bluuebunny/crossref_metadata_2025 huggingface dataset:
Freeze-frame imaging of dendritic calcium signals with TubuTag
Authors: Perez-Alvarez Alberto , Huhn Florian , Dürst Céline D. , Franzelin Andreas , Lamothe-Molina Paul , Oertner Thomas G.
Published: December 2020

The extensive dendritic arbor of neurons is thought to be actively involved in the processing of information. Dendrites contain a rich diversity of ligand- and voltage-activated ion channels as well as metabotropic receptors. In addition, they are capable of releasing calcium from intracellular stores. Under specific conditions, large neurons produce calcium spikes that are locally restricted to a dendritic section. To investigate calcium signaling in dendrites, we introduce TubuTag, a genetically encoded calcium sensor anchored to the cytoskeleton. TubuTag integrates cytoplasmic calcium signals by irreversible photoconversion from green to red fluorescence when illuminated with violet light. To image the mm-long dendritic tree of pyramidal neurons at subcellular resolution, we used a custom two-photon microscope with a large field of view. As the read-out of fluorescence can be performed several hours after photoconversion, TubuTag will help investigating dendritic signal integration and calcium homeostasis in large populations of neurons.
Using big data to estimate whale watching effort
Authors: Almunia Javier , Delponti Patricia , Rosa Fernando
Published: December 2020

The growing concerns about the negative effects caused by whale watching on wild The growing concerns about the negative effects caused by whale watching on wild cetacean populations are evincing the need to measure whale watching effort more precisely. The current alternatives do not provide sufficient information or imply time-consuming and staff intensive tasks that limit their effectiveness to establish the maximum carrying capacity for this touristic activity. A methodology based on big data analysis, using Automatic Information System (AIS) messages, can provide valuable vessel activity information, which is necessary to estimate whale watching effort on cetacean populations. We used AIS data to automatically detect whale watching operations and quantify whale watching effort with high spatial and temporal resolution in the Canary Islands. The results obtained in this study are very encouraging, proving that the methodology is able to estimate seasonal and annual trends in the whale watching effort. The methodology has also proved to be effective in providing detailed spatial information about the whale watching effort, which makes an interesting tool to manage spatial regulations and enforce exclusion zones. The widespread use of AIS devices in maritime navigation provides an enormous potential to easily extend this methodology to other regions worldwide. Any public strategy aimed at the sustainable use of the marine resources should enhance the use of this kind of information technologies, collecting and archiving detailed information on the activity of all the vessels, especially in marine protected areas.
Balanced Functional Module Detection in Genomic Data
Authors: Tritchler David , Towle-Miller Lorin M , Miecznikowski Jeffrey C
Published: December 2020

High dimensional genomic data can be analyzed to understand the effects of multiple variables on a target variable such as a clinical outcome, risk factor or diagnosis. Of special interest are functional modules, cooperating sets of variables affecting the target. Graphical models of various types are often useful for characterizing such networks of variables. In other applications such as social networks, the concept of balance in undirected signed graphs characterizes the consistency of associations within the network. To extend this concept to applications where a set of predictor variables influences an outcome variable, we define balance for functional modules. This property specifies that the module variables have a joint effect on the target outcome with no internal conflict, an efficiency that evolution may use for selection in biological networks. We show that for this class of graphs, observed correlations directly reflect paths in the underlying graph. Consequences of the balance property are exploited to implement a new module discovery algorithm, bFMD, which selects a subset of variables from highdimensional data that compose a balanced functional module. Our bFMD algorithm performed favorably in simulations as compared to other module detection methods that do not consider balance properties. Additionally, bFMD detected interpretable results in a real application for RNA-seq data obtained from The Cancer Genome Atlas (TCGA) for Uterine Corpus Endometrial Carcinoma using the percentage of tumor invasion as the target outcome of interest. bFMD detects sparse sets of variables within highdimensional datasets such that interpretability may be favorable as compared to other similar methods by leveraging balance properties used in other graphical applications.
Unified AI framework to uncover deep interrelationships between gene expression and Alzheimer’s disease neuropathologies
Authors: Beebe-Wang Nicasia , Celik Safiye , Weinberger Ethan , Sturmfels Pascal , De Jager Philip L. , Mostafavi Sara , Lee Su-In
Published: December 2020

