bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empirical evidence of transmission over a school-household network for SARS-CoV-2; exploration of transmission pairs stratified by primary and secondary school
Authors: van Iersel Senna C.J.L. , Backer Jantien A. , van Gaalen Rolina D. , Andeweg Stijn P. , Munday James D. , Wallinga Jacco , van Hoek Albert Jan 
Published: February 2022

AbstractBackgroundChildren play a key role in the transmission of many infectious diseases. They have many of their close social encounters at home or at school. We hypothesized that most of the transmission of respiratory infections among children occur in these two settings and that transmission patterns can be predicted by a bipartite network of schools and households.Aim and methodsTo confirm transmission over a school-household network, SARS-CoV-2 transmission pairs in children aged 4-17 years were analyzed by study year and primary/secondary school. Cases with symptom onset between the 1st of March 2021 and the 4th of April 2021 identified by source and contact-tracing in the Netherlands were included. In this period, primary schools were open and secondary school students attended class at least once per week. Within pairs, spatial distance between the postcodes was calculated as the Euclidean distance.ResultsA total of 4,059 transmission pairs were identified; 51.9% between primary schoolers; 19.6% between primary and secondary schoolers; 28.5% between secondary schoolers. Most (68.5%) of the transmission for children in the same study year occurred at school. In contrast, most of the transmission of children from different study years (64.3%) and most primary-secondary transmission (81.7%) occurred at home. The average spatial distance between infections was 1.2km (median 0.4) for primary school pairs, 1.6km (median 0) for primary-secondary school pairs and 4.1km (median 1.2) for secondary school pairs.ConclusionThe results provide evidence of transmission on a bipartite school-household network. Schools play an important role in transmission within study years, and households play an important role in transmission between study years and between primary and secondary schools. Spatial distance between infections in a transmission pair reflects the smaller school catchment area of primary schools versus secondary schools. Many of these observed patterns likely hold for other respiratory pathogens.
A simple self-decoding model for neural coding
Authors: Bui Thach V. 
Published: February 2022

AbstractNeural coding is an important tool to discover the inner workings of mind. In this work, we propose and consider a simple but novel self-decoding model for neural coding based on the principle that the neuron body represents ongoing stimulus while dendrites are used to store that stimulus as a memory. In particular, suppose t spiking presynaptic neurons transmit any stimulus directly to a population of n postsynaptic neurons, a postsynaptic neuron spikes if it does not connect to an inhibitory presynaptic neuron, and every stimulus is represented by up to d spiking postsynaptic neurons.Our hypothesis is that the brain is organized to functionally satisfy the following six criteria: (i) decoding objective, i.e., there are up to r−1 ≥ 0 additional spiking postsynaptic neurons in response to a stimulus along with the spiking postsynaptic neurons representing the stimulus, (ii) smoothness, i.e., similar stimuli are encoded similarly by the presynaptic neurons, (iii) optimal information transmission, i.e., t is minimized, (iv) optimal energetic cost, i.e., only the t presynaptic neurons and the postsynaptic neurons representing a stimulus spike, (v) low-dimensional representation, i.e., d = o(n), and (vi) sparse coding, i.e., t = o(n).Our finding is that some criteria cause or correlate with others. Let the characteristic set of a postsynaptic neuron be the set of the presynaptic neurons it connects with. We prove that (i) holds if and only if the union of the r characteristic sets of any r postsynaptic neurons is not included in the union of the d characteristic sets of d other postsynaptic neurons. Consequently, (ii) is attained. More importantly, we suggest that the decoding objective (i) and optimal information transmission (iii) play a fundamental role in neural computation, while (v) and (vi) correlate to each other and correlate with (iii) and (iv). We examine our hypothesis by statistically testing functional connectivity network and the presynaptic-postsynaptic connectivity in layer 2 of the medial entorhinal cortex of a rat.
Targeting OLIG2 increases therapeutic responses in SHH medulloblastoma mouse models and patient-derived medulloblastoma organoids
Authors: Li Yuchen , Dismuke Taylor , Lim Chaemin , Bruce Zara C. , Offenhäuser Carolin , Baumgartner Ulrich , Maybury Mellissa , D’Souza Rochelle C. J. , Hassall Timothy , Wainwright Brandon , Stein Gregory , Piper Michael , Johns Terrance G. , Sokolsky-Papkov Marina , Gershon Timothy R. , Day Bryan W. 
Published: February 2022

