bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Sensory Functions in Response to Living in an Extreme Underwater Saturation Environment
Authors: Ari Csilla , Bharwani Sahil , Rehsi Anand , Moss Sara , Schmer-Galunder Sonja , Fiore Stephen , D’Agostino Dominic Paul
Published: April 2020

The present challenges of long duration spaceflight and other missions in extreme environments include changes of sensory functions, including vision impairment and changes in taste perception. In order to monitor and improve astronaut health and performance during long duration spaceflight and future spaceflight missions we studied sensory functions in response to living in an extreme environment during the NASA Extreme Environment Mission Operation (NEEMO) 23. The Aquarius Reef Base is located at 20 m (66 ft) with 2.6 atm (air) pressure inside the habitat, while levels of CO2 are elevated similarly to the International Space Station.

This study assessed the changes in visual acuity and taste perception in 6 NEEMO 23 subjects (2 males, 4 females) 1 day before the mission, during the mission at half time and 1 day post mission. Visual changes were assessed using the NIH Toolbox protocol, while changes in taste perception were measured using solutions containing concentrations of either salty, sweet and bitter flavors in three different concetrations on the side of the tongue and in full mouth.

We observed a trend of decreased salty and bitter taste sensation in the habitat and post mission, compared to baseline, while the sweet taste sensation did not change. When testing the full mouth, the salty taste sensation significantly decreased post mission, compared to baseline at low or medium concentration. Bitter taste sensation significantly decreased at low concentration in habitat and post mission, compared to baseline. At medium concentration the bitter taste sensation significantly decreased post mission, compared to baseline and in‐habitat, while at high concentration it significantly decreased post mission, compared to baseline. There was a signifcant reduction in the Overall Raw and in Overall Uncorrected Vision Scores between baseline and post mission indicating a significant reduction in visual acuity during the 9 days mission that was not restored immediately after the mission.

Living in a saturation environment decreases certain sensory modalities that may persist for an unknown length of time after the exposure. Diminished sensitivity to taste can alter nutritional status and chemosensory changes may also relate to space sickness, stress and psychological factors, while changes in vision may impair operational tasks. These data indicate that mitigation strategies need to be developed and tested in space analog environments.

Support or Funding Information

Ketone Technologies LLC provided partial funding for the study. SIFT provided partial salary for CA.
miR‐92b‐3p‐TSC1 axis is critical for mTOR signaling‐mediated vascular smooth muscle cell proliferation induced by hypoxia
Authors: Lee Jihui , Kang Hara
Published: April 2020

Pulmonary artery smooth muscle cells (PASMCs) undergo proliferation by the mammalian target of rapamycin (mTOR) signaling pathway under hypoxia. Hypoxia induces expression of a specific set of microRNAs (miRNAs) in a variety of cell types. We integrated genomic analyses of both small non‐coding RNA and coding transcripts using next‐generation sequencing (NGS)‐based RNA sequencing with the molecular mechanism of the mTOR signaling pathway in hypoxic PASMCs. These analyses revealed hypoxia‐induced miR‐92b‐3p as a potent regulator of the mTOR signaling pathway. We demonstrated that miR‐92b‐3p directly targets the 3′ UTR of a negative regulator in the mTOR signaling pathway, TSC1. mTOR signaling and consequent cell proliferation were promoted by enforced expression of miR‐92b‐3p but inhibited by knocking down endogenous miR‐92b‐3p. Furthermore, inhibition of miR‐92b‐3p attenuated hypoxia‐induced proliferation of vascular smooth muscle cells (VSMCs). Therefore, this study elucidates a novel role of miR‐92b‐3p as a hypoxamir in the regulation of the mTOR signaling pathway and the pathological VSMC proliferative response under hypoxia. These findings will help us better understand the miRNA‐mediated molecular mechanism of the proliferative response of hypoxic VSMCs through the mTOR signaling pathway.
A Novel Multi‐marker Discovery Approach Identifies New Biomarkers for Parkinson’s Disease in Older People: an EXosomes in PArkiNson Disease (EXPAND) Ancillary Study
Authors: Calvani Riccardo
Published: April 2020

Dopaminergic nigrostriatal denervation and widespread intracellular α‐synuclein accumulation are neuropathologic hallmarks of Parkinson’s disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi‐marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age‐matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO‐CovSel), a multi‐platform regression method developed to handle highly correlated variables organized in multi‐block datasets. The SO‐CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein (MIP)‐1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and MIP‐1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as valuable biomarkers for PD as well as unveil new targets for interventions.