Deep neural networks offer a promising approach for capturing complex, non-linear relationships among variables. Because they require immense sample sizes, their potential has yet to be fully tapped for understanding complex relationships between gene expression and human phenotypes. Encouragingly, a growing number of diseases are being studied through consortium efforts. Here we introduce a new analysis framework, namely MD-AD (Multi-taskDeep learning forAlzheimer’sDisease neuropathology), which leverages an unexpected synergy between deep neural networks and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which (1) require “harmonized” phenotypes (i.e., measured in a highly consistent manner) and (2) tend to capture cohort-level variations, obscuring the subtler true disease signals. Instead, MD-AD incorporates multiple related phenotypes sparsely measured across cohorts, and learns complex, non-linear interactions between genes and phenotypes not discovered using conventional expression data analysis methods (e.g., component analysis and module detection), enabling the model to capture subtler signals than cohort-level variations. Applied to the largest available collection of brain samples (N=1,758), we demonstrate that MD-AD learns a truly generalizable relationship between gene expression program and AD-related neuropathology. The learned program generalizes in several important ways, including recapitulation of the disease progress in animal models and across tissue types, and we show that such generalizability is not achieved by previous statistical paradigms. Its ability to identify genes with high non-linear relevance to neuropathology enabled us to identify a sex-specific relationship between neuropathology and immune response across microglia, providing a nuanced context for association between inflammatory genes and AD.
A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens
Authors: Stevenson Anna J. , McCartney Daniel L. , Shireby Gemma L. , Hillary Robert F. , King Declan , Tzioras Makis , Wrobel Nicola , McCafferty Sarah , Murphy Lee , McColl Barry W. , Redmond Paul , Taylor Adele M. , Harris Sarah E. , Russ Tom C. , Hannon Eilis J , McIntosh Andrew M. , Mill Jonathan , Smith Colin , Deary Ian J. , Cox Simon R. , Marioni Riccardo E. , Spires-Jones Tara L.
Published: December 2020

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain, and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in fivepost-mortembrain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers (‘epigenetic clocks’), and two inflammatory biomarkers (DNA methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent correlations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (β range=0.83-1.14, p≤0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (β=1.32, p=5×10-4); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (β=0.40, p=0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.
Exchange of molecular and cellular information: a hybrid model that integrates stem cell divisions and key regulatory interactions
Authors: Van den Broeck Lisa , Spurney Ryan J. , Fisher Adam P. , Schwartz Michael , Clark Natalie M. , Nguyen Thomas T. , Madison Imani , Gobble Mariah , Long Terri , Sozzani Rosangela
Published: December 2020

Stem cells give rise to the entirety of cells within an organ. Maintaining stem cell identity and coordinately regulating stem cell divisions is crucial for proper development. In plants, mobile proteins, such as WOX5 and SHR, regulate divisions in the root stem cell niche (SCN). However, how these proteins coordinately function to establish systemic behavior is not well understood. We propose a non-cell autonomous role for WOX5 in the CEI and identify a regulator, AN3/GIF1, that coordinates CEI divisions. Here we show with a multiscale hybrid model integrating ODEs and agent-based modeling that QC and CEI divisions have different dynamics. Specifically, by combining continuous models to describe regulatory networks and agent-based rules, we model systemic behavior, which led us to predict cell-type-specific expression dynamics of SHR, SCR, WOX5, AN3, and CYCD6;1, and experimentally validate CEI cell divisions. Conclusively, our results show an interdependency between CEI and QC divisions.

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White matter alterations in glaucoma and vision-deprived brains differ outside the visual system
Authors: Hanekamp Sandra , Ćurčić-Blake Branislava , Caron Bradley , McPherson Brent , Timmer Anneleen , Prins Doety , Boucard Christine C. , Yoshida Masaki , Ida Masahiro , Jansonius Nomdo M. , Pestilli Franco , Cornelissen Frans W.
Published: December 2020

The degree to which glaucoma has effects beyond the eye –in the brain– is unclear. We investigated white matter microstructure (WMM) alterations in 37 tracts of patients with glaucoma, monocular blindness and controls. We used reproducible methods and the advanced cloud computing platformbrainlife.io. White matter tracts were subdivided into seven categories ranging from primarily involved in vision (the visual white matter) to primarily involved in cognition and motor control. WMM in both glaucoma and monocular blind subjects was lower than controls in the visual white matter, suggesting neurodegenerative mechanisms due to reduced sensory inputs. In glaucoma participants WMM differences from controls decreased outside the visual white matter. A test-retest validation approach was used to validate these results. The pattern of results was different in monocular blind participants, where WMM properties increased outside the visual white matter as compared to controls. The pattern of results suggests that whereas in the blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the brain plasticity effects that in other patient groups follow visual loss.
Arabidopsis Casein Kinase 2 triggers Stem Cell Exhaustion under Al Toxicity and Phosphate Deficiency Through activation of the DNA Damage Response pathway
Authors: Pengliang Wei , Demulder Manon , David Pascale , Eekhout Thomas , Yoshiyama Kaoru Okamoto , Nguyen Long , Vercauteren Ilse , Eeckhout Dominique , Galle Margot , De Jaeger Geert , Larsen Paul , Audenaert Dominique , Desnos Thierry , Nussaume Laurent , Loris Remy , De Veylder Lieven
Published: December 2020