SUMMARYRecurrence after therapy is the primary life-threatening complication of medulloblastoma. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, OLIG2-expressing tumour stem cells are crucial to recurrence. We investigated the potential of the small-molecule OLIG2 inhibitor CT-179 to decrease recurrence in patient-derived organoids, mice genetically-engineered to develop SHH-driven MB, and mice with MB patient-derived xenograft (PDX) tumours. We found that OLIG2 mRNA significantly correlated with poor survival in patients with SHH-MB, but not other subgroups. CT-179 rapidly downregulated OLIG2 protein in vitro and displayed nanomolar IC50 values. CT-179 arrested MB cells at G2/M, with degradation of cyclin B1 and phospho-CDK1 inducing apoptosis. In vivo CT-179 induced similar cell cycle changes in MBs in Smo-mutant mice and significantly increased mouse survival. In both MB organoids and mouse models, CT-179 combined with radiotherapy showed greater efficacy than either treatment alone. These data highlight the potential for OLIG2-targeted therapy to improve MB outcomes by targeting recurrent disease.
The development of receptive field tuning properties in mouse binocular primary visual cortex
Authors: Tan Liming , Ringach Dario L. , Trachtenberg Joshua T. 
Published: February 2022

AbstractThe mouse primary visual cortex is a model system for understanding the relationship between cortical structure, function, and behavior (Seabrook et al., 2017; Chaplin and Margrie, 2020; Hooks and Chen, 2020; Saleem, 2020; Flossmann and Rochefort, 2021). Binocular neurons in V1 are the cellular basis of binocular vision, which is required for predation (Scholl et al., 2013; Hoy et al., 2016; La Chioma et al., 2020; Berson, 2021; Johnson et al., 2021). The normal development of binocular responses, however, has not been systematically measured. Here, we measure tuning properties of neurons to either eye in awake mice of either sex from eye-opening to the closure of the critical period. At eye-opening, we find an adult-like fraction of neurons responding to the contralateral-eye stimulation, which are selective for orientation and spatial frequency; few neurons respond to ipsilateral eye and their tuning is immature. Fraction of ipsilateral-eye responses increases rapidly in the first few days after eye opening and more slowly thereafter, reaching adult levels by critical period closure. Tuning of these responses improves with a similar time course. The development and tuning of binocular responses parallels that of ipsilateral-eye responses. Four days after eye-opening, monocular neurons respond to a full range of orientations but become more biased to cardinal orientations. Binocular responses, by contrast, lose their cardinal bias with age. Together, these data provide an in-depth accounting of the development of monocular and binocular responses in the binocular region of mouse V1 using a consistent set of visual stimuli and measurements.Significance statementIn this manuscript, we present a full accounting of the emergence and refinement of monocular and binocular receptive field tuning properties of thousands of pyramidal neurons in mouse primary visual cortex. Our data reveal new features of monocular and binocular development that revise current models on the emergence of cortical binocularity. Given the recent interest in visually guided behaviors in mice that require binocular vision, e.g. predation, our measures will provide the basis for studies on the emergence of the neural circuitry guiding these behaviors.
SciViewer- An interactive browser for visualizing single cell datasets
Authors: Jain Dhawal , Hayat Sikander , Li Xinkai , Charkaborty Joydeep , Srinivasa Pooja , Cho Michael H. , Silverman Edwin K. , Moore Hobert , Kramann Rafael , Laux-Biehlmann Alexis 
Published: February 2022

AbstractSingle-cell sequencing improves our ability to understand biological systems at single-cell resolution and can be used to identify novel drug targets and optimal cell-types for target validation. However, tools that can interactively visualize and provide target-centric views of these large datasets are limited. We present SciViewer (Single-cellInteractiveViewer), a novel tool to interactively visualize, annotate and share single-cell datasets. SciViewer allows visualization of cluster, gene and pathway level information such as clustering annotation, differential expression, pathway enrichment, cell-type specificity, cellular composition, normalized gene expression and comparison across datasets. Further, we provide APIs for SciViewer to interact with publicly available pharmacogenomics databases for systematic evaluation of potential novel drug targets. We provide a module for non-programmatic upload of single-cell datasets. SciViewer will be a useful tool for data exploration and target discovery from single-cell datasets. It is available on GitHub (https://github.com/Dhawal-Jain/SciViewer).
A model of functionally buffered deleterious mutations can lead to signatures of positive selection
Authors: Shen Runxi , Wenzel Miwa , Messer Philipp W , Aquadro Charles F. 
Published: February 2022

