bluuebunny/crossref_metadata_2025 huggingface dataset:
Quotation errors in general science journals
Authors: Smith Neal , Cumberledge Aaron
Published: October 2020

Due to the incremental nature of scientific discovery, scientific writing requires extensive referencing to the writings of others. The accuracy of this referencing is vital, yet errors do occur. These errors are called ‘quotation errors’. This paper presents the first assessment of quotation errors in high-impact general science journals. A total of 250 random citations were examined. The propositions being cited were compared with the referenced materials to verify whether the propositions could be substantiated by those materials. The study found a total error rate of 25%. This result tracks well with error rates found in similar studies in other academic fields. Additionally, several suggestions are offered that may help to decrease these errors and make similar studies more feasible in the future.
Bifidobacteria in two-toed sloths (Choloepus didactylus): phylogenetic characterization of the novel taxon Bifidobacterium choloepi sp. nov.
Authors: Modesto Monica , Satti Maria , Watanabe Koichi , Huang Chien-Hsun , Liou Jong-Shian , Tamura Tomohiko , Saito Satomi , Mori Koji , Huang Lina , Sandri Camillo , Spiezio Caterina , Sgorbati Barbara , Scarafile Donatella , Cammà Cesare , Ancora Massimo , Patavino Claudio , Arita Masanori , Mattarelli Paola
Published: October 2020

Seven bifidobacterial strains were isolated from the faeces of two adult males of the two-toed sloth (Choloepus didactylus) housed in Parco Natura Viva, in Italy. Comparative sequence analysis of 16S rRNA and of five housekeeping (hsp60, rpoB, clpC, dnaJ, dnaG) genes revealed that these strains were classified into two clusters. On the basis of 16S rRNA gene sequence similarity, the type strain of

Bifidobacterium catenulatum

subsp.

kashiwanohense

DSM 21854T (95.4 %) was the closest neighbour to strain in Cluster I (BRDM 6T), whereas the type strain of

Bifidobacterium dentium

DSM 20436T (values were in the range of 98‒99.8 %) was the closest neighbour to the other six strains in Cluster II. The average nucleotide identity (ANI) values of BRDM 6T and of strains in Cluster II with the closely related type strains were 76.0 and 98.9 % (mean value) respectively. Therefore, genotyping based on the genome sequence of the strain BRDM 6T combined with phenotypic analyses clearly revealed that the strain BRDM 6T represents a novel species for which the names Bifidobacterium choloepi sp. nov. (BRDM 6T=NBRC 114053T=BCRC 81222T) is proposed.
Flavobacterium salmonis sp. nov. isolated from Atlantic salmon (Salmo salar) and formal proposal to reclassify Flavobacterium spartansii as a later heterotypic synonym of Flavobacterium tructae
Authors: Kämpfer Peter , Irgang Rute , Glaeser Stefanie P. , Busse Hans-Jürgen , Criscuolo Alexis , Clermont Dominique , Avendaño-Herrera Ruben
Published: October 2020

A Gram-staining-negative non endospore-forming strain, T13(2019)T was isolated from water samples from Atlantic salmon (Salmo salar) fry culture in Chile and studied in detail for its taxonomic position. The isolate shared highest 16S rRNA gene sequence similarities with the type strains of

Flavobacterium chungangense

(98.44 %) followed by

Flavobacterium tructae

and

Flavobacterium spartansii

(both 98.22 %). Menaquinone MK-6 was the predominant respiratory quinone in T13(2019)T. Major polar lipids were phosphatidylethanolamine, an ornithine lipid and the unidentified polar lipids L1, L3 and L4 lacking a functional group. The major polyamine was sym-homospermidine. The fatty acid profile contained major amounts of iso-C15 : 0, iso-C15 : 0 3-OH, iso-C17 : 0 3-OH, C15 : 0, summed feature 3 (C16 : 1
 ω7c and/or iso-C15 : 0 2-OH) and various hydroxylated fatty acids in smaller amounts, among them iso-C16 : 0 3-OH, and C15 : 0 3-OH, which supported the grouping of the isolate into the genus

Flavobacterium

. Physiological/biochemical characterisation and ANI calculations with the type strains of the most closely related species allowed a clear phenotypic and genotypic differentiation. In addition it became obvious, that the type strains of

F. tructae

and

F. spartansii

showed 100 % 16S rRNA gene sequence similarities and ANI values of 97.21%/ 97.59 % and DDH values of 80.40 % [77.5 and 83%]. These data indicate that

F. tructae

and

F. spartansii

belong to the same species and it is proposed that

F. spartansii

is a later heterotypic synonym of

F. tructae

. For strain T13(2019)T (=CIP 111411T=LMG 30298T=CCM 8798T) a new species with the name Flavobacterium salmonis sp. nov. is proposed.
Pelagovum pacificum gen. nov., sp. nov., a novel member of the family Rhodobacteraceae isolated from surface seawater of the Mariana Trench
Authors: Ren Xue-Bing , Cha Qian-Qian , Guo Xiao-Han , He Xiao-Yan , Su Hai-Nan , Qin Qi-Long , Song Xiao-Yan , Chen Xiu-Lan , Zhang Yu-Zhong , Xu Fei , Zhang Xi-Ying
Published: October 2020

