bluuebunny/crossref_metadata_2025_split huggingface dataset:
dsSwissKnife: An R package for federated data analysis
Authors: Dragan Iulian , Sparsø Thomas , Kuznetsov Dmitry , Slieker Roderick , Ibberson Mark 
Published: November 2020

ABSTRACTSummarydsSwissKnifeis an R package that enables several powerful analyses to be performed on federated datasets. The package works alongside DataSHIELD and extends its functionality. We have developed and implementeddsSwissKnifein a large IMI project on type 2 diabetes, RHAPSODY, where data from 10 observational cohorts have been harmonised and federated in CDISC SDTM format and made available for biomarker discovery.Availability and implementationdsSwissKnifeis freely available online athttps://github.com/sib-swiss/dsSwissKnife. The package is distributed under the GNU General Public License version 3.Contactmark.ibberson@sib.swiss
Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology
Authors: Keshishzadeh Sarineh , Garrett Markus , Verhulst Sarah 
Published: November 2020

AbstractOver the past decades, different types of auditory models have been developed to study the functioning of normal and impaired auditory processing. Several models can simulate frequency-dependent sensorineural hearing loss (SNHL), and can in this way be used to develop personalized audio-signal processing for hearing aids. However, to determine individualized SNHL profiles, we rely on indirect and non-invasive markers of cochlear and auditory-nerve (AN) damage. Our progressive knowledge of the functional aspects of different SNHL subtypes stresses the importance of incorporating them into the simulated SNHL profile, but has at the same time complicated the task of accomplishing this on the basis of non-invasive markers. In particular, different auditory evoked potential (AEP) types can show a different sensitivity to outer-hair-cell (OHC), inner-hair-cell (IHC) or AN damage, but it is not clear which AEP-derived metric is best suited to develop personalized auditory models. This study investigates how simulated and recorded AEPs can be used to derive individual AN- or OHC-damage patterns and personalize auditory processing models. First, we individualized the cochlear-model parameters using common methods of frequency-specific OHC-damage quantification, after which we simulated AEPs for different degrees of AN-damage. Using a classification technique, we determined the recorded AEP metric that best predicted the simulated individualized CS profiles. We cross-validated our method using the dataset at hand, but also applied the trained classifier to recorded AEPs from a new cohort to illustrate the generalisability of the method.
Environmental specialization and cryptic genetic divergence in two massive coral species from the Florida Keys Reef Tract
Authors: Rippe John P. , Dixon Groves , Fuller Zachary L. , Liao Yi , Matz Mikhail 
Published: November 2020

ABSTRACTBroadcast-spawning coral species have wide geographic ranges, spanning strong environmental gradients, but it is unclear how much spatially varying selection these gradients actually impose. Strong divergent selection might present a considerable barrier for demographic exchange between disparate reef habitats. We investigated whether the cross-shelf gradient (nearshore - offshore - deep) is associated with spatially varying selection in two common coral species,Montastraea cavernosaandSiderastrea siderea, in the Florida Keys. Toward this end, we generated ade novogenome assembly forM. cavernosaand used 2bRAD to genotype 20 juveniles and 20 adults of both species from each of the three reef zones to identify signatures of selection occurring within a single generation. Unexpectedly, each species was found to be composed of four genetically distinct lineages, with gene flow between them still ongoing but highly reduced in 13.0-54.7% of the genome. Each species includes two sympatric lineages that are only found in the deep (20 m) habitat, while the other lineages are found almost exclusively on the shallower reefs (3-10 m). The two “shallow” lineages ofM. cavernosaare also specialized for either nearshore or offshore: comparison between adult and juvenile cohorts indicates that cross-shelf migrants are more than twice as likely to die before reaching adulthood than local recruits.Siderastrea sidereaandM. cavernosaare among the most ecologically successful species on the degraded Florida Keys Reef Tract, and this work offers important insight on the genomic background of divergent selection and environmental specialization that may in part explain their resilience and broad environmental range.
Major components in the KARRIKIN INSENSITIVE2-ligand signaling pathway are conserved in the liverwort,Marchantia polymorpha
Authors: Mizuno Yohei , Komatsu Aino , Shimazaki Shota , Xie Xiaonan , Ishizaki Kimitsune , Naramoto Satoshi , Kyozuka Junko 
Published: November 2020

