bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking the rates and mechanisms of canopy damage and recovery following Hurricane Maria using multitemporal lidar data
Authors: Leitold Veronika , Morton Douglas C , Martinuzzi Sebastian , Paynter Ian , Uriarte Maria , Keller Michael , Ferraz António , Cook Bruce D , Corp Lawrence A , González Grizelle
Published: March 2021

Hurricane Maria (Category 4) snapped and uprooted canopy trees, removed large branches, and defoliated vegetation across Puerto Rico. The magnitude of forest damages and the rates and mechanisms of forest recovery following Maria provide important benchmarks for understanding the ecology of extreme events. We used airborne lidar data acquired before (2017) and after Maria (2018, 2020) to quantify landscape-scale changes in forest structure along a 439-ha elevational gradient (100 to 800 m) in the Luquillo Experimental Forest. Damages from Maria were widespread, with 73% of the study area losing ≥1 m in canopy height (mean = −7.1 m). Taller forests at lower elevations suffered more damage than shorter forests above 600 m. Yet only 13% of the study area had canopy heights ≤2 m in 2018, a typical threshold for forest gaps, highlighting the importance of damaged trees and advanced regeneration on post-storm forest structure. Heterogeneous patterns of regrowth and recruitment yielded shorter and more open forests by 2020. Nearly 45% of forests experienced initial height loss (<-1 m, 2017-2018) followed by rapid height gain (>1 m, 2018-2020), whereas 21.6% of forests with initial height losses showed little or no height gain, and 17.8% of forests exhibited no structural changes >|1| m in either period. Canopy layers <10 m accounted for most increases in canopy height and fractional cover between 2018-2020, with gains split evenly between height growth and lateral crown expansion by surviving individuals. These findings benchmark rates of gap formation, crown expansion, and canopy closure following hurricane damage.

MANUSCRIPT HIGHLIGHTS

Hurricane Maria gave forests a haircut by toppling trees and shearing branches.

Regrowth after Maria was patchy, with equal areas of height gain and no change.

3-D measures of forest recovery after hurricanes can improve ecosystem models.
Acute vagus nerve stimulation does not affect liking or wanting ratings of food in healthy participants
Authors: Müller Franziska K. , Teckentrup Vanessa , Kühnel Anne , Ferstl Magdalena , Kroemer Nils B.
Published: March 2021

The vagus nerve plays a vital role in the regulation of food intake and vagal afferent signals may help regulate food cue reactivity by providing negative homeostatic feedback. Despite strong evidence from preclinical studies on vagal afferent “satiety” signals in guiding food intake, evidence from human studies is largely inconclusive to date. Here, we investigated the acute effects of left or right transcutaneous auricular vagus nerve stimulation (taVNS) on subjective ratings of wanting and liking of various food and non-food items in 82 healthy participants (46 women, MBMI= 23.1 kg/m2). In contrast to previous reports in patients with depression, we found moderate to anecdotal evidence supporting the absence of taVNS-induced changes in food ratings. To test whether the absence of taVNS effects on food ratings is due to heterogeneity in the sample, we conducted post hoc subgroup analyses by splitting the data according to stimulation side and sex (between-subject factors) as well as caloric density, perceived healthiness, and flavor (sweet vs. savory) of the food (within-subject factors). This multiverse analysis largely supported the absence of taVNS-induced changes since the strongest subgroup effects provided only anecdotal evidence in favor of taVNS-induced changes. We conclude that acute taVNS only has a marginal effect on subjective ratings of food, suggesting that it is an unlikely mechanism for the reported long-term effects of VNS on body weight. In light of an absence of acute taVNS effects on food craving, our results call for future research on the correspondence between acute and chronic effects of vagal afferent stimulation.
Profiles of expressed mutations in single cells reveal subclonal expansion patterns and therapeutic impact of intratumor heterogeneity
Authors: Mehrabadi Farid Rashidi , Marie Kerrie L. , Pérez-Guijarro Eva , Malikić Salem , Azer Erfan Sadeqi , Yang Howard H. , Kızılkale Can , Gruen Charli , Robinson Welles , Liu Huaitian , Kelly Michael C. , Marcelus Christina , Burkett Sandra , Buluç Aydın , Ergün Funda , Lee Maxwell P. , Merlino Glenn , Day Chi-Ping , Sahinalp S. Cenk
Published: March 2021

