bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimates of global SARS-CoV-2 infection exposure, infection morbidity, and infection mortality rates
Authors: Ayoub Houssein H. , Mumtaz Ghina R. , Seedat Shaheen , Makhoul Monia , Chemaitelly Hiam , Abu-Raddad Laith J. 
Published: January 2021

AbstractWe aimed to estimate, albeit crudely and provisionally, national, regional, and global proportions of respective populations that have been infected with SARS-CoV-2, and to assess infection morbidity and mortality rates, factoring both documented and undocumented infections. The estimates were generated by applying mathematical models to 159 countries and territories. The percentage of the world’s population that has been infected as of 31 December 2020 was estimated at 12.56% (95% CI: 11.17-14.05%). It was lowest in the Western Pacific Region at 0.66% (95% CI: 0.59-0.75%) and highest in the Americas at 41.92% (95% CI: 37.95-46.09%). The global infection fatality rate was 10.73 (95% CI: 10.21-11.29) per 10,000 infections. Globally per 1,000 infections, the infection acute-care bed hospitalization rate was 19.22 (95% CI: 18.73-19.51), the infection ICU bed hospitalization rate was 4.14 (95% CI: 4.10-4.18), the infection severity rate was 6.27 (95% CI: 6.18-6.37), and the infection criticality rate was 2.26 (95% CI: 2.24-2.28). If left unchecked with no interventions, the pandemic would eventually cause 8.18 million (95% CI: 7.30-9.18) deaths, 163.67 million (95% CI: 148.12-179.51) acute-care hospitalizations, 33.01 million (95% CI: 30.52-35.70) ICU hospitalizations, 50.23 million (95% CI: 46.24-54.67) severe cases, and 17.62 million (95% CI: 16.36-18.97) critical cases. The global population remains far below the herd immunity threshold and at risk of repeated waves of infection. Global epidemiology reveals immense regional variation in infection exposure and morbidity and mortality rates.
Genome-wide meta-analysis of pneumonia suggests a role for mucin biology and provides novel drug repurposing opportunities
Authors: Reay William R. , Geaghan Michael P. ,   23andMe Research Team, Cairns Murray J. 
Published: January 2021

ABSTRACTPneumonia remains one of the leading causes of death worldwide, particularly amongst the elderly and young children. We performed a genome-wide meta-analysis of lifetime pneumonia diagnosis (N=266,277), that encompassed the largest collection of cases published to date. Genome-wide significant associations with pneumonia were uncovered for the first time beyond the major histocompatibility complex region, with three novel loci, including a signal fine-mapped to a cluster of mucin genes. Moreover, we demonstrated evidence of a polygenic effect of common and low frequency pneumonia associated variation impacting several other mucin genes and O-glycosylation, further suggesting a role for these processes in pneumonia pathophysiology. The pneumonia GWAS was then leveraged to identify drug repurposing opportunities, including evidence that supports the use of lipid modifying agents in the prevention and treatment of the disorder. We also propose how polygenic risk could be utilised for precision drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide novel insights into the genetic architecture of pneumonia susceptibility, with future study warranted to functionally interrogate novel association signals and evaluate the suitability of the compounds prioritised by this study as repositioning candidates.
Induction of a colitogenic phenotype in Th1 cells depends on IL-23R signaling
Authors: Pawlak Mathias , DeTomaso David , zu Horste Gerd Meyer , Lee Youjin , Nyman Jackson , Dionne Danielle , Wang Chao , Wallrapp Antonia , Burkett Patrick R. , Riesenfeld Samantha J. , Anderson Ana C. , Regev Aviv , Xavier Ramnik J. , Yosef Nir , Kuchroo Vijay K. 
Published: January 2021

SummaryThe cytokine receptor IL-23R plays a fundamental role in inflammation and autoimmunity. However, several observations have been difficult to reconcile under the assumption that only Th17 cells critically depend on IL-23 to acquire a pathogenic phenotype. Here, we report that Th1 cells differentiatedin vitrowith IL-12 + IL-21 show similar levels of IL-23R expression as in pathogenic Th17 cells. We demonstrate that IL-23R is required for Th1 cells to acquire a highly colitogenic phenotype. scRNAseq analysis of intestinal T cells enabled us to identify novel regulators induced by IL-23R-signaling in Th1 cells which differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1 cells inhibited induction of colitis. In this process, we were able to uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver of Th1 cell-mediated tissue inflammation and disease.
The secreted tyrosine kinase VLK is essential for normal platelet activation and thrombus formation
Authors: Revollo Leila , Merrill-Skoloff Glenn , De Ceunynck Karen , Dilks James R. , Bordoli Mattia , Peters Christian G. , Noetzli Leila , Ionescu Andreia , Rosen Vicki , Italiano Joseph E. , Whitman Malcolm , Flaumenhaft Robert 
Published: January 2021