A Gram-stain-negative, aerobic, ovoid-rod-shaped bacterium, designated strain SM1903T, was isolated from surface seawater of the Mariana Trench. The strain grew at 15–37 °C (optimum, 35 °C) and with 1–15 % (optimum, 4 %) NaCl. It hydrolysed aesculin but did not reduce nitrate to nitrite and hydrolyse Tween 80. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain SM1903Tformed a separate lineage within the familyRhodobacteraceae, sharing the highest 16S rRNA gene sequence similarity with type strains ofPseudooceanicola antarcticus(95.7 %) andRoseisalinus antarcticus(95.7 %). In phylogenetic trees based on single-copy OCs and whole proteins sequences, strain SM1903Tfell within a sub-cluster encompassed byOceanicola granulosus,Roseisalinus antarcticusandHistidinibacterium lentulumand formed a branch adjacent toOceanicola granulosus. The major cellular fatty acids were summed feature 8 (C18 : 1 ω7cand/or C18 : 1 ω6c), C16 : 0and 11-methyl-C18 : 1 ω7c. The polar lipids mainly comprised phosphatidylglycerol, phosphatidylcholine, one unidentified lipid, one unidentified aminolipid, and one unidentified glycolipid. The solo respiratory quinone was ubiquinone-10. The genomic DNA G+C content of strain SM1903Twas 66.0 mol%. Based on the results of phenotypic, chemotaxonomic, and phylogenetic characterization for strain SM1903T, it is considered to represent a novel species of a novel genus in the familyRhodobacteraceae, for which the namePelagovum pacificumgen. nov., sp. nov. is proposed. The type strain is SM1903T(=MCCC 1K03608T=KCTC 72046T).
The link between CS gas exposure and menstrual cycle issues among female Yellow Vest protesters in France
Authors: Mahfud Yara , Samuel Alexander , Çelebi Elif , Adam-Troian Jais
Published: October 2020

CS teargas is one of the most used tools for crowd-control worldwide. Exposure to CS teargas is known to have consequences on protesters’ health (i.e. eye, skin irritation, respiratory problems), but recent concerns have been raised over its potential gender-specific effects. Indeed, field and clinical observations report cases of menstrual cycle issues among female protesters following high exposure to teargas. The hypothesis of a link between teargas exposure and menstrual cycle issues is plausible from a physiological standpoint, but has not yet been empirically investigated. Using data from a cross-sectional study on Yellow Vests protesters’ health in France, we examined the relationship between exposure to teargas and menstrual cycle issues among female protesters (n = 145). Analyses suggested a positive link between exposure and menstrual cycle perturbations. These results constitute first and preliminary evidence that CS teargas may be linked with menstrual cycle among women, which need corroboration given the importance of this issue. We call for further research on the potential effects of CS teargas on women’s reproductive system.
COVID-CT-Mask-Net: Prediction of COVID-19 from CT Scans Using Regional Features
Authors: Ter-Sarkisov Aram
Published: October 2020

We present COVID-CT-Mask-Net model that predicts COVID-19 from CT scans. The model works in two stages: first, it detects the instances of ground glass opacity and consolidation in CT scans, then predicts the condition from the ranked bounding box detections. To develop the solution for the three-class problem (COVID, common pneumonia and control), we used the COVIDx-CT dataset derived from the dataset of CT scans collected by China National Center for Bioinformation. We use about 5% of the training split of COVIDx-CT to train the model, and without any complicated data normalization, balancing and regularization, and training only a small fraction of the model’s parameters, we achieve a 90.80% COVID sensitivity, 91.62% common pneumonia sensitivity and 92.10% normal sensitivity, and an overall accuracy of 91.66% on the test data (21182 images), bringing the ratio of test/train data to 7.06, which implies a very high capacity of the model to generalize to new data. We also establish an important result, that ranked regional predictions (bounding boxes with scores) in Mask R-CNN can be used to make accurate predictions of the image class. The full source code, models and pretrained weights are available on https://github.com/AlexTS1980/COVID-CT-Mask-Net.
High and increasing prevalence of SARS-CoV-2 swab positivity in England during end September beginning October 2020: REACT-1 round 5 updated report
Authors: Riley Steven , Ainslie Kylie E. C. , Eales Oliver , Walters Caroline E. , Wang Haowei , Atchison Christina , Fronterre Claudio , Diggle Peter J. , Ashby Deborah , Donnelly Christl A. , Cooke Graham , Barclay Wendy , Ward Helen , Darzi Ara , Elliott Paul
Published: October 2020

Background

REACT-1 is quantifying prevalence of SARS-CoV-2 infection among random samples of the population in England based on PCR testing of self-administered nose and throat swabs. Here we report results from the fifth round of observations for swabs collected from the 18th September to 5th October 2020. This report updates and should be read alongside our round 5 interim report.

