bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol use and dementia: new research directions
Authors: Visontay Rachel , Rao Rahul Tony , Mewton Louise
Published: December 2020

Purpose of review

Alcohol is gaining increased recognition as an important risk factor for dementia. This review summarises recent evidence on the relationship between alcohol use and dementia, focusing on studies published from January 2019 to August 2020.

Recent findings

Epidemiological data continues to yield results consistent with protective effects of low-to-moderate alcohol consumption for dementia and cognitive function. However, recent literature highlights the methodological limitations of existing observational studies. The effects of chronic, heavy alcohol use are clearer, with excessive consumption causing alcohol-related brain damage. Several pathways to this damage have been suggested, including the neurotoxic effects of thiamine deficiency, ethanol and acetaldehyde.

Future research would benefit from greater implementation of analytical and design-based approaches to robustly model the alcohol use-dementia relationship in the general population, and should make use of large, consortia-level data. Early intervention to prevent dementia is critical: thiamine substitution has shown potential but requires more research, and psychosocial interventions to treat harmful alcohol use have proven effective. Finally, diagnostic criteria for alcohol-related dementia require formal validation to ensure usefulness in clinical practice.
Laboratory findings in coronavirus disease 2019 (COVID-19) patients: a comprehensive systematic review and meta-analysis
Authors: Karimian Mohammad , Jamshidbeigi Amirreza , Badfar Gholamreza , Azami Milad
Published: December 2020

Background

In early December 2019, the first patient with COVID-19 pneumonia was found in Wuhan, Hubei Province, China. Recent studies have suggested the role of primary laboratory tests in addition to clinical symptoms for suspected patients, which play a significant role in the diagnosis of COVID-19. Therefore, the present study was conducted to evaluate laboratory findings in COVID-19 patients.

Data Sources

PubMed/Medline, Scopus, EMBASE, Web of Science (ISI), Cochrane Library, Ovid, Science Direct, CINAHL and EBSCO.

Study Selection

Cross-sectional of adverse outcomes stratified by the status of ICLs were selected.

Data Extraction

The prevalence of available variables for laboratory tests were extracted.

Results

Finally, 52 studies involving 5490 patients with COVID-19 entered the meta-analysis process. The prevalence of leukopenia, lymphopenia, elevated c-reactive protein (CRP), elevated erythrocyte sedimentation rate (ESR), elevated serum amyloid A, elevated ferritin was estimated to be 20.9% (95%CI: 17.9-24.3), 51.6% (95%CI: 44.0-59.1), 63.6% (95%CI: 57.0-69.8), 62.5% (95%CI: 50.1-73.5), 63.6% (95%CI: 57.0-69.8), 62.5% (95%CI: 50.1-73.5), 74.7% (95%CI: 50.0-89.7), and 72.6% (95%CI: 58.1-83.5), respectively. The prevalence of elevated interleukin-6 was 59.9% (95%CI: 48.2-70.5), CD3 was 68.3% (95%CI: 50.1-82.2), reduced CD4 was 62.0% (95%CI: 51.1-71.6), reduced CD8 was 42.7% (95%CI: 32.2-53.9). The prevalence of elevated troponin-I was 20.6% (95%CI: 9.0-40.5), elevated creatine kinase-MB (CKMB) was 14.7% (95%CI: 7.1-28.0), elevated brain natriuretic peptide (BNP) was 48.9% (95%CI: 30.4-67.7), elevated blood urea nitrogen was 13.1% (95%CI: 6.6-24.4),, elevated creatinine was 7.2% (95%CI: 4.4-11.8), elevated lactate dehydrogenase (LDH) was 53.1% (95%CI: 43.6-62.4), hyperglycemia was 41.1% (95% CI: 28.2-55.5), elevated total bilirubin was 48.9% (95%CI: 30.4-67.7), reduced albumin was 54.7% (95%CI: 38.1-70.2), reduced pre-albumin was 49.0% (95%CI: 26.6-71.8), and reduced PT was 53.1% (95% CI: 43.6-62.4), and D-dimer was 44.9% (95%CI: 31.0-59.6).

Conclusion

This study provides a comprehensive description of laboratory characteristics in patients with COVID-19. The results show that lymphopenia, elevated CRP, elevated ESR, elevated ferritin, elevated serum amyloid A, elevated BNP, reduced albumin, reduced pre-albumin, reduced CD3, reduced CD4, reduced CD8, elevated D-dimer, reduced PT, elevated interleukin-2, elevated interleukin-6, elevated LDH and hyperglycemia are the common findings at the time of admission.
rTPCandnls.multstart: a new pipeline to fit thermal performance curves inR
Authors: Padfield Daniel , O’Sullivan Hannah , Pawar Samraat
Published: December 2020

The quantification of thermal performance curves (TPCs) for biological rates has many applications to problems such as predicting species’ responses to climate change. There is currently no widely used open-source pipeline to fit mathematical TPC models to data, which limits the transparency and reproducibility of the curve fitting process underlying applications of TPCs.

We present a new pipeline inRthat currently allows for reproducible fitting of 24 different TPC models using non-linear least squares (NLLS) regression. The pipeline consists of two packages –rTPCandnls. multstart– that allow multiple start values for NLLS fitting and provides helper functions for setting start parameters. This pipeline overcomes previous problems that have made NLLS fitting and estimation of key parameters difficult or unreliable.

