bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal dynamics of neural responses in human visual cortex
Authors: Groen Iris I.A. , Piantoni Giovanni , Montenegro Stephanie , Flinker Adeen , Devore Sasha , Devinsky Orrin , Doyle Werner , Dugan Patricia , Friedman Daniel , Ramsey Nick , Petridou Natalia , Winawer Jonathan 
Published: August 2021

AbstractNeural responses to visual stimuli exhibit complex temporal dynamics, including sub-additive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low contrast. These phenomena are often studied independently. Here, we demonstrate these phenomena within the same experiment and model the underlying neural computations with a single computational model. We extracted time-varying responses from electrocorticographic (ECoG) recordings from patients presented with stimuli that varied in contrast, duration, and inter-stimulus interval (ISI). Aggregating data across patients yielded 98 electrodes with robust visual responses, covering both earlier (V1-V3) and higher-order (V3a/b, LO, TO, IPS) retinotopic maps. In all regions, the temporal dynamics of neural responses exhibit several non-linear features: peak response amplitude saturates with high contrast and longer stimulus durations; the response to a second stimulus is suppressed for short ISIs and recovers for longer ISIs; response latency decreases with increasing contrast. These features are accurately captured by a computational model comprised of a small set of canonical neuronal operations: linear filtering, rectification, exponentiation, and a delayed divisive normalization. We find that an increased normalization term captures both contrast- and adaptation-related response reductions, suggesting potentially shared underlying mechanisms. We additionally demonstrate both changes and invariance in temporal response dynamics between earlier and higher-order visual areas. Together, our results reveal the presence of a wide range of temporal and contrast-dependent neuronal dynamics in the human visual cortex, and demonstrate that a simple model captures these dynamics at millisecond resolution.Significance StatementSensory inputs and neural responses change continuously over time. It is especially challenging to understand a system that has both dynamic inputs and outputs. Here we use a computational modeling approach that specifies computations to convert a time-varying input stimulus to a neural response time course, and use this to predict neural activity measured in the human visual cortex. We show that this computational model predicts a wide variety of complex neural response shapes that we induced experimentally by manipulating the duration, repetition and contrast of visual stimuli. By comparing data and model predictions, we uncover systematic properties of temporal dynamics of neural signals, allowing us to better understand how the brain processes dynamic sensory information.
Integrated single-cell transcriptomic and epigenetic analyses of cell-state transition and lineage commitment in the embryonic mouse cerebellum
Authors: Khouri-Farah Nagham , Guo Qiuxia , Morgan Kerry , Shin Jihye , Li James Y.H. 
Published: August 2021

ABSTRACTRecent studies using single-cell RNA-seq have revealed cellular heterogeneity in the developing mammalian cerebellum, yet the regulatory logic underlying this cellular diversity remains to be elucidated. Using integrated single-cell RNA and ATAC analyses, we resolved developmental trajectories of cerebellar progenitors and identified putative trans- and cis- elements that control cell state transition. We reverse-engineered gene regulatory networks (GRNs) of each cerebellar cell type. Through in silico simulations and in vivo experiments, we validated the efficacy of GRN analyses and uncovered the molecular control of a newly identified stem zone, the posterior transitory zone (PTZ), which contains multipotent progenitors for granule neurons, Bergmann glia, and choroid plexus epithelium. Importantly, we showed that perturbing cell fate specification of PTZ progenitors causes posterior cerebellar vermis hypoplasia, the most common cerebellar birth defect in humans. Our study provides a foundation for comprehensive studies of developmental programs of the mammalian cerebellum.
The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen
Authors: Malta Tathiane M , Sabedot Thais S , Datta Indrani , Garofano Luciano , Vallentgoed Wies , Varn Frederick S , Aldape Kenneth , D’Angelo Fulvio , Bakas Spyridon , Barnholtz-Sloan Jill S , Gan Hui K , Hasanain Mohammad , Hau Ann-Christin , Johnson Kevin C , Khasraw Mustafa , Kocakavuk Emre , Kouwenhoven Mathilde CM , Migliozzi Simona , Niclou Simone P , Niers Johanna M , Ormond D. Ryan , Paek Sun Ha , Reifenberger Guido , Sillevis Smitt Peter A , Smits Marion , Stead Lucy F , van den Bent Martin J , Van Meir Erwin G , Walenkamp Annemiek , Weiss Tobias , Weller Michael , Westerman Bart A , Ylstra Bauke , Wesseling Pieter , Lasorella Anna , French Pim J , Poisson Laila M ,   The GLASS Consortium, Verhaak Roel GW , Iavarone Antonio , Noushmehr Houtan 
Published: August 2021

SummaryTumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a longitudinally stable epigenome with relatively low levels of global methylation, whereas the epigenome of IDHmut gliomas showed initial high levels genome-wide of DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. By integrating DNA methylation and gene expression data, adaptive changes of putative master regulators of the cell cycle and of differentiation were seen in IDHmut recurrent tumors. Furthermore, relapses of IDHmut tumors were accompanied by histological progression which in turn influenced survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment differed between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment for IDHmut gliomas. Our study provides one of the largest cohorts of paired glioma samples profiled with epigenomics, transcriptomics and genomics; and our results demonstrate that the treatment of IDHmut gliomas reshapes the epigenome towards an IDHwt-like phenotype. Accordingly, the prevalent practice of early genotoxic treatment in this patient population may need to be revisited.
Single-molecule simultaneous profiling of DNA methylation and DNA-protein interactions with Nanopore-DamID
Authors: Cheetham Seth W. , Jafrani Yohaann M. A. , Andersen Stacey B. , Jansz Natasha , Kindlova Michaela , Ewing Adam D. , Faulkner Geoffrey J. 
Published: August 2021

AbstractWe present Nanopore-DamID, a method to simultaneously detect cytosine methylation and DNA-protein interactions from single molecules, via selective sequencing of adenine-labelled DNA. Assaying LaminB1 and CTCF binding with Nanopore-DamID, we identify escape from LAD-associated repression of hypomethylated promoters amidst generalised hypermethylation of LaminB1-associated regulatory elements. We detect novel CTCF binding sites in highly repetitive regions, and allele-specific CTCF binding to imprinted genes and the active X chromosome. Nanopore-DamID highlights the importance of DNA methylation to transcription factor activity.
The COVID-19 Pandemic and Early Child Cognitive Development: A Comparison of Development in Children Born During the Pandemic and Historical References
Authors: Deoni Sean CL , Beauchemin Jennifer , Volpe Alexandra , D’Sa Viren ,   the RESONANCE Consortium
Published: August 2021

ABSTRACTObjectiveTo characterize cognitive function in young children under 3 years of age over the past decade, and test whether children exhibit different cognitive development profiles through the COVID-19 pandemic.Study DesignNeurocognitive data (Mullen Scales of Early Learning, MSEL) were drawn from 700 healthy and neurotypically developing children between 2011 to 2021 without reported positive tests or clinical diagnosis of SARS-CoV-2 infection. We compared MSEL composite measures (general cognition, verbal, and non-verbal development) to test if those measured during 2020 and 2021 differed significantly from historical 2011-2019 values. We also compared MSEL values in a sub-cohort comprising infants 0-16 months of age born during the pandemic vs. infants born prior. In all analyses, we also included measures of socioeconomic status, birth outcome history, and maternal stress.ResultsA significant decrease in mean population MSEL measures was observed in 2021 compared to historical references. Infants born during the pandemic exhibited significantly reduced verbal, non-verbal, and overall cognitive performance compared to children born pre-pandemic. Maternal stress was not found to be associated with observed declines but a higher socioeconomic status was found to be protective.ConclusionsResults reveal a striking decline in cognitive performance since the onset of the COVID-19 pandemic with infants born since mid-2020 showing an average decrease of 27-37 points. Further work is merited to understand the underlying causative factors.
COVID-19 vaccine acceptance among healthcare workers in India: Results from a cross-sectional survey
Authors: Mehta Kayur , Dhaliwal Baldeep K. , Zodpey Sanjay , Loisate Stacie , Banerjee Preetika , Gupta Madhu , Shet Anita 
Published: August 2021

