bluuebunny/crossref_metadata_2025 huggingface dataset:
A Data-Driven Framework for the Accelerated Discovery of CO2 Reduction Electrocatalysts
Authors: Malek Ali , Wang Qianpu , Baumann Stefan , Guillon Olivier , Eikerling Michael , Malek Kourosh
Published: April 2021

Searching for next-generation electrocatalyst materials for electrochemical energy technologies is a time-consuming and expensive process, even if it is enabled by high-throughput experimentation and extensive first-principle calculations. In particular, the development of more active, selective and stable electrocatalysts for the CO2 reduction reaction remains tedious and challenging. Here, we introduce a material recommendation and screening framework, and demonstrate its capabilities for certain classes of electrocatalyst materials for low or high-temperature CO2 reduction. The framework utilizes high-level technical targets, advanced data extraction, and categorization paths, and it recommends the most viable materials identified using data analytics and property-matching algorithms. Results reveal relevant correlations that govern catalyst performance under low and high-temperature conditions.
Bark Effects on Stemflow Chemistry in a Japanese Temperate Forest I. The Role of Bark Surface Morphology
Authors: Oka Ayano , Takahashi Junko , Endoh Yoshikazu , Seino Tatsuyuki
Published: April 2021

Stemflow can be an important pathway for the drainage of precipitation and related solutes through tree canopies to forest soils. As stemflow must drain along bark surfaces, the effects of bark structure on stemflow chemical composition is merited. This study examines the relationship between stemflow chemistry and bark surface structure for six species of varying bark morphology (four deciduous broadleaf trees and two evergreen coniferous trees) at a montane and an urban site in Japan. Stemflow from smooth-barked species contained greater concentrations of solutes that appear to be rinsed from the stem surface (i.e., sea salt aerosols); while, rougher-barked tree species contained greater or less concentrations of solutes that appear to be leached (e.g., Ca2+) or taken-up (e.g., inorganic N) by the bark, respectively. Site-specific atmospheric environments also influenced thee bark-stemflow chemistry relationships—where the greater elemental deposition in the urban plot generally resulted in greater stemflow chemistry than observed in the lower-deposition montane plot. Our results therefore suggest that the dynamics of dry deposition wash-off by stemflow, and the exchange of dissolved solutes between stemflow and the bark surface, are influenced by the surface structure of the bark and the site’s atmospheric environment. Therefore, the interactions between bark surface structure and its surrounding atmospheric environment are important factors in the stemflow-related elemental cycling between the tree and precipitation.
Electroporation-Mediated Genome Editing of Livestock Zygotes
Authors: Lin Jason C. , Van Eenennaam Alison L.
Published: April 2021

The introduction of genome editing reagents into mammalian zygotes has traditionally been accomplished by cytoplasmic or pronuclear microinjection. This time-consuming procedure requires expensive equipment and a high level of skill. Electroporation of zygotes offers a simplified and more streamlined approach to transfect mammalian zygotes. There are a number of studies examining the parameters used in electroporation of mouse and rat zygotes. Here, we review the electroporation conditions, timing, and success rates that have been reported for mice and rats, in addition to the few reports about livestock zygotes, specifically pigs and cattle. The introduction of editing reagents at, or soon after, fertilization can help reduce the rate of mosaicism, the presence of two of more genotypes in the cells of an individual; as can the introduction of nuclease proteins rather than mRNA encoding nucleases. Mosaicism is particularly problematic in large livestock species with long generation intervals as it can take years to obtain non-mosaic, homozygous offspring through breeding. Gene knockouts accomplishedviathe non-homologous end joining pathway have been more widely reported and successfully accomplished using electroporation than have gene knock-ins. Delivering large DNA plasmids into the zygote is hindered by the zona pellucida (ZP), and the majority of gene knock-ins accomplished by electroporation have been using short single stranded DNA (ssDNA) repair templates, typically less than 1 kb. The most promising approach to deliver larger donor repair templates of up to 4.9 kb along with genome editing reagents into zygotes, without using cytoplasmic injection, is to use recombinant adeno-associated viruses (rAAVs) in combination with electroporation. However, similar to other methods used to deliver clustered regularly interspaced palindromic repeat (CRISPR) genome-editing reagents, this approach is also associated with high levels of mosaicism. Recent developments complementing germline ablated individuals with edited germline-competent cells offer an approach to avoid mosaicism in the germline of genome edited founder lines. Even with electroporation-mediated delivery of genome editing reagents to mammalian zygotes, there remain additional chokepoints in the genome editing pipeline that currently hinder the scalable production of non-mosaic genome edited livestock.
Laboratory Effects of COVID-19 Infection in Pregnant Women and Their Newborns: A Systematic Review and Meta-Analysis
Authors: Zhang Clark , Chu Haitao , Pei Y. Veronica , Zhang Jason
Published: April 2021

