bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixed invasive molds among COVID-19 patients
Authors: Singh Vanya , Prasad Amber , Panda Prasan Kumar , Totaganti Manjunath , Tyagi Amit , Thaduri Abhinav , Rao Shalinee , Bairwa Mukesh , Singh Ashok Kumar
Published: August 2021

Purpose

Due to surge in COVID cases during the second wave of the COVID pandemic, the healthcare system collapsed in India with shortage of hospital beds, injudicious use of steroids and other immunomodulators, and poor glycaemic monitoring among a population with pre-existing risk of diabetes. Fungal epidemic was announced amid COVID pandemic with several cases of COVID-associated mucormycosis and aspergillosis being reported. But, there is no data regarding mixed fungal infections in COVID patients.

Materials and Methods

The study presented a series of ten consecutive cases with dual invasive molds in patients infected with SARS-CoV-2. Among patients hospitalized with the diagnosis of COVID in May 2021 at a tertiary care center in North India, ten microbiologically confirmed dual/mixed COVID-associated mucor-aspergillosis (CAMA) were evaluated.

Results

All patients were diabetics with the majority having severe COVID pneumonia (6/10, 60%) either on admission or in the past one month, whilst two were each of moderate (20%) and mild (20%) categories of COVID. The patients were managed with amphotericin-B along with surgical intervention. In this case series, 70% of all CAMA (Rhizopus arrhizuswithAspergillus flavusin seven andAspergillus fumigatusin three patients) patients survived, connoting the critical importance of a high index of clinical suspicion and accurate microbiological diagnosis for managing invasive molds.

Conclusions

Mixed fungal infections i.e. CAMA during COVID and post-COVID periods may be an emerging disease. This outbreak is seen particularly in such patients with uncontrolled diabetes, on steroids, or cocktail therapy, or living in unhygienic environments.We believe that our findings would help gain a better insight into the risk and progression of invasive fungal mixed infections among COVID patients and thus play a pivotal role in diagnosing, classifying, and implementing an effective management strategy for treating similar cases in the future.
Use of compressed sensing to expedite high-throughput diagnostic testing for COVID-19 and beyond
Authors: Waldstein Kody A. , Yi Jirong , Cho Michael Myung , Mudumbai Raghu , Wu Xiaodong , Varga Steven M. , Xu Weiyu
Published: August 2021

The rapid spread of SARS-CoV-2 has placed a significant burden on public health systems to provide rapid and accurate diagnostic testing highlighting the critical need for innovative testing approaches for future pandemics. In this study, we present a novel sample pooling procedure based on compressed sensing theory to accurately identify virally infected patients at high prevalence rates utilizing an innovative viral RNA extraction process to minimize sample dilution. At prevalence rates ranging from 0-14.3%, the number of tests required to identify the infection status of all patients was reduced by 75.6% as compared to conventional testing in primary human SARS-CoV-2 nasopharyngeal swabs and a coronavirus model system. Additionally, our modified pooling and RNA extraction process minimized sample dilution which remained constant as pool sizes increased. Our use of compressed sensing can be adapted to a wide variety of diagnostic testing applications to increase throughput for routine laboratory testing as well as a means to increase testing throughput to combat future pandemics.

Graphical Abstract
Genomic analysis of SARS-CoV-2 variants of concern identified from the ChAdOx1 nCoV-19 immunized patients from Southwest part of Bangladesh
Authors: Al-Emran Hassan M. , Hasan Md. Shazid , Setu Md. Ali Ahsan , Rahman Md. Shaminur , Alam ASM Rubayet Ul , Sarkar Shovon Lal , Islam Md. Tanvir , Islam Mir Raihanul , Rahman Mohammad Mahfuzur , Islam Ovinu Kibria , Jahid Iqbal Kabir , Hossain M. Anwar
Published: August 2021

Introduction

Bangladesh introduced ChAdOx1 nCoV-19 since February, 2021 and in six months, only a small population (3.5%) received their first dose of vaccination like other low-income countries. The remaining populations are struggling with increased rate of infection due to beta and delta variants. Although this uncontrolled COVID-19 pandemic did not leave even the immunized group because of immune escaping capacity of those new variants.

Methods

A total of 4718 nasopharygeal samples were collected from 1stMarch until 15thApril, 2021, of which, 834 (18%) were SARS-CoV-2 positive. Randomly generated 135 positive cases were selected for telephone interview and 108 were available and provided consent. The prevalence of SARS-CoV-2 variants and disease severity among both immunized and unimmunized group was measured. A total of 63 spike protein sequence and 14 whole genome sequences were performed from both groups and phylogenetic reconstruction and mutation analysis were compared.

