bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Mutations 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

Populations 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

Spreading 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

Gastrointestinal 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

The 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

Blufensin1 (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 summary

TaBln1 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

Functional 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

Lateralization 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 Statement

Tactile 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

Long 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

In 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

Ubiquitination 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

The 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.
Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade
Authors: Schellinger Jeffrey N. , Sun Qifei , Pleinis John M. , An Sung-Wan , Hu Jianrui , Mercenne Gaëlle , Titos Iris , Huang Chou-Long , Rothenfluh Adrian , Rodan Aylin R.
Published: July 2021

Central pacemaker neurons regulate circadian rhythms and undergo diurnal variation in electrical activity in mammals and flies. In mammals, circadian variation in the intracellular chloride concentration of pacemaker neurons has been proposed to influence the response to GABAergic neurotransmission through GABAA receptor chloride channels. However, results have been contradictory, and a recent study demonstrated circadian variation in pacemaker neuron chloride without an effect on GABA response. Therefore, whether and how intracellular chloride regulates circadian rhythms remains controversial. Here, we demonstrate a signaling role for intracellular chloride in the Drosophila ventral lateral (LNv) pacemaker neurons. In control flies, intracellular chloride increases in LNv neurons over the course of the morning. Chloride transport through the sodium-potassium-2-chloride (NKCC) and potassium-chloride (KCC) cotransporters is a major determinant of intracellular chloride concentrations. Drosophila melanogaster with loss-of-function mutations in the NKCC encoded by Ncc69 have abnormally low intracellular chloride six hours after lights on, and a lengthened circadian period. Loss of kcc, which is expected to increase intracellular chloride, suppresses the long-period phenotype of Ncc69 mutant flies. Activation of a chloride-inhibited kinase cascade, consisting of the WNK (With No Lysine (K)) kinase and its downstream substrate, Fray, is necessary and sufficient to prolong period length. Fray activation of an inwardly rectifying potassium channel, Irk1, is also required for the long-period phenotype. These results indicate that the NKCC-dependent rise in intracellular chloride in Drosophila LNv pacemaker neurons restrains WNK-Fray signaling and overactivation of an inwardly rectifying potassium channel to maintain normal circadian period length.
Interferon-Induced Transmembrane Proteins Inhibit Infection by the Kaposi’s Sarcoma-Associated Herpesvirus and the Related Rhesus Monkey Rhadinovirus in a Cell Type-Specific Manner
Authors: Hörnich Bojan F. , Großkopf Anna K. , Dcosta Candice J. , Schlagowski Sarah , Hahn Alexander S.
Published: July 2021

The interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral proteins that inhibit the entry of enveloped viruses. We analyzed the effect of IFITMs on the gamma2-herpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and the closely related rhesus monkey rhadinovirus (RRV). We used CRISPR/Cas9-mediated gene knockout to generate A549, human foreskin fibroblast (HFF) and human umbilical vein endothelial cells (HUVEC) with combined IFITM1/2/3 knockout and identified IFITMs as cell type-dependent inhibitors of KSHV and RRV infection in A549 and HFF but not HUVEC. IFITM overexpression revealed IFITM1 as the relevant IFITM that inhibits KSHV and RRV infection. Fluorescent KSHV particles did not pronouncedly colocalize with IFITM-positive compartments. However, we found that KSHV and RRV glycoprotein-mediated cell-cell fusion is enhanced upon IFITM1/2/3 knockout. Taken together, we identified IFITM1 as a cell type-dependent restriction factor of KSHV and RRV that acts at the level of membrane fusion. Strikingly, we observed that the endotheliotropic KSHV circumvents IFITM-mediated restriction in HUVEC despite high IFITM expression, while influenza A virus (IAV) glycoprotein-driven entry into HUVEC is potently restricted by IFITMs even in the absence of interferon.