Amidst the COVID-19 pandemic, there is a need for further research on its manifestation in pregnant women, since they are particularly prone to respiratory pathogens, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), due to physiological changes during pregnancy. Its effects on infants born to mothers with COVID-19 are also not well-studied, and more evidence is needed on vertical transmission of the disease from mother to infant and on the transmission of IgG/IgM antibodies between mother and infant. We aim to systematically review and evaluate the effects of COVID-19 among SARS-CoV-2-positive pregnant women in late pregnancy and neonates with SARS-CoV-2-positive pregnant mothers using blood assays to find indicators of maternal and neonatal complications. We searched for original published articles in Google Scholar, Medline (PubMed), and Embase databases to identify articles in the English language from December 2019 to July 20, 2020. Duplicate entries were searched by their titles, authors, date of publication, and Digital Object Identifier. The selected studies were included based on patient pregnancy on admission, pregnant mothers with laboratory-confirmed COVID-19 virus, maternal/neonatal complications, and blood test results. We excluded duplicate studies, articles where full text was not available, other languages than English, opinions, and perspectives. The meta-analysis using the Generalized Linear Mixed model was conducted using the “meta” and “metaprop” packages in R code. Of the 1,642 studies assessed for eligibility, 29 studies (375 mothers and neonates) were included. Preterm birth rate was 34.2%, and cesarean section rate was 82.7%. Maternal laboratory findings found elevated neutrophils (71.4%; 95% CI: 38.5–90.9), elevated CRP (67.7%; 95%: 50.6–81.1), and low hemoglobin (57.3%; 95% CI: 26.0–87.8). We found platelet count, lactate dehydrogenase, and procalcitonin to be less strongly correlated with preterm birth than between high neutrophil counts (P = 0.0007), low hemoglobin (P = 0.0188), and risk of preterm birth. There is little evidence for vertical transmission. Elevated procalcitonin levels (23.2%; 95% CI: 8.4–49.8) are observed in infants born to mothers with COVID-19, which could indicate risk for neonatal sepsis. These infants may gain passive immunity to COVID-19 through antibody transfer via placenta. These results can guide current obstetrical care during the current SARS-CoV-2 pandemic.
Neutrophils: Need for Standardized Nomenclature
Authors: McKenna Ellen , Mhaonaigh Aisling Ui , Wubben Richard , Dwivedi Amrita , Hurley Tim , Kelly Lynne A. , Stevenson Nigel J. , Little Mark A. , Molloy Eleanor J.
Published: April 2021

Neutrophils are the most abundant innate immune cell with critical anti-microbial functions. Since the discovery of granulocytes at the end of the nineteenth century, the cells have been given many names including phagocytes, polymorphonuclear neutrophils (PMN), granulocytic myeloid derived suppressor cells (G-MDSC), low density neutrophils (LDN) and tumor associated neutrophils (TANS). This lack of standardized nomenclature for neutrophils suggest that biologically distinct populations of neutrophils exist, particularly in disease, when in fact these may simply be a manifestation of the plasticity of the neutrophil as opposed to unique populations. In this review, we profile the surface markers and granule expression of each stage of granulopoiesis to offer insight into how each stage of maturity may be identified. We also highlight the remarkable surface marker expression profiles between the supposed neutrophil populations.
In-Vitro Approaches to Predict and Study T-Cell Mediated Hypersensitivity to Drugs
Authors: Hammond Sean , Thomson Paul , Meng Xiaoli , Naisbitt Dean
Published: April 2021