AbstractTyrosine phosphorylation of extracellular proteins is observed in cell cultures and in vivo, but little is known about the functional roles of tyrosine phosphorylation of extracellular proteins. Vertebrate Lonesome Kinase (VLK) is a broadly expressed secretory pathway tyrosine kinase present in platelet ɑ-granules. It is released from platelets upon activation and phosphorylates substrates extracellularly. Its role in platelet function, however, has not been previously studied. In human platelets, we identified phosphorylated tyrosines mapped to luminal or extracellular domains of transmembrane and secreted proteins implicated in the regulation of platelet activation. To determine the role of VLK in extracellular tyrosine phosphorylation and platelet function, we generated mice with a megakaryocyte/platelet-specific deficiency of VLK. Platelets from these mice are normal in abundance and morphology, but have dramatic changes in function both in vitro and in vivo. Resting and thrombin-stimulated VLK-deficient platelets demonstrate a significant decrease of several tyrosine phosphobands. Functional testing of VLK-deficient platelets shows decreased PAR4- and collagen-mediated platelet aggregation, but normal responses to ADP. Dense granule and α-granule release are reduced in these platelets. Furthermore, VLK-deficient platelets exhibit decreased PAR4-mediated Akt (S473) and Erk1/2(T202/Y204) phosphorylation, indicating altered proximal signaling. In vivo, mice lacking VLK in megakaryocytes/platelets demonstrate strongly reduced platelet accumulation and fibrin formation following laser-injury of cremaster arterioles compared to controls. These studies demonstrate that the secretory pathway tyrosine kinase VLK is critical for stimulus-dependent platelet activation and thrombus formation, providing the first evidence that a secreted protein kinase is required for normal platelet function.
The balance between toxic versus nontoxic microRNAs determines platinum sensitivity in ovarian cancer
Authors: Patel Monal , Wang Yinu , Bartom Elizabeth T. , Dhir Rohin , Nephew Kenneth P. , Matei Daniela , Murmann Andrea E. , Lengyel Ernst , Peter Marcus E. 
Published: January 2021

ABSTRACTNumerous micro(mi)RNAs (short noncoding RNAs that negatively regulate gene expression) have been linked to platinum (Pt) sensitivity and resistance in ovarian cancer (OC). miRNA activity occurs when the guide strand of the miRNA, with its seed sequence (pos. 2-7/8), is loaded into the RNA induced silencing complex (RISC) and targets complementary short seed matches in the 3’ untranslated region of mRNAs. Toxic seeds, targeting genes critical for cancer cell survival, have been found in tumor suppressive miRNAs. Many si- and shRNAs can also kill cancer cells via toxic seeds, the most toxic carrying G-rich 6mer seed sequences. We now show that treatment of OC cells with Pt leads to an increase in RISC-bound miRNAs carrying toxic 6mer seeds and a decrease in miRNAs with nontoxic seeds. Pt-resistant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in OC patients revealed that the ratio between miRNAs with toxic versus miRNAs with nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses.
Direct and indirect effects of high temperatures on fledging success in a cooperatively breeding bird
Authors: Bourne Amanda R. , Ridley Amanda R. , Spottiswoode Claire N. , Cunningham Susan J. 
Published: January 2021