IMPORTANCE

IFITM proteins are the first line of defense against infection by many pathogens, which may also have therapeutic importance, as they, among other effectors, mediate the antiviral effect of interferons. Neither their function against herpesviruses nor their mechanism of action are well understood. We report here that in some cells, but not in, for example, primary umbilical vein endothelial cells, IFITM1 restricts KSHV and RRV, and that, mechanistically, this is likely effected by reducing the fusogenicity of the cell membrane. Further, we demonstrate potent inhibition of IAV glycoprotein-driven infection of cells of extrapulmonary origin by high constitutive IFITM expression.
Isotropic Reconstruction of Electron Tomograms with Deep Learning
Authors: Liu Yun-Tao , Zhang Heng , Wang Hui , Tao Chang-Lu , Bi Guo-Qiang , Zhou Z. Hong
Published: July 2021

Cryogenic electron tomography (cryoET) allows visualization of cellular structures in situ. However, anisotropic resolution arising from the intrinsic “missing-wedge” problem has presented major challenges in visualization and interpretation of tomograms. Here, we have developed IsoNet, a deep learning-based software package that iteratively reconstructs the missing-wedge information and increases signal-to-noise ratio, using the knowledge learned from raw tomograms. Without the need for sub-tomogram averaging, Isonet generates tomograms with significantly reduced resolution anisotropy. Applications of IsoNet to three representative types of cryoET data demonstrate greatly improved structural interpretability: resolving lattice defects in immature HIV particles, establishing architecture of the paraflagellar rod in Eukaryotic flagella, and identifying heptagon-containing clathrin cages inside a neuronal synapse of cultured cells. Therefore, by overcoming two fundamental limitations of cryoET, IsoNet enables functional interpretation of cellular tomograms without sub-tomogram averaging. Its application to high-resolution cellular tomograms should also help identify differently oriented complexes of the same kind for near-atomic resolution sub-tomogram averaging.
HAMdetector: A Bayesian regression model that integrates information to detect HLA-associated mutations
Authors: Habermann Daniel , Kharimzadeh Hadi , Walker Andreas , Li Yang , Yang Rongge , Brumme Zabrina L. , Timm Jörg , Roggendorf Michael , Hoffmann Daniel
Published: July 2021

Motivation

A key process in anti-viral adaptive immunity is that the Human Leukocyte Antigen system (HLA) presents epitopes as Major Histocompatibility Complex I (MHC I) protein-peptide complexes on cell surfaces and in this way alerts CD8+ cytotoxic T-Lymphocytes (CTLs). This pathway exerts strong selection pressure on viruses, favoring viral mutants that escape recognition by the HLA/CTL system, e.g. by point mutations that decrease binding of viral peptides to MHC I. Naturally, such immune escape mutations often emerge in highly variable viruses, e.g. HIV or HBV, as HLA-associated mutations (HAMs), specific to the host HLA alleles and its MHC I proteins. The reliable identification of HAMs is not only important for understanding viral genomes and their evolution, but it also impacts the development of broadly effective anti-viral treatments and vaccines against variable viruses.

By their very nature HAMs are amenable to detection by statistical methods in paired sequence / HLA data. However, HLA alleles are very polymorphic in the human host population which makes the available data relatively sparse and noisy. Under these circumstances, one way to optimize HAM detection is to integrate all relevant information in a coherent model. Bayesian inference offers a principled approach to achieve this.

Results

We present a new regression model for the detection of HAMs. As we choose a Bayesian approach we can include the novel sparsity-inducing priors, and we obtain easily interpretable quantitative information on HAM candidates. The basic model can be extended to include prior information relevant to HAM detection, which we demonstrate by integrating predictions of epitope affinities to MHC I, predictions of epitope peptide processing, and computation of phylogenetic background. This integrative method improves performance in HAM detection considerably over state-of-the-art methods.

Availability

The source code of this software is available at https://github.com/HAMdetector/Escape.jl under a permissive MIT license.

