bluuebunny/crossref_metadata_2025 huggingface dataset:
A triple distinction of cerebellar function for oculomotor learning and fatigue compensation
Authors: Masselink Jana , Cheviet Alexis , Pélisson Denis , Lappe Markus
Published: June 2022

The cerebellum implements error-based motor learning via synaptic gain adaptation of an inverse model, i.e. the mapping of a spatial movement goal onto a motor command. Recently, we modeled the motor and perceptual changes during learning of saccadic eye movements, showing that learning is actually a threefold process. Besides motor recalibration of the inverse model (1), learning also comprises perceptual recalibration of the visuospatial target map (2) and of a forward dynamics model that estimates the saccade size from corollary discharge (3). Yet, the site of perceptual recalibration remains unclear. Here we dissociate cerebellar contributions to the three stages of learning by modeling the learning data of eight cerebellar patients and eight healthy controls. Results showed that cerebellar pathology restrains short-term recalibration of the visuospatial target map and of the inverse model while the forward dynamics model is well informed about the reduced saccade change. Moreover, patients showed uncompensated oculomotor fatigue caused by insufficient upregulation of saccade duration. According to our model, this could induce long-term perceptual compensation, consistent with the overestimation of target eccentricity found in the patients’ baseline data. We conclude that the cerebellum mediates short-term adaptation of the visuospatial target map and of the inverse model, especially by control of saccade duration. The forward dynamics model was not affected by cerebellar pathology.

Author Summary

Achieving a fine-grained understanding of how the cerebellum continuously recalibrates our movements is an ongoing challenge in sensorimotor neuroscience. Recently, we showed that recalibration of saccadic eye movements does not only operate in motor space, i.e. by adjusting the motor command, but also in external and internal visual space, i.e. by adjusting the spatial representation of the target and the internal saccade size. For this purpose, (1) we developed a paradigm that allowed us to monitor changes of the internal saccade size estimated from trans-saccadic target localizations, and (2) we unified the three learning processes in one computational modeling framework. Here we apply this approach to the saccade learning data of patients with a neurodegenerative cerebellar disease. First, we dissociate the cerebellar role in recalibration of these three sites of learning. Second, we show how learning is transposed to saccade kinematics. Third, we provide first insights into the perceptual consequences of cerebellar pathology that, according to our model, may be a mechanism to recover from disease-specific motor deficits. Our modeling framework may help to dissociate the contribution of specific sensorimotor areas to adaptive behavior as well as to improve the understanding of learning deficits and compensatory strategies in the clinical context.
Sphingolipids protect ergosterol in theLeishmania majormembrane from sterol-specific toxins
Authors: Haram Chaitanya S. , Moitra Samrat , Keane Rilee , Matthew Kuhlmann F. , Frankfater Cheryl , Hsu Fong-Fu , Beverley Stephen M. , Zhang Kai , Keyel Peter A.
Published: June 2022

Susceptibility ofLeishmaniato the first line treatment amphotericin B remains poorly understood. Amphotericin B targets ergosterol, so one approach to improving drug efficacy and reducing side effects could be improving access to ergosterol. While the surface exposure of ergosterol inLeishmaniais unknown, sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids. Here, we tested the ability of theLeishmania majorsphingolipids inositol phosphorylceramide (IPC), and ceramide to shelter ergosterol by preventing binding and cytotoxicity of the sterol-specific toxins streptolysin O and perfringolysin O using flow cytometry. In contrast to mammalian systems,Leishmaniasphingolipids did not preclude toxin binding to sterols in the membrane. However, IPC interfered with cytotoxicity. Ceramide reduced perfringolysin O, but not streptolysin O, cytotoxicity in cells. Ceramide sensing was controlled by the toxin L3 loop. Ceramide was sufficient to protectL. majorpromastigotes from amphotericin B. We propose a mechanism whereby pore-forming toxins engage additional lipids like ceramide to determine the optimal environment to sustain pore formation. Thus,L.majoroffers a genetically tractable model organism for understanding toxin-membrane interactions. Furthermore, our findings suggest targeting ceramide may enhance the efficacy of ergosterol-targeting anti-leishmanial drugs.

Abstract Importance

Leishmaniasis is a neglected tropical disease with ∼1.5-2 million new cases and ∼70,000 deaths annually. One first-line treatment for leishmaniasis is liposomal amphotericin B, which is expensive and damages the kidneys. Cost and side effects can be minimized by improving efficacy. To improve efficacy, we must learn how amphotericin’s target—ergosterol—is protected by other components ofLeishmania. The human ergosterol equivalent is protected by components called sphingolipids. We tested the ability of sphingolipids to protect ergosterol using pore-forming toxins. Pore-forming toxins use ergosterol to bind and killLeishmania. Unlike human cells, toxins bound to ergosterol—indicating that they had access—when sphingolipids were present. However, sphingolipids protectedLeishmaniafrom toxins and amphotericin. Thus,Leishmaniaorganizes sterol-protective components differently from humans. Further, toxins andLeishmaniaserve as a system to understand fundamental rules governing sterol-protecting component membrane organization. We can use this information to help improve drugs targeting sterols.
Skin-resident immune cells engulf axonal debris in adult epidermis
Authors: Peterman Eric , Quitevis Elgene , Horton Emma C. , Aelmore Rune L. , White Ethan , Sagasti Alvaro , Rasmussen Jeffrey P.
Published: June 2022