Methods

Representative samples of the population aged 5 years and over in England with sample size ranging from 120,000 to 175,000 people at each round. Prevalence of PCR-confirmed SARS-CoV-2 infection, estimation of reproduction number (R) and time trends between and within rounds using exponential growth or decay models.

Results

175,000 volunteers tested across England between 18th September and 5th October. Findings show a national prevalence of 0.60% (95% confidence interval 0.55%, 0.71%) and doubling of the virus every 29 (17, 84) days in England corresponding to an estimated national R of 1.16 (1.05, 1.27). These results correspond to 1 in 170 people currently swab-positive for the virus and approximately 45,000 new infections each day. At regional level, the highest prevalence is in the North West, Yorkshire and The Humber and the North East with strongest regional growth in North West, Yorkshire and The Humber and West Midlands.

Conclusion

Rapid growth has led to high prevalence of SARS-CoV-2 virus in England, with highest rates in the North of England. Prevalence has increased in all age groups, including those at highest risk. Improved compliance with existing policy and, as necessary, additional interventions are required to control the spread of SARS-CoV-2 in the community and limit the numbers of hospital admissions and deaths from COVID-19.
Network Graph Representation of COVID-19 Scientific Publications to Aid Knowledge Discovery
Authors: Cernile George , Heritage Trevor , Sebire Neil J , Gordon Ben , Schwering Taralyn , Kazemlou Shana , Borecki Yulia
Published: October 2020

Introduction

Numerous scientific journal articles have been rapidly published related to COVID-19 making navigation and understanding of relationships difficult.

Methods

A graph network was constructed from the publicly available CORD-19 database of COVID-19-related publications using an engine leveraging medical knowledgebases to identify discrete medical concepts and an open source tool (Gephi) used to visualise the network.

Results

The network shows connections between disease, medication and procedures identified from title and abstracts of 195,958 COVID-19 related publications (CORD-19 Dataset). Connections between terms with few publications, those unconnected to the main network and those irrelevant were not displayed. Nodes were coloured by knowledgebase and node size related to the number of publications containing the term. The dataset and visualisations made publicly accessible via a webtool.

Conclusion

Knowledge management approaches (text mining and graph networks) can effectively allow rapid navigation and exploration of entity interrelationships to improve understanding of diseases such as COVID-19.
Homeostatic depression shows heightened sensitivity to synaptic calcium
Authors: Yeates Catherine J. , Frank C. Andrew
Published: October 2020

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. TheDrosophila melanogasterneuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content during evoked neurotransmission – again, resulting in normal levels of postsynaptic excitation.

We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapse’s ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we did find loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R –itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.
Enzymatic analysis of yeast cell wall-resident GAPDH and its secretion
Authors: Cohen Michael J. , Philippe Brianne , Lipke Peter N.
Published: October 2020

In yeast, many proteins are found both in the cytoplasmic and extracellular compartments, and consequently it can be difficult to distinguish non-conventional secretion from cellular leakage. We therefore monitored extracellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity of intact cells as a specific marker for non-conventional secretion. Extracellular GAPDH activity was proportional to the number of cells assayed, increased with incubation time, and was dependent on added substrates. Preincubation of intact cells with 100μM dithiothreitol increased the reaction rate, consistent with increased access of the enzyme after reduction of cell wall disulfide crosslinks. Such treatment did not increase cell permeability to propidium iodide, in contrast to effects of higher concentrations of reducing agents. An amine-specific membrane-impermeant biotinylation reagent specifically inactivated extracellular GAPDH. The enzyme was secreted again after a 30-60-minute lag following the inactivation, and there was no concomitant increase in propidium iodide staining. There were about 4 × 104active GAPDH molecules per cell at steady state, and secretion studies showed replenishment to that level one hour after inactivation. These results establish conditions for specific quantitative assays of cell wall proteins in the absence of cytoplasmic leakage and for subsequent quantification of secretion rates in intact cells.

Importance

Eukaryotic cells secrete many proteins, including many proteins that do not follow the classical secretion pathway. Among these, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is unexpectedly found in the walls of yeasts and other fungi, and in extracellular space in mammalian cell cultures. It is difficult to quantify extracellular GAPDH, because leakage of just a little of the very large amount of cytoplasmic enzyme can invalidate the determinations. We used enzymatic assays of intact cells, while also maintaining membrane integrity. The results lead to estimates of the amount of extracellular enzyme, and its rate of secretion to the wall in intact cells. Therefore, enzyme assays under controlled conditions can be used to investigate non-conventional secretion more generally.
Nonameric structures of the cytoplasmic domain of FlhA and SctV in the context of the full-length protein
Authors: Kuhlen Lucas , Johnson Steven , Cao Jerry , Deme Justin C. , Lea Susan M.
Published: October 2020

