bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging gene co-regulation to identify gene sets enriched for disease heritability
Authors: Siewert-Rocks Katherine M. , Kim Samuel S. , Yao Douglas W. , Shi Huwenbo , Price Alkes L.
Published: July 2021

Identifying gene sets that are associated to disease can provide valuable biological knowledge, but a fundamental challenge of gene set analyses of GWAS data is linking disease-associated SNPs to genes. Transcriptome-wide association studies (TWAS) can be used to detect associations between the genetically predicted expression of a gene and disease risk, thus implicating candidate disease genes. However, causal disease genes at TWAS-associated loci generally remain unknown due to gene co-regulation, which leads to correlations across genes in predicted expression. We developed a new method, gene co-regulation score (GCSC) regression, to identify gene sets that are enriched for disease heritability explained by the predicted expression of causal disease genes in the gene set. GCSC regresses TWAS chi-square statistics on gene co-regulation scores reflecting correlations in predicted gene expression; GCSC determines that a gene set is enriched for disease heritability if genes with high co-regulation to the gene set have higher TWAS chi-square statistics than genes with low co-regulation to the gene set, beyond what is expected based on co-regulation to all genes. We verified via simulations that GCSC is well-calibrated, and well-powered to identify gene sets that are enriched for disease heritability explained by predicted expression. We applied GCSC to gene expression data from GTEx (48 tissues) and GWAS summary statistics for 43 independent diseases and complex traits (average N =344K), analyzing a broad set of biological pathways and specifically expressed gene sets. We identified many enriched gene sets, recapitulating known biology. For Alzheimer’s disease, we detected evidence of an immune basis, and specifically a role for antigen presentation, in analyses of both biological pathways and specifically expressed gene sets. Our results highlight the advantages of leveraging gene co-regulation within the TWAS framework to identify gene sets associated to disease.
Breakthrough Symptomatic COVID-19 Infections Leading to Long Covid: Report from Long Covid Facebook Group Poll
Authors: Massey Daisy , Berrent Diana , Krumholz Harlan
Published: July 2021

Vaccines have been shown to be extremely effective in preventing COVID-19 hospitalizations and deaths. However, a question remains whether vaccine breakthrough cases can still lead to Post-Acute Sequelae of SARS-CoV-2 (PASC), also known as Long Covid. To address this question, the Survivor Corps group, a grassroots COVID-19 organization focused on patient support and research, posted a poll to its 169,900 members that asked about breakthrough cases, Long Covid, and hospitalizations. 1,949 people who self-report being fully vaccinated have responded to date. While robust data are needed in a larger, unbiased sample to extrapolate rates to the population, we analyzed the results of this public poll to determine what people were reporting regarding Long Covid after breakthrough infection and to prompt discussion of how breakthrough cases are measured. The poll was posted in the Survivor Corps Facebook group (∼169,900 members). Of the 1,949 participants who responded to the poll, 44 reported a symptomatic breakthrough case and 24 of those reported that the case led to symptoms of Long Covid. 1 of these 24 cases was reported to have led to hospitalization in addition to Long Covid.
Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping
Authors: Bustos Carrillo Fausto Andres , Mercado Brenda Lopez , Monterrey Jairo Carey , Collado Damaris , Saborio Saira , Miranda Tatiana , Barilla Carlos , Ojeda Sergio , Sanchez Nery , Plazaola Miguel , Laguna Harold Suazo , Elizondo Douglas , Arguello Sonia , Gajewski Anna M. , Maier Hannah E. , Latta Krista , Carlson Bradley , Coloma Josefina , Katzelnick Leah , Sturrock Hugh , Balmaseda Angel , Kuan Guillermina , Gordon Aubree , Harris Eva
Published: July 2021

Accurate tracing of epidemic spread over space enables effective control measures. We examined three metrics of infection and disease in a pediatric cohort (N ≈ 3,000) over two chikungunya and one Zika epidemic, and in a household cohort (N=1,793) over one COVID-19 epidemic in Managua, Nicaragua. We compared spatial incidence rates (cases/total population), infection risks (infections/total population), and disease risks (cases/infected population). We used generalized additive and mixed-effects models, Kulldorf’s spatial scan statistic, and intracluster correlation coefficients. Across different analyses and all epidemics, incidence rates considerably underestimated infection and disease risks, producing large and spatially non-uniform biases distinct from biases due to incomplete case ascertainment. Infection and disease risks exhibited distinct spatial patterns, and incidence clusters inconsistently identified areas of either risk. While incidence rates are commonly used to infer infection and disease risk in a population, we find that this can induce substantial biases and adversely impact policies to control epidemics.

