bluuebunny/crossref_metadata_2025_split huggingface dataset:
From computing transition probabilities to word recognition in sleeping neonates, a two-step neural tale
Authors: Fló Ana , Benjamin Lucas , Palu Marie , Dehaene-Lambertz Ghislaine 
Published: July 2021

AbstractExtracting statistical regularities from the environment is a primary learning mechanism, which might support language acquisition. While it is known that infants are sensitive to transition probabilities between syllables in continuous speech, the format of the encoded representation remains unknown. Here we used electrophysiology to investigate how 31 full-term neonates process an artificial language build by the random concatenation of four pseudo-words and which information they retain. We used neural entrainment as a marker of the regularities the brain is tracking in the stream during learning. Then, we compared the evoked-related potentials (ERP) to different triplets to further explore the format of the information kept in memory. After only two minutes of familiarization with the artificial language, we observed significant neural entrainment at the word rate over left temporal electrodes compared to a random stream, demonstrating that sleeping neonates automatically and rapidly extracted the word pattern. ERPs significantly differed between triplets starting or not with the correct first syllable in the test phase, but no difference was associated with later violations in transition probabilities, revealing a change in the representation format between segmentation and memory processes. If the transition probabilities were used to segment the stream, the retained representation relied on syllables’ ordinal position, but still without a complete representation of the words at this age. Our results revealed a two-step learning strategy, probably involving different brain regions.
Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
Authors: Lobanov Sergey V. , McAllister Branduff , McDade-Kumar Mia , Landwehrmeyer G. Bernhard , Orth Michael , Rosser Anne E. ,   for the REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   for the Predict-HD study, Lee Jong-Min , MacDonald Marcy E. , Gusella James F. , Long Jeffrey D. , Ryten Mina , Williams Nigel , Holmans Peter , Massey Thomas H. , Jones Lesley 
Published: July 2021

AbstractBackgroundHuntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat.MethodsWe developed a novel method for calling perfect and imperfect repeats from exome sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis.ResultsWe found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1×10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797.ConclusionsThe association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.
Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated CSPα mutants causes lipofuscin accumulation
Authors: Lee Juhyung , Xu Yue , Saidi Layla , Xu Miao , Zinsmaier Konrad , Ye Yihong 
Published: July 2021

AbstractMutations in DNAJC5 (encoding the J domain-containing HSP70 co-chaperone CSPα) are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent storage material (AFSM) termed lipofuscin. Functionally, CSPα has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how CSPα dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two distinct protein quality control functions of CSPα at endolysosomes and perinuclear vesicles, respectively. We show that the endolysosome-associated CSPα promotes microautophagy of misfolded clients, but is dispensable for MAPS. By contrast, the perinuclear-localized CSPα, regulated by a previously unknown CSPα interactor named CD98hc, is critical for MAPS but unneeded for microautophagy. Importantly, these processes are coupled by CSPα in a J-domain regulated manner. Uncoupling these two processes, as seen in cells lacking CD98hc or expressing ANCL-associated CSPα mutants, generates CSPα-containing AFSMs resembling NCL patient-derived lipofuscin, and also induces neurodegeneration in a Drosophila ANCL model. These findings suggest that blocking MAPS while allowing CSPα-mediated microautophagy disrupts lysosome homeostasis, causing CSPα-associated lipofuscinosis and neurodegeneration.
Ultrafast population coding and axo-somatic compartmentalization
Authors: Zhang Chenfei , Hofmann David , Neef Andreas , Wolf Fred 
Published: July 2021

AbstractPopulations of cortical neurons respond to common input within a millisecond. Morphological features and active ion channel properties were suggested to contribute to this astonishing processing speed. Here we report an exhaustive study of ultrafast population coding for varying axon initial segment (AIS) location, soma size, and axonal current properties. In particular, we studied their impact on two experimentally observed features 1) precise action potential timing, manifested in a wide-bandwidth dynamic gain, and 2) high-frequency boost under slowly fluctuating correlated input. While the density of axonal channels and their distance from the soma had a very small impact on bandwidth, it could be moderately improved by increasing soma size. When the voltage sensitivity of axonal currents was increased we observed ultrafast coding and high-frequency boost. We conclude that these computationally relevant features are strongly dependent on axonal ion channels’ voltage sensitivity, but not their number or exact location. We point out that ion channel properties, unlike dendrite size, can undergo rapid physiological modification, suggesting that the temporal accuracy of neuronal population encoding could be dynamically regulated. Our results are in line with recent experimental findings in AIS pathologies and establish a framework to study structure-function relations in AIS molecular design.
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Authors: Yuste-Checa Patricia , Trinkaus Victoria A. , Riera-Tur Irene , Imamoglu Rahmi , Schaller Theresa , Wang Huping , Dudanova Irina , Hipp Mark S. , Bracher Andreas , Hartl F. Ulrich 
Published: July 2021

AbstractSpreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.
Variable susceptibility of intestinal organoid-derived monolayers to SARS-CoV-2 infection
Authors: Jang Kyung Ku , Kaczmarek Maria E , Dallari Simone , Chen Ying-Han , Tada Takuya , Axelrad Jordan , Landau Nathaniel R. , Stapleford Kenneth A , Cadwell Ken 
Published: July 2021

ABSTRACTGastrointestinal effects associated with COVID-19 are highly variable for reasons that are not understood. In this study, we used intestinal organoid-derived cultures differentiated from primary human specimens as a model to examine inter-individual variability. Infection of intestinal organoids derived from different donors with SARS-CoV-2 resulted in orders of magnitude differences in virus replication in small intestinal and colonic organoid-derived monolayers. Susceptibility to infection correlated with ACE2 expression level and was independent of donor demographic or clinical features. ACE2 transcript levels in cell culture matched the amount of ACE2 in primary tissue indicating this feature of the intestinal epithelium is retained in the organoids. Longitudinal transcriptomics of organoid-derived monolayers identified a delayed yet robust interferon signature, the magnitude of which corresponded to the degree of SARS-CoV-2 infection. Interestingly, virus with the Omicron variant spike protein infected the organoids with the highest infectivity, suggesting increased tropism of the virus for intestinal tissue. These results suggest that heterogeneity in SARS-CoV-2 replication in intestinal tissues results from differences in ACE2 levels, which may underlie variable patient outcomes.
Juvenile Gouldian Finches (Erythrura gouldiae) form sibling sub-groups during social integration
Authors: Kohn Gregory M. , Nugent M. Ryan , Dail Xzavier 
Published: July 2021

ABSTRACTThe formation of social relationships in complex groups is critical in shaping patterns of social organization and behavioral development. In many birds, young individuals remain dependent on their parents for extended periods but must abruptly transition to navigating interactions in the wider group after independence. While lack of social relationships during this period is detrimental in the development of later social skills, little is known about the social relationship’s juveniles form after independence in many bird species. In this study we describe patterns of social interactions in juvenile Gouldian Finches (Erythrura gouldiae) during transitions from family groups into flocks of unfamiliar individuals. A group of 20 juveniles from 4 families were introduced into two flocks. After introductions juveniles showed a gradient of approach rates with most approaches directed towards siblings, followed by juvenile peers, adult females, and lastly adult males. Significant preferences for siblings resulted in the emergence of sibling subgroups within the larger social network. This active self-assortment of siblings suggests that sibling sub-groups are an important bridge linking social connections within the family and the wider group. Such findings suggests that sibling relationships have a critical role in the socialization after independence, as well as structuring the social organization of Gouldian finch flocks.
TaBln1 negatively regulates wheat resistance to stripe rust by reducing Ca2+ influx
Authors: Guo Shuangyuan , Zhang Yanqin , Zeng Peng , Li Min , Zhang Qiong , Li Xing , Xu Quanle , Li Tao , Wang Xiaojie , Kang Zhensheng , Zhang Xinmei 
Published: July 2021

AbstractBlufensin1 (Bln1) has been identified as a negative regulator of basal defense mechanisms that is unique to the cereal grain crops barley, wheat, and rice. However, the molecular mechanisms through which Blufensin1 regulates the wheat immune response are poorly understood. In this study, we found that TaBln1 is significantly induced by Puccinia striiformis f. sp. tritici (Pst) virulent race CYR31 infection. Knockdown the expression of TaBln1 by virus-induced gene silencing reduced Pst growth and development, and enhanced the host defense response. In addition, TaBln1 was found to physically interact with TaCaM3 on the plasma membrane. Silencing TaCaM3 with virus-induced gene silencing increased fungal infection areas and sporulation and reduced wheat resistance to the Pst CYR23 and CYR31. Moreover, we found that the TaCaM3 transcription level could be induced by treatment with chitin but not flg22. Silencing TaCaM3 decreased the Ca2+ influx induced by chitin, but silencing TaBln1 increased the Ca2+ influx in vivo using a non-invasive micro-test technique. Taken together, we identified the wheat negative regulator TaBln1, which interacts with TaCaM3 to impair Ca2+ influx and inhibits plant defenses.One-sentence summaryTaBln1 negatively regulate wheat resistance to stripe rust possibly due to the interaction with TaCaM3 on the plasma membrane, which impairs the calcium influx modulated by TaCaM3.
Autofluorescence microscopy as a label-free tool for renal histology and glomerular segmentation
Authors: Patterson Nathan Heath , Neumann Elizabeth K. , Sharman Kavya , Allen Jamie , Harris Raymond , Fogo Agnes B. , de Caestecker Mark , Caprioli Richard M. , Van de Plas Raf , Spraggins Jeffrey M. 
Published: July 2021

