bluuebunny/crossref_metadata_2025 huggingface dataset:
New Approaches to Cardiovascular Disease and Its Management in Kidney Transplant Recipients
Authors: Aziz Fahad , Jorgenson Margaret , Garg Neetika , Parajuli Sandesh , Mohamed Maha , Raza Farhan , Mandelbrot Didier , Djamali Arjang , Dhingra Ravi
Published: December 2021

Cardiovascular events, including ischemic heart disease, heart failure, and arrhythmia, are common complications after kidney transplantation and continue to be leading causes of graft loss. Kidney transplant recipients have both traditional and transplant-specific risk factors for cardiovascular disease. In the general population, modification of cardiovascular risk factors is the best strategy to reduce cardiovascular events; however, studies evaluating the impact of risk modification strategies on cardiovascular outcomes among kidney transplant recipients are limited. Furthermore, there is only minimal guidance on appropriate cardiovascular screening and monitoring in this unique patient population. This review focuses on the limited scientific evidence that addresses cardiovascular events in kidney transplant recipients. Additionally, we focus on clinical management of specific cardiovascular entities that are more prevalent among kidney transplant recipients (ie, pulmonary hypertension, valvular diseases, diastolic dysfunction) and the use of newer evolving drug classes for treatment of heart failure within this cohort of patients. We note that there are no consensus documents describing optimal diagnostic, monitoring, or management strategies to reduce cardiovascular events after kidney transplantation; however, we outline quality initiatives and research recommendations for the assessment and management of cardiovascular-specific risk factors that could improve outcomes.
A Comparison of the Biomechanical Performance of 3 Negative Pressure Wound Therapy Foams
Authors: Gibson Daniel J.
Published: December 2021

PURPOSE:

The purpose of this study was to compare 3 foam dressings to (1) determine the biomechanical performance of existing negative pressure wound therapy (NPWT) foams and (2) to determine if a test foam is possibly suitable as an antimicrobial “white” foam alternative for use in NPWT.

DESIGN:

A comparison of mechanical performance of 3 foams used for vacuum-assisted NPWT.

SUBJECTS AND SETTING:

Preclinical laboratory study using an in vitro model.

METHODS:

The performance of a “white” foam (polyvinyl alcohol [PVA]), an antimicrobial “black” foam (polyurethane [PU]), and an antimicrobial white foam alternative (test PVA) were tested and compared using 3 mechanically relevant criteria. First, the fluid removal rate was measured for 72 hours. Next, the pressure input was compared to the pressure directly beneath the center of the foam. Finally, the spread of negative pressure beneath the foam was measured and compared.

RESULTS:

Significant differences were found in fluid removal rates; specifically, the PU foam removed fluids faster than the PVA and test PVA foams, and the currently available PVA foams performed similarly. Both the PU and test PVA foams were able to transmit the negative pressure through the center of the dressing, while the typical PVA foam began failing at 140 mm Hg, with 50% of the samples failing at 200 mm Hg. All PU replicate foams evenly distributed the pressure, while 47% to 60% of the test PVA foams and 7% of the typical PVA foams distributed pressures evenly.

CONCLUSIONS:

Study findings suggest that the test PVA foam does not mechanically interfere with NPWT and performs equivalently to currently used foams. These results suggest that the test PVA may be modified and incorporated into a vacuum-assisted NPWT device. In addition, the methods employed in these experiments provide a reproducible means to compare biomechanical compatibility of various NPWT foams, dressings, and subdrape devices.
Radiographic evaluation of lumbar intervertebral disc height index: an intra and inter-rater agreement and reliability study
Authors: Chen Xiaolong , Sima Stone , Sandhu Harvinder S. , Kuan Jeff , Diwan Ashish D.
Published: December 2021

Purpose

To evaluate intra- and inter-rater agreement and reliability of seven reported disc height index (DHI) measurement methods on standing lateral X-ray of lumbar spine.

Methods

The adult patients who had standing lateral X-ray of lumbar spine were recruited. Seven methods were used to measure DHI of each lumbar intervertebral disc level. Bland and Altman’s Limits of Agreement (LOA) with standard difference were calculated to examine intra- and inter-rater agreements between two out of seven methods for DHI. Intra-class correlations (ICC) with 95% confidence intervals were calculated to assess intra- and inter-rater reliability.

Results

The intra-rater reliability in DHI measurements for 288 participants were ICCs from 0.807 (0.794, 0.812) to 0.922 (0.913, 0.946) by rater 1 (SS) and from 0.827 (0.802, 0.841) to 0.918 (0.806, 0.823) by rater 2 (XC). Method 2, 3, and 5 on all segmental levels had bias (95% CI does not include zero) or/and out of the acceptable cut-off proportion (>50%). A total of 609 outliers in 9174 segmental levels’ LOA range. Inter-rater reliability was good-to-excellent in all but method 2 (0.736 (0.712, 0.759)) and method 5 (0.634 (0.598, 0.667)). ICCs of related lines to good-to-excellent reliability methods was excellent in all but only indirect line in method 1 and 4 (ICCs lie in the range from 0.8 to 0.9).

