bluuebunny/crossref_metadata_2025 huggingface dataset:
National Institutes of Health Career Development (K) Awards to Young Surgeons
Authors: Mesquita-Neto Jose Wilson , Dailey William , Weaver Donald , Datta Jashodeep , Macedo Francis I. , Merchant Nipun B.
Published: July 2021

Objective:

To assess contemporary trends in the National Institutes of Health (NIH) Career Development (K) Awards within the Departments of Surgery and its impact on the likelihood of achieving independent R01 grants.

Background:

The NIH provides K-type Career Development Awards to nurture young clinicians toward a productive academic career, thereby maintaining a pipeline of physician-scientists. However, the impact of K awards on career trajectory of surgeons remains unclear.

Methods:

The NIH grant data was queried for all new K08/K23 grants awarded to Departments of Surgery (1999–2019). Principal Investigators’ data and grant-related information was obtained.

Results:

The NIH awarded 298 K08/23 surgical grants ($41,893,170) over the last 2 decades. Median budget increased from $116,370 to $167,508 (P<0.001). Of grantees, 83.2% were MDs, 15.1% MD/PhD, and 1.7% PhDs, with 25.2% being women. Principal Investigators’ were mostly practicing surgeons (91.1%) with fellowship training (82.4%) and young in their careers {4 [interquartile ranges (IQR) 4] years of experience}. Vascular surgery (15.9%), Complex General Surgical Oncology (15.1%), and Trauma/Critical Care (14.6%) were the most frequent specialties. Awards were associated with 3,336 publications [median 8/project (IQR 13)]. The majority of K grantees (77.2%) currently hold an academic faculty position. Only 32.2% of awardees received independent R01 grant funding, at a median of 5.5 years (IQR 5) after their K awards. Sex (P = 0.71), previous fellowship training (P = 0.63), type of surgical specialty (P = 0.72), or MD/PhD degree (P = 0.75) were not associated with increased likelihood of achieving a subsequent R01 award.

Conclusion:

Although the majority of K awardees maintain an academic career, only a limited number of grantees progress to obtain NIH R01 funding. Increased mentorship, financial support, and infrastructure are needed to facilitate career development awardees opportunities to enhance their ability to achieve independent funding.
Out-of-Pocket Costs for Patients Undergoing Thyroid Surgery
Authors: Zheng Feibi , Huang Yongmei , Wright Jason , Kuo Jennifer H.
Published: July 2021

Objective:

The aim of this study was to determine out-of-pocket costs (OOPC) in patients undergoing thyroidectomy for benign and malignant conditions in a commercially insured US population.

Summary Background Data:

Little is known about OOPC for thyroid surgery in the United States.

Methods:

Retrospective cohort study using claims of patients undergoing thyroidectomy from the IBM Watson Marketscan database from 2008 to 2017. OOPCs accrued from 90 days before surgery to 360 days after thyroid surgery were quantified. Costs were divided into expenditures for inpatient care, outpatient care and outpatient drug costs and over three time periods: from 90 days preoperatively to 30 days post operatively, from 30 days post operatively to 90 days postoperatively, and from 90 days to 1 year after surgery.

Results:

A total of 45,971 commercially insured patients aged 18 to 95 years who underwent thyroidectomy were identified after excluding patients who changed coverage and patients on capitated plans. The median OOPC per patient in the study period of 90 days before surgery to 360 days after surgery was $2434 [interquartile range (IQR) $1273–$4226], the median insurance reimbursement was $15,520 (IQR $7653–$29,149). Patients undergoing thyroidectomy for malignant conditions had a median OOPC of $3019 (IQR $1596–$5021) compared to $2271 (IQR $1201–3954) for benign conditions (P < 0.0001).

Patients with preferred provider organization coverage had a median OOPC of $2624 (IQR $1458–$4358) compared to HMO patients with a median OOPC of $1529 (IQR $739 to 3058), and high deductible health plans with a median OOPC of $4265 (IQR $2788–$6210) (P < 0.0001).

Conclusion:

Despite commercial insurance coverage, patients face substantial OOPCs in the surgical management of thyroid disease in the United States.
Aligning Patient Acuity With Resource Intensity After Major Surgery
Authors: Loftus Tyler J. , Balch Jeremy A. , Ruppert Matthew M. , Tighe Patrick J. , Hogan William R. , Rashidi Parisa , Upchurch Gilbert R. , Bihorac Azra
Published: July 2021

Objective:

Develop unifying definitions and paradigms for data-driven methods to augment postoperative resource intensity decisions.

Summary Background Data:

Postoperative level-of-care assignments and frequency of vital sign and laboratory measurements (ie, resource intensity) should align with patient acuity. Effective, data-driven decision-support platforms could improve value of care for millions of patients annually, but their development is hindered by the lack of salient definitions and paradigms.

Methods:

Embase, PubMed, and Web of Science were searched for articles describing patient acuity and resource intensity after inpatient surgery. Study quality was assessed using validated tools. Thirty-five studies were included and assimilated according to PRISMA guidelines.

