bluuebunny/crossref_metadata_2025 huggingface dataset:
Serial interval, basic reproduction number and prediction of COVID-19 epidemic size in Jodhpur, India
Authors: Saurabh Suman , Verma Mahendra Kumar , Gautam Vaishali , Goel Akhil , Gupta Manoj Kumar , Bhardwaj Pankaj , Misra Sanjeev
Published: July 2020

Background

Understanding the epidemiology of COVID-19 is important for design of effective control measures at local level. We aimed to estimate the serial interval and basic reproduction number for Jodhpur, India and to use it for prediction of epidemic size for next one month.

Methods

Contact tracing of SARS-CoV-2 infected individuals was done to obtain the serial intervals. Aggregate and instantaneousR0 values were derived and epidemic projection was done using R software v4.0.0.

Results

From among 79 infector-infectee pairs, the estimated median and 95 percentile values of serial interval were 5.98 days (95% CI 5.39 – 6.65) and 13.17 days (95% CI 11.27 – 15.57), respectively. The overallR0 value in the first 30 days of outbreak was 1.64 (95% CI 1.12 – 2.25) which subsequently decreased to 1.07 (95% CI 1.06 – 1.09). The instantaneousR0 value over 14 days window ranged from a peak of 3.71 (95% CI 1.85 -2.08) to 0.88 (95% CI 0.81 – 0.96) as on 24 June 2020. The projected COVID-19 case-load over next one month was 1881 individuals. Reduction ofR0 from 1.17 to 1.085 could result in 23% reduction in projected epidemic size over the next one month.

Conclusion

Aggressive testing, contact-tracing and isolation of infected individuals in Jodhpur district resulted in reduction ofR0. Further strengthening of control measures could lead to substantial reduction of COVID-19 epidemic size. A data-driven strategy was found useful in surge capacity planning and guiding the public health strategy at local level.
Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia
Authors: Rehbach Kristina , Zhang Hanwen , Das Debamitra , Abdollahi Sara , Prorok Tim , Ghosh Sulagna , Weintraub Sarah , Genovese Giulio , Powell Samuel , Lund Anina , Akbarian Schahram , Eggan Kevin , McCarroll Steven , Duan Jubao , Avramopoulos Dimitrios , Brennand Kristen J.
Published: July 2020

Schizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.
Deviation from baseline mutation burden provides powerful and robust rare-variants association test for complex diseases
Authors: Jiang Lin , Jiang Hui , Dai Sheng , Chen Ying , Song Youqiang , Tang Clara Sze-Man , Wang Binbin , Garcia-Barcelo Maria-Mercedes , Tam Paul , Cherny Stacey S. , Sham Pak Chung , Li Miaoxin
Published: July 2020

The identification of rare variants that contribute to complex diseases is challenging due to low statistical power. Here we propose a novel and powerful rare variants association test based on the deviation of the observed mutational burden in a genomic region from a baseline mutation burden predicted by weighted recursive truncated negative-binomial regression (RUNNER) on genomic features available from public data. Simulation studies show that RUNNER is substantially more powerful than state-of-the-art rare variant association methods (including SKAT, CMC and KBAC), while maintaining correct type 1 error rates under population stratification and in small samples. Applied to real data, RUNNER “rediscovered” known genes of Hirschsprung disease missed by current methods, and detected promising new candidate genes, includingNXPE4for Hirschsprung disease andCXCL16for Alzheimer’s disease. The proposed approach provides a powerful and robust method to identify rare risk variants for complex diseases.
Calmodulin acts as a state-dependent switch to control a cardiac potassium channel opening
Authors: Kang Po Wei , Westerlund Annie M. , Shi Jingyi , White Kelli McFarland , Dou Alex K. , Cui Amy H. , Silva Jonathan R. , Delemotte Lucie , Cui Jianmin
Published: July 2020

Calmodulin (CaM) and PIP2are potent regulators of the voltage-gated potassium channel KCNQ1 (KV7.1), which conducts the IKscurrent important for repolarization of cardiac action potentials. Although cryo-EM structures revealed intricate interactions between the KCNQ1 voltage-sensing domain (VSD), CaM, and PIP2, the functional consequences of these interactions remain unknown. Here, we show that CaM-VSD interactions act as a state-dependent switch to control KCNQ1 pore opening. Combined electrophysiology and molecular dynamics network analysis suggest that VSD transition into the fully-activated state allows PIP2to compete with CaM for binding to VSD, leading to the conformational change that alters the VSD-pore coupling. We identify a motif in the KCNQ1 cytosolic domain which works downstream of CaM-VSD interactions to facilitate the conformational change. Our findings suggest a gating mechanism that integrates PIP2and CaM in KCNQ1 voltage-dependent activation, yielding insights into how KCNQ1 gains the phenotypes critical for its function in the heart.
Evolution of DNA Replication Origin Specification and Gene Silencing Mechanisms
Authors: Hu Y. , Tareen A. , Sheu Y-J. , Ireland W. T. , Speck C. , Li H. , Joshua-Tor L. , Kinney J. B. , Stillman B.
Published: July 2020