Results

A total of 40 respondents (37%, N=108) received single-dose and 2 (2%) received both doses of ChAdOx1 nCoV-19 vaccine which significantly reduce dry cough, loss of appetite and difficulties in breathing compared to none. There was no significant difference in hospitalization, duration of hospitalization or reduction of other symptoms like running nose, muscle pain, shortness of breathing or generalized weakness between immunized and unimmunized group. Spike protein sequence assumed 21 (87.5%) B.1.351, one B.1.526 and two 20B variants in immunized group compared to 27 (69%) B.1.351, 5 (13%) B.1.1.7, 4 (10%) 20B, 2 B.1.526 and one B.1.427 variant in unimmunized group. Those variants were further confirmed by 14 whole genome sequence analysis. Complete genome analysis included seven B.1.351 Beta V2, three B.1.1.7 Alpha V1, one B.1.526 Eta and rest three 20B variant.

Conclusion

Single dose of ChAdOx1 couldn’t prevent the new infection or disease severity by the COVID-19 variants of concern, B.1.351, in Bangladesh.
When does contacting more people lessen the transmission of infectious diseases?
Authors: Mello Bernardo A.
Published: August 2021

A primary concern in epidemics is to minimize the probability of contagion, often resorting to reducing the number of contacted people. However, the success of that strategy depends on the shape of the dose-response curve, which relates the response of the exposed person to the pathogen dose received from surrounding infected people. If the reduction is achieved by spending more time with each contacted person, the pathogen charge received from each infected individual will be larger. The extended time spent close to each person may worsen the expected response if the dose-response curve is concave for small doses. This is the case when the expected response is negligible below a certain dose threshold and rises sharply above it. This paper proposes a mathematical model to calculate the expected response and uses it to identify the conditions when it would be advisable to reduce the contact time with each individual even at the cost of increasing the number of contacted people.
A conceptual modelling framework for estimating the consequences of psoriatic arthritis disease domains
Authors: Chou Jacquelyn W , Maksabedian Hernandez Ervant J , Collier David H , Thom Howard J
Published: August 2021

Objective: Characterize psoriatic arthritis (PsA) heterogeneity and develop a conceptual framework to model the clinical and economic value of treatments on key PsA disease domains.
Methods: We performed a narrative literature review to identify the key PsA disease domains and outcome measures for these and explore the existing evidence base of clinical and economic evaluations of current PsA treatments on key disease domains. We propose an economic modelling framework that could estimate the economic value of PsA treatments on disease domains.
Results: Our literature review identified the following key PsA disease domains: peripheral arthritis, dactylitis, enthesitis, psoriatic spondylitis, skin, and nail lesions, and associated key outcome measures. Our review of the literature, including clinical guidelines, suggests that the evidence base of specific treatment performance on modulating outcomes for a given domain was not strong. We propose an economic modelling framework to estimate the economic value of treatments for addressing specific PsA disease domains. Given existing evidence gaps, we would recommend a cohort-level model with a lifetime horizon, to estimate total social value as well as the cost per outcome and change in cost per symptom avoided. The significant patient heterogeneity in PsA would suggest an individual/patient-level simulation but is likely not feasible with existing data.
Conclusions: PsA is a heterogeneous disease, with a number of key disease domains and variable presentation. A better understanding of the performance of treatments on given disease domains would help support patients, providers, payers, HTA's, and health care policy makers in making personalized treatment decisions.
Ignoring spatial heterogeneity in drivers of SARS-CoV-2 transmission in the US will impede sustained elimination
Authors: Susswein Zachary , Valdano Eugenio , Brett Tobias , Rohani Pejman , Colizza Vittoria , Bansal Shweta
Published: August 2021

To dissect the transmission dynamics of SARS-CoV-2 in the United States, we integrate parallel streams of high-resolution data on contact, mobility, seasonality, vaccination and seroprevalence within a metapopulation network. We find the COVID-19 pandemic in the US is characterized by a geographically localized mosaic of transmission along an urban-rural gradient, with many outbreaks sustained by between-county transmission. We detect a dynamic tension between the spatial scale of public health interventions and population susceptibility as pre-pandemic contact is resumed. Further, we identify regions rendered particularly at risk from invasion by variants of concern due to spatial connectivity. These findings emphasize the public health importance of accounting for the hierarchy of spatial scales in transmission and the heterogeneous impacts of mobility on the landscape of contagion risk.
Predictive Analysis of COVID-19 Spread in Sri Lanka using an Adaptive Compartmental Model: Susceptible-Exposed-Infected-Recovered-Dead (SEIRD) Model
Authors: Rajapaksha R. M. Nayani Umesha , Wijesinghe Millawage Supun Dilara , Thomas Toms K. , Jayasooriya Sujith P. , Gunawardana B. M. W. Indika , Weerasinghe W. M. Prasad Chathuranga , Bhakta Shalini , Assefa Yibeltal
Published: August 2021