Mitigating the risk of drug hypersensitivity reactions is an important facet of a given pharmaceutical, with poor performance in this area of safety often leading to warnings, restrictions and withdrawals. In the last 50 years, efforts to diagnose, manage, and circumvent these obscure, iatrogenic diseases have resulted in the development of assays at all stages of a drugs lifespan. Indeed, this begins with intelligent lead compound selection/design to minimize the existence of deleterious chemical reactivity through exclusion of ominous structural moieties. Preclinical studies then investigate how compounds interact with biological systems, with emphasis placed on modeling immunological/toxicological liabilities. During clinical use, competent and accurate diagnoses are sought to effectively manage patients with such ailments, and pharmacovigilance datasets can be used for stratification of patient populations in order to optimise safety profiles. Herein, an overview of some of thein-vitroapproaches to predict intrinsic immunogenicity of drugs and diagnose culprit drugs in allergic patients after exposure is detailed, with current perspectives and opportunities provided.
Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma
Authors: Huang Lili , Xu Yu , Fang Juemin , Liu Weixing , Chen Jianhua , Liu Zhuqing , Xu Qing
Published: April 2021

Background

Less than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. Thus, it is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy.

Methods

A genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells, and B16-F10 melanoma mice were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.

Results

Here, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and various immunosuppressive factors within tumor-infiltrated Treg cells after treatment with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual PBMCs and the murine melanoma model, limiting the immunosuppression of Treg cells.

Conclusions

Our findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.
How to Manage COVID-19 Vaccination in Immune-Mediated Inflammatory Diseases: An Expert Opinion by IMIDs Study Group
Authors: Ferretti Francesca , Cannatelli Rosanna , Benucci Maurizio , Carmagnola Stefania , Clementi Emilio , Danelli Piergiorgio , Dilillo Dario , Fiorina Paolo , Galli Massimo , Gallieni Maurizio , Genovese Giovanni , Giorgi Valeria , Invernizzi Alessandro , Maconi Giovanni , Maier Jeanette A. , Marzano Angelo V. , Morpurgo Paola S. , Nebuloni Manuela , Radovanovic Dejan , Riva Agostino , Rizzardini Giuliano , Sabiu Gianmarco , Santus Pierachille , Staurenghi Giovanni , Zuccotti Gianvincenzo , Sarzi-Puttini Pier Carlo , Ardizzone Sandro
Published: April 2021

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.
Far-Field Impacts of a Super Typhoon on Upper Ocean Phytoplankton Dynamics
Authors: Qiu Guoqiang , Xing Xiaogang , Chai Fei , Yan Xiao-Hai , Liu Zhiyu , Wang Haili
Published: April 2021

Super typhoon Rammasun (2014) traveled across the South China Sea on July 16–18. Its far-field impacts on phytoplankton dynamics in the upper ocean were documented by a Biogeochemical-Argo (BGC-Argo) float located 200 km to the left of its track. Both surface chlorophyll-a concentration (Chla) and particulate backscattering coefficient (bbp) were observed to increase substantially within two distinct stages. The initial increase occurred during the passage of the typhoon, and the subsequent increase happened 5 days after the typhoon. In contrast, depth-integrated Chla and bbp in the upper 150 m underwent negligible changes throughout the entire period. The key lies in the fact that surface phytoplankton increases in the far-field region resulted from the physically driven vertical redistribution of particles, rather than from biological alternations. The first increase was attributed to the typhoon-induced strong turbulence which deepened the surface mixed layer, and thus entrained subsurface particles to the surface; the second was due to the post-typhoon adiabatic quasi-geostrophic adjustment of the upper ocean that gradually raised the isopycnals (and thus subsurface particles). These results challenge the prevailing wisdom on typhoon impacts, and thus shed new lights on the nature of the upper ocean responses to typhoons from both physical and biological perspectives.
Recent Advances of 4D Printing Technologies Toward Soft Tactile Sensors
Authors: Tang Yuneng , Dai Baiqian , Su Bin , Shi Yusheng
Published: April 2021

Soft tactile sensors (STSs) combine the flexibility and the converting ability between mechanical forces and electrical signals. 4D printing was first introduced in 2013, and attracted great interest because of its versatile functionalities in actuators, artificial muscles, STSs, soft energy harvesting, pneumatic nets, electroactive polymers, and soft electronics. Using the 4D printing concept to fabricate STSs is promising, yet it is at its infant stage. At present, researchers have utilized two types of strategies: one is directly using smart materials through 3D printing manufacturing, and the other is programming codes of components and structures to create controllable changes. This review summarizes the recent research on 4D printing toward STSs and discusses the future perspectives of this emerging field.
A JKR-Like Solution for Viscoelastic Adhesive Contacts
Authors: Violano Guido , Chateauminois Antoine , Afferrante Luciano
Published: April 2021