DNA replication in eukaryotic cells initiates from chromosomal locations, called replication origins, that bind the Origin Recognition Complex (ORC) prior to S phase. Origin establishment is guided by well-defined DNA sequence motifs in Saccharomyces cerevisiae and some other budding yeasts, but most eukaryotes lack sequence-specific origins. At present, the mechanistic and evolutionary reasons for this difference are unclear. A 3.9 Å structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed, among other things, that a loop within Orc2 inserts into a DNA minor groove and an α-helix within Orc4 inserts into a DNA major groove1. We show that this Orc4 α-helix mediates the sequence-specificity of origins in S. cerevisiae. Specifically, mutations were identified within this α-helix that alter the sequence-dependent activity of individual origins as well as change global genomic origin firing patterns. This was accomplished using a massively parallel origin selection assay analyzed using a custom mutual-information-based modeling approach and a separate analysis of whole-genome replication profiling and statistics. Interestingly, the sequence specificity of DNA replication initiation, as mediated by the Orc4 α-helix, has evolved in close conjunction with the gain of ORC-Sir4-mediated gene silencing and the loss of RNA interference.
New GFAP splice isoform (GFAPμ) differentially expressed in glioma translates into 21 kDa N-terminal GFAP protein
Authors: van Bodegraven Emma J. , Sluijs Jacqueline A. , Tan A. Katherine , Robe Pierre A.J.T. , Hol Elly M.
Published: July 2020

The glial fibrillary acidic protein (GFAP) is a type III intermediate filament (IF) protein that is highly expressed in astrocytes, neural stem cells, and in gliomas. Gliomas are a heterogeneous group of primary brain tumors that arise from glia cells or neural stem cells and rely on accurate diagnosis for prognosis and treatment strategies. GFAP is differentially expressed between glioma subtypes and therefore often used as a diagnostic marker. However, GFAP is highly regulated by the process of alternative splicing; many different isoforms have been identified. Differential expression of GFAP isoforms between glioma subtypes suggests that GFAP isoform-specific analyses could benefit diagnostics. In this study we report on the differential expression of a new GFAP isoform between glioma subtypes, GFAPμ. A short GFAP transcript resulting from GFAP exon 2 skipping was detected by RNA sequencing of human glioma. We show that GFAPμ mRNA is expressed in healthy brain tissue, glioma cell lines, and primary glioma cells and that it translates into a~21 kDa GFAP protein. 21 kDa GFAP protein was detected in the IF protein fraction isolated from human spinal cord as well. We further show that induced GFAPμ expression disrupts the GFAP IF network. The characterization of this new GFAP isoform adds on to the numerous previously identified GFAP splice isoforms. It emphasizes the importance of studying the contribution of IF splice variants to specialized functions of the IF network and to glioma diagnostics.

Summary statement

RNA sequencing data of glioma patient material reveals the differential expression of a short GFAP splice isoform,GFAPμ, between glioma subtypes.GFAPμtranslates into a 21 kDa N-terminal GFAP protein which can disrupt the GFAP intermediate filament network.
Allostery through DNA drives phenotype switching
Authors: Rosenblum Gabriel , Elad Nadav , Rozenberg Haim , Wiggers Felix , Hofmann Hagen
Published: July 2020

Allostery is a pervasive principle to regulate protein function. Here, we show that DNA also transmits allosteric signals over long distances to boost the binding cooperativity of transcription factors. Phenotype switching inBacillus subtilisrequires an all-or-none promoter binding of multiple ComK proteins. Using single-molecule FRET, we find that ComK-binding at one promoter site increases affinity at a distant site. Cryo-EM structures of the complex between ComK and its promoter demonstrate that this coupling is due to mechanical forces that alter DNA curvature. Modifications of the spacer between sites tune cooperativity and show how to control allostery, which paves new ways to design the dynamic properties of genetic circuits.
Large-scale curvature sensing by epithelial monolayers depends on active cell mechanics and nuclear mechanoadaptation
Authors: Luciano Marine , Xue Shi-Lei , De Vos Winnok H. , Morata Lorena Redondo , Surin Mathieu , Lafont Frank , Hannezo Edouard , Gabriele Sylvain
Published: July 2020

