bluuebunny/crossref_metadata_2025 huggingface dataset:
Inspecting the interaction between human immunodeficiency virus and the immune system through genetic turnover
Authors: Mazzolini Andrea , Mora Thierry , Walczak Aleksandra M.
Published: April 2023

Chronic infections of the human immunodeficiency virus (HIV) create a very complex coevolutionary process, where the virus tries to escape the continuously adapting host immune system. Quantitative details of this process are largely unknown and could help in disease treatment and vaccine development. Here we study a longitudinal dataset of ten HIV-infected people, where both the B-cell receptors and the virus are deeply sequenced. We focus on simple measures of turnover, which quantify how much the composition of the viral strains and the immune repertoire change between time points. At the single-patient level, the viral–host turnover rates do not show any statistically significant correlation, however, they correlate if one increases the amount of statistics by aggregating the information across patients. We identify an anti-correlation: large changes in the viral pool composition come with small changes in the B-cell receptor repertoire. This result seems to contradict the naïve expectation that when the virus mutates quickly, the immune repertoire needs to change to keep up. However, a simple model of antagonistically evolving populations can explain this signal. If it is sampled at intervals comparable with the sweep time, one population has had time to sweep while the second cannot start a counter-sweep, leading to the observed anti-correlation.

This article is part of the theme issue ‘Interdisciplinary approaches to predicting evolutionary biology’.
Epistasis decreases with increasing antibiotic pressure but not temperature
Authors: Ghenu Ana-Hermina , Amado André , Gordo Isabel , Bank Claudia
Published: April 2023

Predicting mutational effects is essential for the control of antibiotic resistance (ABR). Predictions are difficult when there are strong genotype-by-environment (G × E), gene-by-gene (G × G or epistatic) or gene-by-gene-by-environment (G × G × E) interactions. We quantified G × G × E effects in
Escherichia coli
across environmental gradients. We created intergenic fitness landscapes using gene knock-outs and single-nucleotide ABR mutations previously identified to vary in the extent of G × E effects in our environments of interest. Then, we measured competitive fitness across a complete combinatorial set of temperature and antibiotic dosage gradients. In this way, we assessed the predictability of 15 fitness landscapes across 12 different but related environments. We found G × G interactions and rugged fitness landscapes in the absence of antibiotic, but as antibiotic concentration increased, the fitness effects of ABR genotypes quickly overshadowed those of gene knock-outs, and the landscapes became smoother. Our work reiterates that some single mutants, like those conferring resistance or susceptibility to antibiotics, have consistent effects across genetic backgrounds in stressful environments. Thus, although epistasis may reduce the predictability of evolution in benign environments, evolution may be more predictable in adverse environments.

This article is part of the theme issue ‘Interdisciplinary approaches to predicting evolutionary biology’.
A high-throughput multiplex array for antigen-specific serology with automated analysis
Authors: Rosenberg A.F , Killian J.T. , Green T.J. , Akther J. , Hossain M.E. , Shang Q. , Qiu S. , Guang Y. , Randall T.D. , Lund F.E. , King R.G.
Published: April 2023

High-throughput customizable CBA automated script-based analysis

The utility of high-throughput systems to evaluate antigen-specific antibody (Ab) has been highlighted by the SARS-CoV-2 pandemic. Pathogen-specific Ab levels are often used to assess protection following vaccination and, in the case of novel pathogens, an indication of prior exposure. Several platforms exist to visualize antigen-specific Ab, however most are not quantitative and are difficult to scale for population level studies. Additionally, the sensitivity across platforms differs making direct comparisons between studies difficult. Cytometric bead arrays (CBA) are an attractive platform for antigen-specific Ab measurements as they can be used to assess Ab reactivity against several antigens and of several isotypes to be performed simultaneously. Additionally, CBAs exhibit high sensitivity and can be designed to provide quantitative measurements. Using commercially available particles, a biotin-Streptavidin bead loading strategy, and the inclusion of indirect standards, we describe a flexible system that can be modified to include a variety of antigens. Here we describe two arrays, focused on antigens derived from either β-coronaviruses or influenza virus. To support the high-throughput capacity of this system, we developed a suit of automated software tools, the CBA Toolbox, to process raw data into antigen-reactive IgM, IgA, and IgG concentrations. We describe quality control requirements, assay performance, and normalizations to accurately quantitate antigen-specific Ig.
Elevation and topography shape the diversity of mesoscale landscape-level woody plant species found in temperate evergreen forests
Authors: Watanabe Shuntaro , Maesako Yuri , Inada Tomoya
Published: April 2023