Support or Funding Information

Innovative Medicine Initiative‐Joint Undertaking (IMI‐JU #115621)
The Relation between Immune Cell Mitochondrial Respiration and Brachial Artery Pulse Pressure in Humans
Authors: DeConne Theodore M. , Muñoz Eric R. , Sanjana Faria , Hobson Joshua C. , Martens Christopher R.
Published: April 2020

Elevated pulse pressure (PP) occurs with advancing age due to stiffening of the elastic arteries and is an important risk factor for cardiovascular disease (CVD), even among normotensive adults. Mitochondrial function declines with aging and may contribute to the increase in PP through a mechanism involving oxidative stress and chronic inflammation; two important hallmarks of arterial aging. Emerging evidence indicates that mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) is negatively associated with risk factors for CVD in heart failure; however, the role of impaired mitochondrial function on cardiovascular function in healthy adults is not known. We hypothesized that mitochondrial function would be negatively associated with brachial PP. Twenty‐two healthy adults free of overt CVD (12 M/10 F; age: 56 ± 21 years; age range: 22–78 years; blood pressure, BP: 123 ± 15/72 ± 10 mmHg; PP: 51 ± 11 mmHg) were included in this analysis. PP was determined from brachial artery BP assessed in triplicate in the non‐dominant arm using an automated BP monitor. PBMCs were isolated by density dependent centrifugation and used to assess mitochondrial function by respirometry using an Agilent Seahorse XFp Analyzer. Primary outcome measures included the oxygen consumption rate (OCR) at baseline (basal respiration; BASERESP) and following three serial injections of oligomycin, FCCP and rotenone/antimycin A into the respirometer to determine maximal respiration (MAXRESP). Spare respiratory capacity (SRC), an indicator of how well the cell can respond to an increased energetic demand, ATP‐linked oxygen consumption (ATPO2), and coupling efficiency, which is how well ATPO2 is matched to BASERESP, were also measured. The associations between mitochondrial function and PP were analyzed using multi‐linear regressions correcting for age. PP was not associated with BASERESP (p=0.89, R2=0.10, β=0.01), coupling efficiency (p=0.20, R2=0.18, β= −8.5), or ATPO2 (p=0.33, R2=0.15, β= −0.10). However, PP was inversely associated with MAXRESP (p=0.05, R2=0.28, β= − 0.03) and SRC (PP; p=0.02, R2=0.33, β=−0.04). These data suggest that the impaired mitochondrial respiration may be an important contributor to CVD risk through increases in pulse pressure. Future studies should explore whether these associations are mediated by increases in oxidative stress and inflammatory cytokines.

Support or Funding Information

Funding Sources: P20GM113125, K01AG054731
AMPK can stimulate eEF2 phosphorylation without regulating its cognate kinase eEF2K
Authors: Kumar Eric Anthony , Giles David , Dalby Kevin
Published: April 2020

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/Calmodulin (CaM)‐dependent protein kinase and the only known kinase that phosphorylates T56 of eukaryotic elongation factor 2 (eEF2). Phosphorylation of eEF2 at T56 inhibits its ribosomal affinity, thereby blocking tRNA translocation, and ultimately reducing translation elongation rates. The dysregulation of eEF2K is clinically relevant. Its overexpression positively correlates with poor prognosis in various cancers, such as those overexpressing Myc‐family transcription factors. eEF2K overexpression can promote cancer cell survival during severe nutrient deprivation through an AMPK‐dependent mechanism. AMPK, the ubiquitous cellular energy sensor, has been reported to activate eEF2K by directly phosphorylating it on S398. However, it remains unclear whether eEF2K is regulated directly by AMPK. Here using purified proteins, we show that phosphorylation by AMPK does not affect the in vitro enzymatic properties of eEF2K. We also show that the treatment of MCF10A cells with the allosteric activator of AMPK, A769662, results in the stimulation of AMPK activity. This activation leads to an increase in eEF2(T56) phosphorylation, but no rise in the level of activated eEF2K (as judged by T348 autophosphorylation). Thus, an unknown AMPK‐dependent mechanism that appears to have no impact on the activity status of eEF2K can regulate the level of eEF2 phosphorylation in cells. One possibility is that AMPK regulates a phospho‐eEF2 phosphatase.
Novel Insights into the Role of Soluble Epoxide Hydrolase in Adipogenesis
Authors: Alquraishi Mohammed , Puckett Dexter L. , Chahed Samah L. , BAETTAIEB AHMED
Published: April 2020

Obesity is a growing epidemic that presents a major health problem worldwide. The past decade has seen advances in the identification of specific factors that contribute to this condition. However, despite these strides, there is still much to be learned about the underlying mechanisms. A better understanding of these biochemical mechanisms will enhance our ability to prevent and treat obesity. This study demonstrates that modulation of epoxy fatty acids (EpFA) metabolism in mouse white adipocytes alters cell cycle progression and clonal expansion. In addition, CRISPR/Cas9‐mediated deletion of soluble epoxide hydrolase (sEH), a cytosolic enzyme which hydrolyzes epoxy fatty acids (EpFA) into less active diols, resulted in alterations in adipogenesis. Similar findings were obtained using a selective sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU). Importantly, mice with specific deletion of sEH in the adipose tissue were resistant to high fat feeding and exhibited increased energy expenditure. Taken together, the present study demonstrates that modulation of sEH activity in white adipocytes alters adipocyte differentiation and improves glycemic control. Additionally, our findings suggest that sEH is a physiological modulator of adipogenesis and a potential target for the development of novel anti‐obesity therapeutic strategies.