AbstractSelective pressures on DNA sequences often result in departures from neutral evolution that can be captured by the McDonald-Kreitman (MK) test. However, the nature of such selective forces often remains unknown to experimentalists. Amino acid fixations driven by natural selection in protein coding genes are commonly associated with a genetic arms race or changing biological purposes, leading to proteins with new functionality. Here, we evaluate the expectations of a buffering mechanism driving selective amino acids to fixation, which is motivated by an observed phenotypic rescue of otherwise deleterious nonsynonymous substitutions atbag of marbles(bam) andSex lethal(Sxl). These two important genes inDrosophila melanogasterwere shown to experience strong episodic bursts of natural selection potentially due to infections of the endosymbiotic bacteriaWolbachiaobserved among multipleDrosophilaspecies. Using simulations to implement and evaluate the evolutionary dynamics of aWolbachiabuffering model, we demonstrate that selectively fixed amino acid replacements will occur, but that proportion of adaptive amino acid fixations and the statistical power of the MK test to detect the departure from an equilibrium neutral model are both significantly lower than seen for an arms race/change-in-function model that favors proteins with diversified amino acids.
Utilising TMS-EEG to assess the response to cerebellar-brain inhibition
Authors: Sasaki R , Hand B , Liao WY , Rogasch NC , Fernandez L , Semmler JG , Opie GM 
Published: February 2022

AbstractBackgroundCerebellar-brain inhibition (CBI) is a transcranial magnetic stimulation (TMS) paradigm indexing excitability of cerebellar projections to motor cortex (M1). Stimulation involved with CBI is often considered to be uncomfortable, and alternative ways to index connectivity between cerebellum and the cortex would be valuable. Utilising electroencephalography in conjunction with TMS (combined TMS-EEG) to record the response to CBI has the potential to achieve this, but has not been attempted previously.ObjectiveTo investigate the utility of TMS-EEG for characterising cerebellar-cortical interactions recruited by CBI.MethodsA total of 33 volunteers (25.7 ± 4.9 years, 20 females) participated across three experiments. These investigated EEG responses to CBI induced with a figure-of-eight (F8; experiment 1) or double cone (DC; experiment 2) conditioning coil over cerebellum, in addition to multisensory sham stimulation (experiment 3).ResultsBoth F8 and DC coils suppressed early TMS-evoked EEG potentials (TEPs) produced by TMS to M1 (P < 0.05). Furthermore, the TEP produced by CBI stimulation was related to the motor inhibitory response to CBI recorded in a hand muscle (P < 0.05), but only when using the DC coil. Multisensory sham stimulation failed to modify the M1 TEP.ConclusionsCerebellar conditioning produced changes in the M1 TEP that were not apparent following sham stimulation, and that were related to the motor inhibitory effects of CBI. Our findings therefore suggest it is possible to index the response to CBI using TMS-EEG. In addition, while both F8 and DC coils appear to recruit cerebellar projections, the nature of these may be different.
Targeted transcutaneous cervical spinal cord stimulation promotes upper limb recovery in spinal cord and peripheral nerve injury
Authors: Chandrasekaran Santosh , Bhagat Nikunj A , Ramdeo Richard , Ebrahimi Sadegh , Sharma Pawan D , Stein Adam , Griffin Doug G , Harkema Susan J , Bouton Chad E 
Published: February 2022

