bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonist tendon vibration dampens estimates of persistent inward currents in motor units of the human lower limb
Authors: Pearcey Gregory E P , Khurram Obaid U , Beauchamp James A , Negro Francesco , Heckman Charles J 
Published: August 2022

ABSTRACTWe can readily measure motoneuron discharge patterns in humans due to the one-to-one spike relation between motoneuron and muscle fiber action potentials, which allows us to make inferences about motor commands. Persistent inward currents (PICs), which provide gain control of motoneuronal output, are facilitated by monoaminergic input from the brainstem. This monoaminergic input is greatly diffuse, but resulting PICs are highly sensitive to inhibitory inputs. Antagonist muscle stretch, and thus Ia input from the antagonist decreases PIC magnitudes in the decerebrate cat. In the present study, we explored whether estimates of PICs are altered with vibratory input to antagonist muscles in humans. MUs of the tibialis anterior (TA), soleus (SOL), and medial gastrocnemius (MG) were discriminated using high-density surface electromyography and convolutive blind source separation. We estimated PICs using the paired MU analysis technique, which quantifies discharge rate hysteresis (ΔF) by comparing the discharge rate of a lower-threshold MU at the onset and offset of a higher-threshold MU. Participants performed isometric plantarflexion and dorsiflexion contractions to a peak of 30% of maximal voluntary contraction, with 10 s ascending and descending phases. In half of the trials, we applied vibration to the antagonist tendon and found that ΔF in agonist MUs decreased in the presence of vibration. These findings suggest that inhibition from the antagonist muscle, most likely Ia reciprocal inhibition, can reduce discharge rate hysteresis. This provides insights about non-invasive methods potentially capable of dampening PICs in hyperexcitable motoneurons, which are manifest in some neurological impairments.KEY POINTSPersistent inward currents in motoneurons amplify synaptic inputs and thus have a major impact on motor unit firing patterns.We show that sustained vibration to the antagonist tendon reduces estimates of persistent inward currents (ΔF) of the contracting muscle in both the plantarflexors and dorsiflexors.These findings provide evidence for the important role of sensory input in the control of persistent inward currents in the human.Reciprocal inhibition may help refine neuromodulatory commands to tailor motor unit activation to diverse movement patterns and specific tasks, and loss of inhibition may exacerbate symptoms of neurological impairment.
Fast, accurate local ancestry inference with FLARE
Authors: Browning Sharon R. , Waples Ryan K. , Browning Brian L. 
Published: August 2022

AbstractLocal ancestry is the source ancestry at each point in the genome of an admixed individual. Inferred local ancestry is used for admixture mapping and population genetic analyses. We present FLARE (Fast Local Ancestry Estimation), a new method for local ancestry inference. FLARE achieves high accuracy through the use of an extended Li and Stephens model, and it achieves exceptional computational performance through incorporation of computational techniques developed for genotype imputation. Memory requirements are reduced through on-the-fly compression of reference haplotypes and stored checkpoints. Computation time is reduced through the use of composite reference haplotypes. These techniques allow FLARE to scale to data sets with hundreds of thousands of sequenced individuals and to provide superior accuracy on large-scale data. FLARE is freely available at https://github.com/browning-lab/flare.
Acquirement of the autonomic nervous system modulation evaluated by heart rate variability in medaka (Oryzias latipes)
Authors: Watanabe-Asaka Tomomi , Niihori Maki , Igarashi Kento , Oda Shoji , Iwasaki Ken-ichi , Katada Yoshihiko , Yamashita Toshikazu , Sonobe Hiroki , Terada Masahiro , Baba Shoji A. , Mitani Hiroshi , Mukai Chiaki 
Published: August 2022

AbstractSmall teleosts have recently been established as models of human diseases. However, measuring heart rate by electrocardiography is highly invasive for small fish. The physiological nature and function of vertebrate autonomic nervous system (ANS) modulation of the heart has traditionally been investigated in larvae with an incompletely developed ANS or in anesthetized adults, whose ANS activity may possibly be disturbed under anesthesia. Here, we defined the frequency characteristics of heart rate variability (HRV) modulated by the ANS from observations of heart movement in high-speed movie images and changes in ANS regulation under environmental stimulation in unanesthetized adult medaka (Oryzias latipes), a small teleost.The HRV was significantly reduced by atropine (1 mM) in the 0.25 – 0.65 Hz and by propranolol (100 μM) at 0.65–1.25 Hz range, suggesting that HRV in adult medaka is modulated by both the parasympathetic and sympathetic nervous systems within these frequency ranges. Such modulations of HRV by the ANS were remarkably suppressed in anesthetized adult medaka. Continuous exposure to light suppressed HRV only in the 0.25 – 0.65 Hz range, indicating parasympathetic withdrawal. The power of HRV increased along developmental processes. These results suggest that ANS modulation of the heart in adult medaka is frequency-dependent phenomenon, and that the impact of long-term environmental stimuli on ANS activities can be precisely evaluated in unanesthetized adult fish using this method.
Enhancing the spectral range of plant and bacterial Light-Harvesting pigment-protein complexes with various synthetic chromophores incorporated into lipid vesicles
Authors: Hancock Ashley M. , Swainsbury David J. K. , Meredith Sophie A. , Morigaki Kenichi , Hunter C. Neil , Adams Peter G. 
Published: August 2022

