Determining epitope specificity of T-cell receptors with transformers.

SUMMARY: T-cell receptors (TCRs) on T cells recognize and bind to epitopes presented by the major histocompatibility complex in case of an infection or cancer. However, the high diversity of TCRs, as well as their unique and complex binding mechanisms underlying epitope recognition, make it difficult to predict the binding between TCRs and epitopes. Here, we present the utility of transformers, a deep learning strategy that incorporates an attention mechanism that learns the informative features, and show that these models pre-trained on a large set of protein sequences outperform current strategies. We compared three pre-trained auto-encoder transformer models (ProtBERT, ProtAlbert, and ProtElectra) and one pre-trained auto-regressive transformer model (ProtXLNet) to predict the binding specificity of TCRs to 25 epitopes from the VDJdb database (human and murine). Two additional modifications were performed to incorporate gene usage of the TCRs in the four transformer models. Of all 12 transformer implementations (four models with three different modifications), a modified version of the ProtXLNet model could predict TCR-epitope pairs with the highest accuracy (weighted F1 score 0.55 simultaneously considering all 25 epitopes). The modification included additional features representing the gene names for the TCRs. We also showed that the basic implementation of transformers outperformed the previously available methods, i.e. TCRGP, TCRdist, and DeepTCR, developed for the same biological problem, especially for the hard-to-classify labels. We show that the proficiency of transformers in attention learning can be made operational in a complex biological setting like TCR binding prediction. Further ingenuity in utilizing the full potential of transformers, either through attention head visualization or introducing additional features, can extend T-cell research avenues. AVAILABILITY AND IMPLEMENTATION: Data and code are available on https://github.com/InduKhatri/tcrformer.

Association of vitamin D receptor polymorphisms with cardiometabolic conditions in Pakistani population.

Apart from bone related effects, vitamin D has roles in immune modulation, hypertension, diabetes and cardiovascular diseases. Metabolic functions of vitamin D are mediated after binding with vitamin D receptor (VDR). VDR polymorphisms affect its physiological functions. Several VDR single nucleotide polymorphisms (SNPs) are reported previously. However, VDR polymorphisms causing influence on cardiovascular and metabolic disorders have not been investigated in Pakistani population so far. Therefore, present study was conducted to evaluate the role of VDR polymorphisms (rs2228570 and rs7975232) in the pathobiology of cardiometabolic disorders. In all, 400 cardiometabolic patients and 226 healthy control human adults were enrolled from Faisalabad, Pakistan. Biochemical parameters (serum glucose, liver function test, renal function test and lipid profile) were analyzed by standard kit methods. Genetic analysis was done by ARMS-PCR assay. Data was analyzed in SPSS v20. Regression analysis revealed that GG and AG genotypes of rs2228570 A>G polymorphism significantly increased the risk of hypertension in cardiovascular patients by 5.29 and 5.94 times respectively (GG: OR=5.29, 95% CI=1.63-17.2, p=0.005; AG: OR=5.94, 95% CI=1.70-20.7, p=0.005). However, rs7975232 C>A polymorphism was not correlated with cardiometabolic conditions. In conclusion, GG and AG genotypes of VDR SNP rs2228570 significantly contribute for hypertension in cardiovascular disease patients.

Anti-bacterial and wound healing-promoting effects of zinc ferrite nanoparticles.