AbstractHigh temperatures and low rainfall consistently constrain reproduction in arid-zone bird species. Understanding the mechanisms underlying this pattern is critical for predicting how climate change will influence population persistence and to inform conservation and management. In this study, we analysed Southern Pied Babbler Turdoides nestling survival, daily growth rate and adult investment behaviour during the nestling period over three austral summer breeding seasons. High temperatures were associated with lower body mass, shorter tarsi, and reduced daily growth rates of nestlings. Piecewise structural equation modelling suggests that direct impacts of temperature had the strongest influence, followed by changes in provisioning rates by adults to older nestlings.Adjustments to adult provisioning strategies did not compensate for direct negative effects of high air temperatures on nestling body mass, tarsus and wing length, or daily growth rates. Declining reproductive success during hot weather poses a potentially serious threat to population replacement and persistence as climate change progresses, even for currently common and widespread species. Significantly lower offspring survival as a result of climate warming will likely contribute to the collapse of animal communities well before temperatures regularly approach or exceed lethal tolerance limits. Detailed mechanistic data like these allow us to model the pathways by which high temperature causes nest failure. In turn, this could allow us to design targeted conservation action to effectively mitigate climate effects.
Pose Estimation of Free-Flying Fruit Flies
Authors: Ben-Dov Omri , Beatus Tsevi 
Published: January 2021

AbstractInsect flight is a complex interdisciplinary phenomenon. Understanding its multiple aspects, such as flight control, sensory integration and genetics, often requires the analysis of large amounts of free flight kinematic data. Yet, one of the main bottlenecks in this field is automatically and accurately extracting such data from multi-view videos. Here, we present a model-based method for pose-estimation of free-flying fruit flies from multi-view high-speed videos. To obtain a faithful representation of the fly with minimum free parameters, our method uses a 3D model that mimics two new aspects of wing deformation: a non-fixed wing hinge and a twisting wing surface. The method is demonstrated for free and perturbed flight. Our method does not use prior assumptions on the kinematics apart from the continuity of one wing angle. Hence, this method can be readily adjusted for other insect species.
Programmable Viscoelasticity in Protein-RNA Condensates with Disordered Sticker-Spacer Polypeptides
Authors: Alshareedah Ibraheem , Moosa Mahdi Muhammad , Pham Matthew , Potoyan Davit A. , Banerjee Priya R. 
Published: January 2021

ABSTRACTLiquid-liquid phase separation of multivalent proteins and RNAs drives the formation of biomolecular condensates that facilitate membrane-free compartmentalization of subcellular processes. With recent advances, it is becoming increasingly clear that biomolecular condensates are network fluids with time-dependent material properties. Here, employing microrheology with optical tweezers, we reveal molecular determinants that govern the viscoelastic behavior of condensates formed by multivalent Arg/Gly-rich sticker-spacer polypeptides and RNA. These condensates behave as Maxwell fluids with an elastically-dominant rheological response at shorter timescales and a liquid-like behavior at longer timescales. The viscous and elastic regimes of these condensates can be tuned by the polypeptide and RNA sequences as well as their mixture compositions. Our results establish a quantitative link between the sequence- and structure-encoded biomolecular interactions at the microscopic scale and the rheological properties of the resulting condensates at the mesoscale, enabling a route to systematically probe and rationally engineer biomolecular condensates with programmable mechanics.
Dynamic posttranslational modifications of cytoskeletal proteins unveil hot spots under nitroxidative stress
Authors: Griesser Eva , Vemula Venukumar , Mónico Andreia , Pérez-Sala Dolores , Fedorova Maria 
Published: January 2021

AbstractThe cytoskeleton is a supramolecular structure consisting of interacting protein networks that support cell dynamics in essential processes such as migration and division, as well as in responses to stress. Fast cytoskeletal remodeling is achieved with the participation of regulatory proteins and posttranslational modifications (PTMs). Redox-related PTMs are emerging as critical players in cytoskeletal regulation. Here we used a cellular model of mild nitroxidative stress in which a peroxynitrite donor induced transient changes in the organization of three key cytoskeletal proteins, i.e., vimentin, actin and tubulin. Nitroxidative stress-induced reconfiguration of intermediate filaments, microtubules and actin structures were further correlated with their PTM profiles and dynamics of the PTM landscape. Using high-resolution mass spectrometry, 62 different PTMs were identified and relatively quantified in vimentin, actin and tubulin proteins, including 12 enzymatic, 13 oxidative and 2 nitric oxide-derived modifications as well as 35 modifications by carbonylated lipid peroxidation products, thus evidencing the occurrence of a chain reaction with formation of reactive species and the activation of multiple signaling pathways. Our results unveil the presence of certain modifications under basal conditions and their modulation in response to stress in a target-, residue- and reactive species-dependent manner. Moreover, we identified protein PTM “hot spots”, such as the single cysteine residue of vimentin, supporting its role in PTM cross-talk and redox sensing. Finally, identification of novel PTMs in these proteins may pave the way for unveiling novel cytoskeleton regulatory mechanisms.
Hoxgenes regulate asexual reproductive behavior and tissue segmentation in adult animals
Authors: Arnold Christopher P. , Lozano Analí Migueles , Mann Frederick G. , Lange Jeffrey J. , Seidel Christopher , Alvarado Alejandro Sánchez 
Published: January 2021