AbstractThe Light-Harvesting (LH) pigment-protein complexes found in photosynthetic organisms have the role of absorbing solar energy with high efficiency and transferring it to reaction centre complexes. LH complexes contain a suite of pigments that each absorb light at specific wavelengths, however, the natural combinations of pigments within any one protein complex do not cover the full range of solar radiation. Here, we provide an in-depth comparison of the relative effectiveness of five different organic “dye” molecules (Texas Red, ATTO, Cy7, Dil, DiR) for enhancing the absorption range of two different LH membrane protein complexes (the major LHCII from plants and LH2 from purple phototrophic bacteria). Proteoliposomes were self-assembled from defined mixtures of lipids, proteins and dye molecules and their optical properties were quantified by absorption and fluorescence spectroscopy. Both lipid-linked dyes and alternative lipophilic dyes were found to be effective excitation energy donors to LH protein complexes, without the need for direct chemical or generic modification of the proteins. The Förster theory parameters (e.g., spectral overlap) were compared between each donor-acceptor combination and found to be good predictors of an effective dye-protein combination. At the highest dye-to-protein ratios tested (over 20:1), the effective absorption strength integrated over the full spectral range was increased to ~180% of its natural level for both LH complexes. Lipophilic dyes could be inserted into pre-formed membranes although their effectiveness was found to depend upon favourable physicochemical interactions. Finally, we demonstrated that these dyes can also be effective at increasing the spectral range of surface-supported models of photosynthetic membranes, using fluorescence microscopy. The results of this work provide insight into the utility of self-assembled lipid membranes and the great flexibility of LH complexes for interacting with different dyes.
Assessing the importance of demographic risk factors across two waves of SARS-CoV-2 using fine-scale case data
Authors: Wood A.J. , Sanchez A.R. , Bessell P.R. , Wightman R. , Kao R.R. 
Published: August 2022

AbstractFor the long term control of an infectious disease such as COVID-19, it is crucial to identify the most likely individuals to become infected and the role that differences in demographic characteristics play in the observed patterns of infection. As high-volume surveillance winds down, testing data from earlier periods are invaluable for studying risk factors for infection in detail. Observed changes in time during these periods may then inform how stable the pattern will be in the long term.To this end we analyse the distribution of cases of COVID-19 across Scotland in 2021, where the location (census areas of order 500–1,000 residents) and reporting date of cases are known. We consider over 450,000 individually recorded cases, in two infection waves triggered by different lineages: B.1.1.529 (“Omicron”) and B.1.617.2 (“Delta”). We use random forests, informed by measures of geography, demography, testing and vaccination. We show that the distributions are only adequately explained when considering multiple explanatory variables, implying that case heterogeneity arose from a combination of individual behaviour, immunity, and testing frequency.Despite differences in virus lineage, time of year, and interventions in place, we find the risk factors remained broadly consistent between the two waves. Many of the observed smaller differences could be reasonably explained by changes in control measures.
A cross-sectional audit and survey of Open Science and Data Sharing practices at The Montreal Neurological Institute-Hospital
Authors: Ebrahimzadeh Sanam , Cobey Kelly D. , Presseau Justin , Alayche Mohsen , Willis Jessie Virginia , Moher David 
Published: August 2022