BACKGROUND: Increasing antibiotic resistance continues to focus on research into the discovery of novel antimicrobial agents. Due to its antimicrobial and wound healing-promoting activity, metal nanoparticles have attracted attention for dermatological applications. This study is designed to investigate the scope and bactericidal potential of zinc ferrite nanoparticles (ZnFe2O4 NPs), and the mechanism of anti-bacterial action along with cytocompatibility, hemocompatibility, and wound healing properties. RESULTS: ZnFe2O4 NPs were synthesized via a modified co-precipitation method. Structure, size, morphology, and elemental compositions of ZnFe2O4 NPs were analyzed using X-ray diffraction pattern, Fourier transform infrared spectroscopy, and field emission scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy. In PrestoBlue and live/dead assays, ZnFe2O4 NPs exhibited dose-dependent cytotoxic effects on human dermal fibroblasts. In addition, the hemocompatibility assay revealed that the NPs do not significantly rupture red blood cells up to a dose of 1000 µg/mL. Bacterial live/dead imaging and zone of inhibition analysis demonstrated that ZnFe2O4 NPs showed dose-dependent bactericidal activities in various strains of Gram-negative and Gram-positive bacteria. Interestingly, NPs showed antimicrobial activity through multiple mechanisms, such as cell membrane damage, protein leakage, and reactive oxygen species generation, and were more effective against gram-positive bacteria. Furthermore, in vitro scratch assay revealed that ZnFe2O4 NPs improved cell migration and proliferation of cells, with noticeable shrinkage of the artificial wound model. CONCLUSIONS: This study indicated that ZnFe2O4 NPs have the potential to be used as a future antimicrobial and wound healing drug.

The Interplay between Toxic and Essential Metals for Their Uptake and Translocation Is Likely Governed by DNA Methylation and Histone Deacetylation in Maize.

The persistent nature of lead (Pb) and cadmium (Cd) in the environment severely affects plant growth and yield. Conversely, plants acquire zinc (Zn) from the soil for their vital physiological and biochemical functions. However, the interplay and coordination between essential and toxic metals for their uptake and translocation and the putative underlying epigenetic mechanisms have not yet been investigated in maize. Here, we report that the presence of Zn facilitates the accumulation and transport of Pb and Cd in the aerial parts of the maize plants. Moreover, the Zn, Pb, and Cd interplay specifically interferes with the uptake and translocation of other divalent metals, such as calcium and magnesium. Zn, Pb, and Cd, individually and in combinations, differentially regulate the expression of DNA methyltransferases, thus alter the DNA methylation levels at the promoter of Zinc-regulated transporters, Iron-regulated transporter-like Protein (ZIP) genes to regulate their expression. Furthermore, the expression of histone deacetylases (HDACs) varies greatly in response to individual and combined metals, and HDACs expression showed a negative correlation with ZIP transporters. Our study highlights the implication of DNA methylation and histone acetylation in regulating the metal stress tolerance dynamics through Zn transporters and warns against the excessive use of Zn fertilizers in metal contaminated soils.

Obesity related lung complications and a possible phytochemical therapeutic solution.

Proteases, especially neutrophil elastase (NE), enzyme provide innate immunity in the lung tissues against elastin protein disintegration by microbial attacks. Normally, an antiprotease, called alpha-1-antitrypsin (A1AT), is responsible to keep NE activity in normal range. In most of the leptin-resistant obese subjects, A1AT deficiency develops which leads to a concurrent higher activity of NE. Obesity associated antiprotease-protease imbalance induces various lung complications, i.e. asthma, emphysema, chronic obstructive pulmonary disorders (COPD), cancer, etc. Past studies manifested that plant extracts/compounds reduce human NE activity. This knowledge will help in future to exploit phytochemicals as interventional therapeutic agents to decrease NE over-activity in susceptible obese individuals. Furthermore, the hypothesis discussed in this article will be helpful for researchers working in the fields of lung biology and obesity.

Diabetes mellitus and dietary starch in perspective of blood glycaemic control.

Diabetes mellitus is a complex metabolic disorder which disrupts normal physiological functions of the body cells to take in and utilise glucose effectively. On the other hand, blood glycaemic control remains the primary therapeutic target for diabetic patients. Dietary starch is the main determinant of blood glucose. But dietary starch tolerance levels fluctuate between individuals, which might be due to difference in genetic variants of alpha-amylase enzyme. Additionally, genetic variability of cereal carbohydrates may also influence glucophenotype in terms of a specific glycaemic and biochemical derangement. Therefore, personalised carbohydrate/ starch based diets are needed to ensure optimum blood glycaemic control in diabetic subjects in prospective studies.

Antibiotic susceptibility and drug prescription pattern in uropathogenic Escherichia coli in district Muzaffarabad, Azad Jammu and Kashmir, Pakistan.