While many tissues foldin vivoin a highly reproducible and robust way, epithelial folds remain difficult to reproducein vitro, so that the effects and underlying mechanisms of local curvature on the epithelial tissue remains unclear. Here, we photoreticulated polyacrylamide hydrogels though an optical photomask to create corrugated hydrogels with isotropic wavy patterns, allowed us to show that concave and convex curvatures affect cellular and nuclear shape. By culturing MDCK epithelial cells at confluency on corrugated hydrogels, we showed that the substrate curvature leads to thicker epithelial zones in the valleys and thinner ones on the crest, as well as corresponding density, which can be generically explained by a simple 2D vertex model, leading us to hypothesize that curvature sensing could arise from resulting density/thickness changes. Additionally, positive and negative local curvatures lead to significant modulations of the nuclear morphology and positioning, which can also be well-explained by an extension of vertex models taking into account membrane-nucleus interactions, where thickness/density modulation generically translate into the corresponding changes in nuclear aspect ratio and position, as seen in the data. Consequently, we find that the spatial distribution of Yes associated proteins (YAP), the main transcriptional effector of the Hippo signaling pathway, is modulated in folded epithelial tissues according to the resulting thickness modulation, an effect that disappears at high cell density. Finally, we showed that these deformations are also associated with changes of A-type and B-type lamin expression, significant chromatin condensation and to lower cell proliferation rate. These findings show that active cell mechanics and nuclear mechanoadaptation are key players of the mechanistic regulation of epithelial monolayers to substrate curvature, with potential application for a number ofin vivosituations.
The Evolution of Sex Chromosome Dosage Compensation in Animals
Authors: Chen Jiabi , Wang Menghan , He Xionglei , Yang Jian-Rong , Chen Xiaoshu
Published: July 2020

The evolution of sex chromosomes in the XY or ZW systems shall lead to gene expression dosage problems, as in at least one of the sexes, the sex-linked gene dose has been reduced by half. It has been proposed, most notably by Susumu Ohno for mammals, that the transcriptional output of the whole sex chromosome should be doubled for a complete dosage compensation. However, due to the variability of the existing methods to determine the transcriptional differences betweenSex chromosomes andAutosomes (S:A ratios) in different studies, whether clade-specific results are comparable and whether there is a more general model to explain dosage compensation states remain unanswered. In this study, we collected more than 500 public RNA-seq datasets from multiple tissues and species in major clades (including mammals, birds, fishes, insects, and worms) and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species. We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes. We found that in mammals and birds, the S:A ratio is approximately 0.5, while in insects, fishes and flatworms, the S:A ratio is approximately 1. Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the sex chromosome is significantly correlated with the S:A ratio. In addition, the degree of degradation of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage-compensation mechanism. Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that the dosage sensitivity states of sex chromosomes is a major factor underlying different evolutionary strategies of dosage compensation.
Reward-specific satiety affects subjective value signals in orbitofrontal cortex during multi-component economic choice
Authors: Pastor-Bernier Alexandre , Stasiak Arkadiusz , Schultz Wolfram
Published: July 2020

Sensitivity to satiety constitutes a basic requirement for neuronal coding of subjective reward value. Satiety from natural on-going consumption affects reward functions in learning and approach behavior. More specifically, satiety reduces the subjective economic value of individual rewards during choice between options that typically contain multiple reward components. The unconfounded assessment of economic reward value requires tests at choice indifference between two options, which is difficult to achieve with sated rewards. By conceptualizing choices between options with multiple reward components (‘bundles’), Revealed Preference Theory may offer a solution. Despite satiety, choices against an unaltered reference bundle may remain indifferent when the reduced value of a sated bundle reward is compensated by larger amounts of an unsated reward of the same bundle; then the value loss of the sated reward is indicated by the amount of the added unsated reward. Here we show psychophysically titrated choice indifference in monkeys between bundles of differently sated rewards. Neuronal chosen value signals in orbitofrontal cortex (OFC) followed closely the subjective value change within recording periods of individual neurons. A neuronal classifier distinguishing the bundles and predicting choice substantiated the subjective value change. Choice between conventional single rewards confirmed the neuronal changes seen with two-reward bundles. Thus, reward-specific satiety reduces subjective reward value signals in OFC. With satiety being an important factor of subjective reward value, these results extend the notion of subjective economic reward value coding in OFC neurons.

Significance

On-going consumption reduces the subjective value of rewards to different degrees depending on their individual properties, a phenomenon referred to as sensory-specific satiety. Such value change should be manifested in economic choices, and neuronal signals for subjective economic reward value should be sensitive to reward-specific satiety. We tested monkeys during choice between two options that each contained two different rewards (‘bundles’); the two rewards were prone to different degrees of satiety. On-going reward consumption affected choices in a way that indicated satiety-induced reward-specific change of subjective economic value. Neuronal responses in the monkey orbitofrontal cortex (OFC) followed the differential reduction of subjective economic value. These results satisfy a crucial requirement for subjective reward value coding in OFC neurons.
Release from cell cycle arrest with Cdk4/6 inhibitors generates highly synchronised cell cycle progression in human cell culture
Authors: Wendy Trotter Eleanor , Michael Hagan Iain
Published: July 2020