A closed-form solution for the adhesive contact of soft spheres of linear elastic material is available since 1971 thanks to the work of Johnson, Kendall, and Roberts (JKR). A similar solution for viscoelastic spheres is still missing, though semi-analytical and numerical models are available today. In this note, we propose a closed-form analytical solution, based on JKR theory, for the detachment of a rigid sphere from a viscoelastic substrate. The solution returns the applied load and contact penetration as functions of the contact radius and correctly captures the velocity-dependent nature of the viscoelastic pull-off. Moreover, a simple approach is provided to estimate the stick time, i.e., the delay between the time the sphere starts raising from the substrate and the time the contact radius starts reducing. A simple formula is also suggested for the viscoelastic pull-off force. Finally, a comparison with experimental and numerical data is shown.
Comparison of Clinical Features and CT Temporal Changes Between Familial Clusters and Non-familial Patients With COVID-19 Pneumonia
Authors: Liu Shuyi , Yuan Huanchu , Zhang Bin , Li Wei , You Jingjing , Liu Jing , Zhong Qingyang , Zhang Lu , Chen Luyan , Li Shaolin , Zou Yujian , Zhang Shuixing
Published: April 2021

Purpose: This study aimed to compare the clinical characteristics, laboratory findings, and chest computed tomography (CT) findings of familial cluster (FC) and non-familial (NF) patients with coronavirus disease 2019 (COVID-19) pneumonia.

Methods: This retrospective study included 178 symptomatic adult patients with laboratory-confirmed COVID-19. The 178 patients were divided into FC (n = 108) and NF (n = 70) groups. Patients with at least two confirmed COVID-19 cases in their household were classified into the FC group. The clinical and laboratory features between the two groups were compared and so were the chest CT findings on-admission and end-hospitalization.

Results: Compared with the NF group, the FC group had a longer period of exposure (13.1 vs. 8.9 days, p < 0.001), viral shedding (21.5 vs. 15.9 days, p < 0.001), and hospital stay (39.2 vs. 22.2 days, p < 0.001). The FC group showed a higher number of involved lung lobes on admission (3.0 vs. 2.3, p = 0.017) and at end-hospitalization (3.6 vs. 1.7, p < 0.001) as well as higher sum severity CT scores at end-hospitalization (4.6 vs. 2.7, p = 0.005) than did the NF group. Conversely, the FC group had a lower lymphocyte count level (p < 0.001) and a significantly lower difference in the number of involved lung lobes (Δnumber) between admission and discharge (p < 0.001). Notably, more cases of severe or critical illness were observed in the FC group than in the NF group (p = 0.036).

Conclusions: Patients in the FC group had a worse clinical course and outcome than those in the NF group; thus, close monitoring during treatment and follow-ups after discharge would be beneficial for patients with familial infections.
Role of Clofazimine in Treatment of Mycobacterium avium Complex
Authors: Nasiri Mohammad Javad , Calcagno Tess , Hosseini Sareh Sadat , Hematian Ali , Nojookambari Neda Yousefi , Karimi-Yazdi Mohammadmahdi , Mirsaeidi Mehdi
Published: April 2021

Background: Non-tuberculous mycobacteria (NTM), specifically Mycobacterium avium complex (MAC), is an increasingly prevalent cause of pulmonary dysfunction. Clofazimine has been shown to be effective for the treatment of M. avium complex, but there were no published large-scale analyses comparing clofazimine to non-clofazimine regimens in MAC treatment. The objective of this large-scale meta-analysis was to evaluate patient characteristics and treatment outcomes of individuals diagnosed with MAC and treated with a clofazimine-based regimen.

Methods: We used Pubmed/Medline, Embase, Web of Science, and the Cochrane Library to search for studies published from January 1, 1990 to February 9, 2020. Two reviewers (SSH and NY) extracted the data from all eligible studies and differences were resolved by consensus. Statistical analyses were performed with STATA (version 14, IC; Stata Corporation, College Station, TX, USA).

Results: The pooled success treatment rate with 95% confidence intervals (CI) was assessed using random effect model. The estimated pooled treatment success rates were 56.8% in clofazimine and 67.9% in non-clofazimine groups. Notably, success rates were higher (58.7%) in treatment of HIV patients with disseminated infection.

