bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2–specific Humoral and Cellular Immunities in Kidney Transplant Recipients and Dialyzed Patients Recovered From Severe and Nonsevere COVID-19
Authors: Bertrand Dominique , Hamzaoui Mouad , Drouot Laurent , Lamulle Julie , Hanoy Mélanie , Edet Stéphane , Laurent Charlotte , Lebourg Ludivine , Etienne Isabelle , Lemoine Mathilde , Le Roy Frank , Nezam Dorian , Mauger Eleusis , Boyer Olivier , Guerrot Dominique , Candon Sophie 
Published: January 2022

Background.
Kidney transplantation and dialysis are two major risk factors for severe forms of coronavirus disease 2019 (COVID-19). The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this population remain largely unknown.

Methods.
We report here the analysis of anti–SARS-CoV-2 antibody– and T cell–mediated immune responses in 26 kidney transplant recipients (KTRs) and 11 dialyzed patients (DPs) who recovered from COVID-19.

Results.
After a mean time of 83 ± 26 d post–symptom onset for KTRs and 97 ± 31 d for DPs, 20 KTRs (76.9%) and 10 DPs (90.9%) displayed anti-S1 immunoglobulin G SARS-CoV-2 antibodies (P = 0.34), at similar titers in both groups. SARS-CoV-2–specific interferon-γ–producing T cells were evidenced in 26 KTRs (100%) and 10 DPs (90.9%). Total numbers of SARS-CoV-2–reactive T cells were high and not statistically different between the 2 groups. No correlation between the severity of the disease and the number of reactive T cells was found in KTRs. In 5 KTRs, also evaluated 10 mo after COVID-19, weak or absent antibody response was observed, whereas specific memory T-cell response was detected in all cases.

Conclusion.
T-cell response persisted up to 3 mo post–symptom onset, even in KTRs in whom full immunosuppressive regimen was reinstated at recovery, and seems to be present up to 10 mo after infection. Our findings have implications in the understanding of the natural course of the disease in transplant patients and DPs.
Acute on Chronic Liver Failure: Factors Associated With Transplantation
Authors: Goussous Naeem , Xie Wen , Zhang Talan , Malik Saad , Alvarez-Casas Josue , Gray Stephen H. , Barth Rolf N. , Thuluvath Paul J. , LaMattina John C. 
Published: January 2022

Background.
Acute on chronic liver failure (ACLF) carries a poor prognosis unless liver transplantation is offered. We present risk factors associated with proceeding with liver transplantation in patients with ACLF.

Methods.
A retrospective review of all patients with ACLF who presented to a single transplant center between January 2016 and December 2017 was performed. We compared patients who were transplanted with patients who were not.

Results.
During the study period, 144 patients with ACLF were identified, 86 patients (59.7%) were transplanted, and 58 were not. The transplanted patients had a lower number of failed organs (4 versus 5, P < 0.001) and lower incidence of ACLF grade 3 (76.7% versus 94.8%, P = 0.014) compared with nontransplanted patients. Liver transplantation offered a 1-y survival of 86% as compared to 12% in the nontransplanted group. Hospital charges were significantly higher among transplanted patients as compared with the nontransplanted patients ($227 886 versus $88 900, P < 0.001). Elevated serum lactate was a risk factor in not offering liver transplantation in ACLF patients.

Conclusions.
In appropriately selected patients with ACLF, liver transplantation is feasible and can provide above 86% 1-y patient survival even in grade 3 ACLF.
Identification of eight novel variants acrossPAX3, SOX10, EDNRBandMITFgenes in Waardenburg syndrome with next-generation sequencing
Authors: Lee Chen-Yu , Lo Ming-Yu , Chen You-Mei , Lin Pei-Hsuan , Hsu Chuan-Jen , Chen Pei-Lung , Wu Chen-Chi , Hsu Jacob Shu-jui 
Published: January 2022

AbstractWaardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. A total of 24 patients from 21 Han Taiwanese families were enrolled and underwent comprehensive physical and audiological examination. We applied targeted next-generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. We identified 18 causative variants of WS in our cohort. Of these variants, eight were novel and discovered inPAX3, SOX10, EDNRB, MITFgenes, including missense, nonsense, deletion, and splice site variants. Several patients presented skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.
Reticulospinal drive increases maximal motoneuron output in humans
Authors: Škarabot Jakob , Folland Jonathan P , Holobar Aleš , Baker Stuart N , Del Vecchio Alessandro 
Published: January 2022

AbstractMaximal rate of force development in adult humans is determined by the maximal motoneuron output, however the origin of the underlying synaptic inputs remains unclear. Here, we tested a hypothesis that the maximal motoneuron output will increase in response to a startling cue, a stimulus that purportedly activates the pontomedullary reticular formation neurons that make mono- and disynaptic connections to motoneurons via fast-conducting axons. Twenty-two men were required to produce isometric knee extensor forces “as fast and as hard” as possible from rest to 75% of maximal voluntary force, in response to visual (VC), visual-auditory (VAC), or visual-startling cue (VSC). Motoneuron activity was estimated via decomposition of high-density surface electromyogram recordings over the vastus lateralis and medialis muscles. Reaction time was significantly shorter in response to VSC compared to VAC and VC (i.e., the StartReact effect). The VSC further elicited faster neuromechanical responses including a greater number of discharges per motor unit per second and greater maximal rate of force development, with no differences between VAC and VC. We provide evidence, for the first time, that the synaptic input to motoneurons increases in response to a startling cue, suggesting a contribution of subcortical pathways to maximal motoneuron output in humans, likely originating from the pontomedullary reticular formation.
BOLD cofluctuation ‘events’ are predicted from static functional connectivity
Authors: Ladwig Zach , Seitzman Benjamin A. , Dworetsky Ally , Yu Yuhua , Adeyemo Babatunde , Smith Derek M. , Petersen Steven E. , Gratton Caterina 
Published: January 2022

ABSTRACTRecent work identified single time points (“events”) of high regional cofluctuation in functional Magnetic Resonance Imaging (fMRI) which contain more large-scale brain network information than other, low cofluctuation time points. This suggested that events might be a discrete, temporally sparse signal which drives functional connectivity (FC) over the timeseries. However, a different, not yet explored possibility is that network information differences between time points are driven by sampling variability on a constant, static, noisy signal. Using a combination of real and simulated data, we examined the relationship between cofluctuation and network structure and asked if this relationship was unique, or if it could arise from sampling variability alone. First, we show that events are not discrete – there is a gradually increasing relationship between network structure and cofluctuation; ∼50% of samples show very strong network structure. Second, using simulations we show that this relationship is predicted from sampling variability on static FC. Finally, we show that randomly selected points can capture network structure about as well as events, largely because of their temporal spacing. Together, these results suggest that, while events exhibit particularly strong representations of static FC, there is little evidence that events are unique timepoints that drive FC structure. Instead, a parsimonious explanation for the data is that events arise from a single static, but noisy, FC structure.HIGHLIGHTSPast results suggested high cofluctuation BOLD “events” drive fMRI functional connectivity, FCHere, events were examined in both real fMRI data and a stationary null model to test this modelIn real data, >50% of BOLD timepoints show high modularity and similarity to time- averaged FCStationary null models identified events with similar behavior to real dataEvents may not be a transient driver of static FC, but rather an expected outcome of it.
Data-driven modelling captures dynamics of the circadian clock of Neurospora crassa
Authors: Singh Amit , Li Congxin , Diernfellner Axel C. R. , Höfer Thomas , Brunner Michael 
Published: January 2022