Aluminum (Al) toxicity and inorganic phosphate (Pi) limitation are widespread chronic abiotic and mutually enhancing stresses that profoundly affect crop yield. Both stresses cause a strong inhibition of root growth, resulting from a progressive exhaustion of the stem cell niche. Here, we report on a casein kinase 2 (CK2) inhibitor identified by its capability to maintain a functional root stem cell niche under Al toxic conditions. CK2 operates through phosphorylation of the cell cycle checkpoint activator SUPPRESSOR OF GAMMA RADIATION1 (SOG1), priming its activity under DNA-damaging conditions. In addition to yielding Al tolerance, CK2 and SOG1 inactivation prevents meristem exhaustion under Pi starvation, revealing the existence of a low Pi-induced cell cycle checkpoint that depends on the DNA damage activator ATAXIA-TELANGIECTASIA MUTATED. Overall, our data reveal an important physiological role for the plant DNA damage response pathway under agriculturally limiting growth conditions, opening new avenues to cope with Pi limitation.
Model-based aversive learning in humans is supported by preferential task state reactivation
Authors: Wise Toby , Liu Yunzhe , Chowdhury Fatima , Dolan Raymond J.
Published: December 2020

Harm avoidance is critical for survival, yet little is known regarding the underlying neural mechanisms supporting avoidance when we cannot rely on direct trial and error experience. Neural reactivation, and sequential replay, have emerged as potential candidate mechanisms. Here, during an aversive learning task, in conjunction with magnetoencephalography, we show prospective and retrospective reactivation for planning and learning respectively, coupled to evidence for sequential replay. Specifically, when subjects plan in an aversive context, we find preferential reactivation of subsequently chosen goal states and sequential replay of the preceding path. This reactivation was associated with greater hippocampal theta power. At outcome receipt, unchosen goal states are reactivated regardless of outcome valence. However, replay of paths leading to goal states was directionally modulated by outcome valence, with aversive outcomes leading to stronger reverse replay compared to safe outcomes. Our findings suggest that avoidance behaviour involves simulation of alternative future and past outcome states through hippocampally-mediated reactivation and replay.
3D Genome Contributes to Protein-Protein Interactome
Authors: Shi Yi , Cao Song , Zhang Mingxuan , Su Xianbin , Guo Zehua , Wang Jiayi , Liu Tingting , Shi Hui , He Guang
Published: December 2020

Numerous computational methods have been proposed to predict protein-protein interactions, none of which however, considers the original DNA loci of the interacting proteins in the perspective of 3D genome. Here we retrospect the DNA origins of the interacting proteins in the context of 3D genome and discovered that 1) if a gene pair is more proximate in 3D genome, their corresponding proteins are more likely to interact. 2) signal peptide involvement of PPI affects the corresponding gene-gene proximity in 3D genome space. 3) by incorporating 3D genome information, existing PPI prediction methods can be further improved in terms of accuracy. Combining our previous discoveries, we conjecture the existence of 3D genome driven cellular compartmentalization, meaning the co-localization of DNA elements lead to increased probability of the co-localization of RNA elements and protein elements.
The ecology of Nipah virus in Bangladesh: a nexus of land use change and opportunistic feeding behavior in bats
Authors: McKee Clifton D. , Islam Ausraful , Luby Stephen P. , Salje Henrik , Hudson Peter J. , Plowright Raina K. , Gurley Emily S.
Published: December 2020

Nipah virus is a bat-borne paramyxovirus that produces yearly outbreaks of fatal encephalitis in Bangladesh. Understanding the ecological conditions that lead to spillover from bats to humans can assist in designing effective interventions. To investigate the current and historical processes that drive Nipah spillover in Bangladesh, we analyzed the relationship between spillover events and climatic conditions, the spatial distribution and size ofPteropus mediusroosts, and patterns of land use change in Bangladesh over the last 300 years. We found that 53% of annual variation in winter spillovers is explained by winter temperature, which may affect bat behavior, physiology, and human risk behaviors. We infer from changes in forest cover that a progressive shift in bat roosting behavior occurred over hundreds of years, producing the current system where a majority ofP. mediuspopulations are small (median of 150 bats), occupy roost sites for 10 years or more, live in areas of high human population density, and opportunistically feed on cultivated food resources – conditions that promote viral spillover. Without interventions, continuing anthropogenic pressure on bat populations similar to what has occurred in Bangladesh could result in more regular spillovers of other bat viruses, including Hendra and Ebola viruses.
Boom-bust population dynamics can increase diversity in evolving competitive communities
Authors: Doebeli Michael , Jaque Eduardo Cancino , Ispolatov Iaroslav
Published: December 2020