Advances in single-cell RNA sequencing (scRNAseq) technologies uncovered an unexpected complexity in tumors, underlining the relevance of intratumor heterogeneity to cancer progression and therapeutic resistance. Heterogeneity in the mutational composition of cancer cells is a result of distinct (sub)clonal expansions, each with a distinct metastatic potential and resistance to specific treatments. Unfortunately, due to their low read coverage per cell, scRNAseq datasets are too sparse and noisy to be used for detecting expressed mutations in single cells. Additionally, the large number of cells and mutations present in typical scRNAseq datasets are too large for available computational tools to, e.g., infer distinct subclones, lineages or trajectories in a tumor. Finally, there are no principled methods to assess distinct subclones inferred through single-cell sequencing data and the genomic alterations that seed and potentially cause them. Here we presentTrisicell, a computational toolkit for scalable mutational intratumor heterogeneity inference and assessment from scRNAseq as well as single-cell genome or exome sequencing data.Trisicellallows reliable identification of distinct clonal lineages of a tumor, offering the ability to focus on the most important subclones and the genomic alterations that are associated with tumor proliferation. We comprehensively assessedTrisicellon a melanoma model by comparing distinct lineages and subclones it identifies on scRNAseq data, to those inferred using matching bulk whole exome (bWES) and transcriptome (bWTS) sequencing data from clonal sublines derived from single cells. Our results demonstrate that distinct lineages and subclones of a tumor can be reliably inferred and evaluated based on mutation calls from scRNAseq data through the use ofTrisicell. Additionally, they reveal a strong correlation between aggressiveness and mutational composition, both across the inferred subclones, and among human melanomas. We also appliedTrisicellto infer and evaluate distinct subclonal expansion patterns of the same mouse melanoma model after treatment with immune checkpoint blockade (ICB). After integratively analyzing our cell-specific mutation calls with their expression profiles, we observed that each subclone with a distinct set of novel somatic mutations is strongly associated with a specific developmental status. Moreover, each subclone had developed a unique ICB-resistance mechanism. These results demonstrate thatTrisicellcan robustly utilize scRNAseq data to delineate intratumor heterogeneity and help understand biological mechanisms underlying tumor progression and resistance to therapy.
Sensorimotor temporal recalibration: the contribution of motor-sensory and inter-sensory components
Authors: Arikan Belkis Ezgi , van Kemenade Bianca M. , Fiehler Katja , Kircher Tilo , Drewing Knut , Straube Benjamin
Published: March 2021

Adaptation to delays between actions and sensory feedback is important for efficiently interacting with our environment. Adaptation may rely on predictions of action-feedback pairing (motor-sensory component), or predictions of tactile-proprioceptive sensation from the action and sensory feedback of the action (inter-sensory component). Reliability of temporal information might differ across sensory feedback modalities (e.g. auditory or visual), influencing adaptation. Here, we investigated the role of motor-sensory and inter-sensory components on sensorimotor temporal recalibration for motor-auditory events (button press-tone) and motor-visual events (button press-Gabor patch). In the adaptation phase of the experiment, the motor action-feedback event pairs were presented with systematic temporal delays (0ms or 150ms). In the subsequent test phase, sensory feedback of the action were presented with variable delays. The participants were then asked whether this delay could be detected. To disentangle motor-sensory from inter-sensory component, we varied movements (active button press or passive depression of button) at adaptation and test. Our results suggest that motor-auditory recalibration is mainly driven by motor-sensory component, whereas motor-visual recalibration is mainly driven by inter-sensory component. Recalibration transferred from vision to audition, but not from audition to vision. These results indicate that motor-sensory and inter-sensory components of recalibration are weighted in a modality-dependent manner.
SBGNview: Data Analysis, Integration and Visualization on All Pathways
Authors: Dong Xiaoxi , Vegesna Kovidh , Brouwer Cory , Luo Weijun
Published: March 2021

Pathway analysis is widely used in genomics and omics research, but the data visualization has been highly limited in function, pathway coverage and data format. Here we develop SBGNview a comprehensive solution to address these needs. By adopting the standard SBGN format, SBGNview greatly extend the coverage of pathway based analysis and data visualization to essentially all major pathway databases beyond KEGG, including 5200 reference pathways and over 3000 species. In addition, SBGNview substantially extends current tools in both design and function, including standard coherent input/output formats, high quality graphics convenient for both computational and manual analysis, and flexible and open-end workflow. In addition to pathway analysis and data visualization, SBGNview provides essential infrastructure for SBGN data manipulation and processing. SBGNview is available online:https://github.com/datapplab/SBGNview.
Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity
Authors: Lemarié Fanny L. , Caron Nicholas S. , Sanders Shaun S. , Schmidt Mandi E. , Nguyen Yen T.N. , Ko Seunghyun , Xu Xiaohong , Pouladi Mahmoud A. , Martin Dale D.O. , Hayden Michael R.
Published: March 2021

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in theHTTgene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulate. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.