Novel Corona Virus (COVID-19) is still spreading throughout the world despite various degrees of movement restrictions and the availability of multiple safe and effective vaccines. Modelling in predicting the spread of an epidemic is important for health planning and policies. This study aimed to apply a dynamic Susceptible-Exposed-Infected-Recovered-Deaths (SEIRD) model and simulated it under a range of epidemic conditions using python programme language. The predictions were based on different scenarios from without any preventive measures to several different preventive measures under R0 of 4. The model shows that more weight to personal protection can halt the spread of transmission followed by the closure of public places and interprovincial movement restriction. Results after simulating various scenarios indicate that disregarding personal protective measures can have devastating effects on the local population. Strict adherence, maintaining and monitoring of self-preventive measures are vital towards minimizing the death toll from COVID-19.
Global prediction of candidate R-loop binding and R-loop regulatory proteins
Authors: Fournier Louis-Alexandre , Kumar Arun , Smith Theodore , Su Edmund , Moksa Michelle , Hirst Martin , Stirling Peter C.
Published: August 2021

In the past decade there has been a growing appreciation for R-loop structures as important regulators of the epigenome, telomere maintenance, DNA repair and replication. Given these numerous functions, dozens, or potentially hundreds, of proteins could serve as direct or indirect regulators of R-loop writing, reading, and erasing. In order to understand common properties shared amongst potential R-loop binding proteins (RLBPs) we mined published proteomic studies and distilled 10 features that were enriched in RLBPs compared to the rest of the proteome. We used these RLBP-specific features along with their amino acid composition to create a random forest classifier which predicts the likelihood of a protein to bind to R-loops. In parallel, we employed a whole-genome CRISPR screen coupled with flow-cytometry using the S9.6 monoclonal antibody to sort guide RNAs associated with induction of high S9.6 staining. Known R-loop regulating pathways such as splicing and DNA damage repair are highly enriched in our datasets, and we validate two new R-loop modulating proteins. Together these resources provide a reference to pursue analyses of novel R-loop regulatory proteins.
Immediate Impact of Yogic Breathing on Pulsatile Cerebrospinal Fluid Dynamics
Authors: Yildiz Selda , Grinstead John , Hildebrand Andrea , Oshinski John , Rooney William D. , Lim Miranda M. , Oken Barry
Published: August 2021

Cerebrospinal fluid (CSF), a clear fluid bathing the central nervous system (CNS), undergoes pulsatile movements, and plays a critical role for the removal of waste products from the brain including amyloid beta, a protein associated with Alzheimer’s disease. Regulation of CSF dynamics is critical for maintaining CNS health, and increased pulsatile CSF dynamics may alter brain’s waste clearance due to increased mixing and diffusion. As such, understanding the mechanisms driving CSF movement, and interventions that influence its resultant removal of wastes from the brain is of high scientific and clinical impact. Since pulsatile CSF dynamics is sensitive and synchronous to respiratory movements, we are interested in identifying potential integrative therapies such as yogic breathing to regulate and enhance CSF dynamics, which has not been reported before. Here, we investigated the pre-intervention baseline data from our ongoing randomized controlled trial, and examined whether yogic breathing immediately impacts pulsatile CSF dynamics compared to spontaneous breathing. We utilized our previously established non-invasive real-time phase contrast magnetic resonance imaging (RT-PCMRI) approach using a 3T MRI instrument, and computed and rigorously tested differences in CSF velocities (instantaneous, respiratory, cardiac 1st and 2nd harmonics) at the level of foramen magnum during spontaneous versus four yogic breathing patterns. In examinations of 18 healthy participants (eight females, ten males; mean age 34.9 ± 14 (SD) years; age range: 18-61 years), we discovered immediate increase in cranially-directed velocities of instantaneous-CSF 16% - 28% and respiratory-CSF 60% - 118% during yogic versus spontaneous breathing, with most statistically significant changes during deep abdominal breathing (28%, p=0.0008, and 118%, p=0.0001, respectively). Further, cardiac pulsation was the primary source of pulsatile CSF during all breathing conditions except during deep abdominal breathing, when there was a comparable contribution of respiratory and cardiac 1st harmonic power [0.59 ± 0.78], demonstrating respiration can be the primary regulator of CSF depending on individual differences in breath depth and location. Further work is needed to investigate the impact of sustained training yogic breathing on increased pulsatile CSF dynamics and brain waste clearance for CNS health.
Immune Cell Profiling Reveals MAIT and Effector Memory CD4+ T Cell Recovery Link to Control of Cytomegalovirus Reactivation after Stem Cell Transplant
Authors: Stern Lauren , McGuire Helen M. , Avdic Selmir , de St Groth Barbara Fazekas , Gottlieb David , Abendroth Allison , Blyth Emily , Slobedman Barry
Published: August 2021

Human cytomegalovirus (HCMV) reactivation is a major opportunistic infection after allogeneic haematopoietic stem cell transplantation and has a complex relationship with post-transplant immune reconstitution. Here, we used mass cytometry to comprehensively define global patterns of innate and adaptive immune cell reconstitution at key phases of HCMV reactivation (before detection, initial detection, peak and near resolution) in the first 100 days post-transplant. In addition to identifying patterns of immune reconstitution in those with or without HCMV reactivation, we found mucosal-associated invariant T (MAIT) cell levels at the initial detection of HCMV DNAemia distinguished patients who subsequently developed low-level versus high-level HCMV reactivation. In addition, early recovery of effector-memory CD4+T cells distinguished low-level and high-level reactivation. Our data describe distinct immune signatures that emerged with HCMV reactivation post-HSCT, and highlight MAIT cell levels at the initial detection of reactivation as a potential prognostic marker to guide clinical decisions regarding pre-emptive therapy.
The role of viscoelasticity in long-time cell rearrangement
Authors: Pajic-Lijakovic Ivana , Milivojevic Milan
Published: August 2021