AbstractKARRIKIN INSENSITIVE2 (KAI2) was first identified inArabidopsis thalianaas a receptor of karrikin, a smoke-derived germination stimulant. KAI2 is also considered a receptor of an unidentified endogenous molecule called the KAI2-ligand (KL). Upon KAI2 activation, signals are transmitted through degradation of D53/SMXL proteins via ubiquitination by a Skp-Cullin-F-box (SCF) E3 ubiquitin ligase complex. All components in the KL signaling pathway exist in the liverwortMarchantia polymorpha, namely MpKAI2Aand MpKAI2B, MpMAX2encoding the F-box protein, and MpSMXL, indicating that the signaling pathway became functional in the common ancestor of bryophytes and seed plants. Genetic analysis using knock-out mutants of these KL signaling genes, produced using the CRISPR system, indicated that MpKAI2A, MpMAX2and MpSMXLact in the same genetic pathway and control early gemma growth. Introduction of MpSMXLd53, in which a domain required for degradation is mutated, into wild-type plants caused phenotypes resembling those of the Mpkai2aand Mpmax2mutants. In addition, Citrine fluorescence was detected in tobacco cells transiently transformed with the35S:MpSMXL-Citrinegene construct and treated with MG132, a proteasome inhibitor. On the other hand, introduction of35S:MpSMXLd53-Citrineconferred Citrine fluorescence without MG132 treatment. These findings imply that MpSMXL is subjected to degradation, and that degradation of MpSMXL is crucial for KL signaling inM. polymorpha. We also showed that MpSMXL is negatively regulated by KL signaling. Taken together, this study demonstrates that basic mechanisms in the KL signaling pathway are conserved inM. polymorpha.
Cov-MS: a community-based template assay for clinical MS-based protein detection in SARS-CoV-2 patients
Authors: Van Puyvelde B. , Van Uytfanghe K. , Tytgat O. , Van Oudenhove L. , Gabriels R. , Bouwmeester R. , Daled S. , Van Den Bossche T. , Ramasamy P. , Verhelst S. , De Clerck L. , Corveleyn L. , Debunne N. , Wynendaele E. , De Spiegeleer B. , Judak P. , Roels K. , De Wilde L. , Van Eenoo P. , Reyns T. , Cherlet M. , Dumont E. , Debyser G. , t’Kindt R. , Sandra K. , Gupta S. , Drouin Nicolas , Harms Amy , Hankemeier Thomas , Jones DJL , Gupta P. , Lane D. , Lane C.S. , El Ouadi S. , Vincendet JB. , Morrice N. , Oehrle S. , Tanna N. , Silvester S. , Hannam S. , Sigloch F. , Bhangu-Uhlmann A. , Claereboudt J. , Anderson L. , Razavi M. , Degroeve S. , Cuypers L. , Stove C. , Lagrou K. , Martens G. , Deforce D. , Martens L. , Vissers J.P.C. , Dhaenens M. 
Published: November 2020

AbstractRising population density and global mobility are among the reasons why pathogens such as SARS-CoV-2, the virus that causes COVID-19, spread so rapidly across the globe. The policy response to such pandemics will always have to include accurate monitoring of the spread, as this provides one of the few alternatives to total lockdown. However, COVID-19 diagnosis is currently performed almost exclusively by Reverse Transcription Polymerase Chain Reaction (RT-PCR). Although this is efficient, automatable and acceptably cheap, reliance on one type of technology comes with serious caveats, as illustrated by recurring reagent and test shortages. We therefore developed an alternative diagnostic test that detects proteolytically digested SARS-CoV-2 proteins using Mass Spectrometry (MS). We established the Cov-MS consortium, consisting of fifteen academic labs and several industrial partners to increase applicability, accessibility, sensitivity and robustness of this kind of SARS-CoV-2 detection. This in turn gave rise to the Cov-MS Digital Incubator that allows other labs to join the effort, navigate and share their optimizations, and translate the assay into their clinic. As this test relies on viral proteins instead of RNA, it provides an orthogonal and complementary approach to RT-PCR, using other reagents that are relatively inexpensive and widely available, as well as orthogonally skilled personnel and different instruments. Data are available via ProteomeXchange with identifier PXD022550.
Prolonged presence of replication-competent SARS-CoV-2 in mildly symptomatic individuals: A Report of 2 Cases
Authors: Mendes-Correa Maria Cassia , Leal Fabio E. , Villas-Boas Lucy S. , Witkin Steven S. , de Paula Anderson , Tozetto-Mendonza Tania Regina , Ferreira Noely Evangelista , Curty Gislaine , de Carvalho Pedro Santos , Buss Lewis F. , Costa Silvia F. , da Cunha Carvalho Flavia Mendes , Kawakami Joyce , Taniwaki Noemi Nosomi , Paiao Heuder , da Silva Bizário Joao Carlos , de Jesus Jaqueline Goes , Sabino Ester Cerdeira , Romano Camila Malta , Zetone Grepan Regina Maura , Sesso Antonio 
Published: November 2020