Conclusions: Treatment was more successful in the non-clofazimine group overall. However, HIV patients with disseminated infection had higher treatment response rates than non-HIV patients within the clofazimine group.
Minireview on Novel Anti-infectious Treatment Options and Optimized Drug Regimens for Sepsis
Authors: Hites Maya
Published: April 2021

Sepsis, a life-threatening organ dysfunction caused by a dysregulated response to infection is a major public health concern, as it is a leading cause of mortality and critical illness worldwide. Antibiotics are one of the cornerstones of the treatment of sepsis; administering appropriate antibiotics in a rapid fashion to obtain adequate drug concentrations at the site of the infection can improve survival of patients. Nevertheless, it is a challenge for clinicians to do so. Indeed, clinicians today are regularly confronted with infections due to very resistant pathogens, and standard dosage regimens of antibiotics often do not provide adequate antibiotic concentrations at the site of the infection. We provide a narrative minireview of different anti-infectious treatments currently available and suggestions on how to deliver optimized dosage regimens to septic patients. Particular emphasis will be made on newly available anti-infectious therapies.
The Possible Non-Mutational Causes of FVIII Deficiency: Non-Coding RNAs and Acquired Hemophilia A
Authors: Zimta Alina-Andreea , Hotea Ionut , Brinza Melen , Blag Cristina , Iluta Sabina , Constantinescu Catalin , Bashimov Atamyrat , Marchis-Hund Elisabeth-Antonia , Coudsy Alexandra , Muller-Mohnssen Laetitia , Dirzu Noemi , Gulei Diana , Dima Delia , Serban Margit , Coriu Daniel , Tomuleasa Ciprian
Published: April 2021

Hemophilia type A (HA) is the most common type of blood coagulation disorder. While the vast majority of cases are inherited and caused by mutations in the F8 gene, recent data raises new questions regarding the non-heritability of this disease, as well as how other molecular mechanisms might lead to the development of HA or increase the severity of the disease. Some data suggest that miRNAs may affect the severity of HA, but for some patients, miRNA-based interference might cause HA, in the absence of an F8 mutation. A mechanism in HA installation that is also worth investigating and which could be identified in the future is the epigenetic silencing of the F8 gene that might be only temporarily. Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified.
Go Ask Your Patients! PSS-QoL Reported Perception of Dryness Correlates With Lacrimal and Salivary Flow in Primary Sjögren's Syndrome
Authors: Lackner Angelika , Bosch Philipp , Zenz Sabine , Horwath-Winter Jutta , Rabensteiner Dieter Franz , Hermann Josef , Graninger Winfried , Stradner Martin Helmut
Published: April 2021

Introduction/Objectives: The patient perspective is an essential outcome parameter in the quest for effective therapy in primary Sjögren's Syndrome (PSS). The EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is recommended by EULAR to quantify patient's symptom burden and has been used in several clinical trials. Surprisingly, the patient's perception of dryness quantified with ESSPRI does not correlate with objective measures of salivary or lacrimal flow. Thus, we evaluated a newly developed assessment tool-the Primary Sjögren's Syndrome Quality of Life Questionnaire (PSS-QoL)—for quantifying symptoms of dryness in comparison with the ESSPRI and objective measurements of salivary and lacrimal flow.

Methods: Data of patients from the PSS registry of the Medical University of Graz fulfilling the 2016 ACR/EULAR classification criteria for PSS were analyzed. The patient perspective was analyzed by PSS-QoL, ESSPRI, Xerostomia Inventory (XI) and Ocular Surface Disease Index (OSDI). Sicca signs were measured with Schirmer's test, unstimulated salivary flow test (USF) and stimulated salivary flow test (SSF). ESSDAI (EULAR Sjögren's Syndrome Disease Activity Index) and EGA (Evaluator Global Assessment, numeric rating scale from 0 to 10) were obtained. In addition, free light chains (FLC) κ and λ, rheumatoid factor (RF) IgM and IgA were determined.

Results: Data from 123 PSS patients were analyzed; 91.9% (n = 113) were female, with a mean disease duration of 6.2 (±5.3) years and mean age of 60.1 (±12.4) years. PSS-QoL-dryness revealed significant negative correlations with Schirmer's test (r = −0.31, p < 0.05) and SSF-test (r = −0.390, p < 0.01). In contrast, we found no significant correlation between ESSPRI-dryness and any objective dryness test. Lower perceived dryness was associated with higher immunological activity determined by increased levels of IgG, FLC and RF-IgA. Whereas patients with only subjective signs of dryness had lower immunological activity.