The present research study was done to determine the correlation between antibiotic susceptibility and drug prescription patterns in empirical treatment of uropathogenic Escherichia coli (E. coli) in two hospitals of district Muzaffarabad, Azad Kashmir, Pakistan. One hundred uropathogenic E. coli clinical isolates were collected from UTI patients who attended the Combined Military Hospital (CMH) and Abbas Institute of Medical Sciences (AIMS), district Muzaffarabad, AJK. All isolates were subjected to antibiotic susceptibility against seven commonly prescribed antibiotics by Kirby-Bauer disk diffusion method. However, all the E. coli isolates were susceptible to Imipenem. Eight percent and 10% of isolates from CMH and AIMS were found to be resistant against Nitrofurantoin drug respectively. Similarly, 94% and 74% isolates from CMH and 60% and 64% isolates from AIMS were found to be resistant against Co-trimoxazole and Coamoxiclave, respectively. Pipemedic acid resistance was also detected in 76% and 60% isolates from AIMS and CMH, respectively. Ciprofloxacin resistance was also observed in 54% and 36% isolates from AIMS and CMH, respectively. The finding of the study revealed that both hospitals have different drug susceptibility pattern against uropathogenic E. coli, which may be associated with patterns of drug prescription in empirical treatment of urinary tract infections. There is a vital need for appropriate development of hospital-specific antibiograms to determine appropriate empiric therapy of urinary tract infections.

Auto-controlled Syringe vs Insulin Syringe for Palatal Injections in Children: A Randomized Crossover Trial.

AIM: This study aims to evaluate and compare the efficacy of auto-control syringe (ACS) and insulin syringe (IS) for palatal local anesthesia administration in children. MATERIALS AND METHODS: The study was a double-blind, randomized, and crossover trial, comprising 80 children requiring palatal anesthesia bilaterally (total 160 injections). Palatal anesthesia on one side was delivered with ACS in one appointment and contralaterally with IS in the second appointment. One-week washout period was given between first and second appointments. Each child acted as his own control. Each injection technique subjective and objective pain scores were measured twice (during needle prick and during actual deposition of local anesthesia). Subjective and objective evaluation of pain was measured with Wong-Baker FACES pain rating scale (WB-FPS) and the face, leg, activity, cry, and consolability scale (FLACC), respectively. After concluding second appointment, child was asked about their preference between both ACS and IS. Statistical evaluation was performed using Chi-square test. RESULTS: Child reported less pain score for needle prick with IS as opposed to ACS (p value = 0.000416). There was no significant difference between dentist-reported pain scores between any group for both needle prick and local anesthesia administration. There is no significant difference between child reported pain score during administration of local anesthesia between two groups. Irrespective of pain scores, most of the children (96.5%) preferred IS. CONCLUSION: For palatal local anesthesia administration in children, both IS and auto-controlled syringe have similar efficacy. CLINICAL SIGNIFICANCE: Insulin syringe can serve as an economical alternative to the expensive auto-controlled syringe for palatal injections in children.

Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity.

Leptin protein consists of 167 amino acids, which is mainly secreted from the white adipose tissue. This protein acts on the hypothalamic regions of the brain which control eating behavior, thus playing a significant role in maintaining body's metabolism. Leptin receptors belong to glycoprotein 130 (gp130) family of cytokine receptors and exist in six isoforms (LEPR a-f), and all the isoforms are encoded by LEPR gene; out of these isoforms, the LEPR-b receptor is the 'longest form,' and in most of the cases, mutations in this isoform cause severe obesity. Also, mutations in the leptin gene (LEP) or its receptors gene can lead to obesity. Some biochemical pathways affect the bioactivity of leptin and/or its receptors. To date, eleven pathogenic mutations have been reported in the LEP which are p.L72S, p.N103K, p.R105W, p.H118L, p.S141C, p.W121X c.104_106delTCA, c.135del3bp, c.398delG, c.481_482delCT, and c.163C>T. Different mutations in the LEPR have also been reported as c.2396-1 G>T, c.1675 G>A, p.P316T, etc. In some studies, where leptin was deficient, leptin replacement therapy has shown positive impact by preventing weight gain and obesity.