Results:

Perioperative patient acuity is accurately represented by combinations of demographic, physiologic, and hospital-system variables as input features in models that capture complex, non-linear relationships. Intraoperative physiologic data enriche these representations. Triaging high-acuity patients to low-intensity care is associated with increased risk for mortality; triaging low-acuity patients to intensive care units (ICUs) has low value and imparts harm when other, valid requests for ICU admission are denied due to resource limitations, increasing their risk for unrecognized decompensation and failure-to-rescue. Providing high-intensity care for low-acuity patients may also confer harm through unnecessary testing and subsequent treatment of incidental findings, but there is insufficient evidence to evaluate this hypothesis. Compared with data-driven models, clinicians exhibit volatile performance in predicting complications and making postoperative resource intensity decisions.

Conclusion:

To optimize value, postoperative resource intensity decisions should align with precise, data-driven patient acuity assessments augmented by models that accurately represent complex, non-linear relationships among risk factors.
Neuromodulation in Super-refractory Status Epilepticus
Authors: Stavropoulos Ioannis , Pak Ho Lim , Valentin Antonio
Published: July 2021

Status epilepticus (SE) is a severe condition that needs immediate pharmacological treatment to tackle brain damage and related side effects. In approximately 20% of cases, the standard treatment for SE does not control seizures, and the condition evolves to refractory SE. If refractory status epilepticus lasts more than 24 hours despite the use of anesthetic treatment, the condition is redefined as super-refractory SE (srSE). sRSE is a destructive condition, potentially to cause severe brain damage. In this review, we discuss the clinical neuromodulation techniques for controlling srSE when conventional treatments have failed: electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation. Data show that neuromodulation therapies can abort srSE in >80% of patients. However, no randomized, prospective, and controlled trials have been completed, and data are provided only by retrospective small case series and case reports with obvious inclination to publication bias. There is a need for further investigation into the use of neuromodulation techniques as an early treatment of srSE and to address whether an earlier intervention can prevent long-term complications.
New Horizons in Temporal Lobe Seizure Control
Authors: Velasco Ana L. , Saucedo-Alvarado Pablo E. , Alejandre-Sánchez Mariana , Guzmán-Jiménez Diana E. , González-Garcia Itzel , Velasco Francisco
Published: July 2021

In patients with mesial temporal lobe epilepsy, high-frequency, low-amplitude electrical stimulation (ES) was applied during 3 weeks through contacts of intracranial electrodes that defined the epileptogenic zone. This subacute ES induced cessation of spontaneous seizures, decreased the number of EEG interictal spikes, caused a 10-fold increase in threshold to induce postdischarges, and showed a profound decrease in regional blood flow of the stimulated area in SPECT studies. Autoradiography analysis of surgical specimens from these patients demonstrated increased expression of benzodiazepine receptors and in gamma-aminobutyric acid content, particularly in the parahippocampal cortex. These observations provided evidence of a gamma-aminobutyric acid-mediated antiepileptic effect induced by ES. Several reports of long-term hippocampal ES through internalized neurostimulators have confirmed the antiepileptic effect on mesial temporal lobe–initiated seizures, with preservation of neuropsychological performance, in particular memory functions. The experience of the authors is that the response is optimal in patients without hippocampal sclerosis evidenced by MRI, whereas it is less significant and delayed in patients with hippocampal sclerosis. Other studies reported the best result stimulating through the contacts in the subiculum, the transition between the hippocampus and parahippocampal cortex, that usually escapes to the hippocampal sclerosis. Currently, the effect of ES directed at the subiculum and the parahippocampal cortex in patients with hippocampal sclerosis is under investigation.
Cathodal Transcranial Direct Current Stimulation in Refractory Epilepsy: A Noninvasive Neuromodulation Therapy
Authors: San-Juan Daniel
Published: July 2021

Epilepsy is a chronic disease of the brain that affects individuals of all ages and has a worldwide distribution. According to a 2006 World Health Organization report, 50 million people had epilepsy. Approximately 30% of people with epilepsy have refractory disease despite recent therapeutic developments. Consequently, new treatments are necessary. Transcranial direct current stimulation (tDCS) is a noninvasive method for cortical excitability modulation by subthreshold membrane depolarization or hyperpolarization (cathodal stimulation decreases cortical excitability, whereas anodal stimulation increases it), which has been shown to be safe, economical, and easy to use. The mechanism of action of tDCS is partially understood. Cathodal tDCS in vitro and in vivo animal studies have shown that direct current and cathodal tDCS can successfully induce suppression of epileptiform activity in EEG recordings. Cathodal tDCS has been used in heterogeneous clinical trials in pediatric and adult patients with refractory epilepsy and is well tolerated. A comprehensive review of the clinical trials based on their quality and biases shows evidence that cathodal tDCS in patients with epilepsy is potentially effective. However, additional randomized clinical trials are needed with other etiologies, special populations, additional concomitants therapies, long-term follow-up, and new parameters of stimulation.
Lactobacillus corticis sp. nov., isolated from hardwood bark
Authors: Tohno Masanori , Tanizawa Yasuhiro , Kojima Yoichiro , Sakamoto Mitsuo , Ohkuma Moriya , Kobayashi Hisami
Published: July 2021