AbstractLong-term recovery of limb function is a significant unmet need in people with paralysis. Targeted neuromodulation through epidural stimulation of the spinal cord, when paired with intense physical therapy, has shown promising results towards restoring volitional control of the upper limb in people with tetraplegia. Non-invasive neuromodulation of the cervical spinal cord using transcutaneous spinal cord stimulation (tSCS) has shown similar improvements in upper-limb motor control rehabilitation. However, the potential rehabilitative effects of activating specific cervical spinal segments in a targeted fashion using tSCS has largely remained unexplored. We show in two individuals with SCI that tSCS of the cervical spinal cord resulted in up to 1136% increase in exerted force, with minimal physical therapy. We also show, for the first time, the effectiveness of targeted tSCS in restoring strength (407% increase) and dexterity to the digits in an individual with paralysis of the hand due to a peripheral nerve injury. Furthermore, we believe this is the first study to document a 3-point improvement in sensation in people with SCI or peripheral injury after receiving tSCS. Lastly, participant gains persisted after a one-month period void of stimulation, suggesting tSCS may lead to lasting benefits. Non-invasive targeted spinal cord stimulation shows tremendous promise as a safe and effective therapeutic approach with broad applications.
Risk of Ocular Adverse Events with Taxane Based Chemotherapy
Authors: Sodhi Mohit , Yeung Sonia N. , Maberley David , Mikelberg Frederick , Etminan Mahyar 
Published: February 2022

ABSTRACTOBJECTIVETaxane based chemotherapy agents such as docetaxel and paclitaxel are used for a wide range of cancers. Although much has been published on adverse events related to taxanes, data on ocular outcomes with these very important drugs is scant. We sought to quantify the risk of three ocular adverse events: 1) epiphora, 2) cystoid macular edema (CME) and 3) optic neuropathy with taxane based chemotherapy agents by undertaking a large pharmacoepidemiologic study.DESIGNNew users, retrospective cohort study designSUBJECTS, PARTICIPANTS, CONTROLSWe created a cohort of new users of women matched by age (within one year) on docetaxel or paclitaxel and new users of tamoxifen as controls. Study members were followed to the first incidence of the three outcomes.METHODSDescriptive statistics were used to examine demographics of the exposed and unexposed groups. A Cox model was constructed to compute crude and adjusted hazard ratios. Potential confounders for each outcome were adjusted for.MAIN OUTCOME MEASURESFirst diagnosis of 1) epiphora, 2) cystoid macular edema (CME) or 3) optic neuropathy ascertained using international classification for diseases 9th or 10th division codes.RESULTSFor the epiphora analysis there were 1,824 taxane users (PTX or DTX) and 16,395 tamoxifen users. The crude HR for this association was 7.32 (95%CI: 4.25-16.61) and adjusted HR was 5.15 (95% CI:2.79-9.54). For the CME analysis there were 1,909 taxane user and 16,524 tamoxifen users. The crude HR for CME comparing taxane users to tamoxifen users was 1.37 (95% CI: 0.72-2.60) and adjusted HR was 1.33 (95% CI: 0.70-2.53). For optic neuropathy there were 1,913 taxane users and 16,566 tamoxifen users. The crude HR was 4.43 (95% CI:1.10-17.82) and the adjusted HR was 4.44 (95% CI:1.04-18.87). When we restricted our analysis to only cases of toxic optic neuropathy the aged-matched HR remained elevated (HR=7.24, 95% CI: 1.13-46.36).CONCLUSIONIn a cohort of women who were using taxane chemotherapy agents, there was an elevated risk for epiphora, optic neuropathy and a less precise increase in risk for cystoid macular edema. Ophthalmologists and oncologists should be aware of these adverse events in women with breast cancer who use these drugs.
Relative Virulence of SARS-CoV-2 Among Vaccinated and Unvaccinated Individuals Hospitalized with SARS-CoV-2
Authors: Grima Alicia A. , Murison Kiera R. , Simmons Alison E. , Tuite Ashleigh R. , Fisman David N. 
Published: February 2022