Plant species richness is influenced by complex interactions between biotic and abiotic factors that operate on different spatial scales. Since spatial scales vary continuously in nature, it is expected that multiple factors simultaneously affect species richness and composition at an intermediate spatial scale (i.e., the mesoscale landscape level). Previous studies have shown that local topography and elevation are important factors for shaping mesoscale landscape-level plant species richness; however, the relative importance of these factors has rarely been examined. Here, we used spatially explicit woody plant survey data to investigate the relative importance of topography, elevation, and disturbance at the mesoscale landscape level. We found that topography and elevation are important drivers of plant species richness and composition at the mesoscale landscape level and affect different components (i.e., the number of species and species composition, respectively). Our study also found that closely-related species coexisted along the elevational gradient, suggesting that niche partitioning among closely-related species is a fundamentally important feature of mesoscale species richness pattern. Furthermore, we found that specialization in a habitat of closely-related species can be established even within a limited environmental gradient. This suggests that biotic interactions among closely-related species may be an important factor driving habitat specialization, and biotic interactions may play an important role in shaping landscape-scale biodiversity patterns.
Physcomitrella SUN2 mediates MTOC association to the nuclear envelope and facilitates chromosome alignment during spindle assembly
Authors: Yoshida Mari W. , Oguri Noiri , Goshima Gohta
Published: April 2023

Plant cells lack centrosomes and instead utilise acentrosomal microtubule organising centres (MTOCs) to rapidly increase the number of microtubules at the onset of spindle assembly. Although several proteins required for MTOC formation have been identified, how the MTOC is positioned at the right place is not known. Here, we show that the inner nuclear membrane protein SUN2 is required for MTOC association with the nuclear envelope (NE) during mitotic prophase in the mossPhyscomitrium patens. In actively dividing protonemal cells, microtubules accumulate around the NE during prophase. In particular, regional MTOC is formed at the apical surface of the nucleus. However, microtubule accumulation around the NE was impaired and apical MTOCs were mislocalised insun2knockout (KO) cells. In addition, chromosome distribution in the nucleus was skewed, suggesting that SUN2 mediates the linking of microtubules with chromosomes. Upon nuclear envelope breakdown (NEBD), the mitotic spindle was assembled with mislocalised MTOC, which were a source of microtubules insun2KO plants. However, completion of chromosome alignment in the spindle was delayed; in severe cases, the chromosome was transiently detached from the spindle body. SUN2 tended to localise to the apical surface of the nucleus during prophase in a microtubule-dependent manner. Based on these results, we propose that SUN2 facilitates the attachment of microtubules to chromosomes during spindle assembly by linking them prior to NEBD. Furthermore, this study suggests that trans-NE microtubule-chromosome linking, a well-known function of SUN in animals and yeast, is conserved in plants.
Staphylococcus aureusbiofilm secreted factors cause mucosal damage, mast cell infiltration and goblet cell hyperplasia in a rat rhinosinusitis model
Authors: Houtak Ghais , Nepal Roshan , Bouras George , Shaghayegh Gohar , Bennett Catherine , Finnie John , Fenix Kevin , Psaltis Alkis James , Wormald Peter-John , Vreugde Sarah
Published: April 2023

Chronic Rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinus mucosa. Despite being a common health issue, the exact cause of CRS is yet to be understood. However, research suggests thatStaphylococcus aureus, particularly in the biofilm form, drives the disease. This study aimed to investigate the impact of long-term exposure to secreted factors ofStaphylococcus aureusbiofilm (SABSF), harvested from clinical isolates of non-CRS carriers and CRS patients, on the nasal mucosa in a rat model.

Wistar rats were randomised (n=5/group) to receive daily intranasal instillations of 40 μL (200 μg/μL) SABSF for 28 days or vehicle control withS. aureusisolated from the sinuses of a non-CRS carrier, a type 2 endotype CRS with nasal polyps (CRSwNP) patient, and a non-type 2 endotype CRS without nasal polyps (CRSsNP) patient. The sinonasal samples of the rats were then analysed through histopathology and transcriptome profiling.

The results showed that all three intervention groups displayed significant lymphocytic infiltration (p≤0.05). However, only the SABSF collected from the CRSwNP patient caused significant mucosal damage, mast cell infiltration, and goblet cell hyperplasia compared to the control. The transcriptomics results indicated that SABSF significantly enriched multiple inflammatory pathways and showed distinct transcriptional expression differences between the control group and the SABSF collected from CRS patients (p≤0.05). Additionally, the SABSF challenges induced the expression of IgA and IgG but not IgE.

In conclusion, thisin vivostudy indicates that long-term exposure to SABSF leads to an inflammatory response in the nasal mucosa with increased severity forS. aureusisolated from a CRSwNP patient. The findings of this study shed light on the role ofS. aureusin the development of CRS and could inform future research and treatment efforts.
Impact of pathogen genetics on clinical phenotypes in a population ofTalaromyces marneffeifrom Vietnam
Authors: Sephton-Clark Poppy , Nguyen Thu , Hoa Ngo Thi , Ashton Philip , van Doorn H. Rogier , Ly Vo Trieu , Le Thuy , Cuomo Christina A.
Published: April 2023