Each approach used to synchronise cell cycle progression of human cell lines presents a unique set of challenges. Induction synchrony with agents that transiently block progression through key cell cycle stages are popular, but change stoichiometries of cell cycle regulators, invoke compensatory changes in growth rate and, for DNA replication inhibitors, damage DNA. The production, replacement, or manipulation of a target molecule must be exceptionally rapid if the interpretation of phenotypes in the cycle under study are to remain independent of impacts upon progression through the preceding cycle. We show how these challenges are avoided by exploiting the ability of the Cdk4/6 inhibitors, palbociclib, ribociclib and abemaciclib to arrest cell cycle progression at the natural control point for cell cycle commitment: the restriction point. After previous work found no change in the coupling of growth and division during recovery from CDK4/6 inhibition, we find high degrees of synchrony in cell cycle progression. Although we validate CDK4/6 induction synchronisation with hTERT-RPE-1, THP1 and H1299, it is effective in other lines and avoids the DNA damage that accompanies synchronisation by thymidine block/release. Competence to return to cycle after 72 hours arrest enables out of cycle target induction/manipulation, without impacting upon preceding cycles.
Discrimination of regular and irregular rhythms by accumulation of time differences
Authors: Espinoza-Monroy Marisol , de Lafuente Victor
Published: July 2020

Perceiving the temporal regularity in a sequence of repetitive sensory events facilitates the preparation and execution of relevant behaviors with tight temporal constraints. How we estimate temporal regularity from repeating patterns of sensory stimuli is not completely understood. We developed a decision-making task in which participants had to decide whether a train of visual, auditory, or tactile pulses, had a regular or an irregular temporal pattern. We tested the hypothesis that subjects categorize stimuli as irregular by accumulating the time differences between the predicted and observed times of sensory pulses defining a temporal rhythm. Results show that instead of waiting for a single large temporal deviation, participants accumulate timing-error signals and judge a pattern as irregular when the amount of evidence reaches a decision threshold. Model fits of bounded integration showed that this accumulation occurs with negligible leak of evidence. Consistent with previous findings, we show that participants perform better when evaluating the regularity of auditory pulses, as compared with visual or tactile stimuli. Our results suggest that temporal regularity is estimated by comparing expected and measured pulse onset times, and that each prediction error is accumulated towards a threshold to generate a behavioral choice.
Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
Authors: Yurkovetskiy Leonid , Wang Xue , Pascal Kristen E. , Tomkins-Tinch Christopher , Nyalile Thomas , Wang Yetao , Baum Alina , Diehl William E. , Dauphin Ann , Carbone Claudia , Veinotte Kristen , Egri Shawn B. , Schaffner Stephen F. , Lemieux Jacob E. , Munro James , Rafique Ashique , Barve Abhi , Sabeti Pardis C. , Kyratsous Christos A. , Dudkina Natalya , Shen Kuang , Luban Jeremy
Published: July 2020

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.
Memory destabilization and reconsolidation dynamically regulate the PKMζ maintenance mechanism
Authors: Bernabo Matteo , Nader Karim
Published: July 2020

Useful memory must balance between stability and malleability. This puts effective memory storage at odds with plasticity processes like reconsolidation. What becomes of memory maintenance processes during synaptic plasticity is unknown. Here we examined the fate of the memory maintenance protein PKMζ during memory destabilization and reconsolidation. We found that NMDA receptor activation and proteasome activity induced a transient reduction in PKMζ protein following retrieval. During reconsolidation, new PKMζ was synthesized to re-store the memory. Failure to synthesize new PKMζ during reconsolidation impaired memory but uninterrupted PKMζ translation was not necessary for maintenance itself. Finally, NMDA receptor activation was necessary to render memories vulnerable to the amnesic effect of PKMζ-antisense. These findings outline a transient collapse and renewal of the PKMζ memory maintenance mechanism during plasticity. We argue that dynamic changes in PKMζ protein levels can serve as an exemplary model of the molecular changes underlying memory destabilization and reconsolidation.
Antagonistic epistasis of Hnf4α and FoxO1 networks through enhancer interactions in β-cell function
Authors: Kuo Taiyi , Du Wen , Miyachi Yasutaka , Dadi Prasanna K. , Jacobson David A. , Accili Domenico
Published: July 2020

Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components, and are known to act through β-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature β-cells leads to increased selection of FoxO1 enhancers by Hnf4α. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of β-cell dysfunction with an antagonistic network regulating glycolysis, including β-cell “disallowed” genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.
Astroglial Calcium Signaling Encodes Sleep Need inDrosophila
Authors: Blum Ian D. , Keleş Mehmet F. , Baz El-Sayed , Han Emily , Park Kristen , Luu Skylar , Issa Habon , Brown Matt , Ho Margaret C.W. , Tabuchi Masashi , Liu Sha , Wu Mark N.
Published: July 2020