The processes and mechanisms underlying the origin and maintenance of biological diversity have long been of central importance in ecology and evolution. The competitive exclusion principle states that the number of coexisting species is limited by the number of resources, or by the species’ similarity in resource use. Natural systems such as the extreme diversity of unicellular life in the oceans provide counter examples. It is known that mathematical models incorporating population fluctuations can lead to violations of the exclusion principle. Here we use simple eco-evolutionary models to show that a certain type of population dynamics, boom-bust dynamics, can allow for the evolution of much larger amounts of diversity than would be expected with stable equilibrium dynamics. Boom-bust dynamics are characterized by long periods of almost exponential growth (boom) and a subsequent population crash due to competition (bust). When such ecological dynamics are incorporated into an evolutionary model that allows for adaptive diversification in continuous phenotype spaces, desynchronization of the boom-bust cycles of coexisting species can lead to the maintenance of high levels of diversity.
Topological Learning for Brain Networks
Authors: Songdechakraiwut Tananun , Chung Moo K.
Published: December 2020

This paper proposes a novel topological learning framework that can integrate networks of different sizes and topology through persistent homology. This is possible through the introduction of a new topological loss function that enables such challenging task. The use of the proposed loss function bypasses the intrinsic computational bottleneck associated with matching networks. We validate the method in extensive statistical simulations with ground truth to assess the effectiveness of the topological loss in discriminating networks with different topology. The method is further applied to a twin brain imaging study in determining if the brain network is genetically heritable. The challenge is in overlaying the topologically different functional brain networks obtained from the resting-state functional magnetic resonance imaging (fMRI) onto the template structural brain network obtained through the diffusion tensor imaging (DTI).
Major diversification of caribou shaped by glacial cycles before the Last Glacial Maximum
Authors: Taylor Rebecca S. , Manseau Micheline , Klütsch Cornelya F. C. , Polfus Jean L. , Steedman Audrey , Hervieux Dave , Kelly Allicia , Larter Nicholas C. , Gamberg Mary , Schwantje Helen , Wilson Paul J.
Published: December 2020

Pleistocene glacial cycles influenced the diversification of high-latitude wildlife species through recurrent periods of range contraction, isolation, divergence, and expansion from refugia and subsequent admixture of refugial populations. For many taxa, research has focused on genetic patterns since the Last Glacial Maximum (LGM), however glacial cycles before the LGM likely impacted genomic variation which may influence contemporary genetic patterns. We investigate diversification and the introgressive history of caribou (Rangifer tarandus) in western Canada using 33 high-coverage whole genomes coupled with larger-scale mitochondrial data. Contrary to the well-established paradigm that caribou ecotypes and contemporary genetic diversity arose from two major lineages in separate refugia during the LGM, a Beringian-Eurasian (BEL) and a North American (NAL) lineage, we found that the major diversifications of caribou occurred much earlier at around 110 kya, the start of the last glacial period. Additionally, we found effective population sizes of some caribou reaching ~700,000 to 1,000,000 individuals, one of the highest recorded historical effective population sizes for any mammal species thus far. Mitochondrial analyses dated introgression events prior to the LGM dating to 20-30 kya and even more ancient at 60 kya, coinciding with colder periods with extensive ice coverage, further demonstrating the importance of glacial cycles and events prior to the LGM in shaping demographic history. Reconstructing the origins and differential introgressive history has implications for predictions on species responses under climate change. Our results highlight the need to investigate pre-LGM demographic patterns to fully reconstruct the origin of species diversity, especially for high-latitude species.
Novel TREM2 splicing isoform that lacks the V-set immunoglobulin domain is abundant in the human brain
Authors: Kiianitsa Kostantin , Kurtz Irina , Beeman Neal , Matsushita Mark , Chien Wei-Ming , Raskind Wendy H. , Korvatska Olena
Published: December 2020

TREM2 is an immunoglobulin-like receptor expressed by certain myeloid cells, such as macrophages, dendritic cells, osteoclasts and microglia. In the brain, TREM2 plays an important role in the immune function of microglia, and its dysfunction is linked to various neurodegenerative conditions in humans. Ablation of TREM2 or its adaptor protein TYROBP causes Polycystic Lipo-Membranous Osteodysplasia with Sclerosing Leukoencephalopathy (also known as Nasu-Hakola disorder) with early onset of dementia, while some missense variants in TREM2 are associated with an increased risk of late-onset Alzheimer’s disease. Human TREM2 gene is a subject to alternative splicing, and its major, full-length canonical transcript encompasses 5 exons. Herein, we report a novel alternatively spliced TREM2 isoform without exon 2 (Δe2), which constitutes a sizable fraction of TREM2 transcripts and has highly variable inter-individual expression in the human brain (average frequency 10%; range 3.7-35%). The protein encoded by Δe2 lacks a V-set immunoglobulin domain from its extracellular part but retains its transmembrane and cytoplasmic domains. We demonstrated Δe2 protein expression in TREM2-positive THP-1 cells, in which the expression of full-length transcript was precluded by CRISPR/Cas9 disruption of the exon 2 coding frame. In “add-back” experiments, overexpression of full-length, but not Δe2 TREM2, restored phagocytic capacity and promoted interferon type I response in the knockout cells. Our findings suggest that expression of a Δe2 splice isoform may modify the dosage of full-length transcript potentially weakening some TREM2 receptor functions in the human brain.
Phase separation of chromatin brush driven by enzymatic reaction dynamics of histone posttranslational modifications
Authors: Yamamoto Tetsuya , Sakaue Takahiro , Schiessel Helmut
Published: December 2020