Talaromycosis, a severe and invasive fungal infection caused byTalaromyces marneffei, is difficult to treat and impacts those living in endemic regions of southeast Asia, India, and China. While 30% of infections result in mortality, our understanding of the genetic basis of pathogenesis for this fungus is limited. To address this, we apply population genomics and genome wide association study approaches to a cohort of 336T. marneffeiisolates collected from patients who enrolled in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial in Vietnam. We find that isolates from northern and southern Vietnam form two distinct geographical clades, with isolates from southern Vietnam associated with increased disease severity. Leveraging longitudinal isolates, we identify multiple instances of disease relapse linked to unrelated strains, highlighting the potential for multi-strain infections. In more frequent cases of persistent talaromycosis caused by the same strain, we identify variants arising over the course of patient infections that impact genes predicted to function in the regulation of gene expression and secondary metabolite production. By combining genetic variant data with patient metadata for all 336 isolates, we identify pathogen variants significantly associated with multiple clinical phenotypes. In addition, we identify genes and genomic regions under selection across both clades, highlighting loci undergoing rapid evolution, potentially in response to external pressures. With this combination of approaches, we identify links between pathogen genetics and patient outcomes and identify genomic regions that are altered duringT. marneffeiinfection, providing an initial view of how pathogen genetics affects disease outcomes.
Regulation of Human PINK1 ubiquitin kinase by Serine167, Serine228 and Cysteine412 phosphorylation
Authors: Waddell Andrew D. , Ojha Hina , Agarwal Shalini , Clarke Christopher J. , Terriente-Felix Ana , Zhou Houjiang , Kakade Poonam , Knebel Axel , Shaw Andrew M. , Gourlay Robert , Varghese Joby , Soares Renata F. , Toth Rachel , Macartney Thomas , Eyers Patrick A. , Morrice Nick , Bayliss Richard , Whitworth Alexander J. , Eyers Claire E. , Muqit Miratul M. K.
Published: April 2023

Loss-of-function mutations in the human PINK1 kinase (hPINK1) are causative of early-onset Parkinson’s disease (PD). Activation ofhPINK1 induces phosphorylated ubiquitin to initiate removal of damaged mitochondria by autophagy. Previously we solved the structure of the insect PINK1 orthologue,Tribolium castaneumPINK1, and showed that autophosphorylation of Ser205 was critical for ubiquitin interaction and phosphorylation (Kumar, Tamjar, Waddell et al., 2017). Here we report new findings on the regulation ofhPINK1 by phosphorylation. We reconstituteE. coliexpressedhPINK1 activityin vitroby direct incorporation of phosphoserine at the equivalent site Serine 228 (pSer228), providing direct evidence for a role for Ser228 phosphorylation inhPINK1 activation. Furthermore, using mass spectrometry, we identify six novel Ser/Thr autophosphorylation sites including regulatory Serine167 phosphorylation (pSer167), which in addition to pSer228 is required for ubiquitin recognition and phosphorylation. Strikingly, we also detect phosphorylation of a conserved Cysteine412 (pCys412) residue in thehPINK1 activation segment. Structural modelling suggests that pCys412 inhibits ubiquitin recognition and we demonstrate that mutation of Cys412 to Ala rendershPINK1 more active towards ubiquitin when expressed in human cells. These results outline new insights intohPINK1 activation by pSer167 and pSer228 and a novel inhibitory mechanism mediated by pCys412. These findings will aid in the development of small molecule activators ofhPINK1.
A survey of Rare Disease awareness among healthcare professionals and researchers in India
Authors: Vashishta Laxmikant , Bapat Purna , Bhattacharya Yashodhara , Choudhury Mohua Chakraborty , Chirmule Narendra , D’Costa Susan , Jindani Shilpa , Rao Manohar , Sheth Smritie
Published: April 2023

Rare diseases (RDs) are diseases that occur infrequently and affect a small fraction of the population. Although these diseases individually affect small number of people, together they affect 400 million people globally at any given time. In India, where resources are scarce, healthcare infrastructure and policy framework are focused on mitigating diseases that affect many people. Further, the level of RD awareness among healthcare professionals, researchers, and general public is considerably low. As a result, many cases of RDs remain unreported, undiagnosed, and untreated. To frame policies regarding RDs, it is crucial to understand the current level of RD awareness among healthcare professional and researchers, as they are key stakeholders in diagnosis, treatment, policy making, and drug development. We conducted an exploratory survey to understand the current level of RD awareness among healthcare professionals and researchers based on identification of an RD, time for diagnosis, treatment options, and relationship with family history and geographic location. We noted that our respondents have considerably low level of RD awareness. They correctly identified the importance of family history but failed to realize the association with geographic location. After presenting the survey findings, we have made recommendation to improve RD awareness in India. Our findings will be helpful to design awareness campaigns and frame relevant policies.
Arabidopsis lateral shoots display two distinct phases of growth angle control
Authors: De Angelis Martina , Kepinski Stefan
Published: April 2023