During a study on the biodiversity of bacteria that inhabit woody biomass, we isolated a strain coded B40T from hardwood bark used as a compost ingredient in Japan. The strain, characterized as B40T, is a Gram-stain-positive, rod-shaped, non-motile, non-spore-forming and catalase-negative bacterium. This novel isolate showed growth at 30–50 °C, at pH 3.5–7.5 and in the presence of up to 4 % (w/v) NaCl. Its major fatty acids include C16:0, C18:1 ω9c and summed feature 8. The genomic DNA G+C content of strain B40T is 42.2 mol%. Results of 16S rRNA gene sequence-based phylogenetic analysis indicated that strain B40T belongs to the genus

Lactobacillus

and the closest neighbours of strain B40T are

Lactobacillus gigeriorum

202T (95.7 %),

Lactobacillus pasteurii

CRBIP 24.76T (95.6 %),

Lactobacillus psittaci

DSM 15354T (95.4 %),

Lactobacillus fornicalis

TV1018T (95.4 %) and

Lactobacillus jensenii

ATCC 25258T (95.2 %). The amino acid sequence-based phylogenetic analyses of 489 shared protein-encoding genes showed that the strain forms a phylogenetically independent lineage in the genus

Lactobacillus

but could not be assigned to any known species. Strain B40T has an average nucleotide identify of <70.2 % and a digital DNA–DNA hybridization value of 19.2 % compared with the strains of other closely related

Lactobacillus

species. Differential genomic, phenotypic and chemotaxonomic properties, in addition to phylogenetic analyses, indicated that strain B40T represents a novel species of the genus

Lactobacillus

, for which the name Lactobacillus corticis sp. nov. is proposed. The strain type is B40T (=JCM 32597T=DSM 107967T).
The six steps of the F1-ATPase rotary catalytic cycle
Authors: Sobti Meghna , Ueno Hiroshi , Noji Hiroyuki , Stewart Alastair G.
Published: July 2021

F1FoATP synthase interchanges phosphate transfer energy and proton motive force via a rotary catalysis mechanism. When isolated, its F1-ATPase catalytic core can hydrolyze ATP, rotating its γ rotor subunit. Although previous structural studies have contributed greatly to understanding rotary catalysis in F1, the structure of one major conformational state detected in single-molecule studies, termed the binding dwell state, has not yet been determined. Here, by exploiting a temperature-sensitive F1-ATPase mutant fromBacillusPS3, the structure of this binding dwell state was established together with that of the catalytic dwell state. Each state showed three catalytic β subunits in different conformations, providing the complete set of six β subunit conformational states taken up during catalysis cycle. These structures provide molecular details for the power-stroke conformational change that occurs upon ATP binding and induces a ~80° γ subunit rotation, as well as a second torque-generating conformational change, triggered by hydrolysis and product release, that produces a ~40° rotation. This study also identifies a putative phosphate-releasing tunnel that indicates how ADP and phosphate releasing steps are coordinated. Overall these findings provide a structural basis for the entire F1-ATPase rotary catalysis cycle.
Anatomically informed multi-level fiber tractography
Authors: Zhylka Andrey , Leemans Alexander , Pluim Josien , De Luca Alberto
Published: July 2021

Diffusion weighted MR imaging can assist preoperative planning by reconstructing the trajectory of eloquent fiber pathways. A common task is the delineation of the corticospinal tract in its full extent because lesions to this bundle can severely affect the quality of life. However, this is challenging as existing tractography algorithms typically produce either incomplete results or multiple false-positive tracts. In this work, we suggest a novel approach to fiber tractography that reconstructs multi-level structures by progressively taking into account previously unused fiber orientations. Anatomical priors are used in order to minimize the number of false-positive pathways. The devised method was evaluated on synthetic data with different noise levels. Additionally, it was tested on in-vivo data by reconstructing the corticospinal tract and it was compared to conventional deterministic and probabilistic approaches. The corticospinal tract reconstructed by our method includes lateral projections that could not be observed with deterministic methods, while avoiding spurious tracts reconstructed by probabilistic tractography. Furthermore, the proposed algorithm preserves the neuroanatomical topology of the pathways to a larger extent as compared to probabilistic tractography.
DoChaP: The Domain Change Presenter
Authors: Gal-Oz Shani T. , Haiat Nimrod , Eliyahu Dana , Shani Guy , Shay Tal
Published: July 2021

