bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conserved neuropeptidergic regulation of intestinal integrity in invertebrate models of aging
Authors: Singh Anupama , Kaduskar Bhagyashree , Reddy Kirthi C , Kumsta Caroline , Bier Ethan , Hansen Malene , Chalasani Sreekanth H 
Published: February 2022

AbstractAge-related decline in intestinal barrier function impacts survival across species, but the underlying cell intrinsic and extrinsic factors remain unclear. Here, we demonstrate a role for neuropeptides in regulating aging-associated increases in intestinal leakiness. Adult-specific knockdown of insulin-like peptides daf-28 or ins-7 in C. elegans neurons or dilp3 in D. melanogaster neurons improves intestinal integrity and lifespan of these animals, respectively. Neuropeptide knockdowns activate intestinal DAF-16/FOXO transcription factor that likely increases expression of epithelial barrier components. Furthermore, age-associated changes in neuronal DAF-28 peptide secretion mirrors C. elegans reproductive span and overexpression of this peptide suppresses the improved intestinal health in long-lived germline-less animals. Collectively, we show that intestinal integrity is subject to neuronal regulation, and this neuropeptidergic axis may be modulated by the animal’s germline.
Fish as model systems to study epigenetic drivers in human self-domestication and neurodevelopmental cognitive disorders
Authors: Anastasiadi Dafni , Piferrer Francesc , Wellenreuther Maren , Burraco Antonio Benítez 
Published: February 2022

AbstractModern humans exhibit phenotypic traits that are shared across independent domestication events, suggesting the human self-domestication hypothesis. Epigenetic changes may facilitate early self-domestication in humans, since they can be the first layer of response to a novel environment. Here, we argue that fish provide model systems to study epigenetic drivers in human self-domestication. To do this, we compare genes that carry epigenetic changes in early domesticates of European sea bass with 1) anatomically modern humans and 2) neurodevelopmental cognitive disorders with abnormal self-domestication traits, i.e., schizophrenia, Williams syndrome and autism spectrum disorders. We found that genes with epigenetic changes in fish and in modern vs ancient humans were shared and were involved in processes like limb morphogenesis and phenotypes like abnormal snout morphology and hypopigmentation. Moreover, early domestication in fish and neurodevelopmental cognitive impairment in humans affected paralogue genes involved in processes such as neural crest differentiation and ectoderm differentiation. We conclude that parallel epigenetic changes may occur at the initial steps of domestication in absence of deliberate selection in phylogenetically distant vertebrates. These findings pave the way for future studies using fish as models to investigate epigenetic changes as drivers of human-self domestication and as triggers of cognitive disorders.
Improving ascertainment of suicidal ideation and suicide attempt with natural language processing
Authors: Bejan Cosmin A. , Ripperger Michael , Wilimitis Drew , Ahmed Ryan , Kang JooEun , Robinson Katelyn , Morley Theodore J. , Ruderfer Douglas M. , Walsh Colin G. 
Published: February 2022

AbstractMethods relying on diagnostic codes to identify suicidal ideation and suicide attempt in Electronic Health Records (EHRs) at scale are suboptimal because these phenotypes are heavily under-coded. We propose to improve the ascertainment of suicide phenotypes using natural language processing (NLP). We developed information retrieval methodologies to search over 200 million notes from the Vanderbilt EHR. Suicide query terms were extracted using word2vec. A weakly supervised approach was designed to label cases of suicidal outcomes. The NLP validation of the top 200 retrieved patients showed high performance for suicidal ideation (area under the receiver operator curve [AUROC]: 98.6, 95% confidence interval [CI]: 97.1−99.5) and suicide attempt (AUROC: 97.3, 95% CI: 95.2−98.7). Case extraction produced the best performance when combining NLP and diagnostic codes and when accounting for negated suicide expressions in notes. Overall, we demonstrated that scalable and accurate NLP methods can be developed to identify suicide phenotypes in EHRs to enhance prevention efforts, predictive models, and precision medicine.
Functional Plasticity in Chromosome-Microtubule Coupling on the Evolutionary Time Scale
Authors: Sankaranarayanan Sundar Ram , Polisetty Satya Dev , Das Kuladeep , Dumbrepatil Arti , Medina-Pritchard Bethan , Singleton Martin , Jeyaprakash A. Arockia , Sanyal Kaustuv 
Published: February 2022