Sleep is under homeostatic control, whereby increasing wakefulness generates sleep need and triggers sleep drive. However, the molecular and cellular pathways by which sleep need is encoded are poorly understood. In addition, the mechanisms underlying both how and when sleep need is transformed to sleep drive are unknown. Here, usingex vivoandin vivoimaging, we show inDrosophilathat astroglial Ca2+signaling increases with sleep need. We demonstrate that this signaling is dependent on a specific L-type Ca2+channel and is required for homeostatic sleep rebound. Thermogenetically increasing Ca2+in astrocytes induces persistent sleep behavior, and we exploit this phenotype to conduct a genetic screen for genes required for the homeostatic regulation of sleep. From this large-scale screen, we identify TyrRII, a monoaminergic receptor required in astrocytes for sleep homeostasis. TyrRII levels rise following sleep deprivation in a Ca2+-dependent manner, promoting further increases in astrocytic Ca2+and resulting in a positive-feedback loop. These data suggest that TyrRII acts as a gate to enable the transformation of sleep need to sleep drive at the appropriate time. Moreover, our findings suggest that astrocytes then transmit this sleep need to the R5 sleep drive circuit, by upregulation and release of the interleukin-1 analog Spätzle. These findings define astroglial Ca2+signaling mechanisms encoding sleep need and reveal dynamic properties of the sleep homeostatic control system.
Cryo-EM Structures Delineate a pH-Dependent Switch that Mediates Endosomal Positioning of SARS-CoV-2 Spike Receptor-Binding Domains
Authors: Zhou Tongqing , Tsybovsky Yaroslav , Olia Adam S. , Gorman Jason , Rapp Micah A. , Cerutti Gabriele , Chuang Gwo-Yu , Katsamba Phinikoula S. , Nazzari Alexandra , Sampson Jared M. , Schon Arne , Wang Pengfei D. , Bimela Jude , Shi Wei , Teng I-Ting , Zhang Baoshan , Boyington Jeffrey C. , Sastry Mallika , Stephens Tyler , Stuckey Jonathan , Wang Shuishu , Friesner Richard A. , Ho David D. , Mascola John R. , Shapiro Lawrence , Kwong Peter D.
Published: July 2020

The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the ACE2 receptor and to facilitate virus entry. Antibodies can engage RBD but some, such as CR3022, fail to inhibit entry despite nanomolar spike affinity. Here we show the SARS-CoV-2 spike to have low unfolding enthalpy at serological pH and up to 10-times more unfolding enthalpy at endosomal pH, where we observe significantly reduced CR3022 affinity. Cryo-EM structures -at serological and endosomal pH- delineated spike recognition of up to three ACE2 molecules, revealing RBD to freely adopt the 'up' conformation. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning and spike shedding of antibodies like CR3022. An endosomal mechanism involving spike-conformational change can thus facilitate immune evasion from RBD-'up'-recognizing antibody.
An early cell shape transition drives evolutionary expansion of the human forebrain
Authors: Benito-Kwiecinski Silvia , Giandomenico Stefano L. , Sutcliffe Magdalena , Riis Erlend S. , Freire-Pritchett Paula , Kelava Iva , Wunderlich Stephanie , Martin Ulrich , Wray Greg , Lancaster Madeline A.
Published: July 2020

The human brain has undergone rapid expansion since humans diverged from other great apes, but the mechanism of this human-specific enlargement is still unknown. Here, we use cerebral organoids derived from human, gorilla and chimpanzee cells to study developmental mechanisms driving evolutionary brain expansion. We find that the differentiation of neuroepithelial cells to neurogenic radial glia is a protracted process in apes, involving a previously unrecognized transition state characterized by a change in cell shape. Furthermore, we show that human organoids are larger due to a delay in this transition. Temporally resolved RNA-seq from human and gorilla organoids reveals differences in gene expression patterns associated with cell morphogenesis, and in particular highlightsZEB2, a known regulator of epithelial-mesenchymal transition and cell shape. We show, through loss- and gain-of-function experiments, thatZEB2promotes the progression of neuroepithelial differentiation, and its ectopic overexpression in human is sufficient to trigger a premature transition. Thus, by mimicking the nonhuman ape expression in human organoids, we are able to force the acquisition of nonhuman ape architecture, establishing for the first time, an instructive role of neuroepithelial cell shape in human brain expansion.
Cell Type-Specific Chromatin Accessibility Analysis in the Mouse and Human Brain
Authors: Rocks Devin , Jaric Ivana , Tesfa Lydia , Greally John M. , Suzuki Masako , Kundakovic Marija
Published: July 2020

The Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) is becoming increasingly popular in the neuroscience field where chromatin regulation is thought to be involved in neurodevelopment, activity-dependent gene regulation, hormonal and environmental responses, and the pathophysiology of neuropsychiatric disorders. The advantages of using this assay include a small amount of material needed, relatively simple and fast protocol, and the ability to capture a range of gene regulatory elements with a single assay. However, with increasing interest in chromatin research, it is an imperative to have feasible, reliable assays that are compatible with a range of neuroscience study designs in both animals and humans. Here we tested three different protocols for neuronal chromatin accessibility analysis, including a varying brain tissue freezing method followed by fluorescent-activated nuclei sorting (FANS) and the ATAC-seq analysis. Our study shows that the cryopreservation method impacts the number of open chromatin regions that can be identified from frozen brain tissue using the cell-type specific ATAC-seq assay. However, we show that all three protocols generate consistent and robust data and enable the identification of functional regulatory elements, promoters and enhancers, in neuronal cells. Our study also implies that the broad biological interpretation of chromatin accessibility data is not significantly affected by the freezing condition. In comparison to the mouse brain analysis, we reveal the additional challenges of doing chromatin analysis onpost mortemhuman brain tissue. However, we also show that these studies are revealing important cell type-specific information about gene regulation in the human brain. Overall, the ATAC-seq coupled with FANS is a powerful method to capture cell-type specific chromatin accessibility information in the mouse and human brain. Our study provides alternative brain preservation methods that generate high quality ATAC-seq data while fitting in different study designs, and further encourages the use of this method to uncover the role of epigenetic (dys)regulation in healthy and malfunctioning brain.
From spatial value to panopticon: study of organizational changes in riverside areas in Poznań
Authors: Wechta Przemysław
Published: July 2020

Purpose

The aim of the article is to analyze the process of creating spatial value. The object of the analysis concerns the riverside areas of the city of Poznan. The study focuses on spontaneous practices that are outside the legal regulations, thanks to less-visited places which have gained popularity among residents and disciplinary techniques introduced by government officials in response to such activities.

Design/methodology/approach

At the theoretical level, the study is primarily based on Florian Znaniecki's spatial value concept and Michel Foucault's concept of power. The empirical research study includes quantitative (questionnaire-based interviews) and qualitative methods (expert interviews and content analysis).

Findings

Identification of the method of creating spatial value which does not require direct financial outlays; determination of disciplinary techniques used by government officials ultimately led to a reduction in the spatial value.

Originality/value

The article reveals the hidden mechanisms of functioning of the authority that defends itself against the reduction of its powers. It is an alternate way of analyzing and interpreting organizational changes in urban space to the one promoted by the Poznan authorities. The results can be used in various ways. Researchers representing the critical trend of urban research can interpret the process of creating spatial value by residents in terms of community, resistance and alternates to the actions of the authorities. From this point of view, the research study is interventional and exposing in nature. On the other hand, for city decision makers allowing the possibility to consume alcohol in a given area can be an effective, low-cost way of revitalizing it. Research can also be useful in assessing the effectiveness of particular disciplinary techniques by public officers.
Into the wild blueberry (Vaccinium angustifolium) rhizosphere microbiota
Authors: Morvan Simon , Meglouli Hacène , Lounès‐Hadj Sahraoui Anissa , Hijri Mohamed
Published: July 2020

The ability of wild blueberries to adapt to their harsh environment is believed to be closely related to their symbiosis with ericoid mycorrhizal fungi, which produce enzymes capable of organic matter mineralization. Although some of these fungi have been identified and characterized, we still know little about the microbial ecology of wild blueberry. Our study aims to characterize the fungal and bacterial rhizosphere communities of Vaccinium angustifolium (the main species encountered in wild blueberry fields). Our results clearly show that the fungal order Helotiales was the most abundant taxon associated with V. angustifolium. Helotiales contains most of the known ericoid mycorrhizal fungi which are expected to dominate in such a biotope. Furthermore, we found the dominant bacterial order was the nitrogen‐fixing Rhizobiales. The Bradyrhizobium genus, whose members are known to form nodules with legumes, was among the 10 most abundant genera in the bacterial communities. In addition, Bradyrhizobium and Roseiarcus sequences significantly correlated with higher leaf‐nitrogen content. Overall, our data documented fungal and bacterial community structure differences in three wild blueberry production fields.
What is (s)he Worth? Exploring Mechanisms and Boundary Conditions of the Relationship Between CEO Extraversion and Pay
Authors: Malhotra Shavin , Shen Winny , Zhu PengCheng
Published: July 2020