Article summary line

Inferring measures of spatial risk from case-only data can substantially bias estimates, thereby weakening and potentially misdirecting measures needed to control an epidemic.
Neuron-Glia Signaling Regulates the Onset of the Antidepressant Response
Authors: Yao Vicky , Aly Ammar , Kalik Salina , Gresack Jodi , Wang Wei , Handler Annie , Schaefer Anne , Troyanskaya Olga , Greengard Paul , Chottekalapanda Revathy U.
Published: July 2021

Commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) take weeks to achieve therapeutic benefits1, 2. The underlying mechanisms of why antidepressants take weeks or months to reverse depressed mood are not understood. Using a single cell sequencing approach, we analyzed gene expression changes in mice subjected to stress-induced depression and determined their temporal response to antidepressant treatment in the cerebral cortex. We discovered that both glial and neuronal cell populations elicit gene expression changes in response to stress, and that these changes are reversed upon treatment with fluoxetine (Prozac), a widely prescribed selective serotonin reuptake inhibitor (SSRI). Upon reproducing the molecular signaling events regulated by fluoxetine3 in a cortical culture system, we found that these transcriptional changes are serotonin-dependent, require reciprocal neuron-glia communication, and involve temporally-specified sequences of autoregulation and cross-regulation between FGF2 and BDNF signaling pathways. Briefly, stimulation of Fgf2 synthesis and signaling directly regulates Bdnf synthesis and secretion cell-non-autonomously requiring neuron-glia interactions, which then activates neuronal BDNF-TrkB signaling to drive longer-term neuronal adaptations4–6 leading to improved mood. Our studies highlight temporal and cell type specific mechanisms promoting the onset of the antidepressant response, that we propose could offer novel avenues for mitigating delayed onset of antidepressant therapies.
Mathematical constraints on FST: multiallelic markers in arbitrarily many populations
Authors: Alcala Nicolas , Rosenberg Noah A.
Published: July 2021

Interpretations of values of the FST measure of genetic differentiation rely on an understanding of its mathematical constraints. Previously, it has been shown that FST values computed from a biallelic locus in a set of multiple populations and FST values computed from a multiallelic locus in a pair of populations are mathematically constrained as a function of the frequency of the allele that is most frequent across populations. We generalize from these cases to report here the mathematical constraint on FST given the frequency M of the most frequent allele at a multiallelic locus in a set of multiple populations. Using coalescent simulations of an island model of migration with an infinitely-many-alleles mutation model, we argue that the joint distribution of FST and M helps in disentangling the separate influences of mutation and migration on FST. Finally, we show that our results explain a puzzling pattern of microsatellite differentiation: the lower FST in an interspecific comparison between humans and chimpanzees than in the comparison of chimpanzee populations. We discuss the implications of our results for the use of FST.
Delineating Medical Education: Bibliometric Research Approach(es)
Authors: Maggio Lauren A. , Ninkov Anton , Frank Jason R. , Costello Joseph A. , Artino Anthony R.
Published: July 2021

Background

The field of medical education remains poorly delineated such that there is no broad consensus of the articles and journals that comprise “the field.” This lack of consensus has implications for conducting bibliometric studies and other research designs (e.g., systematic reviews); it also challenges the field to compare citation scores in the field and across others and for an individual to identify themselves as “a medical education researcher.” Other fields have utilized bibliometric field delineation, which is the assigning of articles or journals to a certain field in an effort to define that field.

Process

In this Research Approach, three bibliometric field delineation approaches -- information retrieval, core journals, and journal co-citation -- are introduced. For each approach, the authors describe their attempt to apply it in the medical education context and identify related strengths and weaknesses. Based on co-citation, the authors propose the Medical Education Journal List 24 (MEJ-24), as a starting point for delineating medical education and invite the community to collaborate on improving and potentially expanding this list.

Pearls

As a research approach, field delineation is complicated, and there is no clear best way to delineate the field of medical education. However, recent advances in information and computer science provide potentially more fruitful approaches to deal with the complexity of the field. When considering these emerging approaches, researchers should consider collaborating with bibliometricians.

Bibliometric approaches rely on available metadata for articles and journals, which necessitates that researchers examine the metadata prior to analysis to understand its strengths and weaknesses, and to assess how this might affect their data interpretation. While using bibliometric approaches for field delineation is valuable, it is important to remember that these techniques are only as good as the research team’s interpretation of the data, which suggests that an expanded research approach is needed to better delineate medical education, an approach that includes active discussion within the medical education community.
Low dose rate γ-irradiation protects Drosophila melanogaster chromosomes from double strand breaks and telomere fusions by modulating the expression of the esi-RNA biogenesis factor Loquacious
Authors: Porrazzo A. , Cipressa F. , De Gregorio A. , De Pittà C. , Sales G. , Ciapponi L. , Morciano P. , Esposito G. , Tabocchini M.A. , Cenci G.
Published: July 2021