Although collective cell migration (CCM) is a highly coordinated and ordered migratory mode, perturbations in the form of mechanical waves appear even in 2D. These perturbations caused by the viscoelastic nature of cell rearrangement are involved in various biological processes, such as embryogenesis, wound healing and cancer invasion. The mechanical waves, as a product of the active turbulence occurred at low Reynolds number, represent an oscillatory change in cell velocity and the relevant rheological parameters. The velocity oscillations, in the form of forward and backward flows, are driven by: viscoelastic force, surface tension force, and traction force. The viscoelastic force represents a consequence of inhomogeneous distribution of cell residual stress accumulated during CCM. This cause-consequence relation is considered on a model system such as the cell monolayer free expansion. The collision of forward and backward flows causes an increase in cell packing density which has a feedback impact on the tissue viscoelasticity and on that base influences the tissue stiffness. The evidence of how the tissue stiffness is changed near the cell jamming is conflicting. To fill this gap, we discussed the density driven change in the tissue viscoelasticity by accounting for the cell pseudo-phase transition from active (contractile) to passive (non-contractile) state appeared near cell jamming in the rheological modeling consideration.
Genetic diversity of wild and cultivatedCoffeacanephora in northeastern DR Congo and the implications for conservation
Authors: Abeele Samuel Vanden , Janssens Steven B. , Anio Justin Asimonyio , Bawin Yves , Depecker Jonas , Kambale Bienfait , Mwanga Ithé Mwanga , Ebele Tshimi , Ntore Salvator , Stoffelen Piet , Vandelook Filip
Published: August 2021

Premise

Many cultivated coffee varieties descend fromCoffea canephora, commonly known as Robusta coffee. The Congo Basin has a century long history of Robusta coffee cultivation and breeding, and is hypothesized to be the region of origin of many of the cultivated Robusta varieties. Since little is known about the genetic composition ofC. canephorain this region, we assessed the genetic diversity of wild and cultivatedC. canephorashrubs in the Democratic Republic of the Congo.

Methods

Using 18 microsatellite markers, we studied the genetic composition of wild and backyard-grownC. canephorashrubs in the Tshopo and Ituri provinces, and from the INERA Yangambi Coffee Collection. We assessed genetic clustering patterns, genetic diversity, and genetic differentiation between populations.

Key results

Genetic differentiation was relatively strong between wild and cultivatedC. canephorashrubs, and both gene pools harbored multiple unique alleles. Strong genetic differentiation was also observed between wild populations. The level of genetic diversity in wild populations was similar to that of the INERA Yangambi Coffee Collection, but local wild genotypes were mostly missing from that collection. Shrubs grown in the backyards were genetically similar to the breeding material from INERA Yangambi.

Conclusions

MostC. canephorathat is grown in local backyards originated from INERA breeding programs, while a few shrubs were obtained directly from surrounding forests. The INERA Yangambi Coffee Collection could benefit from an enrichment with local wild genotypes, to increase the genetic resources available for breeding purposes, as well as to support ex situ conservation.
Bisphosphonate drugs have actions outside the skeleton and inhibit the mevalonate pathway in alveolar macrophages
Authors: Munoz Marcia A. , Fletcher Emma K. , Skinner Oliver P. , Jurczyluk Julie , Kristianto Esther , Hodson Mark P. , Sun Shuting , Ebetino Frank H. , Croucher David R. , Hansbro Philip M. , Center Jacqueline R. , Rogers Michael J.
Published: August 2021

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently-labelled bisphosphonate is internalised by alveolar macrophages and peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
Reprogramming of the intestinal epithelial-immune cell interactome during SARS-CoV-2 infection
Authors: Poletti Martina , Treveil Agatha , Csabai Luca , Gul Leila , Modos Dezso , Madgwick Matthew , Olbei Marton , Bohar Balazs , Valdeolivas Alberto , Turei Denes , Verstockt Bram , Triana Sergio , Alexandrov Theodore , Saez-Rodriguez Julio , Stanifer Megan L. , Boulant Steeve , Korcsmaros Tamas
Published: August 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an unprecedented worldwide health problem. Although the primary site of infection is the lung, growing evidence points towards a crucial role of the intestinal epithelium. Yet, the exact effects of viral infection and the role of intestinal epithelial-immune cell interactions in mediating the inflammatory response are not known. In this work, we apply network biology approaches to single-cell RNA-seq data from SARS-CoV-2 infected human ileal and colonic organoids to investigate how altered intracellular pathways upon infection in intestinal enterocytes leads to modified epithelial-immune crosstalk. We point out specific epithelial-immune interactions which could help SARS-CoV-2 evade the immune response. By integrating our data with existing experimental data, we provide a set of epithelial ligands likely to drive the inflammatory response upon infection. Our integrated analysis of intra- and inter-cellular molecular networks contribute to finding potential drug targets, and suggest using existing anti-inflammatory therapies in the gut as promising drug repurposing strategies against COVID-19.
Atmospheric particulate matter aggravates CNS demyelination via TLR-4/NF-κB-mediated microglia pathogenic activities
Authors: Han Bing , Li Xing , Deng Si-Ying , Ye Ze-Qing , Ai Ruo-Song , Deng Xin , Ma Wen , Xiao Shun , Wang Jing-Zhi , Wang Li-Mei , Xie Chong , Zhang Yan , Xu Yan , Zhang Yuan
Published: August 2021