Shoot growth angle is a fundamental determinant of plant form. In their later development, lateral branches maintain gravitropic setpoint angles (GSAs) in which growth is set and maintained relative to gravity. The typically non-vertical GSAs are the product of an auxin-dependent antigravitropic offset that counteracts underlying gravitropic response in the branch (Roychoudhryet al., 2013). Here we describe an earlier phase of branch development in which the young lateral shoot grows rootward, independently of gravity, promoting a spreading growth habit. In normal development, this phase of growth is terminated with the onset of the GSA programme, with branches then growing upwards to assume their mature form. The biophysical basis of the early rootward phase of branch growth can be traced back to greater cell proliferation on the upper, adaxial side that upon expansion, drives asymmetric growth. Our data indicate that cytokinin is involved in this process and that the transcription factor TCP1 is an important regulator of lateral shoot adaxial identity and differential ad-abaxial cell proliferation.
Changes in Protein Turn-over rates Regulate Tryptophan and Glucosinolate Biosynthesis, IAA Transport and Photosynthesis inArabidopsisGrowth and Defense Transitions
Authors: Abukhalaf Mohammad , Proksch Carsten , Thieme Domenika , Ziegler Jörg , Hoehenwarter Wolfgang
Published: April 2023

An organism continuously experiences shifts in biological states necessitating extensive rearrangement of physiology and molecular order of the cell. Here we model transitions between optimal growth conditions (homeostasis), fully induced pattern triggered immunity (PTI) and back inArabidopsis thaliana, chronologically measuring changes in protein synthesis and degradation rates, transcript, protein and phytohormone abundance of 99 targets using qPCR and LC-MS parallel reaction monitoring (PRM). Temporally changing synthesis and degradation rates were primary determinants of abundance, next to changes in mRNA levels, of tryptophan, glucosinolate (GS) biosynthesis and photosynthesis associated (PAP) proteins particularly in the earlier establisher phases but also in fully induced PTI. While transcripts returned to growth levels 3 to 16 hours post elicitation, protein levels remained at fully induced PTI levels up to 16 hours into the transitory phase back to optimal growth. A notable exception were polar auxin transporters PIN3 and PIN7 levels which decreased in PTI but quickly returned to initial homeostasis levels after transition, although global auxin levels only decreased by 20%. Tryptophan, GS and JA biosynthesis proteins all increased in abundance in the wild type and themyc234mutant background linking induction of the tryptophan and GS biosynthesis pathways to flg22 treatment and PTI independent of MYC2 and homologs. PAPs abundance was depleted in fully induced PTI however not in themyc234mutant linking this active immune response to these bHLH transcription factors. FERREDOXIN-NADP(+)-OXIDOREDUCTASE (FNR1) synthesis rates decreased while its degradation rate increased in the earlier PTI establisher phase. FNR1 is the penultimate protein in the photosynthetic electron transfer chain and imparts electrons onto NADP+however in its absence electrons are used for oxygen photoreduction and H2O2production, an active defense compound. Thus FNR1 may be a molecular switch that switches photosystem activity between growth and defense under post-transcriptional control. Themyc234mutation generally led to delayed changes in transcript and protein abundance and also abolished IAA depletion. Protein turn-over rates of a set of PAPs were affected in the mutant suggesting a possible positive role of the transcription factors in controlling post-transcriptional regulatory processes in PTI induction.
The small mycobacterial ribosomal protein, bS22, modulates aminoglycoside accessibility to its 16S rRNA helix-44 binding site
Authors: Majumdar Soneya , Deep Ayush , Sharma Manjuli R. , Canestrari Jill , Stone Melissa , Smith Carol , Koripella Ravi K. , Keshavan Pooja , Banavali Nilesh K. , Wade Joseph T. , Gray Todd A. , Derbyshire Keith M. , Agrawal Rajendra K.
Published: April 2023

Treatment of tuberculosis continues to be challenging due to the widespread latent form of the disease and the emergence of antibiotic-resistant strains of the pathogen,Mycobacterium tuberculosis. Bacterial ribosomes are a common and effective target for antibiotics. Several second line anti-tuberculosis drugs, e.g. kanamycin, amikacin, and capreomycin, target ribosomal RNA to inhibit protein synthesis. However,M. tuberculosiscan acquire resistance to these drugs, emphasizing the need to identify new drug targets. Previous cryo-EM structures of theM. tuberculosisandM. smegmatisribosomes identified two novel ribosomal proteins, bS22 and bL37, in the vicinity of two crucial drug-binding sites: the mRNA-decoding center on the small (30S), and the peptidyl-transferase center on the large (50S) ribosomal subunits, respectively. The functional significance of these two small proteins is unknown. In this study, we observe that anM. smegmatisstrain lacking thebs22gene shows enhanced susceptibility to kanamycin compared to the wild-type strain. Cryo-EM structures of the ribosomes lacking bS22 in the presence and absence of kanamycin suggest a direct role of bS22 in modulating the 16S rRNA kanamycin-binding site. Our structures suggest that amino-acid residue Lys-16 of bS22 interacts directly with the phosphate backbone of helix 44 of 16S rRNA to influence the micro-configuration of the kanamycin-binding pocket. Our analysis shows that similar interactions occur between eukaryotic homologues of bS22, and their corresponding rRNAs, pointing to a common mechanism of aminoglycoside resistance in higher organisms.
Integrated Phenomics and Genomics reveals genetic loci associated with inflorescence growth inBrassica napus
Authors: Williams Kevin , Hepworth Jo , Nichols Bethany S , Corke Fiona , Woolfenden Hugh , Paajanen Pirita , Steuernagel Burkhard , Østergaard Lars , Morris Richard J , Doonan John H , Wells Rachel
Published: April 2023