The nuclei of undifferentiated cells show uniform decompacted chromatin while during development nuclei decrease in size and foci of condensed chromatin appear, reminiscent of phase separation. This study is motivated by recent experiments that suggest that the unbinding of enzymes that chemically modify (acetylate) histone tails causes decompaction of condensed chromatin. Here we take into account the enzymatic reactions of histone modifications to predict the phase separation of chromatin in a model system, the chromatin brush, which mimics chromatin at the proximity of a nuclear membrane. The model contains ‘activators’ and ‘silencers’, which change the state of the nucleosomes to (transcriptionally) active or inactive via the Michaelis-Menten kinetics. Our theory predicts that the chromatin brush will phase separate when the brush height is reduced below a threshold height. The phase separation is driven by an anti-correlation: Activators change the state of nucleosomes to the active state suppressing the binding of silencers to these nucleosomes andvice versa.
Mass allelic exchange: enabling sexual genetics inEscherichia coli
Authors: Khetrapal Varnica , Yong Liyana Ow , Chen Swaine L.
Published: December 2020

Despite dramatic advances in genomics, connecting genotypes to phenotypes is still challenging. Sexual genetics combined with linkage analysis is a powerful solution to this problem but generally unavailable in bacteria. We build upon a strong negative selection system to invent Mass Allelic Exchange (MAE), which enables hybridization of arbitrary (including pathogenic) strains ofE. coli. MAE reimplements the natural phenomenon of random crossovers, enabling classical linkage analysis. We demonstrate the utility of MAE with virulence-related gain-of-function screens, discovering that transfer of a single operon from a uropathogenic strain is sufficient for enabling a commensalE. colito form large intracellular bacterial collections within bladder epithelial cells. MAE thus enables assaying natural allelic variation inE. coli(and potentially other bacteria), complementing existing loss-of-function genomic techniques.

One Sentence Summary

We create F1 hybrids ofE. coliusing MAE, bringing the power of linkage analysis to bear on phenotypic diversity (including virulence)
A two-arm, randomized, controlled, multi-centric, open-label Phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19
Authors: Kumar Suresh , de Souza Rosemarie , Nadkar Milind , Guleria Randeep , Trikha Anjan , Joshi Shashank R. , Loganathan Subramanian , Vaidyanathan Sivakumar , Marwah Ashwani , Athalye Sandeep N.
Published: December 2020

An uncontrolled increase in cytokine production may lead to systemic hyperinflammation, vascular hypo-responsiveness, increased endothelial permeability, hypercoagulation, multi-organ dysfunction and eventually death in moderate to severely ill COVID-19 patients. Targeting T-cells, an important driver of the hyperinflammatory response, in the treatment of COVID-19, could potentially reduce mortality and improve survival rates. Itolizumab is an anti-CD6 humanized monoclonal antibody with an immunomodulating action on Teffector cells that downregulates T-cell activation, proliferation and subsequent production of various chemokines and cytokines. The efficacy and safety of Itolizumab for the treatment of cytokine release syndrome in patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 was evaluated in a multi-centric, open-label, two-arm, controlled, randomized, phase 2 study. Eligible patients were randomized (2:1) to arm A (best supportive care + Itolizumab) and arm B (best supportive care). The primary outcome of interest was reduction in all-cause mortality 30 days after enrolment. Thirty-six patients were screened, 5 were treated as first dose sentinels and the rest were randomized, whilst 4 patients were considered screen failures. Two patients in the Itolizumab treatment arm discontinued prior to receiving the first dose and were replaced. At the end of 1 month, there were 3 deaths in arm B, and none in arm A (p= 0.0296). At the end of the follow-up period, more patients in Arm A had improved SpO2 without increasing FiO2 (p=0.0296), improved PaO2 (p=0.0296), and reduction in IL-6 (43 pg/ml vs 212 pg/ml; p=0.0296) and tumor necrotic factor-α (9 pg/ml vs 39 pg/ml; p=0.0253) levels. Itolizumab was generally safe and well tolerated, and transient lymphopenia (11 patients in Arm A) and infusion reactions (7 patients) were the commonly reported treatment related safety events. These encouraging results indicate that larger clinical trials are warranted to establish the role of Itolizumab in controlling immune hyperactivation in COVID-19.
Rho GTPase transcriptional activity and breast cancer risk: A Mendelian randomization analysis
Authors: Kazmi Nabila , Robinson Tim , Zheng Jie , Kar Siddhartha , Martin Richard M , Ridley Anne J
Published: December 2020

Background

Rho GTPases are a family of 20 intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. Rho GTPases are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR).