Highlights

Palmitoylation of mHTT is reduced in multiple transgenic HD mouse models

HTT palmitoylation decreases with increasing polyQ length in HD patient cells

mHTT-lowering in mouse brains does not rescue aberrant palmitoylation

mHTT palmitoylation in HD patient-derived cells can be rescued via APT inhibition

Promoting palmitoylation reduces mHTT aggregation and cytotoxicityin vitro
Little evidence that Eurasian jays (Garrulus glandarius) protect their caches by responding to cues about a conspecific’s desire and visual perspective
Authors: Amodio Piero , Farrar Benjamin G. , Krupenye Christopher , Ostojić Ljerka , Clayton Nicola S.
Published: March 2021

Corvids appear to be capable of adjusting their behaviour according to another’s perspective, knowledge and desire. For example, Eurasian jays have been found to employ a variety of cache protection strategies to minimise cache loss by responding to cues about the visual perspective or current desire of an observing conspecific. However, it is not known whether these jays (or any other corvid) can integrate multiple cues about different mental states and perform the optimal response accordingly. Across five experiments, we found little evidence that our Eurasian jays responded to either the visual perspective or current desire of another agent. In Experiments 1 and 2 we investigated whether Eurasian jays can limit the risk of cache loss by responding simultaneously to cues about the desire and perspective of a potential conspecific pilferer. Building on established paradigms, we used opaque and clear barriers to manipulate the observer’s visual access to cache locations, and specific satiety to manipulate the observer’s desire towards different types of food. Across both experiments the jays’ caching pattern provided no evidence that they could integrate information about the observer’s desire and perspective. Moreover, the results were also inconsistent with the previously reported effects that jays protect their caches by responding to either the visual access or specific satiety of the observer independently. To gain further insight into these unexpected results, we conducted three more experiments. In Experiments 3 and 4, we attempted to replicate the previous finding that Eurasian jays prefer to cache behind an opaque barrier over a clear barrier when observed by a conspecific than when caching in private. In Experiment 5, we further investigated the previous finding that jays preferentially cache a type of food that had been eaten to satiety by a conspecific over a food that had not been eaten by the conspecific. Experiments 3, 4 and 5 found no significant effects in the direction of the previously reported effects, questioning their robustness. We conclude by discussing the implications of our study for the field of corvid cognition and highlight several key issues that affect the reliability of comparative cognition research.
Sexual antagonism in haplodiploids
Authors: Hitchcock Thomas J. , Gardner Andy , Ross Laura
Published: March 2021

Females and males may face different selection pressures, such that alleles conferring a benefit in one sex may be deleterious in the other. Such sexual antagonism has received a great deal of theoretical and empirical attention, almost all of which has focused on diploids. However, a sizeable minority of animals display an alternative haplodiploid mode of inheritance, encompassing both arrhenotoky, whereby males develop from unfertilized eggs, and paternal genome elimination (PGE), whereby males receive but do not transmit a paternal genome. Alongside unusual genetics, haplodiploids often exhibit social ecologies that modulate the relative value of females and males. Here we develop a series of evolutionary-genetic models of sexual antagonism for haplodiploids, incorporating details of their molecular biology and social ecology. We find that: 1) PGE promotes female-beneficial alleles more than arrhenotoky, and to an extent determined by the timing of elimination – and degree of silencing of – the paternal genome; 2) sib-mating relatively promotes female-beneficial alleles, as do other forms of inbreeding, including limited male-dispersal, oedipal-mating, and the pseudo-hermaphroditism ofIcerya purchasi; 3) resource competition between related females relatively inhibits female-beneficial alleles; and 4) sexual antagonism foments conflicts between parents and offspring, endosymbionts and hosts, and maternal-origin and paternal-origin genes.
Haplotype-aware pantranscriptome analyses using spliced pangenome graphs
Authors: Sibbesen Jonas A. , Eizenga Jordan M. , Novak Adam M. , Sirén Jouni , Chang Xian , Garrison Erik , Paten Benedict
Published: March 2021

Pangenomics is emerging as a powerful computational paradigm in bioinformatics. This field uses population-level genome reference structures, typically consisting of a sequence graph, to mitigate reference bias and facilitate analyses that were challenging with previous reference-based methods. In this work, we extend these methods into transcriptomics to analyze sequencing data using the pantranscriptome: a population-level transcriptomic reference. Our novel toolchain can construct spliced pangenome graphs, map RNA-seq data to these graphs, and perform haplotype-aware expression quantification of transcripts in a pantranscriptome. This workflow improves accuracy over state-of-the-art RNA-seq mapping methods, and it can efficiently quantify haplotype-specific transcript expression without needing to characterize a sample’s haplotypes beforehand.
A rapid, cost efficient and simple method to identify current SARS-CoV-2 variants of concern by Sanger sequencing part of the spike protein gene
Authors: Jørgensen Tue Sparholt , Blin Kai , Kuntke Franziska , Salling Henrik K. , Michaelsen Thomas Y , Albertsen Mads , Larsen Helene
Published: March 2021