AbstractIt has been estimated that individuals with COVID-19 can shed replication-competent virus up to a maximum of twenty days after initiation of symptoms. This report describes two patients with mild forms of the disease who shed replication-competent virus for 24 and 37 days, respectively, after symptom onset.
A Structural Signature Motif Enlightens the Origin and Diversification of Nuclear Receptors
Authors: Beinsteiner Brice , Markov Gabriel V. , Erb Stéphane , Chebaro Yassmine , McEwen Alastair , Cianférani Sarah , Laudet Vincent , Moras Dino , Billas Isabelle M.L. 
Published: November 2020

AbstractNuclear receptors are ligand-activated transcription factors that modulate gene regulatory networks from embryonic development to adult physiology and thus represent major targets for clinical interventions in many diseases. Most nuclear receptors function either as homodimers or as heterodimers. The dimerization is crucial for gene regulation by nuclear receptors, by extending the repertoire of binding sites in the promoters or the enhancers of target genes via combinatorial interactions. Here, we focused our attention on an unusual structural variation of the α-helix, called π-turn that is present in helix H7 of the ligand-binding domain of RXR and HNF4. By tracing back the complex evolutionary history of the π-turn, we demonstrate that it was present ancestrally and then independently lost in several nuclear receptor lineages. Importantly, the evolutionary history of the π-turn motif is parallel to the evolutionary diversification of the nuclear receptor dimerization ability from ancestral homodimers to derived heterodimers. We then carried out structural and biophysical analyses, in particular through point mutation studies of key RXR signature residues and showed that this motif plays a critical role in the network of interactions stabilizing homodimers. We further showed that the π-turn was instrumental in allowing a flexible heterodimeric interface of RXR in order to accommodate multiple interfaces with numerous partners and critical for the emergence of high affinity receptors. Altogether, our work allows to identify a functional role for the π-turn in oligomerization of nuclear receptors and reveals how this motif is linked to the emergence of a critical biological function. We conclude that the π-turn can be viewed as a structural exaptation that has contributed to enlarging the functional repertoire of nuclear receptors.
Effectiveness of remdesivir with and without dexamethasone in hospitalized patients with COVID-19
Authors: Garibaldi Brian T. , Wang Kunbo , Robinson Matthew L. , Zeger Scott L. , Roche Karen Bandeen , Wang Mei-Cheng , Alexander G. Caleb , Gupta Amita , Bollinger Robert , Xu Yanxun 
Published: November 2020

ABSTRACTRationaleRemdesivir and dexamethasone reduced the severity of COVID-19 in clinical trials. However, their individual or combined effectiveness in clinical practice remains unknown.ObjectivesTo examine the effectiveness of remdesivir with or without dexamethasone.MethodsWe conducted a multicenter, retrospective cohort study between March 4 and August 29, 2020. Eligible COVID cases were hospitalized patients treated with remdesivir with or without dexamethasone. We applied a Cox proportional hazards model with propensity score matching to estimate the effect of these treatments on clinical improvement by 28 days (discharge or a 2-point decrease in WHO severity score) and 28-day mortality.Measurements and Main ResultsOf 2485 COVID-19 patients admitted between March 4 and August 29, 2020, 342 received remdesivir and 157 received remdesivir plus dexamethasone. Median age was 60 years; 45% were female; 81% were non-white. Remdesivir recipients on room air or nasal cannula oxygen had a faster time to clinical improvement (median 5.0 days [IQR 4.0, 8.0], remdesivir vs. 7.0 days [IQR 5.0, 12.0], control; adjusted hazard ratio (aHR) 1.55 [1.28; 1.87]), yet those requiring higher levels of respiratory support did not benefit. Remdesivir recipients had lower, but statistically insignificant, 28-day mortality (7.6% [23 deaths], remdesivir vs. 14.9% [45 deaths], control). Adding dexamethasone trended toward lower 28-day mortality compared to remdesivir alone (5.1% [8 deaths] vs. 9.2% [17 deaths]; aHR 0.14 [0.02; 1.03]).ConclusionsRemdesivir offered a significantly faster time to clinical improvement among a cohort of predominantly non-white patients hospitalized with COVID-19, particularly with mild-moderate disease. Remdesivir plus dexamethasone may reduce mortality.
Social patterning and stability of intention to accept a COVID-19 vaccine in Scotland: Will those most at risk accept a vaccine?
Authors: Williams Lynn , Flowers Paul , McLeod Julie , Young David , Rollins Lesley ,   CATALYST project team
Published: November 2020