A fundamental challenge to the production of climate-resilient crops is how to measure dynamic yield-relevant responses to the environment, such as growth rate, at a scale which informs mechanistic understanding and accelerates breeding. The timing, duration and architectural characteristics of inflorescence growth are crucial for optimising crop productivity and have been targets of selection during domestication. We report a robust and versatile procedure for computationally assessing environmentally-responsive flowering dynamics. In the oilseed crop,Brassica napus,there is wide variation in flowering response to winter cold (vernalization). We subjected a diverse set ofB. napusaccessions to different vernalization temperatures and monitored shoot responses using automated image acquisition. We developed methods to computationally infer multiple aspects of flowering from this dynamic data, enabling characterisation of speed, duration and peaks of inflorescence development across different crop types. We input these multiple traits to genome- and transcriptome-wide association studies, and identified potentially causative variation ina prioriphenology genes (includingEARLY FLOWERING3)for known traits and in uncharacterised genes for computed traits. These results could be used in marker assisted breeding to design new ideotypes for improved yield and better adaptation to changing climatic conditions.
The structure of the neurotoxin palytoxin determined by MicroED
Authors: Gillman Cody , Patel Khushboo , Unge Johan , Gonen Tamir
Published: April 2023

Palytoxin (PTX) is a potent neurotoxin found in marine animals that can cause serious symptoms such as muscle contractions, haemolysis of red blood cells and potassium leakage. Despite years of research, very little is known about the mechanism of PTX. However, recent advances in the field of cryoEM, specifically the use of microcrystal electron diffraction (MicroED), have allowed us to determine the structure of PTX. It was discovered that PTX folds into a hairpin motif and is able to bind to the extracellular gate of Na,K-ATPase, which is responsible for maintaining the electrochemical gradient across the plasma membrane. These findings, along with molecular docking simulations, have provided important insights into the mechanism of PTX and can potentially aid in the development of molecular agents for treating cases of PTX exposure.
DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum
Authors: Bonnell Victoria A. , Zhang Yuning , Brown Alan S. , Horton John , Josling Gabrielle A. , Chiu Tsu-Pei , Rohs Remo , Mahony Shaun , Gordân Raluca , Llinás Manuel
Published: April 2023

Development of the human malaria parasite,Plasmodium falciparum,is regulated by a limited number of sequence-specific transcription factors (TFs). However, the mechanisms by which these TFs recognize genome-wide binding sites is still largely unknown. To address TF specificity, we investigated the binding of two TF subsets that either bind CACACA or GTGCAC DNA sequence motifs and further characterized PfAP2-G and PfAP2-EXP which bind unique DNA motifs (GTAC and TGCATGCA). We interrogated the impact of DNA sequence and chromatin context onP. falciparumTF binding by integrating high-throughputin vitroandin vivobinding assays, DNA shape predictions, epigenetic post-translational modifications, and chromatin accessibility. We determined that DNA sequence context minimally impacts binding site selection for CACACA-binding TFs, while chromatin accessibility, epigenetic patterns, co-factor recruitment, and dimerization contribute to differential binding. In contrast, GTGCAC-binding TFs prefer different DNA sequence context in addition to chromatin dynamics. Finally, we find that TFs that preferentially bind divergent DNA motifs may bind overlapping genomic regionsin vivodue to low-affinity binding to other sequence motifs. Our results demonstrate that TF binding site selection relies on a combination of DNA sequence and chromatin features, thereby contributing to the complexity ofP. falciparumgene regulatory mechanisms.

Key Points

Sequence and chromatin context determine differential DNA-binding specificity ofP. falciparumTFs

TFs with paralogous DNA-binding domains inP. falciparumare not functionally redundant

TFs with differing sequence-specificity can co-occupy sites through low-affinity DNA interactions
A broad-spectrum α-glucosidase of glycoside hydrolase family 13 fromMarinovumsp., a member of theRoseobacterclade
Authors: Li Jinling , Mui Janice W.-Y. , da Silva Bruna M. , Pires Douglas E.V. , Ascher David B. , Soler Niccolay Madiedo , Goddard-Borger Ethan D. , Williams Spencer J.
Published: April 2023

