bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody
Authors: Piepenbrink Michael S. , Park Jun-Gyu , Desphande Ashlesha , Loos Andreas , Ye Chengjin , Basu Madhubanti , Sarkar Sanghita , Chauvin David , Woo Jennifer , Lovalenti Philip , Erdmann Nathaniel B. , Goepfert Paul A. , Truong Vu L. , Bowen Richard A. , Walter Mark R. , Martinez-Sobrido Luis , Kobie James J. 
Published: March 2022

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.
Effects of immunomodulatory peptides derived from a soil bacterium on cecal microbiota of broilers challenged with Clostridium perfringens
Authors: Li Xiaoying , Li Guiguan , Peng Qianning , Sun Yuli , Li Yong , Li Haitao , Ren Jun 
Published: March 2022

AbstractBrevibacillus texasporus peptide (BT peptide) is immunomodulatory in poultry as a feed additive to substitute antibiotics. In the present study we performed 16S rRNA gene sequencing to compare development of the cecal microbial communities in Clostridium perfringens-challenged broilers fed basal diet only or with either BT peptide (48 ppm) or antibiotics mixture (20 ppm bacitracin zinc and 40 ppm colistin sulfate). 240 chicks were randomly assigned into each treatment and a total of 65 cecal samples were collected at the beginning, during seven challenge days and one week post challenge. The composition of microbial communities was clearly distinguishable over time. Treatments with challenge and the antibiotics mixture were associated with increased diversity and with higher relative abundances of Alistipes sp. CHKCI003 and Faecalibacterium and lower abundance of Escherichia coli (all p < 0.05). At the termination of the trial, the cecal microbiota in broilers supplemented with BT peptide was dominated by members of Bacteroidaceae. Predicted function analysis reveals significant enrichment of genes involved in ion-coupled transporters and sugar and biotin metabolism in the BT peptide treatment. Taken together, our results suggest that BT peptide and commonly used antibiotics have different influences on modulating the composition of cecal microbiota in broilers.
SNP calling parameters have minimal impact on population structure and divergence time estimates for the rice blast fungus
Authors: Latorre Sergio M. , Langner Thorsten , Malmgren Angus , Win Joe , Kamoun Sophien , Burbano Hernán A. 
Published: March 2022

ABSTRACTObjectivesAccurate single-nucleotide polymorphisms (SNP) calls are crucial for robust evolutionary and population genetic inferences in genomic analyses. Such inferences can reveal the time-scales and processes associated with the emergence and spread of pandemic plant pathogens, such as the rice blast fungus Magnaporthe oryzae (Syn. Pyricularia oryzae). However, the specificity and sensitivity of SNP calls depend on the filtering parameters applied to the data. Here, we used a benchmarking approach to evaluate the impact of SNP calling on different population genetic analyses of the rice blast fungus, namely genetic clustering, topology of phylogenetic reconstructions and estimation of evolutionary rates.ResultsTo benchmark SNP calling parameters, we generated a gold standard set of validated SNPs by sequencing nine M. oryzae genomes with both Illumina short-reads and Oxford Nanopore Technologies (ONT). We used the gold standard set of SNPs to identify the SNP calling parameter configuration that maximizes sensitivity and specificity. We found that the choice of parameter configurations can substantially change the number of ascertained SNPs, preferentially affecting SNPs segregating at low population frequency. However, SNP calling parameter configurations did not significantly affect the clustering of isolates in clonal lineages, the monophyly of each clonal lineage, and the estimation of evolutionary rates. We leverage the evolutionary rates obtained from each SNP calling parameter configuration to generate divergence time estimates that take into account the uncertainty associated with both the estimation of evolutionary rates and SNP calling. Our analysis indicates that M. oryzae clonal lineage expansions took place ~300 years ago.
Measuring the response to visually presented faces in the human lateral prefrontal cortex
Authors: Nikel Lara , Sliwinska Magdalena W , Kucuk Emel , Ungerleider Leslie G. , Pitcher David 
Published: March 2022