Methods

MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding.

Results

We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI): 1.03, 1.09; P=5.65×10-5) and OR 1.22 (95% CI: 1.11, 1.35; P=5.22×10−5) in normal breast tissue and blood respectively). The direction of association was consistent for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was inversely associated with overall and ER+ breast cancer risk. The evidence from colocalization analyses strongly supported the MR results particularly for RHOD.

Conclusions

Our study suggests a potential causal role of increased RHOD gene expression, and a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.
Performance of saliva specimens for the molecular detection of SARS-CoV-2 in the community setting: does sample collection method matter?
Authors: Fernández-González Marta , Agulló Vanesa , de la Rica Alba , Infante Ana , Carvajal Mar , García José Alberto , Gonzalo-Jiménez Nieves , Cuartero Claudio , Ruiz Montserrat , de Gregorio Carlos , Sánchez Manuel , Masiá Mar , Gutiérrez Félix
Published: December 2020

Background

Data on the performance of saliva specimens for diagnosing COVID-19 in ambulatory patients are scarce and inconsistent. We assessed saliva-based specimens for detecting SARS-CoV-2 by RT-PCR in the community setting and compared three different collection methods.

Method

Prospective study conducted in three primary care centres. RT-PCR was performed in paired nasopharyngeal swabs (NPS) and saliva samples collected from outpatients with a broad clinical spectrum of illness. To assess differences in collection methods, saliva specimens were obtained in a different way in each of the participating centres: supervised collection (SVC), oropharyngeal washing (OPW) and self-collection (SC).

Results

NPS and saliva pairs of samples from 577 patients (median age 39 years, 44% men, 42% asymptomatic) were collected and tested, and 120 (20.8%) gave positive results. The overall agreement with NPS and kappa coefficients (KƘ) for SVC, OPW and SC were 95% (Ƙ=0.85), 93.4% (Ƙ=0.76), and 93.3% (Ƙ=0.76), respectively. The sensitivity (95% CI) of the saliva specimens varied from 86% (72.6-93.7) for SVC to 66.7% (50.4-80) for SC samples. The sensitivity was higher in samples with lower cycle threshold (Ct) values. The best performance of RT-PCR was observed for SVC, with sensitivity (95% CI) for Ct values ≤32 of 97% (82.5-99.8) in symptomatic, and 88.9% (50.7-99.4) in asymptomatic individuals.

Conclusions

Saliva is an acceptable specimen for the detection of SARS-CoV-2 in the community setting. Specimens collected under supervision perform comparably to NPS and can effectively identify individuals with higher risk of transmission in real life conditions.
Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK
Authors: Carmichael Polly , Butler Gary , Masic Una , Cole Tim J , De Stavola Bianca L , Davidson Sarah , Skageberg Elin M. , Khadr Sophie , Viner Russell
Published: December 2020

Background

In adolescents with severe and persistent gender dysphoria (GD), gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with the aim of delaying irreversible and unwanted pubertal body changes. Evidence of outcomes of pubertal suppression in GD is limited.

Methods

We undertook an uncontrolled prospective observational study of GnRHa as monotherapy in 44 12-15 year olds with persistent and severe GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR) total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured interviews were conducted on GnRHa.

Results

44 patients had data at 12 months follow-up, 24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones.

There was no change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24 months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9); BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm index at 36 months. Most participants reported positive or a mixture of positive and negative life changes on GnRHa. Anticipated adverse events were common.

Conclusions

Overall patient experience of changes on GnRHa treatment was positive. We identified no changes in psychological function. Changes in BMD were consistent with suppression of growth. Larger and longer-term prospective studies using a range of designs are needed to more fully quantify the benefits and harms of pubertal suppression in GD.
CDH26 amplifies airway epithelial IL-4 receptor α signaling in asthma
Authors: Feng Yuchen , Chen Shengchong , Chang Chenli , Wu Wenliang , Chen Dian , Gao Jiali , Chen Gongqi , Yi Lingling , Zhen Guohua
Published: December 2020

Background

Activation of interleukin (IL)-4 receptor (R) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. Cadherin-26 (CDH26), a cadherin implicated in polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. We hypothesize that CDH26 plays a role in airway epithelial IL-4R signaling in asthma.