Conclusion

Following structured protocol, intra- and inter-rater reliability was good-to-excellent for most DHI measurement methods on X-ray. However, in the presence of vertebral rotation, one should exercise caution in using complicated methods to define vertebral landmarks.
Use of rapid molecular tuberculosis diagnostics across Brazil’s incarcerated population
Authors: Fajer Elinor B. , Costa Fernanda Dockhorn , Pelissari Daniele Maria , Diaz Quijano Fredi Alexander , de Brito Artemir Coelho , Totumi Cunha Eunice Atsuko , Croda Julio , Andrews Jason R. , Walter Katharine S.
Published: December 2021

Background

Incarcerated individuals in Brazil are at high-risk of tuberculosis (TB), but their access to World Health Organization recommended diagnostics is poorly understood.

Methods

We conducted a retrospective cross-sectional study of newly diagnosed TB cases in Brazil’s notifiable disease registry, which includes information on diagnostic tests performed, from January 2015 through December 2018. We quantified reported use of TB diagnostics across incarcerated and non-incarcerated populations and tested for municipality-level factors associated with diagnostic usage among the incarcerated population with generalized linear regression.

Results

Between 2015 and 2018, 258,014 individuals were newly diagnosed with TB, including 27,400 (10.6%) incarcerated individuals. Among these, 27.5% had an Xpert MTB/RIF test reported; 71.5% had sputum smear; 34.1% had culture; 70.9% had chest radiography. Xpert MTB/RIF use was greater among incarcerated than non-incarcerated individuals (36.2% vs 26.5%, p<0.001). However, we found spatial heterogeneity in state-level use of both Xpert MTB/RIF (range: 4.7-72.4% cases diagnosed) and chest radiography (range: 11.7-88.4%) in prisons. We identified seven municipalities with large incarcerated populations (>5000) with rates of Xpert MTB/RIF usage below the national average in incarcerated individuals.

Conclusion

Prioritizing expansion of rapid molecular diagnostics in prisons, particularly in regions with limited current usage of molecular diagnostics, will be an essential component of TB control.
Increased risk of psychiatric sequelae of COVID-19 is highest early in the clinical course
Authors: Coleman Ben , Casiraghi Elena , Blau Hannah , Chan Lauren , Haendel Melissa , Laraway Bryan , Callahan Tiffany J , Deer Rachel R , Wilkins Ken , Reese Justin , Robinson Peter N
Published: December 2021

Background

COVID-19 has been shown to increase the risk of adverse mental health consequences. A recent electronic health record (EHR)-based observational study showed an almost two-fold increased risk of new-onset mental illness in the first 90 days following a diagnosis of acute COVID-19.

Methods

We used the National COVID Cohort Collaborative, a harmonized EHR repository with 2,965,506 COVID-19 positive patients, and compared cohorts of COVID-19 patients with comparable controls. Patients were propensity score-matched to control for confounding factors. We estimated the hazard ratio (COVID-19:control) for new-onset of mental illness for the first year following diagnosis. We additionally estimated the change in risk for new-onset mental illness between the periods of 21-120 and 121-365 days following infection.

Findings

We find a significant increase in incidence of new-onset mental disorders in the period of 21-120 days following COVID-19 (3.8%, 3.6-4.0) compared to patients with respiratory tract infections (3%, 2.8-3.2). We further show that the risk for new-onset mental illness decreases over the first year following COVID-19 diagnosis compared to other respiratory tract infections and demonstrate a reduced (non-significant) hazard ratio over the period of 121-365 days following diagnosis. Similar findings are seen for new-onset anxiety disorders but not for mood disorders.

Interpretation

Patients who have recovered from COVID-19 are at an increased risk for developing new-onset mental illness, especially anxiety disorders. This risk is most prominent in the first 120 days following infection.

Funding

National Center for Advancing Translational Sciences (NCATS).
Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity
Authors: Tsuo Kristin , Zhou Wei , Wang Ying , Kanai Masahiro , Namba Shinichi , Gupta Rahul , Majara Lerato , Nkambule Lethukuthula L. , Morisaki Takayuki , Okada Yukinori , Neale Benjamin M. ,   Global Biobank Meta-analysis Initiative, Daly Mark J. , Martin Alicia R.
Published: December 2021