AbstractNeuroimaging studies have identified multiple face-selective areas. In the current study we compared the functional response of the face area in the lateral prefrontal cortex to that of other face-selective areas. In Experiment 1 participants (N=32) were scanned viewing videos containing faces, bodies, scenes, objects, and scrambled objects. We identified a face-selective area in the right inferior frontal gyrus (rIFG). In Experiment 2 participants (N=24) viewed the videos or static images. Results showed that the rIFG, posterior superior temporal sulcus (pSTS) and occipital face area (OFA) exhibited a greater response to moving than static faces. In Experiment 3 participants (N=18) viewed face videos presented in the contralateral and ipsilateral visual fields. Results showed that the face areas in the IFG and pSTS responded equally to faces in both visual fields, while the OFA and fusiform face area (FFA) showed a contralateral bias. These experiments suggest two conclusions; firstly, in all three experiments the face area in the IFG was not as reliably identified as face areas in the occipitotemporal cortex. Secondly, the similarity of the response patterns in the IFG and pSTS face areas suggests that the areas are functionally connected, a conclusion consistent with neuroanatomical and functional connectivity evidence.
Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis
Authors: Dupuy Pierre , Ghosh Shreya , Adefisayo Oyindamola , Buglino John , Shuman Stewart , Glickman Michael 
Published: March 2022

ABSTRACTAntibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that mycobacterial DinB1 abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous −1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced −1 frameshift mutagenesis. DinB1 also promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.
Sleep-like changes in neural processing emerge during sleep deprivation in early auditory cortex
Authors: Marmelshtein Amit , Nir Yuval 
Published: March 2022

AbstractInsufficient sleep is commonplace in modern lifestyle and can lead to grave outcomes, yet the changes in neuronal activity accumulating over hours of extended wakefulness remain poorly understood. Specifically, which aspects of cortical processing are affected by sleep deprivation (SD), and whether they also affect early sensory regions, remains unclear. Here, we recorded spiking activity in rat auditory cortex along with polysomnography while presenting sounds during SD followed by recovery sleep. We found that frequency tuning, onset responses, and spontaneous firing rates were largely unaffected by SD. By contrast, SD decreased entrainment to rapid (≥20 Hz) click-trains, increased population synchrony, and increased the prevalence of sleep-like stimulus-induced silent periods, even when ongoing activity was similar. Recovery NREM sleep was associated with similar effects as SD with even greater magnitude, while auditory processing during REM sleep was similar to vigilant wakefulness. Our results show that processes akin to those in NREM sleep invade the activity of cortical circuits during SD, already in early sensory cortex.
LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression
Authors: Jiao Ji-Wei , Zhan Xiu-Hui , Wang Juan-Juan , He Li-Xia , Guo Zhen-Chang , Xu Xiu-E , Liao Lian-Di , Huang Xin , Wen Bing , Xu Yi-Wei , Hu Hai , Neufeld Gera , Chang Zhi-Jie , Zhang Kai , Xu Li-Yan , Li En-Min 
Published: March 2022

AbstractLysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2Δ13 splice variant also function as novel deacetylases that trigger metabolic reprogramming during malignant transformation. Integrated transcriptomic and metabolomic analysis revealed that L2Δ13-overexpressing transgenic mice displayed perturbed glucose and lipid metabolism, which was associated with increased hepatic fibrosis and enhanced formation of precancerous lesions induced by chemical carcinogens, such as carbon tetrachloride and N-nitrosomethylbenzylamine. Furthermore, both LOXL2 and L2Δ13 boosted glucose metabolism of esophageal tumor cells, thereby facilitating tumor cell proliferation in vitro and in vivo. Mechanistically, LOXL2 and L2Δ13 interacted physically with several glycolic proteins including aldolase A to enhance their enzymatic activities and mobilization from the actin cytoskeleton. Using SILAC followed by proteomic analysis, we identified LOXL2 as a deacetylase targeting metabolic proteins in esophageal cancer. Importantly, both LOXL2 and L2Δ13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2Δ13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2Δ13.
ULK4 and Fused/STK36 interact to mediate assembly of a motile flagellum
Authors: McCoy Ciaran J. , Paupelin-Vaucelle Humbeline , Gorilak Peter , Beneke Tom , Varga Vladimir , Gluenz Eva 
Published: March 2022