Alternative RNA splicing results in multiple transcripts of the same gene, possibly encoding for different protein isoforms with different protein domains and functionalities. Whereas it is possible to manually determine the effect of a specific alternative splicing event on the domain composition of a particular encoded protein, the process requires the tedious integration of several data sources; it is therefore error prone and its implementation is not feasible for genome-wide characterization of domains affected by differential splicing. To fulfill the need for an automated solution, we developed the Domain Change Presenter (DoChaP), a web server for the visualization of the exon–domain association. DoChaP visualizes all transcripts of a given gene, the domains of the proteins that they encode, and the exons encoding each domain. The visualization enables a comparison between the transcripts and between the protein isoforms they encode for. The organization and visual presentation of the information makes the structural effect of each alternative splicing event on the protein structure easily identified. To enable a study of the conservation of the exon structure, alternative splicing, and the effect of alternative splicing on protein domains, DoChaP also facilitates an inter-species comparison of domain–exon associations. DoChaP thus provides a unique and easy-to-use visualization of the exon–domain association and its conservation between transcripts and orthologous genes and will facilitate the study of the functional effects of alternative splicing in health and disease.
An unconventional conductance is required for pacemaking of nigral dopamine neurons
Authors: Jehasse Kevin , Massotte Laurent , Hartmann Sebastian , Vitello Romain , Ringlet Sofian , Vitello Marie , Chua Han Chow , Pless Stephan A. , Engel Dominique , Liégeois Jean-François , Lakaye Bernard , Roeper Jochen , Seutin Vincent
Published: July 2021

Although several ionic mechanisms are known to control rate and regularity of the pacemaker in dopamine (DA) neurons from the substantia nigra pars compacta (SNc), a conductance essential for pacing has yet to be defined. Here we provide pharmacological evidence that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidine (XG), an established blocker of gating pore currents in mutant voltage gated sodium channels, selectively stops pacemaking of DA SNc neurons and is without effect on the main pore of their voltage-gated channels. We isolated a voltage-dependent, non-inactivating XG-sensitive current of 20-25 pA which operates in the relevant subthreshold range and is carried by both Na+ and Cl- ions. While the molecular identity of this conductance remains to be determined, we show that this XG-sensitive current is crucial to sustain pacemaking in these neurons.
Data Augmentation Through Monte Carlo Arithmetic Leads to More Generalizable Classification in Connectomics
Authors: Kiar Gregory , Chatelain Yohan , Salari Ali , Evans Alan C. , Glatard Tristan
Published: July 2021

Machine learning models are commonly applied to human brain imaging datasets in an effort to associate function or structure with behaviour, health, or other individual phenotypes. Such models often rely on low-dimensional maps generated by complex processing pipelines. However, the numerical instabilities inherent to pipelines limit the fidelity of these maps and introduce computational bias. Monte Carlo Arithmetic, a technique for introducing controlled amounts of numerical noise, was used to perturb a structural connectome estimation pipeline, ultimately producing a range of plausible networks for each sample. The variability in the perturbed networks was captured in an augmented dataset, which was then used for an age classification task. We found that resampling brain networks across a series of such numerically perturbed outcomes led to improved performance in all tested classifiers, preprocessing strategies, and dimensionality reduction techniques. Importantly, we find that this benefit does not hinge on a large number of perturbations, suggesting that even minimally perturbing a dataset adds meaningful variance which can be captured in the subsequently designed models.

GRAPHICAL ABSTRACT

This paper demonstrates how Monte Carlo Arithmetic, a dataagnostic perturbation technique, can be used for dataset augmentation during the generation of structural connectomes and improve downstream phenotypic prediction.
Comparative genomics of peroxisome biogenesis proteins: making sense of the PEX mess
Authors: Jansen Renate L.M. , Molina Carlos Santana , van den Noort Marco , Devos Damien P. , van der Klei Ida J.
Published: July 2021

PEX genes encode proteins involved in peroxisome biogenesis and proliferation. Using a comparative genomics approach, we clarify the evolutionary relationships between the 37 known PEX proteins in a representative set of eukaryotes, including all common model organisms, pathogenic unicellular eukaryotes and human. A large number of previously unknown PEX orthologs were identified. We analysed all PEX proteins, their conservation and domain architecture and defined the minimum set of PEX proteins that is required to make a peroxisome. The molecular processes in peroxisome biogenesis in different organisms were put into context, showing that peroxisomes are not static organelles in eukaryotic evolution. Organisms that lack peroxisomes still contain a few PEX proteins, which probably play a role in alternative processes. Finally, the relationships between PEX proteins of two large families, the Pex11 and Pex23 families, were clarified, thereby contributing to the understanding of their complicated and sometimes incorrect nomenclature. We provide an exhaustive overview of this important eukaryotic organelle.
Making an equal system equitable: Proposing a sex-adjusted MELDNa score for liver transplantation allocation
Authors: Sealock Julia M. , Ziogas Ioannis A. , Zhao Zhiguo , Ye Fei , Alexopoulos Sophoclis P. , Matsuoka Lea , Chen Guanhua , Davis Lea K.
Published: July 2021

Background & Aims

Liver allocation is determined by the model for end-stage liver disease (MELD), a scoring system based on four laboratory measurements. During the MELD era, sex disparities in liver transplant have increased and there are no modifications to MELD based on sex. We use data from electronic health records (EHRs) to describe sex differences in MELD labs and propose a sex adjustment.