Atmospheric Particulate Matter (PM) is one of the leading environmental risk factors for the global burden of disease. Increasing epidemiological studies demonstrated that PM plays a significant role in CNS demyelinating disorders; however, there is no direct testimony of this, and yet the molecular mechanism by which the occurrence remains unclear. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that PM exposure aggravates neuroinflammation, myelin injury, and dysfunction of movement coordination ability via boosting microglial pro-inflammatory activities, in both the pathological demyelination and physiological myelinogenesis animal models. Indeed, pharmacological disturbance combined with RNA-seq and ChIP-seq suggests that TLR-4/NF-κB signaling mediated a core network of genes that control PM-triggered microglia pathogenicity. In summary, our study defines a novel atmospheric environmental mechanism that mediates PM-aggravated microglia pathogenic activities, and establishes a systematic approach for the investigation of the effects of environmental exposure in neurologic disorders.

Significance

An atmospheric trigger, the respirable particulate matter boost microglia pathogenic activities in the context of CNS demyelination by activating TLR-4/NF-κB signaling axis in animal models of immune- and toxicity-induced demyelination, as well as myelinogenesis during postnatal development.
Noncanonical Notch signals have opposing roles during cardiac development
Authors: Miyamoto Matthew , Andersen Peter , Sulistio Edrick , Liu Xihe , Murphy Sean , Kannan Suraj , Nam Lucy , Miyamoto William , Tampakakis Emmanouil , Hibino Narutoshi , Uosaki Hideki , Kwon Chulan
Published: August 2021

The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stagespecific roles during cardiac development.
Preferential associations of soil fungal taxa under mixed compositions of eastern American tree species
Authors: Kutos Steve , Barnes Elle M. , Bhutada Arnav , Lewis J.D.
Published: August 2021

Soil fungi are vital to forest ecosystem functions, in part through their role mediating tree responses to environmental factors, as well as directly through effects on resource cycling. While the distribution of these key taxa may vary with a suite of abiotic and biotic factors, the relative role of host species identity on soil fungal community composition and function remains unresolved. In this study, we used a combination of amplicon sequencing and enzymatic assays to assess soil fungal composition and associated function under three tree species,Quercus rubra, Betula nigra, andAcer rubrum, planted individually and in all combinations in a greenhouse, with added fungal inoculum collected below mature field trees. Across treatments, fungal communities were dominated by the phylum Ascomycota, followed by Basidiomycota and Mortierellomycota. Nonetheless, fungal communities differed between each of the solo planted treatments, suggesting at least some taxa may associate preferentially with these tree species. Additionally, fungal community composition under mixed sapling treatments broadly differed from solo saplings. The data also suggests that there were larger enzymatic activities in the solo treatments as compared with all mixed treatments. This difference may be due to the greater relative abundance of saprobic taxa found in the solo treatments. This study provides evidence of the importance of tree identity on soil microbial communities and functional changes to forest soils.
Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudo-modularity
Authors: Powers Natalie R. , Billings Timothy , Paigen Kenneth , Petkov Petko M.
Published: August 2021

PRDM9 is a DNA-binding histone methyltransferase that designates and activates recombination hotspots in mammals by locally trimethylating lysines 4 and 36 of histone H3. In mice, we recently reported two independently produced point mutations at the same residue, glu360pro (Prdm9EP) and glu360lys (Prdm9EK), which severely reduce its H3K4 and H3K36 methyltransferase activitiesin vivo. Prdm9EPis slightly less hypomorphic thanPrdm9EK, but both mutations reduce both the number and amplitude of PRDM9-dependent H3K4me3 and H3K36me3 peaks in spermatocytes. While both mutations cause infertility with complete meiotic arrest in males,Prdm9EP, but notPrdm9EK, is compatible with some female fertility. When we tested the effects of these mutationsin vitro, bothPrdm9EPandPrdm9EKabolished H3K4 and H3K36 methyltransferase activity in full-length PRDM9. However, in the isolated PRDM9 PR/SET domain, these mutations selectively compromised H3K36 methyltransferase activity, while leaving H3K4 methyltransferase activity intact. The difference in these effects on the PR/SET domain versus the full-length protein show that PRDM9 is not an intrinsically modular enzyme; its catalytic domain is influenced by its tertiary structure and possibly by its interactions with DNA and other proteinsin vivo. These two informative mutations illuminate the enzymatic chemistry of PRDM9, and potentially of PR/SET domains in general, reveal the minimal threshold of PRDM9-dependent catalytic activity for female fertility, and potentially have some practical utility for genetic mapping and genomics.
Diffusely abnormal white matter converts to T2 lesion volume in the absence of acute inflammation
Authors: Dadar M. , Mahmoud S. , Narayanan S. , Collins DL. , Arnold DL. , Maranzano J.
Published: August 2021