We demonstrate howrTPCandnls.multstartcan be combined with other packages inRto robustly and reproducibly fit multiple models to multiple TPC datasets at once. In addition, we show how model selection or averaging, weighted model fitting, and bootstrapping can easily be implemented within the pipeline.

This new pipeline provides a flexible and reproducible approach that makes the challenging task of fitting multiple TPC models to data accessible to a wide range of users.
The alleviation of neuropathic pain behaviours by a single injection of a synthetic substance P-botulinum conjugate persists for up to 120d and can be restored with a second injection of conjugate
Authors: Maiarù Maria , Leese Charlotte , Davletov Bazbek , Hunt Stephen P.
Published: December 2020

There is an urgent need for new pain-relieving therapies. We have previously shown using mouse models of persistent pain that a single intrathecal injection of substance P conjugated to the light chain of botulinum toxin (SP-BOT) silenced neurons in the dorsal horn of the spinal cord and alleviated mechanical hypersensitivity. The SP-BOT construct selectively silenced neurokinin 1 receptor positive (NK1R+) neurons in the superficial dorsal horn of the spinal cord. A subset of these NK1R+ neurons are nociceptive projection neurons and convey injury-related information to the brainstem, initiating and maintaining programmes of escape and recovery essential for healing. Previously, we observed a reduction in mechanical hypersensitivity in a spared nerve injury (SNI) model of neuropathic pain state after intrathecal injection of SP-BOT over the lumbar spinal cord and lasting for up to 40 days. In this latest study, we have extended these observations and now show that thermal and affective measures of pain behaviour were also alleviated by a single intrathecal injection of SP-BOT. By introducing SNI 30 days, 60 days, 90 days or 120 days after injection of SP-BOT we have established that NK1R+ spinal neurons in the superficial lamina of the dorsal horn were silenced for up to 120 days following a single intrathecal injection of the botulinum construct. We also show that behavioural alleviation of neuropathic pain symptoms could be reinstated by a second injection of SP-BOT at 120 days. Taken together this research demonstrates that this recently developed botulinum toxin conjugate provides a powerful new way of providing long term pain relief without toxicity following a single injection and also has a therapeutic potential for repeated dosing when pain begins to return.
The phagocytosis oxidase/Bem1p (PB1) domain-containing protein PB1CP negatively regulates the NADPH oxidase RBOHD in plant immunity
Authors: Goto Yukihisa , Maki Noriko , Sklenar Jan , Derbyshire Paul , Menke Frank L.H. , Zipfel Cyril , Kadota Yasuhiro , Shirasu Ken
Published: December 2020

Perception of pathogen-associated molecular patterns (PAMPs) by surface-localized pattern-recognition receptors activates RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) through direct phosphorylation by BOTRYTIS-INDUCED KINASE 1 (BIK1) and induces the production of reactive oxygen species (ROS). ROS have direct antimicrobial properties but also serve as signaling molecules to activate additional defense responses such as stomatal closure. RBOHD activity must be tightly controlled to avoid the detrimental effects of ROS, but little is known about RBOHD downregulation.

To better understand the regulation of RBOHD, we used co-immunoprecipitation of RBOHD coupled with mass spectrometry analysis to identify RBOHD-associated proteins.

Among RBOHD-associated proteins, we identified PHAGOCYTOSIS OXIDASE/ BEM1P (PB1) DOMAIN-CONTAINING PROTEIN (PB1CP). We found that PB1CP negatively regulates RBOHD and the resistance against the fungal pathogenColletotrichum higginsianum. PB1CP directly interacts with RBOHDin vitro, and PAMP treatment increases the interactionin vivo. PB1CP is localized at the cell periphery and in cytoplasm, but PAMP treatment induces PB1CP relocalization to small endomembrane compartments.PB1CPoverexpression reduces plasma membrane localization of RBOHD, suggesting that PB1CP down-regulates RBOHD function by relocalizing it away from the plasma membrane.

We reveal a novel negative regulation mechanism of ROS production through the relocalization of RBOHD by PB1CP.
GENERATION AND CHARACTERIZATION OF IMMORTALIZED MOUSE CORTICAL ASTROCYTES FROM WILDTYPE AND CONNEXIN43 KNOCKOUT MICE
Authors: Cibelli Antonio , Lopez-Quintero Sandra Veronica , McCutcheon Sean , Scemes Eliana , Spray David C. , Stout Randy F. , Suadicani Sylvia O. , Thi Mia M. , Urban-Maldonado Marcia
Published: December 2020