Contact

daniel.habermann@uni-due.de, daniel.hoffmann@uni-due.de
Macrophages govern antiviral responses in human lung tissues protected from SARS-CoV-2 infection
Authors: Kenney Devin J. , O’Connell Aoife K. , Turcinovic Jacquelyn , Montanaro Paige , Hekman Ryan M. , Tamura Tomokazu , Berneshawi Andrew R. , Cafiero Thomas R. , Abdullatif Salam Al , Blum Benjamin , Goldstein Stanley I. , Heller Brigitte L. , Gertje Hans P. , Bullitt Esther , Trachtenberg Alexander J. , Chavez Elizabeth , Sheikh Amira , Kurnick Susanna , Grosz Kyle , Bosmann Markus , Ericsson Maria , Huber Bertrand R. , Saeed Mohsan , Balazs Alejandro B. , Francis Kevin P. , Klose Alexander , Paragas Neal , Campbell Joshua D. , Connor John H. , Emili Andrew , Crossland Nicholas A. , Ploss Alexander , Douam Florian
Published: July 2021

The majority of SARS-CoV-2 infections among healthy individuals result in asymptomatic to mild disease. However, the immunological mechanisms defining effective lung tissue protection from SARS-CoV-2 infection remain elusive. Unlike mice solely engrafted with human fetal lung xenograft (fLX), mice co-engrafted with fLX and a myeloid-enhanced human immune system (HNFL mice) are protected against SARS-CoV-2 infection, severe inflammation, and histopathology. Effective control of viral infection in HNFL mice associated with significant macrophage infiltration, and the induction of a potent macrophage-mediated interferon response. The pronounced upregulation of the USP18-ISG15 axis (a negative regulator of IFN responses), by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology. Altogether, our work shed light on unique cellular and molecular correlates of lung tissue protection during SARS-CoV-2 infection, and underscores macrophage IFN responses as prime targets for developing immunotherapies against coronavirus respiratory diseases.

HIGHLIGHTS

Mice engrafted with human fetal lung xenografts (fLX-mice) are highly susceptible to SARS-CoV-2.

Co-engraftment with a human myeloid-enriched immune system protected fLX-mice against infection.

Tissue protection was defined by a potent and well-balanced antiviral response mediated by infiltrating macrophages.

Protective IFN response was dominated by the upregulation of the USP18-ISG15 axis.
Robust and efficient online auditory psychophysics
Authors: Zhao Sijia , Brown Christopher A. , Holt Lori L. , Dick Frederic
Published: July 2021

Most human auditory psychophysics research has historically been conducted in carefully controlled environments with calibrated audio equipment, and over potentially hours of repetitive testing with expert listeners. Here, we operationally define such conditions as having high ‘auditory hygiene’. From this perspective, conducting auditory psychophysical paradigms online presents a serious challenge, in that results may hinge on absolute sound presentation level, reliably estimated perceptual thresholds, low and controlled background noise levels, and sustained motivation and attention. We introduce a set of procedures that address these challenges and facilitate auditory hygiene for online auditory psychophysics. First, we establish a simple means of setting sound presentation levels. Across a set of four level-setting conditions conducted in person, we demonstrate the stability and robustness of this level setting procedure in open air and controlled settings. Second, we test participants’ tone-in-noise thresholds using widely adopted online experiment platforms and demonstrate that reliable threshold estimates can be derived online in approximately one minute of testing. Third, using these level and threshold setting procedures to establish participant-specific stimulus conditions, we show that an online implementation of the classic probe-signal paradigm can be used to demonstrate frequency-selective attention on an individual-participant basis, using a third of the trials used in recent in-lab experiments. Finally, we show how threshold and attentional measures relate to well-validated assays of online participants’ in-task motivation, fatigue, and confidence. This demonstrates the promise of online auditory psychophysics for addressing new auditory perception and neuroscience questions quickly, efficiently, and with more diverse samples. Code for the tests is publicly available through Pavlovia and Gorilla.
Causal inference using deep-learning variable selection identifies and incorporates direct and indirect causalities in complex biological systems
Authors: Fan Zhenjiang , Kernan Kate F. , Benos Panayiotis V. , Canna Scott W. , Carcillo Joseph A. , Kim Soyeon , Park Hyun Jung
Published: July 2021