Discussion: Patients' perception of dryness assessed by PSS-QoL correlates with objective measurements of salivary gland function while ESSPRI-dryness did not. Based on the PSS-QoL and objective measures of dryness two distinct groups of PSS patients could be distinguished, which may have implications in daily practice and future clinical studies.
Molecular Programming of Drought-Challenged Trichoderma harzianum-Bioprimed Rice (Oryza sativa L.)
Authors: Bashyal Bishnu Maya , Parmar Pooja , Zaidi Najam Waris , Aggarwal Rashmi
Published: April 2021

Trichoderma biopriming enhances rice growth in drought-stressed soils by triggering various plant metabolic pathways related to antioxidative defense, secondary metabolites, and hormonal upregulation. In the present study, transcriptomic analysis of rice cultivar IR64 bioprimed with Trichoderma harzianum under drought stress was carried out in comparison with drought-stressed samples using next-generation sequencing techniques. Out of the 2,506 significant (p < 0.05) differentially expressed genes (DEGs), 337 (15%) were exclusively expressed in drought-stressed plants, 382 (15%) were expressed in T. harzianum-treated drought-stressed plants, and 1,787 (70%) were commonly expressed. Furthermore, comparative analysis of upregulated and downregulated genes under stressed conditions showed that 1,053 genes (42%) were upregulated and 733 genes (29%) were downregulated in T. harzianum-treated drought-stressed rice plants. The genes exclusively expressed in T. harzianum-treated drought-stressed plants were mostly photosynthetic and antioxidative such as plastocyanin, small chain of Rubisco, PSI subunit Q, PSII subunit PSBY, osmoproteins, proline-rich protein, aquaporins, stress-enhanced proteins, and chaperonins. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis states that the most enriched pathways were metabolic (38%) followed by pathways involved in the synthesis of secondary metabolites (25%), carbon metabolism (6%), phenyl propanoid (7%), and glutathione metabolism (3%). Some of the genes were selected for validation using real-time PCR which showed consistent expression as RNA-Seq data. Furthermore, to establish host–T. harzianum interaction, transcriptome analysis of Trichoderma was also carried out. The Gene Ontology (GO) analysis of T. harzianum transcriptome suggested that the annotated genes are functionally related to carbohydrate binding module, glycoside hydrolase, GMC oxidoreductase, and trehalase and were mainly upregulated, playing an important role in establishing the mycelia colonization of rice roots and its growth. Overall, it can be concluded that T. harzianum biopriming delays drought stress in rice cultivars by a multitude of molecular programming.
Mitochondrial Chaperones and Proteases in Cardiomyocytes and Heart Failure
Authors: Chen Zee , Huang Lei , Tso Alexandria , Wang Shijia , Fang Xi , Ouyang Kunfu , Han Zhen
Published: April 2021

Heart failure is one of the leading causes of morbidity and mortality worldwide. In cardiomyocytes, mitochondria are not only essential organelles providing more than 90% of the ATP necessary for contraction, but they also play critical roles in regulating intracellular Ca2+ signaling, lipid metabolism, production of reactive oxygen species (ROS), and apoptosis. Because mitochondrial DNA only encodes 13 proteins, most mitochondrial proteins are nuclear DNA-encoded, synthesized, and transported from the cytoplasm, refolded in the matrix to function alone or as a part of a complex, and degraded if damaged or incorrectly folded. Mitochondria possess a set of endogenous chaperones and proteases to maintain mitochondrial protein homeostasis. Perturbation of mitochondrial protein homeostasis usually precedes disruption of the whole mitochondrial quality control system and is recognized as one of the hallmarks of cardiomyocyte dysfunction and death. In this review, we focus on mitochondrial chaperones and proteases and summarize recent advances in understanding how these proteins are involved in the initiation and progression of heart failure.
Stress Alters the Effect of Alcohol on Catecholamine Dynamics in the Basolateral Amygdala
Authors: Deal Alex L. , Park Jinwoo , Weiner Jeff L. , Budygin Evgeny A.
Published: April 2021