We transduced mouse cortical astrocytes cultured from four litters of embryonic wildtype (WT) and connexin43 (Cx43) null mouse pups with lentiviral vector encoding hTERT and measured expression of astrocyte-specific markers up to passage 10 (p10). The immortalized cell lines thus generated (designated IWCA and IKOCA, respectively) expressed biomarkers consistent with those of neonatal astrocytes, including Cx43 from wildtype but not from Cx43-null mice, lack of Cx30, and presence of Cx26. AQP4, the water channel that is found in high abundance in astrocyte end-feet, was expressed at moderately high levels in early passages, and its mRNA and protein declined to low but still detectable levels by p10. The mRNA levels of the astrocyte biomarkers aldehyde dehydrogenase 1 (ALDH1), glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP) remained relatively constant during successive passages. GS protein expression was maintained while GFAP declined with cell passaging but was still detectable at p10. Both mRNA and protein levels of glutamate transporter 1 (GLT-1) declined with passage number. Immunostaining at corresponding times was consistent with the data from Western blots and provided evidence that these proteins were expressed at appropriate intracellular locations. Consistent with our goal of generating immortalized cell lines in which Cx43 was either functionally expressed or absent, IWCA cells were found to be well coupled with respect to intercellular dye transfer and similar to primary astrocyte cultures in terms of time course of junction formation, electrical coupling strength and voltage sensitivity. Moreover, barrier function was enhanced in co-culture of the IWCA cell line with bEnd.3 microvascular endothelial cells. In addition, immunostaining revealed oblate endogenous Cx43 gap junction plaques in IWCA that were similar in appearance to those plaques obtained following transfection of IKOCA cells with fluorescent protein tagged Cx43. Re-expression of Cx43 in IKOCA cells allows experimental manipulation of connexins and live imaging of interactions between connexins and other proteins. We conclude that properties of these cell lines resemble those of primary cultured astrocytes, and they may provide useful tools in functional studies by facilitating genetic and pharmacological manipulations in the context of an astrocyte-appropriate cellular environment.
A multifaceted microRNA turnover complex fromCaenorhabditis elegans
Authors: Singh Mohini , Wani Adil R. , Kundu Pradipta , Chatterjee Saibal
Published: December 2020

microRNAs are known to regulate expression of more than two third of all the eukaryotic genes by post-transcriptional means, and regulation of these tiny regulators play an important role in determining their activities. Here, we report a macromolecular microRNA turnover complex, whose components are crucial to microRNA homeostasis and development inCaenorhabditis elegans. Biochemical investigations with the purified complex in an isolated system not only unfolded the roles of the individual subunits critical for the functionality of the complex, but also unraveled the different modes of operations and regulatability of this biological machine. Our results reveal that this complex is highly receptive and capable of switching between an ATP-dependent and ATP-independent mode of operation depending on the availability of ATP in its environment, which might allow the complex to function dynamically during different physiological conditions.
Feature-based Quality Assessment of Middle Cerebral Artery Occlusion Using 18F-fluorodeoxyglucose Positron Emission Tomography
Authors: He Wuxian , Tang Hongtu , Li Jia , Hou Chenze , Shen Xiaoyan , Li Chenrui , Liu Huafeng , Yu Weichuan
Published: December 2020

Background

The association between brain metabolic change and ischemic stroke has attracted a lot of attention in the research community. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is widely used to measure the metabolism. In experiments, ischemic stroke is usually induced through middle cerebral artery occlusion (MCAO), and quality assessment of this procedure is of vital importance. However, an assessment method based on FDG PET images is still lacking. Herein, we propose an image feature-based protocol to assess the quality of the procedure.

Methods

We performed permanent MCAO to a total of 161 Sprague-Dawley rats. FDG micro-PET images were acquired both before and after the MCAO procedure. Triphenyl tetrazolium chloride (TTC) staining was also conducted to obtain ground truth of the infarct volume. After preprocessing of the PET images, a combination of 3D scale invariant feature transform (SIFT) and support vector machine (SVM) was applied to extract features and train a classifier that can assess the quality of the MCAO procedure.

Results

106 rats and 212 images were used as training data to construct the classification model. The SVM classifier achieved over 98% accuracy in cross validation. 10 rats with TTC results showing infarction in the ipsilateral brain region served as validation data. Their images were tested by the classifier and all of them were categorized into the correct group. Finally, the remaining 45 rats from a separate experiment were treated as independent test data. The prediction accuracy for these 90 images reached the level of 91%. An online interface was constructed for users to upload their images and obtain the assessment results.

Conclusion

This feature-based protocol provides a convenient, accurate and reliable tool to assess the quality of the MCAO procedure in FDG PET study.
ProALIGN: Directly learning alignments for protein structure prediction via exploiting context-specific alignment motifs
Authors: Kong Lupeng , Ju Fusong , Zheng Wei-Mou , Zhu Jianwei , Sun Shiwei , Xu Jinbo , Bu Dongbo
Published: December 2020

Template-based modeling (TBM), including homology modeling and protein threading, is one of the most reliable techniques for protein structure prediction. It predicts protein structure by building an alignment between the query sequence under prediction and the templates with solved structures. However, it is still very challenging to build the optimal sequence-template alignment, especially when only distantly-related templates are available. Here we report a novel deep learning approach ProALIGN that can predict much more accurate sequence-template alignment. Like protein sequences consisting of sequence motifs, protein alignments are also composed of frequently-occurring alignment motifs with characteristic patterns. Alignment motifs are context-specific as their characteristic patterns are tightly related to sequence contexts of the aligned regions. Inspired by this observation, we represent a protein alignment as a binary matrix (in which 1 denotes an aligned residue pair) and then use a deep convolutional neural network to predict the optimal alignment from the query protein and its template. The trained neural network implicitly but effectively encodes an alignment scoring function, which reduces inaccuracies in the handcrafted scoring functions widely used by the current threading approaches. For a query protein and a template, we apply the neural network to directly infer likelihoods of all possible residue pairs in their entirety, which could effectively consider the correlations among multiple residues. We further construct the alignment with maximum likelihood, and finally build structure model according to the alignment.