AbstractBackgroundRemarkable scientific progress has enabled expeditious development of effective vaccines against COVID-19. While healthcare workers (HCWs) have been at the frontlines for the pandemic response, vaccine acceptance amongst them needs further study.MethodsA web-based survey to assess vaccine acceptance and preparedness in India was disseminated to HCWs working in various settings between January and February 2021, shortly after the launch of India’s vaccination campaign. Descriptive statistics were used to examine respondent demographics and Likert scale responses. Binomial logistic regression analyses were used to identify factors associated with vaccine acceptance.ResultsThe survey yielded 624 respondents from 25 states and five union territories in India; 53.5% were male, and median age was 37 years (IQR 32-46). Amongst all respondents, 84.1% (525/624) supported COVID-19 vaccines, and 63.2% (141/223) of those unvaccinated at the time of survey administration were willing to accept a vaccine. Reliability on government sources, healthcare providers or scientific journal articles for COVID-19 related information was reported by 66.8%, while confidence in social media for this information was reported by only 4.5%. Factors independently associated with vaccine acceptance included advancing age (aOR 3.50 [95% CI, 1.04-11.76] for those above 45 years), evidence of vaccine effectiveness and safety (aOR 3.78 [95% CI 1.15-12.38]), and provision of free/no-cost vaccine (aOR 2.63 [95% CI, 1.06-6.50]). Most respondents (80%) were confident about their hospital being equipped to efficiently rollout COVID-19 vaccines to the general population.ConclusionsOverall attitudes towards COVID-19 vaccination and preparedness were positive among HCWs in India, although acceptance was lower among healthier and younger HCWs. Data availability on vaccine safety and effectiveness, and cost considerations were important for acceptance. Targeted interventions are needed to improve vaccine acceptance amongst HCWs, since they are critical in promoting vaccine acceptance amongst the general population.
HDAC9structural variants disruptingTWIST1transcriptional regulation lead to craniofacial and limb malformations
Authors: Hirsch Naama , Dahan Idit , D’haene Eva , Avni Matan , Vergult Sarah , Vidal-García Marta , Magini Pamela , Graziano Claudio , Severi Giulia , Bonora Elena , Nardone Anna Maria , Brancati Francesco , Fernández-Jaén Alberto , Rory Olson J. , Hallgrimsson Benedikt , Birnbaum Ramon Y. 
Published: August 2021

AbstractStructural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the Histone deacetylase 9 (HDAC9) protein-coding sequence are associated with disruption ofTWIST1regulatory elements that reside withinHDAC9sequence. Based on SVs within theHDAC9-TWIST1locus, we defined the 3’ HDAC9 sequence (~500Kb) as a criticalTWIST1regulatory region, encompassing craniofacialTWIST1enhancers and CTCF sites. Deletions of eitherTwist1enhancers (eTw5-7Δ/Δ) or Ctcf site (CtcfΔ/Δ) within the Hdac9 protein-coding sequence in mice led to decreasedTwist1expression and altered anterior\posterior limb expression patterns of Shh pathway genes. This decreased Twist1 expression results in a smaller sized and asymmetric skull and polydactyly that resemblesTwist1+/-mouse phenotype. Chromatin conformation analysis revealed thatthe Twist1promoter region interacts withHdac9sequences that encompassTwist1enhancers and a Ctcf site and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entireHdac9sequence (Hdac9INV/+) in mice that does not disruptHdac9expression but repositionsTwist1regulatory elements showed decreasedTwist1expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidated essential components ofTWIST1transcriptional machinery that reside within theHDAC9sequence, suggesting that SVs, encompassing protein-coding sequence, such asHDAC9, could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene, such asTWIST1.
An ultrapotent neutralizing bispecific antibody with broad spectrum against SARS-CoV-2 variants
Authors: Zhang Hui , Huang Haohui , Li Rong , Zhang Lu , Wang Zhiwei , Li Jiaping , Chen Junyou , Su Huafei , Zheng Dandan , Su Ziqi , Wang Li , Deng Chunping , Pei shujun , Zhu Shenghua , Li Chan , Yuan Yaochang , Yue Haitao , Wang Yanqun , Li Xiaobo , Liu Cuihua , Yu Jinchen , Zhang Hui , Li Shengfeng , Huang Xianming 
Published: August 2021