Somatosensory neurons extend enormous peripheral axons to the skin, where they detect diverse environmental stimuli. Somatosensory peripheral axons are easily damaged due to their small caliber and superficial location. Axonal damage results in Wallerian degeneration, creating vast quantities of cellular debris that phagocytes must remove to maintain organ homeostasis. The cellular mechanisms that ensure efficient clearance of axon debris from stratified adult skin are unknown. Here, we establish zebrafish scales as a tractable model to study axon degeneration in the adult epidermis. Using this system, we demonstrate that skin-resident immune cells known as Langerhans cells engulf the majority of axon debris. In contrast to immature skin, adult keratinocytes do not significantly contribute to debris removal, even in animals lacking Langerhans cells. Our study establishes a powerful new model for studying Wallerian degeneration and identifies a new function for Langerhans cells in maintenance of adult skin homeostasis following injury. These findings have important implications for pathologies that trigger somatosensory axon degeneration.
The Caenorhabditis elegans centrosome is surrounded by a membrane reticulum, the centriculum, that affects centrosome size and function
Authors: Maheshwari Richa , Rahman Mohammad M. , Drey Seth , Onyundo Megan , Fabig Gunar , Martinez Michael A. Q. , Matus David Q. , Müller-Reichert Thomas , Cohen-Fix Orna
Published: June 2022

Centrosomes are membraneless organelles that nucleate microtubules. At their core is a pair of centrioles that recruit pericentriolar material (PCM), a phase-separated condensate. In many cell types, including human cells, centrosomes are surrounded by endoplasmic reticulum-derived membranes of unknown structure and function. Using volume electron microscopy, we show that the C. elegans centrosome is surrounded by a membrane reticulum that we call the centriculum, for centrosome-associated membrane reticulum. Increasing centriculum size by genetic means led to expansion of the PCM and increased microtubule nucleation capacity, an unexpected finding given that the PCM is a membraneless condensate. We provide evidence that the centriculum serves as a microtubule “filter” by limiting the number of microtubules that can elongate fully. We also show the centriculum fuses with the nuclear envelope during mitosis. We propose that this fusion contributes to nuclear envelope breakdown by transducing forces from the elongating spindle to the nuclear membranes.
Constitutive Inhibition of Transient Receptor Potential Canonical Type 6 (TRPC6) by O-GlcNAcylation at Threonine-221
Authors: Mishra Sumita , Ma Junfeng , Sasaki Masayuki , Farinelli Federica , Page Richard C. , Ranek Mark J. , Zachara Natasha , Kass David A
Published: June 2022

Transient receptor potential canonical type 6 (TRPC6) is a non-voltage gated cation channel that principally conducts calcium to regulate signaling in cardiac, vascular, neuronal and other cells. Abnormally increased TRPC6 expression/conductance and genetic gain of function mutations contribute to fibrosis, hypertrophy, proteinuria, and edema, notably linked to its stimulation of nuclear factor of activated T-cells (NFAT) signaling. Hyperglycemia (HG) also activates TRPC6/NFAT as a cause of diabetic renal disease. While prior work linked HG-TRPC6 activation to oxidant stress, the role of another major HG modification - O-GlcNAcylation, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated, TRPC6 and O-GlcNAc transferase proteins interact, this modification potently suppresses basal channel conductance and NFAT activity, and it is unaltered by HG. Proteomics identifies O-GlcNAcylation at Ser14, Thr70, and Thr221 in the N-terminus ankyrin-4 (AR4) and neighboring linker (LH1) domains of TRPC6. Of these, T221 is most impactful as a T221A mutation increases basal NFAT activity 11-fold, TRPC6 conductance 75-80% vs wild-type, and when expressed in cardiomyocytes amplifies NFAT-pro-hypertrophic gene expression. T221 is highly conserved and mutating homologs in TRPC3 and TRPC7 also markedly elevates basal NFAT activity. Molecular models predict electrostatic interactions between T221 O-GlcNAc and Ser199, Glu200, and Glu246, and we find similarly elevated NFAT activity from alanine substitutions at these coordinating sites as well. Thus, O-GlcNAcylation at T221 and its interaction with coordinating residues in AR4-LH1 is required for basal TRPC6 channel conductance and regulation of NFAT.
Effect of Hypokalemia on Screening for Primary Aldosteronism
Authors: Rizer Nicholas W , Ding Xiruo , Cohen Debbie L , Herman Daniel S
Published: June 2022

Context

Primary aldosteronism (PA) is a common, underdiagnosed, and treatable cause of hypertension. Guidelines recommend testing for hypokalemia, but current practices and their impact are unknown.

Objective

To estimate the impact of hypokalemia on the results of PA screening in clinical practice.