Tested on three independent datasets with in total 6,688 protein alignment targets and 80 CASP13 TBM targets, our method achieved much better alignments and 3D structure models than the existing methods including HHpred, CNFpred, CEthreader and DeepThreader. These results clearly demonstrate the effectiveness of exploiting the context-specific alignment motifs by deep learning for protein threading.
Technical Note: A fast and robust integrator of delay differential equations in DCM for electrophysiological data
Authors: Schöbi Dario , Do Cao-Tri , Frässle Stefan , Tittgemeyer Marc , Heinzle Jakob , Stephan Klaas Enno
Published: December 2020

Dynamic causal models (DCMs) of electrophysiological data allow, in principle, for inference on hidden, bulk synaptic function in neural circuits. The directed influences between the neuronal elements of modeled circuits are subject to delays due to the finite transmission speed of axonal connections. Ordinary differential equations are therefore not adequate to capture the ensuing circuit dynamics, and delay differential equations (DDEs) are required instead. Previous work has illustrated that the integration of DDEs in DCMs benefits from sophisticated integration schemes in order to ensure rigorous parameter estimation and correct model identification. However, integration schemes that have been proposed for DCMs either emphasise speed (at the possible expense of accuracy) or robustness (but with computational costs that are problematic in practice).

In this technical note, we propose an alternative integration scheme that overcomes these shortcomings and offers high computational efficiency while correctly preserving the nature of delayed effects. This integration scheme is available as open-source code in the Translational Algorithms for Psychiatry-Advancing Science (TAPAS) toolbox and can be easily integrated into existing software (SPM) for the analysis of DCMs for electrophysiological data. While this paper focuses on its application to the convolution-based formalism of DCMs, the new integration scheme can be equally applied to more advanced formulations of DCMs (e.g. conductance based models). Our method provides a new option for electrophysiological DCMs that offers the speed required for scientific projects, but also the accuracy required for rigorous translational applications, e.g. in computational psychiatry.
neoDL: A novel neoantigen intrinsic feature-based deep learning model identifies IDH wild-type glioblastomas with the longest survival
Authors: Sun Ting , He Yufei , Li Wendong , Liu Guang , Li Lin , Wang Lu , Xiao Zixuan , Han Xiaohan , Wen Hao , Liu Yong , Chen Yifan , Wang Haoyu , Li Jing , Fan Yubo , Zhang Wei , Zhang Jing
Published: December 2020

Background

IDH wild-type glioblastoma (GBM) is the most aggressive tumor in the central nervous system in spite of extensive therapies. Neoantigen based personalized immune therapies achieve promising results in melanoma and lung cancer, but few neoantigen based models perform well in IDH wild-type GBM. Unlike the neoantigen load and occurrence that are well studied and often found useless, the association between neoantigen intrinsic features and prognosis remain unclear in IDH wild-type GBM.

Results

We presented a novel neoantigen intrinsic feature-based deep learning model (neoDL) to stratify IDH wild-type GBMs into subgroups with different survivals. We first calculated a total of 2928 intrinsic features for each neoantigen and filtered out those not associated with survival, followed by applying neoDL in the TCGA data cohort. Leave one out cross validation (LOOCV) in the TCGA demonstrated that neoDL successfully classified IDH wild-type GBMs into different prognostic subgroups, which was further validated in an independent data cohorts from Asian population. Long-term survival IDH wild-type GBMs identified by neoDL were found characterized by 12 protective neoantigen intrinsic features and enriched in development and cell cycle.

Conclusions

Our results provide a novel model, neoDL, that can be therapeutically exploited to identify IDH wild-type GBM with good prognosis who will most likely benefit from neoantigen based personalized immunetherapy.
Variation in mtDNA haplotypes suggests a complex history of reproductive strategy inCannabis sativa
Authors: Attia Ziv , Pogoda Cloe S. , Vergara Daniela , Kane Nolan C.
Published: December 2020

Cannabisis one example in angiosperms that appears to have a recent origin of dioecy and X/Y sex chromosomes. Several evolutionary explanations for this transition have been proposed, with the most parsimonious beginning with a mitochondrial mutation leading to cytoplasmic male sterility (CMS). Our study utilized 73Cannabis sativawhole genome shotgun libraries to reveal eight different mtDNA haplotypes. The most common haplotype contained 60 of the 73 individuals studied and was composed of only dioecious individuals. However, other haplotypes contained a mix of dioecious and monoecious individuals, so haplotype alone does not predict dioecy. From these haplotype groupings we further examined the fully annotated mitochondrial genomes of four hemp individuals and looked for genetic variation affecting reproductive strategy (e.g., monoecious vs. dioecious strategies). Specifically, we searched for markers associated with CMS and for gene rearrangements within these mitochondrial genomes. Our results revealed highly syntenic mitochondrial genomes that contained approximately 60 identifiable sequences for protein coding genes, tRNAs and rRNAs and no obvious rearrangements or chimeric genes. We find no clear evidence that the different reproductive patterns are due to easily identifiable CMS mutations. Our results refute the simplest hypothesis that there was a single recent origin of dioecy in a monoecious ancestor. Instead, the story of the evolution of dioecy is likely much more complex. Further exploration of the nuclear and mitochondrial genomes and their interaction is required to fully understandCannabis’ mating strategies and the possible existence of CMS in this species.
Multiple timescales of sensory-evidence accumulation across the dorsal cortex
Authors: Pinto Lucas , Tank David W. , Brody Carlos D.
Published: December 2020