Support or Funding Information

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.
Influence of Uracil‐Guanine mispair on the Structure of the DNA and the surrounding water
Authors: Zahran Mai , Melo Ivan
Published: April 2020

The process of repairing damaged bases in DNA molecules plays an important role in the maintaining the information stored in the DNA. How are repair enzymes able to efficiently find the mutated base pair to repair? We hypothesized that two factors may facilitate the recognition. The first is the structural changes in the mutated DNA, the second is the changes in the thermodynamic properties of the water surrounding the DNA. Here we investigate the effects of a Uracil‐Guanine mispair on the structure of the DNA as well as on the static and dynamic properties of the surrounding water. We performed molecular dynamics simulations of the mutated and non mutated DNA molecules, and calculated the structure parameters, and the distribution and dynamics of the water molecules near the DNA structures. We show a distinct structural difference for the Uracil‐Guanine mispair and a different dynamical behaviour of the water molecules which slow down near the mutated base. Both factors seem to enhance the ability of the enzyme to recognize the target mutated base pair.

Support or Funding Information

We thank NYCCT for their support.
Zyflamend Induces Apoptosis in Pancreatic Cancer cells via Modulation of the JNK Pathway
Authors: Puckett Dexter L. , Alquraishi Mohammed , Chahed Samah L. , Donohoe Dallas R. , Whelan Jay , BAETTAIEB AHMED
Published: April 2020

Current pharmacological therapies and treatments targeting pancreatic neuroendocrine tumors (PNETs) have proven ineffective, far too often. Therefore, there is an urgent need for alternative therapeutic approaches. Zyflamend, a combination of anti‐inflammatory herbal extracts, that has proven to be effective in various in vitro and in vivo cancer platforms, shows promise. However, its effects on pancreatic cancer, in particular, remain largely unexplored. Herein, we demonstrate that Zyflamend treatment decreased cell proliferation in a dose‐dependent manner, concomitant with increased apoptotic cell death and cell cycle arrest at the G2/M phase. At the molecular level, treatment with Zyflamend led to the induction of ER stress, autophagy, and the activation of c‐Jun N‐terminal kinase (JNK) pathway. Notably, pharmacological inhibition of JNK abrogated the pro‐apoptotic effects of Zyflamend. Furthermore, Zyflamend exacerbated the effects of streptozotocin and adriamycin‐induced ER stress, autophagy, and apoptosis. These studies identify Zyflamend as a potential novel approach to treat pancreatic cancer via modulation of the JNK pathway.

Support or Funding Information

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.
Cannabidiol (CBD) Improves Cognition and Decreases Anxiety in the SAMP8 Mouse Model of Alzheimer’s
Authors: Farr Susan Anne , Goodland Monica N. , Niehoff Michael L. , Young Benjamin J.
Published: April 2020

The use of cannabidiol (CBD) has grown rapidly over the last few years. CBD has been purported to work on a range of conditions, including anxiety, epilepsy, pain, and psychosis. There has been recent interest in CBD as a treatment for age‐related cognitive disorders due to its anti‐inflammatory properties. Here, we tested the effects of chronic CBD administration on learning and memory in the SAMP8 mouse model of Alzheimer’s disease. SAMP8 mice develop an age‐related impairment in learning and memory which corresponds to an increase in amyloid‐β (Aβ), hyperphosphorylated tau, oxidative stress, impaired efflux of Aβ across the blood‐brain barrier and neuroinflammation. SAMP8 mice starting at 11 months of age were treated with CBD (0, 3 or 30 mg/kg) daily via oral administration for 60 days. A 3 month old SAMP8 group receiving vehicle served as an unimpaired control. After 30 days of treatment, learning and memory (T‐maze and novel object recognition), activity in open field, anxiety in the elevated plus maze, and strength were assessed. Mice which received CBD 30 mg/kg had significant improvement in learning and memory in the T‐maze, taking fewer trials to reach criterion than 12 month old vehicle treated mice. CBD improved object recognition memory of 12 month old SAMP8 mice, which spent significantly more time with the novel object in the 24‐hour retention test than the age‐matched vehicle treated controls. While there was no difference in total distance traveled measured by open field activity, the mice that that received CBD displayed decreased anxiety in the elevated + maze at both 3 and 30 mg/kg/day doses compared to the age‐matched control. The mice that received 3 mg/kg/day had significantly less anxiety than the young control group. CBD had no significant effects on the measures of strength in the aged mice. Our results indicate that CBD improves both spatial and recognition memory and decreases anxiety. CBD is a potential treatment for age‐related dementia.

