study is to isolate and identify Salmonella from chicken samples distributed in the Tehran market using the Gold standard culture method and PCR techniques based on specific genes, invA and ent. During the years 2022-2023, sampling was performed using swabs from the liver and intestinal contents of distributed chickens in the Tehran province, with a total of 120 samples taken under aseptic conditions. The samples were initially enriched in buffered peptone water (BPW) for pre-enrichment overnight. Then, the samples were incubated in selective enrichment media, including TT broth and RVS medium, at temperatures of 37°C and 42°C, respectively, for 18 to 24 hours. Organisms that grew in the liquid medium and produced turbidity were transferred to selective media (XLD and BGA) and incubated overnight at 37°C for isolation. Suspicious Salmonella colonies were selected for DNA extraction, and PCR technique was performed using specific primers that targeted the invA and ent genes in Salmonella. The results indicated that 94 samples were Salmonella using the PCR technique. Of these, 71 samples were positive based on the invA gene, and 23 samples were positive based on the ent gene. Although the culture technique is the Gold standard, PCR is a faster and more accurate method. Rapid detection through PCR can enable the identification of Salmonella contamination in food items and the implementation of necessary measures for disease control and prevention.

Keywords: culture, PCR, salmonella spp, salmonella enteritidis

Procedia PDF Downloads 65
3797 The Effects of High-frequency rTMS Targeting the Mirror Neurons on Improving Social Awareness in ASD, the Preliminary Analysis of a Pilot Study

Authors: Mitra Assadi, Md. Faan

Abstract:

Background: Autism Spectrum Disorder (ASD) in a common neurodevelopmental disorder with limited pharmacological interventions. Transcranial Magnetic Stimulation (rTMS) has produced promising results in ASD, although there is no consensus regarding optimal targets or stimulation paradigms. A prevailing theory in ASD attributes the core deficits to dysfunction of the mirror neurons located in the inferior parietal lobule (IPL) and inferior frontal gyrus (IFG). Methods: Thus far, 11 subjects with ASD, 10 boys and 1 girl with the mean age of 13.36 years have completed the study by receiving 10 session of high frequency rTMS to the IPL. The subjects were randomized to receive stimulation on the left or right IPL and sham stimulation to the opposite side. The outcome measures included the Social Responsiveness Scale – Second Edition (SRS-2) and Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency task. Results: None of the 11 subjects experienced any adverse effects. The rTMS did not produce any improvement in verbal fluency, nor there was any statistically significant difference between the right versus left sided stimulation. Analysis of social awareness on SRS-2 (SRS-AWR) indicated a close to significant effect of the treatment with a small to medium effect size. After removing a single subject with Level 3 ASD, we demonstrated a close to significant improvement on SRS-AWR with a large effect size. The analysis of the data 3-month post TMS demonstrated return of the SRS-AWR values to baseline. Conclusion: This preliminary analysis of the 11 subjects who have completed our study thus far shows a favorable response to high frequency rTMS stimulation of the mirror neurons/IPL on social awareness. While the decay of the response noted during the 3-month follow-up may be considered a limitation of rTMS, the presence of the improvement, especially the effect size despite the small sample size, is indicative of the efficacy of this technique.

Keywords: rTMS, autism, scoial cognition, mirror neurons

Procedia PDF Downloads 62
3796 The Value of Online News: Addressing the Problem of Online Investment Fraud Crimes in Thailand

Authors: Thapthep Paprach, Benya Lertsuwan

Abstract:

Investment fraud is not a new criminal, but there are still more victims during the Internet of Things era. This kind of criminal has been classified as a national and transnational financial crime problem all over the world. In Thailand, the country has also been attacked by this kind of crime. This research concerns whether the mass media that is supposed to cover news about online investment scams realized and warned Thais about this crime. Thus, this study explores the value of news about investment fraud in terms of frequency. The methodology uses web crawling from the top 5 news agency websites that have the most access. We pull out all information reporting about investment fraud. The findings revealed that the ‘Khaosod’ news agency was the first rank in reporting on investment crime. On the other hand, ‘Matichon’ was the least reported. Thairat news agencies frequently reported such criminals from midnight to very early in the morning, while other news agencies reported during the daytime. The results between the frequency of news reporting about investment fraud and the monthly number of victim reports are not correlated. Although the most cases reported to Thai police were in February 2023, but the most news reported was in January 2023. In conclusion, there might be a negative correlation between the amount of investment fraud news reported and the number of victims.