Type three secretion is the mechanism of protein secretion found in bacterial flagella and injectisomes. At its centre is the export apparatus (EA), a complex of five membrane proteins through which secretion substrates pass the inner membrane. While the complex formed by four of the EA proteins has been well characterised structurally, little is known about the structure of the membrane domain of the largest subunit, FlhA in flagella, SctV in injectisomes. Furthermore, the biologically relevant nonameric assembly of FlhA/SctV has been infrequently observed and differences in conformation of the cytoplasmic portion of FlhA/SctV between open and closed states have been suggested to reflect secretion system specific differences. FlhA has been shown to bind to chaperone-substrate complexes in an open state, but in previous assembled ring structures, SctV is in a closed state. Here, we identify FlhA and SctV homologues that can be recombinantly produced in the oligomeric state and study them using cryo-electron microscopy. The structures of the cytoplasmic domains from both FlhA and SctV are in the open state and we observe a conserved interaction between a short stretch of residues at the N-terminus of the cytoplasmic domain, known as FlhAL/SctVL, with a groove on the adjacent protomer’s cytoplasmic domain, which stabilises the nonameric ring assembly.
A delayed modulation of solar ultraviolet radiation on the COVID-19 transmission reflects an incubation period
Authors: He Maosheng , Fang Keyan , Zhou Feifei , Ou Tinghai , Chen Deliang
Published: October 2020

Laboratory experiments have revealed the meteorological sensitivity of the coronavirus disease 2019 (COVID-19) virus. However, no consensus has been reached about how outdoor meteorological conditions modulate the virus transmission as it is also constrained by non-meteorological conditions. Here, we find that statistically, non-meteorological factors constrain the growth rate of cumulative confirmed cases least when the cases in a country arrive around 1300–3200. The least-constrained growth rate correlates with the ultraviolet flux and temperature significantly (correlation coefficientsr=-0.55±0.09 and -0.40±0.10 atp <0.01, respectively), but not with precipitation, humidity, and wind. The ultraviolet correlation exhibits a delay of about seven days, providing a meteorological measure of the incubation period. Our work reveals a seasonality of COVID-19 and a high risk of a pandemic resurgence in winter, implying a need for seasonal adaption in public policies.

One-sentence summary

A delayed modulation of ultraviolet radiation on the COVID-19 transmission provides independent evidence for a 7-day incubation period and implies a strong seasonality
Countering the potential re-emergence of a deadly infectious disease - information warfare, identifying strategic threats, launching countermeasures
Authors: Ali Rex N. , Rubin Harvey , Sarkar Saswati
Published: October 2020

Eradicated infectious diseases like smallpox can re-emerge through accident or designs of bioterrorists, and perpetrate heavy casualties. Currently, only a small percentage of the populace is vaccinated, and their protection is likely to have waned. Most therefore are susceptible today. And when the disease re-emerges the susceptible individuals may be manipulated by disinformation on Social Media to refuse vaccines. Thus, a combination of countermeasures consisting of antiviral drugs and vaccines and a range of policies for their application need to be investigated. Opinions as to receptivity of vaccines evolve with time through social exchanges over networks that overlap with but are not identical to the disease propagation networks. These couple the spread of the biological and information contagion and necessitate a joint investigation of the two. Towards these, we develop a computationally tractable metapopulation epidemiological model that captures the joint spatio-temporal evolution of smallpox and opinion dynamics. The computations based on the model show that opinion dynamics has a substantial impact on the fatality count. Towards understanding how perpetrators are likely to seed the infection we identify a) the initial distribution of infected individuals that maximize the overall fatality count regardless of mobility patterns, and b) which habitation structures are more vulnerable to outbreaks. We assess the relative efficacy of different countermeasures and conclude that a combination of vaccines and drugs minimizes the fatalities, and by itself, for smallpox, drugs reduce fatalities more than the vaccine. Accordingly, we assess the efficacies of three separate policies for administering the drugs and identify the best among them for various parameter combinations. When the availability of the drug is finite, we show that increase in its supply substantially reduces the overall fatality. Our findings lead to policy recommendations for public health and urban design authorities towards thwarting smallpox and other infectious disease outbreaks.
A pilot study of discovery and validation of peritoneal endometriosis biomarkers in peritoneal fluid and serum
Authors: Loy See Ling , Zhou Jieliang , Cui Liang , Tan Tse Yeun , Ee Tat Xin , Min Chern Bernard Su , Yen Chan Jerry Kok , Lee Yie Hou
Published: October 2020

Objective

To identify potential serum biomarkers in women with peritoneal endometriosis (PE) by first looking at its source in the peritoneal fluid (PF).

Design

Case-control pilot studies, comprising independent discovery and validation sets.

Setting

KK Women’s and Children’s Hospital, Singapore.