In 2020, the novel coronavirus, SARS-CoV-2, caused a pandemic, which is still raging at the time of writing this. Many countries have set up high throughput RT-qPCR based diagnostics for people with COVID-19 symptoms and for the wider population. In addition, with the use of whole genome sequencing (WGS) new lineages of SARS-CoV-2 have been identified that have been associated with increased transmissibility or altered vaccine efficacy, so-called Variants of Concern (VoC). WGS is generally too labor intensive and expensive to be applied to all positive samples from the diagnostic tests, and often has a turnaround time too long to enable VoC focused contact tracing. Here, we propose to use Sanger sequencing for the detection of common variants of concern and key mutations in early 2021, using a single set of the recognized ARTIC Network primers. The proposed setup relies entirely on materials and methods already in use in diagnostic RT-qPCR labs and on existing infrastructure from companies that have specialized in cheap and rapid turnaround Sanger sequencing. In addition, we provide an automated mutation calling software (https://github.com/kblin/covid-spike-classification). We have validated the setup on 195 SARS-CoV-2 positive samples, and we were able to profile >85% of RT-qPCR positive samples, where the last 15% largely stem from samples with low viral count. At approximately 4€ per sample in material cost, with minimal hands-on time, little data handling, and a turnaround time of less than 30 hours, the setup is simple enough to be implemented in any SARS-CoV-2 RT-qPCR diagnostic lab. Our protocol provides results that can be used to focus contact-tracing efforts and it is cheap enough for the tracking and surveillance of all positive samples for emerging variants such as B.1.1.7, B.1.351 and P.1 as of January 2021.
Circulating interleukin-6 levels and incident ischemic stroke: a systematic review and meta-analysis of population-based cohort studies
Authors: Papadopoulos Andreas , Palaiopanos Konstantinos , Björkbacka Harry , Peters Annette , de Lemos James A. , Seshadri Sudha , Dichgans Martin , Georgakis Marios K.
Published: March 2021

Objective

To determine the association between circulating interleukin-6 (IL-6) levels and risk of incident ischemic stroke in the general population.

Methods

Following the PRISMA guidelines, we systematically searched the literature for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effect meta-analyses and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS).

Results

We identified 11 studies (n=27,411 individuals; 2,669 incident stroke cases) meeting our eligibility criteria. Overall, quality of the included studies was high (median 8 out of 9 NOS points). In meta-analyses, 1-standard deviation increment in circulating IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias.

Conclusions

Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.
Clinical Utility of Automatable Prediction Models for Improving Palliative and End-Of-Life Care Outcomes: Towards Routine Decision Analysis Before Implementation
Authors: Taseen Ryeyan , Ethier Jean-François
Published: March 2021

Objective

To evaluate the clinical utility of automatable prediction models for increasing goals-of-care discussions among hospitalized patients at the end-of-life.

Materials and Methods

We developed three Random Forest models and updated the Modified Hospital One-year Mortality Risk model: alternative models to predict one-year mortality (proxy for EOL status) using admission-time data. Admissions from July 2011-2016 were used for training and those from July 2017-2018 were used for temporal validation. We simulated alerts for admissions in the validation cohort and modelled alternative scenarios where alerts lead to code status orders (CSOs) in the EHR. We linked actual CSOs and calculated the expected risk difference (eRD), the number needed to benefit (NNB) and the net benefit (NB) of each model for the patient-centered outcome of a CSO among EOL hospitalizations.

Results

Models had a C-statistic of 0.79-0.86 among unique patients. A CSO was documented during 2599 of 3773 hospitalizations at the EOL (68.9%). At a threshold that identified 10% of eligible admissions, the eRD ranged from 5.4% to 10.7% (NNB 5.4-10.9 alerts). Under usual care, a CSO had a 34% PPV for EOL status. Using this to inform the relative cost of FPs, only two models improved NB over usual care. A RF model with diagnostic predictors had the highest clinical utility by either measure, including in sensitivity analyses.

Discussion

Automatable prediction models with acceptable temporal validity differed meaningfully in their expected ability to improve patient-centered outcomes over usual care.