Asthma is a complex disease that affects millions of people and varies in prevalence by an order of magnitude across geographic regions and populations. However, the extent to which genetic variation contributes to these disparities is unclear, as studies probing the genetics of asthma have been primarily limited to populations of European (EUR) descent. As part of the Global Biobank Meta-analysis Initiative (GBMI), we conducted the largest genome-wide association study of asthma to date (153,763 cases and 1,647,022 controls) via meta-analysis across 18 biobanks spanning multiple countries and ancestries. Altogether, we discovered 179 genome-wide significant loci (p < 5×10−8) associated with asthma, 49 of which are not previously reported. We replicate well-known associations such as IL1RL1 and STAT6, and find that overall the novel associations have smaller effects than previously-discovered loci, highlighting our substantial increase in statistical power. Despite the considerable range in prevalence of asthma among biobanks, from 3% to 24%, the genetic effects of associated loci are largely consistent across the biobanks and ancestries. To further investigate the polygenic architecture of asthma, we construct polygenic risk scores (PRS) using a multi-ancestry approach, which yields higher predictive power for asthma in non-EUR populations compared to PRS derived from previous asthma meta-analyses. Additionally, we find considerable genetic overlap between asthma age-of-onset subtypes, as well as between asthma and chronic obstructive pulmonary disease (COPD) but minimal overlap in enriched biological pathways. Our work underscores the multifactorial nature of asthma development and offers insight into the shared genetic architecture of asthma that may be differentially perturbed by environmental factors and contribute to variation in prevalence.
De Novo Pyrimidine Synthesis is a Targetable Vulnerability in IDH Mutant Glioma
Authors: Shi Diana D. , Savani Milan R. , Levitt Michael M. , Wang Adam C. , Endress Jennifer E. , Bird Cylaina E. , Buehler Joseph , Stopka Sylwia A. , Regan Michael S. , Lin Yu-Fen , Gao Wenhua , Khanal Januka , Xu Min , Huang Bofu , Jennings Rebecca B. , Bonal Dennis M. , Martin-Sandoval Misty S. , Dang Tammie , Gattie Lauren C. , Lee Sungwoo , Asara John M. , Kornblum Harley I. , Mak Tak W. , Looper Ryan E. , Nguyen Quang-De , Signoretti Sabina , Gradl Stefan , Sutter Andreas , Jeffers Michael , Janzer Andreas , Lehrman Mark A. , Zacharias Lauren G. , Mathews Thomas P. , Richardson Timothy E. , Cahill Daniel P. , DeBerardinis Ralph J. , Ligon Keith L. , Ly Peter , Agar Nathalie Y. R. , Abdullah Kalil G. , Harris Isaac S. , Kaelin William G. , McBrayer Samuel K.
Published: December 2021

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH mutant gliomas. Mechanistically, this vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus
Authors: Kleijwegt Constance , Bressac Florent , Cohen Camille , Texier Pascale , Simonet Thomas , Schaeffer Laurent , Lomonte Patrick , Corpet Armelle
Published: December 2021

Promyelocytic Leukemia Nuclear Bodies (PML NBs) are nuclear membrane-less organelles physically associated with chromatin underscoring their crucial role in genome function. The H3.3 histone chaperone complex HIRA accumulates in PML NBs upon senescence, viral infection or IFN-I treatment in primary cells. Yet, the molecular mechanisms of this partitioning and its function in regulating histone dynamics have remained elusive. By using specific approaches, we identify intermolecular SUMO-SIM interactions as an essential mechanism for HIRA recruitment in PML NBs. Upon IFN-I stimulation, PML is required for interferon-stimulated genes (ISGs) transcription and PML NBs become juxtaposed to ISGs loci at late time points of IFN-I treatment. HIRA and PML are necessary for the prolonged H3.3 deposition at the transcriptional end sites of ISGs, well beyond the peak of transcription. Though, HIRA accumulation in PML NBs is dispensable for H3.3 deposition on ISGs. Hence, we describe an independent role of PML NBs as nuclear depot centers to regulate HIRA distribution in the nucleus, as a consequence of the availability of the pool of H3.3-H4 dimers or chromatin compaction. We thus uncover a dual function for PML/PML NBs in regulating ISGs transcription and H3.3 deposition at ISGs, and in modulating the nuclear distribution of HIRA upon inflammatory response.
Inverse PI by NMR: Analysis of Ligand 1H-Chemical Shifts in the Protein-Bound State
Authors: Platzer Gerald , Mayer Moriz , Böttcher Jark , Geist Leonhard , Fuchs Julian E. , McConnell Darryl B. , Konrat Robert
Published: December 2021

The study of protein-ligand interactions via protein-based NMR generally relies on the detection of chemical-shift changes induced by ligand binding. However, the chemical shift of the ligand when bound to the protein is rarely discussed, since it is not readily detectable. In this work we use protein deuteration in combination with [1H-1H]-NOESY NMR to extract 1H chemical shift values of the ligand in the bound state. The chemical shift perturbations (CSPs) experienced by the proton ligand resonances (free vs bound) are an extremely rich source of information on protein-ligand complexes. Besides allowing for the detection of intermolecular CH-π interactions and elucidation of the protein-bound ligand conformation, the CSP information can be used to analyse (de)solvation effects in a site-specific manner. In conjunction with crystal structure information, it is possible to distinguish protons whose desolvation penalty is compensated for upon protein-binding, from those that are not. Combined with the previously reported PI by NMR technique for the protein-based detection of intermolecular CH-π interactions, this method represents another important step towards the ultimate goal of Interaction-Based Drug Discovery.
Capturing cognitive events embedded in the real-world using mobile EEG and Eye-Tracking
Authors: Ladouce Simon , Mustile Magda , Dehais Frédéric
Published: December 2021