Epigenetic regulation of inflammatory cytokines and associated genes in human malignancies.

Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies.

Elevated serum level of human alkaline phosphatase in obesity.

OBJECTIVE: To investigate a correlation between serum alkaline phosphatase level and body mass index in human subjects. METHODS: The comparative cross-sectional study was carried out at the National Institute for Biotechnology and Genetic Engineering, Faisalabad, Pakistan, from April 2012 to June 2013. Blood serum alkaline phosphatase levels were estimated and the subjects were divided into three sub-groups on the basis of their body mass. INDEX: normal weight (<25kg/m2), overweight (25-27kg/m2) and obese (>27kg/m2) subjects. The serum samples were used for the estimation of clinically important biochemical parameters, using commercial kits on clinical chemistry analyser. RESULTS: Of the 197 subjects, 97(49%) were obese and 100(51%) were non-obese. The serum alkaline phosphatase level increased in obese (214±6.4 IU/L) compared to the non-obese subjects (184.5±5 IU/L). Furthermore, a significant linear relationship (r=0.3;p-0.0001) was found between serum alkaline phosphatase and body mass index. Other biochemical variables were not correlated to the body mass index. CONCLUSIONS: Over activity and higher amounts of alkaline phosphatase were linked to the development of obesity.

Bilateral femoral shaft fractures in osteomalacia: A case report and literature review.

INTRODUCTION AND IMPORTANCE: When two non-traumatic femoral shaft fractures happen at the same time, they are usually not caused by high-energy trauma or medical conditions like osteomalacia caused by poor nutrition, long-term bisphosphonate medication use, or steroid use. Because this phenomenon is connected to inadequate bone mineralization and bone metabolism, it occurs when a bone is consistently under high stress. CASE PRESENTATION: A 40-year-old lady with a medical history of osteomalacia, including continuous vitamin D replacement therapy, showed up at the emergency room complaining of discomfort and swelling in her right thigh caused by a fall. During the emergency examination, X-rays showed a subtrochanteric fracture with a short oblique fracture line and a displaced oblique fracture in the right femoral shaft, but no fragmentation in the left femoral shaft. Osteomalacia caused the bilateral femoral shaft fracture in which the patient was identified as being displaced. We planned a surgical correction that included a closed reduction with intramedullary nailing and distal static screws on the right side, as well as intramedullary nailing followed by locking screw insertion on the left. Following the operation, the avoidance of bisphosphonate medications gained precedence. CLINICAL DISCUSSION: Patients of any age who come with bone pain, non-traumatic fractures, and muscle weakness should have their blood vitamin D, ALP levels, and BMD evaluated for osteomalacia. If a conventional X-ray shows normal, an MRI or bone scan of both hips is recommended to rule out any underlying fatigue fractures. Finding and treating the underlying cause of osteomalacia can help improve the prediction. CONCLUSION: Intramedullary nailing with screws is the most effective treatment for femoral shaft fractures. Improving patient outcomes relies on identifying and treating the underlying cause of osteomalacia. Given the patient's history and condition, avoiding bisphosphonate medicines following surgery was a primary priority in this case.

Complications and Revision Surgery in Orthopedics Focusing on Traumatology.

BACKGROUND: Orthopedic traumatology, a vital component of orthopedic surgery, poses significant challenges in managing complications and necessitating revision surgeries. These challenges impact clinical outcomes, healthcare economics, and patient well-being. OBJECTIVE: This study aimed to provide insights that informed clinical decision-making and improved patient outcomes by thoroughly examining the range of complications encountered in orthopedic traumatology. Specifically, the research focused on the indications, techniques, and outcomes of revision surgeries. METHODOLOGY: This retrospective cohort research looked at orthopedic traumatology complications and revision procedures over a thorough two-year period from March 2021 to March 2023 at Hayatabad Medical Complex in Peshawar, Pakistan. The following information was gathered from 316 patients receiving orthopedic surgery for traumatic injuries: demographics, kinds of trauma, surgical methods, complications, indications, methods, and results of revision surgery. For data analysis, chi-square tests and descriptive statistics were used, with the goal of finding patterns and correlations within the research population. RESULTS: The average age of the 316 patients was 42.5 years, and 64.76% of them were male (n = 192). The most frequent kind of trauma (n = 218; 69.01%) was fractures, which were mostly brought on by falls (n = 147; 46.52%). The most common surgical method (n = 138; 43.67%) was found to be internal fixation, which was followed by external fixation (n = 67; 21.20%). The most common complication (n = 78; 24.68%) was surgical site infection, which resulted in revision procedures mostly for infection (n = 68; 21.52%) and implant failure (n = 56; 17.72%). Debridement was the most often used revision approach (n = 95; 30.10%), and it was substantially correlated with surgical outcomes, such as increased function (31%) and full resolution (36%). CONCLUSION: This research emphasizes the need to maximize patient outcomes for improved well-being and highlights the crucial role that careful care plays in managing complications and revision operations in orthopedic traumatology.