It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute γ-irradiation, is significantly reduced when flies are previously exposed to a protracted dose of 0.4Gy delivered at a dose rate of 2.5mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TF frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and unveils unprecedented epigenetic routes involved in radioresistance.
Transcriptomic Analysis of Human Sensory Neurons in Painful Diabetic Neuropathy Reveals Inflammation and Neuronal Loss
Authors: Hall Bradford E. , Macdonald Emma , Cassidy Margaret , Yun Sijung , Sapio Matthew R. , Ray Pradipta , Doty Megan , Nara Pranavi , Burton Michael D. , Shiers Stephanie , Ray-Chaudhury Abhik , Mannes Andrew J. , Price Theodore J. , Iadarola Michael J. , Kulkarni Ashok B.
Published: July 2021

Pathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as ‘sharp’ and ‘burning’ and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain. DPN occurs in distal extremities resulting in the characteristic “glove and stocking” pattern. Accordingly, the L4 and L5 DRGs, which contain the perikarya of primary afferent neurons innervating the foot, were analyzed from five DPN patients and compared with seven controls. Transcriptom e analyses identified 844 differentially expressed genes. We observed increases in levels of inflammation-associated genes from macrophages in DPN patients that may contribute to increased pain hypersensitivity and, conversely, there were frequent decreases in neuronally-related genes. The elevated inflammatory gene profile and the accompanying downregulation of multiple neuronal genes provide new insights into intraganglionic pathology and mechanisms causing neuropathic pain in DPN patients with T2DM.
Accelerated epigenetic aging and inflammatory/immunological profile (ipAGE) in patients with chronic kidney disease
Authors: Yusipov Igor , Kondakova Elena , Kalyakulina Alena , Krivonosov Mikhail , Lobanova Nadezhda , Bacalini Maria Giulia , Franceschi Claudio , Vedunova Maria , Ivanchenko Mikhail
Published: July 2021

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). This failure can be related to a phenotype of accelerated aging. In this work we considered 76 subjects with end-stage renal disease (ESRD) and 83 healthy controls. We evaluated two measures that can be informative of the rate of aging, i.e. whole blood DNA methylation using the Illumina Infinium EPIC array and plasma levels of a selection of inflammatory/immunological proteins using Multiplex Immunoassays. We demonstrated accelerated aging in terms of the most common epigenetic age estimators in CKD patients. We developed a new predictor of age based on inflammatory/immunological profile (ipAGE) and confirmed age acceleration in CKD patients. Finally, we evaluated the relationship between epigenetic age predictors and ipAGE and further identified the inflammatory/immunological biomarkers differentially expressed between cases and controls. In summary, our data show an accelerated aging phenotype in CKD patients sustained by inflammatory processes.
Respiratory Viral Sequencing Panel identifies SARS-CoV-2 variants, transmission and other co-circulating viruses in Georgia, USA: A Diagnostic and Epidemiologic Tool for Mass Surveillance in COVID-19 Pandemic
Authors: Sahajpal Nikhil S , Mondal Ashis K , Njau Allan , Petty Zachary , Chen Jiani , Ananth Sudha , Ahluwalia Pankaj , Williams Colin , Ross Ted M , Chaubey Alka , DeSantis Grace , Schroth Gary P. , Bahl Justin , Kolhe Ravindra
Published: July 2021

Background

In the current phase of COVID-19 pandemic, we are facing two serious public health challenges that include deficits in SARS-CoV-2 variant monitoring, and neglect of other co-circulating respiratory viruses. Additionally, accurate assessment of the evolution, extent and dynamics of the outbreak are required to understand the transmission of the virus amongst seemingly unrelated cases and provide critical epidemiological information. To address these challenges, we evaluated a new high-throughput next-generation sequencing (NGS), respiratory viral panel (RVP) that includes 40 viral pathogens with the aim of analyzing viral subtypes, mutational variants of SARS-CoV-2, model to understand the spread of the virus in the state of Georgia, USA, and to assess other circulating viruses in the same population.

Methods

This study evaluated a total of 522 samples that included 483 patient samples and 42 synthetic positive control material. The performance metrics were calculated for both clinical and reference control samples by comparing detection results with the RT-PCR assay. The limit of detection (LoD) studies were conducted as per the FDA guidelines. Inference and visualization of the phylogeny of the SARS-CoV-2 sequences were performed through the Nextstrain Command-Line Interface (CLI) tool, utilizing the associated augur and auspice toolkits.