Cortical areas seem to form a hierarchy of intrinsic timescales, but whether this is causal to cognitive behavior remains unknown. In particular, decisions requiring the gradual accrual of sensory evidence over time recruit widespread areas across this hierarchy. Here, we causally tested the hypothesis that this recruitment is related to the intrinsic integration timescales of these widespread areas. We trained mice to accumulate evidence over seconds while navigating in virtual reality, and optogenetically silenced the activity of many cortical areas during different brief trial epochs. We found that the inactivation of different areas primarily affected the evidence-accumulation computation per se, rather than other decision-related processes. Specifically, we observed selective changes in the weighting of evidence over time, such that frontal inactivations led to deficits on longer timescales than posterior cortical ones. Likewise, large-scale cortical Ca2+ activity during task performance displayed different temporal integration windows matching the effects of inactivation. Our findings suggest that distributed cortical areas accumulate evidence by leveraging their hierarchy of intrinsic timescales.
Genetic and phylogenetic analysis of dissimilatory iodate-reducing bacteria identifies potential niches across the world’s oceans
Authors: Reyes-Umana Victor , Henning Zachary , Lee Kristina , Barnum Tyler P. , Coates John D.
Published: December 2020

Iodine is oxidized and reduced as part of a biogeochemical cycle that is especially pronounced in the oceans, where the element naturally concentrates. The use of oxidized iodine in the form of iodate (IO3-) as an electron acceptor by microorganisms is poorly understood. Here, we outline genetic, physiological, and ecological models for dissimilatory IO3-reduction to iodide (I-) by a novel estuarine bacterium,Denitromonas iodocresceransstrain IR-12,sp. nov. Our results show that dissimilatory iodate reduction (DIR) by strain IR-12 is molybdenum-dependent and requires an IO3-reductase (idrA) and likely other genes in a mobile cluster with a conserved association across known and predicted DIR microorganisms (DIRM). Based on genetic and physiological data, IO3-is likely reduced to hypoiodous acid (HIO), which rapidly disproportionates into IO3-and iodide (I-), in a respiratory pathway that provides an energy yield equivalent to that of nitrate or perchlorate respiration. Consistent with the ecological niche expected of such a metabolism,idrAis enriched in the metagenome sequence databases of marine sites with a specific biogeochemical signature and diminished oxygen. Taken together, these data suggest that DIRM help explain the disequilibrium of the IO3-:I-concentration ratio above oxygen minimum zones and support a widespread iodine redox cycle mediated by microbiology.
Structural basis for broad coronavirus neutralization
Authors: Sauer Maximilian M. , Tortorici M. Alexandra , Park Young-Jun , Walls Alexandra C. , Homad Leah , Acton Oliver , Bowen John , Wang Chunyan , Xiong Xiaoli , de van der Schueren Willem , Quispe Joel , Hoffstrom Benjamin G. , Bosch Berend-Jan , McGuire Andrew T. , Veesler David
Published: December 2020

Three highly pathogenic β-coronaviruses crossed the animal-to-human species barrier in the past two decades: SARS-CoV, MERS-CoV and SARS-CoV-2. SARS-CoV-2 has infected more than 64 million people worldwide, claimed over 1.4 million lives and is responsible for the ongoing COVID-19 pandemic. We isolated a monoclonal antibody, termed B6, cross-reacting with eight β-coronavirus spike glycoproteins, including all five human-infecting β-coronaviruses, and broadly inhibiting entry of pseudotyped viruses from two coronavirus lineages. Cryo-electron microscopy and X-ray crystallography characterization reveal that B6 binds to a conserved cryptic epitope located in the fusion machinery and indicate that antibody binding sterically interferes with spike conformational changes leading to membrane fusion. Our data provide a structural framework explaining B6 cross-reactivity with β-coronaviruses from three lineages along with proof-of-concept for antibody-mediated broad coronavirus neutralization elicited through vaccination. This study unveils an unexpected target for next-generation structure-guided design of a pan-coronavirus vaccine.
Ticks convert pathogenicCoxiellainto endosymbionts
Authors: Brenner Amanda E. , Muñoz-Leal Sebastián , Sachan Madhur , Labruna Marcelo B. , Raghavan Rahul
Published: December 2020