Methods

We measured airway resistance, mucus production, airway inflammation, and Il-4Rα expression in Cdh26-/- and WT mice after allergen sensitization and challenge. We explored the role of CDH26 in IL-4R signaling, mucin genes and eosinophilic chemokine expression in cultured bronchial epithelial cells and bronchial brushings from asthma patients.

Results

Cdh26 deficiency nearly blocked airway mucus overproduction, and suppressed AHR and airway eosinophilia in a murine model of allergic airway disease. Interestingly, Il-4Rα expression in airway epithelium was markedly reduced in Cdh26-/- mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R, -induced IL-4Rα and IL-13Rα1 expression, and suppressed the downstream Jak1 and Stat6 phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC, MUC5B and eosinophilic chemokines CCL11, CCL24, CCL26 expression. In contrast, CDH26 overexpression intensified IL-13-induced activation of IL-4Rα signaling. In asthma patients, CDH26 was the only one upregulated of 11 cadherins in bronchial brushings. CDH26 expression significantly correlated with epithelial IL-4Rα, MUC5AC expression, sputum eosinophilia and fractional exhaled nitric oxide (FeNO).

Conclusion

Taken together, CDH26 is an amplifier of epithelial IL-4R signaling in asthma, and may represent a therapeutic target for airway mucus overproduction.
Behavioral Inhibition and Dual Mechanisms of Anxiety Risk: Disentangling Neural Correlates of Proactive and Reactive Control
Authors: Valadez Emilio A. , Troller-Renfree Sonya V. , Buzzell George A. , Henderson Heather A. , Chronis-Tuscano Andrea , Pine Daniel S. , Fox Nathan A.
Published: December 2020

Background

Behavioral inhibition (BI) is a temperament style characterized by heightened reactivity and negative affect in response to novel people and situations, and it is a strong predictor of anxiety problems later in life. However, not all BI children develop anxiety problems and mounting evidence suggests that how one manages their cognitive resources (cognitive control) influences anxiety risk. The present study tests whether more (proactive control) or less (reactive control) planful cognitive strategies moderate relations between BI and anxiety.

Methods

Participants included 144 adolescents (55.9% female) whose temperament was assessed during toddlerhood. In adolescence (Mage= 15.4 years), participants completed an AX Continuous Performance Test while EEG was recorded in order to disentangle neural activity related to proactive (cue-locked P3b) and reactive (probe-locked N2) control.

Results

BI was associated with greater total anxiety scores only among adolescents with smaller ΔP3bs and larger ΔN2s – a pattern consistent with decreased reliance on proactive strategies and increased reliance on reactive strategies. Additionally, a larger ΔP3b was associated with greater total anxiety scores.

Conclusions

BI relates to risk for anxiety specifically among adolescents who rely less on proactive strategies and more on reactive control strategies. Results further suggest that proactive control differentiates a BI-related etiological pathway to anxiety from a more general pathway to anxiety occurring regardless of BI level. Thus, developmental context (i.e., temperament) moderates the association between anxiety and proactive control. The present study is the first to characterize how proactive and reactive control uniquely relate to pathways toward anxiety risk.
Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+T cellsin vivo
Authors: Simonetti Francesco R. , Zhang Hao , Soroosh Garshasb P. , Duan Jiayi , Rhodehouse Kyle , Hill Alison L. , Beg Subul A. , McCormick Kevin , Raymond Hayley , Nobles Christopher L. , Everett John , Kwon Kyungyoon J. , White Jennifer A. , Lai Jun , Margolick Joseph B. , Hoh Rebecca , Deeks Steven G. , Bushman Frederic D. , Siliciano Janet D. , Siliciano Robert F.
Published: December 2020

Clonal expansion of infected CD4+T cells is a major mechanism of HIV-1 persistence and a barrier to cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here we show that it is possible to link antigen responsiveness, full proviral sequence, integration site, and T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated Cytomegalovirus (CMV)- and Gag-responding CD4+T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2,STAT5B, MKL1), proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ-integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.
Adaptive cell invasion maintains organ homeostasis
Authors: Peloggia Julia , Münch Daniela , Meneses-Giles Paloma , Romero-Carvajal Andrés , McClain Melainia , Pan Y. Albert , Piotrowski Tatjana
Published: December 2020