Conclusion

Decision-analysis should precede implementation of automated prediction models for improving palliative and EOL care outcomes.
An EMG-assisted Muscle-Force Driven Finite Element Analysis Pipeline to Investigate Joint- and Tissue-Level Mechanical Responses in Functional Activities: Towards a Rapid Assessment Toolbox
Authors: Esrafilian A. , Stenroth L. , Mononen M. E. , Vartiainen P. , Tanska P. , Karjalainen P. A. , Suomalainen J. S. , Arokoski J. , Lloyd D. G. , Korhonen R. K.
Published: March 2021

Joint tissue mechanics (e.g., stress and strain) are believed to have a major involvement in the onset and progression of musculoskeletal disorders, e.g., knee osteoarthritis (KOA). Accordingly, considerable efforts have been made to develop musculoskeletal finite element (MS-FE) models to estimate highly-detailed tissue mechanics that predict cartilage degeneration. However, creating such models is time-consuming and requires advanced expertise. This limits these complex, yet promising MS-FE models to research applications with few participants and making the models impractical for clinical assessments. Also, these previously developed MS-FE models are not assessed for any activities other than the gait. This study introduces and validates a semi-automated rapid state-of-the-art MS-FE modeling and simulation toolbox incorporating an electromyography (EMG) assisted MS model and a muscle-force driven FE model of the knee with fibril-reinforced poro(visco)elastic cartilages and menisci. To showcase the usability of the pipeline, we estimated joint- and tissue-level knee mechanics in 15 KOA individuals performing different daily activities. The pipeline was validated by comparing the estimated muscle activations and joint mechanics to existing experimental data. Also, to examine the importance of EMG-assisted MS analyses, results were compared against outputs from the same FE models but driven by static-optimization-based MS models. The EMG-assisted MS-FE pipeline bore a closer resemblance to experiments, compared to the static-optimization-based MS-FE pipeline. More importantly, the developed pipeline showed great potentials as a rapid MS-FE analysis toolbox to investigate multiscale knee mechanics during different activities of individuals with KOA.
Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity
Authors: Melhem Hassan , Kaya Berna , Kaymak Tanay , Wuggenig Philipp , Flint Emilio , Roux Julien , Cavelti-Weder Claudia , Balmer Maria L. , Walser Jean-Claude , Morales Rodrigo A. , Riedel Christian U. , Liberali Prisca , Villablanca Eduardo J. , Niess Jan Hendrik
Published: March 2021

Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell type-specific deletion ofGpr35in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible toCitrobacter rodentiuminfection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.
CNAHap: a germline haplotyping method using tumor allele-specific copy number alteration
Authors: Tan Bowen , Chen Lingxi , Jia Wenlong , Wang Yanfei , Li Hechen , Li Shuai Cheng
Published: March 2021

Haplotype phasing is indispensable to study human genetics. The pervasiveness of large copy number variant segments in solid tumors brings possibilities to resolve long germline phasing blocks utilizing allele imbalance in tumor data. Although there exist such studies, none of them provide easy-use software based on availability and usability. Herein, we present a novel tool, CNAHap, to determine the allele-specific copy number in tumor and then phase germline variants according to the imbalanced alleles in tumor genomes. We also provide interactive web interfaces to visualize the copy number and phase landscape from CNAHap. Onin silicodatasets, CNAHap demonstrates higher allele-specific copy number calling accuracy than the benchmark tool and generates long phasing blocks. As a case study on Hepatocellular carcinoma, CNAHap successfully generates huge phase blocks with the averages of N50 and N90 as 25M and 7M, respectively, and finds the Olfactory receptor family is recurrent amplified. Our results illustrate the efficacy of CNAHap in determining tumor allele-specific copy numbers and their long germline haplotypes. CNAHap is available athttps://github.com/bowentan/CNAHapand the CNAHap visualization web interfaces are hosted atbio.oviz.org.
Stimulus presentation can enhance spiking irregularity across subcortical and cortical regions
Authors: Fayaz Saleh , Fakharian Mohammad Amin , Ghazizadeh Ali
Published: March 2021

Stimulus presentation is believed to quench neural response variability as measured by fano-factor (FF). However, the relative contribution of within trial spike irregularity (nΨ) and trial to trial rate variability (nRV) to FF reduction has remained elusive. Here, we introduce a principled approach for accurate estimation of variability components for a doubly stochastic point process which unlike previous methods allows for a time varying nΨ (aka ϕ). Notably, analysis across multiple subcortical and cortical areas showed across the board reduction in rate variability. However, unlike what was previously thought, spiking irregularity was not constant in time and was even enhanced in some regions abating the quench in the post-stimulus FF. Simulations confirmed plausibility of a time varying nΨ arising from within and between pool correlations of excitatory and inhibitory neural inputs. By accurate parsing of neural variability, our approach constrains candidate mechanisms that give rise to observed rate variability and spiking irregularity within brain regions.
Measuring hidden phenotype: Quantifying the shape of barley seeds using the Euler Characteristic Transform
Authors: Amézquita Erik J. , Quigley Michelle Y. , Ophelders Tim , Landis Jacob B. , Koenig Daniel , Munch Elizabeth , Chitwood Daniel H.
Published: March 2021