In complex diseases, causal structure learning across biological variables is critical to identify modifiable triggers or potential therapeutic agents. A limitation of existing causal learning methods is that they cannot identify indirect causal relations, those that would interact through latent mediating variables. We developed the first computational method that identifies both direct and indirect causalities, causal inference using deep-learning variable-selection (causalDeepVASE). To accurately identify indirect causalities and incorporate them with direct causalities, causalDeepVASE develops a deep neural network approach and extends a flexible causal inference method. In simulated and biological data of various contexts, causalDeepVASE outperforms existing methods in identifying expected or validated causal relations. Further, causalDeepVASE facilitates a systematic understanding of complex diseases. For example, causalDeepVASE uniquely identified a possible causal relation between IFNγ and creatinine suggested in a polymicrobial sepsis model. In future biomedical studies, causalDeepVASE can facilitate the identification of driver genes and therapeutic agents.
ACE2 binding is an ancestral and evolvable trait of sarbecoviruses
Authors: Starr Tyler N. , Zepeda Samantha K. , Walls Alexandra C. , Greaney Allison J. , Veesler David , Bloom Jesse D.
Published: July 2021

Two different sarbecoviruses have caused major human outbreaks in the last two decades1,2. Both these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 via the spike receptor-binding domain (RBD)2–6. However, binding to ACE2 orthologs from humans, bats, and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses7–11. Here, we use high-throughput assays12 to trace the evolutionary history of ACE2 binding across a diverse range of sarbecoviruses and ACE2 orthologs. We find that ACE2 binding is an ancestral trait of sarbecovirus RBDs that has subsequently been lost in some clades. Furthermore, we demonstrate for the first time that bat sarbecoviruses from outside Asia can bind ACE2. In addition, ACE2 binding is highly evolvable: for many sarbecovirus RBDs there are single amino-acid mutations that enable binding to new ACE2 orthologs. However, the effects of individual mutations can differ markedly between viruses, as illustrated by the N501Y mutation which enhances human ACE2 binding affinity within several SARS-CoV-2 variants of concern12 but severely dampens it for SARS-CoV-1. Our results point to the deep ancestral origin and evolutionary plasticity of ACE2 binding, broadening consideration of the range of sarbecoviruses with spillover potential.
Selenium in wheat from farming to food
Authors: Wang Min , Li Baoqiang , Li Shuang , Song Ziwei , Kong Fanmei , Zhang Xiaocun
Published: July 2021

Selenium (Se) plays an important role in human health. Approximately 80% of the world’s population does not consume enough Se which recommended by WHO (World Health Organization). Wheat is an important staple food and Se source for most people in the world. This article summarizes literatures about Se from 1936 to 2020 to investigate Se in wheat farming soil, wheat, and its derived foods. Se fortification and the recommended Se level in wheat were also discussed. Results showed that Se contents in wheat farming soil, grain, and its derived foods around the world were 3.8–552 (mean, 220.99), 0–8,270 (mean, 347.30), and 15–2,372 (mean, 211.86) μg·kg−1, respectively. Adopting suitable agronomic measures could effectively realize Se fortification in wheat. The contents in grain, flour, and its derived foods could be improved from 93.94 to 1,181.92, 73.06 to 1,007.75, and 86.90 to 587.61 μg·kg−1 in average after leaf Se fertilizer application in the field. There was a significant positive correlation between Se content in farming soil and grain, and it was extremely the same between foliar Se fertilizer concentration rate and grain Se increased rate. The recommended Se fortification level in cultivation of wheat in China, India, and Spain was 18.53–23.96, 2.65–3.37, and 3.93–9.88 g·hm−2 respectively. Milling processing and food type could greatly affect Se content of wheat derived food and should be considered seriously to meet people’s Se requirement by wheat.

TOC graphic
Decoding molecular and cellular heterogeneity of nucleus accumbens with high-throughput scRNA-seq and MERFISH
Authors: Chen Renchao , Blosser Timothy R. , Djekidel Mohamed N. , Hao Junjie , Bhattacherjee Aritra , Chen Wenqiang , Tuesta Luis M. , Zhuang Xiaowei , Zhang Yi
Published: July 2021