Mammalian inner ear and fish lateral line sensory hair cells depend on fluid motion to transduce environmental signals and elicit a response. In mammals, actively maintained ionic homeostasis of the cochlear and vestibular fluid (endolymph) is essential for hair cell function and numerous mammalian hearing and vestibular disorders arise from disrupted endolymph ion homeostasis. Lateral line hair cells, however, are openly exposed to the aqueous environment with fluctuating ionic composition. How sensory transduction in the lateral line is maintained during environmental changes of ionic composition is not fully understood. Using lineage labeling,in vivotime lapse imaging and scRNA-seq, we discovered highly motile skin-derived cells that invade mature mechanosensory organs of the zebrafish lateral line and differentiate into Neuromast-associated (Nm) ionocytes. Furthermore, the invasive behavior is adaptive as it is triggered by drastic fluctuations in environmental stimuli. Our findings challenge the notion of an entirely placodally-derived lateral line and identify Nm ionocytes as regulators of mechanosensory hair cell function by modulating the ionic microenvironment. The discovery of lateral line ionocytes provides an experimentally accessiblein vivosystem to study cell invasion and migration, as well as the physiological adaptation of vertebrate organs to changing environmental conditions.
The N-glycosylation sites and Glycan-binding ability of S-protein in SARS-CoV-2 Coronavirus
Authors: Chen Wentian , Hui Ziye , Ren Xiameng , Luo Yijie , Shu Jian , Yu Hanjie , Li Zheng
Published: December 2020

The emerging acute respiratory disease, COVID-19, caused by SARS-CoV-2 Coronavirus (SARS2 CoV) has spread fastly all over the word. As a member of RNA viruses, the glycosylation of envelope glycoprotein plays the crucial role in protein folding, evasing host immune system, invading host cell membrane, even affecting host preference. Therefore, detail glyco-related researches have been adopted in the Spike protein (S-protein) of SARS2 CoV from the bioinformatic perspective. Phylogenic analysis of S-protein sequences revealed the evolutionary relationship of N-glycosylation sites in different CoVs. Structural comparation of S-proteins indicated their similarity and distributions of N-glycosylation sites. Further potential sialic acid or galactose affinity domains have been described in the S-protein by docking analysis. Molecular dynamic simulation for the glycosylated complexus of S-protein-ACE2 implied that the complicate viral binding of receptor-binding domain may be influenced by peripheric N-glycans from own and adjacent monoers. These works will contribute to investigate the N-glycosylation in S-protein and explain the highly contagious of COVID-19.
Synergistic stabilization of a double mutant in CI2 from anin-celllibrary screen
Authors: Hamborg Louise , Granata Daniele , Olsen Johan G. , Roche Jennifer Virginia , Pedersen Lasse Ebdrup , Nielsen Alex Toftgaard , Lindorff-Larsen Kresten , Teilum Kaare
Published: December 2020

Most single point mutations destabilize folded proteins. Mutations that stabilize a protein typically only have a small effect and multiple mutations are often needed to substantially increase the stability. Multiple point mutations may act synergistically on the stability, and it is not straightforward to predict their combined effect from the individual contributions. Here, we have applied an efficientin-cellassay to select variants of the barley chymotrypsin inhibitor 2 with increased stability. We find two variants that are more than 3.8 kJ/mol more stable than the wild-type. In one case the increased stability is the effect of the single substitution D55G. The other case is a double mutant, L49I/I57V, which is 5.1 kJ/mol more stable than the sum of the effects of the individual mutations. In addition to demonstrating the strength of our selection system for finding stabilizing mutations, our work also demonstrate how subtle conformational effects may modulate stability.
A pomegranate peel extract as inhibitor of SARS-CoV-2 Spike binding to human ACE2 (in vitro): a promising source of novel antiviral drugs
Authors: Tito Annalisa , Colantuono Antonio , Pirone Luciano , Pedone Emilia , Intartaglia Daniela , Giamundo Giuliana , Conte Ivan , Vitaglione Paola , Apone Fabio
Published: December 2020

Plant extracts are rich in bioactive compounds, such as polyphenols, sesquiterpenes and triterpenes, with potential antiviral activities. As the dramatic outbreak of the pandemic COVID-19, caused by the SARS-CoV-2 virus, thousands of scientists are working tirelessly trying to understand the biology of this new virus and the disease pathophysiology, with the main goal to discover effective preventive treatments and therapeutic agents. Plant-derived secondary metabolites may play key roles in preventing and counteracting the rapid spread of SARS-CoV-2 infections by inhibiting the activity of several viral proteins, in particular those involved in the virus entry into the host cells and its replication. In this study, by using differentin vitroapproaches, we uncovered the role of a pomegranate peel extract in attenuating the interaction between the SARS-CoV-2 Spike glycoprotein and the human Angiotensin-Converting Enzyme 2 (ACE2) receptor, and in inhibiting the activity of the virus 3CL protease. Although further studies will be determinant to assess the efficacy of this extractin vivo, our results open up new promising opportunities to employ natural extracts for the development of effective and innovative therapies in the fight against SARS-CoV-2.