AbstractThe Dam1 complex is essential for mitotic progression across evolutionarily divergent fungi. Upon analyzing amino acid (aa) sequences of Dad2, a Dam1 complex subunit, we identified a conserved 10-aa-long Dad2 signature sequence (DSS). An arginine residue (R126) in the DSS is essential for viability inSaccharomyces cerevisiaethat possesses point centromeres. The corresponding arginine residues are functionally important but not essential for viability inCandida albicansandCryptococcus neoformans,both carry several kilobases long regional centromeres. The purified recombinant Dam1 complex containing either Dad2ΔDSSor Dad2R126Afailed to bind microtubules (MTs) or form any visible rings like the wild-type complex. Intriguingly, functional analysis revealed that the requirement of the conserved arginine residue for chromosome biorientation and mitotic progression reduced with increasing centromere length. We propose that plasticity of the invariant arginine of Dad2 in organisms with regional centromeres is achieved by conditional elevation of the kinetochore protein(s) to enable multiple kinetochore MTs (kMTs) to bind to each chromosome. The capacity of a chromosome to bind multiple kMTs may mask deleterious effects of such lethal mutations.
Metagenomic binning with assembly graph embeddings
Authors: Lamurias Andre , Sereika Mantas , Albertsen Mads , Hose Katja , Nielsen Thomas Dyhre 
Published: February 2022

AbstractDespite recent advancements in sequencing technologies and assembly methods, obtaining high-quality microbial genomes from metagenomic samples is still not a trivial task. Current metagenomic binners do not take full advantage of assembly graphs and are not optimized for long-read assemblies. Deep graph learning algorithms have been proposed in other fields to deal with complex graph data structures. The graph structure generated during the assembly process could be integrated with contig features to obtain better bins with deep learning.We propose GraphMB, which uses graph neural networks to incorporate the assembly graph into the binning process. We test GraphMB on long-read datasets of different complexities, and compare the performance with other binners in terms of the number of High Quality (HQ) genome bins obtained. With our approach, we were able to obtain unique bins on all real datasets, and obtain more bins on most datasets. In particular, we obtained on average 17.5% more HQ bins when compared to state-of-the-art binners and 13.7% when aggregating the results of our binner with the others. These results indicate that a deep learning model can integrate contig-specific and graph-structure information to improve metagenomic binning. GraphMB is available fromhttps://github.com/MicrobialDarkMatter/GraphMB.
Biogeographical history shapes evolution of reproduction in a global warming scenario
Authors: Santos Marta A. , Antunes Marta A. , Grandela Afonso , Carromeu-Santos Ana , Quina Ana S. , Santos Mauro , Matos Margarida , Simões Pedro 
Published: February 2022

AbstractAdaptive evolution might be critical for animal populations to thrive on the fast-changing natural environments. Ectotherms are particularly vulnerable to global warming and, although their limited coping ability has been suggested, few real-time evolution experiments have directly accessed their evolutionary potential. Here, we report a long-term experimental evolution study addressing the evolution of thermal reaction norms, after ∼30 generations under different thermal environments. We analyzed the evolutionary dynamics ofDrosophila subobscurapopulations as a function of the thermally variable environments in which they evolved and their distinct biogeographical background. Our results showed clear differences between the historically differentiated populations: while the northernD. subobscurapopulations showed a temporal increase in performance at higher temperatures, their southern counterparts presented the opposite pattern. This suggests that the northern populations might be better equipped to cope with the current rising temperatures. Remarkably, no effect of thermal selection was found. The lack of a clear long-term adaptive response at higher temperatures after evolution under a global warming scenario raises concerns about the evolutionary potential of ectotherms. Our results highlight the complex nature of thermal responses in face of environmental heterogeneity and emphasize the importance of considering intra-specific variation in thermal evolution studies.
Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade
Authors: Trøstheim Martin , Eikemo Marie , Haaker Jan , Frost J. James , Leknes Siri 
Published: February 2022

AbstractNon-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10-0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (∼60 minutes), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78-100%) and some DOR blockade (10% with naltrexone and 48-74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ∼30 minutes. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.
Meaningful Local Signaling in Sinoatrial Node Identified by Random Matrix Theory
Authors: Norris Chloe F. , Maltsev Anna V 
Published: February 2022