The study of cognitive processes underlying natural behaviours implies to depart from computerized paradigms and artificial experimental probes. The aim of the present study is to assess the feasibility of capturing neural markers of visual attention (P300 Event-Related Potentials) in response to objects embedded in a real-world environment. To this end, electroencephalography and eye-tracking data were recorded while participants attended stimuli presented on a tablet and while they searched for books in a library. Initial analyses of the library data revealed P300-like features shifted in time. A Dynamic Time Warping analysis confirmed the presence of P300 ERP in the library condition. Library data were then lag-corrected based on cross-correlation co-efficients. Together these approaches uncovered P300 ERP responses in the library recordings. These findings high-light the relevance of scalable experimental designs, joint brain and body recordings and template-matching analyses to capture cognitive events during natural behaviours.
E-cadherin mediated Apical Membrane Initiation Site localisation
Authors: Liang Xuan , Weberling Antonia , Hii Chun Yuan , Zernicka-Goetz Magdalena , Buckley Clare E
Published: December 2021

Individual cells within de novo polarising tubes and cavities must integrate their forming apical domains into a centralised apical membrane initiation site (AMIS). This is necessary to enable organised lumen formation within multi-cellular tissue. Despite the well documented importance of cell division in localising the AMIS, we have found a division-independent mechanism of AMIS localisation that relies instead on Cadherin-mediated cell-cell adhesion. Our study of de novo polarising mouse embryonic stem cells (mESCs) cultured in 3D suggest that cell-cell adhesion localises apical proteins such as PAR-6 to a centralised AMIS. Unexpectedly, we also found that mESC cell clusters lacking functional E-cadherin still formed a lumen-like cavity in the absence of AMIS localisation but did so at a later stage of development via a ‘closure’ mechanism, instead of via hollowing. This work suggests that there are two, interrelated mechanisms of apical polarity localisation: cell adhesion and cell division. Alignment of these mechanisms in space allows for redundancy in the system and ensures the development of a coherent epithelial structure within a growing organ.
Strength-frequency curve for micromagnetic neurostimulation through EPSPs on rat hippocampal neurons and numerical modeling of magnetic microcoil (μcoil)
Authors: Saha Renata , Faramarzi Sadegh , Bloom Robert P. , Benally Onri J. , Wu Kai , di Girolamo Arturo , Tonini Denis , Keirstead Susan A. , Low Walter C. , Netoff Theoden I. , Wang Jian-Ping
Published: December 2021

Objective

The objective of this study was to measure the effect of micromagnetic stimulation (μMS) on hippocampal neurons, by using single microcoil (μcoil) prototype,MagneticPen(MagPen). MagPen will be used to stimulate the CA3 region magnetically and excitatory post synaptic potential (EPSP) response measurements will be made from the CA1 region. The threshold for micromagnetic neurostimulation as a function of stimulation frequency of the current driving the μcoil will be demonstrated. Finally, the optimal stimulation frequency of the current driving the μcoil to minimize power will be estimated.

Approach

A biocompatible, watertight, non-corrosive prototype, MagPen was built, and customized such that it is easy to adjust the orientation of the μcoil and its distance over the hippocampal tissue in anin vitrorecording setting. Finite element modeling (FEM) of the μcoil design was performed to estimate the spatial profiles of the magnetic flux density (in T) and the induced electric fields (in V/m). The induced electric field profiles generated at different values of current applied to the μcoil can elicit a neuron response, which was validated by numerical modeling. The modeling settings for the μcoil were replicated in experiments on rat hippocampal neurons.

Main results

The preferred orientation of MagPen over the Schaffer Collateral fibers was demonstrated such that they elicit a neuron response. The recorded EPSPs from CA1 region due to μMS at CA3 region were validated by applying tetrodotoxin (TTX). Application of TTX to the hippocampal slice blocked the EPSPs from μMS while after prolonged TTX washout, a partial recovery of the EPSP from μMS was observed. Finally, it was interpreted through numerical analysis that increasing frequency of the current driving the μcoil, led to a decrease in the current amplitude threshold for micromagnetic neurostimulation.

Significance

This work reports that micromagnetic neurostimulation can be used to evoke population EPSP responses in the CA1 region of the hippocampus. It demonstrates the strengthfrequency curve for μMS and its unique features related to orientation dependence of the μcoils, spatial selectivity and stimulation threshold related to distance dependence. Finally, the challenges related to μMS experiments were studied including ways to overcome them.
TWISTED DWARF1 regulates Arabidopsis stamen development by differential activation of ABCB-mediated auxin transport
Authors: Liu Jie , Ghelli Roberta , Cardarelli Maura , Geisler Markus
Published: December 2021

Despite clear evidence that a local accumulation of auxin is likewise critical for male fertility, much less is known about the components that regulate auxin-controlled stamen development.

In this study, we analyzed physiological and morphological parameters in mutants of key players of ABCB-mediated auxin transport and spatially and temporally dissected their expression on the protein level as well as auxin fluxes in the Arabidopsis stamens. Our analyses revealed that the FKBP42, TWISTED DWARF1 (TWD1), promotes stamen elongation and, to a lesser extent, anther dehiscence, as well as pollen maturation and thus is required for seed development. Most of the described developmental defects in twd1 are shared with the abcb1 abcb19 mutant, which can be attributed to the fact that TWD1 - as a described ABCB chaperon - is a positive regulator of ABCB1 and ABCB19-mediated auxin transport. However, reduced stamen number was dependent on TWD1 but not on investigated ABCBs, suggesting additional actors down-stream of TWD1. We predict an overall housekeeping function for ABCB1 during earlier stages, while ABCB19 seems to be responsible for the key event of rapid elongation at later stages of stamen development. Our data indicate that TWD1 controls stamen development by differential activation of ABCB-mediated auxin transport in the stamen.