AbstractObjectivesTo audit all publications produced by Montreal Neurological Institute-Hospital researchers regarding open science practices and to survey Neuro-based researchers about barriers and facilitators to data sharing.Setting, design and participantsIn the first study, we retrieved 313 unique publications and collated all Neuro publications from 2019 and extracted information from each article pertaining to data sharing and other open science practices. We included all empirical papers and pre-prints that were reported in English. In the second study, one hundred twenty-four participants (out of 553) completed the survey, a response rate of 22.42%. We surveyed all Neuro researchers.Primary and secondary outcomesfor the audit we examined data sharing and open science practices. For the survey, we asked participants about their data sharing practices.ResultsWe found that 66.5% of these publications (n=208) included a data sharing statement. Overall, 74.5% (n=155) of articles had data that was publicly available. When examining broader open science practices, rates of compliance tended to be lower. For example, 94.9% (n=297) of publications failed to register a protocol. Among participants who had published a first or last authored paper in the past year, most participants, 53 of 74 (71.62%), reported that they had openly shared their research data. Less than half of the participants 37.50% (n=45) reported having engaged in training related to data sharing within the last 12 months.ConclusionWe found that half of all publications included in the audit shared data. Participants indicated an appetite for resources for learning about data sharing signaling a willingness to perform better.Strengths and limitations of this studyTo serve as a baseline to benchmark for improvements in data sharing and other open science practicesTo measure progress over time.The results of the study cannot be generalized.It is hard to measure changes in the community.
Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents
Authors: Cao Yunlong , Jian Fanchong , Zhang Zhiying , Yisimayi Ayijiang , Hao Xiaohua , Bao Linlin , Yuan Fei , Yu Yuanling , Du Shuo , Wang Jing , Xiao Tianhe , Song Weiliang , Zhang Ying , Liu Pulan , An Ran , Wang Peng , Wang Yao , Yang Sijie , Niu Xiao , Zhang Yuhang , Gu Qingqing , Shao Fei , Hu Yaling , Yin Weidong , Zheng Aihua , Wang Youchun , Qin Chuan , Jin Ronghua , Xiao Junyu , Xie Xiaoliang Sunney 
Published: August 2022

AbstractSARS-CoV-2 Omicron sublineages have escaped most RBD-targeting therapeutic neutralizing antibodies (NAbs), which proves the previous NAb drug screening strategies deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following the criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection. Our screening strategy can also be applied to identify broad-spectrum NAb drugs against other fast-evolving viruses, such as influenza viruses.
Haplotype-based inference of recent effective population size in modern and ancient DNA samples
Authors: Fournier Romain , Reich David , Palamara Pier Francesco 
Published: August 2022

1AbstractIndividuals sharing recent ancestors are likely to co-inherit large identical-by-descent (IBD) genomic regions. The distribution of these IBD segments in a population may be used to reconstruct past demographic events such as effective population size variation, but accurate IBD detection is difficult in ancient DNA (aDNA) data and in underrepresented populations with limited reference data. In this work, we introduce an accurate method for inferring effective population size variation during the past ~2,000 years in both modern and aDNA data, called HapNe. HapNe infers recent population size fluctuations using either IBD sharing (HapNe-IBD) or linkage disequilibrium (HapNe-LD), which does not require phasing and can be computed in low coverage data, including data sets with heterogeneous sampling times. HapNe showed improved accuracy in a range of simulated demographic scenarios compared to currently available methods for IBD-based and LD-based inference of recent effective population size, while requiring fewer computational resources. We applied HapNe to several modern populations from the 1, 000 Genomes Project, the UK Biobank, the Allen Ancient DNA Resource, and recently published samples from Iron Age Britain, detecting multiple instances of recent effective population size variation across these groups.
Energy dissipation in early detection of cellular responses to metabolic challenges
Authors: Bento Rafael N. , Rendas Miguel A. , Semedo Valdir A. R. , Marques Cátia F. , Justino Gonçalo. C. , Bernardes Carlos E. S. , da Piedade Manuel E. Minas , Antunes Fernando 
Published: August 2022

SUMMARYMetabolic alterations have been recognized to underly the etiology of many diseases. Herein, cellular energy dissipation was evaluated as a novel non-specific global biomarker of metabolic alterations. Energy dissipation, measured as heat by microcalorimetry, was maximal during Saccharomyces cerevisiae adaptation to growth conditions before fast proliferation took place. This response was further augmented by 95 % in media where nutrient assimilation was more difficult, and by 133 % under sub-optimal non-carbon nutrient levels. In this last case, the increase in energy dissipation (1) reflected changes in amino acid and glycolytic metabolism and (2) anticipated changes in the growth curve significantly later observed by traditional microbiological measurements. It was, therefore, an early marker of adaptive responses that compensated for sub-optimal nutrient levels and maintained phenotypic stability. Compensatory responses buffer systems against perturbations and delay the onset of diseases. Microcalorimetry can, therefore, provide a biomarker development platform for early disease-diagnosis.HIGHLIGHTSEnergy dissipation measurements detect cell responses to metabolic challenges.The detection by microcalorimetry occurs considerably earlier than by traditional microbiological measurements.Sub-optimal non-carbon nutrient levels impact energy dissipation long before cell proliferation.Energy dissipation is highly sensitive to increased nutrient assimilation difficulty.
Molecular and structural characterization of lenalidomide-mediated sequestration of eIF3i
Authors: Lin Zhi , Shen Dacheng , Yang Bo , Woo Christina M. 
Published: August 2022