Methods

We extracted lab values for creatinine, International Normalized Ratio of prothrombin rate, bilirubin, and sodium from EHRs at Vanderbilt University Medical Center (VUMC) and the All of Us Research Project to determine sex differences in lab traits. We calculated MELDNa scores within liver transplant recipients, non-transplanted liver disease cases, and non-liver disease controls separately. To account for sex differences in lab traits in MELDNa scoring, we created a sex-adjusted MELDNa map which outputs adjusted female scores mapped to male scores of equal liver disease severity. Using waitlist data from the Liver Simulated Allocation Modeling, we conducted simulations to determine if the sex-adjusted scores reduced sex disparities.

Results

All component MELDNa lab values and calculated MELDNa scores yielded significant sex differences within VUMC (n=623,931) and All of Us (n=56,715) resulting in MELDNa scoring that disadvantaged females who, despite greater decompensation traits, had lower MELDNa scores. In simulations, the sex-adjusted MELDNa score modestly increased female transplantation rate and decreased overall death.

Conclusions

Our results demonstrate pervasive sex differences in all labs used in MELDNa scoring and highlight the need and utility of a sex-adjustment to the MELDNa protocol.

Lay Summary

Liver transplant waitlist position is determined by a score called MELDNa, which is calculated using four laboratory values. Once on the waitlist, males are more likely to receive a transplant, while females are more likely to die or be removed due to illness. We demonstrate that all four laboratory values in the MELDNa score show significant sex differences that disadvantage females in liver transplant. We created a sex-adjusted score that increases female transplantation rate and decreases death among both sexes in simulations.
Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing
Authors: Koneswarakantha Björn , Ménard Timothé
Published: July 2021

Background

As investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

Methods

We modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

Results

We could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

Conclusion

Continuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times.
Absence of SARS-CoV-2 antibodies in pre-pandemic plasma from children and adults in Vietnam
Authors: Van Vinh Chau Nguyen , Thanh Nhan Le Nguyen , Nguyet Lam Anh , Kha Tu Nguyen Thi , Thu Hong Nguyen Thi , Huy Man Dinh Nguyen , Bich Ty Dinh Thi , Truc Nhu Le Nguyen , Yen Lam Minh , Khanh Truong Huu , Quang Minh Ngo Ngoc , Han Ny Nguyen Thi , Anderson Danielle , Wang Lin-Fa , van Doorn H. Rogier , Hung Nguyen Thanh , Thanh Tran Tan , Thwaites Guy , Van Tan Le ,   OUCRU COVID-19 research group
Published: July 2021

We tested pre-pandemic (2015-2019) plasma samples from 148 Vietnamese children, and 100 Vietnamese adults at high risk of zoonotic infections, for antibodies against SARS-CoV-2 nucleocapsid and spike proteins. None was positive, indicating no prior serological cross-reactivity with SARS-CoV-2 that might explain the low numbers of COVID-19 in Vietnam.
The DocMaps Framework for representing assertions on research products in an extensible, machine-readable, and discoverable format
Authors: McDowell Gary S. , Polka Jessica K. , Ross-Hellauer Tony , Stein Gabriel
Published: July 2021

Peer review of a research product varies widely depending on the publishers and platforms involved in the process. As scholarly publishing is disrupted by new innovations, peer review processes become more heterogeneous, placing an increasing burden on the researcher in understanding how they can communicate their scholarship. New ways to model such processes, and increase transparency, trust, and experimentation in scholarly publishing are needed. Many are emerging but can tend to focus on the needs of creators, and not those of readers, funders, and the whole scholarly publishing ecosystem. They may not place focus on representing editorial practices in ways that can be reliably aggregated, surfaced, and queried; are often limited to traditional peer review processes; and cannot capture the full range of editorial practices and events needed to accommodate alternative publication, review, and curation models. To support researchers in a world of experimentation in scholarly publishing, we propose a machine-readable, extensible, and discoverable framework for representing and surfacing review and editorial processes. Working with a Technical Committee composed of interested parties by employing a modified Delphi Method, we developed initial guiding principles and proposals towards an object-level editorial metadata framework compatible with a broad range of possible futures for scholarly publishing. We present the results of this process with a proposal and example use cases for DocMaps, a framework for representing object-level assertions.
Palmitoylation targets the Calcineurin phosphatase to the Phosphatidylinositol 4-kinase complex at the plasma membrane
Authors: Ulengin-Talkish Idil , Parson Matthew AH , Jenkins Meredith L , Roy Jagoree , Shih Alexis ZL , St-Denis Nicole , Gulyas Gergo , Balla Tamas , Gingras Anne-Claude , Várnai Péter , Conibear Elizabeth , Burke John E , Cyert Martha S.
Published: July 2021