Integrating human capital theories and the status incongruity hypothesis at the upper echelons, we examine for whom extraversion, the personality trait that has been most strongly and consistently implicated in leader success, influences Chief Executive Officer (CEO) pay. To assess the personality traits of CEOs, we used a computerized text analysis approach on the language spoken by CEOs in conference calls. Using a sample of firms listed on the S&P 1500, we find that more extraverted CEOs earned higher pay, indicating that this was a trait valued by boards. Additionally, this relationship was due to enhanced firm performance; specifically, market performance. However, a critical boundary condition is that the relationship between CEO extraversion and pay was weaker for female (vs. male) CEOs, despite the market responding equally positively to extraverted female and male CEOs. Thus, the monetary benefits of higher levels of extraversion did not extend to female CEOs and likely reflects backlash. Supplemental analyses revealed that this devaluation of more extraverted female (vs. male) CEOs was mitigated when the CEO was also the chairperson of the board (i.e., CEO duality) or under conditions of greater female representation on the board of directors.
Make every species count: fastachar software for rapid determination of molecular diagnostic characters to describe species
Authors: Merckelbach Lucas M. , Borges Luísa M. S.
Published: July 2020

Only a fraction of species found so far has been described, particularly cryptic species uncovered by molecular data. The latter might require the use of molecular data for its diagnosis, but it is important to make use of the diagnostic content of the molecular data itself. The molecular character‐based model provides discrete molecular diagnostic characters within DNA sequences that can be used in species descriptions fulfilling the requirement of most codes of nomenclature for a character‐based description of species. Here, we introduce fastachar, a software developed to extract molecular diagnostic characters from one or several taxonomically informative DNA markers of a selected taxon compared with those of other taxa in a single step. The input data consist of a single file with aligned sequences in the fasta format, which can be created using alignment software such as mega or geneious. fastachar is an easy‐to‐use software with a graphical interface. Thus, the software does not require the user to have any knowledge of the underlying programming environment (Python). We hope this software, based on the method proposed by Jörger and Schrödl (Frontiers in Zoology, 10, 59, 2013) to describe cryptic species, will encourage researchers to take the final step in taxonomy: the formal description of species. We propose the use of this method and fastachar also for the inclusion of molecular data in the description of any species. fastachar is released as open‐source software under GNU General Public License V3 and is freely available for all major operating systems from https://github.com/smerckel/FastaChar.
Bee foraging preferences on three willow (Salix) species: Effects of species, plant sex, sampling day and time of day
Authors: Mosseler Alex , Major John , Ostaff Don , Ascher John
Published: July 2020

Our objective was to examine how bee foraging preferences on dioecious willows are influenced by plant sex, time of day, by sampling date on multiple sites and across different willow species. In a common garden experiment examining diurnal pollinator visitation patterns of Andrena bees (andrenids), there was a strong preference for male willow plants: 87% of visitations on male plants of Salix eriocephala (ERI) and 71% on males of S. interior (INT). The significant plant sex × time of day interaction was not a result of a change in bee preference for a certain plant sex during a certain part of the day but rather the result of diurnal changes in the magnitude of the preference of andrenid bees for male willow plants. Visits to male flower catkins were highest in the morning and early afternoon, peaking at midday. Visits to female catkins showed a more uniform, lower frequency visitation pattern throughout the day. In a larger field test at a reclaimed former coal mine site, which included S. cordata (COR) as well as ERI and INT, there were no sampling date × plant sex or sampling date × plant sex × willow species interactions. This indicates no plant sex switching behaviour by sampling date for the three willow species. Preference for male plants was greatest on the first sampling day and the proportion of male preference continued to decline until the fourth and final sampling day. On the mine site, 17 of the 25 Apoidea bee species identified were andrenids, and they represented 92% of the 744 individual bees collected while foraging on willow catkins. In addition, the overall number of observed and collected Apoidea bees visiting available flowering willow plants showed that the preference for male plants was 83%, 72% and 91%, for ERI, INT and COR, respectively. We discuss possibilities for promoting populations of native bees to increase commercial fruit and berry crop pollination by using willows as natural sources of pollen and nectar, thereby reducing costs of production associated with the annual importation of commercial bees.
Enhanced local and systemic inflammatory cytokine mRNA expression in women with endometriosis evokes compensatory adaptive regulatory mRNA response that mediates immune suppression and impairs cytotoxicity
Authors: Björk Emma , Vinnars Marie‐Therese , Nagaev Ivan , Nagaeva Olga , Lundin Eva , Ottander Ulrika , Mincheva‐Nilsson Lucia
Published: July 2020

Problem

Endometriosis is a disease characterized by ectopic implantation of endometrium and impaired immune responses. To explore its pathogenic mechanisms, we studied the local and systemic cytokine mRNA profiles and their role in the immunity of patients with endometriosis and healthy controls.

Method of Study

mRNA for eleven cytokines defining cytotoxic Th1, humoral Th2, regulatory Tr1/Th3, and inflammatory cytokine profiles was characterized locally in endometriotic tissue and endometrium, and systemically in PBMCs from women with endometriosis and healthy controls, using real‐time qRT‐PCR. In addition, immunohistochemical stainings with monoclonal antibodies were performed looking for T regulatory cells in endometriotic lesions.