AbstractIn spite of the successful development of effective countermeasures against Covid-19, variants have and will continue to emerge that could compromise the efficacy of currently approved neutralizing antibodies and vaccines. Consequently, novel and more efficacious agents are urgently needed. We have developed a bispecific antibody, 2022, consisting of two antibodies, 2F8 and VHH18. 2F8 was isolated from our proprietary fully synthetic human IDEAL (Intelligently Designed and Engineered Antibody Library)-VH/VL library and VHH18 is a single domain antibody isolated from IDEAL-nanobody library. 2022 was constructed by attaching VHH18 to the C-terminal of Fc of 2F8. 2022 binds two non-overlapping epitopes simultaneously on the RBD of the SARS-CoV-2 spike protein and blocks the binding of RBD to human angiotensin-converting enzyme 2 (ACE2). 2022 potently neutralizes SARS-CoV-2 and all of the variants tested in both pseudovirus and live virus assays, including variants carrying mutations known to resist neutralizing antibodies approved under EUA and that reduce the protection efficiency of current effective vaccines. The half-maximum inhibitory concentration (IC50) of 2022 is 270 pM, 30 pM, 20 pM, and 1 pM, for wild-type, alpha, beta, and delta pseudovirus, respectively. In the live virus assay, 2022 has an IC50 of 26.4 pM, 13.3 pM, and 88.6 pM, for wild-type, beta, and delta live virus, respectively. In a mouse model of SARS-CoV-2, 2022 showed strong prophylactic and therapeutic effects. A single administration of 2022 intranasal (i.n.) or intraperitoneal (i.p.) 24 hours before virus challenge completely protected all mice from bodyweight loss, as compared with up to 20% loss of bodyweight in placebo treated mice. In addition, the lung viral titers were undetectable (FRNT assay) in all mice treated with 2022 either prophylactically or therapeutically, as compared with around 1×105pfu/g lung tissue in placebo treated mice. In summary, bispecific antibody 2022 showed potent binding and neutralizing activity across a variety of SARS-CoV-2 variants and could be an attractive weapon to combat the ongoing waves of the COVID-19 pandemic propagated mainly by variants, especially, the much more contagious delta variant.
Laterally transferred macrophage mitochondria act as a signaling source promoting cancer cell proliferation
Authors: Kidwell Chelsea U. , Casalini Joseph R. , Pradeep Soorya , Scherer Sandra D. , Greiner Daniel , Johnson Jarrod S. , Olson Gregory S. , Rutter Jared , Welm Alana L. , Zangle Thomas A. , Roh-Johnson Minna 
Published: August 2021

AbstractLateral transfer of mitochondria occurs in many physiological and pathological conditions. Given that mitochondria provide essential energy for cellular activities, mitochondrial transfer is currently thought to promote the rescue of damaged cells. We report that mitochondrial transfer occurs between macrophages and breast cancer cells, leading to increased cancer cell proliferation. Unexpectedly, transferred macrophage mitochondria are dysfunctional, lacking mitochondrial membrane potential. Rather than performing essential mitochondrial activities, transferred mitochondria accumulate reactive oxygen species which activates ERK signaling, indicating that transferred mitochondria act as a signaling source that promotes cancer cell proliferation. We also demonstrate that pro-tumorigenic M2-like macrophages exhibit increased mitochondrial transfer to cancer cells. Collectively, our findings reveal how mitochondrial transfer is regulated and leads to sustained functional changes in recipient cells.One-Sentence SummaryLateral transfer of macrophage mitochondria acts as a ROS signaling source, regulating cancer cell proliferation through ERK signaling.
Liver Organoid and T Cell Coculture Models Cytotoxic T Cell Responses against Hepatitis C Virus
Authors: Natarajan Vaishaali , Simoneau Camille R , Erickson Ann L , Meyers Nathan L , Baron Jody L , Cooper Stewart , McDevitt Todd C , Ott Melanie 
Published: August 2021