Glycoside hydrolases (GHs) are a diverse group of enzymes that catalyze the hydrolysis of glycosidic bonds. The Carbohydrate-Active enZymes (CAZy) classification organizes GHs into families based on sequence data and function, with fewer than 1% of the predicted proteins characterized biochemically. Consideration of genomic context can provide clues to infer possible enzyme activities for proteins of unknown function. We used the MultiGeneBLAST tool to discover a gene cluster inMarinovumsp., a member of the marineRoseobacterclade, that encodes homologues of enzymes belonging to the sulfoquinovose monooxygenase pathway for sulfosugar catabolism. This cluster lacks a gene encoding a classical family GH31 sulfoquinovosidase candidate, but which instead includes an uncharacterized family GH13 protein (MsGH13) that we hypothesized could be a non-classical sulfoquinovosidase. Surprisingly, recombinantMsGH13 lacks sulfoquinovosidase activity and is a broad spectrum α-glucosidase that is active on a diverse array of α-linked disaccharides, including: maltose, sucrose, nigerose, trehalose, isomaltose, and kojibiose. Using AlphaFold, a 3D model for theMsGH13 enzyme was constructed that predicted its active site shared close similarity with an α-glucosidase fromHalomonassp. H11 of the same GH13 subfamily that shows narrower substrate specificity.
Deep Learning for Flexible and Site-Specific Protein Docking and Design
Authors: McPartlon Matt , Xu Jinbo
Published: April 2023

Protein complexes are vital to many biological processes and their understanding can lead to the development of new drugs and therapies. Although the structure of individual protein chains can now be predicted with high accuracy, determining the three-dimensional structure of a complex remains a challenge. Protein docking, the task of computationally determining the structure of a protein complex given the unbound structures of its components (and optionally binding site information), provides a way to predict protein complex structure. Traditional docking methods rely on empirical scoring functions and rigid body simulations to predict the binding poses of two or more proteins. However, they often make unrealistic assumptions about input structures, and are not effective at accommodating conformational flexibility or binding site information. In this work, we present DockGPT (Generative Protein Transformer for Docking), an end-to-end deep learning method for flexible and site-specific protein docking that allows conformational flexibility and can effectively make use of binding site information. Tested on multiple benchmarks with unbound and predicted monomer structures as input, we significantly outperform existing methods in both accuracy and running time. Our performance is especially pronounced for antibody-antigen complexes, where we predict binding poses with high accuracy even in the absence of binding site information. Finally, we highlight our method’s generality by extending it to simultaneously dock and co-design the sequence and structure of antibody complementarity determining regions targeting a specified epitope.
Motility-Induced Phase Separation Mediated by Bacterial Quorum Sensing
Authors: Ridgway Wesley J. M. , Dalwadi Mohit P. , Pearce Philip , Chapman S. Jonathan
Published: April 2023

We study motility-induced phase separation (MIPS) in living active matter, in which cells interact through chemical signalling, or quorum sensing. In contrast to previous theories of MIPS, our multiscale continuum model accounts explicitly for genetic regulation of signal production and motility. Through analysis and simulations, we derive a new criterion for the onset of MIPS that depends on features of the genetic network. Furthermore, we identify and characterise a new type of oscillatory instability that occurs when gene regulation inside cells promotes motility in higher signal concentrations.
Identification and prediction of G-quadruplex RNA-binding proteins with roles in transcription and phase separation
Authors: Luige Johanna , Armaos Alexandros , Tartaglia Gian Gaetano , Vang Ørom Ulf Andersson
Published: April 2023

RNA-binding proteins are central for many biological processes and their large-scale identification has demonstrated a broad range of functions. RNA G-quadruplexes are important regulatory elements occurring in both coding and non-coding transcripts, yet our knowledge of their structure-based interactions is limited. Here starting from theoretical prediictions, we show experimentally that a large number of chromatin-binding proteins bind to RNA G-quadruplexes and we classify these based on their RNA G-quadruplex-binding potential. Combining experimental identification of nuclear RNA G-quadruplex-binding proteins with computational analysis, we create a prediction tool that can assign probability score for a protein that it binds RNA G-quadruplexes. We show that predicted G-quadruplex RNA-binding proteins exhibit high degree of protein disorder and hydrophilicity, and suggest involvement in both transcription and phase-separation into membrane-less organelles, particularly the nucleolus. Finally, we present this tool as a web application for estimating RNA G4-binding propensity for proteins of interest athttp://service.tartaglialab.com/new_submission/clever_G4_classifier.
The carboxyl-terminal sequence of PUMA binds to both anti-apoptotic proteins and membranes
Authors: Pemberton James M. , Nguyen Dang , Osterlund Elizabeth J. , Schormann Wiebke , Pogmore Justin P. , Hirmiz Nehad , Leber Brian , Andrews David W.
Published: April 2023