Calcineurin, the conserved protein phosphatase and target of immunosuppressants, is a critical mediator of Ca2+ signaling. To discover novel calcineurin-regulated processes we examined an understudied isoform, CNAβ1. We show that unlike canonical cytosolic calcineurin, CNAβ1 localizes to the plasma membrane and Golgi due to palmitoylation of its divergent C-terminal tail, which is reversed by the ABHD17A depalmitoylase. Palmitoylation targets CNAβ1 to a distinct set of membrane-associated interactors including the phosphatidylinositol 4-kinase (PI4KA) complex containing EFR3B, PI4KA, TTC7B and FAM126A. Hydrogen-deuterium exchange reveals multiple calcineurin-PI4KA complex contacts, including a calcineurin-binding peptide motif in the disordered tail of FAM126A, which we establish as a calcineurin substrate. Calcineurin inhibitors decrease PI4P production during Gq-coupled GPCR signaling, suggesting that calcineurin dephosphorylates and promotes PI4KA complex activity. In sum, this work discovers a new calcineurin-regulated signaling pathway highlighting the PI4KA complex as a regulatory target and revealing that dynamic palmitoylation confers unique localization, substrate specificity and regulation to CNAβ1.
An analytical pipeline for DNA Methylation Array Biomarker Studies
Authors: Lu Jennifer , Korbie Darren , Trau Matt
Published: July 2021

DNA methylation is one of the most commonly studied epigenetic biomarkers, due to its role in disease and development. The Illumina Infinium methylation arrays still remains the most common method to interrogate methylation across the human genome, due to its capabilities of screening over 480, 000 loci simultaneously. As such, initiatives such as The Cancer Genome Atlas (TCGA) have utilized this technology to examine the methylation profile of over 20,000 cancer samples. There is a growing body of methods for pre-processing, normalisation and analysis of array-based DNA methylation data. However, the shape and sampling distribution of probe-wise methylation that could influence the way data should be examined was rarely discussed. Therefore, this article introduces a pipeline that predicts the shape and distribution of normalised methylation patterns prior to selection of the most optimal inferential statistics screen for differential methylation. Additionally, we put forward an alternative pipeline, which employed feature selection, and demonstrate its ability to select for biomarkers with outstanding differences in methylation, which does not require the predetermination of the shape or distribution of the data of interest.

Availability

The Distribution test and the feature selection pipelines are available for download at: https://github.com/uqjlu8/DistributionTest
Twisting DNA by Salt
Authors: Cruz-León Sergio , Vanderlinden Willem , Müller Peter , Forster Tobias , Staudt Georgina , Lin Yi-Yun , Lipfert Jan , Schwierz Nadine
Published: July 2021

The structure and properties of DNA depend on the environment, in particular the ion atmosphere. Here, we investigate how DNA twist -one of the central properties of DNA- changes with concentration and identity of the surrounding ions. To resolve how cations influence the helical twist, we combine single-molecule magnetic tweezer experiments and extensive all- atom molecular dynamics simulations. Two interconnected trends are observed for monovalent alkali and divalent alkaline earth cations. First, DNA twist increases monotonously with increasing concentration for all ions investigated. Second, for a given salt concentration, DNA twist strongly depends on cation identity. At 100 mM concentration, DNA twist increases as Ba2+ < Na+ < K+ < Rb+ < Li+ ≈ Cs+ < Sr2+ < Mg2+ < Ca2+. Our molecular dynamics simulations reveal that preferential binding of the cations to the DNA backbone or the nucleobases has opposing effects on DNA twist and provides the microscopic explanation of the observed ion specificity. However, the simulations also reveal shortcomings of existing force field parameters for Cs+ and Sr2+. The comprehensive view gained from our combined approach provides a foundation for understanding and predicting cation-induced structural changes both in nature and in DNA nanotechnology.
The (non) accuracy of mitochondrial genomes for family level phylogenetics: the case of erebid moths (Lepidoptera; Erebidae)
Authors: Ghanavi Hamid Reza , Twort Victoria , Hartman Tobias Joannes , Zahiri Reza , Wahlberg Niklas
Published: July 2021

The use of molecular data to study evolutionary history of different organisms, revolutionized the field of systematics. Now with the appearance of high throughput sequencing (HTS) technologies more and more genetic sequence data is available. One of the important sources of genetic data for phylogenetic analyses has been mitochondrial DNA. The limitations of mitochondrial DNA for the study of phylogenetic relationships have been thoroughly explored in the age of single locus phylogenies. Now with the appearance of genomic scale data, more and more mitochondrial genomes are available. Here we assemble 47 mitochondrial genomes using whole genome Illumina short reads of representatives of the family Erebidae (Lepidoptera), in order to evaluate the accuracy of mitochondrial genome application in resolving deep phylogenetic relationships. We find that mitogenomes are inadequate for resolving subfamily level relationships in Erebidae, but given good taxon sampling, we see its potential in resolving lower level phylogenetic relationships.
Reciprocal changes in voltage-gated potassium and subthreshold inward currents help maintain firing dynamics of AVPV kisspeptin neurons during the estrous cycle
Authors: Starrett J. Rudolph , DeFazio R. Anthony , Moenter Suzanne M.
Published: July 2021

