Life Sciences Commons^™

High-Resolution Cryo-Electron Microscopy Structure Of Photosystem Ii From The Mesophilic Cyanobacterium, Synechocystis Sp. Pcc 6803, Christopher J. Gisriel, Jimin Wang, Jinchan Liu, David A. Flesher, Krystle M. Reiss, Hao-Li Huang, Ke R. Yang, William H. Armstrong, M. R. Gunner, Victor S. Batista, Richard J. Debus, Gary W. Brudvig

Publications and Research

Photosystem II (PSII) enables global-scale, light-driven water oxidation. Genetic manipulation of PSII from the mesophilic cyanobacterium Synechocystis sp. PCC 6803 has provided insights into the mechanism of water oxidation; however, the lack of a highresolution structure of oxygen-evolving PSII from this organism has limited the interpretation of biophysical data to models based on structures of thermophilic cyanobacterial PSII. Here, we report the cryo-electron microscopy structure of PSII from Synechocystis sp. PCC 6803 at 1.93-Å resolution. A number of differences are observed relative to thermophilic PSII structures, including the following: the extrinsic subunit PsbQ is maintained, the C terminus of the …

Cryptococcus Neoformans Melanization Incorporates Multiple Catecholamines To Produce Polytypic Melanin, Rosanna P. Baker, Christine Chrissian, Ruth E. Stark, Arturo Casadevall

Publications and Research

Melanin is a major virulence factor in pathogenic fungi that enhances the ability of fungal cells to resist immune clearance. Cryptococcus neoformans is an important human pathogenic fungus that synthesizes melanin from exogenous tissue catecholamine precursors during infection, but the type of melanin made in cryptococcal meningoencephalitis is unknown. We analyzed the efficacy of various catecholamines found in brain tissue in supporting melanization using animal brain tissue and synthetic catecholamine mixtures reflecting brain tissue proportions. Solid-state NMR spectra of the melanin pigment produced from such mixtures yielded more melanin than expected if only the preferred constituent dopamine had been incorporated, …

Elevated Growth And Biomass Along Temperate Forest Edges, Luca L. Morreale, Jonathan R. Thompson, Xiaojing Tang, Andrew B. Reinmann, Lucy R. Hutyra

Publications and Research

Fragmentation transforms the environment along forest edges. The prevailing narrative, driven by research in tropical systems, suggests that edge environments increase tree mortality and structural degradation resulting in net decreases in ecosystem productivity. We show that, in contrast to tropical systems, temperate forest edges exhibit increased forest growth and biomass with no change in total mortality relative to the forest interior. We analyze > 48,000 forest inventory plots across the north-eastern US using a quasi- experimental matching design. At forest edges adjacent to anthropogenic land covers, we report increases of 36.3% and 24.1% in forest growth and biomass, respectively. Inclusion of …

Inter-Subject Correlation While Listening To Minimalist Music: A Study Of Electrophysiological And Behavioral Responses To Steve Reich’S Piano Phase, Tysen Dauer, Duc T. Nguyen, Nick Gang, Jacek P. Dmochowski, Jonathan Berger, Blair Kaneshiro

Publications and Research

Musical minimalism utilizes the temporal manipulation of restricted collections of rhythmic, melodic, and/or harmonic materials. One example, Steve Reich’s Piano Phase, offers listeners readily audible formal structure with unpredictable events at the local level. For example, pattern recurrences may generate strong expectations which are violated by small temporal and pitch deviations. A hyper-detailed listening strategy prompted by these minute deviations stands in contrast to the type of listening engagement typically cultivated around functional tonal Western music. Recent research has suggested that the inter-subject correlation (ISC) of electroencephalographic (EEG) responses to natural audio-visual stimuli objectively indexes a state of “engagement,” demonstrating …

Exploration Of Dark Chemical Genomics Space Via Portal Learning: Applied To Targeting The Undruggable Genome And Covid-19 Anti-Infective Polypharmacology, Tian Cai, Li Xie, Muge Chen, Yang Liu, Di He, Shuo Zhang, Cameron Mura, Philip Boume, Lei Xie