Anti-apoptotic proteins such as BCL-XLpromote cell survival by sequestering pro-apoptotic BCL-2 family members, an activity that frequently contributes to tumorigenesis. Thus, the development of small-molecule inhibitors for anti-apoptotic proteins, termed BH3-mimetics, is revolutionizing how we treat cancer. BH3 mimetics kill cells by displacing sequestered pro-apoptotic proteins to initiate tumor-cell death. Recent evidence has demonstrated that in live cells the BH3-only proteins PUMA and BIM resist displacement by BH3-mimetics, while others like tBID do not. Analysis of the molecular mechanism by which PUMA resists BH3-mimetic mediated displacement from full-length anti-apoptotic proteins (BCL-XL, BCL-2, BCL-W and MCL-1) reveals that both the BH3-motif and a novel binding site within the carboxyl-terminal sequence (CTS) of PUMA contribute to binding. Together these sequences bind to anti-apoptotic proteins, which effectively “double-bolt locks” the proteins to resist BH3-mimetic displacement. The pro-apoptotic protein BIM has also been shown to double-bolt lock to anti-apoptotic proteins however, the novel binding sequence in PUMA is unrelated to that in the CTS of BIM and functions independent of PUMA binding to membranes. Moreover, contrary to previous reports, we find that when exogenously expressed, the CTS of PUMA directs the protein primarily to the endoplasmic reticulum (ER) rather than mitochondria and that residues I175 and P180 within the CTS are required for both ER localization and BH3-mimetic resistance. Understanding how PUMA resists BH3-mimetic displacement will be useful in designing more efficacious small-molecule inhibitors of anti-apoptotic BCL-2 proteins.
Reviewing the critical challenges that influence the adoption of the e-learning system in higher educational institutions in the era of the COVID-19 pandemic
Authors: Abdelfattah Fadi , Al Alawi Abrar Mohammed , Dahleez Khalid Abed , El Saleh Ayman
Published: April 2023

Purpose

This paper aims to review the critical challenges and factors influencing the successful adoption of electronic learning (e-learning) systems in higher educational institutions before and during the current propagation of the coronavirus disease 2019 (COVID-19) pandemic.

Design/methodology/approach

This study undertook a literature review concerning the in-depth revision of previous studies published in 2020 and 2021. A total of 100 out of 170 selected research papers were adopted to identify and recognise the factors restricting the application of e-learning systems.

Findings

The findings determine and illuminate the most challenging factors that impact the successful application of online learning, particularly during the wide propagation of the COVID-19 pandemic. The review of the literature provides evidence that technological, organisational and behavioural issues constitute significant drivers that frontier the facilitation of the e-learning process in higher educational institutions.

Practical implications

The current paper suggests a guide for managers and scholars in educational institutions and acts as a roadmap for practitioners and academics in the educational field and policymakers as this research spotlights the significant factors challenging the e-learning process before and during the pandemic crisis.

Originality/value

The provided in-depth literature review in this research will support the researchers and system designers with a comprehensive review and recent studies conducted before and during the COVID-19 pandemic considering the factors limiting the e-learning process. This paper formulates a valuable contribution to the body of knowledge that will assist the stakeholders in the higher educational institutions' context.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/OIR-02-2022-0085.
The funding effect on citation and social attention: the UN Sustainable Development Goals (SDGs) as a case study
Authors: Dorta-González Pablo , Dorta-González María Isabel
Published: April 2023

Purpose

Academic citation and social attention measure different dimensions in the impact of research results. The authors quantify the contribution of funding to both indicators considering the differences attributable to the research field and access type.

Design/methodology/approach

Citation and social attention accumulated until the year 2021 of more than 367 thousand research articles published in the year 2018 are studied. The authors consider funding acknowledgments (FAs) in the research articles. The data source is Dimensions, and the units of study are research articles in the United Nation (UN) Sustainable Development Goals (SDGs).

Findings

Most cited goals by researchers do not coincide with those that arouse greater social attention. A small proportion of articles accumulates a large part of the citations and most of the social attention. Both citation and social attention grow with funding. Thus, funded research has a greater probability of being cited in academic articles and mentioned in social media. Funded research receives on average two to three times more citations and 2.5 to 4.5 times more social attention than unfunded research. Moreover, the open access (OA) modalities gold and hybrid have the greatest advantages in citation and social attention due to funding.

Research limitations/implications

Specific topics were studied in a specific period. Studying other topics and/or different time periods might result in different findings.

Practical implications

When funding to publish in open or hybrid access journals is not available, it is advisable to self-archiving the pre-print or post-print version in a freely accessible repository.

Social implications

Although cautiously, it is also advisable to consider the social impact of the research to complement the scientific impact in the evaluation of the research.

Originality/value

The joint evaluation of the effect of both funding and OA on social attention.
How can people benefit, and who benefits most, from using socialisation‐oriented social media at work? An affordance perspective
Authors: Wang Bin , Liu Yukun , Qian Jing , Parker Sharon K.
Published: April 2023

Past research has predominantly regarded (private) socialisation‐oriented social media (SoSM) use at work as a counterproductive behaviour and has thus focussed more on its dark side. However, given the prevalence of social media in today's work life and the various affordances this technology can have, social media might have important bright sides. In this research, drawing on the affordance perspective, we propose that the day‐to‐day use of SoSM at work is positively associated with perceptions of social connectedness, which is further positively associated with life satisfaction and task performance. We examined our hypotheses using an experience sampling study of 134 full‐time employees in China across 10 consecutive workdays. The results of multilevel modelling showed that, as expected, daily SoSM use at work related positively with employees' perceptions of social connectedness, which in turn predicted their daily life satisfaction and daily task performance. We also found that the relationship between daily SoSM use at work and perceived social connectedness was stronger for employees with higher, rather than lower, perceived workloads. We suggest this moderating effect occurs because social media is an efficient medium, providing greater affordances, through which busy workers can meet their belongingness needs. Overall, our study sheds light on the previously less‐studied positive effects of social media use at work.
The effect of sperm DNA fragmentation on ICSI outcomes depending on oocyte quality
Authors: Braga Daniela Paes Almeida Ferreira , Setti Amanda , Morishima Christina , Provenza Rodrigo R. , Iaconelli Assumpto , Borges Edson
Published: April 2023

Background

Sperm deoxyribonucleic acid (DNA) fragmentation is commonly encountered in spermatozoa, and the oocyte assumes responsibility for repairing sperm DNA fragmentation during the oocyte–embryo transition.