Support or Funding Information

Pilot funding from the Edward A. Doisy Department of Biochemistry and Molecular Biology at Saint Louis University
Gas6‐Axl Double Knockout in Mice Decreases Skeletal Muscle mass Despite Elevated Anabolic Intracellular Signaling
Authors: Olsen Zachary E. , Mervis Matthew J. , Matsumura Marc S. , Hirschi-Budge Kelsey M. , Arroyo Juan A. , Reynolds Paul R. , Thomson David
Published: April 2020

Growth arrest specific‐6 (Gas6) is a signaling factor that has been shown to contribute to growth and survival in various cell types. It functions primarily by activating the receptor tyrosine kinase Axl. Very little is known about the role of Gas6‐Axl in skeletal muscle. Therefore, we studied muscle size and anabolic signaling in Gas6‐Axl double knock‐out mice (dKO). Hindlimb muscle mass was decreased in dKO mice. Skeletal muscle phosphorylation of Akt was not affected by genotype. However, extracellular signal‐related kinase (Erk), ribosomal protein subunit 6 (S6) and p70S6 kinase (S6k) phosphorylation was elevated in dKO muscles. We conclude, therefore, that anabolic signaling through these pathways does not explain the difference in muscle mass between genotypes. We speculate that the elevated anabolic signaling in dKO muscles is perhaps an adaptive compensation for other impaired anabolic processes in these muscles.

Support or Funding Information

This work was supported by a grant from the Flight Attendant’s Medical Research Institute (FAMRI) and a BYU Graduate Research Fellowship.
A novel therapeutic opportunity for the most aggressive sub‐type of pancreatic cancer: Targeting keratin 17 dependency on nuclear export
Authors: Bai Ji Dong (Karen) , Leiton Cindy V. , Pan Chun-Hao , Escobar-Hoyos Luisa , Shroyer Kenneth R.
Published: April 2020

Introduction and hypotheses

The purpose of this study was to uncover a novel targeted therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). We previously discovered that keratin 17 (K17) is an independent negative prognostic biomarker for PDAC, where high K17 expression is associated with decreased patient survival. In our pre‐clinical mouse model, PDACs that overexpress K17 were four times more likely than controls to result in fatality within 7 weeks, suggesting that K17 drives tumor aggression. We determined that K17 functions as an oncoprotein by translocating into the nucleus of PDAC cells and enhances XPO‐1‐ mediated nuclear export and degradation of tumor suppressor proteins (TSPs).

Here, we hypothesized that 1) K17 depends on nuclear export to drive tumor aggression and is highly sensitive to nuclear inhibition, compared to K17‐negative PDACs, and 2) blocking K17 enhanced XPO‐1‐mediated nuclear export causes enhanced apoptosis and cell cycle arrest.

Methods and results

To test the hypothesis that K17 depends on nuclear export to drive tumor aggression and is more sensitive to nuclear inhibition than K17‐negative PDACs, we performed pre‐clinical studies in mouse models and orthotopically implanted isogenic murine PDAC cells (LSL‐KrasG12D, LSL‐Trp53R172HPdx‐1‐Cre, KPC) that expressed human K17 (KPC‐K17) or not (KPC‐EV) in immunocompetent animals. After animal randomization, mice were treated three times weekly via oral gavage with selinexor, an inhibitor of the nuclear exporter, XPO‐1, that is currently in phase 2 clinical trials. We found that selinexor inhibited the growth of K17‐positive PDACs in mice, compared to K17‐negative PDACs, suggesting that K17sensitizes PDACs to selinexor treatment. To determine if this decreased tumor growth was due to a tumor‐cell nuclear export blockage, we performed in vitro studies and found that KPC‐K17 cells elicited a four‐fold increase in cell death and a two‐fold increase in G1/S cell cycle arrest compared to KPC‐EV cells. In addition, selinexor treatment led to nuclear retention of K17. To test the dependency of KPC‐K17 cells to K17‐mediated nuclear export, we challenged the cells to chemotherapeutic and targeted therapeutic agents that induce nuclear import inhibition (ivermectin), G1/S transition inhibition (palbociclib), and DNA‐damage (oxaliplatin). In contrast to selinexor treatment, there were no differences in cell death or cell cycle arrest between KPC‐K17 and KPC‐EV cells upon treatment with these compounds.

Conclusions

Our results suggest that K17‐positive tumors are specifically vulnerable to inhibition of nuclear export. Given that K17 expression is a biomarker that drives tumor aggression in PDACs, our results suggest that treatment with selinexor is a novel therapeutic opportunity for the most aggressive sub‐type of pancreatic cancer.

Support or Funding Information

Pancreatic Cancer Action Network
Exposure of Rats to Permethrin, Pyridostigmine or Diethyl‐M‐Toluamide (DEET) Attenuates Skeletal Muscle Function.
Authors: Navarrrete Viridiana , Rodriguez Antonio , Galera Leonor , Garate Elva Alejandra , villarreal Francisco , Ramirez-Sanchez Israel
Published: April 2020

Background

Gulf War Illness (GWI) is a chronic multi‐symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War. GWI mainly affects nervous and skeletal muscle (SkM) systems yielding cognitive deficit, depression, muscle pain, weakness, intolerance to exercise and fatigue. Military personnel was exposed to toxic substances such as insecticides and repellents like permetrim (PM), N;N‐diethyl‐m‐toluamide (DEET), and pyridostigmine (PB) provided as a prophylactic for a nerve gas attack.