Publications and Research

Advances in biomedicine are largely fueled by exploring uncharted territories of human biology. Machine learning can both enable and accelerate discovery, but faces a fundamental hurdle when applied to unseen data with distributions that differ from previously observed ones—a common dilemma in scientific inquiry. We have developed a new deep learning framework, called Portal Learning , to explore dark chemical and biological space. Three key, novel components of our approach include: (i) end-to-end, step-wise transfer learning, in recognition of biology’s sequence-structure-function paradigm, (ii) out-of-cluster meta-learning, and (iii) stress model selection. Portal Learning provides a practical solution to the out-of-distribution (OOD) …

Genome-Scale Data Reveal Deep Lineage Divergence And A Complex Demographic History In The Texas Horned Lizard (Phrynosoma Cornutum) Throughout The Southwestern And Central Us, Nicholas Finger, Keaka Farleigh, Jason T. Bracken, Adam D. Leaché, Olivier François, Ziheng Yang, Tomas Flouri, Tristan Charran, Tereza Jezkova, Dean A. Williams, Christopher Blair

Publications and Research

The southwestern and central US serve as an ideal region to test alternative hypotheses regarding biotic diversification. Genomic data can now be combined with sophisticated computational models to quantify the impacts of paleoclimate change, geographic features, and habitat heterogeneity on spatial patterns of genetic diversity. In this study we combine thousands of genotyping-by-sequencing (GBS) loci with mtDNA sequences (ND1) from the Texas Horned Lizard (Phrynosoma cornutum) to quantify relative support for different catalysts of diversification. Phylogenetic and clustering analyses of the GBS data indicate support for at least three primary populations. The spatial distribution of populations appears concordant …

Phylogenomics Of Alligator Lizards Elucidate Diversification Patterns Across The Mexican Transition Zone And Support The Recognition Of A New Genus, Christopher Blair, Robert W. Bryson Jr, Uri O. García-Vázquez, Adrián Nieto-Montes De Oca, David Lazcano, John E. Mccormack, John Klicka

Publications and Research

Genomic data continue to advance our understanding of species limits and biogeographic patterns. However, there is still no consensus regarding appropriate methods of phylogenomic analysis that make the best use of these heterogeneous data sets. In this study, we used thousands of ultraconserved element (UCE) loci from alligator lizards in the genus Gerrhonotus to compare and contrast species trees inferred using multiple contemporary methods and provide a time frame for biological diversification across the Mexican Transition Zone (MTZ). Concatenated maximum likelihood (ML) and Bayesian analyses provided highly congruent results, with differences limited to poorly supported nodes. Similar topologies were inferred …

Competition And Geography Underlie Speciation And Morphological Evolution In Indo-Australasian Monitor Lizards, Carlos J. Pavón-Vázquez, Ian G. Brennan, Alexander Skeels, J. Scott Keogh

Publications and Research

How biotic and abiotic factors act together to shape biological diversity is a major question in evolutionary biology. The recent availability of large datasets and development of new methodological approaches provide new tools to evaluate the predicted effects of ecological interactions and geography on lineage diversification and phenotypic evolution. Here, we use a near complete phylogenomic-scale phylogeny and a comprehensive morphological dataset comprising more than a thousand specimens to assess the role of biotic and abiotic processes in the diversification of monitor lizards (Varanidae). This charismatic group of lizards shows striking variation in species richness among its clades and multiple …

Oligomerization Of Mutant P53 R273h Is Not Required For Gain-Of-Function Chromatin Associated Activities, George K. Annor, Nour Elshabassy, Devon Lundine, Don-Gerard Conde, Gu Xiao, Viola Ellison, Jill Bargonetti

Publications and Research

The TP53 gene is often mutated in cancer, with missense mutations found in the central DNA binding domain, and less often in the C-terminal oligomerization domain (OD). These types of mutations are found in patients with the rare inherited cancer predisposition disorder called Li-Fraumeni syndrome. We previously found that mutant p53 (mtp53) R273H associates with replicating DNA and promotes the chromatin association of replication-associated proteins mini-chromosome maintenance 2 (MCM2), and poly ADP-ribose polymerase 1(PARP1). Herein, we created dual mutants in order to test if the oligomerization state of mtp53 R273H played a role in chromatin binding oncogenic gain-of-function (GOF) activities. …