Both symbiotic and pathogenic bacteria in the family Coxiellaceae cause morbidity and mortality in humans and animals. For instance,Coxiella-like endosymbionts (CLEs) improve the reproductive success of ticks — a major disease vector, whileCoxiella burnetiiis the etiological agent of human Q fever and uncharacterized coxiellae cause infections in both animals and humans. To better understand the evolution of pathogenesis and symbiosis in this group of intracellular bacteria, we sequenced the genome of a CLE present in the soft tickOrnithodoros amblus(CLEOA) and compared it to the genomes of other bacteria in the order Legionellales. Our analyses confirmed that CLEOA is more closely related toC. burnetii, the human pathogen, than to CLEs in hard ticks, and showed that most clades of CLEs contain both endosymbionts and pathogens, indicating that several CLE lineages have evolved independently from pathogenicCoxiella. We also determined that the last common ancestor of CLEOA andC. burnetiiwas equipped to infect macrophages, and that even though HGT contributed significantly to the evolution ofC. burnetii, most acquisition events occurred primarily in ancestors predating the CLEOA-C. burnetiidivergence. These discoveries clarify the evolution ofC. burnetii, which previously was assumed to have emerged when an avirulent tick endosymbiont recently gained virulence factors via HGT. Finally, we identified several metabolic pathways, including heme biosynthesis, that are likely critical to the intracellular growth of the human pathogen but not the tick symbiont, and show that the use of heme analogs is a promising approach to controllingC. burnetiiinfections.
Effect of An Inverted Seated Position with Upper Arm Blood Flow Restriction on Measures of Elbow Flexors Neuromuscular Performance
Authors: Ahmadi Hamid , Herat Nehara , Alizadeh Shahab , Button Duane C , Granacher Urs , Behm David G.
Published: December 2020

Purpose

The objective of the investigation was to determine the concomitant effects of upper arm blood flow restriction (BFR) and inversion on elbow flexors neuromuscular responses.

Methods

Randomly allocated, 13 volunteers performed four conditions in a within-subject design: rest (control, 1-min upright position without BFR), control (1-min upright with BFR), 1-min inverted (without BFR), and 1-min inverted with BFR. Evoked and voluntary contractile properties, before, during and after a 30-s maximum voluntary contraction (MVC) exercise intervention were examined as well as pain scale.

Results

Inversion induced significant pre-exercise intervention decreases in elbow flexors MVC (21.1%,,p=0.02) and resting evoked twitch (29.4%,,p=0.03) forces. The 30-s MVC induced significantly greater pre- to post-test decreases in potentiated twitch force (,p<0.0009) during inversion (↓75%) than upright (↓65.3%) conditions. Overall, BFR decreased MVC force 4.8% (,p=0.05). For upright position, BFR induced 21.0% reductions in M-wave amplitude (,p=0.04). There were no significant differences for electromyographic activity or voluntary activation as measured with the interpolated twitch technique. For all conditions, there was a significant increase in pain scale between the 40-60 s intervals and post-30-s MVC (upright<inversion, and without BFR<BFR).

Conclusion

The concomitant application of inversion with elbow flexors BFR only amplified neuromuscular performance impairments to a small degree. Individuals who execute forceful contractions when inverted or with BFR should be cognizant that force output may be impaired.
Placebo analgesia does not reduce empathy for naturalistic depictions of others’ pain in a somatosensory specific way
Authors: Hartmann Helena , Riva Federica , Rütgen Markus , Lamm Claus
Published: December 2020

Empathy for pain involves the affective-motivational and sensory-discriminative pain network. The shared representations account postulates that sharing another’s pain recruits underlying brain functions also engaged during first-hand pain. Critically, causal evidence for this has only been shown for affective pain processing, while the specific contribution of one’s own somatosensory system to empathy remains controversial. Experimental paradigms used in previous studies did not a) direct attention towards a specific body part or b) employed naturalistic depictions of others’ pain, which could explain the absence of somatosensory effects. In this preregistered fMRI study, we thus aimed to test whether a causal manipulation of first-hand pain affects processing of empathy in a somatotopically- matched manner. Forty-five participants underwent a placebo analgesia induction in the right hand and observed pictures of right vs. left hands in pain. We found neither behavioral nor neural evidence for laterality-specific modulation of empathy for pain. However, exploratory analyses revealed a general effect of the placebo on empathy, and higher brain activity in bilateral anterior insula when viewing others’ hands in pain corresponding to one’s own placebo hand. These results refine our knowledge regarding the mechanisms underlying empathy for pain by specifying the influence of first-hand pain on empathic responding.
Heartbeat and Somatosensory Perception
Authors: Al Esra , Iliopoulos Fivos , Nikulin Vadim V. , Villringer Arno
Published: December 2020

Our perception of the external world is influenced by internal bodily signals. For example, we recently showed that timing of stimulation along the cardiac cycle and spontaneous fluctuations of heartbeat-evoked potential (HEP) amplitudes influence somatosensory perception and the associated neural processing (Al et al., 2020). While cardiac phase affected detection sensitivity and late components of the somatosensory-evoked potentials (SEPs), HEP amplitudes affected detection criterion and both early and late SEP components. In a new EEG study, we investigate whether these results are replicable in a modified paradigm, which includes two succeeding temporal intervals. Only in one of these intervals, subjects received a weak electrical finger stimulation and then performed a yes/no and two-interval forced-choice detection task. Our results confirm the previously reported cardiac cycle and prestimulus HEP effects on somatosensory perception and evoked potentials. In addition, we obtain two new findings: A source analysis in these two studies shows that the increased likelihood of conscious perception goes along with HEP fluctuations in parietal and posterior cingulate regions, known to play important roles in interoceptive processes. Furthermore, HEP amplitudes are shown to decrease when subjects engage in the somatosensory task compared to their resting state condition. Our findings are consistent with the view that HEP amplitudes are a marker of interoceptive (versus exteroceptive) attention and provide a neural underpinning for this view.
Wnt/beta-catenin signalling is dispensable for adult neural stem cell homeostasis and activation
Authors: Austin Sophie H. L. , Harris Lachlan , Paun Oana , Rigo Piero , Guillemot François , Urbán Noelia
Published: December 2020