Patient(s)

Women with laparoscopically confirmed PE and absence of endometriosis (control).

Intervention(s)

None.

Main Outcome Measure(s)

In the discovery set, we used untargeted liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics, multivariable and univariable analyses to generate global metabolomic profiles of PF for endometriosis and to identify potential metabolites that could distinguish PE (n=10) from controls (n=31). Using targeted metabolomics, we validated the identified metabolites in PF and sera of cases (n=16 PE) and controls (n=19). We performed the area under the receiver-operating characteristics curve (AUC) analysis to evaluate the diagnostic performance of PE metabolites.

Result(s)

In the discovery set, PF phosphatidylcholine (34:3) and phenylalanyl-isoleucine were significantly increased in PE than controls groups, with AUC 0.77 (95% confidence interval 0.61-0.92; p=0.018) and AUC 0.98 (0.95-1.02; p<0.001), respectively. In the validation set, phenylalanyl-isoleucine retained discriminatory performance to distinguish PE from controls in both PF (AUC 0.77; 0.61-0.92; p=0.006) and serum samples (AUC 0.81; 0.64-0.99; p=0.004).

Conclusion(s)

Our preliminary results propose phenylalanyl-isoleucine as a potential biomarker of PE, which may be used as a minimally-invasive diagnostic biomarker of PE.
Virus detection and identification in minutes using single-particle imaging and deep learning
Authors: Shiaelis Nicolas , Tometzki Alexander , Peto Leon , McMahon Andrew , Hepp Christof , Bickerton Erica , Favard Cyril , Muriaux Delphine , Andersson Monique , Oakley Sarah , Vaughan Alison , Matthews Philippa C. , Stoesser Nicole , Crook Derrick , Kapanidis Achillefs N. , Robb Nicole C.
Published: October 2020

The increasing frequency and magnitude of viral outbreaks in recent decades, epitomized by the current COVID-19 pandemic, has resulted in an urgent need for rapid and sensitive diagnostic methods. Here, we present a methodology for virus detection and identification that uses a convolutional neural network to distinguish between microscopy images of single intact particles of different viruses. Our assay achieves labeling, imaging and virus identification in less than five minutes and does not require any lysis, purification or amplification steps. The trained neural network was able to differentiate SARS-CoV-2 from negative clinical samples, as well as from other common respiratory pathogens such as influenza and seasonal human coronaviruses. Additionally, we were able to differentiate closely related strains of influenza, as well as SARS-CoV-2 variants. Single-particle imaging combined with deep learning therefore offers a promising alternative to traditional viral diagnostic and genomic sequencing methods, and has the potential for significant impact.
Intra-operative Laxity Following Total Knee Arthroplasty is Highly Variable and Different Than Osteoarthritic and Normal Knees
Authors: Siston Robert A. , Hutter Erin E. , Ewing Joseph A. , Hall Rachel K. , Granger Jeffrey F. , Beal Matthew D.
Published: October 2020

Background

Achieving a stable joint is an important yet challenging part of total knee arthroplasty (TKA). Neither manual manipulation of the knee nor instrumented sensors biomechanically characterize knee laxity or objectively characterize how TKA changes the laxity of an osteoarthritic (OA) knee. Therefore, the purposes of this study were: 1) objectively characterize changes in knee laxity due to TKA, 2) objectively determine whether TKA resulted in equal amounts of varus-valgus motion under a given load (i.e., balance) and 3) determine how TKA knee laxity and balance differ from values seen in non-osteoarthritic knees.

Methods

Two surgeons used a custom navigation system and intra-operative device to record varus-valgus motion under quantified loads in a cohort of 31 patients (34 knees) undergoing primary TKA. Similar data previously were collected from a cohort of 42 native cadaveric knees.

Results

Performing a TKA resulted in a “looser knee” on average, but great variability existed within and between surgeons. Under the maximum applied moment, 20 knees were “looser” in the varus-valgus direction, while 14 were “tighter”. Surgeon 1 generally “loosened” knees (OA laxity 6.1°±2.3°, TKA laxity 10.1°±3.6°), while Surgeon 2 did not substantially alter knee laxity (OA laxity 8.2°±2.4°, TKA laxity 7.5°±3.3°). TKA resulted in balanced knees, and, while several differences in laxity were observed between OA, TKA, and cadaveric knees, balance was only different under the maximum load between OA and cadaveric knees.

Conclusions

Large variability exists within and between surgeons suggests in what is considered acceptable laxity and balance of the TKA knee when it is assessed by only manual manipulation of the leg. Knees were “balanced” yet displayed different amounts of motion under applied load.

Clinical Relevance

Our results suggest that current assessments of knee laxity may leave different patients with biomechanically different knees. Objective intra-operative measurements should inform surgical technique to ensure consistency across different patients.