Diffusely abnormal white matter (DAWM), characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive MS (SPMS). However, little is known about changes of DAWM over time and their relation to focal white matter lesions (FWML).

The objectives of this work were: 1) To characterize the longitudinal evolution of FWML, DAWM, and DAWM that transforms into FWML, and 2) To determine whether gadolinium enhancement, known to be associated with the development of new FWML, is also related to DAWM voxels that transform into FWML.

Our data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks and 2677 scans of 686 RRMS participants, followed for 96 weeks. FWML and DAWM were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, DAWM voxels at each visit that transformed into FWML on the last MRI scan as well as their overlap with gadolinium enhancing lesion masks were identified.

Our results showed that the average yearly rate of conversion of DAWM-to-FWML was 1.27cc for SPMS and 0.80cc for RRMS. FWML in SPMS participants significantly increased (t=3.9; p=0.0001) while DAWM significantly decreased (t=-4.3 p<0.0001) and the ratio FWML:DAWM increased (t=12.7; p<0.00001). RRMS participants also showed an increase in the FWML:DAWM Ratio (t=6.9; p<0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal New T2 lesion formation in the infrequent scans of the RRMS and SPMS cohorts, respectively. In comparison, only 0.1% and 0.0% of DAWM-to-FWML voxels overlapped with gadolinium enhancement.

We conclude that DAWM transforms into FWML over time, in both RRMS and SPMS. DAWM appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.
Genetic diversity of local and introduced cassava germplasm in Burundi using DArTseq molecular analyses
Authors: Pierre Niyonzima , Wamalwa Lydia Nanjala , Muiru William Maina , Simon Bigirimana , Kanju Edward , Ferguson Morag Elizabeth , Ndavi Malu Muia , Tumwegamire Silver
Published: August 2021

In Burundi, most of small-scale farmers still grow traditional cassava landraces that are adapted to local conditions and have been selected for consumer preferred attributes. They tend to be susceptible, in varying degrees, to devastating cassava viral diseases such as Cassava Brown Steak Disease (CBSD) and Cassava Mosaic Disease (CMD) with production annual losses of US$1 billion annually. For long term resistance to the disease, several breeding strategies have been proposed. A sound basis for a breeding program is to understand the genetic diversity of both landraces and elite introduced breeding cultivars. This will also assist in efforts to conserve landraces ahead of the broad distribution of improved varieties which have the possibility of replacing landraces. Our study aimed at determining the genetic diversity and relationships of local landraces and introduced elite germplasm using morphological and simple nucleotide polymorphism (SNP) markers as well as identifying a core set of germplasm from the local varieties to be used in the cassava breeding program. A total of 118 cultivars were characterized for morphological trait variation based on leaf, stem and root traits, and genetic variation using SNP markers. Results of morphological characterization based on Ward’s Method revealed three main clusters and five accessions sharing similar characteristics. Molecular characterization identified over 18,000 SNPs and six main clusters and three pairs of duplicates which should be pooled together as one cultivar to avoid redundancy. Results of population genetic analysis showed low genetic distance between populations and between local landraces and elite germplasm. Accessions that shared similar morphological traits were divergent at the molecular level indicating that clustering using morphological traits was inconsistent. Despite the variabilities found within the collection, it was observed that cassava germplasm in Burundi have a narrow genetic base.
Interaction between β-lactoglobulin and EGCG under high-pressure by molecular dynamics simulation
Authors: Huang Yechuan , Zhang Xicai , Suo Huayi
Published: August 2021

The binding between β-lactoglobulin and epigallocatechin gallate (EGCG) under the pressure of 600 MPa was explored using molecular docking and molecular dynamics (MD) simulation. EGCG bound mainly in two regions with site 1 in internal cavity of the β-barrel and site 2 on the surface of protein. 150 ns MD was performed starting from the structure with the lowest binding energy at the two sites in molecular docking, respectively, it was found that the system fluctuated greatly when small molecule bound to site 2 at 0.1 MPa. The protein fluctuation and solvent accessible surface area became smaller under high-pressure. The binding of small molecules made the protein structure more stable with increasing of α-helix and β-sheet, while high-pressure destroyed α-helix of protein. The binding free energy of small molecules at site 1was higher than that at site 2 under 0.1 MPa, with higher van der Waals and hydrophobic interaction at site 1 while more hydrogen bonds at site 2. The binding free energy of both sites decreased under high-pressure, especially at site 1, causing binding free energy at site 1 was lower than that at site 2 under high-pressure.
Integrating genomics and multivariate evolutionary quantitative genetics: A case study of multivariate constraints on sexual selection inDrosophila serrata
Authors: Reddiex Adam J. , Chenoweth Stephen F.
Published: August 2021