Adult mouse hippocampal neural stem cells (NSCs) generate new neurons that integrate into existing hippocampal networks and modulate mood and memory. These NSCs are largely quiescent and are stimulated by niche signals to activate and produce neurons. Wnt/β-catenin signalling acts at different steps along the hippocampal neurogenic lineage and has been shown to promote the proliferation of intermediate progenitor cells. However, whether it has a direct role in the regulation of NSCs still remains unclear. Here we used Wnt/β-catenin reporters and transcriptomic data fromin vivoandin vitromodels to show that both active and quiescent adult NSCs respond to Wnt/β-catenin signalling. Wnt/β-catenin stimulation instructed neuronal differentiation of active NSCs and promoted the activation or differentiation of quiescent NSCs in a dose-dependent manner. However, we found that inhibiting NSCs response to Wnt, by conditionally deleting β-catenin, did not affect their activation or maintenance of their stem cell characteristics. Together, our results indicate that whilst NSCs do respond to Wnt/β-catenin stimulation in a dose-dependent and state-specific manner, Wnt/β-catenin signalling is not cell-autonomously required to maintain NSC homeostasis, which could reconcile some of the contradictions in the literature as to the role of Wnt/β-catenin signalling in adult hippocampal NSCs.
Investigating expression of a human optimizedcas9transgene inNeurospora crassa
Authors: Burrell Natalie , Rhoades Nicholas A. , Boyd Amy , Mierendorf Jim , Yusifov Aykhan , Harvey Austin , Edwards Kevin , Vogel Laura , Hammond Thomas M.
Published: December 2020

The CRISPR-associated Cas9 enzyme is used in molecular biology to engineer the genomes of a wide range of organisms. While Cas9 can be injected or transfected into a target cell to achieve the desired goal, there are situations where stable expression of Cas9 within a target organism is preferable. Here, we show that the model filamentous fungusNeurospora crassais recalcitrant to heterologous expression of a human-optimized version ofStreptococcus pyogenes cas9. Furthermore, partial optimization ofcas9by synonymous codon exchange failed to improve its expression in the fungus. Finally, we show that transgene expression can be detected whencas9Hssequences are placed in the 3’ UTR regions of transgene-derived mRNAs, but not when the same sequences are in the translated part of the transgene-derived mRNA. This finding suggests that the primary obstacle to highcas9Hsexpression levels inN. crassais translational in nature.
Deep mining of early antibody response in COVID-19 patients yields potent neutralisers and reveals high level of convergence
Authors: Bullen Georgia , Galson Jacob D. , Villar Pedro , Moreels Lien , Ledsgaard Line , Mattiuzzo Giada , Hall Gareth , Bentley Emma M. , Masters Edward W. , Tang David , Millett Sophie , Tongue Danielle , Brown Richard , Diamantopoulos Ioannis , Parthiban Kothai , Tebbutt Claire , Leah Rachael , Chaitanya Krishna , Pazeraitis Deividas , Surade Sachin B. , Ashiru Omodele , Crippa Lucia , Cowan Richard , Bowler Matthew W. , Campbell Jamie I. , Lee Wing-Yiu Jason , Carr Mark D. , Matthews David , Pfeffer Paul , Hufton Simon E. , Sawmynaden Kovilen , Osbourn Jane , McCafferty John , Karatt-Vellatt Aneesh
Published: December 2020

Passive immunisation using monoclonal antibodies will play a vital role in the fight against COVID-19. Until now, the majority of anti-SARS-CoV-2 antibody discovery efforts have relied on screening B cells of patients in the convalescent phase. Here, we describe deep-mining of the antibody repertoires of hospitalised COVID-19 patients using a combination of phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralising antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded potent neutralising antibodies with distinct mechanisms of action, including the identification of a novel non-ACE2 receptor blocking antibody that is not expected to be affected by any of the major viral variants reported. The study highlighted the presence of potent neutralising antibodies with near germline sequences within both the IgG and IgM pools at early stages of infection. Furthermore, we highlight a highly convergent antibody response with the same sequences occurring both within this study group and also within the responses described in previously published anti-SARS-CoV-2 studies.
Design of Specific Primer Set for Detection of B.1.1.7 SARS-CoV-2 Variant using Deep Learning
Authors: Lopez-Rincon Alejandro , Perez-Romero Carmina A. , Tonda Alberto , Mendoza-Maldonado Lucero , Claassen Eric , Garssen Johan , Kraneveld Aletta D.
Published: December 2020