Level of Evidence

Level II prospective observational study
A 3D Structural Interactome to Explore the Impact of Evolutionary Divergence, Population Variation, and Small-molecule Drugs on SARS-CoV-2-Human Protein-Protein Interactions
Authors: Wierbowski Shayne D. , Liang Siqi , Chen You , Andre Nicole M. , Lipkin Steven M. , Whittaker Gary R. , Yu Haiyuan
Published: October 2020

The recent COVID-19 pandemic has sparked a global public health crisis. Vital to the development of informed treatments for this disease is a comprehensive understanding of the molecular interactions involved in disease pathology. One lens through which we can better understand this pathology is through the network of protein-protein interactions between its viral agent, SARS-CoV-2, and its human host. For instance, increased infectivity of SARS-CoV-2 compared to SARS-CoV can be explained by rapid evolution along the interface between the Spike protein and its human receptor (ACE2) leading to increased binding affinity. Sequence divergences that modulate other protein-protein interactions may further explain differences in transmission and virulence in this novel coronavirus. To facilitate these comparisons, we combined homology-based structural modeling with the ECLAIR pipeline for interface prediction at residue resolution, and molecular docking with PyRosetta. This enabled us to compile a novel 3D structural interactome meta-analysis for the published interactome network between SARS-CoV-2 and human. This resource includes docked structures for all interactions with protein structures, enrichment analysis of variation along interfaces, predicted ΔΔG between SARS-CoV and SARS-CoV-2 variants for each interaction, predicted impact of natural human population variation on binding affinity, and a further prioritized set of drug repurposing candidates predicted to overlap with protein interfaces†. All predictions are available online†for easy access and are continually updated when new interactions are published.

† Some sections of this pre-print have been redacted to comply with current bioRxiv policy restricting the dissemination of purely in silico results predicting potential therapies for SARS-CoV-2 that have not undergone thorough peer-review. The results section titled “Prioritization of Candidate Inhibitors of SARS-CoV-2-Human Interactions Through Binding Site Comparison,” Figure 4, Supplemental Table 9, and all links to our web resource have been removed. Blank headers left in place to preserve structure and item numbering. Our full manuscript will be published in an appropriate journal following peer-review.
Global Constraints within the Developmental Program of theDrosophilaWing
Authors: Alba Vasyl , Carthew James E. , Carthew Richard W. , Mani Madhav
Published: October 2020

Organismal development is a complex process, involving a vast number of molecular constituents interacting on multiple spatio-temporal scales in the formation of intricate body structures. Despite this complexity, development is remarkably reproducible and displays tolerance to both genetic and environmental perturbations. This robust-ness implies the existence of hidden simplicities in developmental programs. Here, using theDrosophilawing as a model system, we develop a new quantitative strategy that enables a robust description of biologically salient phenotypic variation. Analyzing natural phenotypic variation across a highly outbred population, and variation generated by weak perturbations in genetic and environmental conditions, we observe a highly constrained set of wing phenotypes. Remarkably, the phenotypic variants can be described by a single integrated mode that corresponds to a non-intuitive combination of structural variations across the wing. This work demonstrates the presence of constraints that funnel environmental inputs and genetic variation into phenotypes stretched along a single axis in morphological space. Our results provide quantitative insights into the nature of robustness in complex forms while yet accommodating the potential for evolutionary variations. Methodologically, we introduce a general strategy for finding such invariances in other developmental contexts.
Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
Authors: Botte Mathieu , Ulrich Alexander K. C. , Adaixo Ricardo , Gnutt David , Brockmann Andreas , Bucher Denis , Chami Mohamed , Bocquet Nicolas , Ebbinghaus-Kintscher Ulrich , Puetter Vera , Becker Andreas , Egner Ursula , Stahlberg Henning , Hennig Michael , Holton Simon J.
Published: October 2020

The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.
In SituOptical Quantification of Extracellular Electron Transfer using Plasmonic Metal Oxide Nanocrystals
Authors: Graham Austin J. , Gibbs Stephen L. , Cabezas Camila A. Saez , Wang Yongdan , Green Allison M. , Milliron Delia J. , Keitz Benjamin K.
Published: October 2020

Extracellular electron transfer (EET) is a critical form of microbial metabolism that enables respiration on a variety of inorganic substrates, including metal oxides. However, quantifying current generated by electroactive bacteria has been predominately limited to biofilms formed on electrodes. To address this, we developed a platform for quantifying EET flux from cell suspensions using aqueous dispersions of infrared plasmonic tin-doped indium oxide nanocrystals. Tracking the change in optical extinction during electron transfer enabled quantification of current generated by planktonicShewanella oneidensiscultures. Using this method, we differentiated between starved and actively respiring cells, between cells of varying genotype, and between cells engineered to differentially express a key EET gene using an inducible genetic circuit. Overall, our results validate the utility of colloidally stable plasmonic metal oxide nanocrystals as quantitative biosensors in native biological environments and contribute to a fundamental understanding of planktonicS. oneidensiselectrophysiology using simplein situspectroscopy.
Re-emergence and diversification of a specialised antennal lobe morphology in ithomiine butterflies
Authors: Morris Billy J , Couto Antoine , Aydin Asli , Montgomery Stephen H
Published: October 2020