Results

The performance metrics calculated using both the clinical samples and the reference controls revealed a PPA, NPA and accuracy of 95.98%, 85.96% and 94.4%, respectively. The LoD was determined to be 10 copies/ml with all 25 replicates detected across two different runs. The clade for pangolin lineage B that contains certain distant variants, including P4715L in ORF1ab, Q57H in ORF 3a and, S84L in ORF8 covarying with the D614G spike protein mutation were the most prevalent, early in the pandemic, in Georgia, USA. In our analysis, isolates from the same county formed paraphyletic groups, which indicated virus transmission between counties.

Conclusion

The study demonstrates the clinical and public health utility of the NGS-RVP to identify novel variants that can provide actionable information to prevent or mitigate emerging viral threats, models that provide insights into viral transmission patterns and predict transmission/ resurgence of regional outbreaks and provide critical information on co-circulating respiratory viruses that might be independent factors contributing to the global disease burden.
Trial-wise exposure to visual appetitive cues increases physiological arousal but not temporal discounting
Authors: Knauth Kilian , Peters Jan
Published: July 2021

Humans and many animals devalue future rewards as a function of time (temporal discounting). Increased discounting has been linked to various psychiatric conditions, including substance-use-disorders, behavioral addictions and obesity. Despite its high intra-individual stability, temporal discounting is partly under contextual control. One prominent manipulation that has been linked to increases in discounting is the exposure to highly arousing appetitive cues. However, results from trial-wise cue exposure studies appear highly mixed, and changes in physiological arousal were not adequately controlled. Here we tested the effects of appetitive (erotic), aversive and neutral visual cues on temporal discounting in thirty-five healthy male participants. The contribution of single-trial physiological arousal was assessed using comprehensive monitoring of autonomic activity (pupil size, heart rate, electrodermal activity). Physiological arousal was elevated following aversive and in particular erotic cues. In contrast to our pre-registered hypothesis, if anything, we observed decreased temporal discounting following erotic cue exposure. Aversive cues tended to increase decision noise. Computational modeling revealed that trial-wise arousal only accounted for minor variance over and above aversive and erotic condition effects, arguing against a general effect of physiological arousal on temporal discounting.
Heat-inactivated modified vaccinia virus Ankara boosts Th1-biased cellular and humoral immune responses as a vaccine adjuvant by activating the STING-mediated cytosolic DNA-sensing pathway
Authors: Yang Ning , Garzia Aitor , Meyer Cindy , Tuschl Thomas , Merghoub Taha , Wolchok Jedd D. , Deng Liang
Published: July 2021

Background

Protein or peptide-based subunit vaccines are promising platforms for combating human cancers and infectious diseases. However, one primary concern regarding subunit vaccines is the relatively weak immune responses induced by proteins or peptides. Therefore, developing novel and effective vaccine adjuvants is critical for the success of subunit vaccines. Modified vaccinia virus (MVA) is a safe and effective vaccine against smallpox and monkeypox. In this study, we explored the potential of heat-inactivated MVA (heat-iMVA) as a novel vaccine adjuvant.

Methods

We co-administered heat-iMVA with a model antigen, chicken ovalbumin (OVA), either intramuscularly or subcutaneously twice, two weeks apart, and analyzed anti-OVA specific CD8+ and CD4+ T cells in the spleens and skin draining lymph nodes (dLNs) and serum anti-OVA IgG1 and IgG2c antibodies. We also compared the adjuvanticity of heat-iMVA with several known vaccine adjuvants, including complete Freund’s adjuvant (CFA) and AddaVax, an MF59-like preclinical grade nano-emulsion. In addition, we tested whether co-administration of heat-iMVA plus tumor neoantigen peptides or irradiated tumor cells improves antitumor efficacy in a B16-F10 therapeutic vaccination model. Using Stimulator of Interferon Genes (STING) or Batf3-deficient mice, we evaluated the contribution of the STING pathway and Batf3-dependent CD103+/CD8α DCs in heat-iMVA-induced immunity.

Results

Co-administration of protein- or peptide-based immunogens with heat-iMVA dramatically enhances Th1-biased cellular and humoral immune responses. This adjuvant effect of heat-iMVA is dependent on the STING-mediated cytosolic DNA-sensing pathway, and the antigen-specific CD8+ T cell response requires Batf3-dependent CD103+/CD8α+ dendritic cells (DCs). Heat-iMVA infection of bone marrow-derived DCs (BMDCs) promoted antigen cross-presentation, whereas live MVA infection did not. RNA-seq analyses revealed that heat-iMVA is a more potent activator of the STING pathway than live MVA. Additionally, combining tumor neoantigen peptides or irradiated tumor cells with heat-iMVA delayed tumor growth and extended the median survival in B16-F10 therapeutic vaccination models.