AbstractEukaryotic circadian clocks are based on self-sustaining, cell-autonomous oscillatory feedback loops that can synchronize with the environment via recurrent stimuli (zeitgebers) such as light. The components of biological clocks and their network interactions are becoming increasingly known, calling for a quantitative understanding of their role for clock function. However, the development of data-driven mathematical clock models has remained limited by the lack of sufficiently accurate data. Here we present a comprehensive model of the circadian clock of Neurospora crassa that describe free-running oscillations in constant darkness and entrainment in light-dark cycles. To parameterize the model, we measured high-resolution time courses of luciferase reporters of morning and evening specific clock genes in WT and a mutant strain. Fitting the model to such comprehensive data allowed estimating parameters governing circadian phase, period length and amplitude, and the response of genes to light cues. Our model suggests that functional maturation of the core clock protein Frequency (FRQ) causes a delay in negative feedback that is critical for generating circadian rhythms.
A murine Wac model exhibits phenotypes relevant to DeSanto-Shinawi Syndrome
Authors: Stafford April M , Pacheco-Vergara Maria , Uhl Katie L , Jager Tara E , Li Xiaopeng , Jeong Juhee , Vogt Daniel 
Published: January 2022

AbstractSeveral monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments, including autism, attention deficit hyperactivity disorder (ADHD) and seizures. Limited studies and resources are available to make meaningful headway into the underlying mechanisms that result in these symptoms. One such example, DeSanto-Shinawi Syndrome (DESSH), is a rare disorder caused by mutations in the WAC gene. Those diagnosed with DESSH experience craniofacial alterations as well as cognitive symptoms that include autism, ADHD and seizures. However, no thorough studies from a mammalian model exist to understand how these changes occur. To overcome this, we generated constitutive murine Wac mutants and assessed phenotypes that are relevant to humans diagnosed with DESSH. Wac mutants have craniofacial, anatomical, behavioral and seizure susceptibility that are relevant to DESSH; this new model is suited to study some of the core symptoms of DESSH and the biology of Wac.
Wolbachia promotes its own uptake by host cells
Authors: Nevalainen Lindsay , Newton Irene L.G. 
Published: January 2022

AbstractWolbachia pipientis is an incredibly widespread bacterial symbiont of insects, present in an estimated 25-52% of species worldwide. Wolbachia is faithfully maternally transmitted both in a laboratory setting and in the wild. In an established infection, Wolbachia is primarily intracellular, residing within host-derived vacuoles that are associated with the endoplasmic reticulum. However, Wolbachia also frequently transfer between host species, requiring an extracellular stage to their life cycle. Indeed, Wolbachia has been moved between insect species for the precise goal of controlling populations. The use of Wolbachia in this application requires we better understand how it initiates and establishes new infections. Here we designed a novel method for live-tracking Wolbachia during infection using a combination of stains and microscopy. We show that live Wolbachia are taken up by host cells at a much faster rate than dead Wolbachia cells, indicating that Wolbachia play a role in their own uptake and that Wolbachia colonization is not just a passive process. We also show that the host actin cytoskeleton must be intact for this to occur, and that drugs that disrupt the actin cytoskeleton effectively abrogate Wolbachia uptake. The development of this live infection assay will assist in future efforts to characterize Wolbachia factors used during host infection.
Transient RNA structures cause aberrant influenza virus replication and innate immune activation
Authors: French Hollie , Pitré Emmanuelle , Oade Michael S. , Elshina Elizaveta , Bisht Karishma , King Alannah , Bauer David L.V. , te Velthuis Aartjan J.W. 
Published: January 2022