How an organism’s sensory system functions is central to how it navigates its environment and meets the behavioural challenges associated with survival and reproduction. Comparing sensory systems across species can reveal how facets of behaviour and ecology promote adaptive shifts in the relative importance of certain environmental cues. The insect olfactory system is prominent model for investigating how ecological factors impact sensory reception and processing. Notably work in Lepidoptera led to the discovery of vastly expanded structures, termed a macroglomerular complex (MGC), within the primary olfactory processing centre. These structures typically process pheromonal cues and provide a classic example of how variation in size can influence the functional processing of sensory cues. Though prevalent across moths, the MGC was lost during the early evolution of butterflies, consistent with evidence that courtship initiation in butterflies is primarily reliant upon visual cues, rather than long distance olfactory signals like pheromones. However, a MGC has recently been reported to be present in a species of ithomiine,Godryis zavaleta, suggesting this once lost neural adaptation has re-emerged in this clade. Here, we show that MGC’s, or MGC-like morphologies, are indeed widely distributed across the ithomiine tribe, and vary in both structure and the prevalence of sexual dimorphism. Based on patterns of variation across species with different chemical ecologies, we suggest that this structure is involved in the processing of both plant and pheromonal cues, of interlinked chemical constitution, and has evolved in conjunction with the increased importance and diversification of plant derived chemicals cues in ithomiines.
ELOVL2 is required for robust visual function in zebrafish
Authors: Dasyani Manish , Gao Fangyuan , Xu Qianlan , Fossan Donald Van , Zhang Ellis , Pinto Antonio F. M. , Saghatelian Alan , Skowronska-Krawczyk Dorota , Chao Daniel L.
Published: October 2020

Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) play critical roles in membrane stability and cell signaling within the retina.Elovl2, an elongase involved in synthesis of long chain polyunsaturated fatty acids (LC-PUFAs), has recently been implicated in regulating aging in the mammalian retina. In this work, we characterize the expression and function ofelovl2in retina development in embryonic zebrafish. Whole mountin situhybridization showselovl2is expressed in the Müller glia in embryonic and adult zebrafish. Lipidomics analysis ofelovl2crispants whole embryos at day 2 and eyes at day 7 demonstrated significant changes in lipids composition, especially on the level of lipids containing docosahexaenoic acid (DHA). Histological analysis of zebrafish lackingelovl2revealed increased retinal thickness compared to controls at day 7 without gross disruptions of retinal architecture. Finally,elovl2crispants showed differences in the visual motor reflex light off (VMR-OFF) at day 7 compared to controls. In sum, inactivation ofelovl2in zebrafish embryos caused changes in lipid composition and in visual behavior further confirming the important role of LC-PUFAs in healthy vision.
Do auditory mismatch responses differ between acoustic features?
Authors: An HyunJung , Kei Shing Ho , Auksztulewicz Ryszard , Schnupp Jan W.
Published: October 2020

Mismatch negativity (MMN) is the electroencephalographic (EEG) waveform obtained by subtracting event-related potential (ERP) responses evoked by unexpected deviant stimuli from responses evoked by expected standard stimuli. While the MMN is thought to reflect an unexpected change in an ongoing, predictable stimulus, it is unknown whether MMN responses evoked by changes in different stimulus features have different magnitudes, latencies, and topographies. The present study aimed to investigate whether MMN responses differ depending on whether sudden stimulus change occur in pitch, duration, location or vowel identity respectively.

To calculate ERPs to standard and deviant stimuli, EEG signals were recorded in normal-hearing participants (N=20; 13 males, 7 females) who listened to roving oddball sequences of artificial syllables. In the roving paradigm, any given stimulus is repeated several times to form a standard, and then suddenly replaced with a deviant stimulus which differs from the standard. Here, deviants differed from preceding standards along one of four features (pitch, duration, vowel or interaural level difference). The feature levels were individually chosen to match behavioral discrimination performance.

We identified neural activity evoked by unexpected violations along all four acoustic dimensions. Evoked responses to deviant stimuli increased in amplitude relative to the responses to standard stimuli. A univariate (channel-by-channel) analysis yielded no significant differences between MMN responses following violations of different features. However, in a multivariate analysis (pooling information from multiple EEG channels), acoustic features could be decoded from the topography of mismatch responses, although at later latencies than those typical for MMN. These results support the notion that deviant feature detection may be subserved by a different process than general mismatch detection.
Aggregation of Cohorts for Histopathological Diagnosis with Deep Morphological Analysis
Authors: Park Jeonghyuk , Chung Yul Ri , Kong Seo Taek , Kim Yeong Won , Park Hyunho , Kim Kyungdoc , Kim Dong-Il , Jung Kyu-Hwan
Published: October 2020