Keywords: investment fraud, news value, online news report, Ponzi schemes, Romance scam

Procedia PDF Downloads 72
3795 The Behavior and Satisfaction of Tourists Affecting the Sustainable Tourism at the Amphawa Floating Market in Samut Songkhram Province

Authors: Chanpen Meenakorn

Abstract:

This research aims to study; (1) behavior of the tourists affecting the satisfaction level of tourism at the Amphawa floating market in Samut Songkhram province, (2) to study the satisfaction level of tourism at the Amphawa floating market. The research method will use quantitative research; data was collected by questionnaires distributed to the tourist who visits the Amphawa floating market for 480 samples. Data was analyzed by SPSS software to process descriptive statistic including frequency, percentage, mean, standard deviation and inferential statistic is t-test, F-test, and chi-square. The results showed that the behavior of tourists had known tourist attractions in the province comes from the mouth of relatives and friends suggested that he come here before and the reasons to visit is to want to pay homage to the various temples for the frequency to visit travel an average of 2-4 times and  the satisfaction of the tourists in the province found that the satisfaction level of tourists in the province at the significant level of the place, convenient  and services have a high level of satisfaction.

Keywords: amphawa floating market behavior of the tourists, satisfaction level, sustainable tourism, Samut Songkhram province

Procedia PDF Downloads 357
3794 Realizing Teleportation Using Black-White Hole Capsule Constructed by Space-Time Microstrip Circuit Control

Authors: Mapatsakon Sarapat, Mongkol Ketwongsa, Somchat Sonasang, Preecha Yupapin

Abstract:

The designed and performed preliminary tests on a space-time control circuit using a two-level system circuit with a 4-5 cm diameter microstrip for realistic teleportation have been demonstrated. It begins by calculating the parameters that allow a circuit that uses the alternative current (AC) at a specified frequency as the input signal. A method that causes electrons to move along the circuit perimeter starting at the speed of light, which found satisfaction based on the wave-particle duality. It is able to establish the supersonic speed (faster than light) for the electron cloud in the middle of the circuit, creating a timeline and propulsive force as well. The timeline is formed by the stretching and shrinking time cancellation in the relativistic regime, in which the absolute time has vanished. In fact, both black holes and white holes are created from time signals at the beginning, where the speed of electrons travels close to the speed of light. They entangle together like a capsule until they reach the point where they collapse and cancel each other out, which is controlled by the frequency of the circuit. Therefore, we can apply this method to large-scale circuits such as potassium, from which the same method can be applied to form the system to teleport living things. In fact, the black hole is a hibernation system environment that allows living things to live and travel to the destination of teleportation, which can be controlled from position and time relative to the speed of light. When the capsule reaches its destination, it increases the frequency of the black holes and white holes canceling each other out to a balanced environment. Therefore, life can safely teleport to the destination. Therefore, there must be the same system at the origin and destination, which could be a network. Moreover, it can also be applied to space travel as well. The design system will be tested on a small system using a microstrip circuit system that we can create in the laboratory on a limited budget that can be used in both wired and wireless systems.

Keywords: quantum teleportation, black-white hole, time, timeline, relativistic electronics

Procedia PDF Downloads 70
3793 Variations in Heat and Cold Waves over Southern India

Authors: Amit G. Dhorde

Abstract:

It is now well established that the global surface air temperatures have increased significantly during the period that followed the industrial revolution. One of the main predictions of climate change is that the occurrences of extreme weather events will increase in future. In many regions of the world, high-temperature extremes have already started occurring with rising frequency. The main objective of the present study is to understand spatial and temporal changes in days with heat and cold wave conditions over southern India. The study area includes the region of India that lies to the south of Tropic of Cancer. To fulfill the objective, daily maximum and minimum temperature data for 80 stations were collected for the period 1969-2006 from National Data Center of India Meteorological Department. After assessing the homogeneity of data, 62 stations were finally selected for the study. Heat and cold waves were classified as slight, moderate and severe based on the criteria given by Indias' meteorological department. For every year, numbers of days experiencing heat and cold wave conditions were computed. This data was analyzed with linear regression to find any existing trend. Further, the time period was divided into four decades to investigate the decadal frequency of the occurrence of heat and cold waves. The results revealed that the average annual temperature over southern India shows an increasing trend, which signifies warming over this area. Further, slight cold waves during winter season have been decreasing at the majority of the stations. The moderate cold waves also show a similar pattern at the majority of the stations. This is an indication of warming winters over the region. Besides this analysis, other extreme indices were also analyzed such as extremely hot days, hot days, very cold nights, cold nights, etc. This analysis revealed that nights are becoming warmer and days are getting warmer over some regions too.