Structure Of A Monomeric Photosystem Ii Core Complex From A Cyanobacterium Acclimated To Far-Red Light Reveals The Functions Of Chlorophylls D And F, Christopher J. Gisriel, Gaozhong Shen, Ming-Yang Ho, Vasily Kurashov, David A. Flesher, Jimin Wang, William H. Armstrong, John H. Golbeck, Marilyn R. Gunner, David J. Vinyard, Richard J. Debus, Gary W. Brudvig, Donald A. Bryant

Publications and Research

Far-red light (FRL) photoacclimation in cyanobacteria provides a selective growth advantage for some terrestrial cyanobacteria by expanding the range of photosynthetically active radiation to include far-red/near-infrared light (700–800 nm). During this photoacclimation process, photosystem II (PSII), the water:plastoquinone photooxidoreductase involved in oxygenic photosynthesis, is modified. The resulting FRL-PSII is comprised of FRL-specific core subunits and binds chlorophyll (Chl) d and Chl f molecules in place of several of the Chl a molecules found when cells are grown in visible light. These new Chls effectively lower the energy canonically thought to define the “red limit” for light required to drive photochemical …

Insights Into Using Plants In Management Of Viral Diseases., Vyacheslav Dushenkov, Anna Dushenkov

Publications and Research

Botanical therapeutics possess a unique potential in the treatment of viral diseases. The pharmacological base and clinical use of botanical therapeutics have been extensively reviewed. The mode of action(s) may be built either on the direct interference with the virus's ability to enter human cells, virus replication, or exerting immune-modulatory and anti-inflammatory effects. The adjuvant treatment with botanical therapeutics has the potential to result in advances in symptom resolution, decrease in disease burden and shortening its duration.

Type Vi Secretion System Mutations Reduced Competitive Fitness Of Classical Vibrio Cholerae Biotype, Benjamin Kostiuk, Francis J. Santoriello, Laura Diaz-Satizabal, Fabiana Bisaro, Kyung-Jo Lee, Anna N. Dhody, Daniele Provenzano, Daniel Unterweger, Stefan Pukatzki

Publications and Research

The gram-negative bacterium Vibrio cholerae is the causative agent of the diarrhoeal disease cholera and is responsible for seven recorded pandemics. Several factors are postulated to have led to the decline of 6th pandemic classical strains and the rise of El Tor biotype V. cholerae, establishing the current 7th pandemic. We investigated the ability of classical V. cholerae of the 2nd and 6th pandemics to engage their type six secretion system (T6SS) in microbial competition against non-pandemic and 7th pandemic strains. We report that classical V. cholerae underwent sequential mutations in T6SS genetic determinants that initially exposed 2nd pandemic strains …

The Temperature-Dependent Conformational Ensemble Of Sars-Cov-2 Main Protease (Mpro), Ali Ebrahim, Blake T. Riley, Desigan Kumaran, Babak Andi, Martin R. Fuchs, Sean Mcsweeney, Daniel A. Keedy

Publications and Research

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M^pro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M^pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M^pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M^pro, including …

Cryo-Em Structure Of Mechanosensitive Channel Ynai Using Sma2000: Challenges And Opportunities, Claudio Catalano, Danya Ben-Hail, Weihua Qiu, Paul Blount, Amedee Des Georges, Youzhong Guo

Publications and Research

Mechanosensitive channels respond to mechanical forces exerted on the cell membrane and play vital roles in regulating the chemical equilibrium within cells and their environment. Highresolution structural information is required to understand the gating mechanisms of mechanosensitive channels. Protein-lipid interactions are essential for the structural and functional integrity of mechanosensitive channels, but detergents cannot maintain the crucial native lipid environment for purified mechanosensitive channels. Recently, detergent-free systems have emerged as alternatives for membrane protein structural biology. This report shows that while membrane-active polymer, SMA2000, could retain some native cell membrane lipids on the transmembrane domain of the mechanosensitive-like YnaI channel, …