AbstractDuring infection, the influenza A virus RNA polymerase produces both full-length and aberrant RNA molecules, such as defective viral genomes (DVG) and mini viral RNAs (mvRNA). Subsequent innate immune activation involves the binding of host pathogen receptor retinoic acid-inducible gene I (RIG-I) to viral RNAs. However, not all influenza A virus RNAs are strong RIG-I agonists. Here we show that potent innate immune activation by mvRNAs is determined by transient RNA structures, called template loops (t-loop) that stall the viral RNA polymerase. The effect of t-loops depends on the formation of an RNA duplex near the template entry and exit channels of the RNA polymerase, and their effect is enhanced by mutation of the template exit path from the RNA polymerase active site. Overall, these findings provide a mechanism that links aberrant viral replication to the activation of the innate immune response.
Preparing for the unknown: How working memory provides a link between perception and anticipated action
Authors: Rösner Marlene , Sabo Melinda , Klatt Laura-Isabelle , Wascher Edmund , Schneider Daniel 
Published: January 2022

AbstractWhat mechanisms underlie the transfer of a working memory representation into a higher-level code for guiding future actions? Electrophysiological correlates of attentional selection and motor preparation processes within working memory were investigated in two retrospective cuing tasks. In the first experiment, participants stored the orientation and location of a grating. Subsequent feature cues (selective vs. neutral) indicated which feature would be the target for later report. The oscillatory response in the mu and beta frequency range with an estimated source in the sensorimotor cortex contralateral to the responding hand was used as correlate of motor preparation. Mu/beta suppression was stronger following the selective feature cues compared to the neutral cue, demonstrating that purely feature-based selection is sufficient to form a prospective motor plan. In the second experiment, another retrospective cue was included to study whether knowledge of the task at hand is necessary to initiate motor preparation. Following the feature cue, participants were cued to either compare the stored feature(s) to a probe stimulus (recognition task) or to adjust the memory probe to match the target feature (continuous report task). An analogous suppression of mu oscillations was observed following a selective feature cue, even ahead of task specification. Further, a subsequent selective task cue again elicited a mu/beta suppression, which was stronger after a continuous report task cue. This indicates that working memory is able to flexibly store different types of information in higher-level mental codes to provide optimal prerequisites for all required action possibilities.Highlights•Selectively cueing features results in an overall performance benefit•Feature-based attention is sufficient to form a prospective motor plan•Prospective motor preparation can be initiated ahead of task specification•Retro-active task specification leads to forming of higher-level action codes•Different tasks requirements result in different prospective action plans
Selecting an effective amplitude threshold for neural spike detection
Authors: Zhang Zheng , Constandinou Timothy G. 
Published: January 2022

AbstractThis paper assesses and challenges whether commonly used methods for defining amplitude thresholds for spike detection are optimal. This is achieved through empirical testing of single amplitude thresholds across multiple recordings of varying SNR levels. Our results suggest that the most widely used noise-statistics-driven threshold can suffer from parameter deviation in different noise levels. The spike-noise-driven threshold can be an ideal approach to set the threshold for spike detection, which suffers less from the parameter deviation and is robust to sub-optimal settings.
TooT-SC: Predicting Eleven Substrate Classes of Transmembrane Transport Proteins
Authors: Alballa Munira , Butler Gregory 
Published: January 2022

AbstractBackgroundTransporters form a significant proportion of the proteome and play an important role in mediating the movement of compounds across membranes. Transport proteins are difficult to characterize experimentally, so there is a need for computational tools that predict the substrates transported in order to annotate the large number of genomes being sequenced. Recently we developed a dataset of eleven substrate classes from Swiss-Prot using the ChEBI ontology as the basis for the definition of the classes.ResultsWe extend our earlier work TranCEP, which predicted seven substrate classes, to the new dataset with eleven substrate classes. Like TranCEP, TooT-SC combines pairwise amino acid composition (PAAC) of the protein, with evolutionary information captured in a multiple sequence alignment (MSA) using TM-Coffee, and restriction to important positions of the alignment using TCS. Our experimental results show that TooT-SC significantly outperforms the state-of-the-art predictors, including our earlier work, with an overall MCC of 0.82 and the MCC for the eleven classes ranging from 0.66 to 1.00.ConclusionTooT-SC is a useful tool with high performance covering a broad range of substrate classes. The results quantify the contribution made by each type of information used during the prediction process. We believe the methodology is applicable more generally for protein sequence analysis.
T cell transcription factor expression evolves as adaptive immunity matures in granulomas fromMycobacterium tuberculosis-infected cynomolgus macaques
Authors: Grant Nicole L. , Maiello Pauline , Klein Edwin , Lin Philana Ling , Borish H. Jacob , Tomko Jaime , Frye L. James , White Alexander G. , Kirschner Denise E. , Mattila Joshua T. , Flynn JoAnne L. 
Published: January 2022

SUMMARYMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. We identified and compared the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques. Original granulomas differed in transcription factor expression within adaptive lymphocytes with those at 12 weeks showing higher frequencies of CD8+T-bet+T cells, while increases in CD4+T-bet+T cells were observed at 20 weeks post-infection. The appearance of T-bet+adaptive T cells at 12 and 20 weeks was coincident with a reduction in bacterial burden, suggesting their critical role inMtbcontrol. This study highlights the evolution of T cell responses within lung granulomas, suggesting that vaccines promoting the development and migration of T-bet+T cells would enhance mycobacterial control.
Deconstructing the role of iron and heme in the structure of healthy human gut microbial communities
Authors: Celis Arianna I. , Relman David A. , Huang Kerwyn Casey 
Published: January 2022

SummaryThe response of the human gut microbiome to disruptions is often difficult to discern without model systems that remove the complexity of the host environment. Fluctuations in iron availability provide a case in point: the responses of pathogenic bacteria to iron in vitro are much better understood than those of the indigenous human gut commensal microbiota. In a clinical study of iron supplementation in healthy humans, we identified gradual, participant-specific microbiota shifts correlated with bacterial iron internalization. To identify direct effects due to taxon-specific iron sensitivity, we used stool samples from these participants as inocula to derive in vitro communities. Iron supplementation of these communities caused small shifts in structure, similar to in vivo, whereas iron deprivation dramatically inhibited growth with irreversible and cumulative reduction in diversity and replacement of some dominant species. Sensitivity of individual species to iron deprivation during growth in axenic culture generally predicted iron dependency in a community context. Finally, exogenous heme acted as a source of inorganic iron to prevent depletion of some community members. Our results highlight the complementarity of in vivo and in vitro studies in deconstructing how environmental factors affect gut microbiome structure.
S-Acylation Regulates the Membrane Association and Activity of Calpain-5
Authors: Gal Jozsef , Bondada Vimala , Mashburn Charles B. , Rodgers David W. , Croall Dorothy E. , Geddes James W. 
Published: January 2022

AbstractCalpain-5 (CAPN5) is a member of the calpain family of calcium-activated neutral thiol proteases. CAPN5 is partly membrane associated, despite its lack of a transmembrane domain. Unlike classical calpains, CAPN5 contains a C-terminal C2 domain. C2 domains often have affinity to lipids, mediating membrane association. We recently reported that the C2 domain of CAPN5 was essential for its membrane association and the activation of its autolytic activity. However, despite the removal of the C2 domain by autolysis, the N-terminal fragment of CAPN5 remained membrane associated. S-acylation, also referred to as S-palmitoylation, is a reversible post-translational lipid modification of cysteine residues that promotes membrane association of soluble proteins. In the present study several S-acylated cysteine residues were identified in CAPN5 with the acyl-PEG exchange method. Data reported here demonstrate that CAPN5 is S-acylated on up to three cysteine residues including Cys-4 and Cys-512, and likely Cys-507. The D589N mutation in a potential calcium binding loop within the C2 domain interfered with the S-acylation of CAPN5, likely preventing initial membrane association. Mutating specific cysteine residues of CAPN5 interfered with both its membrane association and the activation of CAPN5 autolysis. Taken together, our results suggest that the S-acylation of CAPN5 is critical for its membrane localization which appears to favor its enzymatic activity.