AbstractThe sinoatrial node (SAN) is the pacemaker of the heart. Recently calcium signals, believed to be crucially important in rhythm generation, have been imaged in intact SAN and shown to be heterogeneous in various regions of the SAN and shown to be heterogeneous in various regions of the SAN with a lot of analysis relying on visual inspection rather than mathematical tools. Here we apply methods of random matrix theory (RMT) developed for financial data and various biological data sets including β-cell collectives and EEGs to analyse correlations in SAN calcium signals using eigenvalues and eigenvectors of the correlation matrix. We use principal component analysis (PCA) to locate signalling modules corresponding to localization properties the eigenvectors corresponding to high eigenvalues. We find that the top eigenvector captures the common response of the SAN to action potential. In some cases, the eigenvector corresponding to the second highest eigenvalue yields a pacemaker region whose calcium signals predict the action potential. Furthermore, using new analytic methods, we study the relationship between covariance coefficients and distance, and find that even inside the central zone, there are non-trivial long range correlations, indicating intercellular interactions in most cases. Lastly, we perform an analysis of nearest-neighbor eigenvalue distances and find that it coincides with universal Wigner surmise under all available experimental conditions, while the number variance, which captures eigenvalue correlations, is sensitive to experimental conditions. Thus RMT application to SAN allows to remove noise and the global effects of the action potential and thereby isolate the local and meaningful correlations in calcium signalling.
Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1
Authors: Schwarz Madeline M. , Price David A. , Ganaie Safder S. , Feng Annie , Mishra Nawneet , Hoehl Ryan M. , Fatma Farheen , Stubbs Sarah H. , Whelan Sean P.J. , Cui Xiaoxia , Egawa Takeshi , Leung Daisy W. , Amarasinghe Gaya K. , Hartman Amy L. 
Published: February 2022

AbstractOropouche orthobunyavirus (OROV; Peribunyaviridae) is a mosquito-transmitted virus that causes widespread cases of human febrile illness in South America, with occasional progression to neurologic effects. Host entry factors mediating cellular entry of OROV are undefined. Here, we show that OROV requires the host protein low density lipoprotein-related protein 1 (Lrp1) for cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. Thus, Lrp1 is an important host factor required for infection of cells by OROV. Taken together with our results showing that Lrp1 is a newly identified receptor for Rift Valley fever virus (RVFV), Lrp1 may play a broader role in cellular infection by bunyaviruses than previously appreciated.
Hypoxia promotes osteogenesis via regulation of the mito-nuclear communication
Authors: Pouikli Andromachi , Maleszewska Monika , Parekh Swati , Nikopoulou Chrysa , Bonfiglio Juan-Jose , Mylonas Constantine , Sandoval Tonantzi , Schumacher Anna-Lena , Hinze Yvonne , Matic Ivan , Tessarz Peter 
Published: February 2022

ABSTRACTBone marrow mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. Several studies have highlighted the critical role of hypoxia (low oxygen concentration) in the regulation of stem cell function, reporting differentiation defects following a switch to normoxia (high oxygen concentration). However, the molecular events triggering changes in stem cell fate decisions in response to high oxygen remain elusive. Here, we study the impact of normoxia in the mito-nuclear communication, with regards to stem cell differentiation. We show that normoxia-cultured MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces rewiring of metabolism, resulting in high acetyl-CoA levels, histone hypo-acetylation occurs due to trapping of acetyl-CoA inside mitochondria, likely due to lower CiC activity. Strikingly, restoring the cytosolic acetyl-CoA pool via acetate supplementation remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is heavily perturbed in response to high oxygen and identify CiC as a novel, oxygen-sensitive regulator of MSC function.
Microbes are potential key players in the evolution of life histories and aging inCaenorhabditis elegans
Authors: Santos Josiane , Matos Margarida , Flatt Thomas , Chelo Ivo M 
Published: February 2022