Conclusions

Heat-iMVA induces type I interferon (IFN) production and antigen cross-presentation via a STING-dependent mechanism in DCs. Co-administration of heat-iMVA with peptide antigen generates strong Th1-biased cellular and humoral immunity. Collectively, our results demonstrate that heat-iMVA is a safe and potent vaccine adjuvant.
Lateral habenula M2 muscarinic receptor control of neuronal activity and cocaine seeking behavior
Authors: Wolfe Clara I.C. , Hwang Eun-Kyung , Zapata Agustin , Hoffman Alexander F. , Lupica Carl R.
Published: July 2021

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.
The cold-drought tolerance trade-off in temperate woody plants constrains range size, but not range filling
Authors: Puglielli Giacomo , Tordoni Enrico , Humphreys Aelys M. , Kalwij Jesse M. , Hutchings Michael J. , Laanisto Lauri
Published: July 2021

Interspecific differences in plant species’ ranges are shaped by complex mechanistic interactions, which have so far remained largely beyond the reach of comprehensive models and explanations. Previous attempts to find underlying mechanisms by examining physiological tolerances to cold and heat separately have yielded contradictory results. Here we test the hypothesis that, instead of examining single stressors, abiotic stress tolerance syndromes that involve trade-offs between multiple abiotic stressors (namely drought, cold, waterlogging and shade), will provide reliable explanations.

We compiled a dataset of actual range size and range filling (the ratio between actual and potential species range) as range metrics for 331 temperate woody plants species from Europe and North America. Tolerance syndromes were expressed as two PCA axes. One axis reflects a drought-cold/waterlogging tolerance trade-off (cold/wet-drought trade-off), the second axis represents a shade tolerance spectrum. Phylogenetic generalized linear mixed models were used to model the range metric-tolerance axes relationships using latitude as an additional main effect, and phylogeny and plant functional type as random effects.

Actual range scaled negatively with the cold/wet-drought tolerance trade-off axis, mostly independently of latitude and continent. Thus, cold/wet-tolerant species had the largest ranges and drought tolerant species the smallest. The sign (−) of the relationship was independent of phylogeny and plant functional type. In contrast, range filling depended on latitude. However, deciduous and evergreen species displayed different distributions of range metrics and tolerance syndromes. No significant relationships with the shade tolerance spectrum were found.

Our findings demonstrate that the cold/wet-drought trade-off partly explains interspecific range size differences. However, this trade-off did not explain range filling. We also showed that fundamental adaptations of species also significantly influence range sizes – stress avoidance through the deciduous habit also explained interspecific differences in range size.
Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies
Authors: Davis Luke K. , Ford Ian J. , Hoogenboom Bart W.
Published: July 2021

The rapid (< 1 ms) transport of biological material to and from the cell nucleus is regulated by the nuclear pore complex (NPC). At the core of the NPC is a permeability barrier consisting of intrinsically disordered Phe-Gly (FG) nucleoporins (FG Nups). Various types of nuclear transport receptors (NTRs) facilitate transport by partitioning in the FG Nup assembly, overcoming the barrier by their affinity to the FG Nups, and comprise a significant fraction of proteins in the NPC barrier. In previous work, we revealed that the experimental binding of the NTRs NTF2 and – the larger – Impβ to different planar assemblies of FG Nups follows a universal physical law defined by negative cooperativity, which was further validated by a minimal physical model that treated the FG Nups as flexible homopolymers and the NTRs as uniformly cohesive spheres Zahn et al. (2016). Here, we build upon our original study by first parametrizing our model to experimental data, and next to predict the effects of crowding by different types of NTRs. We show how varying the amounts of one type of NTR modulates how the other NTR penetrates the FG Nup assembly. Notably, at similar and physiologically relevant NTR concentrations, our model predicts demixed phases of NTF2 and Impβ within the FG Nup assembly. The functional implication of NTR phase separation is that NPCs may sustain separate transport pathways that are determined by inter-NTR competition.
A Combined Spectroscopic and Molecular Modeling Study on Structure-Function-Dynamics under Chemical Modification: Alpha-Chymotrypsin with Formalin Preservative
Authors: Biswas Pritam , Adhikari Aniruddha , Pal Uttam , Mondal Susmita , Mukherjee Dipanjan , Ghosh Ria , Saha-Dasgupta Tanusri , Chowdhury Sudeshna Shyam , Das Ranjan , Pal Samir Kumar
Published: July 2021