ABSTRACTFunctional tissue units (FTUs) composed of multiple cells like the glomerulus in the kidney nephron play important roles in health and disease. Histological staining is often used for annotation or segmentation of FTUs, but chemical stains can introduce artefacts through experimental factors that influence analysis. Secondly, many molecular -omics techniques are incompatible with common histological stains. To enable FTU segmentation and annotation in human kidney without the need for histological staining, we detail here the use of widefield autofluorescence (AF) microscopy as a simple, label-free modality that provides detailed renal morphology comparable to periodic acid-Schiff (PAS) stained tissue in both formalin-fixed paraffin-embedded (FFPE) and fresh frozen samples and with no tissue processing beyond sectioning. We demonstrate automated deep learning-based glomerular unit recognition and segmentation on PAS and AF images of the same tissue section from 9 fresh frozen samples and 9 FFPE samples. All training comparisons were carried out using registered AF microscopy and PAS stained whole slide images originating from the same section, and the recognition models were built with the exact same training and test examples. Measures of recognition performance, such as the Dice-Sorensen coefficient, the true positive rate, and the positive predictive value differed less than 2% between standard PAS and AF microscopy for both preservation methods. These results demonstrate that AF is a potentially powerful tool to study human kidney tissue, that it can serve as a label-free source for automated and manual annotation of tissue structures.
Ipsilateral stimulus encoding in primary and secondary somatosensory cortex of awake mice
Authors: Pala Aurélie , Stanley Garrett B. 
Published: July 2021

AbstractLateralization is a hallmark of somatosensory processing in the mammalian brain. However, in addition to their contralateral representation, unilateral tactile stimuli also modulate neuronal activity in somatosensory cortices of the ipsilateral hemisphere. The cellular organization and functional role of these ipsilateral stimulus responses in awake somatosensory cortices, especially regarding stimulus coding, are unknown. Here, we targeted silicon probe recordings to the vibrissa region of primary (S1) and secondary (S2) somatosensory cortex of awake head-fixed mice of either sex while delivering ipsilateral and contralateral whisker stimuli. Ipsilateral stimuli drove larger and more reliable responses in S2 than in S1, and activated a larger fraction of stimulus-responsive neurons. Ipsilateral stimulus-responsive neurons were rare in layer 4 of S1, but were located in equal proportion across all layers in S2. Linear classifier analyses further revealed that decoding of the ipsilateral stimulus was more accurate in S2 than S1, while S1 decoded contralateral stimuli most accurately. These results reveal substantial encoding of ipsilateral stimuli in S1 and especially S2, consistent with the hypothesis that higher cortical areas may integrate tactile inputs across larger portions of space, spanning both sides of the body.S1ignificance StatementTactile information obtained by one side of the body is represented in the activity of neurons of the opposite brain hemisphere. However unilateral tactile stimulation also modulates neuronal activity in the other, or ipsilateral, brain hemisphere. This ipsilateral activity may play an important role in the representation and processing of tactile information, in particular when the sense of touch involves both sides of the body. Our work in the whisker system of awake mice reveals that neocortical ipsilateral activity, in particular that of deep layer excitatory neurons of secondary somatosensory cortex (S2), contains information about the presence and the velocity of unilateral tactile stimuli, which supports a key role for S2 in integrating tactile information across both body sides.
Inducing oncolytic cell death in human cancer cells by the long non-coding RNA let-A
Authors: Birbaumer Tosca , Schlumpf Tommy Beat , Seimiya Makiko , Jiang Yanrui , Paro Renato 
Published: July 2021

SummaryLong non-coding (lnc) RNAs contain functional elements that play important regulatory roles in a variety of processes during development, normal physiology, as well as disease. We recently discovered a new lncRNA, we named let-A, expressed from the evolutionary conserved let-7-Complex locus in Drosophila. This RNA induces cell death in Drosophila cancer cells. Here we show that ectopic expression of Drosophila let-A is also exerting an oncolytic toxicity in several human cancer cell lines, but shows almost no effect in more differentiated or cell lines derived from normal tissue. We demonstrate that let-A RNA prepared by in vitro transcription and provided in the growth medium is sufficient to induce cell death both in human and Drosophila cancer cells. The activity of in vitro transcribed let-A is most efficient in its full length, but requires prior modification/processing to become active. let-A induces a reduction of nucleolar size in treated cells. We show exo/endocytosis and Toll signaling pathway to be necessary for let-A-induced toxicity. Our findings indicate let-A exhibits an evolutionary conserved anti-cancer function, making it a promising molecule for tumor treatments.
Tillage intensity and plant rhizosphere selection shape bacterial-archaeal assemblage diversity and nitrogen cycling genes
Authors: Cloutier Mara L. C. , Alcaide Tiffanie , Duiker Sjoerd W. , Bruns Mary Ann 
Published: July 2021