AbstractMicrobes can have profound effects on host fitness and health and the appearance of late-onset diseases. Host-microbe interactions thus represent a major environmental context for healthy aging of the host and might also mediate trade-offs between life-history traits in the evolution of host senescence. Here, we have used the nematodeCaenorhabditis elegansto study how host-microbe interactions may modulate the evolution of life histories and aging. We first characterized the effects of two non-pathogenic and one pathogenicEscherichia colistrains, together with the pathogenicSerratia marcescensDB11 strain, on population growth rates and survival ofC. elegansfrom five different genetic backgrounds. We then focused on an outbredC. eleganspopulation, to understand if microbe-specific effects on the reproductive schedule and in traits such as developmental rate and survival were also expressed in the presence of males and standing genetic variation, which could be relevant for the evolution ofC. elegansand other nematode species in nature. Our results show that host-microbe interactions have a substantial host-genotype-dependent impact on the reproductive aging and survival of the nematode host. Although both pathogenic bacteria reduced host survival in comparison with benign strains, they differed in how they affected other host traits. Host fertility and population growth rate were affected byS. marcescensDB11 only during early adulthood, whereas this occurred at later ages with the pathogenicE. coliIAI1. In both cases, these effects were largely dependent on the host genotypes. Given such microbe-specific genotypic differences in host life history, we predict that the evolution of reproductive schedules and senescence might be critically contingent on host-microbe interactions in nature.
Multicenter international assessment of a SARS-CoV-2 RT-LAMP test for point of care clinical application
Authors: Lu Suying , Duplat David , Benitez-Bolivar Paula , León Cielo , Villota Stephany D , Veloz-Villavicencio Eliana , Arévalo Valentina , Jaenes Katariina , Guo Yuxiu , Cicek Seray , Robinson Lucas , Peidis Philippos , Pearson Joel D , Woodgett Jim , Mazzulli Tony , Ponce Patricio , Restrepo Silvia , González John M , Bernal Adriana , Guevara-Suarez Marcela , Pardee Keith , Cevallos Varsovia E , González Camila , Bremner Rod 
Published: February 2022

AbstractContinued waves, new variants, and limited vaccine deployment mean that SARS-CoV-2 tests remain vital to constrain the COVID-19 pandemic. Affordable, point-of-care (PoC) tests allow rapid screening in non-medical settings. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) is an appealing approach. A crucial step is to optimize testing in low/medium resource settings. Here, we optimized RT-LAMP for SARS-CoV-2 and human β-actin, and tested clinical samples in multiple countries. “TTTT” linker primers did not improve performance, and while guanidine hydrochloride, betaine and/or Igepal-CA-630 enhanced detection of synthetic RNA, only the latter two improved direct assays on nasopharygeal samples. With extracted clinical RNA, a 20 min RT-LAMP assay was essentially as sensitive as RT-PCR. With raw Canadian nasopharygeal samples, sensitivity was 100% (95% CI: 67.6% - 100%) for those with RT-qPCR Ct values ≤ 25, and 80% (95% CI: 58.4% - 91.9%) for those with 25 < Ct ≤ 27.2. Highly infectious, high titer cases were also detected in Colombian and Ecuadorian labs. We further demonstrate the utility of replacing thermocyclers with a portable PoC device (FluoroPLUM). These combined PoC molecular and hardware tools may help to limit community transmission of SARS-CoV-2.
Cryo-EM structures of Doravirine and Rilpivirine with HIV-1 Reverse Transcriptase/DNA Aptamer – Nonnucleoside Inhibitor Resistance by E138K and M184I Mutations
Authors: Singh Abhimanyu K. , De Wijngaert Brent , Bijnens Marc , Uyttersprot Kris , Nguyen Hoai , Martinez Sergio E. , Schols Dominique , Herdewijn Piet , Pannecouque Christophe , Arnold Eddy , Das Kalyan 
Published: February 2022

AbstractStructures trapping a verity of functional and conformational states of HIV-1 reverse transcriptase (RT) have been determined by X-ray crystallography. These structures have played important roles in understanding the mechanisms of catalysis, inhibition and drug resistance, and in driving drug design. However, structures of several desired complexes of RT could not be obtained even after many crystallization or crystal soaking experiments. The ternary complexes of doravirine and rilpivirine with RT/DNA are such examples.Structural study of HIV-1 RT by single-particle cryo-EM has been challenging due to the enzyme’s relatively smaller size and higher flexibility. We optimized a protocol for rapid structure determination of RT complexes by cryo-EM and determined six structures of wild-type and E138K/M184I mutant RT/DNA in complexes with the nonnucleoside inhibitors rilpivirine, doravirine, and nevirapine. RT/DNA/rilpivirine and RT/DNA/doravirine complexes have structural differences between them and from the representative conformation of RT/DNA/nevirapine (or efavirenz); the primer grip in the RT/DNA/doravirine and the YMDD motif in the RT/DNA/rilpivirine complexes have large shifts. The DNA primer 3’-end in the doravirine-bound structure is positioned at the active site, but the complex is in a non-productive state. In the mutant RT/DNA/rilpivirine structure, I184 is stacked with the DNA such that their relative positioning can influence rilpivirine in the pocket. Simultaneously, E138K mutation widens the NNRTI-binding pocket entrance, potentially contributing to a faster rate of rilpivirine dissociation by E138K/M184I mutant RT, as reported by earlier kinetic studies. These structural differences have implications for drug design and for understanding molecular mechanisms of drug resistance.