In evolutionary quantitative genetics, the genetic variance-covariance matrix,G, and the vector of directional selection gradients,β, are key parameters for predicting multivariate selection responses and genetic constraints. Historically, investigations ofGandβhave not overlapped with those dissecting the genetic basis of quantitative traits. Thus, it remains unknown whether these parameters reflect pleiotropic effects at individual loci. Here, we integrate multivariate GWAS withGandβestimation in a well-studied system of multivariate constraint; sexual selection on male cuticular hydrocarbons (CHCs) inDrosophila serrata. In a panel of wild-derived resequenced lines, we augment genome-based REML, (GREML) to estimateGalongside multivariate SNP effects, detecting 532 significant associations from 1,652,276 SNPs. Constraint was evident, withβlying in a direction ofGwith low evolvability. Interestingly, minor frequency alleles typically increased male CHC-attractiveness suggesting opposing natural selection onβ. SNP effects were significantly misaligned with the major eigenvector ofG,gmax, but well aligned to the second and third eigenvectorsg2andg3. We discuss potential factors leading to these varied results including multivariate stabilising selection and mutational bias. Our framework may be useful as researchers increasingly access genomic methods to study multivariate selection responses in wild populations.
“At that moment, understanding the donation is crucial to make a decision”:A qualitative study exploring the process of postmortem brain tissue donation after suicide
Authors: Padoan Carolina Stopinski , Garcia Lucas França , Crespo Kleber Cardoso , Longaray Vanessa Kenne , Martini Murilo , Contessa Julia Carmargo , Kapczinski Flávio , de Oliveira Francine Hehn , Goldim José Roberto , da Silva Magalhães Pedro Vieira
Published: August 2021

Background

The direct examination of postmortem brain tissue can provide valuable help in refining knowledge on the pathophysiology and genetics of neuropsychiatric disorders. Obtaining postmortem consent for the donation of brain tissue after death by suicide can be difficult, as families may be overwhelmed by a violent and unexpected death. Examining the process of brain donation can inform on how the request can best be conducted, examining the existing barriers and enhancing communication, to the benefit of proxy donors.

Methods

This is a qualitative study, in which we employed in-depth interviews to investigate the donation process. Family members of decedents who were eligible for brain tissue donation were asked to consider the donation; irrespective of their decision, they were invited for an interview on the donation process at least 2 months after the suicide. Data collection and analyses were carried out according to a grounded theory framework, and collection, coding, and theorization occurred simultaneously.

Findings

Forty-one people participated in this study — 32 family members who had consented to donation and 9 who refused it. Five key themes emerged from our data analysis: the context of the families of potential donors, the invitation to talk to the research team, the experience with the request protocol, the participants’ assessment of the experience, and their participation in the study as an opportunity to heal. We arranged the main categories around 3 central stages of the experience described by participants: before the donation request, the request, and after the request.

Conclusions

The participants indicated that a brain donation request that is respectful and tactful can be made without adding to the family distress brought on by suicide and is viewed in a highly positive lens in the months following the event. Having an adequate understanding of tissue donation for research was crucial for satisfactory decision-making. Meeting with the donation team was considered a chance to talk to mental health professionals about suicide. Pondering brain donation was seen as an opportunity to transform the meaning of the death and invest it with a modicum of solace for being able to contribute to research.
Automated differentiation of malignant and benign primary solid liver lesions on MRI: an externally validated radiomics model
Authors: Starmans Martijn P.A. , Miclea Razvan L. , Vilgrain Valerie , Ronot Maxime , Purcell Yvonne , Verbeek Jef , Niessen Wiro J. , Ijzermans Jan N.M. , de Man Rob A. , Doukas Michail , Klein Stefan , Thomeer Maarten G.
Published: August 2021

Background & Aims

Distinguishing malignant from benign primary solid liver lesions is highly important for treatment planning. However, diagnosis on radiological imaging is challenging. In this study, we developed a radiomics model based on magnetic resonance imaging (MRI) to distinguish the most common malignant and benign primary solid liver lesions, and externally validated the model in two centers.

