Miracle-dz/UniFAR-FTUs huggingface dataset:
HIV skews the SARS-CoV-2 B cell response towards an extrafollicular maturation pathway

Background HIV infection dysregulates the B cell compartment, affecting memory B cell formation and the antibody response to infection and vaccination. Understanding the B cell response to SARS-CoV-2 in people living with HIV (PLWH) may explain the increased morbidity, reduced vaccine efficacy, reduced clearance, and intra-host evolution of SARS-CoV-2 observed in some HIV-1 coinfections. Methods We compared B cell responses to COVID-19 in PLWH and HIV negative (HIV-ve) patients in a cohort recruited in Durban, South Africa, during the first pandemic wave in July 2020 using detailed flow cytometry phenotyping of longitudinal samples with markers of B cell maturation, homing and regulatory features. Results This revealed a coordinated B cell response to COVID-19 that differed significantly between HIV-ve and PLWH. Memory B cells in PLWH displayed evidence of reduced germinal center (GC) activity, homing capacity and class-switching responses, with increased PD-L1 expression, and decreased Tfh frequency. This was mirrored by increased extrafollicular (EF) activity, with dynamic changes in activated double negative (DN2) and activated naïve B cells, which correlated with anti-RBD-titres in these individuals. An elevated SARS-CoV-2 specific EF response in PLWH was confirmed using viral spike and RBD bait proteins. Conclusions Despite similar disease severity, these trends were highest in participants with uncontrolled HIV, implicating HIV in driving these changes. EF B cell responses are rapid but give rise to lower affinity antibodies, less durable long-term memory, and reduced capacity to adapt to new variants. Further work is needed to determine the long-term effects of HIV on SARS-CoV-2 immunity, particularly as new variants emerge. Funding This work was supported by a grant from the Wellcome Trust to the Africa Health Research Institute (Wellcome Trust Strategic Core Award [grant number 201433/Z/16/Z]). Additional funding was received from the South African Department of Science and Innovation through the National Research Foundation (South African Research Chairs Initiative, [grant number 64809]), and the Victor Daitz Foundation.
Kinetic Characterization and Computational Modeling of the Escherichia coli Heptosyltransferase II: Exploring the Role of Protein Dynamics in Catalysis for a GT-B Glycosyltransferase

Glycosyltransferases (GTs) are enzymes that are uniquely adapted to promote the formation of a glycosidic bond between a sugar molecule and a wide variety of substrates. Heptosyltransferase II (HepII) is a GT involved in the lipopolysaccharide (LPS) biosynthetic pathway that transfers the seven-carbon sugar (L-glycero-D-manno-heptose; Hep) onto a lipid anchored glycopolymer (heptosylated Kdo2-Lipid A, Hep-Kdo2-Lipid A or HLA). LPS plays a key role in Gram-negative bacterial sepsis as a stimulator of the human immune response and has been used as an adjuvant in vaccines. As such, ongoing efforts towards inhibition of LPS biosynthetic enzymes to aid development of novel antimicrobial therapeutics has driven significant effort towards the characterization of these enzymes. Three heptosyltransferases are involved in the inner-core biosynthesis, with E. coli HepII being the last to be quantitatively characterized in vivo, as described herein. HepII shares modest sequence similarity with heptosyltransferase I (HepI) while maintaining a high degree of structural homology. Here we report the first kinetic and biophysical characterization of HepII and demonstrate the properties of HepII that are shared by HepI to include sugar donor promiscuity, and sugar acceptor induced secondary structural changes which results in significant thermal stabilization. HepII also has an increased catalytic efficiency and a significantly tighter binding affinity for both of its substrates, with an insensitivity to the number of acyl chains on the sugar acceptor. Additionally, a structural model of the HepII ternary complex, refined by molecular dynamics simulations, was developed to probe potentially important substrate-protein contacts and revealed the potential of Tryptophan (Trp) residues responsible for reporting on ligand binding. As was previously described for HepI, Tryptophan fluorescence in HepII allowed observation of substrate induced changes in Trp fluorescence intensity which enabled determination of substrate dissociation constants. Combined, these efforts meaningfully enhance our understanding of the Heptosyltransferase family of enzymes and will aid in future efforts to design novel, potent and specific inhibitors for this family of enzymes.
Codon optimization, not gene content, predicts XYLose metabolism in budding yeasts