Enzyme conformations can be altered via modification of its amino acid residues, side chains and large-scale domain modifications, which are closely linked to its function. Herein, we have addressed the role of residue modification in catalytic activity and molecular recognition of an enzyme alpha-chymotrypsin (CHT) in presence of covalent cross-linker formalin. Optical spectroscopy studies exhibit reduced catalytic activity of the enzyme with increased formalin concentration. Polarization gated anisotropy studies of a fluorophore 8-anilino-1- napthelenesulfonic acid (ANS) in CHT show a dip rise pattern in presence of formalin which is consistent with the generation of multiple ANS binding sites in the enzyme owing to modifications of its local amino acid residues. Molecular docking study on minimal local residue modifications in CHT reveals formation of a stable enzyme-substrate complex even with the serine-histidine cross-linked enzyme which prohibits product formation giving rise to reduced catalytic activity.
Epigenetic Malleability at Core Promoter Regulates Tobacco PR-1a Expression after Salicylic Acid Treatment
Authors: Lodhi Niraj , Singh Mala , Srivastava Rakesh , Sawant Samir V. , Tuli Rakesh
Published: July 2021

Tobacco’s PR-1a gene is induced by pathogen attack or exogenous application of Salicylic Acid (SA). However, the epigenetic modifications of the most important inducible promoter of the PR-1a gene are not understood clearly.

Nucelosome mapping and chromatin immunoprecipitation assay were used to define the histone modification on the PR-1a promoter.

Here, we report the epigenetic modifications over core promoter lead to disassembly of nucleosome (spans from −102 to +55 bp,masks TATA and transcription initiation) and repressor complex in induced state. ChIP assays demonstrate repressive chromatin of dimethylation at H3K9 and H4K20 of core promoter maintain uninduced state. While, active chromatin marks di and trimethylation of H3K4, acetylation of H3K9 and H4K16 are increased and lead the induction of PR-1a following SA treatment. TSA enhances expression of PR-1a by facilitating the histone acetylation, however increased expression of negative regulator (SNI1) of AtPR1, suppresses its expression in Arabidopsis thaliana’s mutants.

Constitutive expression of AtPR1 in Histone Acetyl Transferases (HATs), LSD1, and SNI1 suggests that its inactive state is indeed maintained by a repressive complex and this strict regulation of pathogenesis related genes is conserved across species.

Histone methylation and acetylation regulation of tobacco PR-1a promoter are significant for disassembly of the nucleosome and repressor proteins during induction.
Molecular Learning of a Soft-Disks Fluid
Authors: Zammataro Luca
Published: July 2021

This work is based on the Equivalence between Molecular Dynamics and Neural Network. It provides learning proofs in a Lennard-Jones (LJ) fluid, presented as a network of particles having non-bonded interactions. I describe the fluid’s learning as the property of an order that emerges as an adaptation in establishing equilibrium with energy and thermal conservation. The experimental section demonstrates the fluid can be trained with logic-gates patterns. The work goes beyond Molecular Computing’s application, explaining how this model uses its intrinsic minimizing properties in learning and predicting outputs. Finally, it gives hints for a theory on real chemistry’s computational universality.
Driving Native-like Zonal Enthesis Formation in Engineered Ligaments Using Mechanical Boundary Conditions and β-Tricalcium Phosphate
Authors: Brown M. Ethan , Puetzer Jennifer L.
Published: July 2021

Fibrocartilaginous entheses are structurally complex tissues that translate load from elastic ligaments to stiff bone via complex zonal organization with gradients in organization, mineralization, and cell phenotype. Currently, these gradients, necessary for long-term mechanical function, are not recreated in soft tissue-to-bone healing or engineered replacements, leading to high failure rates. Previously, we developed a culture system which guides ligament fibroblasts to develop aligned native-sized collagen fibers using high density collagen gels and mechanical boundary conditions. These constructs hold great promise as ligament replacements, however functional ligament-to-bone attachments, or entheses, are required for long-term function in vivo. The objective of this study was to investigate the effect of compressive mechanical boundary conditions and the addition of beta tricalcium phosphate (βTCP), a known osteoconductive agent, on the development of zonal ligament-to-bone entheses. We found that compressive boundary clamps, that restrict cellular contraction and produce a zonal tensile-compressive environment, guide ligament fibroblasts to produce 3 unique zones of collagen organization, and zonal accumulation of glycosaminoglycans (GAGs), type II and type X collagen by 6 weeks of culture, ultimately resulting in similar organization and composition as immature bovine entheses. Further, βTCP under the clamp enhanced the maturation of these entheses, leading to increased GAG accumulation, sheet-like mineralization, and significantly improved tensile moduli, suggesting the initiation of endochondral ossification. This culture system produced some of the most organized entheses to date, closely mirroring early postnatal enthesis development, and provides an in vitro platform to better understand the cues that drive enthesis maturation in vivo.
How alginate lyase produces quasi-monodisperse oligosaccharides: a normal mode analysis-based docking and molecular dynamics simulation study
Authors: Xu Hengyue , Gao Qi , Ming Dengming
Published: July 2021