Stimulatory effects of smoke solution and biogas digestate slurry application on photosynthesis, growth, and methylation profiling of solanum tuberosum.

Biostimulants are obtained from various sources like plants, animals, microorganisms, and industrial by-products as well as waste material. Their utilization in agriculture practices is being increased that is giving positive results. The purpose of the current study was to use plant-derived smoke (SMK) solution and biogas digestate (BGD) slurry as biostimulant to elucidate their impact on potato (Solanum tuberosum) performance. The experiment was conducted in lab as well as field conditions, and SMK and BGD solutions were prepared in varying concentrations such as SMK 1:500, SMK 1:250, BGD 50:50, and BGD 75:25. Foliar applications were performed thrice during experiments and data were collected related to photosynthesis, growth, pigments, and genome-wide methylation profiling. Net photosynthesis rate (A) and water use efficiency (WUE) were found higher in SMK- and BGD-treated lab and field grown plants. Among pigments, BGD-treated plants depicted higher levels of Chl a and Chl b while SMK-treated plants showed higher carotenoid levels. Alongside, enhancement in growth-related parameters like leaf number and dry weight was also observed in both lab- and field-treated plants. Furthermore, DNA methylation profile of SMK- and BGD-treated plants depicted variation compared to control. DNA methylation events increased in all the treatments compared to control except for SMK 1:500. These results indicate that smoke and slurry both act as efficient biostimulants which result in better performance of plants. Biostimulants also affected the genome-wide DNA methylation profile that resultantly might have changed the plant gene expression profiling and played its role in plant responsiveness to these biostimulants. However, there is need to elucidate a possible synergistic effect of SMK and BGD on plant growth along with gene expression profiling.

The effect of cultivar, sowing date and transplant location in field on bolting of Welsh onion (Allium fistulosum L.).

BACKGROUND: Bolting reduces the quality and commercial yield of Welsh onion (Allium fistulosum L.) in production. However, seed production is directly dependent on flower induction and bolting. The Welsh onion belongs to the green plant vernalisation type, specific seedling characteristics and sufficient accumulated time at low temperature are indispensible for the completion of its vernalisation process. Only if these conditions for vernalisation are fulfilled, the plants will bolt in the following year. The present investigation evaluated the effects of cultivar, sowing date and transplant location in field on the bolting of Welsh onion at the Horticultural Farm of the College of Horticulture, Northwest A&F University, Yangling, Shannxi Province, China in two succeeding production years: 2010-2011 and 2011-2012. A strip split plot layout within a randomised complete block design with three replications was used. RESULTS: The results revealed that all three factors (cultivar, sowing date and transplant location) and their interaction had significant effects on the initiation and final rate of bolting observed by 30 April. The earliest bolting date (14 February, 2011 and 15 February, 2012) and the highest bolting rate (100% in 2011 and 62% in 2012) occurred when the JinGuan cultivar was sown on 20 August and transplanted in a plastic tunnel, whereas the latest date and lowest rate (no bolting observed until 30 April) of bolting occurred when the XiaHei cultivar was sown on 29 September and transplanted in an open field. CONCLUSIONS: These results suggest that we can control bolting in Welsh onion production by choosing an appropriate cultivar, sowing date and transplant location. Choosing a late bolting cultivar, such as cultivar XiaHei, sowing around October, and transplanting in the open field can significantly delay bolting, while a sowing date in late August should be selected for seed production, and the seedlings should be transplanted in a plastic tunnel to accelerate development of the flower buds.