Xylose is the second most abundant monomeric sugar in plant biomass. Consequently, xylose catabolism is an ecologically important trait for saprotrophic organisms, as well as a fundamentally important trait for industries that hope to convert plant mass to renewable fuels and other bioproducts using microbial metabolism. Although common across fungi, xylose catabolism is rare within Saccharomycotina, the subphylum that contains most industrially relevant fermentative yeast species. Several yeasts unable to consume xylose have been previously reported to possess complete predicted xylolytic metabolic pathways, suggesting the absence of a gene-trait correlation for xylose metabolism. Here, we measured growth on xylose and systematically identify XYL pathway orthologs across the genomes of 332 budding yeast species. We found that most yeast species possess complete predicted xylolytic pathways, but pathway presence did not correlate with xylose catabolism. We then quantified codon usage bias of XYL genes and found that codon optimization was higher in species able to consume xylose. Finally, we showed that codon optimization of XYL2, which encodes xylitol dehydrogenase, positively correlated with growth rates in xylose medium. We conclude that gene content cannot predict xylose metabolism; instead, codon optimization is now the best predictor of xylose metabolism from yeast genome sequence data. Significance Statement In the genomic era, strategies are needed for the prediction of metabolic traits from genomic data. Xylose metabolism is an industrially important trait, but it is not found in most yeast species heavily used in industry. Because xylose metabolism appears rare across budding yeasts, we sought to identify a computational means of predicting which species are capable of xylose catabolism. We did not find a relationship between gene content and xylose metabolism traits. Rather, we found that codon optimization of xylolytic genes was higher in species that can metabolize xylose, and that optimization of one specific gene correlated with xylose-specific growth rates. Thus, codon optimization is currently the only means of accurately predicting xylose metabolism from genome sequence data.
Assessment of urinary exosome NHE3 as a biomarker of acute kidney injury

The diagnosis of acute kidney injury (AKI) traditionally depends on the serum creatinine (SCr) and urine output, which lack sufficient sensitivity and specificity. Urinary exosome as a biomarker has unique advantages. To assessed whether urinary exosome Na+/H+ exchanger isoform 3 (NHE3) protein as a nonivasive diagnostic biomarker of AKI, we constructed 4 AKI rat models: cisplatin (7.5mg/kg) injection intraperitoneally (IP), furosemide (20mg/kg, IP) with low NaCl (0.03%) diet, low NaCl (0.03%) diet with candesartan (1mg/kg, IP) and bilaterally ischemia and reperfusion(I/R) injury for 40 minutes. Besides, we assessed 6 sepsis associated AKI patients and 6 healthy volunteers. Urinary exosomes were extracted by ultra-centrifugation and NHE3 protein abundance was tested by immunoblotting in all AKI rats and human subjects. The isolated cup-shape particles with an average diameter of 70nm and enrichment in CD63 were identified as exosomes. NHE3 abundance was 6 times higher in exosome than in original urine. In cisplatin induced AKI rats, urinary exosome NHE3 was increased at day 2, 1 day earlier than the increases of serum creatinine creatinine (SCr) and blood urea nitrogen (BUN). In additional rats, urinary exosome NHE3 decreased along with the decline of SCr after EPO pretreatment. In volume depletion AKI induced by furosemide injection with low NaCl diet, urinary exosome NHE3 expression was higher than control. In low NaCl diet with candesartan related AKI, urinary exosome NHE3 was elevated at day 5, 2 days earlier than SCr. In I/R injury AKI, urinary exosome NHE3 was also raised compared with control. In humans, the urinary exosome NHE3 level was also elevated in sepsis associated AKI patients in comparison with the healthy volunteers. Then urinary exosome NHE3 protein may be used as a noninvasive diagnostic biomarker of AKI. Impact Statement The high non-recognition acute kidney injury (AKI) is due to lacking of alarming symptoms or specific early biomarkers. Urinary exosome as a biomarker has unique advantages. In our study, we detected urinary exosome NHE3 protein abundance in 4 different cause of AKI rat model. Urinary exosome NHE3 was increased in all 4 AKI, and even elevated earlier than SCr in some cases. Another novel point was we established a new AKI model of low NaCl diet with candesartan injection, which was common in patients with hypertension or proteinuria clinically. The detailed methods and mechanisms of this new AKI model were presented in another article being submitted. Third, we are not limited to animals, but also selected sepsis associated AKI patients to study. The conclusion that urinary exosome NHE3 may be used as a diagnosis biomarker of AKI has important clinical application value.
Neuroanatomy of stomatopod central complexes offers putative neural substrate for oriented behaviors in crustaceans