The SARS-CoV-2 variant B.1.1.7 lineage, also known as clade GR from Global Initiative on Sharing All Influenza Data (GISAID), Nextstrain clade 20B, or Variant Under Investigation in December 2020 (VUI – 202012/01), appears to have an increased transmissability in comparison to other variants. Thus, to contain and study this variant of the SARS-CoV-2 virus, it is necessary to develop a specific molecular test to uniquely identify it. Using a completely automated pipeline involving deep learning techniques, we designed a primer set which is specific to SARS-CoV-2 variant B.1.1.7 with >99% accuracy, starting from 8,923 sequences from GISAID. The resulting primer set is in the region of the synonymous mutation C16176T in the ORF1ab gene, using the canonical sequence of the variant B.1.1.7 as a reference. Furtherin-silicotesting shows that the primer set’s sequences do not appear in different viruses, using 20,571 virus samples from the National Center for Biotechnology Information (NCBI), nor in other coronaviruses, using 487 samples from National Genomics Data Center (NGDC). In conclusion, the presented primer set can be exploited as part of a multiplexed approach in the initial diagnosis of Covid-19 patients, or used as a second step of diagnosis in cases already positive to Covid-19, to identify individuals carrying the B.1.1.7 variant.
Genome-wide binding analyses of HOXB1 revealed a novel DNA binding motif associated with gene repression
Authors: Singh Narendra Pratap , De Kumar Bony , Paulson Ariel , Parrish Mark , Scott Carrie , Zhang Ying , Florens Laurence , Krumlauf Robb
Published: December 2020

Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in ES cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motifHB1RE(HOXB1responseelement).In vitrotemplate binding assays showed that HOXB1, PBX1 and MEIS can bind to this motif.In vivo,this motif is sufficient to direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novelHB1REmotif contributes to HOXB1 function in part through a repressive role in gene expression.
Homology modeling and functional characterization of multidrug effluxor Mta protein from Bacillus Atrophaeus: An explanatory insilico approach
Authors: Rahman Mohammad Rejaur , Chowdhury Ishtiak Malique , Banik Anik , Sajib Emran Hossain
Published: December 2020

Phenotypically similar to B. subtilis, Bacillus atrophaeus is a Gram-positive, aerobic, spore-forming bacteria. It is a black-pigmented bacterial genus. Therefore, it is of interest to study the uncharacterized proteins in the genome. For a detailed computational sequence-structure-function analysis using available data and resources, an uncharacterized protein Mta (AKL87074.1) in the genome was selected. In this study, attempts were made to study the physicochemical properties, predict secondary structure, modeling the 3-D protein, pocket identification, protein-protein interaction and phylogenetic analysis of Mta protein. The predicted active site using CASTp is analyzed for understanding their multidrug resistance function. Because Mta is a MerR family member, these investigations on these functional aspects could lead us for better understanding of antibiotic resistance phenomenon.
SARS-CoV-2 highly conserved s2m element dimerizes via a kissing complex and interacts with host miRNA-1307-3p
Authors: Imperatore Joshua A. , Cunningham Caylee L. , Pellegrene Kendy A. , Brinson Robert G. , Marino John P. , Evanseck Jeffrey D. , Mihailescu Mihaela Rita
Published: December 2020

The ongoing COVID-19 pandemic highlights the necessity for a more fundamental understanding of the coronavirus life cycle. The causative agent of the disease, SARS-CoV-2, is being studied extensively from a structural standpoint in order to gain insight into key molecular mechanisms required for its survival. Contained within the untranslated regions of the SARS-CoV-2 genome are various conserved stem-loop elements that are believed to function in RNA replication, viral protein translation, and discontinuous transcription. While the majority of these regions are variable in sequence, a 41-nucleotide s2m element within the 3’ UTR is highly conserved among coronaviruses and three other viral families. In this study, we demonstrate that the s2m element of SARS-CoV-2 dimerizes by forming an intermediate homodimeric kissing complex structure that is subsequently converted to a thermodynamically stable duplex conformation. This process is aided by the viral nucleocapsid protein, potentially indicating a role in mediating genome dimerization. Furthermore, we demonstrate that the s2m element interacts with multiple copies of host cellular miRNA-1307-3p. Taken together, our results highlight the potential significance of the dimer structures formed by the s2m element in key biological processes and implicate the motif as a possible therapeutic drug target for COVID-19 and other coronavirus-related diseases.
Large palindromes on the primate X Chromosome are preserved by natural selection
Authors: Jackson Emily K. , Bellott Daniel W. , Cho Ting-Jan , Skaletsky Helen , Hughes Jennifer F. , Pyntikova Tatyana , Page David C.
Published: December 2020

Mammalian sex chromosomes carry large palindromes that harbor protein-coding gene families with testis-biased expression. However, there are few known examples of sex-chromosome palindromes conserved between species. We identified 26 palindromes on the human X Chromosome, constituting more than 2% of its sequence, and characterized orthologous palindromes in the chimpanzee and the rhesus macaque using a clone-based sequencing approach that incorporates full-length nanopore reads. Many of these palindromes are missing or misassembled in the current reference assemblies of these species’ genomes. We find that 12 human X palindromes have been conserved for at least 25 million years, with orthologs in both chimpanzee and rhesus macaque. Insertions and deletions between species are significantly depleted within the X palindromes’ protein-coding genes compared to their non-coding sequence, demonstrating that natural selection has preserved these gene families. Unexpectedly, the spacers that separate the left and right arms of palindromes are a site of localized structural instability, with 7 of 12 conserved palindromes showing no spacer orthology between human and rhesus macaque. Analysis of the 1000 Genomes Project dataset revealed that human X-palindrome spacers are enriched for deletions relative to arms and flanking sequence, including a common spacer deletion that affects 13% of human X Chromosomes. This work reveals an abundance of conserved palindromes on primate X Chromosomes, and suggests that protein-coding gene families in palindromes (most of which remain poorly characterized) promote X-palindrome survival in the face of ongoing structural instability.