Keywords: heat wave, cold wave, southern India, decadal frequency

Procedia PDF Downloads 124
3792 An Experimental Investigation of the Effect of Control Algorithm on the Energy Consumption and Temperature Distribution of a Household Refrigerator

Authors: G. Peker, Tolga N. Aynur, E. Tinar

Abstract:

In order to determine the energy consumption level and cooling characteristics of a domestic refrigerator controlled with various cooling system algorithms, a side by side type (SBS) refrigerator was tested in temperature and humidity controlled chamber conditions. Two different control algorithms; so-called drop-in and frequency controlled variable capacity compressor algorithms, were tested on the same refrigerator. Refrigerator cooling characteristics were investigated for both cases and results were compared with each other. The most important comparison parameters between the two algorithms were taken as; temperature distribution, energy consumption, evaporation and condensation temperatures, and refrigerator run times. Standard energy consumption tests were carried out on the same appliance and resulted in almost the same energy consumption levels, with a difference of %1,5. By using these two different control algorithms, the power consumptions character/profile of the refrigerator was found to be similar. By following the associated energy measurement standard, the temperature values of the test packages were measured to be slightly higher for the frequency controlled algorithm compared to the drop-in algorithm. This paper contains the details of this experimental study conducted with different cooling control algorithms and compares the findings based on the same standard conditions.

Keywords: control algorithm, cooling, energy consumption, refrigerator

Procedia PDF Downloads 366
3791 Application of Ground Penetrating Radar and Light Falling Weight Deflectometer in Ballast Quality Assessment

Authors: S. Cafiso, B. Capace, A. Di Graziano, C. D’Agostino

Abstract:

Systematic monitoring of the trackbed is necessary to assure safety and quality of service in the railway system. Moreover, to produce effective management of the maintenance treatments, the assessment of bearing capacity of the railway trackbed must include ballast, sub-ballast and subgrade layers at different depths. Consequently, there is an increasing interest in obtaining a consistent measure of ballast bearing capacity with no destructive tests (NDTs) able to work in the physical and time restrictions of railway tracks in operation. Moreover, in the case of the local railway with reduced gauge, the use of the traditional high-speed track monitoring systems is not feasible. In that framework, this paper presents results from in site investigation carried out on ballast and sleepers with Ground Penetrating Radar (GPR) and Light Falling Weight Deflectometer (LWD). These equipment are currently used in road pavement maintenance where they have shown their reliability and effectiveness. Application of such Non-Destructive Tests in railway maintenance is promising but in the early stage of the investigation. More specifically, LWD was used to estimate the stiffness of ballast and sleeper support, as well. LWD, despite the limited load (6 kN in the trial test) applied directly on the sleeper, was able to detect defects in the bearing capacity at the Sleeper/Ballast interface. A dual frequency GPR was applied to detect the presence of layers’ discontinuities at different depths due to fouling phenomena that are the main causes of changing in the layer dielectric proprieties within the ballast thickness. The frequency of 2000Mhz provided high-resolution data to approximately 0.4m depth, while frequency of 600Mhz showed greater depth penetration up to 1.5 m. In the paper literature review and trial in site experience are used to identify Strengths, Weaknesses, Opportunities, and Threats (SWOT analysis) of the application of GPR and LWD for the assessment of bearing capacity of railway track-bed.

Keywords: bearing capacity, GPR, LWD, no destructive test, railway track

Procedia PDF Downloads 125
3790 Developing a Regulator for Improving the Operation Modes of the Electrical Drive Motor

Authors: Baghdasaryan Marinka

Abstract:

The operation modes of the synchronous motors used in the production processes are greatly conditioned by the accidentally changing technological and power indices.  As a result, the electrical drive synchronous motor may appear in irregular operation regimes. Although there are numerous works devoted to the development of the regulator for the synchronous motor operation modes, their application for the motors working in the irregular modes is not expedient. In this work, to estimate the issues concerning the stability of the synchronous electrical drive system, the transfer functions of the electrical drive synchronous motors operating in the synchronous and induction modes have been obtained.  For that purpose, a model for investigating the frequency characteristics has been developed in the LabView environment. Frequency characteristics for assessing the transient process of the electrical drive system, operating in the synchronous and induction modes have been obtained, and based on their assessment, a regulator for improving the operation modes of the motor has been proposed. The proposed regulator can be successfully used to prevent the irregular modes of the electrical drive synchronous motor, as well as to estimate the operation state of the drive motor of the mechanism with a changing load.