Vernalization treatment induces site-specific DNA hypermethylation at the VERNALIZATION-A1 (VRN-A1) locus in hexaploid winter wheat.

BACKGROUND: Certain temperate species require prolonged exposure to low temperature to initiate transition from vegetative growth to flowering, a process known as vernalization. In wheat, winter cultivars require vernalization to initiate flowering, making vernalization requirement a trait of key importance in wheat agronomy. The genetic bases of vernalization response have been largely studied in wheat, leading to the characterization of a regulation pathway that involves the key gene VERNALIZATION1 (VRN1). While previous studies in wheat and barley have revealed the functional role of histone modification in setting VRN1 expression, other mechanisms might also be involved. Here, we were interested in determining whether the cold-induced expression of the wheat VRN-A1 gene is associated with a change in DNA methylation. RESULTS: We provide the first DNA methylation analysis of the VRN-A1 gene, and describe the existence of methylation at CG but also at non CG sites. While CG sites show a bell-shape profile typical of gene-body methylation, non CG methylation is restricted to the large (8.5 kb) intron 1, in a region harboring fragments of transposable elements (TEs). Interestingly, cold induces a site-specific hypermethylation at these non CG sites. This increase in DNA methylation is transmitted through mitosis, and is reset to its original level after sexual reproduction. CONCLUSIONS: These results demonstrate that VRN-A1 has a particular DNA methylation pattern, exhibiting rapid shift within the life cycle of a winter wheat plant following exposure to particular environmental conditions. The finding that this shift occurs at non CG sites in a TE-rich region opens interesting questions onto the possible consequences of this type of methylation in gene expression.

Plant disease detection model for edge computing devices.

In this paper, we address the question of achieving high accuracy in deep learning models for agricultural applications through edge computing devices while considering the associated resource constraints. Traditional and state-of-the-art models have demonstrated good accuracy, but their practicality as end-user available solutions remains uncertain due to current resource limitations. One agricultural application for deep learning models is the detection and classification of plant diseases through image-based crop monitoring. We used the publicly available PlantVillage dataset containing images of healthy and diseased leaves for 14 crop species and 6 groups of diseases as example data. The MobileNetV3-small model succeeds in classifying the leaves with a test accuracy of around 99.50%. Post-training optimization using quantization reduced the number of model parameters from approximately 1.5 million to 0.93 million while maintaining the accuracy of 99.50%. The final model is in ONNX format, enabling deployment across various platforms, including mobile devices. These findings offer a cost-effective solution for deploying accurate deep-learning models in agricultural applications.

Lymphocyte detection for cancer analysis using a novel fusion block based channel boosted CNN.

Tumor-infiltrating lymphocytes, specialized immune cells, are considered an important biomarker in cancer analysis. Automated lymphocyte detection is challenging due to its heterogeneous morphology, variable distribution, and presence of artifacts. In this work, we propose a novel Boosted Channels Fusion-based CNN "BCF-Lym-Detector" for lymphocyte detection in multiple cancer histology images. The proposed network initially selects candidate lymphocytic regions at the tissue level and then detects lymphocytes at the cellular level. The proposed "BCF-Lym-Detector" generates diverse boosted channels by utilizing the feature learning capability of different CNN architectures. In this connection, a new adaptive fusion block is developed to combine and select the most relevant lymphocyte-specific features from the generated enriched feature space. Multi-level feature learning is used to retain lymphocytic spatial information and detect lymphocytes with variable appearances. The assessment of the proposed "BCF-Lym-Detector" show substantial improvement in terms of F-score (0.93 and 0.84 on LYSTO and NuClick, respectively), which suggests that the diverse feature extraction and dynamic feature selection enhanced the feature learning capacity of the proposed network. Moreover, the proposed technique's generalization on unseen test sets with a good recall (0.75) and F-score (0.73) shows its potential use for pathologists' assistance.