Shape plays a fundamental role in biology. Traditional phenotypic analysis methods measure some features but fail to measure the information embedded in shape comprehensively. To extract, compare, and analyze this information embedded in a robust and concise way, we turn to Topological Data Analysis (TDA), specifically the Euler Characteristic Transform. TDA measures shape comprehensively using mathematical representations based on algebraic topology features. To study its use, we compute both traditional and topological shape descriptors to quantify the morphology of 3121 barley seeds scanned with X-ray Computed Tomography (CT) technology at 127 micron resolution. The Euler Characteristic Transform measures shape by analyzing topological features of an object at thresholds across a number of directional axes. A Kruskal-Wallis analysis of the information encoded by the topological signature reveals that the Euler Characteristic Transform picks up successfully the shape of the crease and bottom of the seeds. Moreover, while traditional shape descriptors can cluster the seeds based on their accession, topological shape descriptors can cluster them further based on their panicle. We then successfully train a support vector machine (SVM) to classify 28 different accessions of barley based exclusively on the shape of their grains. We observe that combining both traditional and topological descriptors classifies barley seeds better than using just traditional descriptors alone. This improvement suggests that TDA is thus a powerful complement to traditional morphometrics to comprehensively describe a multitude of “hidden” shape nuances which are otherwise not detected.
Occupation as a risk factor for progression of chronic kidney disease: retrospective cohort study
Authors: Takada Daisuke , Kunisawa Susumu , Kikuno Akira , Iritani Tomoko , Imanaka Yuichi
Published: March 2021

Background

Several social determinants of health are associated with the progression of chronic kidney disease (CKD). We compared the risk of CKD progression among 18 occupational classifications using an annual health-checkup database.

Methods

We used the annual health checkup data and health insurance claims data of the Japan Health Insurance Association in Kyoto prefecture between April 2012 and March 2016. The primary outcome for survival analysis was defined as a more than 30% change in the estimated glomerular filtration rate (eGFR) from the first health checkup. We used the Cox proportional-hazards model for time-to-event analyses to estimate the hazard ratio, and 95% CIs for the primary outcome, adjusting for age, sex, eGFR, body mass index, blood pressure, blood sugar, dyslipidemia, uric acid, urinary protein, and existence of kidney diseases at first health checkup.

Results

We analyzed 239,506 employees, and 1,736 (0.7%) individuals whose eGFR had decreased by 30% or more; the mean follow-up period was 2.8 years (standard deviation: 1.2 years). When we compared the risk for “manufacturing,” five categories of industries (“information and communications”; “transport and postal services”; “accommodations, eating and drinking services”; “living-related and personal services and amusement service”; “medical, health care and welfare”) were associated with a decline in the risk of eGFR after adjusting for the confounding factors and/or mediators.

Conclusions

We provided evidence that the risk of CKD progression depends on occupation type. Further research is needed to confirm the mechanism and causal relationships involved.
The effects of emotional valence and intensity on cognitive and affective empathy after insula lesions
Authors: Holtmann Olga , Franz Marcel , Moenig Constanze , Tenberge Jan-Gerd , Preul Christoph , Schwindt Wolfram , Bruchmann Maximilian , Melzer Nico , Miltner Wolfgang H.R. , Straube Thomas
Published: March 2021

The insula plays a central role in empathy. However, the complex structure of empathic deficits following insular damage is not fully understood. While previous lesion research has shown variable deficits in patients with insular damage on basic discrimination tasks or self-report measures, it is unclear in how far patients with insular damage are impaired in cognitive (CE) and affective empathy (AE) functions depending on valence and arousal of stimuli using an ecologically valid paradigm. In the present study, patients with insular lesions (n= 20) and demographically-matched healthy controls (n= 24) viewed 16 videos (duration: 60 sec each) that varied in terms of valence and emotional intensity. The videos showed a person (target) reporting on a personal life event. In CE conditions, subjects continuously rated the affective state of the target, while in AE conditions they continuously rated their own affect. Mean Squared Error (MSE) assessed deviations between subject and target ratings (CE: deviation between targets’ and participants’ ratings of targets’ emotions; AE: deviation between targets’ and participants’ self-ratings of emotion). Patients differed from controls only in negative, low intensity AE, rating their own affective state less negative than the target rated his/her affect. This deficit was not related to trait empathy, neuropsychological or clinical parameters, or laterality of lesion. Our findings provide important insights into the profile of social cognition impairment after insular damage. Empathic functions may be widely spared after insular damage in a naturalistic, dynamic setting, potentially due to the intact interpretation of social context cues by residual networks outside the lesion. The particular role of the insula in AE for negative states may evolve specifically in situations that bear higher uncertainty, which points to a threshold role of the insula in online ratings of AE.
A fluorescent nanosensor paint reveals the heterogeneity of dopamine release from neurons at individual release sites
Authors: Elizarova S. , Chouaib A. , Shaib A. , Mann F. , Brose N. , Kruss S. , Daniel J.A.
Published: March 2021