The nucleus accumbens (NAc) plays an important role in regulating multiple behaviors and its dysfunction has been linked to many neural disorders. However, the molecular, cellular and anatomic heterogeneity underlying its functional diversity remains incompletely understood. Here, we generate a cell census of the mouse NAc using high-throughput single cell RNA sequencing and multiplexed error-robust FISH, revealing a high level of cell heterogeneity in this brain region. We show that the transcriptional and spatial diversity of neuron subtypes underlie NAc’s anatomic and functional heterogeneity, and possibly contribute to the pathogenesis of different neurological disorders. These findings explain how the seemingly simple neuronal composition of the NAc achieves its highly heterogenous structure and diverse functions. Collectively, our study generates a spatially resolved cell taxonomy for understanding the NAc structure and function, which demonstrates the importance of combining molecular and spatial information in revealing the fundamental features of the nervous system.
Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease
Authors: Ghosh Baishakhi , Loube Jeffrey , Thapa Shreeti , Capodanno Erin , Mahmud Saborny , Girgis Mirit , Chen Si , Nishida Kristine , Ying Linyan , Swaby Carter , Wally Ara , Bhowmik Debarshi , Zaykaner Michael , Mitzner Wayne , Sidhaye Venkataramana K.
Published: July 2021

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, characterized by a progressive decline in lung function, alveolar loss (emphysema), and airflow limitation due to excessive mucus secretion (chronic bronchitis), that can occur even after the injurious agent is removed. It is slated to rise to the 3rd leading cause of death due to chronic disease by 2030 globally, and the 4th leading cause of death due to chronic disease in the USA. While there is substantial evidence indicating loss of E-cadherin in the lung epithelium of patients with COPD, it is not known if this is causal to the disease. We investigated if loss of E-cadherin can result in lung disease using in both in vitro models of primary, differentiated human cells and in mouse models. Using a cell type-specific promoter using Cre/LoxP mice system to knock-out E- cadherin in ciliated and alveolar epithelial cell (Type 1 and Type 2) populations in adult mouse models, we determined that loss of E-cadherin caused airspace enlargement, as well as increased airway hyperresponsiveness indicating that it does have a causative role in causing COPD. Strategies to upregulate CDH1 (encodes for E-cadherin) in CHBEs and cigarette-smoke injured NHBEs can rescue the dysfunctional epithelium.
Cortical spheroids display oscillatory network dynamics
Authors: Sevetson Jessica L. , Theyel Brian , Hoffman-Kim Diane
Published: July 2021

Three-dimensional brain cultures can facilitate the study of central nervous system function and disease, and one of the most important components that they present is neuronal activity on a network level. Here we demonstrate network activity in rodent cortical spheroids while maintaining the networks intact in their 3D state. Networks developed by nine days in culture and became more complex over time. To measure network activity, we imaged neurons in rat and mouse spheroids labelled with a calcium indicator dye, and in mouse spheroids expressing GCaMP. Network activity was evident when we electrically stimulated spheroids, was abolished with glutamatergic blockade, and was altered by GABAergic blockade or partial glutamatergic blockade. We quantified correlations and distances between somas with micron-scale spatial resolution. Spheroids seeded at as few as 4,000 cells gave rise to emergent network events, including oscillations. These results are the first demonstration that self-assembled rat and mouse spheroids exhibit network activity consistent with in vivo network events. These results open the door to experiments on neuronal networks that require fewer animals and enable high throughput experiments on network-perturbing alterations in neurons and glia.
The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB
Authors: Di Meo Danila , Ravindran Priyadarshini , Dhumale Pratibha , Püschel Andreas W.
Published: July 2021

Neurons are highly polarized cells that display characteristic differences in the organization of their organelles in axons and dendrites. Mitochondria are of particular importance for neuronal homeostasis due to their high metabolic demand. The kinases SadA and SadB (SadA/B) promote the formation of distinct axonal and dendritic extensions during the development of cortical and hippocampal neurons. Here, we show that SadA/B are required for the axon-specific dynamics of mitochondria. The interaction with Ankyrin B (AnkB) stimulates the activity of SadA/B that function as regulators of mitochondrial dynamics through the phosphorylation of Tau. Suppression of SadA/B or AnkB in cortical neurons induces the elongation of mitochondria by disrupting the balance of fission and fusion. The normal dynamics of axonal mitochondria could be restored by mild actin destabilization. Thus, the elongation after a loss of SadA/B results from an excessive stabilization of actin filaments and reduction of Drp1 recruitment to mitochondria.
Altered cortical processing of sensory input in Huntington disease mouse models
Authors: Sepers Marja D. , Mackay James P. , Koch Ellen , Xiao Dongsheng , Mohajerani Majid H. , Chan Allan W. , Smith-Dijak Amy I. , Ramandi Daniel , Murphy Timothy H. , Raymond Lynn A.
Published: July 2021