Methods

We studied electronic health records for adults who received longitudinal care within a large, integrated health system between 2007 and 2017 and underwent paired blood aldosterone and renin testing. Patients were grouped based on concurrent blood potassium concentrations.

Results

We found that 2,940 (82%) of the 3,571 patients screened for PA had concurrent potassium testing. Among all patients with a negative PA screen, 18% of patients did not have concurrent potassium testing and 14% of those tested were hypokalemic. Of the screen-negative hypokalemic patients, 77% were not retested. Among patients with repeated screens, we found that initial potassium concentration was a predictor of PA screen positivity on repeat. A one standard deviation lower initial potassium concentration was associated with a 74% higher odds of screen positivity on repeat, independent of initial aldosterone and renin results.

Conclusions

In-practice clinical data demonstrate that unrecognized and uncorrected hypokalemia contributes to the underdiagnosis of PA. Universal potassium testing and rescreening for PA in the setting of hypokalemia would likely substantially improve the identification and thereby management of PA.
Use of Internally Validated Machine and Deep Learning Models to Predict Outcomes of Percutaneous Nephrolithotomy using data from the BAUS PCNL audit
Authors: Geraghty Robert M , Finch William , Fowler Sarah , Sriprasad Seshadri , Smith Daron , Dickinson Andrew , Gall Zara , Somani Bhaskar K
Published: June 2022

Background

Machine (ML) and Deep learning (DL) are subsets of artificial intelligence that use data to build algorithms. These can be used to predict specific outcomes. To date there have been a few small studies on post-PCNL outcomes.

Objective

We aimed to build and internally validate ML/DL models for post-PCNL transfusion and infection using a comprehensive national database.

Design

Machine Learning study using prospective national database. Eight machine learning models for 11 outcomes using 43 predictors. Models were ‘complete-case’ analyses.

Setting

National database

Participants

Patients undergoing PCNL in the UK between 2014-2019.

Outcome Measurements

Diagnostic accuracy statistics including overall accuracy, area-under-the-curve (AUC), sensitivity and specificity.

Results and Limitations

4412 patients were included, with 3088 in the training set and 1324 in the test set. The models predicted need for transfusion and post-operative infection with a very high degree of accuracy (99%) and high AUC (0.99-1.00). Unfortunately, the remainder of the outcomes did not achieve the same high levels. These two outcomes were therefore included in the provisional web-based application: https://endourology.shinyapps.io/PCNL_Prediction_tool/

Conclusions

This is the largest machine learning study on post-PCNL outcomes to date. These models can predict the need for post-PCNL transfusion and post-PCNL infection at an individual level with excellent accuracy. Further work will be done on model tuning and external validation.

Patient Summary

We used a national database of people having a major kidney stone operation (PCNL). Using this data, we built and tested 8 machine learning models for 11 different outcomes from the operation. Using this method, we can give individual predictions for the likely need for a blood transfusion and development of an infection. We have developed an app to allow surgeons to calculate an individual patient’s risk prior to surgery.
DNA methylation analysis of archival lymphoreticular tissues in Creutzfeldt-Jakob disease and the prevalence of vCJD infection in the UK
Authors: Guntoro Fernando , Viré Emmanuelle , Giordani Chiara , Darwent Lee , Hummerich Holger , Linehan Jacqueline , Sinka Katy , Jaunmuktane Zane , Brandner Sebastian , Collinge John , Mead Simon
Published: June 2022

The exposure of the UK and other European populations to bovine spongiform encephalopathy (BSE) prions caused human variant Creutzfeldt-Jakob Disease (vCJD) and a prolonged public health crisis. Throughout, a key question has been the prevalence of vCJD prion infection in the UK population. vCJD has several distinct features including immunohistochemically detectable abnormal prion protein (PrP) in peripheral lymphoreticular system tissues (LRS eg. tonsil, appendix). Surveys have detected abnormal PrP in the LRS of the UK population, but it remains unclear if these represent carriers of vCJD infection, some other form of prion infection, or another phenomenon altogether. Concern about the infectiousness of these possible carriers has been used to justify precautionary, expensive and ongoing health protection measures. Archival appendix samples are formalin fixed and paraffin embedded, a process that makes conventional assays of prion infection challenging. Here, we sought to use methylation array technology that assays >850,000 sites where chemically stable DNA modification occurs to develop a computational method to classify tissue samples by prion disease status. We assembled nearly 450 lymphoreticular tissue samples from patients with different prion diseases following biopsy or autopsy, and non-prion disease patients following tonsillectomy and appendicectomy, either frozen or processed as formalin fixed or formalin fixed paraffin embedded. DNA was extracted, bisulphite converted and assayed using Illumina Infinium Methylation EPIC (850K) BeadChips. Data were normalised and filtered, then analysed by case-control study, t-distributed stochastic neighbour embedding plots, and random forest classification methods. We show substantial differences in DNA methylation between prion diseases cases and controls, which can be exploited to classify LRS samples with reasonable levels of accuracy (82-97%). Archival appendix samples with abnormal PrP were most similar to, and classified with, control appendix samples, rather than prion disease samples; several interpretations are compatible with these findings.
The timid invasion
Authors: Eccard Jana A. , Mazza Valeria , Holland Celia , Stuart Peter
Published: June 2022