The neurotransmitter dopamine is released from discrete axonal structures called varicosities. Its release is essential in behaviour and is critically implicated in prevalent neuropsychiatric diseases. Existing dopamine detection methods are not able to detect and distinguish discrete dopamine release events from multiple varicosities. This prevents an understanding of how dopamine release is regulated across populations of discrete varicosities. Using a near infrared fluorescent (980 nm) dopamine nanosensor ‘paint’ (AndromeDA), we show that action potential-evoked dopamine release is highly heterogeneous across release sites and also requires molecular priming. Using AndromeDA, we visualize dopamine release at up to 100 dopaminergic varicosities simultaneously within a single imaging field with high temporal resolution (15 images/s). We find that ‘hotspots’ of dopamine release are highly heterogeneous and are detected at only ~17% of all varicosities. In neurons lacking Munc13 proteins, which prime synaptic vesicles, dopamine release is abolished during electrical stimulation, demonstrating that dopamine release requires vesicle priming. In summary, AndromeDA reveals the spatiotemporal organization of dopamine release.
Fast model-based ordination with copulas
Authors: Popovic Gordana C. , Hui Francis K. C. , Warton David I.
Published: March 2021

Visualising data is a vital part of analysis, allowing researchers to find patterns, and assess and communicate the results of statistical modeling. In ecology, visualisation is often challenging when there are many variables (often for different species or other taxonomic groups) and they are not normally distributed (often counts or presence-absence data). Ordination is a common and powerful way to overcome this hurdle by reducing data from many response variables to just two or three, to be easily plotted.

Ordination is traditionally done using dissimilarity-based methods, most commonly non-metric multidimensional scaling (nMDS). In the last decade however, model-based methods for unconstrained ordination have gained popularity. These are primarily based on latent variable models, with latent variables estimating the underlying, unobserved ecological gradients.

Despite some major benefits, a major drawback of model-based ordination methods is their speed, as they typically taking much longer to return a result than dissimilarity-based methods, especially for large sample sizes.

We introduce copula ordination, a new, scalable model-based approach to unconstrained ordination. This method has all the desirable properties of model-based ordination methods, with the added advantage that it is computationally far more efficient. In particular, simulations show copula ordination is an order of magnitude faster than current model-based methods, and can even be faster than nMDS for large sample sizes, while being able to produce similar ordination plots and trends as these methods.
Effects of short-term isolation on social animals’ behavior: an experimental case study of Japanese macaque
Authors: Morita T , Toyoda A , Aisu S , Kaneko A , Suda-Hashimoto N , Adachi I , Matsuda I , Koda H
Published: March 2021

One of the goals in animal socioecology is to understand the functions and dynamics of group living. While observations of free-ranging animals are a crucial source of information, an experimental investigation that manipulates the size or composition, or both, of animal groups in captivity can also bring complementary contributions to the research inquiry. When paired with an automatic data collection by biologging technology, experimental studies on captive animals also allow for big data analyses based on recent machine learning techniques. As an initial exploration of this research paradigm, the present study inquired to what extent isolation of captive Japanese macaques (Macaca fuscata) changed their movement patterns. Using three-dimensional location trajectories of the macaques that were systematically collected via Bluetooth Low Energy beacons and a deep neural network, we estimated the identifiability of whether a macaque was behaving in isolation or in group. We found that the neural network identified the isolation vs. in-group conditions with more than 90% accuracy from a five-minute location trajectory, suggesting that the isolation caused notable changes from the canonical group-living behaviors. In addition, the isolation made each individual more identifiable from one another based on their location trajectories.
Laboratory mice with a wild microbiota generate strong allergic immune responses
Authors: Ma Junjie , Classon Cajsa H. , Stark Julian M. , Li Muzhen , Huang Huey-Jy , Vrtala Susanne , Rosshart Stephan P. , Nylén Susanne , Coquet Jonathan M.
Published: March 2021