Highlight

By using a mix of phenotypical and imaging analyses, we here identify and functionally characterize a new master regulator of flower development.
Time-sensitive prefrontal involvement in associating confidence with task performance illustrates metacognitive introspection in monkeys
Authors: Cai Yudian , Jin Zhiyong , Zhai Chenxi , Wang Huimin , Wang Jijun , Tang Yingying , Kwok Sze Chai
Published: December 2021

Metacognition refers to the ability to be aware of one’s own cognition. Ample evidence indicates that metacognition in the human primate is highly dissociable from cognition, specialized across domains, and subserved by distinct neural substrates. However, these aspects remain relatively understudied in macaque monkeys. In the present study, we investigated the functionality of macaque metacognition by combining a confidence proxy, hierarchical Bayesian meta-d′ computational modelling, and a single-pulse transcranial magnetic stimulation technique. We found that Brodmann area 46d (BA46d) played a critical role in supporting metacognition independent of task performance; we also found that the critical role of this region in meta-calculation was time-sensitive. Additionally, we report that macaque metacognition is highly domain-specific with respect to memory and perception decisions. These findings carry implications for our understanding of metacognitive introspection within the primate lineage.
Cataract Surgery Outcomes and Postoperative Patient Compliance in Limited English Proficiency Patients at a County Hospital
Authors: Yard Colleen C. , Walter Kayla R. , Zhao Ning O. , Chuang Alice Z. , Mankiewicz Kimberly A. , Crowell Eric L.
Published: December 2021

Background/Aims

Investigate the role of language barriers in cataract surgery outcomes at a county hospital.

Methods

Retrospective chart review of patients who underwent cataract surgery March 2018-February 2019 at Lyndon B. Johnson Hospital. Patients who underwent cataract surgery combined with another procedure or had severe glaucoma or proliferative diabetic retinopathy were excluded. Patients were classified into limited English proficient (LEP) or English proficient (non-LEP) groups based on language preferences. Demographics, baseline ocular characteristics, intraoperative complications, postoperative BCVA (best-corrected visual acuity), complications, and compliance were recorded. The primary outcome was incidence of poor visual outcomes (BCVA<20/40) at the postoperative 1-month visit.

Results

354 patients (199 [56%] LEP and 155 [44%] non-LEP) with 125 (35%) males and a mean age 66.1 (±10.9) years were included. LEP patients were about 5 years older than non-LEP patients (P<0.001) and were mostly Hispanic (172 [86%] LEP vs. 36 [26%] non-LEP, P<0.001). The baseline ocular characteristics were similar (P >0.05), except severity of cataract (125 [63%] NSC grade >2+ for LEP vs 70 [51%] for non-LEP, P =0.03). No significant differences in intraoperative complications (P =0.18), incidence of poor vision (P =0.59), postoperative cystoid macular edema (P =0.32), and compliance with the postoperative drop regimen (P =0.11) were noted.

Conclusion

There were no statistically significant differences in incidence of poor vision, complications, or compliance. However, there was a trend toward significance, showing that language barriers may lead to more advanced disease and compliance issues with postoperative medications.

SYNOPSIS

Language barriers may lead to compliance issues with postoperative medication regimens, as shown by the difference in postoperative care adherence rates between limited English proficient and English proficient patients.
Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions
Authors: Choi Kyuhyun , Piasini Eugenio , Cifuentes-Vargas Luigim , Díaz-Hernández Edgar , Henderson Nathan T. , Subramaniyan Manivannan , Gerfen Charles R. , Fuccillo Marc V.
Published: December 2021

Fronto-striatal circuits have been extensively implicated in the cognitive control of behavioral output for both social and appetitive rewards. The functional diversity of prefrontal cortical populations is strongly dependent on their synaptic targets, with control of motor output strongly mediated by connectivity to the dorsal striatum. Despite evidence for functional diversity along the anterior-posterior axis of the dorsomedial striatum (DMS), it is unclear how distinct fronto- striatal sub-circuits support neural computations essential for action selection. Here we identify prefrontal populations targeting distinct DMS subregions and characterize their functional roles. We first performed neural circuit tracing to reveal segregated prefrontal populations defined by anterior/posterior dorsomedial striatal target. We then probed the functional relevance of these parallel circuits via in vivo calcium imaging and temporally precise causal manipulations during a feedback-based 2-alternative choice task. Single-photon imaging revealed circuit-specific representations of task-relevant information with prelimbic neurons targeting anterior DMS (PL::A- DMS) uniquely encoded choices and responses to negative outcomes, while prelimbic neurons targeting posterior DMS (PL::P-DMS) encoded internal representations of value and positive outcomes contingent on prior choice. Consistent with this distributed coding, optogenetic inhibition of PL::A-DMS circuits strongly impacted choice monitoring and behavioral control in response to negative outcomes while perturbation of PL::P-DMS signals impaired task engagement and strategies following positive outcomes. Di-synaptic retrograde tracing uncovered differences in afferent connectivity that may underlie these pathways functional divergence. Together our data uncover novel PL populations engaged in distributed processing for action control.