Polysaccharide degradation products are widely used in medicine, health food, textile and other industries. The preparation of monosaccharides by enzymatic degradation is a key technology in bio industrial production. Unfortunately, most of the known digested products are complex oligosaccharide mixtures, which limit their industrial processing and application. In this study, we explored a docking technique based on normal mode analysis to examine the possible cleavage mechanism of an alginate lyase (AlyB) from Birio Splendidus, which contains the catalytic domain of polysaccharide lyase family 7 (PL7) and a CBM32 sugar binding module, and was observed to produce trisaccharide products with quasi-monosaccharide distribution. We compared the molecular interactions of the enzyme with the natural alginates, the polyMG whose products has the quasi-monodisperse distribution of tri-saccharide and two synthetic polysaccharides, the polyM and polyG whose products has a wider distribution of oligosaccharides. Our calculations quantitatively show that there are a series of deterministic conformational changes in the catalytic pocket, which control the specificity of the substrate; at the same time, it determines the uniformity of the final product together with the spatial position of the key catalytic sites. The dynamic simulations revealed that CBM domain plays a key role in assisting the release of tri-saccharides. Our data highlights the important role of enzyme flexibility in determining product uniformity, which may provide new insight into design of enzymes for the production of high-value mono-distributed oligosaccharides.
Bats host the most virulent—but not the most dangerous—zoonotic viruses
Authors: Guth Sarah , Mollentze Nardus , Renault Katia , Streicker Daniel G. , Visher Elisa , Boots Mike , Brook Cara E.
Published: July 2021

Identifying virus characteristics associated with the largest public health impacts on human populations is critical to informing zoonotic risk assessments and surveillance strategies. Efforts to assess “zoonotic risk” often use trait-based analyses to identify which viral and reservoir host groups are most likely to source zoonoses but have not fully addressed how and why the impacts of zoonotic viruses vary in terms of disease severity (‘virulence’), capacity to spread within human populations (‘transmissibility’), or total human mortality (‘death burden’). We analyzed trends in human case fatality rates, transmission capacities, and total death burdens across a comprehensive dataset of mammalian and avian zoonotic viruses. Bats harbor the most virulent zoonotic viruses even when compared to birds, which alongside bats, have been hypothesized to be “special” zoonotic reservoirs due to molecular adaptations that support the physiology of flight. Reservoir host groups more closely related to humans—in particular, Primates—harbor less virulent, but more highly transmissible viruses. Importantly, disproportionately high human death burden, arguably the most important metric of zoonotic risk, is not associated with any animal reservoir, including bats. Our data demonstrate that mechanisms driving death burdens are diverse and often contradict trait-based predictions. Ultimately, total human mortality is dependent on context-specific epidemiological dynamics, which are shaped by a combination of viral traits and conditions in the animal host population and across and beyond the human-animal interface. Understanding the conditions that predict high zoonotic burden in humans will require longitudinal studies of epidemiological dynamics in wildlife and human populations.

Significance statement

The clear need to mitigate zoonotic risk has fueled increased viral discovery in specific reservoir host taxa. We show that a combination of viral and reservoir traits can predict zoonotic virus virulence and transmissibility in humans, supporting the hypothesis that bats harbor exceptionally virulent zoonoses. However, pandemic prevention requires thinking beyond zoonotic capacity, virulence, and transmissibility to consider collective ‘burden’ on human health. For this, viral discovery targeting specific reservoirs may be inefficient as death burden correlates with viral, not reservoir, traits, and depends on context-specific epidemiological dynamics across and beyond the human-animal interface. These findings suggest that longitudinal studies of viral dynamics in reservoir and spillover host populations may offer the most effective strategy for mitigating zoonotic risk.
Transmembrane signalling by a bionic receptor: biological input and output, chemical mechanism of signal transduction
Authors: Løvschall Kaja B. , Monge Pere , Nielsen Line F. , Stevanovic Sandra , Walther Raoul , Zelikin Alexander N.
Published: July 2021

Signal transduction through sealed biological membranes is among the most important evolutionary achievements. Herein, we focus on the development of artificial signal transduction mechanisms and engineer a bionic receptor with capacity of transduction of biological signals across biological membranes using tools of chemistry. The bionic receptor described in this work exhibits similarity with the natural counterpart in the most essential characteristics: in having an exofacial ligand for signal capture, in being membrane anchored, and in featuring a releasable secondary messenger molecule, which performs enzyme activation in the endo volume. The main difference with the natural receptors is that signal transduction across the lipid bilayer was performed using the tools of organic chemistry, namely a self-immolative linker. The highest novelty of our work is that the artificial signalling cascade designed herein achieved transmembrane activation of enzymatic activity, as is the hallmark of activity by natural signalling receptors.
Green self-immolative polymer: molecular antenna to collect and propagate the signal for zymogen activation
Authors: Montasell Mireia Casanovas , Monge Pere , Carmali Sheiliza , Dias Loiola Livia Mesquita , Andersen Dante Guldbrandsen , Løvschall Kaja Borup , Søgaard Ane Bretschneider , Kristensen Maria Merrild , Pütz Jean Maurice , Zelikin Alexander N.
Published: July 2021