Methods

Three months old male Wistar rats were used for all experiments (n=50). Control group (n=10) were provided water (oral), 70% ethanol (applied to back skin). The PB group (n=10) were given pyridostigmine 1.3 mg/kg/day by oral gavage. The PM group (n=10) were dosed at 0.13 mg/kg/day (back of shaved skin in 70% ethanol). The DEET group (n=10) were dosed at 40 mg/kg/day (back skin in ethanol). A physically restrained group (n=10) was also included with animals being restrained for 5 min/day (in rat plexiglass holders). Treatments were provided daily for 3 weeks. At 6 weeks, animals were subjected to treadmill and front limb strength testing followed by euthanasia and SkM (gastrocnemius) muscles collected for histological and biochemical analysis.

Results

Animals exposed to chemicals did not evidence changes in body weight or food intake. The front limb strength of the animals was recorded weekly. Significant strength increases were recorded in control, PM, DEET and restricted groups. However, in the PB group strength increases were not detected showing ~ 35% decrease vs. contros. At the end of the treatment phase, overall physical endurance was evaluated on a treadmill. This evaluation demonstrated that the groups administered with the different chemical agents (PM, PB and DEET) significantly blunted the fatigue resistance time (on average 12 minutes) vs. controls (18 min). The gastrocnemius mass (weight) of animals exposed to PB, PM and DEET were significantly decreased by ~15% vs. controls. Gastrocnemius myofiber cross area measurements (CSA) were measured and results demonstrate that in the PB, PM and DEET groups it is significantly decreased by ~13% vs. controls. Oxidative stress levels were assessed in muscles and we observed that groups administered with DEET, PM and PB increased carbonyl protein content (average >40 nmol/ml) vs. controls (25 nmol/ml). The plasma levels of the pro‐inflammatory cytokines IL‐1b, TNF‐a, and IFN‐g were elevated only in the PB group (vs. controls) with no differences noted with the other chemical agents.

Conclusions

Exposure of rodents to equivalent human doses of associated GWI chemicals leads to a loss of muscle mass and strength and/or function. These effects are likely related to increases in oxidative stress and/or pro‐inflammatory cytokines.
The role of D‐loop synthesis and progression in trinucleotide repeat stability via a break induced replication (BIR) model.
Authors: Sanders Emma A. , Polleys Erica J. , Freudenreich Catherine H.
Published: April 2020

Homologous recombination (HR) is a complex, multi‐step process, that has been linked to increasing instability of trinucleotide repeats in Saccharomyces cerevisiae. One step of HR, formation and progression of the D‐loop, involves the invasion of ssDNA into a homologous sequence in the genome. Due to the involvement of a variety of polymerases and accessory factors during D‐loop synthesis and progression, it is possible to hypothesize that there is a high risk of slippage and stalling which could lead to changes in length (instability) of a CAG repeat. Break induced replication (BIR) is a genomic repair process that involves the progression of a D‐loop over long tracts of DNA, and thus is a good model to analyze this structure. In this project an assay system, involving a galactose inducible HO double strand break, results in the formation of a D‐loop due to homology to the URA3 gene on both the left and right arms of chromosome V. Repair through this tract of DNA on the right arm of chromosome V has been characterized through measures of viability, PCR of trinucleotide repeat tract, as well as Southern and Western blots. The characterization of this repair currently leads to the ultimate goal of discerning the impact of different DNA repair mutants on tract length changes within the assay system.

Support or Funding Information

Tufts University, Freudenreich Lab
Gastric Distension‐induced Nodose Ganglionic Cell Responses Using a High‐throughput Multi‐electrode Array in the Ferret
Authors: Harms Jonathan E. , Miller Derek , Shulgach Jonathan A. , Nanivadekar Ameya C. , Fulton Stephanie , Sciullo Michael , Fisher Lee E. , Yates Bill J. , Horn Charles C.
Published: April 2020

The nodose ganglion (NG) contains cell bodies of gastrointestinal afferents, which play critical roles in metabolic and feeding disorders and gastrointestinal and inflammatory diseases. To further understand the population coding of nodose ganglionic signals, we used a 32‐chan multi‐electrode array (MEA; 4×8, 400 μm pitch; Blackrock Microsystems) to record single‐unit responses with 3 main objectives: (1) determine the stability of multiple single‐unit responses during several hours of in vivo electrophysiological recording; (2) measure the activation patterns of these neurons to prototypical stimulation, such as gastric distension; and (3) investigate the phenotypes of nodose neurons using mechanical probing and vagus nerve electrical stimulation to determine conduction velocities. Acute experiments were performed in anesthetized ferrets using inhalational isoflurane (~2.5%) anesthesia. MEAs were inserted in the nodose ganglion using a pneumatic inserter, and a balloon‐catheter was advanced into the stomach through a small incision on the lateral edge of the gastric fundus. Two volumes of saline, 10 and 20 ml, were infused into the balloon to provide distension. Nerve cuff electrodes were placed on the abdominal vagus trunk to determine conduction velocity. Ganglionic single‐unit activity was successfully recorded from the NG for up to 5.3 h. In our preliminary analysis using spike sorting on each channel (MKsort, https://github.com/ripple‐neuro/mksort; Matlab), we were able to identify a total of 233 units in 6 animals (16 to 55 units per animal). Gastric balloon distension produced >20% increase in neuronal activity in an average of 48% of units to 10 ml inflation and 56% of units to 20 ml inflation. These results demonstrate the feasibility to record multiple single‐unit responses from the ferret NG to provide insight into gastric‐related population coding. Future effort could focus on delineating the physiological roles of these gastric neurons for the design of neuromodulation devices, which could be used to treat diseases involving vagal sensory input such as obesity and the chronic nausea associated with gastroparesis.