Prelimbic cortex engages A- and P-DMS via distinct circuits

PL::A-DMS and PL::P-DMS pathways encode divergent aspects of a simple goal-directed task

PL::A-DMS pathways shape responding to negative outcomes via multiple mechanisms

PL::P-DMS pathways guide engagement and choices in response to positive outcomes

Afferent connectomes of PL neurons defined by A-P DMS target are distinct
Tertiary lymphoid structures induced by CXCL13-producing CD4+ T cells increase tumor infiltrating CD8+ T cells and B cells in ovarian cancer
Authors: Ukita Masayo , Hamanishi Junzo , Yoshitomi Hiroyuki , Yamanoi Koji , Takamatsu Shiro , Ueda Akihiko , Suzuki Haruka , Hosoe Yuko , Furutake Yoko , Taki Mana , Abiko Kaoru , Yamaguchi Ken , Nakai Hidekatsu , Baba Tsukasa , Matsumura Noriomi , Yoshizawa Akihiko , Ueno Hideki , Mandai Masaki
Published: December 2021

Background

Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. The presence of TLS is associated with a favorable prognosis in most solid malignancies. The recognition of the relevance of TLS to cancer has led to a growing interest in TLS as an immunomodulatory target to enhance tumor immunity, although how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood.

Methods

TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression were investigated in high grade serous ovarian cancer (HGSC) specimens. CXCL13 expression, which is strongly associated with TLS, and its localization in immune cells, were examined. We explored the tumor microenvironment for CXCL13 secretion by adding various inflammatory cytokines in vitro. The induction of TLS by CXCL13 was examined in a mouse model of ovarian cancer.

Results

CXCL13 gene expression correlated with TLS formation and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. The coexistence of CD8+ T cells and B-cell lineages in the TME was associated with a better prognosis of HGSC and was closely related to the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as the TLS matured. Although TGF-β was reported to stimulate CXCL13 production, our in vitro results revealed that CXCL13 secretion was promoted in CD4+ T cells under TGF-β + IL-2-restricted conditions and in CD8+ T cells under TGF-β + IL-12-rich conditions. In a mouse model of ovarian cancer, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells.

Conclusions

TLS formation was promoted by CXCL13-producing CD4+ T cells and TLSs facilitated the coordinated antitumor responses of cellular and humoral immunity in ovarian cancer.
ANXA2 enhances virus replication through negatively regulating cGAS-STING and RLRs-mediated signal pathway
Authors: Xue Mengdi , Liu Hongyang , Zhang Zhaoxia , Feng Chunying , Zhang Kunli , Liu Xiaohong , Ye Guangqiang , Zhou Qiongqiong , Li Changyao , Weng Changjiang , Huang Li
Published: December 2021

Host nucleic acid receptors can recognize the viral DNA or RNA upon virus infection, which further triggers multiple signal pathways to promote the translocation of the interferon regulatory factor 3 (IRF3) into nucleus and produce type I interferon (IFN), leading to the host antiviral response. Here, we report a novel negative regulator Annexin A2 (ANXA2) that regulates type I IFN production through multiple mechanisms. Ectopic expression of ANXA2 inhibited the production of type I IFN induced by DNA- and RNA viruses and enhanced virus replication, while knockout of ANXA2 expression enhanced the production of type I IFN and inhibited virus replication. Mechanistically, ANXA2 not only disrupted MDA5 recruiting MAVS, but also inhibited the interaction between MAVS and TRAF3 upon RNA virus infection. In addition, ANXA2 impacted the translocation of STING from endoplasmic reticulum to Golgi apparatus upon DNA virus infection. Interestingly, ANXA2 also inhibited IRF3 phosphorylation and nuclear translocation through competing with TANK-binds kinase 1 (TBK1) and inhibitor-κB kinase ε (IKKε) for binding to IRF3. Anxa2 deficiency in vivo increased the production of type I IFN, which resulted in suppression of encephalomyocarditis virus (EMCV) replication. Our findings reveal that ANXA2, as a negative regulator of type I IFN production, plays an important role in regulating the host antiviral responses.

Author summary

Annexin is a family of evolutionarily conserved multi-gene proteins, which are widely distributed in various tissues and cells of plants and animals. These proteins can reversibly bind to phospholipid membranes and to calcium ions (Ca2+). To date, several studies have confirmed that some members of the Annexin family regulate the antiviral innate immune response. Until now, regulation of the production of type I IFN by ANXA2 is not reported. In this study, ANXA2 were found to strongly inhibit the production of type I IFN, leading to increased virus replication while knockout of ANXA2 expression inhibited virus replication by increasing the amount of IFN. Compared with wild-type littermates, ANXA2 deficiency mice produced more type I IFN to inhibit virus replication. Our results provide methanistic insights into the novel role of ANXA2 in the antiviral innate immune responses.
Rice leaves undergo a rapid metabolic reconfiguration during a specific stage of primordium development
Authors: Cox Naomi , Walker Heather J. , Pitman James K. , Quick W. Paul , Smith Lisa M. , Fleming Andrew J.
Published: December 2021