There have been substantial efforts in using deep learning (DL) to diagnose cancer from digital images of pathology slides. Existing algorithms typically operate by training deep neural networks (DNNs) either specialized in specific cohorts or an aggregate of all cohorts when there are only a few images available for the target cohort. A trade-off between decreasing the number of models and their cancer detection performance was evident in our experiments with The Cancer Genomic Atlas (TCGA) dataset, with the former approach achieving higher performance at the cost of having to acquire large datasets from the cohort of interest. Constructing annotated datasets for individual cohorts is extremely time-consuming, with the acquisition cost of such datasets growing linearly with the number of cohorts. Another issue associated with developing cohort-specific models is the difficulty of maintenance: all cohort-specific models may need to be adjusted when a new DL algorithm is to be used, where training even a single model may require a non-negligible amount of computation, or when more data is added to some cohorts. In resolving the sub-optimal behavior of a universal cancer detection model trained on an aggregate of cohorts, we investigated how cohorts can be grouped to augment a dataset without increasing the number of models linearly with the number of cohorts. This study introduces several metrics which measure the morphological similarities between cohort pairs and demonstrates how the metrics can be used to control the trade-off between performance and the number of models.
KlebsiellaMALDI TypeR: a web-based tool forKlebsiellaidentification based on MALDI-TOF mass spectrometry
Authors: Bridel Sébastien , Watts Stephen C. , Judd Louise M. , Harshegyi Taylor , Passet Virginie , Rodrigues Carla , Holt Kathryn E. , Brisse Sylvain
Published: October 2020

Motivation

Klebsiellaspecies are increasingly multidrug resistant pathogens affecting human and animal health and are widely distributed in the environment. Among these, theKlebsiella pneumoniaespecies complex (KpSC), which includes seven phylogroups, is an important cause of community and hospital infections. In addition, theKlebsiella oxytocaspecies complex (KoSC) also causes hospital infections and antibiotic-associated haemorrhagic colitis. The unsuitability of widely used clinical microbiology methods to distinguish species within each of these species complexes leads to high rates of misidentifications that are masking the true clinical significance and potential epidemiological specificities of individual species.

Results

We developed a web-based tool,KlebsiellaMALDI TypeR, a platform-independent and user-friendly application that enables uploading raw data from MALDI-TOF mass spectrometer to identifyKlebsiellaisolates at the species complex and phylogroup levels. The tool is based on a database of previously identified biomarkers that are specific for either the species complex, individual phylogroups, or related phylogroups, and is available athttps://maldityper.pasteur.fr.
Agonist efficiency from concentration-response curves: structural implications and applications
Authors: Indurthi D. C. , Auerbach A.
Published: October 2020

Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC50) that indicates potency, a high-concentration asymptote that indicates efficacy and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC50and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η values is bimodal with population means at 51% (including ACh, nornicotine and DMPP) and 40% (including epibatidine, varenicline and cytisine). The value of η is related inversely to the size of the agonist’s head-group, with high-versus low-efficiency ligands having an average volume of 70 Å3versus 102 Å3. Most binding site mutations have only a small effect on ACh efficiency except for αY190A (35%), αW149A (60%) and those at αG153 (42%). If η is known, the midpoint and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC50of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.

Statement of significance

Receptors are molecular machines that convert chemical energy from agonist binding into mechanical energy of a global conformational change that generates a cell response. Agonists are distinguished by their potency (proportional to affinity) and efficacy, but also by the efficiency at which their binding energy is applied to receptor activation. Here we show that agonist efficiency can be estimated from a single concentrationresponse curve, and estimate efficiencies of 20 nicotinic receptor agonists. These have a bimodal distribution with larger agonists belonging to the lower-efficiency population. We further show that mutations of some binding site residues alter efficiency, and that knowledge of agonist efficiency simplifies and extends dose-response curve analysis.
Overexpression of MutS impairs DNA mismatch repair and causes cell division defect inE.coli
Authors: Iyer V Rajesh , Moharir Shivranjani C , Kumar Satish
Published: October 2020

MutS and its homologues, from prokaryotes to humans, recognize and bind to DNA mismatches generated during DNA replication, initiate DNA mismatch repair and ensures 100-200 fold increase in replication fidelity. InE.coli, through post transcriptional regulation, at least three mechanisms mediate decline of MutS intracellular concentrations during stress conditions. To understand the significance of this multifold regulation, we overexpressed MutS inE.coliand found that it led to impairment of DNA mismatch repair as reflected by preferential accumulation of transition mutations in spontaneous base pair substitution spectrum. This phenomenon was dependent on MutS-mismatch affinity and interaction. Higher MutS overexpression levels promoted DNA double strand breaks, inhibited cell division and resultantly caused a manifold increase inE.colicell length. This cell division defect involved a novel MutS-FtsZ interaction and impediment of FtsZ ring function. Our findings may have relevance for cancers where mismatch proteins are known to be overexpressed.