Kisspeptin-expressing neurons in the anteroventral-periventricular nucleus (AVPV) are part of a neural circuit generating the gonadotropin-releasing hormone (GnRH) surge. This process is estradiol-dependent and occurs on the afternoon of proestrus in female mice. On proestrus, AVPV kisspeptin neurons express more kisspeptin and exhibit higher frequency action potentials and burst firing compared to diestrus, which is characterized by a pulsatile rather than a prolonged surge of GnRH secretion. We hypothesized changes in voltage-gated potassium conductances shape activity profiles of these cells in a cycle-dependent manner. Whole-cell voltage-clamp recordings of GFP-identified AVPV kisspeptin neurons in brain slices from diestrous and proestrous mice revealed three subcomponents of the voltage-sensitive K+ current: fast-inactivating, slow-inactivating, and residual. During proestrus, the V50 of inactivation of the fast-inactivating current was depolarized and the amplitude of the slow-inactivating component was reduced compared to diestrus; the residual component was consistent across both stages. Computational models were fit to experimental data, including published estrous-cycle effects on other voltage-gated currents. Computer simulations suggest proestrus-typical K+ currents are suppressive compared to diestrus. Interestingly, larger T-type, persistent-sodium, and hyperpolarization-activated currents during proestrus compensate for this suppressive effect while also enabling post-inhibitory rebound bursting. These findings suggest modulation of voltage-gated K+ and multiple subthreshold depolarizing currents across the negative to positive feedback transition maintain AVPV kisspeptin neuron excitability in response to depolarizing stimuli. These changes also enable firing in response to hyperpolarization, providing a net increase in neuronal excitability, which may contribute to activation of this population leading up to the preovulatory GnRH surge.

Significance Statement

GnRH neurons provide the central signal to initiate ovulation by releasing a surge of hormone. GnRH neurons are regulated by other cells including those expressing kisspeptin, a potent stimulator of GnRH secretion. Kisspeptin neurons in the anteroventral-periventricular nucleus (AVPV) express more kisspeptin and become more active during the afternoon of proestrus, the phase of the rodent estrous (reproductive) cycle when the GnRH surge occurs. We found voltage-dependent potassium currents in AVPV kisspeptin neurons change with phase of the estrous cycle. Firing simulations indicated these changes are suppressive if occurring in isolation. But proestrous-typical increases in subthreshold depolarizing currents overcome this suppression and promote greater excitability by increasing rebound firing, possibly contributing to the preovulatory activation of this system.
Partitioning gene-mediated disease heritability without eQTLs
Authors: Weiner Daniel J. , Gazal Steven , Robinson Elise B. , O’Connor Luke J.
Published: July 2021

Unknown SNP-to-gene regulatory architecture complicates efforts to link noncoding GWAS associations with genes implicated by sequencing or functional studies. eQTLs are used to link SNPs to genes, but expression in bulk tissue explains a small fraction of disease heritability. A simple but successful approach has been to link SNPs with nearby genes, but the fraction of heritability mediated by these genes is unclear, and gene-proximal (vs. gene-mediated) heritability enrichments are attenuated accordingly. We propose the Abstract Mediation Model (AMM) to estimate (1) the fraction of heritability mediated by the closest or kth-closest gene to each SNP and (2) the mediated heritability enrichment of a gene set (e.g. genes with rare-variant associations). AMM jointly estimates these quantities by matching the decay in SNP enrichment with distance from genes in the gene set. Across 47 complex traits and diseases, we estimate that the closest gene to each SNP mediates 27% (SE: 6%) of heritability, and that a substantial fraction is mediated by genes outside the ten closest. Mendelian disease genes are strongly enriched for common-variant heritability; for example, just 21 dyslipidemia genes mediate 25% of LDL heritability (211x enrichment, P = 0.01). Among brain-related traits, genes involved in neurodevelopmental disorders are only about 4x enriched, but gene expression patterns are highly informative, with detectable differences in per-gene heritability even among weakly brain-expressed genes.
An information theoretic method to resolve millisecond-scale spike timing precision in a comprehensive motor program
Authors: Putney Joy , Niebur Tobias , Conn Rachel , Sponberg Simon
Published: July 2021

Sensory inputs in nervous systems are often encoded at the millisecond scale in a temporally precise code. There is now a growing appreciation for the prevalence of precise timing encoding in motor systems. Animals from moths to birds control motor outputs using precise spike timing, but we largely do not know at what scale timing matters in these circuits due to the difficulty of recording a complete set of spike-resolved motor signals and relatively few methods for assessing spike timing precision. We introduce a method to estimate spike timing precision in motor circuits using continuous MI estimation at increasing levels of added uniform noise. This method can assess spike timing precision at fine scales for encoding rich motor output variation. We demonstrate the advantages of this approach compared to a previously established discrete information theoretic method of assessing spike timing precision. We use this method to analyze a data set of simultaneous turning (yaw) torque output and EMG recordings from the 10 primary muscles ofManduca sextaas tethered moths visually tracked a robotic flower moving with a 1 Hz sinusoidal trajectory. We know that all 10 muscles in this motor program encode the majority of information about yaw torque in spike timings, but we do not know whether individual muscles receive information encoded at different levels of precision. Using the continuous MI method, we demonstrate that the scale of temporal precision in all motor units in this insect flight circuit is at the sub-millisecond or millisecond-scale, with variation in precision scale present between muscle types. This method can be applied broadly to estimate spike timing precision in sensory and motor circuits in both invertebrates and vertebrates.
The 4.4 Å structure of the giant Melbournevirus virion belonging to the Marseilleviridae family
Authors: Burton-Smith Raymond N. , Narayana Reddy Hemanth Kumar , Svenda Martin , Abergel Chantal , Okamoto Kenta , Murata Kazuyoshi
Published: July 2021