Objectives

This study aimed to investigate whether the effect of sperm DNA fragmentation on intracytoplasmic sperm injection outcomes depends on the incidence of oocyte dimorphisms.

Materials and methods

For the present cohort, 2942 fertilized oocytes from 525 patients submitted to intracytoplasmic sperm injection cycles were assessed. The present study was conducted in a private in vitro fertilization center affiliated to a university from June 2016 to July 2019. Semen samples were divided into the following two groups depending on the sperm DNA fragmentation index: a low fragmentation index group (<30% sperm DNA fragmentation, n = 1468) and a high fragmentation index group (≥30% sperm DNA fragmentation, n = 486). In addition, mature oocytes were examined before sperm injection, and intracytoplasmic and extracytoplasmic defects were recorded. The effect of the sperm DNA fragmentation index on laboratory and clinical intracytoplasmic sperm injection outcomes (depending on the presence of oocyte defects) was evaluated.

Results

Significant increases in the rates of fertilization, high‐quality embryo, implantation, and pregnancy were noted for cycles with <30% sperm DNA fragmentation than cycles with ≥30% sperm DNA fragmentation (regardless of the presence of oocyte dimorphisms). The presence of dimorphisms significantly impacted laboratory and clinical outcomes. The lowest fertilization and high‐quality embryo rates were observed when a high sperm DNA fragmentation index was associated with the presence of dark cytoplasm, vacuoles, resistant membrane, and non‐resistant membrane. The lowest implantation and pregnancy rates were observed when a high sperm DNA fragmentation index was associated with the presence of vacuoles, defective perivitelline space, and fragmented polar body. The effect of sperm DNA fragmentation on miscarriage rates was significantly influenced by the presence of centrally located cytoplasmic granulation, a defective perivitelline space and non‐resistant membrane.

Conclusion

A high sperm DNA fragmentation index increases the likelihood of miscarriage in intracytoplasmic sperm injection cycles, an effect that may potentially be magnified by the presence of oocyte dysmorphisms.
Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment‐free remission period after imatinib discontinuation: Results of the French Nilo post‐STIM study
Authors: Dulucq Stéphanie , Rigal‐Huguet Françoise , Nicolini Franck E. , Cony‐Makhoul Pascale , Escoffre‐Barbe Martine , Gardembas Martine , Legros Laurence , Rousselot Philippe , Liu Jixing , Rea Delphine , De Mas Véronique , Hayette Sandrine , Raynaud Sophie , Lacoste‐Roussillon Caroline , Robbesyn Fanny , Klein Emilie , Morisset Stéphane , Mahon François‐Xavier , Etienne Gabriel
Published: April 2023

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first‐line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic‐phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%–83.7%) and 42.1% (95% CI: 25%–71%) respectively (NCT #01774630).
Impacts of climate change on the distribution of riverine endemic fish species in Iran, a biodiversity hotspot region
Authors: Makki Toktam , Mostafavi Hossein , Matkan Ali Akbar , Aghighi Hossein , Valavi Roozbeh , Chee Yung En , Teimori Azad
Published: April 2023

Iran is one of the world's fish biodiversity hotspots. Most riverine fish species in this country are currently under threat by human activities. In addition to those threats, climate change is expected to alter rainfall and temperature regimes, imposing further limitations, particularly to endemic fishes. Therefore, understanding how these species respond to climate change is an important issue in the conservation of Iranian freshwater biodiversity.

This study aimed to predict the potential distribution of 16 endemic fish species under two climate change scenarios (i.e., RCP 4.5 and RCP 8.5) in river habitats of Iran in the 2050s and the 2080s. The analysis is conducted using the MaxEnt model. Seven environmental variables were used for modelling: maximum width, elevation, river slope, the basins occupied by the target species, average annual precipitation, annual mean temperature, and the temperature difference between the coldest and hottest months of the year .

The validation of the model for each species showed that AUC (area under the ROC curve) scores range from 0.87 to 0.99. Under optimistic (RCP 4.5) and pessimistic (RCP 8.5) scenarios in the 2050s and the 2080s, species will face four different outcomes to their habitat range: reduction (three species), expansion (five species), reduction and expansion (seven species) and no change (one species).

It is concluded that most species that are unique in their geographical area will face serious challenges from climate change. Delineating species range changes under climate change scenarios can help prioritise conservation measures for these valuable species. Considering our results, the translocation of species to new locations also should be investigated.