Support or Funding Information

This research was supported by funding from the NIH SPARC Common Fund Program (award #U18TR002205).
Intestinal fungi as regulators of obesity and glucose tolerance
Authors: Al Abdallah Qusai , Mims Tahliyah , Watts Sydney , Pingili Ajeeth , Bajwa Aman , Teng Bin , Makowski Liza , Han Joan C. , Pierre Joseph Francis
Published: April 2020

Obesity is an emerging health crisis in westernized societies that is associated with numerous comorbidities and chronic diseases. While drivers of obesity are undoubtedly multifactorial, the gut microbiome is a recognized contributor alongside diet, genetics, and environmental factors. In addition to the abundant bacterial populations, other organisms inhabit the gut, such as fungi, but remain underexplored in metabolism research. Our objective was the determine whether intestinal fungi regulate host phenotype in the setting of obesity.
We hypothesized that disturbance of intestinal fungal communities negatively shape host metabolic outcomes. We first assessed whether skewing of intestinal fungal populations through low doses of antifungal drugs influenced metabolic phenotype. Antifungals targeting yeasts ‐ including fluconazole (Fluco) and 5‐flurocytosine (5‐FC) ‐ induced body fat increases under high fat diet, while antifungals targeting mold and vehicle controls did not. Metagenomic sequencing confirmed Fluco and 5‐FC elevated molds, including Cladosporium and Aspergillus, while eliminating yeasts, including Candida and Saccharomyces. Further analysis demonstrated Fluco resulted in increased proinflammatory immune markers in peripheral white adipose tissues and reduced glucose tolerance. These effects were not observed in our germ‐free administered Fluco, suggesting intestinal microbes are required for the metabolic alteration. Since molds were elevated by Fluco and 5‐FC treatment, we next colonized germ‐free mice with Cladosporium and observed increased body fat percentage, reduction in glucose tolerance, and increased proinflammatory (M1) macrophage populations in white adipose tissues via flow cytometry, compared with controls. In vitro bone marrow derived macrophages confirmed Cladosporium conidia and mycelia induce M1 macrophage polarization, with mycelia being more immunostimulatory. We conclude that disturbances in gut fungal communities may drive changes in adiposity, glucose tolerance, and immune profiles, with implications for obesity. These findings raise critical questions about the novel, but often overlooked, role of intestinal eukaryotes in obesity and inflammation research and further highlight the need to examine the interkingdom dynamics when studying intestinal microorganisms.
Repressor Activator Protein 1 Worsens Cardiomyopathy in Diet‐induced Type 2 Diabetic Mice
Authors: WANG LIN , LIU Hao , CAI Yin , ZHANG Liangqing , Irwin Michael G , XIA Zhengyuan
Published: April 2020

Background

Diabetic cardiomyopathy is defined by the structural and functional abnormalities of the myocardium in the absence of other cardiac risk factors in diabetic patients. In diabetes, the increment of fatty acid metabolism and subsequently cardiac inefficiency and myocardial lipid accumulation may underlie the pathology of diabetic cardiomyopathy. The telomeric protein repressor activator protein 1 (Rap1) is an identified regulator that regulates gene transcription by binding to non‐telomeric sites. In particular, Rap1 can bind to nuclear PPARα (an important transcriptional regulator of lipid metabolism) loci, and regulate transcription of PPARα and its target genes, including CD36 (fatty acid transporter). However, the effects of Rap1 on diabetic cardiomyopathy are largely unknown. Thus, the present study investigated if Rap1 deficiency protects against diabetic cardiomyopathy and explored the underlying mechanisms.

Methods and Results

High fat diet feeding is a widely used protocol to induce type 2 diabetes in mice. Upon high fat feeding (60% fat) for 12 weeks, male Rap1 knockout (KO) mice displayed significantly reduced body weight gain compared with their wild type (WT) littermates. The glucose tolerance test and insulin tolerance test showed that Rap1 deficiency in the high fat diet fed‐mice led to improved glucose intolerance and insulin action. Furthermore, Rap1 deficiency attenuates high fat diet‐induced cardiac structural remodeling and dysfunction in mice, as evidenced by significantly reduction in left ventricular internal dimension in systole (LVIDs), left ventricular mass, increment in ejection fraction (EF) and fractional shortening (FS), as well as improving of myocardial performance index (MPI). These changes were associated with remarkable reductions in the mRNA and protein expression of PPARα and CD36 in the myocardium of high fat fed‐Rap1 KO mice, indicating that Rap1 deficiency may protect against diabetic cardiomyopathy via the suppression of PPARα/CD36 signaling.

Conclusion

In summary, these results suggest that Rap1 impairment has cardioprotective consequences in the high fat diet‐induced diabetes model, identifying a new dimension in the roles of endogenous Rap1.