Dietary Diversity And Nutrient Intake Of Han And Dongxiang Smallholder Farmers In Poverty Areas Of Northwest China, Zhuo Wang, Youhai Chen, Shihua Tang, Siqi Chen, Shaoqing Gong, Xinyin Jiang, Liang Wang, Ying Zhang

Publications and Research

This study aimed to evaluate the status of dietary diversity and nutrient intake among Han and Dongxiang smallholder farmers in poor rural areas of northwest China. In this cross-sectional study, dietary intake was assessed in 499 smallholder farmers aged 18–75 years from two nationally designated impoverished counties in Gansu Province, China, using three consecutive 24 h dietary recalls. The dietary diversity score (DDS) and nutrient adequacy ratio (NAR) were adopted to assess dietary diversity and micronutrient adequacy, respectively. The mean DDS (range from 1 to 9) in participants was relatively low (3.81 ± 1.01). Consumption of grains was excessive, while …

Clock Time Of First Eating Episode And Prospective Risk Of All-Cause Mortality In Us Adults, Ashima K. Kant, Barry I. Graubard

Publications and Research

Background: There is increasing recognition that morning or evening preference is associated with time of eating, metabolic health, and morbidity. However, few studies have examined the association of time of eating with mortality.

Objective: To examine the association of time of first recalled ingestive episode with prospective risk of all-cause mortality.

Design: We used mortality-linked data from the National Health and Nutrition Examination Surveys (NHANES) conducted in 1988-1994 and 1999-2014 (n=34609; age >40 y). Quartiles (Q1-Q4) of clock time of first eating episode self-reported in the baseline 24-h dietary recall was the exposure. Follow-up time from date of NHANES examination …

Regulatory Non-Coding Rnas Modulate Transcriptional Activation During B Cell Development, Mary Attaway, Tzippora Chwat-Edelstein, Bao Q. Vuong

Publications and Research

B cells play a significant role in the adaptive immune response by secreting immunoglobulins that can recognize and neutralize foreign antigens. They develop from hematopoietic stem cells, which also give rise to other types of blood cells, such as monocytes, neutrophils, and T cells, wherein specific transcriptional programs define the commitment and subsequent development of these different cell lineages. A number of transcription factors, such as PU.1, E2A, Pax5, and FOXO1, drive B cell development. Mounting evidence demonstrates that non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), modulate the expression of these transcription factors directly by binding …

Expression, Purification And Refolding Of A Human Na V 1.7 Voltage Sensing Domain With Native-Like Toxin Binding Properties, Ryan V. Schroder, Leah S. Cohen, Ping Wang, Joekeem D. Arizala, Sébastien F. Poget

Publications and Research

The voltage-gated sodium channel NaV1.7 is an important target for drug development due to its role in pain perception. Recombinant expression of full-length channels and their use for biophysical characterization of interactions with potential drug candidates is challenging due to the protein size and complexity. To overcome this issue, we developed a protocol for the recombinant expression in E. coli and refolding into lipids of the isolated voltage sensing domain (VSD) of repeat II of NaV1.7, obtaining yields of about 2 mg of refolded VSD from 1 L bacterial cell culture. This VSD is known to be involved in the …

Globe Mosquito Habitat Mapper Citizen Science Data 2017–2020, Russanne Low, Rebecca Boger, Peder Nelson, Matteo Kimura

Publications and Research

The GLOBE Program's GLOBE Observer application is a free citizen science mobile data collection and visualization tool compatible with iOS and Android operating systems. Citizen scientists armed with the app can report the mosquito larval habitats they identify using the GLOBE Mosquito Habitat Mapper tool. This data can complement the climate, weather, and land cover data obtained from satellite measurements by scientists who develop risk models for mosquito-borne diseases. Public participation in mosquito surveillance research provides the opportunity to obtain the volume, velocity and variety of data needed to fight the threat of vector-borne diseases, especially in under-resourced communities with …