Leaf development is crucial to establish the photosynthetic competency of plants. It is a process that requires coordinated changes in cell number and differentiation, transcriptomes, metabolomes and physiology. However, despite the importance of leaf formation for our major crops, early developmental processes for rice have not been comprehensively described. Here we detail the temporal developmental trajectory of early rice leaf development and connect morphological changes to metabolism. In particular, a developmental index based on the patterning of epidermal differentiation visualised by electron microscopy enabled high resolution staging of early growth for single primordium metabolite profiling. These data demonstrate that a switch in the constellation of tricarboxylic acid (TCA) cycle metabolites defines a narrow window towards the end of the P3 stage of leaf development. Taken in the context of other data in the literature, our results substantiate that this phase of rice leaf growth, equivalent to a change of primordium length from around 5 to 7.5 mm, defines a major shift in rice leaf determination towards a photosynthetically defined structure. We speculate that efforts to engineer rice leaf structure should focus on the developmental window prior to these determining events.

Highlight

Rice leaves undergo a shift in fundamental metabolism during a very early and narrow developmental window which co-incides with them acquiring the ability to capture light for photosynthesis
On eco-evolutionary dynamics of phenologies in competitive communities and their robustness to climate change
Authors: Cortier Thomas , Loeuille Nicolas
Published: December 2021

Global changes currently cause temporal shifts in the favourable conditions for different phases of species life cycles. Phenologies characterizing temporal presence, may adapt through heritable evolution in response to these changes. Given a community context, this evolution may cause a change in the phenology overlap and thus a change of interspecific interactions such as competition. Using a model in which phenologies compete and coevolve, we study the conditions under which diversity emerges, as well as their annual distribution. We find that the environment richness (food quantity, light, pollinators…) and competition constrain the diversity and spread of phenologies. A robust pattern of phenologies distribution emerges consistent with Swedish flowering observations. Once a stable community is reached, we apply a progressive change in environmental conditions. We found that adaptation eventually restored diversity, but that the simulated change often led to numerous extinctions due to increased competition. The percentage of diversity lost depends on the speed of change and on the initial diversity. Phenologies already pre-adapted to the new environmental conditions drive the restoration of diversity after the change. We finally study a spatial version of the model in which local communities are organized along an environmental gradient. Pre-change, allowing dispersal decreases the local adaptation of phenologies to their local fixed environmental conditions. Dispersal however largely enhances the maintenance of biodiversity in changing environments, though its benefits are not homogeneous in space. Evolution remains the only rescue mechanism for southern phenotypes.
Invertebrate-induced priority effects and secondary metabolites control fungal community composition in dead wood
Authors: Lunde Lisa Fagerli , Jacobsen Rannveig , Kauserud Håvard , Boddy Lynne , Nybakken Line , Sverdrup-Thygeson Anne , Birkemoe Tone
Published: December 2021

During decomposition of organic matter, microbial communities may follow different successional trajectories depending on the initial environment and colonizers. The timing and order of the assembly history can lead to divergent communities through priority effects. We explored how assembly history and resource quality affected fungal dead wood communities and decomposition, 1.5 and 4.5 years after tree felling. Additionally, we investigated the effect of invertebrate exclusion during the first two summers. For aspen (Populus tremula) logs, we measured initial resource quality of bark and wood, and surveyed the fungal communities by DNA metabarcoding at different time points during succession. We found that a gradient in fungal community composition was related to resource quality and discuss how this may reflect tolerance-dominance trade-offs in fungal life history strategies. As with previous studies, the initial amount of bark tannins was negatively correlated with wood decomposition rate over 4.5 years. The initial fungal community explained variation in community composition after 1.5, but not 4.5 years, of succession. Although the assembly history of initial colonizers may cause alternate trajectories in successional communities, our results indicate that the communities may easily converge with the arrival of secondary colonizers. We also identified a strong invertebrate-induced priority effect of fungal communities, even after 4.5 years of succession, thereby adding crucial knowledge to the importance of invertebrates in affecting fungal community development. By measuring and manipulating aspects of assembly history and resource quality that have rarely been studied, we expand our understanding of the complexity of fungal community dynamics.
Structure ofMycobacterium tuberculosisCya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases
Authors: Mehta Ved , Khanppnavar Basavraj , Schuster Dina , Kantarci Ilayda , Vercellino Irene , Kosturanova Angela , Iype Tarun , Stefanic Sasa , Picotti Paola , Korkhov Volodymyr M.
Published: December 2021

Mycobacterium tuberculosisadenylyl cyclase (AC) Rv1625c / Cya is an evolutionary ancestor of the mammalian membrane ACs and a model system for studies of their structure and function. Although the vital role of ACs in cellular signaling is well established, the function of their transmembrane (TM) regions remains unknown. Here we describe the cryo-EM structure of Cya bound to a stabilizing nanobody at 3.6 Å resolution. The TM helices 1-5 form a structurally conserved domain that facilitates the assembly of the helical and catalytic domains. The TM region contains discrete pockets accessible from the extracellular and cytosolic side of the membrane. Neutralization of the negatively charged extracellular pocket Ex1 destabilizes the cytosolic helical domain and reduces the catalytic activity of the enzyme. The TM domain acts as a functional component of Cya, guiding the assembly of the catalytic domain and providing the means for direct regulation of catalytic activity in response to extracellular ligands.