Support or Funding Information

The authors’ work was supported by The General Research Fund (17117217M, 17123718M, Research Grants Council of Hong Kong) and The National Natural Science Foundation of China (No. 81800245).
Early prediction of mortality risk among severe COVID-19 patients using machine learning
Authors: Hu Chuanyu , Liu Zhenqiu , Jiang Yanfeng , Zhang Xin , Shi Oumin , Xu Kelin , Suo Chen , Wang Qin , Song Yujing , Yu Kangkang , Mao Xianhua , Wu Xuefu , Wu Mingshan , Shi Tingting , Jiang Wei , Mu Lina , Tully Damien C , Xu Lei , Jin Li , Li Shusheng , Tao Xuejin , Zhang Tiejun , Chen Xingdong
Published: April 2020

Background

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading globally. The number of deaths has increased with the increase in the number of infected patients. We aimed to develop a clinical model to predict the outcome of severe COVID-19 patients early.

Methods

Epidemiological, clinical, and first laboratory findings after admission of 183 severe COVID-19 patients (115 survivors and 68 nonsurvivors) from the Sino-French New City Branch of Tongji Hospital were used to develop the predictive models. Five machine learning approaches (logistic regression, partial least squares regression, elastic net, random forest, and bagged flexible discriminant analysis) were used to select the features and predict the patients’ outcomes. The area under the receiver operating characteristic curve (AUROC) was applied to compare the models’ performance. Sixty-four severe COVID-19 patients from the Optical Valley Branch of Tongji Hospital were used to externally validate the final predictive model.

Results

The baseline characteristics and laboratory tests were significantly different between the survivors and nonsurvivors. Four variables (age, high-sensitivity C-reactive protein level, lymphocyte count, and d-dimer level) were selected by all five models. Given the similar performance among the models, the logistic regression model was selected as the final predictive model because of its simplicity and interpretability. The AUROCs of the derivation and external validation sets were 0.895 and 0.881, respectively. The sensitivity and specificity were 0.892 and 0.687 for the derivation set and 0.839 and 0.794 for the validation set, respectively, when using a probability of death of 50% as the cutoff. The individual risk score based on the four selected variables and the corresponding probability of death can serve as indexes to assess the mortality risk of COVID-19 patients. The predictive model is freely available at https://phenomics.fudan.edu.cn/risk_scores/.

Conclusions

Age, high-sensitivity C-reactive protein level, lymphocyte count, and d-dimer level of COVID-19 patients at admission are informative for the patients’ outcomes.
Proteome-wide analysis of differentially-expressed SARS-CoV-2 antibodies in early COVID-19 infection
Authors: Zhang Xiaomei , Wu Xian , Wang Dan , Lu Minya , Hou Xin , Wang Hongye , Liang Te , Dai Jiayu , Duan Hu , Xu Yingchun , Li Yongzhe , Yu Xiaobo
Published: April 2020

Rapid and accurate tests that detect IgM and IgG antibodies to SARS-CoV-2 proteins are essential in slowing the spread of COVID-19 by identifying patients who are infected with COVID-19. Using a SARS-CoV-2 proteome microarray developed in our lab, we comprehensively profiled both IgM and IgG antibodies in forty patients with early-stage COVID-19, influenza, or non-influenza who had similar symptoms. The results revealed that the SARS-CoV-2 N protein is not an ideal biomarker for COVID-19 diagnosis because of its low immunogenicity, thus tests that rely on this marker alone will have a high false negative rate. Our data further suggest that the S protein subunit 1 receptor binding domain (S1-RBD) might be the optimal antigen for IgM antibody detection, while the S protein extracellular domain (S1+S2ECD) would be the optimal antigen for both IgM and IgG antibody detection. Notably, the combination of all IgM and IgG biomarkers can identify 87% and 73.3% COVID-19 patients, respectively. Finally, the COVID-19-specific antibodies are significantly correlated with the clinical indices of viral infection and acute myocardial injury (p≤0.05). Our data may help understand the function of anti-SARS-CoV-2 antibodies and improve serology tests for rapid COVID-19 screening.
Health Education for Parents During the COVID-19 Outbreak Public Health Education for Parents During the Outbreak of COVID-19: A Rapid Review
Authors: Li Weiguo , Liao Jing , Li Qinyuan , Baskota Muna , Wang Xingmei , Tang Yuyi , Zhou Qi , Wang Xiaoqing , Luo Xufei , Ma Yanfang , Fukuoka Toshio , Ahn Hyeong Sik , Lee Myeong Soo , Chen Yaolong , Luo Zhengxiu , Liu Enmei
Published: April 2020

Background

It is well-known that public health education plays a crucial role in the prevention and control of emerging infectious diseases, but how health providers should advise families and parents to obtain health education information is a challenging question. With COVID-19 (Coronavirus disease 2019) spreading around the world, this rapid review aims to answer that question and thus to promote evidence-based decision making in health education policy and practice.