All insects studied to date possess a centrally located group of neuropils, known collectively as the central complex, that has been implicated in sensory integration and motor action selection. Among the functions prescribed to the central complex, none is perhaps as intriguing as its role in orientation and navigation. Neurobiological correlates of both current and desired headings have been described in insect CXs. Despite the diversity of arthropods, understanding of the CX as a navigational center originates entirely from terrestrial insects. Stomatopod crustaceans, commonly referred to as mantis shrimps, form an order of predatory marine crustaceans with intricate and diverse visual systems that maintain the distinction of being the only fully aquatic animal known to utilize the navigational strategy of path integration. They utilize idiothetic, celestial, and landmark cues to orient in the benthos. Here, we investigate the neuroanatomy of adult and developing mantis shrimp central complexes and associated neuropils to begin understanding this brain region in a sensorially and behaviorally complex crustacean.
Imputation and polygenic score performances of human genotyping arrays in diverse populations

Regardless of the overwhelming use of next-generation sequencing technologies, microarray-based genotyping combined with the imputation of untyped variants remains a cost-effective means to interrogate genetic variations across the human genome. This technology is widely used in genome-wide association studies (GWAS) at bio-bank scales, and more recently, in polygenic score (PGS) analysis to predict and to stratify disease risk. Over the last decade, human genotyping arrays have undergone a tremendous growth in both number, and content making a comprehensive evaluation of their performances became more important. Here, we performed a comprehensive performance assessment for 23 available human genotyping arrays in 6 ancestry groups using diverse public, and in-house datasets. The analyses focus on performance estimation of derived imputation (in terms of accuracy and coverage) and PGS (in term of concordance to PGS estimated from whole genome sequencing data) in three different traits and diseases. We found that the arrays with a higher number of SNPs are not necessarily the ones with higher imputation performance, but the arrays that are well-optimized for the targeted population could provide very good imputation performance. In addition, PGS estimated by imputed SNP array data is highly correlated to PGS estimated by whole genome sequencing data in most of cases. When optimal arrays are used, the correlations of key PGS metrics between two types of data can be higher than 0.97, but interestingly, arrays with high density can result in lower PGS performance. Our results suggest the importance of properly selecting a suitable genotyping array for PGS applications. Finally, we developed a web tool that provide interactive analyses of tag SNP contents and imputation performance based on population and genomic regions of interest. This study would act as a practical guide for researchers to design their genotyping arrays-based studies. The tool is available at: https://genome.vinbigdata. org/tools/saa/
Local IGF‐I Prevents Sepsis‐Induced Muscle Atrophy

This study tests the hypothesis that local IGF‐I bioavailability regulates muscle protein balance and that muscle‐directed IGF‐I can selectively maintain muscle mass during sepsis. Increasing or decreasing bioavailable IGF‐I within muscle of mice by local injection of Leu24‐Ala31‐IGF‐I or IGFBP‐1, respectively, produced proportional changes in 4EBP1 and S6K1 phosphorylation ‐ surrogate markers of protein synthesis. In a second study, a time‐release pellet (5‐days) containing IGF‐I was implanted in the gastrocnemius and a placebo implanted in the contralateral muscle after sepsis. The gastrocnemius from septic mice with the placebo was atrophied and IGF‐I protein reduced. In contrast, local release of IGF‐I increased IGF‐I within the adjacent muscle to basal control levels, and was associated with proportional increases in muscle weight/protein. Locally‐directed IGF‐I increased the mass/protein of the exposed gastrocnemius in septic mice, and this was associated with increased phosphorylation of 4EBP1 and S6K1. Local IGF‐I selectively prevented the sepsis‐induced increase in muscle atrogin‐1 and IL‐6 mRNA. In conclusion, muscle‐directed IGF‐I prevents the characteristic sepsis‐induced atrophic response resulting from an increase in muscle protein synthesis and potentially from decreased proteolysis, without effecting metabolic processes in distant organs. (GM 38032)
An average-case analysis of bin packing with uniformly distributed item sizes

Author(s): Lueker, George S. | Abstract: We analyze the one-dimensional bin-packing problem under the assumption that bins have unit capacity, and that items to be packed are drawn from a uniform distribution on [0,1]. Building on some recent work by Frederickson, we give an algorithm which uses n/2+0(n^½) bins on the average to pack n items. (Knodel has achieved a similar result.) The analysis involves the use of a certain 1-dimensional random walk. We then show that even an optimum packing under this distribution uses n/2+0(n^1/2) bins on the average, so our algorithm is asymptotically optimal, up to constant factors on the amount of wasted space. Finally, following Frederickson, we show that two well-known greedy bin-packing algorithms use no more bins than our algorithm; thus their behavior is also in asymptotically optimal in this sense.
Dietary 18:3 and Long Chain n‐3 PUFA Protected Rats from Fructose‐Induced Oxidative and Endoplasmic Reticulum Stress in Visceral Adipose Tissue