One-Sentence Summary

Structure ofM. tuberculosismembrane adenylyl cyclase Cya
Fatigue Metabolites of Large Yellow Croaker and Construction of Swimming Model
Authors: Chai Ruoyu , Yin Heng , Huo Runming , Shui Xiaomei , Wang Hanying , Huang Ling , Wang Ping
Published: December 2021

A trend in large yellow croaker (Larimichthys crocea) aquaculture is to establish new production sites that are suitable for extreme weather conditions. However, continuous and strong currents can harm fish welfare. To determine the location of the net cage, it is necessary to assess the swimming ability of large yellow croaker. Currently, our research on large yellow croakers is focusing on behavior analysis. This article investigates the effect of swimming large yellow croakers on metabolites in the body by examining the preferred speed of the group and the endurance swimming ability of single-tailed fish. We evaluated the factors that influence the large yellow croaker’s swimming fatigue by quantifying the content of metabolites and constructed the endurance swimming model using those results. Various results showed large yellow croaker populations tend to grow in low-velocity environments, and this matches their traditional habitat. The samples were taken at different swimming times at a flow rate of 0.35 m/s. According to the results of the metabolite content determination, blood glucose levels is closely related to swimming ability in large yellow croakers. The content of liver glycogen, which regulates blood glucose concentration, decreases in a certain linear relationship. The endurance swimming model of large yellow croaker was constructed according to the changes of liver glycogen content. The goals of this article are to provide a deeper understanding of the physiological characteristics of large yellow croaker swimming, and to provide a reference for choosing fishing and cage sites for large yellow croaker.
Gut bacteria-derived sphingolipids alter innate immune responses to oral cholera vaccine antigens
Authors: Chac Denise , Heller Fred J. , Banna Hasan Al , Kaisar M. Hasanul , Chowdhury Fahima , Bhuiyan Taufiqur Rahman , Akter Afroza , Khan Ashraful Islam , Dumayas Mia G , Markiewicz Susan M , Rice Amelia , Karmakar Polash Chandra , Dash Pinki , LaRocque Regina C. , Ryan Edward T. , Minot Samuel S , Harris Jason B. , Qadri Firdausi , Weil Ana A.
Published: December 2021

The degree of protection conferred after receiving an oral cholera vaccine (OCV) varies based on age, prior exposure toVibrio cholerae, and unknown factors. Recent evidence suggests that the microbiota may mediate some of the unexplained differences in oral vaccine responses. We used metagenomic sequencing of the microbiota at the time of vaccination, and then related microbial features to immune responses after OCV using a reference-independent gene-level analysis. We found that the presence of sphingolipid-producing bacteria was associated with the development of protective immune responses after OCV. We experimentally tested these results by stimulating human macrophages withBacteroides xylanisolvensmetabolites and found that sphingolipid-containing extracts increased innate immune responses to OCV antigens. Our findings demonstrate a new analytic method for translating metagenomic sequencing data into strain-specific results associated with a biological outcome, and in validating this tool, we identified that microbe-derived sphingolipids impact in vitro immune responses to OCV antigens.
Alcohol intake and hypertensive disorders of pregnancy: a negative control analysis in the ALSPAC cohort
Authors: Martin Florence Z , Fraser Abigail , Zuccolo Luisa
Published: December 2021

Abstract

Introduction

Alcohol intake increases blood pressure, yet estimates of associations between maternal intake and hypertensive disorders of pregnancy (HDP) are sparse and range from null to a protective effect. Here we estimated the association of maternal drinking during pregnancy with preeclampsia and gestational hypertension (separately and jointly, as HDP). We used partner’s alcohol intake as a negative control exposure, beverage type-specific models, and a range of sensitivity analyses to strengthen causal inference and reduce the influence of bias.

Methods

We performed a prospective cohort study using data on self-reported alcohol intake in the UK Avon Longitudinal Study of Parents And Children (ALSPAC) and HDP ascertained from obstetric notes. Multivariable multinomial regression models were adjusted for confounders and mutually adjusted for partner’s or maternal alcohol intake in the negative control analysis. We also performed a beverage type analysis of the effect of beer and wine separately on HDP risk, due to different social patterning associated with different drinks. Sensitivity analyses assessed the robustness of results to assumptions of no recall bias, no residual confounding, and no selection bias.

Results

Of the 8,999 women eligible for inclusion, 1,490 developed HDP (17%). Both maternal and partner’s drinking were associated with decreased HDP odds (mutually adjusted odds ratio 0.86, 95% confidence interval 0.77 to 0.96, P-value=0.008 and 0.82, 0.70 to 0.97, P=0.018, respectively). We demonstrate the validity of the negative control analyses using the same approach for smoking as the exposure. This confirmed an inverse association for maternal but not partner’s smoking, as expected. Estimates were more extreme for increasing levels of wine intake compared to increasing levels of beer. Multiple sensitivity analyses did not alter our conclusions.

Conclusion

We observed an inverse relationship between alcohol intake during pregnancy and risk of HDP for both maternal and, more surprisingly, partner’s drinking. We speculate that this is more likely to be due to common environmental exposures shared between pregnant women and their partners, rather than a true causal effect. This warrants further investigation using different study designs, including Mendelian randomisation.