AbstractUnc-51-like kinase (ULK) family serine-threonine protein kinase homologs have been linked to the function of motile cilia in diverse species. Mutations in Fused/STK36 and ULK4 in mice resulted in hydrocephalus and other phenotypes consistent with ciliary defects. How either protein contributes to the assembly and function of motile cilia is not well understood. Here we studied the phenotypes of ULK4 and Fused gene knockout (KO) mutants in the flagellated protist Leishmania mexicana. Both KO mutants exhibited a variety of structural defects of the flagellum cytoskeleton. Biochemical approaches indicate spatial proximity of these proteins and indicates a direct interaction between the N-terminus of LmxULK4 and LmxFused. Both proteins display a dispersed localisation throughout the cell body and flagellum, with enrichment near the flagellar base and tip. Fused/STK36 was previously shown to localise to mammalian motile cilia and we demonstrate here that ULK4 also localises to the motile cilia in mouse ependymal cells. Taken together these data suggest a model where the pseudokinase ULK4 is a positive regulator of the kinase Fused/STK36 in a pathway required for stable assembly of motile cilia.Summary StatementKnockout phenotypes in Leishmania, and confirmation of ULK4 ciliary localisation in mouse, show ULK4 and Fused/STK36 interact in a conserved pathway for stable assembly of motile cilia.
A photoswitchable ligand targeting β1-adrenoceptor enables light-control of the cardiac rhythm
Authors: Duran-Corbera Anna , Faria Melissa , Ma Yuanyuan , Prats Eva , Dias André , Catena Juanlo , Martinez Karen L. , Raldua Demetrio , Llebaria Amadeu , Rovira Xavier 
Published: March 2022

SummaryCatecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of the heart. Although both β1- and β2-AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1-AR have proven this receptor as the main target for the therapeutic effects of beta blockers in heart. Here, we report a new strategy for the spatiotemporal control of β1-AR activation by means of light-regulated drugs with a high level of β1-/β2-AR selectivity. All reported molecules allow for an efficient real time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo-2, can be reversibly photocontrolled. Strikingly, pAzo-2 also enables a dynamic cardiac rhythm management on alive zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1-AR in native environments using light.
Elevated HLA-E and NKG2A as a Consequence of Chronic Immune Activation Defines Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer
Authors: Ranti D. , Wang Y.A. , Daza J. , Bieber C. , Salomé B. , Merritt E. , Cavallo J.A. , Hegewisch-Solloa E. , Mace E.M. , Farkas A.M. , Shroff S. , Patel F. , Tran M. , Strandgaard T. , Lindskrog S. V. , Dyrskjøt L. , Qi J. , Patel M. , Geanon D. , Kelly G. , de Real R.M. , Lee B. , Kim-Schulze S. , Thin T.H. , Garcia-Barros M. , Beaumont K.G. , Ravichandran H. , Hu Y. , Wang Y-C. , Wang L. , LaRoche D. , lee Y. , Sebra R.P. , Brody R. , Elemento O. , Tocheva A. , Hopkins B. D. , Wiklund P. , Zhu J. , Galsky M.D. , Bhardwaj N. , Sfakianos J.P. , Horowitz A. 
Published: March 2022

AbstractMycobacterium bovis Bacillus Calmette-Guerin (BCG), the first-line treatment for non-muscle invasive bladder cancer (NMIBC), promotes the production of inflammatory cytokines, particularly interferon (IFN)-γ. Prolonged inflammation and IFN-γ exposure are known to cause an adaptive immune response, enabling immune escape and proliferation by tumor cells. We investigated HLA-E and NKG2A, a novel T and NK cell checkpoint pathway, as a driver of adaptive resistance in BCG unresponsive NMIBC. We observed ubiquitous inflammation in all patients after BCG immunotherapy, regardless of recurrence status. IFN-γ was shown to drive tumor expression of HLA-E and PD-L1. Further, NKG2A-expressing NK and CD8 T cells were enriched in BCG unresponsive tumors and with enhanced capacity for cytolytic functions. Strikingly, in situ spatial analyses revealed that HLA-EHIGH tumors are activated to recruit NK and T cells via chemokine production, potentially sparing HLA-ELOW tumors that would otherwise be susceptible to lysis. Finally, blood-derived NK cells retained anti-tumor functions at the time of tumor recurrence. These data support combined NKG2A and PD-L1 blockade for BCG unresponsive disease.
Climate biogeography ofArabidopsis thaliana:linking distribution models and individual variation
Authors: Yim Christina , Bellis Emily S. , DeLeo Victoria L. , Gamba Diana , Muscarella Robert , Lasky Jesse R. 
Published: March 2022