SummaryHoxgenes are highly conserved transcription factors renowned for their roles in the segmental patterning of the embryonic anterior-posterior (A/P) axis1. Emerging evidence forHoxgene expression and function in postnatally derived structures has fueled interest in their additional roles beyond embryogenesis2,3. We report novel functions forHoxgenes in A/P adult tissue segmentation and transverse fission behavior underlying asexual reproduction in the planarian flatworm,Schmidtea mediterranea.Silencing of each of the planarianHoxfamily members identified 5Hoxgenes required for asexual reproduction. Among these, silencing ofhox3genes resulted in supernumerary segments, while silencing ofpost2beliminated segmentation altogether. The opposing roles ofhox3andpost2bin segmentation are paralleled in their respective regulation of fission behavior. Silencing ofhox3increased the frequency of fission behavior initiation, while silencing ofpost2beliminated fission behavior entirely. Furthermore, we identified a network of downstream effector genes mediatingHoxgene regulation of asexual reproduction, thereby providing insight into their respective mechanisms of action. Our study establishes postembryonic roles forHoxgenes in regulating the emergence of tissue segmentation and specific behaviors associated with asexual reproduction in adult animals.
TWO-SIGMA-G: A New Competitive Gene Set Testing Framework for scRNA-seq Data Accounting for Inter-Gene and Cell-Cell Correlation
Authors: Van Buren Eric , Hu Ming , Cheng Liang , Wrobel John , Wilhelmsen Kirk , Su Lishan , Li Yun , Wu Di 
Published: January 2021

AbstractWe propose TWO-SIGMA-G, a competitive gene set test for scRNA-seq data. TWO-SIGMA-G uses a mixed-effects regression model based on our previously published TWO-SIGMA to test for differential expression at the gene-level. This regression-based model provides flexibility and rigor at the gene-level in (1) handling complex experimental designs, (2) accounting for the correlation between biological replicates, and (3) accommodating the distribution of scRNA-seq data to improve statistical inference. Moreover, TWO-SIGMA-G uses a novel approach to adjust for inter-gene-correlation (IGC) at the set-level to control the set-level false positive rate. Simulations demonstrate that TWO-SIGMA-G preserves type-I error and increases power in the presence of IGC compared to other methods. Application to two datasets identified HIV-associated Interferon pathways in xenograft mice and pathways associated with Alzheimer’s disease progression in humans.
Long-term monitoring reveals topographical features and vegetation explain winter habitat use of an Arctic rodent
Authors: von Beckerath Xaver , Benadi Gita , Gilg Olivier , Sittler Benoît , Yannic Glenn , Klein Alexandra-Maria , Eitzinger Bernhard 
Published: January 2021

AbstractCollapsing lemming cycles have been observed across the Arctic, presumably due to global warming creating less favorable winter conditions. The quality of wintering habitats, such as depth of snow cover, plays a key role in sustaining population dynamics of arctic lemmings. However, few studies so far investigated habitat use during the arctic winter. Here, we used a unique long-term time series to test whether lemmings are associated with topographical and vegetational habitat features for their winter refugi. We examined yearly numbers and distribution of 22,769 winter nests of the collared lemmingDicrostonyx groenlandicusfrom an ongoing long-term research on Traill Island, Northeast Greenland, collected between 1989 and 2019, and correlated this information with data on dominant vegetation types, elevation and slope. We specifically asked if lemming nests were more frequent at sites with preferred food plants such asDryas octopetala x integrifoliaand at sites with increased snow cover. We found that the number of lemming nests was highest in areas with a high proportion ofDryasheath, but also correlated with other vegetation types which suggest some flexibility in resource use of wintering lemmings. Conversely, they showed a distinct preference for sloped terrain, probably as it enhances the formation of deep snow drifts which increases the insulative characteristics of the snowpack and protection from predators. With global warming, prime lemming winter habitats may become scarce through alteration of snow physical properties, potentially resulting in negative consequence for the whole community of terrestrial vertebrates.
Dorsal color variation among subspecies of the “Oregon” Dark-eyed Junco complex
Authors: Yang Elisa T. , Unitt Philip , Mason Nicholas A. 
Published: January 2021