Approach & Results

Datasets were retrospectively collected from three tertiary referral centers (A, B and C) including data from affiliated hospitals sent for revision. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. For each patient, only a T2-weighted MRI was included. A radiomics model was developed on dataset A using a combination of machine learning approaches, and internally evaluated on dataset A through cross-validation. Next, the model was externally validated on datasets B and C, and compared to scoring by two experienced abdominal radiologists on dataset C. In the resulting dataset, in total, 486 patients were included (A: 187, B: 98 and C: 201). Despite substantial MRI acquisition heterogeneity, the radiomics model developed on dataset A had a mean area under the receiver operating characteristic curve (AUC) of 0.78 in the internal validation on dataset A, and a similar AUC in the external validations (B: 0.74, C: 0.76). In dataset C, the two radiologists showed moderate agreement (Cohen’s κ: 0.61) and achieved AUCs of 0.86 and 0.82, respectively.

Conclusions

Our radiomics model using T2-weighted MRI only can non-invasively distinguish malignant from benign primary solid liver lesions. External validation indicated that our model is generalizable despite substantial differences in the acquisition protocols.
Whole-brain connectivity during encoding: age-related differences and associations with cognitive and brain structural decline
Authors: Capogna Elettra , Sneve Markus H. , Raud Liisa , Folvik Line , Ness Hedda , Walhovd Kristine B. , Fjell Anders M. , Vidal-Piñeiro Didac
Published: August 2021

There is a limited understanding of age differences in functional connectivity during memory encoding. In the present study, a sample of cognitively healthy adult participants (n=488), a subsample of whom had longitudinal cognitive and brain structural data spanning 8 years back, underwent fMRI while performing an associative memory encoding task. We investigated 1) age changes in whole-brain connectivity during memory encoding; whether 2) encoding connectivity patterns overlap with the activity signatures of specific cognitive processes and whether 3) connectivity changes associated with memory encoding related to longitudinal brain structural and cognitive changes. Age was associated with decreased intranetwork connectivity and increased connectivity during encoding. Task-connectivity between mediotemporal and posterior parietal regions – which overlapped with areas involved in mental imagery – was related to better memory performance only in older age. The connectivity patterns supporting memory performance in older age reflected preservation of thickness of the medial temporal cortex. These investigations collectively indicate that functional patterns of connectivity should be interpreted in accordance with a maintenance rather than a compensation account.
Rapid and strain-specific resistance evolution ofStaphylococcus aureusagainst inhibitory molecules secreted byPseudomonas aeruginosa
Authors: Niggli Selina , Schwyter Lukas , Poveda Lucy , Grossmann Jonas , Kümmerli Rolf
Published: August 2021

Pseudomonas aeruginosaandStaphylococcus aureusfrequently occur together in polymicrobial infections, and there is evidence that their interactions negatively affect disease outcome in patients. At the molecular level, interactions between the two bacterial species are well-described, withP. aeruginosausually being the dominant species suppressingS. aureusthrough a variety of inhibitory molecules. However, in chronic infections the two species interact over prolonged periods of time, andS. aureusmight be able to evolve resistance against inhibitory molecules deployed byP. aeruginosa. Here, we used experimental evolution to test this hypothesis by exposing three differentS. aureusstrains (Cowan I, 6850, JE2) to the growth-inhibitory supernatant ofP. aeruginosaPAO1 over 30 days. Prior to evolution, we found thatS. aureusstrains were inhibited by secreted compounds regulatorily controlled by the PQS quorum-sensing system ofP. aeruginosa. Following evolution,S. aureusstrains were no longer inhibited: we observed that phenotypic adaptations were strain-specific and involved the up-regulation of virulence traits, such as staphyloxanthin production and the formation of small colony variants. At the genetic level, mutations in membrane transporters were the most frequent evolutionary targets. Our work indicates that adaptations ofS. aureusto co-infecting pathogens occurs rapidly and involves both virulence traits and membrane transporters involved in drug resistance. Thus, pathogen evolution could promote species co-existence, complicate treatment options and therefore worsen disease outcome.
Crystal structure and Hirshfeld surface analysis of (Z)-2-amino-4-(2,6-dichlorophenyl)-5-(1-hydroxyethylidene)-6-oxo-1-phenyl-1,4,5,6-tetrahydropyridine-3-carbonitrile
Authors: Naghiyev Farid N. , Pavlova Anastasiya V. , Khrustalev Victor N. , Akkurt Mehmet , Khalilov Ali N. , Akobirshoeva Anzurat A. , Mamedov İbrahim G.
Published: August 2021

The molecular conformation of the title compound, C20H15Cl2N3O2, is stabilized by an intramolecular O—H...O hydrogen bond, forming an S(6) ring motif. The central pyridine ring is almost planar [maximum deviation = 0.074 (3) Å]. It subtends dihedral angles of 86.10 (15) and 87.17 (14)°, respectively, with the phenyl and dichlorophenyl rings, which are at an angle of 21.28 (15)° to each other. The =C(—OH)CH3 group is coplanar. In the crystal, molecules are linked by intermolecular N—H...N and C—H...N hydrogen bonds, and N—H...π and C—H...π interactions, forming a three-dimensional network. The most important contributions to the crystal packing are from H...H (33.1%), C...H/H...C (22.5%), Cl...H/H...Cl (14.1%), O...H/H...O (11.9%) and N...H/H...N (9.7%) interactions.