In biological invasion processes animal behavior moderates the success of invasive species, and the native fauna’s ability to adapt. The importance of behavioral syndromes and flexibility of invading species for invasion success remains debated. We investigated behavior of rodents, the bank vole (Myodes glareolus) currently invading Ireland, and the native wood mouse (Apodemus sylvaticus) that declines with vole invasion, at replicated sites at pre-invasion, edge, and source of the invasion. We found that individual rodents varied consistently in risk-taking behaviors, and mice had not adapted to the presence of invasive voles. Voles at the invasion edge were more careful but also more flexible compared to voles the invasion source. The ability to develop timid and flexible phenotypes may contribute to the invasion success of rodents worldwide.
Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model
Authors: Martin-Flores Nuria , Podpolny Marina , McLeod Faye , Workman Isaac , Crawford Karen , Ivanov Dobril , Leonenko Ganna , Escott-Price Valentina , Salinas Patricia C.
Published: June 2022

Increasing evidence supports a role for deficient Wnt signaling in Alzheimer’s disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPPNL-G-F/NL-G-FAD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3β signaling with a concomitant increase in inhibitory synapses signaling via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.
FtsZ phosphorylation brings about growth arrest upon DNA damage in Deinococcus radiodurans
Authors: Chaudhary Reema , Mishra Shruti , Maurya Ganesh Kumar , Misra Hari S
Published: June 2022

The polymerization/depolymerization dynamics of FtsZ plays the pivotal role in cell division in majority bacteria. Deinococcus radiodurans, a radiation resistant bacterium, shows an arrest of growth in response to DNA damage, despite no change in the level of FtsZ. This bacterium does not deploy LexA/RecA type of DNA damage response and cell cycle regulation, and its genome does not encode homologs of E. coli’s SulA, which attenuate FtsZ functions in response to DNA damage in different bacteria. A radiation responsive Ser/Thr quinoprotein kinase (RqkA) characterized for its role in radiation resistance in this bacterium, could phosphorylate several cognate proteins including FtsZ (drFtsZ) at Serine 235 (S235) and Serine 335 (S335) residues. Here, we report the detailed characterization of S235 and S335 phosphorylation effect in the regulation of drFtsZ functions, and demonstrated that the phospho-mimetic replacements of these residues in drFtsZ had grossly affected its functions that could result in cell cycle arrest in response to DNA damage in D. radiodurans. Interestingly, the phospho-ablative replacements were found to be nearly similar to drFtsZ while phospho-mimetic mutant showed the loss of signatures characteristics to wild type enzyme including the arrest in its dynamics under normal conditions. The post-bleaching recovery kinetics for drFtsZ and phospho-mimetic mutant was nearly similar at 2h post irradiation recovery but found to be different under normal conditions. These results highlighted the role of S/T phosphorylation in the regulation of drFtsZ functions and cell cycle arrest in response to DNA damage and is first time demonstrated in this prokaryote.
Bayesian parameter estimation for phosphate dynamics during hemodialysis
Authors: Bangsgaard Katrine O. , Andersen Morten , Heaf James G. , Ottesen Johnny T.
Published: June 2022

Hyperphosphatemia in patients with renal failure is associated with increased vascular calcification and mortality. Hemodialysis is a conventional treatment for patients with hyperphosphatemia. Phosphate kinetics during hemodialysis may be described by a diffusion process and modeled by ordinary differential equations. We propose a Bayesian model approach for estimating patient-specific parameters for phosphate kinetics during hemodialysis. The Bayesian approach allows us to both analyze the full parameter space using uncertainty quantification and to compare two types of hemodialysis treatments, the conventional single-pass and the novel multiple-pass treatment. We validate and test our models on synthetic and real data. The results show limited identifiability of the model parameters when only single-pass data are available, and that the Bayesian model greatly reduces the relative standard deviation compared to existing estimates. Moreover, the analysis of the Bayesian models reveal improved estimates with reduced uncertainty when considering consecutive sessions and multiple-pass treatment compared to single-pass treatment.
Biomolecular Condensate Regulates Enzymatic Activity under Crowded Milieu: Synchronization of Liquid-Liquid Phase separation and Enzymatic Transformation
Authors: Saini Bhawna , Mukherjee Tushar Kanti
Published: June 2022