A Conserved Structural Role For The Walker-A Lysine In P-Loop Containing Kinases, Fatlum Hajredini, Ranajeet Ghose

Publications and Research

Bacterial tyrosine kinases (BY-kinases) and shikimate kinases (SKs) comprise two structurally divergent P-loop containing enzyme families that share similar catalytic site geometries, most notably with respect to their Walker-A, Walker-B, and DxD motifs. We had previously demonstrated that in BY-kinases, a specific interaction between the Walker-A and Walker-B motifs, driven by the conserved “catalytic” lysine housed on the former, leads to a conformation that is unable to efficiently coordinate Mg²⁺•ATP and is therefore incapable of chemistry. Here, using enhanced sampling molecular dynamics simulations, we demonstrate that structurally similar interactions between the Walker-A and Walker-B motifs, also mediated by …

Editorial: Pathogens, Pathobionts, And Autoimmunity, Linda A. Spatz, Gregg J. Silverman, Judith A. James

Publications and Research

No abstract provided.

During Natural Viewing, Neural Processing Of Visual Targets Continues Throughout Saccades, Atanas D. Stankov, Jonathan Touryan, Stephen Gordon, Anthony J. Ries, Jason Ki, Lucas C. Parra

Publications and Research

Relatively little is known about visual processing during free-viewing visual search in realistic dynamic environments. Free-viewing is characterized by frequent saccades. During saccades, visual processing is thought to be suppressed, yet we know that the presaccadic visual content can modulate postsaccadic processing. To better understand these processes in a realistic setting, we study here saccades and neural responses elicited by the appearance of visual targets in a realistic virtual environment. While subjects were being driven through a 3D virtual town, they were asked to discriminate between targets that appear on the road. Using a system identification approach, we separated overlapping …

Aurora Kinase A Inhibition Reverses The Warburg Effect And Elicits Unique Metabolic Vulnerabilities In Glioblastoma, Trang T. T. Nguyen, Enyuan Shang, Chang Shu, Sungsoo Kim, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Hee Won Yang, Hasan Orhan Akman, Catarina M. Quinzii, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N. Bruce, Peter Canoll, Markus D. Siegelin

Publications and Research

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was …

Threshold Concentration And Random Collision Determine The Growth Of The Huntingtin Inclusion From A Stable Core, Sen Pei, Theresa C. Swayne, Jeffrey F. Morris, Lesley Emtage

Publications and Research

The processes underlying formation and growth of unfolded protein inclusions are relevant to neurodegenerative diseases but poorly characterized in living cells. In S. cerevisiae, inclusions formed by mutant huntingtin (mHtt) have some characteristics of biomolecular condensates but the physical nature and growth mechanisms of inclusion bodies remain unclear. We have probed the relationship between concentration and inclusion growth in vivo and find that growth of mHtt inclusions in living cells is triggered at a cytoplasmic threshold concentration, while reduction in cytoplasmic mHtt causes inclusions to shrink. The growth rate is consistent with incorporation of new material through collision and coalescence. …

A Cross-Level Information Transmission Network Forhierarchical Omics Data Integration And Phenotypeprediction From A New Genotype, Di He, Lei Xie

Publications and Research

Motivation: An unsolved fundamental problem in biology is to predict phenotypes from a new genotype under environmental perturbations. The emergence of multiple omics data provides new opportunities but imposes great challenges in the predictive modeling of genotype-phenotype associations. Firstly, the high-dimensionality of genomics data and the lack of coherent labeled data often make the existing supervised learning techniques less successful. Secondly, it is challenging to integrate heterogeneous omics data from different resources. Finally,few works have explicitly modeled the information transmission from DNA to phenotype, which involves multiple intermediate molecular types. Higher-level features (e.g. gene expression) usually have stronger discriminative …

A New Function For Amyloid-Like Interactions: Cross-Beta Aggregates Of Adhesins Form Cell-To-Cell Bonds, Peter N. Lipke, Marion Mathelié-Guinlet, Albertus Viljoen, Yves F. Dufrêne