Methods

We systematically searched the literature on health education during COVID-19, SARS (severe acute respiratory syndrome) and MERS (middle east respiratory syndrome) epidemics in Medline (via PubMed), Cochrane Library, EMBASE, Web of Science, CBM (China Biology Medicine disc), CNKI (China National Knowledge Infrastructure), and Wanfang Data from their inception until March 31, 2020. The potential bias of the studies was assessed by Joanna Briggs Institute Prevalence Critical Appraisal Tool.

Results

Of 1067 papers found, 24 cross-sectional studies with a total of 35,967 participants were included in this review. The general public lacked good knowledge of SARS and MERS at the early stage of epidemics. Some people’s knowledge, attitude and practice (KAP) of COVID-19 had been improved, but the health behaviors of some special groups including children and their parents need to be strengthened. Negative emotions including fear and stigmatization occurred during the outbreaks. Reliable health information was needed to improve public awareness and mental health for infectious diseases. Health information from nonprofit, government and academic websites was more accurate than privately owned commercial websites and media websites.

Conclusions

For educating and cultivating children, parents should obtain information from the official websites of authorities such as the World Health Organization (WHO) and national Centers for Disease Control, or from other sources endorsed by these authorities, rather than from a general search of the internet or social media.
The Effect of Selenium on Hashimoto’s Thyroiditis; Systemic Review and Metaanalysis
Authors: Alijani Ehsan
Published: April 2020

Background

Selenium forms a significant component of seleno-proteins in the body. Seleno-methionine is integrated into proteins instead of methionine and acts as a storage pool. In proteins, the active form of Selenium is seleno-cysteine.in this review we aim to prevail the results of selenium effect on thyroid status in recent clinical trials. The systemic review aims to find out the correlation between supplementation of Selenium and anti-TPO antibodies and T4 levels in Hashimoto’s Thyroiditis. Selenium supplementation decreases the level of anti-TPO antibodies. The supplementation of Selenium increases the level of T4 levels.

Methods

The mean and standard deviation (SD) of all 8 studies was were calculated. One of the researches had all the information in figures, and only the levels of anti-TPO antibodies and FT4 were obtained. Heterogenicity was estimated using I2.

Results

The p-value calculated for Anti-TPO by SPSS of the eight groups had a p-value of 0.142. The p-value calculated for T4 levels by SPSS of the five groups had a p-value of 0.239. The heterogenicity test was zero after the I2 test. The studies that were included in the systematic review were assessed by Prisma diagram and selected among the articles resulted from search keywords selenium and anti tpo and hashimotho thyroiditis on different data sources. All the participants were evaluated by sex, ages, duration of the study and the levels of anti tpo ab and thyroxin (t4) and then using SPSS software to deploy metanalysis in the systematic review.

Conclusion

in 6 of 8 studies it was a relation of selenium and thyroid status, whereas 2 studies were not. As We ran meta analysis on the data we realized that there is not significant desired effect from selenium on thyroid antibodies against previous metanalysis done by other researchers.
Modeling quarantine during epidemics and mass-testing using drones
Authors: Sedov Leonid , Krasnochub Alexander , Polishchuk Valentin
Published: April 2020

We extend the classical SIR epidemic spread model by introducing the “quarantined” compartment. We solve (numerically) the differential equations that govern the extended model and quantify how quarantining “flattens the curve” for the proportion of infected population over time. Furthermore, we explore the potential of using drones to deliver tests, enabling mass-testing for the infection; we give a method to estimate the drone fleet needed to deliver the tests in a metropolitan area. Application of our models to COVID-19 spread in Sweden shows how the proposed methods could substantially decrease the peak number of infected people, almost without increasing the duration of the epidemic.
ProtTox: Toxin identification from Protein Sequences
Authors: Muthiah Sathappan , Datta Debanjan , Islam Mohammad Raihanul , Butler Patrick , Warren Andrew , Ramakrishnan Naren
Published: April 2020

Toxin classification of protein sequences is a challenging task with real world applications in healthcare and synthetic biology. Due to an ever expanding database of proteins and the inordinate cost of manual annotation, automated machine learning based approaches are crucial. Approaches need to overcome challenges of homology, multi-functionality, and structural diversity among proteins in this task. We propose a novel deep learning based method ProtTox, that aims to address some of the shortcomings of previous approaches in classifying proteins as toxins or not. Our method achieves a performance of 0.812 F1-score which is about 5% higher than the closest performing baseline.
Mediodorsal thalamus contributes to the timing of instrumental actions
Authors: Lusk Nicholas , Meck Warren H. , Yin Henry H.
Published: April 2020

The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico-basal ganglia-thalamocortical loop. In this study we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, without playing a direct role in regulating ongoing performance.

Significance Statement

The mediodorsal nucleus of the thalamus (MD) is strongly connected with the prefrontal cortex and basal ganglia, areas which have been implicated in interval timing. Previous work has shown that the MD contributes to working memory and learning of action-outcome contingencies, but its role in behavioral timing is poorly understood. Using an operant temporal production task, we showed that inactivation of the MD significantly impaired timing behavior.
Transcriptome Comparison of organ of Corti in mice, chick and zebrafish
Authors: Guo Sen , Hu Zhengqing
Published: April 2020

Disclaimer

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. The authors would like to redesign and perform additional experimental work. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.