Cellular crowding plays a key role in regulating the enzymatic reactivity in physiological conditions, which is challenging to realize in the dilute phase. Enzymes drive a wide range of complex metabolic reactions with high efficiency and selectivity under extremely heterogeneous and crowded cellular environments. However, the molecular interpretation behind the enhanced enzymatic reactivity under a crowded milieu is poorly understood. Herein, using horseradish peroxidase (HRP) and glucose oxidase (GOx) cascade pair, we demonstrate for the first time that macromolecular crowding induces liquid-liquid phase separation (LLPS) via the formation of liquid-like condensates/droplets and thereby increases the intrinsic catalytic efficiencies of HRP and GOx. Both these enzymes undergo crowding induced homotypic LLPS via enthalpically driven multivalent electrostatic as well as hydrophobic interactions. Using a set of kinetic and microscopic experiments, we show that precise synchronization of spontaneous LLPS and enzymatic transformations is key to realize the enhanced enzymatic activity under the crowded environments. Our findings reveal an unprecedented enhancement (91–205-fold) in the catalytic efficiency (kcat/Km) of HRP at pH 4.0 within the droplet phase relative to that in the bulk aqueous phase in the presence of different crowders. In addition, we have shown that other enzymes also undergo spontaneous LLPS under macromolecular crowding, signifying the generality of this phenomenon under the crowded environments. More importantly, coalescence driven highly regulated GOx/HRP cascade reactions within the fused droplets have been demonstrated with enhanced activity and specificity under the crowded environments. The present discovery highlights the active role of membraneless condensates in regulating the enzymatic efficacy for complex metabolic reactions under the crowded cellular environments and may find significant importance in the field of biocatalysis.
Development and Evaluation of RT-LAMP Assays to Identify Variants of SARS-CoV-2
Authors: Park Gun-Soo , Kim Seong-Jun , Maeng Jin-Soo
Published: June 2022

Emergence of new variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during current pandemic of Coronavirus Disease 2019 (COVID-19) and several waves of infections by some of variants emphasized the importance of continuous surveillance. While genomic surveillance through whole genome sequencing is performed as a standard method, identification of known variants through mutation-targeting molecular diagnosis such as qRT-PCR is also useful for timely investigation. However, there are limited studies regarding the concurrent detection and identification of SARS-CoV-2 variants through a LAMP-based method. In this study, we developed and evaluated RT-LAMP assays to detect characteristic deletions of SARS-CoV-2 variants. In addition, we evaluated a fluorescent probe mediated method for identification of single nucleotide substitution by RT-LAMP. Finally, we discussed restrictions and perspectives regarding pathogen screening and surveillance of variants by RT-LAMP based on our observations.
Robust phylodynamic analysis of genetic sequencing data from structured populations
Authors: Scire Jérémie , Barido-Sottani Joëlle , Kühnert Denise , Vaughan Timothy G. , Stadler Tanja
Published: June 2022

The multi-type birth-death model with sampling is a phylodynamic model which enables quantification of past population dynamics in structured populations, based on phylogenetic trees. The BEAST 2 package bdmm implements an algorithm for numerically computing the probability density of a phylogenetic tree given the population dynamic parameters under this model. In the initial release of bdmm, analyses were limited computationally to trees consisting of up to approximately 250 genetic samples. We implemented important algorithmic changes to bdmm which dramatically increase the number of genetic samples that can be analyzed, and improve the numerical robustness and efficiency of the calculations. Including more samples leads to improved precision of parameter estimates, particularly for structured models with a high number of inferred parameters. Furthermore, we report on several model extensions to bdmm, inspired by properties common to empirical datasets. We apply this improved algorithm to two partly overlapping datasets of Influenza A virus HA sequences sampled around the world, one with 500 samples, the other with only 175, for comparison. We report and compare the global migration patterns and seasonal dynamics inferred from each dataset. In that way, we show what information is gained by analyzing the bigger dataset which became possible with the presented algorithmic changes to bdmm. In summary, bdmm allows for robust, faster and more general phylodynamic inference of larger datasets.
Dynamics of spike time encoding in the olfactory bulb
Authors: Werth Jesse C. , Einhorn Matthew , Cleland Thomas A.
Published: June 2022

In the mammalian olfactory bulb (OB), gamma oscillations in the local field potential are generated endogenously during odor sampling. Such oscillations arise from dynamical systems that generate organized periodic behavior in neural circuits, and correspond to spike timing constraints at fine timescales. While the cellular and network mechanisms of gamma oscillogenesis in the OB are reasonably well established, it remains unclear how these fine-timescale dynamics serve to represent odors. Are patterns of spike synchrony on the gamma timescale replicable and odor-specific? Does the transformation to a spike-timing metric embed additional computations? To address these questions, we used OB slices to examine the spike timing dynamics evoked by “fictive odorants” generated via spatiotemporally patterned optogenetic stimulation of olfactory sensory neuron axonal arbors. We found that a small proportion of mitral/tufted cells phase-lock strongly to the fast oscillations evoked by fictive odorants, and exhibit tightly coupled spike-spike synchrony on the gamma timescale during this stimulation. Moreover, the specific population of synchronized neurons differed based on the “quality”, but not the “concentration”, of the fictive odorant presented, and was conserved across multiple presentations of the same fictive odorant. Given the established selectivity of piriform cortical pyramidal neurons for inputs synchronized on this timescale, we conclude that spike synchronization on a milliseconds timescale is a metric by which the OB encodes and exports afferent odor information in a concentration-invariant manner. As a corollary, mitral/tufted cell spikes that are not organized in time may not contribute effectively to the ensemble odor representation.
Spectral neural approximations for models of transcriptional dynamics
Authors: Gorin Gennady , Carilli Maria , Chari Tara , Pachter Lior
Published: June 2022