AbstractBackgroundThe rapid development of safe and effective vaccines against the SARS-CoV-2 virus has been a singular scientific achievement. Confounding due to health seeking behaviours and differential testing by vaccination status may bias analyses towards an apparent increase in infection severity following vaccination. We sought to determine whether risks of intensive care unit (ICU) admission and death were diminished significantly by vaccination, even in individuals for whom vaccination failed to prevent hospitalization.MethodsWe used data from Ontario, Canada’s Case and Contact Management database, merged to a provincial vaccination dataset (COVaxON) to create a time-matched cohort of individuals who were hospitalized with SARS-CoV-2 infection. Each vaccinated individual was matched to up to five unvaccinated individuals based on test date of positive SARS-CoV-2 infection. Risk of ICU admission and death were evaluated using multivariable conditional logistic regression. Unmatched exploratory analyses were performed to identify sources of heterogeneity in vaccine effects.ResultsIn 20,064 individuals (3,353 vaccinated and 16,711 unvaccinated) hospitalized with infection due to SARS-CoV-2 between January 1st, 2021 and January 5th, 2022, vaccination with 1, 2, or 3 doses significantly reduced the risk of ICU admission and death. An inverse dose-response relationship was observed between vaccine doses received and both outcomes (adjusted odds ratio (aOR) for ICU admission per additional dose: 0.66, 95% CI 0.62 to 0.71; aOR for death per additional dose: 0.78, 95% CI 0.72 to 0.84). The reduction in risk was greater for ICU admission than for death (P for heterogeneity <0.05), but no significant differences in risk were seen based on infecting variant of concern (VOC).InterpretationWe identified a decrease in the risk of ICU admission and death in vaccinated individuals compared to unvaccinated, time-matched controls, even when vaccines failed to prevent infection sufficiently severe to cause hospitalization. Even with diminished efficacy of vaccines against infection with novel VOCs, vaccines remain an important tool for reduction of ICU admission and mortality.
Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
Authors: Zhang Cheng , Shi Mengnan , Kim Woonghee , Arif Muhammad , Klevstig Martina , Li Xiangyu , Yang Hong , Bayram Cemil , Bolat Ismail , Tozlu Özlem Özdemir , Hacımuftuoglu Ahmet , Yıldırım Serkan , Wei Yongjun , Shi Xiaojing , Nielsen Jens , Turkez Hasan , Uhlen Mathias , Boren Jan , Mardinoglu Adil 
Published: February 2022

AbstractBackground & AimsNon-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the treatment of the disease. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here, the aim is to investigate the effect of PKLR in in vivo model and perform drug repositioning to identify a drug candidate for treatment of NAFLD.MethodsBiopsies from liver, muscle, white adipose tissue and heart were obtained from control and PKLR knockout mice fed with chow and high sucrose diets. Lipidomics as well as transcriptmics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were finally tested in both in vitro and in vivo models to evaluated their toxicity and efficacy.ResultsThe Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drugs were identified as potential inhibitor of PKLR by the drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues.ConclusionIn conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical experiment.
2-Arachodonoylglycerol-mediated endocannabinoid signaling modulates mechanical hypersensitivity associated with alcohol withdrawal in mice
Authors: Morgan Amanda , Adank Danielle , Johnson Keenan , Blunt Emily , Patel Sachin 
Published: February 2022

ABSTRACTAlcohol use disorder (AUDs) commonly co-occurs in patients with chronic pain, and a major barrier to achieving abstinence and preventing relapse is the emergence of hyperalgesia during alcohol withdrawal. Elucidating novel therapeutic approaches to target hyperalgesia associated with alcohol withdrawal could have important implications for the treatment of AUD. Here we examined the role of 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid (eCB) signaling in the regulation of hyperalgesia associated with alcohol withdrawal in mice and tested the hypothesis that pharmacological augmentation of 2-AG signaling could reduce hyperalgesia during withdrawal. After 72 hours of withdrawal from a continuous access two-bottle choice drinking paradigm, male and female mice exhibited increased mechanical but not thermal hypersensitivity, which normalized by 7 days. This effect was reversed by pretreatment with the monoacylglycerol lipase (MAGL) inhibitor JZL184, which elevates levels of 2-AG. The effects of JZL184 were prevented by coadministration of either a CB1 or CB2 antagonist. Inhibition of the 2-AG synthetic enzyme diacylglycerol lipase (DAGL) with DO34 exacerbated mechanical hypersensitivity during alcohol withdrawal, causing an earlier onset and persistent hypersensitivity even one week into withdrawal. Our findings demonstrate the critical role of 2-AG signaling in the bidirectional regulation of mechanical sensitivity during alcohol withdrawal, with enhancement of 2-AG levels reducing sensitivity, and inhibition of 2-AG synthesis exacerbating sensitivity. These data suggest 2-AG augmentation could represent a novel approach to the treatment of alcohol withdrawal-associated hyperalgesia and AUD in patients with comorbid pain disorders.