ABSTRACTLenalidomide is a ligand of the E3 ligase substrate adaptor cereblon (CRBN) that achieves its clinical effects in part by promotion of substrate recruitment and degradation. In contrast to prior substrates, eIF3i is recruited but not degraded upon complex formation with lenalidomide and CRBN, although the structural details and mechanistic outcomes of this interaction are unresolved. Here, we characterize the structural basis and mechanistic outcomes of lenalidomide-induced sequestration of eIF3i from the eIF3 complex. Identification of the binding interface on eIF3i by a covalent lenalidomide probe and chemical proteomics rationalizes the sequestration event. We further connect eIF3i and CRBN to known lenalidomide effects on angiogenic markers, Akt1 phosphorylation, and associated antiangiogenesis phenotypes. Finally, we find that eIF3i sequestration is observed in MM.1S and MOLM13 cells after the degradation of other substrates, such as IKZF1. The defined binding interface elucidated by chemical proteomics, and connection of eIF3i sequestration to phenotypic outcomes of lenalidomide open future directions in designing new chemical adaptors for protein sequestration as a strategy to selectively control translational profiles and downstream cellular function.
The Hypoxia-regulated Ectonucleotidase CD73 is a Host Determinant of HIV Latency
Authors: Sperber Hannah S. , Raymond Kyle A. , Bouzidi Mohamed S. , Ma Tongcui , Valdebenito Silvana , Eugenin Eliseo , Roan Nadia R. , Deeks Steven G. , Winning Sandra , Fandrey Joachim , Schwarzer Roland , Pillai Satish K. 
Published: August 2022

SUMMARYDeciphering the mechanisms underlying viral persistence is critical to achieving a cure for HIV infection. We implemented a systems approach to discover molecular signatures of HIV latently-infected CD4+ T cells, identifying the immunosuppressive, adenosine-producing ectonucleotidase CD73 as a key surface marker of latent cells. Hypoxic conditioning, reflecting the lymphoid tissue microenvironment, increased the frequency of CD73+ CD4+ T cells and promoted HIV latency. Transcriptomic profiles of CD73+ CD4+ T cells favored viral quiescence, immune evasion, and cell survival. CD73+ CD4+ T cells were capable of harboring a functional HIV reservoir and reinitiating productive infectionex vivo. CD73 or adenosine receptor blockade facilitated latent HIV reactivationin vitro, mechanistically linking adenosine signaling to viral quiescence. Finally, tissue imaging of lymph nodes from HIV-infected individuals on antiretroviral therapy revealed spatial association between CD73 expression and HIV persistencein vivo. Our findings warrant development of HIV cure strategies targeting the hypoxia-CD73-adenosine axis.
Optimal construction of a functional interaction network from pooled library CRISPR fitness screens
Authors: Gheorghe Veronica , Hart Traver 
Published: August 2022

AbstractFunctional interaction networks, where edges connect genes likely to operate in the same biological process or pathway, can be inferred from CRISPR knockout screens in cancer cell lines. Genes with similar knockout fitness profiles across a sufficiently diverse set of cell line screens are likely to be co-functional, and these “coessentiality” networks are increasingly powerful predictors of gene function and biological modularity. While several such networks have been published, most use different algorithms for each step of the network construction process. In this study, we identify an optimal measure of functional interaction and test all combinations of options at each step – essentiality scoring, sample variance and covariance normalization, and similarity measurement – to identify best practices for generating a functional interaction network from CRISPR knockout data. We show that Bayes Factor and Ceres scores give the best results, that Ceres outperforms the newer Chronos scoring scheme, and that covariance normalization is a critical step in network construction. We further show that Pearson correlation, mathematically identical to ordinary least squares after covariance normalization, can be extended by using partial correlation to detect and amplify signals from “moonlighting” proteins which show context-dependent interaction with different partners.
Plasmodium falciparumhas evolved multiple mechanisms to hijack human immunoglobulin M
Authors: Ji Chenggong , Shen Hao , Su Chen , Li Yaxin , Chen Shihua , Sharp Thomas H. , Xiao Junyu 
Published: August 2022

AbstractPlasmodium falciparumcauses the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to facilitateP. falciparumclearance. A number ofP. falciparumproteins hijack IgM, leading to immune evasion and severe disease. However, the underlying molecular mechanisms remain unknown. Here, using high-resolution cryo-electron microscopy, we delineate howP. falciparumproteins VAR2CSA, TM284VAR1, DBLMSP, and DBLMSP2 target IgM. Each protein binds IgM in a different manner, and together they present a variety of Duffy-binding-like domain-IgM interaction modes. We further show that these proteins interfere directly with IgM-mediated complement activation, with VAR2CSA exhibiting the most potent inhibitory effect. Structural analyses suggest that VAR2CSA occludes the congregation of the complement C1 complex on IgM. These results underscore the importance of IgM for the adaptation ofP. falciparumto humans, and provide critical insights into the immune evasion mechanism ofP. falciparum.