The advent of high-throughput transcriptomics provides an opportunity to advance mechanistic understanding of transcriptional processes and their connections to cellular function at an un-precedented, genome-wide scale. These transcriptional systems, which involve discrete, stochastic events, are naturally modeled using Chemical Master Equations (CMEs), which can be solved for probability distributions to fit biophysical rates that govern system dynamics. While CME models have been used as standards in fluorescence transcriptomics for decades to analyze single species RNA distributions, there are often no closed-form solutions to CMEs that model multiple species, such as nascent and mature RNA transcript counts. This has prevented the application of standard likelihood-based statistical methods for analyzing high-throughput, multi-species transcriptomic datasets using biophysical models. Inspired by recent work in machine learning to learn solutions to complex dynamical systems, we leverage neural networks and statistical understanding of system distributions to produce accurate approximations to a steady-state bivariate distribution for a model of the RNA life-cycle that includes nascent and mature molecules. The steady-state distribution to this simple model has no closed-form solution and requires intensive numerical solving techniques: our approach reduces likelihood evaluation time by several orders of magnitude. We demonstrate two approaches, where solutions are approximated by (1) learning the weights of kernel distributions with constrained parameters, or (2) learning both weights and scaling factors for parameters of kernel distributions. We show that our strategies, denoted by kernel weight regression (KWR) and parameter scaled kernel weight regression (psKWR), respectively, enable broad exploration of parameter space and can be used in existing likelihood frameworks to infer transcriptional burst sizes, RNA splicing rates, and mRNA degradation rates from experimental transcriptomic data.

Statement of significance

The life-cycles of RNA molecules are governed by a set of stochastic events that result in heterogeneous gene expression patterns in genetically identical cells, resulting in the vast diversity of cellular types, responses, and functions. While stochastic models have been used in the field of fluorescence transcriptomics to understand how cells exploit and regulate this inherent randomness, biophysical models have not been widely applied to high-throughput transcriptomic data, as solutions are often intractable and computationally impractical to scale. Our neural approximations of solutions to a two-species transcriptional system enable efficient inference of rates that drive the dynamics of gene expression, thus providing a scalable route to extracting mechanistic information from increasingly available multi-species single-cell transcriptomics data.
Dynamic top-down biasing implements rapid adaptive changes to individual movements
Authors: Tian Lucas Y , Warren Timothy L. , Brainard Michael S.
Published: June 2022

Complex behaviors depend on the coordinated activity of neural ensembles in interconnected brain areas. The behavioral function of such coordination, often measured as co-fluctuations in neural activity across areas, is poorly understood. One hypothesis is that rapidly varying co-fluctuations may be a signature of moment-by-moment task-relevant influences of one area on another. We tested this possibility for error-corrective adaptation of birdsong, a form of motor learning which has been hypothesized to depend on the top-down influence of a higher-order area, LMAN, in shaping moment-by-moment output from a primary motor area, RA. In paired recordings of LMAN and RA in singing birds, we discovered a neural signature of a top-down influence of LMAN on RA, quantified as an LMAN-leading co-fluctuation between these areas. During learning, this cofluctuation strengthened in a premotor temporal window linked to the specific movement, sequential context, and acoustic modification associated with learning. Moreover, transient perturbation of LMAN activity specifically within this premotor window caused rapid occlusion of pitch modifications, consistent with LMAN conveying a temporally localized motor-biasing signal. Combined, our results reveal a dynamic top-down influence of LMAN on RA that varies on the rapid timescale of individual movements and is flexibly linked to contexts associated with learning. This finding indicates that inter-area co-fluctuations can be a signature of dynamic top-down influences that support complex behavior and its adaptation.
Leptospira enrichment culture followed by ONT Nanopore sequencing allows better detection of Leptospira presence and diversity in water and soil samples
Authors: Gorman Myranda , Xu Ruijie , Prakoso Dhani , Salvador Liliana C.M. , Rajeev Sreekumari
Published: June 2022

Background

Leptospirosis, a life-threatening disease in humans and animals, is one of the most widespread global zoonosis. Contaminated soil and water are the major transmission sources in humans and animals. Clusters of disease outbreaks are common during rainy seasons.

Methodology/Principal Findings

In this study, to detect the presence of Leptospira, we applied PCR, direct metagenomic sequencing, and enrichment culture followed by metagenomic sequencing on water and soil samples. Direct sequencing and enrichment cultures followed by PCR or sequencing effectively detected pathogenic and nonpathogenic Leptospira compared to direct PCR and 16S amplification-based metagenomic sequencing in soil or water samples. Among multiple culture media evaluated, Ellinghausen-McCullough-Johnson-Harris (EMJH) media containing antimicrobial agents was superior in recovering and detecting Leptospira from the environmental samples. Our results show that enrichment culture followed by PCR can be used to confirm the presence of pathogenic Leptospira in environmental samples. Metagenomic sequencing on enrichment cultures effectively detects the abundance and diversity of Leptospira spp from environmental samples.