AbstractVaccination is central to controlling COVID-19. Its success relies on having safe and effective vaccines and also on high levels of uptake by the public over time. Addressing questions of population-level acceptability, stability of acceptance and sub-population variation in acceptability are imperative. Using a prospective design, a repeated measures two-wave online survey was conducted to assess key sociodemographic variables and intention to accept a COVID-19 vaccine. The first survey (time 1) was completed by 3436 people during the period of national lockdown in Scotland and the second survey (n = 2016) was completed two months later (time 2) when restrictions had been eased. At time one, 74% reported being willing to receive a COVID-19 vaccine. Logistic regression analyses showed that there were clear sociodemographic differences in intention to accept a vaccine for COVID-19 with intention being higher in participants of white ethnicity in comparison to Black, Asian, and minority ethnic (BAME) groups, and in those with higher income levels and higher education levels. Intention was also higher in those who were ‘shielding’ due to underlying medical conditions. Our results suggest that future interventions such as mass media and social marketing need to be targeted to a range of sub-populations and diverse communities.
Accelerating Medicines Partnership: Parkinson’s Disease. Genetic Resource
Authors: Iwaki Hirotaka , Leonard Hampton L. , Makarious Mary B. , Bookman Matt , Landin Barry , Vismer David , Casey Bradford , Gibbs J. Raphael , Hernandez Dena G. , Blauwendraat Cornelis , Vitale Daniel , Song Yeajin , Kumar Dinesh , Dalgard Clifton L. , Sadeghi Mahdiar , Dong Xianjun , Misquitta Leonie , Scholz Sonja W. , Scherzer Clemens R. , Nalls Mike A. , Biswas Shameek , Singleton Andrew B ,   Uniformed Services University of the Health Sciences Associates,   AMP PD Whole Genome Sequencing Working Group,   AMP PD consortium
Published: November 2020

AbstractBackgroundWhole-genome sequencing (WGS) data is available from several large studies across a variety of diseases and traits. However, massive storage and computation resources are required to use these data, and, to achieve the sufficient power for discoveries, harmonization of multiple cohorts is critical.ObjectivesThe Accelerating Medicines Partnership Parkinson’s Disease (AMP PD) program has developed a research platform for Parkinson’s disease (PD) which integrates the storage and analysis of WGS data, RNA expression data, and clinical data, harmonized across multiple cohort studies.MethodsThe version 1 release contains WGS data derived from 3,941 participants from 4 cohorts. Samples underwent joint genotyping by the TOPMed Freeze 9 Variant Calling Pipeline. We performed descriptive analyses of these WGS data using the AMP PD platform.ResultsThe clinical diagnosis of participants in version 1 release includes 2,005 idiopathic PD patients, 963 healthy controls, 64 prodromal subjects, 62 clinically diagnosed PD subjects without evidence of dopamine deficit (SWEDD) and 705 participants of genetically enriched cohorts carrying PD risk associated GBA variants or LRRK2 variants in which 304 were affected. We did not observe a significant enrichment of pathogenic variants in the idiopathic PD group, but the polygenic risk score (PRS) was higher in PD both in non-genetically enriched cohorts and genetically enriched cohorts. The population analysis showed a correlation between genetically enriched cohorts and Ashkenazi Jewish ancestry.ConclusionsWe describe the genetic component of the AMP PD platform, a solution to democratise data access and analysis for the PD research community.(d) Financial Disclosure/CoI
Transposable Element activation promotes neurodegeneration in aDrosophilamodel of Huntington’s disease
Authors: Casale Assunta Maria , Liguori Francesco , Ansaloni Federico , Cappucci Ugo , Finaurini Sara , Spirito Giovanni , Persichetti Francesca , Sanges Remo , Gustincich Stefano , Piacentini Lucia 
Published: November 2020