Effect of dietary n‐6/n‐3 polyunsaturated fatty acids (PUFA) ratio on the fructose‐induced adipose tissue oxidative and endoplasmic reticulum (ER) stress was not explored previously. Here, we studied the effect of diets containing n‐6 PUFA & α‐linolenic acid (ALA, 18:3 n‐3 PUFA) and n‐6 PUFA & long chain n‐3 PUFA (docosahexanoic acid and eicosapentaenoic acid, DHA and EPA) in the ratio of 2:1 and 5:1 respectively on fructose‐induced oxidative and ER stress in adipose tissue.
Three Dimensional (3D) Virtual Human Cadaver, Anatomage: An effective teaching tool for Human Anatomy

In an attempt to explore the innovative ways to introduce the knowledge of the human body in terms of its structures and functions, we have first time introduced three dimensional (3D) virtual human cadaver, Anatomage in our human anatomy classes, and discuss whether the use of Anatomage enhances the understanding/knowledge of the human body as determined by their class average with or without using anatomage. We have observed that the use of Anatomage in their teaching significantly increase their class average. Moreover, we also discuss the limitations and advantages of Anatomage as an effective teaching tool to teach human anatomy.
Tissue specific regulation of kappa opioid receptors and Nr4a2 expression by acrylamide

Acrylamide is a monomer with established human neurotoxic actions. Public concern was lately heightened by the finding that acrylamide is formed in starch‐based foods cooked at high temperatures. However, the extent of neurotoxicity particularly in children is not understood. The primary objective of this project was to assess gene expression and translational changes induced by acrylamide in juvenile rats. Animals were administered acrylamide daily (p.o., 30 mg/kg doses, n=6) for 21 days. Neurobehavioral effects were assessed and gene expression changes were evaluated in different brain regions, spinal cord, and sciatic nerve. Quantitative RT‐PCR followed by western blot analyses were conducted. Acrylamide treatment induced significant behavioral symptoms. Gene expression changes identified differentially expressed genes that play a role in neuronal development, pain pathways, and control of motor function. Western blot analyses revealed a significant decrease (p<0.05) in expression of kappa opioid receptors (KOR) in motor cortex and cerebellar tissues, while the expression was significantly increased in the sciatic nerve (p<0.01). The current study revealed that acrylamide‐caused down regulation of KOR expression in motor cortex and cerebellum. Such an effect might be responsible for the enhanced pain sensation observed in animal studies as well as in workers who have high acrylamide exposure.
Mathematical Models and Monte Carlo Algorithms for Physically Based Rendering

Algorithms for image synthesis render photo-realistic imagery, given the description of a scene. Physically based rendering specifically stresses the physical correctness of the algorithms and their results. The algorithms perform an accurate simulation of the behaviour of light, in order to faithfully render global illumination effects such as soft shadows, glossy reflections and indirect illumination. In this dissertation we investigate image-based Monte Carlo rendering algorithms. We pay special attention to their correctness, their versatility and their efficiency. First of all, we discuss theoretical frameworks that describe the global illumination problem. These formal mathematical models are the first step to ensure the correctness of the eventual results. Moreover, they allow to apply standard numerical techniques to compute a solution. We give an overview of existing models, which are based on the rendering equation and the potential equation. We then introduce a model based on a new concept, called the global reflectance distribution function. It combines the ideas of radiance and potential into a single function, which is defined by a set of two integral equations. We later show that, while the three models are equivalent, a straightforward Monte Carlo approach to solve them leads to entirely different rendering algorithms. We chose to apply Monte Carlo methods because of their versatility. First, we give an overview of Monte Carlo techniques in general. The variance of a technique provides a measure for the stochastic errors on its results. The basic strategy of Monte Carlo methods is to reduce the variance by averaging the results of large numbers of samples. Convergence is slow, however. Variance reduction techniques therefore try to improve the efficacy of the individual samples, by taking into account information about the integrand. We discuss techniques such as stratified sampling, importance sampling, the combining of estimators, control variates, Russian roulette and next event estimation. We stress their unbiasedness, which ensures that the estimators always converge to the exact solution. We specifically analyse aspects that are of importance for the global illumination problem and we present a few improvements to existing techniques. Finally, we apply the Monte Carlo methods to the mathematical models of the global illumination problem. The different models give rise to entirely different algorithms. The rendering equation leads to the well-known path tracing algorithm, while the potential equation leads to the light tracing algorithm. We discuss their strengths and weaknesses. We study the application of the variance reduction techniques and present results from practical experiments. The global reflectance distribution function and its equations give rise to a new algorithm, which we have called bidirectional path tracing. This algorithm proves to have superior qualities for rendering typical indirectly illuminated interior scenes.