Members of Marseilleviridae, one family of icosahedral giant viruses classified in 2012 have been identified worldwide in all types of environments. The virion shows a characteristic internal membrane extrusion at the five-fold vertices of the capsid, but its structural details need to be elucidated. We now report the 4.4 Å cryo-electron microscopy structure of the Melbournevirus capsid. An atomic model of the major capsid protein (MCP) shows a unique cup structure on the trimer that accommodates additional proteins. A polyalanine model of the penton base protein shows internally extended N- and C-terminals, which indirectly connect to the internal membrane extrusion. The Marseilleviruses share the same orientational organisation of the MCPs as PBCV-1 and CroV, but do not appear to possess a protein akin to the “tape measure” of these viruses. Minor capsid proteins named PC-β, zipper, and scaffold are proposed to control the dimensions of the capsid during assembly.
Increased intestinal permeability in an orally-reactive peanut allergy model identifies Angiopoietin like-4 as a biomarker
Authors: Steinbach Erin C. , Smeekens Johanna M. , Roy Satyaki , Toyonaga Takahiko , Cornaby Caleb , Perini Layna , Berglind Ana , Kulis Michael D. , Kim Edwin H. , Ferris Martin T. , Furey Terrence S. , Burks A. Wesley , Sheikh Shehzad Z.
Published: July 2021

Peanut allergy reaction severity correlates with increased intestinal epithelial cell (IEC) barrier permeability. CC027/GeniUnc mice develop peanut allergy by intragastric administration of peanut proteins without adjuvant. We report that peanut-allergic CC027/GeniUnc mice showed increased IEC barrier permeability and systemic peanut allergen Ara h 2 after challenge. Jejunal epithelial cell transcriptomics showed effects of peanut allergy on IEC proliferation, survival, and metabolism, and revealed IEC-predominant angiopoietin like-4 (Angptl4) as a unique feature of CC027/GeniUnc peanut allergy. CC027/GeniUnc mice and peanut-allergic pediatric patients demonstrated significantly higher serum Angptl4 and ANGPTL4 compared to control C3H/HeJ mice and non-peanut-allergic but atopic patients, respectively, highlighting its potential as a biomarker of peanut allergy.
Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma
Authors: Daniszewski Maciej S. , Senabouth Anne , Liang Helena H. , Han Xikun , Lidgerwood Grace E. , Hernández Damián , Sivakumaran Priyadharshini , Clarke Jordan E. , Lim Shiang Y. , Lees Jarmon G. , Rooney Louise , Gulluyan Lerna , Souzeau Emmanuelle , Graham Stuart L. , Chan Chia-Ling , Nguyen Uyen , Farbehi Nona , Gnanasambandapillai Vikkitharan , McCloy Rachael A. , Clarke Linda , Kearns Lisa , Mackey David A , Craig Jamie E. , MacGregor Stuart , Powell Joseph E. , Pébay Alice , Hewitt Alex W.
Published: July 2021

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared to those from healthy individuals. We performed single-cell RNA-sequencing of a total of 330,569 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 2,235 significant loci across all cell types, 58 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 54 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
Population model of Temnothorax albipennis as a distributed dynamical system II: secret of “chemical reaction” in collective house-hunting in ant colonies is unveiled by operator methods
Authors: Qiu Siwei
Published: July 2021

The collective intelligence of animal groups is a complex algorithm for computer scientist and a many-body problem for physics of living system. We show how the time evolution of features in such a system, like number of ants in particular state for colonies, can be mapped to many-body problems in non-equilibrium statistical mechanics. There exist role transitions of active and passive ant between distributed functions, including exploration, assessing, recruiting and transportation in the house-hunting process. Theoretically, such a process can be approximately described as birth-death process where large number of particles living in the Fock space and particles of one sub-type transfer to a different sub-type with some probability. Started from the master equation with constrain of the quorum criterion, we express the evolution operator as a functional integral mapping from operators acting on Fock space in number representation to functional space in coherent state representation. We then read out the action from the evolution operator, and we use least action principal equations of motion, which are the number field equations. The equations we get are couple ordinary differential equations, which can faithfully describe the original master equation, and hence fully describe the system. This method provides us differential equation-based algorithm, which allow us explore parameter space with respect to more complicated agent-based algorithm. The algorithm also allows exploring stochastic process with memory in a Markovian way, which provide testable prediction on collective decision making.