Keywords: electrical drive system, synchronous motor, regulator, stability, transition process

Procedia PDF Downloads 150
3789 Age and Population Structure of the Goby Parapocryptes Serperaster in the Mekong Delta, Vietnam, Based on Length-Frequency and Otolith Analyses

Authors: Quang Minh Dinh, Jian Guang Qin, Sabine Dittmann, Dinh Dac Tran

Abstract:

The age and population structure the dermal gopy Parapocryptes serperaster were studied using length distributions, otolith and von Bertalanffy model in the Mekong Delta over a whole year through monthly sampling. The sex ratio of P. serperaster was near 1:1, and von Bertalanffy growth parameters were L∞= 25.2 cm, K = 0.74 yr-1, and t0 = -0.22 yr-1. Fish size at first entry to fishery was 14.6 cm, and fishing mortality (1.57 yr-1) and natural mortality (1.51 yr-1) accounted for 51% and 49% of the total mortality (3.07 yr-1), respectively. Relative yield-per-recruit and biomass-per-recruit analyses revealed the levels of maximum exploitation yield (Emax = 0.83), maximum economic yield (E0.1 = 0.71) and the yield at 50% reduction of exploitation (E0.5 = 0.37). Otoliths from 164 female and 196 male gobies were readable, and the otolith morphometry data were used for age identification. The mean age estimated by reading otolith annual rings and by analysing length frequency distribution was consistent. This study shows that the otolith morphometry is a reliable method for aging this goby and possibly also applicable for other tropical gobies. The fishery analysis indicates that this goby stock has not been overexploited in the Mekong Delta.

Keywords: Parapcryptes serperaster, otolith, age, pulation structure, Vietnam

Procedia PDF Downloads 647
3788 The Effect of Normal Cervical Sagittal Configuration in the Management of Cervicogenic Dizziness: A 1-Year Randomized Controlled Study

Authors: Moustafa Ibrahim Moustafa

Abstract:

The purpose of this study was to determine the immediate and long term effects of a multimodal program, with the addition of cervical sagittal curve restoration and forward head correction, on severity of dizziness, disability, frequency of dizziness, and severity of cervical pain. 72 patients with cervicogenic dizziness, definite hypolordotic cervical spine, and forward head posture were randomized to experimental or a control group. Both groups received the multimodal program, additionally, the study group received the Denneroll cervical traction. All outcome measures were measured at three intervals. The general linear model indicated a significant group × time effects in favor of experimental group on measures of anterior head translation (F=329.4 P < .0005), cervical lordosis (F=293.7 P < .0005), severity of dizziness (F=262.1 P < .0005), disability (F=248.9 P < .0005), frequency of dizziness (F=53.9 P < .0005), and severity of cervical pain (F=350.1 P < .0005). The addition of Dennroll cervical traction to a multimodal program can positively affect dizziness management outcomes.

Keywords: randomized controlled trial, traction, dizziness, cervical

Procedia PDF Downloads 299
3787 Transcriptional Differences in B cell Subpopulations over the Course of Preclinical Autoimmunity Development

Authors: Aleksandra Bylinska, Samantha Slight-Webb, Kevin Thomas, Miles Smith, Susan Macwana, Nicolas Dominguez, Eliza Chakravarty, Joan T. Merrill, Judith A. James, Joel M. Guthridge

Abstract:

Background: Systemic Lupus Erythematosus (SLE) is an interferon-related autoimmune disease characterized by B cell dysfunction. One of the main hallmarks is a loss of tolerance to self-antigens leading to increased levels of autoantibodies against nuclear components (ANAs). However, up to 20% of healthy ANA+ individuals will not develop clinical illness. SLE is more prevalent among women and minority populations (African, Asian American and Hispanics). Moreover, African Americans have a stronger interferon (IFN) signature and develop more severe symptoms. The exact mechanisms involved in ethnicity-dependent B cell dysregulation and the progression of autoimmune disease from ANA+ healthy individuals to clinical disease remains unclear. Methods: Peripheral blood mononuclear cells (PBMCs) from African (AA) and European American (EA) ANA- (n=12), ANA+ (n=12) and SLE (n=12) individuals were assessed by multimodal scRNA-Seq/CITE-Seq methods to examine differential gene signatures in specific B cell subsets. Library preparation was done with a 10X Genomics Chromium according to established protocols and sequenced on Illumina NextSeq. The data were further analyzed for distinct cluster identification and differential gene signatures in the Seurat package in R and pathways analysis was performed using Ingenuity Pathways Analysis (IPA). Results: Comparing all subjects, 14 distinct B cell clusters were identified using a community detection algorithm and visualized with Uniform Manifold Approximation Projection (UMAP). The proportion of each of those clusters varied by disease status and ethnicity. Transitional B cells trended higher in ANA+ healthy individuals, especially in AA. Ribonucleoprotein high population (HNRNPH1 elevated, heterogeneous nuclear ribonucleoprotein, RNP-Hi) of proliferating Naïve B cells were more prevalent in SLE patients, specifically in EA. Interferon-induced protein high population (IFIT-Hi) of Naive B cells are increased in EA ANA- individuals. The proportion of memory B cells and plasma cells clusters tend to be expanded in SLE patients. As anticipated, we observed a higher signature of cytokine-related pathways, especially interferon, in SLE individuals. Pathway analysis among AA individuals revealed an NRF2-mediated Oxidative Stress response signature in the transitional B cell cluster, not seen in EA individuals. TNFR1/2 and Sirtuin Signaling pathway genes were higher in AA IFIT-Hi Naive B cells, whereas they were not detected in EA individuals. Interferon signaling was observed in B cells in both ethnicities. Oxidative phosphorylation was found in age-related B cells (ABCs) for both ethnicities, whereas Death Receptor Signaling was found only in EA patients in these cells. Interferon-related transcription factors were elevated in ABCs and IFIT-Hi Naive B cells in SLE subjects of both ethnicities. Conclusions: ANA+ healthy individuals have altered gene expression pathways in B cells that might drive apoptosis and subsequent clinical autoimmune pathogenesis. Increases in certain regulatory pathways may delay progression to SLE. Further, AA individuals have more elevated activation pathways that may make them more susceptible to SLE.

Keywords:

Procedia PDF Downloads 173
3786 Raman and Dielectric Relaxation Investigations of Polyester-CoFe₂O₄ Nanocomposites

Authors: Alhulw H. Alshammari, Ahmed Iraqi, S. A. Saad, T. A. Taha

Abstract:

In this work, we present for the first time the study of Raman spectra and dielectric relaxation of polyester polymer-CoFe₂O₄ (5.0, 10.0, 15.0, and 20.0 wt%) nanocomposites. Raman spectroscopy was applied as a sensitive structural identification technique to characterize the polyester-CoFe₂O₄ nanocomposites. The images of AFM confirmed the uniform distribution of CoFe₂O₄ inside the polymer matrix. Dielectric relaxation was employed as an important analytical technique to obtain information about the ability of the polymer nanocomposites to store and filter electrical signals. The dielectric relaxation analyses were carried out on the polyester-CoFe₂O₄ nanocomposites at different temperatures. An increase in dielectric constant ε₁ was observed for all samples with increasing temperatures due to the alignment of the electric dipoles with the applied electric field. In contrast, ε₁ decreased with increasing frequency. This is attributed to the difficulty for the electric dipoles to follow the electric field. The α relaxation peak that appeared at a high frequency shifted to higher frequencies when increasing the temperature. The activation energies for Maxwell-Wagner Sillar (MWS) changed from 0.84 to 1.01 eV, while the activation energies for α relaxations were 0.54 – 0.94 eV. The conduction mechanism for the polyester- CoFe₂O₄ nanocomposites followed the correlated barrier hopping (CBH) model.

Keywords: AC conductivity, activation energy, dielectric permittivity, polyester nanocomposites

Procedia PDF Downloads 104
3785 Use of Zikani’s Ribosome Modulating Agents for Treating Recessive Dystrophic & Junctional Epidermolysis Bullosa with Nonsense Mutations

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

Abstract:

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

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

Procedia PDF Downloads 95