Results

We found a downregulation of mRNA for cytokines mediating cytotoxicity and antibody response and an upregulation of inflammatory and T‐regulatory cytokines in the endometriotic tissues and endometrium from the patients with endometriosis, suggesting enhanced local inflammation and priming of an adaptive regulatory response. Consistent with those findings, there was an abundancy of T regulatory cells in the endometriotic lesions.

Conclusions

The ectopic implantation seen in endometriosis could be possible as a consequence of increased inflammation and priming of adaptive T regulatory cells, resulting in impaired cytotoxicity and enhanced immune suppression.
Pregnancy with COVID‐19: Management considerations for care of severe and critically ill cases
Authors: Chen Lian , Jiang Hai , Zhao Yangyu
Published: July 2020

Pregnant women are a potentially highly vulnerable population due to anatomical, physiological, and immunological changes under the COVID‐19 pandemic. Issues related to pregnancy with COVID‐19 attracted widespread attention from researchers. A large number of articles were published aiming to elaborate clinical characteristics and outcomes of pregnant women infected with COVID‐19, in order to provide evidence for management. The existing data suggest that the overall prognosis of pregnancy with COVID‐19 is promising when compared with that of other previous coronaviruses. There is still maternal morbidity and mortality related to COVID‐19 reported. However, the optimal management of severe and critically ill cases of COVID‐19–infected pregnancy is poorly clarified. The possibility of postpartum exacerbation in pregnancy with COVID‐19 is also worthy of attention for obstetricians. This review makes further elaboration of the above issues.
A decade of grafting techniques as a sole treatment for Peyronie’s disease
Authors: Ragheb Ahmed , Eraky Ahmed , Osmonov Daniar
Published: July 2020

Background

Peyronie's disease (PD) can be a cosmetically and functionally devastating condition. Surgical approaches have been proposed in the chronic stages of PD as plication or plaque incision/excision with grafting to preserve penile size in complex cases. Although several surgeons nowadays are inclined toward the utilization of non‐autologous grafts owing to the ease of their preparation and availability, synthetic graft procedures still await more technical improvements and supporting evidence before their consideration for standard care.

Objectives

In this review, our goal is to facilitate an insight into the most promising grafting materials used for the management of PD and techniques associated.

Materials and methods

A PubMed review was conducted for all the studies on our topic within the past ten years (January 2009 until December 2019). The outcome parameters we documented and compared comprised of operative time, follow‐up time, postoperative penile cosmesis and function, and, finally, overall patient satisfaction related to each technique.

Results

Our search yielded 23 English‐written original study articles in addition to a single case report on the various grafting techniques utilized as the sole treatment for PD, each demonstrating different outcomes and points of comparison.

Conclusion

A successful grafting procedure for PD requires an appropriately tailored surgical modality and an experienced surgeon. Nevertheless, proper preoperative patient counseling on all aspects of his condition and opted treatment modality while setting clear and realistic expectations remains key for overall patient satisfaction.
Association of clinical predictors with recurrence of atrial fibrillation after catheter ablation
Authors: Li Ang , Chen Yue , Wang Wei , Su Li , Ling Zhiyu
Published: July 2020

Background

Recurrence rate after radiofrequency catheter ablation (RFCA) remains high, and further investigation on predictors of recurrence is needed.

Objects

To identify risk factors of atrial fibrillation (AF) recurrence in patients undergoing RFCA.

Methods

We retrospectively studied 257 patients with AF who underwent RFCA preceded by transthoracic echocardiographic and pulmonary vein CT examination from 2016 to 2019. Electrocardiogram examination was performed at baseline, 1, 3, 6 months, and 1 year after RFCA. We divided patients into two groups based on AF recurrence including recurrence group (n = 79) and nonrecurrence group (n = 178). The crude and independent association between clinical variables and AF recurrence was evaluated with logistic regression analysis. Specificity and positive predictive value of relevant factors for AF recurrence were performed by ROC curve.

Results

Of these AF patients, 174 (68%) was paroxysmal AF and 83 (32%) was persistent AF. The multivariate logistic regression demonstrated that AF duration (OR = 1.008, 95% CI 1.002–1.013, p = .008), pulmonary arterial hypertension (PAH; OR = 2.313, 95% CI 1.031–5.192, p = .042), and low‐density lipoprotein cholesterol (LDL‐C; OR = 1.646, 95% CI 1.129–2.398, p = .010) were independently correlated with recurrence of AF. For predicting AF recurrence, the specificity and sensitivity of AF duration were 30.1% and 87.3%, and for LDL‐C, the specificity and sensitivity of AF duration were 60.6% and 60.5%, respectively.

Conclusions

Atrial fibrillation duration, PAH, and LDL‐C might be independent risk factors for the recurrence of AF after RFCA.