AbstractIn agriculture, adoption of reduced tillage practices is a widespread adaptation to global change. The cessation of plowing reduces erosion, slows soil organic matter oxidation, and promotes soil carbon accrual, but it can also result in the development of potential N2O spots from denitrification activity. In this study, we hypothesized that 16S rRNA-based composition of bacterial-archaeal assemblages would differ in agricultural soils subjected for forty years to a range of disturbance intensities, with annual moldboard plowing (MP) being the most intensive. No-till planting (NT) represented tillage management with the least amount of disturbance, while chisel-disking (CD), a type of conservation tillage, was intermediate. All long-term tillage plots had been planted with the same crops grown in a three-year crop rotation (corn-soybean-small grain+cover crop), and both bulk and rhizosphere soils were analyzed from the corn and soybean years. We also evaluated denitrification gene markers by quantitative PCR at multiple points (three growth stages of corn and soybean). Tillage intensity, soil compartment (bulk or rhizosphere), crop year, growth stage, and interactions all exerted effects on community diversity and composition. Compared to MP and CD, NT soils had lower abundances of denitrification genes, higher abundances of nitrate ammonification genes, and higher abundances of taxa at the family level associated with the inorganic N cycle processes of archaeal nitrification and anammox. Soybean rhizospheres exerted stronger selection on community composition and diversity relative to corn rhizospheres. Interactions between crop year, management, and soil compartment had differential impacts on N gene abundances related to denitrification and nitrate ammonification. Opportunities for managing hot spots or hot moments for N losses from agricultural soils may be discernible through improved understanding of tillage intensity effects, although weather and crop type are also important factors influencing how tillage influences microbial assemblages and N use.
Structural and functional characterization of ubiquitin variant inhibitors for the JAMM-family deubiquitinases STAMBP and STAMBPL1
Authors: Guo Yusong , Liu Qi , Mallette Evan , Caba Cody , Hou Feng , Fux Julia , LaPlante Gabriel , Dong Aiping , Zhang Qi , Zheng Hui , Tong Yufeng , Zhang Wei 
Published: July 2021

AbstractUbiquitination is one of the most crucial post-translational protein modifications involved in a myriad of biological pathways. This process is reversed by deubiquitinases (DUBs) that deconjugate the ubiquitin (Ub) moiety or poly-Ub chains from substrates. In the past decade, tremendous efforts have been focused on targeting DUBs for drug discovery. However, most chemical compounds with inhibitory activity for DUBs suffer from mild potency and low selectivity. To overcome these obstacles, we developed a phage display-based protein engineering strategy for generating Ub variant (UbV) inhibitors and have previously successfully applied it to the Ub-specific protease (USP) family of cysteine proteases. In this work, we leveraged the UbV platform to target STAMBP, a member of the JAB1/MPN/MOV34 (JAMM) metalloprotease family of DUB enzymes. We identified two UbVs (UbVSP.1 and UbVSP.3) that bind to STAMBP with high affinity but differ in their selectivity for the closely related paralog STAMBPL1. We determined the STAMBPL1-UbVSP.1 complex structure by X-ray crystallography, revealing hotspots of the tight JAMM-UbV interaction. Finally, we show that UbVSP.1 and UbVSP.3 are potent inhibitors of the STAMBP isopeptidase activity, far exceeding the reported small-molecule inhibitor BC-1471. This work demonstrates that UbV technology is suitable to develop tool molecules for metalloproteases. These tools can be used to understand the cellular function of JAMM family DUBs.
Regional cytoarchitecture of the adult and developing mouse enteric nervous system
Authors: Hamnett Ryan , Dershowitz Lori B. , Sampathkumar Vandana , Wang Ziyue , De Andrade Vincent , Kasthuri Narayanan , Druckmann Shaul , Kaltschmidt Julia A. 
Published: July 2021

AbstractThe enteric nervous system (ENS) populates the gastrointestinal (GI) tract and controls GI function. In contrast to the central nervous system, macrostructure of the ENS has been largely overlooked. Here, we visually and computationally demonstrate that the ENS is organized in circumferential stripes that regionally differ in development and neuronal composition. This characterization provides a blueprint for future understanding of region-specific GI function and identifying ENS structural correlates of GI disorders.