Allergic disorders are caused by a combination of hereditary and environmental factors. The hygiene hypothesis postulates that early life microbial exposures impede the development of subsequent allergic disease. However, unambiguous evidence that microbes reduce the development of allergic disorders is still lacking. Recently developed ‘wildling’ mice contain a rich and diverse commensal and encounter a repertoire of microbes typical of the wild, with pathogenic potential. Here, we probed the hygiene hypothesis by comparing the development of allergic inflammation in wildlings to that of genetically identical mice lacking diverse microbial exposure. We find that wildlings develop stronger allergic inflammation in response to house dust mites with allergic T cell responses driven not only by cognate peptide antigens, but also by innate cytokines. In all, the results suggest that high microbial content and diversity potentiates, rather than restricts, allergic immune responses.

One sentence summary

Strong allergic inflammation in the face of rich and diverse microbial exposures
A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency
Authors: Rota Ioanna A. , Handel Adam E. , Klein Fabian , Maio Stefano , Dhalla Fatima , Deadman Mary E. , Cheuk Stanley , Newman Joseph A , Michaels Yale S. , Zuklys Saulius , Prevot Nicolas , Hublitz Philip , Charles Philip D. , Gkazi Athina Soragia , Adamopoulou Eleni , Qasim Waseem , Davies E. Graham , Hanson Celine , Pagnamenta Alistair T. , Camps Carme , Dreau Helene M. , White Andrea , James Kieran , Fischer Roman , Gileadi Opher , Taylor Jenny C. , Fulga Tudor , Lagerholm B. Christoffer , Anderson Graham , Sezgin Erdinc , Holländer Georg A.
Published: March 2021

The transcription factor FOXN1 is a master regulator of thymic epithelial cell development and function. Here we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multi-molecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are significantly altered in a patient with a mutant FOXN1 which is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog, selectively impairs mouse thymic epithelial cell (TEC) differentiation revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
Associations Between Task-Related Modulation of Motor-Evoked Potentials and EEG Event-Related Desynchronization in Children with ADHD
Authors: Ewen Joshua B. , Puts Nicolaas A. , Mostofsky Stewart H. , Horn Paul S. , Gilbert Donald L.
Published: March 2021

Children with attention-deficit/hyperactivity disorder (ADHD) have previously shown a decreased magnitude of event-related desynchronization (ERD) during a finger-tapping task, with a large between-group effect. Because the neurobiology underlying several TMS measures have been studied in multiple contexts, we compared ERD and three TMS measures (Resting Motor Threshold [RMT], Short-Interval Cortical Inhibition [SICI] and Task-Related Up-Modulation [TRUM]) within 14 participants with ADHD (ages 8-12y) and 17 control children. The TD group showed a correlation between greater RMT and greater magnitude of alpha (10-13Hz, here) ERD, and there was no diagnostic interaction effect, consistent with a rudimentary model of greater needed energy input to stimulate movement. Similarly, inhibition measured by SICI was also greater in the TD group when the magnitude of movement-related ERD was higher; there was a miniscule diagnostic interaction effect. Finally, TRUM during a response-inhibition task showed an unanticipated pattern: in TD children, the greater TMS task modulation (TRUM) was associated with a smaller magnitude of ERD during finger-tapping. The ADHD group showed the opposite direction of association: greater TRUM was associated with larger-magnitude ERD. Prior EEG results have demonstrated specific alterations of task-related modulation of cortical physiology, and the current results provide a fulcrum for multimodal study.
Perceiving and remembering speech depend on multifractal nonlinearity in movements producing and exploring speech
Authors: Bloomfield Lauren , Lane Elizabeth , Mangalam Madhur , Kelty-Stephen Damian G.
Published: March 2021

Speech perception and memory for speech require active engagement. Gestural theories have emphasized mainly the effect of speaker’s movements on speech perception. They fail to address the effects of listener movement, focusing on communication as a boundary condition constraining movement among interlocutors. The present work attempts to break new ground by using multifractal geometry of physical movement as a common currency for supporting both sides of the speaker-listener dyads. Participants self-paced their listening to a narrative, after which they completed a test of memory querying their narrative comprehension and their ability to recognize words from the story. The multifractal evidence of nonlinear interactions across timescales predicted the fluency of speech perception. Self-pacing movements that enabled listeners to control the presentation of speech sounds constituted a rich exploratory process. The multifractal nonlinearity of this exploration supported several aspects of memory for the perceived spoken language. These findings extend the role of multifractal geometry in the speaker’s movements to the narrative case of speech perception. In addition to posing novel basic research questions, these findings make a compelling case for calibrating multifractal structure in text-to-speech synthesizers for better perception and memory of speech.