The current rodent study applied in vivo fast-scan cyclic voltammetry (FSCV), paired with a pharmacological approach, to measure the release of the catecholamines (CA) dopamine (DA) and norepinephrine (NE) in the basolateral amygdala (BLA) following locus coeruleus (LC) stimulation. The primary goal was to determine if exposure to either social (social defeat) or non-social (forced swim) stress altered LC-evoked catecholamine release dynamics in the BLA. We used idazoxan (α2 adrenergic receptor antagonist) and raclopride (D2 dopamine receptor antagonist) to confirm the presence of NE and DA, respectively, in the measured CA signal. In non-stressed rats, injection of idazoxan, but not raclopride, resulted in a significant increase in the detected CA signal, indicating the presence of NE but not DA. Following exposure to either stress paradigm, the measured CA release was significantly greater after injection of either drug, suggesting the presence of both NE and DA in the LC-induced CA signal after social or non-social stress. Furthermore, acute administration of alcohol significantly decreased the CA signal in stressed rats, while it did not have an effect in naïve animals. Together, these data reveal that, while LC stimulation primarily elicits NE release in the BLA of control animals, both social and non-social stress unmask a novel dopaminergic component of LC catecholamine signaling. Future studies will be needed to identify the specific neural mechanism(s) responsible for these plastic changes in LC-BLA catecholamine signaling and to assess the possible contribution of these changes to the maladaptive behavioral phenotypes that develop following exposure to these stressors.
Quantifying Cognitive Impairment After Sleep Deprivation at Different Times of Day: A Proof of Concept Using Ultra-Short Smartphone-Based Tests
Authors: Holding Benjamin C. , Ingre Michael , Petrovic Predrag , Sundelin Tina , Axelsson John
Published: April 2021

Cognitive functioning is known to be impaired following sleep deprivation and to fluctuate depending on the time of day. However, most methods of assessing cognitive performance remain impractical for environments outside of the lab. This study investigated whether 2-min smartphone-based versions of commonly used cognitive tests could be used to assess the effects of sleep deprivation and time of day on diverse cognitive functions. After three nights of normal sleep, participants (N = 182) were randomised to either one night of sleep deprivation or a fourth night of normal sleep. Using the Karolinska WakeApp (KWA), participants completed a battery of 2-min cognitive tests, including measures of attention, arithmetic ability, episodic memory, working memory, and a Stroop test for cognitive conflict and behavioural adjustment. A baseline measurement was completed at 22:30 h, followed by three measurements the following day at approximately 08:00 h, 12:30 h, and 16:30 h. Sleep deprivation led to performance impairments in attention, arithmetic ability, episodic memory, and working memory. No effect of sleep deprivation was observed in the Stroop test. There were variations in attention and arithmetic test performance across different times of day. The effect of sleep deprivation on all cognitive tests was also found to vary at different times of day. In conclusion, this study shows that the KWA’s 2-min cognitive tests can be used to detect cognitive impairments following sleep deprivation, and fluctuations in cognitive performance relating to time of day. The results demonstrate the potential of using brief smartphone-based tasks to measure a variety of cognitive abilities within sleep and fatigue research.
COVID-19 Dysautonomia
Authors: Goodman Brent P. , Khoury Julie A. , Blair Janis E. , Grill Marie F.
Published: April 2021

Objective: To report a case series of dysautonomia associated with COVID-19 infection.

Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing.

Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia.

Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.
Bilingualism: A Global Public Health Strategy for Healthy Cognitive Aging
Authors: Mendis Sahan Benedict , Raymont Vanessa , Tabet Naji
Published: April 2021

Dementia is a global public health priority which cost global societies $818 billion in 2015 and is disproportionately impacting low and middle-income countries (LMICs). With limited availability of disease modifying drugs to treat Alzheimer's disease (AD), researchers have increasingly focused on preventative strategies which may promote healthy cognitive aging and mitigate the risk of cognitive impairment in aging. Lifelong bilingualism has been presented as both a highly debated and promising cognitive reserve factor which has been associated with better cognitive outcomes in aging. A recent metanalysis has suggested that bilingual individuals present on average 4.05 years later with the clinical features of AD than monolinguals. Bilinguals are also diagnosed with AD ~2.0 years later than monolingual counterparts. In this perspective piece we critically evaluate the findings of this metanalysis and consider the specific implications of these findings to LMICs. Furthermore, we appraise the major epidemiological studies conducted globally on bilingualism and the onset of dementia. We consider how both impactful and robust studies of bilingualism and cognition in older age may be conducted in LMICs. Given the limited expenditure and resources available in LMICs and minimal successes of clinical trials of disease modifying drugs we propose that bilingualism should be positioned as an important and specific public health strategy for maintaining healthy cognitive aging in LMICs. Finally, we reflect upon the scope of implementing bilingualism within the education systems of LMICs and the promotion of bilingualism as a healthy cognitive aging initiative within government policy.
Emerging Disease-Modifying Therapies in Neurodegeneration With Brain Iron Accumulation (NBIA) Disorders
Authors: Iankova Vassilena , Karin Ivan , Klopstock Thomas , Schneider Susanne A.
Published: April 2021

Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4′-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4′-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.
Autotitrating Bilevel Positive Airway Pressure in Large Vessel Steno-Occlusive Stroke Patients With Suspected Sleep Apnea: A Multicenter Randomized Controlled Study
Authors: Barlinn Kristian , Jakubicek Stanislava , Siepmann Timo , Chernyshev Oleg Y. , Pallesen Lars-Peder , Wienecke Miriam , Hermann Wiebke , Graehlert Xina , Alexandrov Anne W. , Vosko Milan , Puetz Volker , Reichmann Heinz , Bodechtel Ulf , Mikulik Robert , Barlinn Jessica , Alexandrov Andrei V.
Published: April 2021

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke.

Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0–2], stroke recurrence, and mortality at 90 days were assessed.

Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5–18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: −2.0, IQR = 7 points vs. −0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified.

Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted.

Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01812993.
Selective Vagus Nerve Stimulation as a Therapeutic Approach for the Treatment of ARDS: A Rationale for Neuro-Immunomodulation in COVID-19 Disease
Authors: Mastitskaya Svetlana , Thompson Nicole , Holder David
Published: April 2021

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury. It is induced by sepsis, aspiration, and pneumonia, including that caused by SARS coronavirus and human influenza viruses. The main pathophysiological mechanism of ARDS is a systemic inflammatory response. Vagus nerve stimulation (VNS) can limit cytokine production in the spleen and thereby dampen any systemic inflammation and inflammation-induced tissue damage in the lungs and other organs. However, the effects of increased parasympathetic outflow to the lungs when non-selective VNS is applied may result in bronchoconstriction, increased mucus secretion and enhance local pulmonary inflammatory activity; this may outweigh the beneficial systemic anti-inflammatory action of VNS. Organ/function-specific therapy can be achieved by imaging of localized fascicle activity within the vagus nerve and selective stimulation of identified organ-specific fascicles. This may be able to provide selective neuromodulation of different pathways within the vagus nerve and offer a novel means to improve outcome in ARDS. This has motivated this review in which we discuss the mechanisms of anti-inflammatory effects of VNS, progress in selective VNS techniques, and a possible application for ARDS.
Gut Microbiota Influence Lipid Metabolism of Skeletal Muscle in Pigs
Authors: Wu Choufei , Lyu Wentao , Hong Qihua , Zhang Xiaojun , Yang Hua , Xiao Yingping
Published: April 2021

Gut microbiota is recognized as a strong determinant of host physiology including fat metabolism and can transfer obesity-associated phenotypes from donors to recipients. However, the relationship between gut microbiota and intramuscular fat (IMF) is still largely unknown. Obese Jinhua pigs (JP) have better meat quality that is associated with higher IMF content than lean Landrace pigs (LP). The present study was conducted to test the contribution of gut microbiota to IMF properties by transplanting fecal microbiota of adult JP and LP to antibiotics-treated mice. Similar to JP donors, the mice receiving JP's microbiota (JM) had elevated lipid and triglyceride levels and the lipoprotein lipase activity, as well as reduced mRNA level of angiopoietin-like 4 (ANGPTL4) in the gastrocnemius muscles, compared to those in mice receiving LP's microbiota (LM). High-throughput 16S rRNA sequencing confirmed that transplantation of JP and LP feces differently reconstructed the gut microbiota in both jejunum and colon of mouse recipients. In colonic samples, we observed an elevated ratio of Firmicutes to Bacteroidetes and increased abundance of genus Romboutsia in JM, which were positively correlated with obesity. Furthermore, the abundance of Akkermansia decreased in JM, which is positively correlated with lean. Colonic concentrations of acetate (P = 0.047) and butyrate (P = 0.014) were significantly lower in JM than in LM, and consistently, the terminal genes for butyrate synthesis, butyryl CoA: acetate CoA transferase were less abundant in colonic microbiota of JM. Taken together, these gut microbiota of obese JP intrinsically promotes IMF accumulation and can transfer the properties to mouse recipients. Manipulation of intestinal microbiota will, therefore, have the potential to improve the meat quality and flavor of pigs and even to ameliorate the metabolic syndrome in human.