Chemical zymogens of three different types were established herein around protein cysteinome, in each case converting the protein thiol into a disulfide linkage: zero length Z0, polyethylene glycol based ZPEG, and ZLA that features a fast-depolymerizing fuse polymer. The latter was a polydisulfide based on a naturally occurring water-soluble lipoic acid. Three zymogen designs were applied to cysteinyl proteases and a kinase and in each case, enzymatic activity was successfully masked in full and reactivated by small molecule reducing agents. However, only ZLA could be reactivated by protein activators, demonstrating that the macromolecular fuse escapes the steric bulk created by the protein globule, collects activation signal in solution, and relays it to the enzyme active site. This afforded first-in-class chemical zymogens that are activated via protein-protein interactions. For ZLA, we also document a “chain transfer” bioconjugation mechanism and a unique zymogen exchange reaction between two proteins.
A comprehensive collection of transcriptome data to support life cycle analysis of the poplar rust fungus Melampsora larici-populina
Authors: Guerillot Pamela , Morin Emmanuelle , Kohler Annegret , Louet Clémentine , Duplessis Sébastien
Published: July 2021

Melampsora larici-populina is an obligate biotrophic plant pathogen responsible for the poplar rust disease. This fungus belongs to the taxonomical order Pucciniales and exhibits a complex heteroecious and macrocyclic life cycle, i.e. it has the capacity to infect two unrelated host plants, larch and poplar, and to form five distinct spore types through the year. The M. larici-populina genome has been sequenced and annotated in 2011 and since, different transcriptomic analyses were conducted at different stages with oligoarrays and later on with RNA-Seq covering most of its life cycle. Here, we collected published transcriptome data for the poplar rust fungus, transposed them for the version 2 of the genome now available at the Joint Genome Institute Mycocosm website and performed normalization of different oligoarray datasets on one hand, and of RNA-Seq on the other hand. We report a comprehensive normalized dataset for this fungus, made available for the community, which allows life cycle transcriptomics analysis.
Miniature inverted-repeat transposable elements drive rapid microRNA diversification in angiosperms
Authors: Guo Zhonglong , Kuang Zheng , Tao Yihan , Wang Haotian , Wan Miaomiao , Hao Chen , Shen Fei , Yang Xiaozeng , Li Lei
Published: July 2021

MicroRNAs (miRNAs) are rapidly evolving endogenous small RNAs programing organism function and behavior. Although models for miRNA origination have been proposed based on sporadic cases, the genomic mechanisms driving swift diversification of the miRNA repertoires in plants remain elusive. Here, by comprehensively analyzing 20 phylogenetically representative plant species, we identified miniature inverted-repeat transposable elements (MITEs) as the predominant genomic sources for de novo miRNAs in angiosperms. Our data illustrated a transposition-transcription process whereby properly sized MITEs transposed into active genic regions could be converted into new miRNAs, termed MITE-miRNAs, in as few as 20 generations. We showed that this molecular domestication mechanism leads to a possible evolutionary arms race between the MITEs and the host genomes that rapidly and continuously changes the miRNA repertoires. We found that the MITE-miRNAs are selected for targeting genes associated with plant adaptation and habitat expansion, thereby constituting a genomic innovation potentially underlying angiosperm megadiversity.
Distinct mechanisms underlie H2O2 sensing in C. elegans head and tail
Authors: Quintin Sophie , Aspert Théo , Ye Tao , Charvin Gilles
Published: July 2021

Environmental oxidative stress threatens cellular integrity and should therefore be avoided by living organisms. Yet, relatively little is known about environmental oxidative stress perception. Here, using microfluidics, we showed that like I2 pharyngeal neurons, the tail phasmid PHA neurons function as oxidative stress sensing neurons in C. elegans, but display different responses to H2O2 and light. We uncovered that different but related receptors, GUR-3 and LITE-1, mediate H2O2 signaling in I2 and PHA neurons. Still, the peroxiredoxin PRDX-2 is essential for both, and might promote H2O2-mediated receptor activation. Our work demonstrates that C. elegans can sense a broad range of oxidative stressors using partially distinct H2O2 signaling pathways in head and tail sensillae, and paves the way for further understanding of how the integration of these inputs translates into the appropriate behavior.

Graphical abstract