AbstractHuntington’s disease (HD) is a late-onset, autosomal dominant disorder characterized by progressive motor dysfunction, cognitive decline and psychiatric disturbances. The most prominent pathological manifestation is a selective loss of medium-sized spiny neurons of the striatum. The disease is caused by a CAG repeat expansion in theIT15gene, which elongates a stretch of polyglutamine at the amino-terminal of the HD protein, Huntingtin (Htt). Despite the accumulation of an impressive amount of data on the molecular basis of neurodegeneration, no therapeutic treatments are available and new pharmacological targets are needed.Transposable Elements (TEs) are mobile genetic elements that constitute a large fraction of eukaryotic genomes. Retrotransposons (RTEs) replicate through an RNA intermediate and represent approximately 40% and 30% of the human andDrosophilagenomes. Mounting evidence suggests that mammalian RTEs are normally active during neurogenesis and may be involved in diseases of the nervous system.Here we show that TE expression and mobilization are increased in aDrosophila melanogasterHD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target.
A Low-Cost Mass Spectrometry-Based Approach for Quantifying Purines in Placental Extracts
Authors: Rodriguez Ruslan , Konovets Igor , Ralchenko Serhii , Kharkhota Maxsim , Kostyuk Andrij , Kosach Victoriia , Voronina Irina , Filimonova Natalia , Obolenskaya Maria 
Published: November 2020

AbstractHyperhomocysteinemia is a medical condition characterized by an abnormally high level of homocysteine in the blood associated with multiple human pathologies including preeclampsia – the most feared complication of pregnancy, with placenta playing the central role in the pathogenesis of preeclampsia. The developing placenta is highly sensitive to different adverse factors but its response to hyperhomocysteinemia is not fully clear. Previously we have demonstrated the activation of reactions of methionine cycle and the transsulfuration pathway in placental explants cultivated with homocysteine. The reactions of the methionine cycle are tightly connected with reactions of the folate cycle, encompassing reactions ofde novopurine biosynthesis, which are crucial for the developing placenta, as they support rapid ATP generation to maintain energy status and increased biosynthesis of macromolecules. The sensitivity ofde novopurine biosynthesis to hyperhomocysteinemia is not known. The aim of this study was to evaluate the impact of homocysteine on placentalde novopurine biosynthesis.MethodsWe developed a simplified method to measure the level of all and newly formed purines by HPLC/ESI-MS, using a stable isotope glycine to label newly synthesized purines. The developed method proved to be highly sensitive, interday repeatable and intraday reproducible. We applied a method for placental explants from the first and third trimesters of gestation and MCF7 cells cultivated with 20 μM and 40 μM homocysteine corresponding to its concentrations at mild and intermediate hyperhomocysteinemia.ResultsThe developed method proved to be highly sensitive, interday repeatable and intraday reproducible. The content of total purines in placental explants from the first trimester of gestation was around 9.0 μmol/g wet tissues at specified conditions of cultivation. The newly formed purines comprised around 1 % of total purines, decreased steadily in explants cultivated with 20 μM and 40 μM homocysteine, and reached the values characteristic for explants from third trimester cultivated without homocysteine, 4.0 μmol/g wet tissues. The effect of homocysteine reproduced with MCF7 cells.ConclusionHomocysteine in concentrations characteristic of mild and intermediate hyperhomocysteinemia induces the down regulation ofde novopurine biosynthesis in placental explants, and implies the shift of metabolic pathway to homocysteine remethylation and transsulfuration at the expense ofde novopurine biosynthesis.
A human stem cell-derived neurosensory-epithelial circuitry on-a-chip to model herpes simplex virus reactivation
Authors: Mazzara Pietro Giuseppe , Criscuolo Elena , Rasponi Marco , Massimino Luca , Muggeo Sharon , Palma Cecilia , Castelli Matteo , Clementi M Massimo , Burioni Roberto , Mancini Nicasio , Broccoli Vania , Clementi Nicola 
Published: November 2020

AbstractBoth emerging viruses and well-known viral pathogens endowed with neurotropism can either impair directly the neuronal functions or induce physio-pathological changes by diffusing from the periphery through neurosensory-epithelial connections. However, the current lack of anin vitrosystem modeling the connectivity between human neurons and peripheral tissues excludes the analysis of viral latency and reactivation and the assessment of natural/artificial induced anti-viral immunity. In this study, we developed the first stable topographic neurosensory-epithelial connection on-a-chip using human stem cell derived dorsal root ganglia (DRG) sensory neurons. Bulk and single cell transcriptomics showed that different combinations of key receptors for Herpes Simplex Virus 1 (HSV-1) are expressed by each sensory neuronal cell type. This neuronal-epithelial circuitry enabled a detailed analysis of the HSV infectivity faithfully modeling its dynamics and cell type specificity. The reconstitution of an organized connectivity between human sensory neurons and keratinocytes into microfluidic chips provides for the first time a powerfulin vitroplatform to model viral latency and reactivation of human viral pathogens.