Publications and Research

Amyloid structures assemble through a repeating type of bonding called “cross-β”, in which identical sequences in many protein molecules form β-sheets that interdigitate through side chain interactions. We review the structural characteristics of such bonds. Single cell force microscopy (SCFM) shows that yeast expressing Als5 adhesin from Candida albicans demonstrate the empirical characteristics of cross-β interactions. These properties include affinity for amyloid-binding dyes, birefringence, critical concentration dependence, repeating structure, and inhibition by anti-amyloid agents. We present a model for how cross-β bonds form in trans between two adhering cells. These characteristics also apply to other fungal adhesins, so the mechanism …

Decoding The Roles Of Astrocytes And Hedgehog Signaling In Medulloblastoma, Terence Teixeira Duarte, Silvia Aparecida Teixeira, Luis Gonzalez-Reyes, Rui Manuel Reis

Publications and Research

The molecular evolution of medulloblastoma is more complex than previously imagined, as emerging evidence suggests that multiple interactions between the tumor cells and components of the tumor microenvironment (TME) are important for tumor promotion and progression. The identification of several molecular networks within the TME, which interact with tumoral cells, has provided new clues to understand the tumorigenic roles of many TME components as well as potential therapeutic targets. In this review, we discuss the most recent studies regarding the roles of astrocytes in supporting sonic hedgehog (SHH) subgroup medulloblastoma (MB) and provide an overview of MB progression through SHH …

Case 3847 – Simopithecus Oswaldi Andrews, 1916 (Currently Theropithecus Oswaldi; Mammalia, Primates, Cercopithecidae), Proposed Conservation By Reversal Of Precedence With Cynocephalus Atlanticus Thomas, 1884., Eric Delson, David M. Alba, Stephen R. Frost, Dagmawit Abebe Getahun, Christopher C. Gilbert

Publications and Research

The purpose of this application, under Articles 23.9.3 and 81.1 of the Code, is to conserve the usage of the species-group name Simopithecus oswaldi Andrews, 1916 by giving it precedence over its senior subjective synonym Cynocephalus atlanticus Thomas, 1884. Theropithecus is a common to dominant member of the extinct primate community across Africa after 4 million years ago (Jablonski & Frost, 2010) and often co-occurred with extinct humans (Hominini); fossils are also known rarely across Eurasia (Roberts et al., 2014). Most fossil samples are currently included in Theropithecus oswaldi (Andrews, 1916), which is often divided into chrono-geographic subspecies. Cynocephalus atlanticus …

Development Of An Online General Biology Open Educational Resource (Oer) Laboratory Manual, Dmitry Y. Brogun, Azure N. Faucette, Kristin Polizzotto, Farshad Tamari

Publications and Research

Currently, many academic institutions are using one or more variations of online modalities due to the COVID-19 pandemic, and science educators face a unique challenge with distance-learning laboratories. Many resources to engage students in virtual, interactive laboratory activities exist, but we found that high costs and/or overlooked content left gaps for several topics typically taught in a general, introductory biology course for undergraduate biology majors (e.g., organismal biology). Additionally, resources for an online lab must be identified and curated from multiple sources, requiring intense demands on the instructors’ time. To meet this need and to overcome the financial burden of …

Bcr Affinity Influences T-B Interactions And B Cell Development In Secondary Lymphoid Organs, Alec J. Wishnie, Tzippora Chwat-Edelstein, Mary Attaway, Bao Q. Vuong

Publications and Research

B cells produce high-affinity immunoglobulins (Igs), or antibodies, to eliminate foreign pathogens. Mature, naïve B cells expressing an antigen-specific cell surface Ig, or B cell receptor (BCR), are directed toward either an extrafollicular (EF) or germinal center (GC) response upon antigen binding. B cell interactions with CD4+ pre-T follicular helper (pre- Tfh) cells at the T-B border and effector Tfh cells in the B cell follicle and GC control B cell development in response to antigen. Here, we review recent studies demonstrating the role of B cell receptor (BCR) affinity in modulating T-B interactions and the subsequent differentiation of B …