Huntington disease (HD), a hereditary neurodegenerative disorder, manifests as progressively impaired movement and cognition. Although early abnormalities of neuronal activity in striatum are well established in HD models, there are fewer in vivo studies of the cortex. Here, we record local field potentials (LFPs) in YAC128 HD model mice versus wild-type mice. In multiple cortical areas, limb sensory stimulation evokes a greater change in LFP power in YAC128 mice. Mesoscopic imaging using voltage-sensitive dyes reveal more extensive spread of evoked sensory signals across the cortical surface in YAC128 mice. YAC128 layer 2/3 sensory cortical neurons ex vivo show increased excitatory events, which could contribute to enhanced sensory responses in vivo. Cortical LFP responses to limb stimulation, visual and auditory input are also significantly increased in zQ175 HD mice. Results presented here extend knowledge of HD beyond ex vivo studies of individual neurons to the intact cortical network.
A unified framework for measuring selection on cellular lineages and traits
Authors: Yamauchi Shunpei , Nozoe Takashi , Okura Reiko , Kussell Edo , Wakamoto Yuichi
Published: July 2021

Intracellular states probed by gene expression profiles and metabolic activities are intrinsically noisy, causing phenotypic variations among cellular lineages. Understanding the adaptive and evolutionary roles of such variations requires clarifying their linkage to population growth rates. Extending a cell lineage statistics framework, here we show that a population’s growth rate can be expanded by fitness cumulants of any cell lineage trait. The expansion enables quantifying the contribution of each fitness cumulant, such as variance and skewness, to population growth. We introduce a function that contains all the essential information of cell lineage statistics, including mean lineage fitness and selection strength. We reveal a relation between fitness heterogeneity and population growth rate response to perturbation. We apply the framework to experimental cell lineage data from bacteria to mammalian cells, revealing that third or higher-order cumulants’ contributions are negligible under constant growth conditions but could be significant in regrowing processes from growth-arrested conditions. Furthermore, we identify cellular populations in which selection leads to an increase of fitness variance among lineages. The framework assumes no particular growth models or environmental conditions, and is thus applicable to various biological phenomena for which phenotypic heterogeneity and cellular proliferation are important.
Traces of semantization - from episodic to semantic memory in a spiking cortical network model
Authors: Chrysanthidis Nikolaos , Fiebig Florian , Lansner Anders , Herman Pawel
Published: July 2021

Episodic memory is the recollection of past personal experiences associated with particular times and places. This kind of memory is commonly subject to loss of contextual information or “semantization”, which gradually decouples the encoded memory items from their associated contexts while transforming them into semantic or gist-like representations. Novel extensions to the classical Remember/Know behavioral paradigm attribute the loss of episodicity to multiple exposures of an item in different contexts. Despite recent advancements explaining semantization at a behavioral level, the underlying neural mechanisms remain poorly understood. In this study, we suggest and evaluate a novel hypothesis proposing that Bayesian-Hebbian synaptic plasticity mechanisms might cause semantization of episodic memory. We implement a cortical spiking neural network model with a Bayesian-Hebbian learning rule called Bayesian Confidence Propagation Neural Network (BCPNN), which captures the semantization phenomenon and offers a mechanistic explanation for it. Encoding items across multiple contexts leads to item-context decoupling akin to semantization. We compare BCPNN plasticity with the more commonly used spike-timing dependent plasticity (STDP) learning rule in the same episodic memory task. Unlike BCPNN, STDP does not explain the decontextualization process. We also examine how selective plasticity modulation of isolated salient events may enhance preferential retention and resistance to semantization. Our model reproduces important features of episodicity on behavioral timescales under various biological constraints whilst also offering a novel neural and synaptic explanation for semantization, thereby casting new light on the interplay between episodic and semantic memory processes.