Conclusions/Significance

The selection of methodology is critical when testing environmental samples for the presence of Leptospira. Selective enrichment culture improves Leptospira detection efficacy by PCR or metagenomic sequencing and can be used successfully to understand the presence and diversity of pathogenic Leptospira during environmental surveillance.

Author Summary

Leptospirosis, a life-threatening disease in humans and animals, is one of the most widespread global zoonosis. Contaminated soil and water are major sources of transmission in humans and animals. For this reason, clusters of disease outbreaks are common during the rainy season. In this study, Leptospira enrichment cultures followed by PCR and sequencing detected pathogenic and nonpathogenic Leptospira in soil and water samples. The pathogenic and intermediate groups of Leptospira were more prevalent in soil samples tested. Metagenomic sequencing on enrichment culture is effective in detecting the abundance and diversity of various Leptospira spp. in environmental samples. Soil samples in proximity to water may be an ideal niche for Leptospira growth and survival and may be an appropriate sample of choice for testing.
Bystander memory-phenotype conventional CD4+T cells exacerbating autoimmune neuroinflammation
Authors: Cho Min-Zi , Lee Hong-Gyun , Yoon Jae-Won , Kim Gil-Ran , Koo Ja-Hyun , Taneja Reshma , Edelson Brian T. , Lee You Jeong , Choi Je-Min
Published: June 2022

Memory-phenotype (MP) CD4+T cells are a substantial population of conventional T cells that exist in steady-state mice, and their immunologic functions in autoimmune disease have not yet been studied. In this work, we unveil a unique phenotype of MP CD4+T cells by analyzing single-cell transcriptomics and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+T cells exist regardless of germ and food-antigen which are composed of heterogenous effector subpopulations. Distinct subpopulations of MP CD4+T cells are specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells have TCR-independent effector functions. Especially, CCR6highMP CD4+T cells are major responders to IL-1β and IL-23 without MOG35-55antigen reactivity, which gives them pathogenic-Th17 characteristics and allows them to contribute to autoimmune encephalomyelitis. We identified Bhlhe40 in CCR6highMP CD4+T cells drives the expression of GM-CSF, contributing to CNS pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal heterogeneity of MP CD4+T cells that can contribute to autoimmune neuroinflammation in bystander manner synergistically with antigen-specific T cells.
Tetraaquadodekakis-μ2-chlorido-diiodido-octahedro-hexaniobium(12 Nb—Nb) tetrahydrofuran octasolvate
Authors: Schröder Florian , Köckerling Martin
Published: June 2022

The title compound, [Nb6Cl12I2(H2O)4]·8THF (THF is tetrahydrofuran, C4H8O), comprises an uncharged niobium cluster unit surrounded by THF solvent molecules. The edges of the {Nb6} octahedron are μ
2-coordinated by twelve chlorido ligands. Four in-plane (equatorial plane) aqua ligands and two iodido ligands coordinating above and below the plane are bound at the corners of the {Nb6} atomic octahedron. O—H...O hydrogen bonds are formed between the aqua ligands and the THF solvent molecules; one THF molecule is disordered over two positions with the major component having a site occupancy of 0.64 (2).
Australian parents' and children's food-related interactions during the COVID-19 pandemic
Authors: Nanayakkara Janandani , Boddy Gail , Aydin Gozde , Kombanda Krupa Thammaiah , Larsson Christel , Worsley Anthony , Margerison Claire , Booth Alison O.
Published: June 2022

Purpose

During the COVID-19 pandemic people worldwide in the same household spent more time together and school children engaged in remote learning throughout extended lockdowns and restrictions. The present study aimed to explore parents' perceptions of their involvement and enjoyment in food-related interactions with their children during coronavirus disease 2019 (COVID-19)-associated lockdowns/restrictions and changes in their children's food intake, especially children's lunches during the remote learning period.

Design/methodology/approach

Data from parents (n = 136) were collected via an online survey in 2020. Parents' responses to closed-ended questions were analysed via descriptive statistics and open-ended responses were analysed thematically.

Findings

Most parents (62%) reported that they interacted more with their school-aged (5–17 years) children about food during COVID-19 compared to pre-pandemic times. These interactions included cooking, menu planning, eating, conversations around food, and gardening. Most parents (74%) prepared meals with their children during the pandemic and most of them (89%) reported that they enjoyed it. Most parents (n = 91 out of 121) perceived that their children's lunches during remote learning were different to when attending school in person and these changes included eating hot and home-cooked food and more elaborate meals.

Originality/value

This study sheds important insights into a sample of Australian parents' food-related interactions with their school-aged children during the COVID-19 pandemic and associated lockdowns and parents' observations and perceptions of changes in the children's food intake during the remote learning period.
Do open access journals have a greater citation impact? A study of journals in library and information science
Authors: Khan Daud , Ashar Mohammad , Yuvaraj Mayank
Published: June 2022

Purpose

This study aims to investigate the research and citation impact of open access (OA) journals versus non-OA journals being published in the spectrum of library and information science (LIS) across the world and to further ascertain whether OA journals have greater citation counts than subscription-based journals in LIS discipline.