AbstractAIMPatterns of individual variation are key to testing hypotheses about the mechanisms underlying biogeographic patterns. However, it is challenging to gather data on individual-level variation at large spatial scales. Model organisms are potentially important systems for biogeographical studies, given the available range-wide natural history collections, and the importance of providing biogeographical context to their genetic and phenotypic diversity.LOCATIONGlobalTAXONArabidopsis thaliana(“Arabidopsis”)METHODSWe fit occurrence records to climate data, and then projected the distribution of Arabidopsis under last glacial maximum, current, and future climates. We confronted model predictions with individual performance measured on 2,194 herbarium specimens, and we asked whether predicted suitability was associated with life-history and genomic variation measured on ∼900 natural accessions.RESULTSThe most important climate variables constraining the Arabidopsis distribution were winter cold in northern and high elevation regions and summer heat in southern regions. Herbarium specimens from regions with lower habitat suitability in both northern and southern regions were smaller, supporting the hypothesis that the distribution of Arabidopsis is constrained by climate-associated factors. Climate anomalies partly explained interannual variation in herbarium specimen size, but these did not closely correspond to local limiting factors identified in the distribution model. Late-flowering genotypes were absent from the lowest suitability regions, suggesting slower life histories are only viable closer to the center of the realized niche. We identified glacial refugia farther north than previously recognized, as well as refugia concordant with previous population genetic findings. Lower latitude populations, known to be genetically distinct, are most threatened by future climate change. The recently colonized range of Arabidopsis was well-predicted by our native-range model applied to certain regions but not others, suggesting it has colonized novel climates.MAIN CONCLUSIONSIntegration of distribution models with performance data from vast natural history collections is a route forward for testing biogeographical hypotheses about species distributions and their relationship with evolutionary fitness across large scales.
Application of high-throughput, high-depth, targeted single-nucleus DNA sequencing in pancreatic cancer
Authors: Zhang Haochen , Karnoub Elias-Ramzey , Umeda Shigeaki , Chaligné Ronan , Masilionis Ignas , McIntyre Caitlin A. , Hayashi Akimasa , Sashittal Palash , Zucker Amanda , Mullen Katelyn , Makohon-Moore Alvin , Iacobuzio-Donahue Christine A. 
Published: March 2022

AbstractDespite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high throughput single-cell DNA sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimized a highly automated nuclei extraction workflow that achieved fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic adenocarcinoma (PDAC) patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals novel genomic evolution patterns of PDAC as well.
Hippo Signaling Cofactor, WWTR1, at the Crossroads of Human Trophoblast Progenitor Self-Renewal and Differentiation
Authors: Ray Soma , Saha Abhik , Ghosh Ananya , Roy Namrata , Kumar Ram P , Meinhardt Gudrun , Mukerjee Abhirup , Gunewardena Sumedha , Kumar Rajnish , Knöfler Martin , Paul Soumen 
Published: March 2022

ABSTRACTHealthy progression of human pregnancy relies on cytotrophoblast progenitor (CTB) self-renewal and their differentiation towards multi-nucleated syncytiotrophoblasts (STBs) and invasive extravillous trophoblasts (EVTs). However, underlying molecular mechanisms that fine-tune CTB self-renewal or direct their differentiation towards STBs or EVTs during human placentation are poorly defined. Here, we show that hippo signaling cofactor WW Domain Containing Transcription Regulator 1 (WWTR1) is a master regulator of trophoblast fate choice during human placentation. Using human trophoblast stem cells (human TSCs), primary CTBs and human placental explants, we demonstrate that WWTR1 promotes self-renewal in human CTBs and is essential for their differentiation to EVTs. In contrast, WWTR1 prevents induction of STB fate in undifferentiated CTBs. Our single-cell RNA-sequencing analyses in first-trimester human placenta along with mechanistic analyses in human TSCs revealed that WWTR1 fine-tunes trophoblast fate by directly regulating Wnt signaling components. Importantly, our analyses of placentae from pathological pregnancies show that extreme preterm birth (gestational time ≤28weeks) and intrauterine growth restriction along with preeclampsia (IUGR/PE) are often associated with loss of WWTR1 expression in CTBs. In summary, our findings establish a critical importance of WWTR1 at the crossroads of human trophoblast progenitor self-renewal vs. differentiation. It plays positive instructive roles to promote CTB self-renewal and EVT differentiation and safeguards undifferentiated CTBs from obtaining the STB fate.SIGNIFICANCEHuman pregnancy relies on formation of the transient organ placenta and trophoblast cells are the major building blocks of the placenta. A defect in trophoblast progenitor self-renewal or their differentiation is associated with either pregnancy loss or pathological pregnancies, yet underlying molecular mechanisms that regulate trophoblast differentiation are poorly understood. In this study, we discovered that WWTR1, a transcription cofactor and a component of conserved Hippo signaling pathway, optimizes trophoblast progenitor self-renewal and is essential for their differentiation into the invasive extravillous trophoblast cell lineage. Our findings establish WWTR1 as a critical regulator for success in human placentation and progression of a healthy pregnancy.