AbstractHepatitis C virus (HCV) remains a global public health challenge with an estimated 71 million people chronically infected, with surges in new cases and no effective vaccine. New methods are needed to study the human immune response to HCV sincein vivoanimal models are limited andin vitrocancer cell models often show dysregulated immune and proliferative responses. Here we developed a CD8+T cell and adult stem cell liver organoid system using a microfluidic chip to coculture 3D human liver organoids embedded in extracellular matrix with HLA-matched primary human T cells in suspension. We then employed automated phase contrast and immunofluorescence imaging to monitor T cell invasion and morphological changes in the liver organoids. This microfluidic coculture system supports targeted killing of liver organoids when pulsed with a peptide specific for HCV nonstructural protein 3 (NS3) (KLVALGINAV) in the presence of patient-derived CD8+T cells specific for KLVALGINAV. This demonstrates the novel potential of the coculture system to molecularly study adaptive immune responses to HCV in anin vitrosetting using primary human cells.
Quality-preserving low-cost probabilistic 3D denoising with applications to Computed Tomography
Authors: Horenko Illia , Pospisil Lukas , Vecchi Edoardo , Albrecht Steffen , Gerber Alexander , Rehbock Beate , Stroh Albrecht , Gerber Susanne 
Published: August 2021

AbstractWe propose a pipeline for a synthetic generation of personalized Computer Tomography (CT) images, with a radiation exposure evaluation and a lifetime attributable risk (LAR) assessment. We perform a patient-specific performance evaluation for a broad range of denoising algorithms (including the most popular Deep Learning denoising approaches, wavelets-based methods, methods based on Mumford-Shah denoising etc.), focusing both on accessing the capability to reduce the patient-specific CT-induced LAR and on computational cost scalability. We introduce a parallel probabilistic Mumford-Shah denoising model (PMS), showing that it markedly-outperforms the compared common denoising methods in denoising quality and cost scaling. In particular, we show that it allows an approximately 22-fold robust patient-specific LAR reduction for infants and a 10-fold LAR reduction for adults. Using a normal laptop the proposed algorithm for PMS allows a cheap and robust (with the Multiscale Structural Similartity index > 90%) denoising of very large 2D videos and 3D images (with over 107voxels) that are subject to ultra-strong Gaussian and various non-Gaussian noises, also for Signal-to-Noise Ratios much below 1.0. The code is provided for open access.One-sentence summaryProbabilisitc formulation of Mumford-Shah principle (PMS) allows a cheap quality-preserving denoising of ultra-noisy 3D images and 2D videos.
Vision-dependent specification of cell types and function in the developing cortex
Authors: Cheng Sarah , Butrus Salwan , Tan Liming , Xu Vincent , Sagireddy Srikant , Trachtenberg Joshua T. , Shekhar Karthik , Zipursky S. Lawrence 
Published: August 2021

ABSTRACTThe role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA-sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. Vision-dependent regulation of one of these genes, encoding the inhibitory synaptic cell adhesion molecule IGSF9b, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell type-specific gene expression programs.
Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics
Authors: Tsai Kaitlyn , Stojković Vanja , Lee D. John , Young Iris D. , Szal Teresa , Vazquez-Laslop Nora , Mankin Alexander S. , Fraser James S. , Fujimori Danica Galonić 
Published: August 2021

ABSTRACTThe antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. In this study, we determined that the second-generation oxazolidinone radezolid also induces stalling with alanine at the penultimate position. However, the molecular basis for context-specificity of these inhibitors has not been elucidated. In this study, we determined high-resolution cryo-EM structures of both linezolid and radezolid-stalled ribosome complexes. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling by forcing the antibiotic to adopt a conformation that narrows the hydrophobic alanine pocket. Together, the structural and biochemical findings presented in this work provide molecular understanding of context-specific inhibition of translation by clinically important oxazolidinone antibiotics.