Design/methodology/approach

A total of 116 LIS journals (58 OA and 58 non-OA) were chosen from Scimago website. After selecting the journals, Publish or Perish software program was used to retrieve the publications and their corresponding academic citations by using International Standard Serial Number of journals from Google Scholar for the period of 2011–2018. The non-parametric Mann–Whitney U-test was applied on various research and citation indicators, namely, citation count, citations per author, citations per paper; g-index, h-index, hI norm and hI annual through SPSS.

Findings

Findings of the study demonstrate that non-OA journals in LIS have a significant citation advantage over OA journals. Moreover, Mann–Whitney U-test analysis rejected all the eight null hypotheses and reveals that non-OA journals in LIS discipline have greater citation counts, citations per author, citations per paper; g-index, h-index, hI norm and hI annual than OA journals.

Originality/value

To the best of the authors’ knowledge, this is the first study that embarks upon a whole-scale investigation of citation impact of OA and non-OA journals in LIS, which has implications for both research and practice. This study would serve as a reference guide to all involved in scholarly communication activities including academic communities, librarians, research funders, publishers and policymakers for publishing research work, grant funding, designing policies and subscriptions.
How does lesson study promote district education reform? – A case study of a district in Shanghai
Authors: An Guiqing , Chen Yanru , Fang Yanping , Liu Jingwen
Published: June 2022

Purpose

Lesson study (LS) is generally regarded as a pathway for teachers' professional development and a method for teachers' instructional research. LS has been regarded as having the potential to drive large-scale reform but little is known about how it does so from a district level. Therefore, this paper aims to reveal how lesson study promote district education reform.

Design/methodology/approach

This study offers an in-depth case study of how District Y of Shanghai, China, took LS as the primary method in promoting its District Project of Building Curriculum Leadership in Schools. By analyzing the key project documents and achievements in project promotion, and interviews with the major Project leaders at District and school levels, this study explored the practice and impact of LS as a tool to promote district reform.

Findings

In the District Project, LS has been a medium to address each individual school's real problems of practice and turn them into reform vision and reform will in alignment with District goals. Five levels of school curriculum texts have been planned, designed, translated, implemented, reflected on, updated and mutually adjusted systematically through LS to ensure consistency in transforming District reform vision into classroom practice. Different models of teaching-research community building were found in sampled project schools and professional expertise was built with district support to promote reform. The curriculum leadership development through LS has shaped reform leader schools and formed a collection of LS exemplars circulated in schools as high-quality curriculum packages, which laid the foundation for district-wide reform.

Originality/value

The innovative practice of LS in China's education reform has expanded its reach from within one classroom to the entire district curriculum system and made it an important tool to drive large-school district-based education reform.
Supply chain transparency for sustainability – an intervention-based research approach
Authors: Adhi Santharm Balakrishnan , Ramanathan Usha
Published: June 2022

Purpose

The COVID-19 pandemic has impacted all manufacturing sectors from basic products to luxury goods including the automobile industry. This has necessitated a new line of research on competency building, transparency, and sustainability in automotive supply chains. In this study, the authors examine the competencies required to improve the automotive supply chain routine operations to address the parts supply crisis from multitier suppliers in the post-COVID-19 environment. The authors also propose a list of competencies required in the automotive supply chains to deploy the transparency for sustainability (TfS) framework on a long-term basis.

Design/methodology/approach

The authors have adapted a cross-case study process using intervention-based research and a design science approach for use in this study and used multiple sources for data collection such as published literature, operational experience, and critical opinions of original equipment manufacturer representatives. The research design includes interviews with global OEMs practitioners as one of the relevant sources of information.

Findings

The impact of the COVID-19 pandemic outbreak on automotive manufacturing operations and global supply chains is unprecedented. The TfS framework cycle has been validated using the real-world semiconductor supply crisis which deals with multitier sustainable supply chain management (MTSSCM), and the authors found that there are competency gaps when compared with existing literature. The list of key competencies identified along with the formulation of design propositions to facilitate both the supply crisis and collaboration among automotive firms to enhance their business performance were also presented.

Research limitations/implications

The COVID-19 pandemic is impacting the automobile sector significantly. This situation has created many opportunities and obstacles, but this paper only considers the automotive semi-conductor shortage situation, which may be resolved in the near future when there are more installed capacities. Therefore, it is unclear whether the proposed responses will result in long-term solutions. Further adjustments may be needed to revisit the TfS framework. The research paper only addresses the automotive side of the current supply crisis, but more sustainability issues may arise in the future, which need to be dealt with separately.

Practical implications

Research findings may prove particularly interesting to global automotive vehicle manufacturers, suppliers and policy makers who are seeking to understand multitier supply networks to resolve the current challenges associated with the post-COVID-19 pandemic situation.

Originality/value

In addition to contributing to developing competency requirements, this study enhances the evolving research stream of MTSSCM by linking it to wider research applications of intervention-based research coupled with design science.