AbstractInitial descriptions of avian subspecies were based on expert opinions of geographic variation in phenotypes and are inherently subjective. Although best practices for subspecies delimitation continue to be debated, reassessing subspecies limits with current, quantitative methods is important toward refining and improving taxonomic treatments. Plumage coloration is the basis of many subspecies diagnoses, but is potentially problematic because of the historical lack of quantitative methods to quantify color. Recently developed methods, such as colorimetry, provide repeatable measurements of color variation that can be used to reassess subspecies limits. In this study, we reassess color variation among subspecies of the Oregon Dark-eyed Junco (Junco hyemalis [oreganus Group]) complex, in which differences in back and hood color were established as diagnostic characters. We measured back and hood brightness and hue in 206 museum specimens among five Oregon Dark-eyed Junco subspecies using a colorimeter. We then compared mean measurements among subspecies and conducted a discriminant function analysis to assess how well dorsal color predicted subspecies. Our data correctly classified only 67.9% of males and 82.5% of females to their presumed subspecies. Furthermore, no adjacent subspecies pairs passed the “75% rule” due to extensive overlap in plumage characters. Thus, back color alone is not as effective in diagnosing Oregon Dark-eyed Junco subspecies as originally described, suggesting a possible taxonomic revision. Specifically, similarity in phenotypic and genetic data suggests that some combination ofthurberi,montanus, andshufeldtimay be lumped to recognize broad, clinal variation in dorsal color alongside clinal variation in other phenotypes and extensive gene flow.
Novel bisubstrate inhibitors for protein N-terminal acetyltransferase D
Authors: Deng Youchao , Deng Sunbin , Ho Yi-Hsun , Gardner Sarah M. , Huang Zhi , Marmorstein Ronen , Huang Rong 
Published: January 2021

ABSTRACTProtein N-terminal acetyltransferase D (NatD, NAA40) that specifically acetylates the alpha-N-terminus of histone H4 and H2A has been implicated in various diseases, but no inhibitor has been reported for this important enzyme. Based on the acetyl transfer mechanism of NatD, we designed and prepared a series of highly potent NatD bisubstrate inhibitors by covalently linking coenzyme A to different peptide substrates via an acetyl or propionyl spacer. The most potent bisubstrate inhibitor displayed an apparentKi value of 1.0 nM. Biochemical studies indicated that bisubstrate inhibitor is competitive to the peptide substrate and noncompetitive to the cofactor, suggesting NatD undergoes an ordered Bi-Bi mechanism. We also demonstrated that these inhibitors are highly specific towards NatD, displaying about 1,000-fold selectivity over other closely related acetyltransferases. High-resolution crystal structures of NatD bound to two of these inhibitors revealed the molecular basis for their selectivity and inhibition mechanism, providing a rational path for future inhibitor development.
CTP andparScoordinate ParB partition complex dynamics and ParA-ATPase activation for ParABS-mediated DNA partitioning
Authors: Taylor James A. , Seol Yeonee , Budhathoki Jagat , Neuman Keir C. , Mizuuchi Kiyoshi 
Published: January 2021

AbstractParABS partition systems, comprising the centromere-like DNA sequenceparS,theparS-binding ParB-CTPase and the nucleoid-binding ParA-ATPase, ensure faithful segregation of bacterial chromosomes and low-copy-number plasmids. F-plasmid partition complexes containing ParBFandparSFmove by generating and following a local concentration gradient of nucleoid-bound ParAF. However, the process through which ParBFactivates ParAF-ATPase has not been defined. We studied CTP- andparSF-modulated ParAF—ParBFcomplex assembly, in which DNA-bound ParAF-ATP dimers are activated for ATP hydrolysis by interacting with two ParBFN-terminal domains. CTP orparSFenhances the ATPase rate without significantly accelerating ParAF—ParBFcomplex assembly. Together,parSFand CTP accelerate ParAF—ParBFassembly without further significant increase in ATPase rate. Magnetic-tweezers experiments showed that CTP promotes multiple ParBFloading ontoparSF-containing DNA, generating condensed partition complex-like assemblies. We propose that ParBFin the partition complex adopts a conformation that enhances ParBF—ParBFand ParAF—ParBFinteractions promoting efficient partitioning.