bluuebunny/crossref_metadata_2025 huggingface dataset:
Autopsy Cardiac Troponin I Plasma Levels Can Be Elevated in Myocardial Infarction Type 3
Authors: Omalu Bennet , Diu Stephanie , Paudel Nirmal , Parson Susan J. , Hammers Jennifer L.
Published: January 2021

Aims

The definition of myocardial infarction (MI) type 3 does not include the possible elevation of postmortem biomarkers if measured at autopsy. We determined postmortem cardiac troponin I (cTnI) levels in plasma samples obtained at autopsy in patients who died from MI type 3 to determine whether cTnI plasma levels may be elevated.

Methods and Results

Using a chemiluminescent microparticle immunoassay system, we determined postmortem cTnI plasma levels at autopsy performed within 24 hours of death in every decedent who died from MI type 3, confirmed by an autopsy. Over 2 years, autopsy confirmed 52 decedents who died from MI type 3 due to coronary atherosclerotic disease. The age range and mean age were 40 to 78 and 60.6 years, respectively, 38 (73%) men and 14 (27%) women. Ten percent of the decedents exhibited postmortem cTnI plasma levels that were within the normal reference levels (0.01–0.30 ng/mL). Ninety percent of the decedents exhibited elevated cTnI plasma levels at autopsy, which ranged from 0.31 to greater than 4400 ng/mL. Sixty-nine percent of our decedents showed severe/significant (75%–100%) luminal occlusion in 2 or 3 major coronary arteries.

Conclusions

If cTnI plasma levels are measured in autopsy blood samples after sudden and unexpected death due to MI type 3, highly elevated cTnI plasma levels may be detected. We propose that the current MI type 3 definition be slightly modified to include the possible elevation of cTnI plasma levels if measured at autopsy in the immediate postmortem period.
Complete Clinicopathological Case Report of a Young Patient Dying of COVID-19–Related Stroke
Authors: Taylor Laura D. , Ameen Ozayr Saleh , Zaharie Stefan-Dan
Published: January 2021

The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has revealed diverse neurological manifestations of coronavirus disease 2019 (COVID-19). This case report begins with a background review of the neurological effects of COVID-19, focusing on stroke, neuroinflammation, and coagulopathy. It then describes the clinical course and autopsy findings of a young patient presenting with COVID-19–associated stroke. The formal neuropathological examination is presented, along with the systemic and brain histological features. Interesting aspects include multiterritory hemorrhagic infarctions, microinfarcts throughout the cortex and white matter, and prominent mixed inflammatory cell cuffing of intracerebral blood vessels distant from the infarcts.
Telemedicine in the Coronavirus Disease 2019 Pandemic
Authors: Chen Yuxi , Kathirithamby Dona Rani , Li Jinpu , Candelario-Velazquez Coral , Bloomfield Andrew , Ambrose Anne Felicia
Published: January 2021

In the spring of 2020, coronavirus disease 2019 evolved into a worldwide pandemic, forcing traditional face-to-face healthcare to a standstill. Telemedicine was quickly adopted as a major tool for pediatric rehabilitation services. This article describes the national legislative response of the United States to the coronavirus disease 2019 pandemic and the opportunities and challenges of implementing telemedicine in pediatric rehabilitation outpatient settings, consultations, as well as physician and patient education. The feasibility of performing a remote pediatric musculoskeletal and neurological tele-evaluation is also discussed. Although challenges exist, telemedicine has demonstrated its potential and has proven to be a practical system. Future developments in technology and accessibility, in addition to support from government and third-party payers, have the potential to make telemedicine an effective and vital platform in a coordinated healthcare system.
Pain Symptoms in COVID-19
Authors: Şahin Tülay , Ayyildiz Aylin , Gencer-Atalay Kardelen , Akgün Cem , Özdemir Haci Mustafa , Kuran Banu
Published: January 2021

Objective

The clinical manifestations of COVID-19 range from mild symptoms to severe pneumonia and severe organ damage. When evaluated specifically for pain, the data so far have shown that myalgia, headache, and chest pain can be seen in patients at varying rates; myalgia and headache, especially, are among the initial symptoms.

Design

This retrospective chart review, followed by a descriptive survey design study, was carried out by examining patients afflicted with COVID-19. After discharge, patients were asked about the severity and the body region of their pain, their use of analgesics, their mood and mental health, and their overall quality of life.

Results

A total of 206 patients with a mean age of 56.24 ± 16.99 yrs were included in the study. Pain during COVID-19 was found to be higher compared with the preinfectious and postinfectious states. The most frequent painful areas were reported to be the neck and back before the infection, whereas the head and limbs during the infection. The most frequently used analgesic during infection was paracetamol. There was no relationship between the patients’ pain and anxiety and depression; the quality of life was found to be worse in patients with persistent pain.

Conclusions

This study showed that the head and limbs were the most common painful body regions during COVID-19. It was also found that pain can continue in the postinfection period.
Clustering of Social and Physical Pain Variables and Their Association With Mortality in Two Population-Based Cohorts
Authors: Kroenke Candyce H. , Alexeeff Stacey , Kushi Lawrence H. , Kwan Marilyn L. , Matthews Karen A.
Published: January 2021

Objective

Social pain and physical pain are related bidirectionally, but how these variables cluster in the population is unknown.

Methods

This study included 2833 women from the Study of Women’s Health Across the Nation (SWAN), a community-based cohort of middle-aged women, and 3972 women from the Pathways Study, a population-based cohort of women diagnosed with American Joint Committee on Cancer stages I–IV breast cancer diagnosed between 2005 and 2013. Women provided data on measures related to social pain (social network size, social support, loneliness, social well-being) and physical pain (sensitivity to pain, bodily pain) at study baseline. Analyzing each cohort separately, we used latent class analysis to evaluate social-physical pain clusters, logistic regression to evaluate predictors of categorization into clusters, and Cox proportional hazards models to evaluate associations of clusters with all-cause mortality. We also performed a meta-analysis to combine cohort mortality associations.

Results

Each cluster analysis produced a “low social-physical pain” cluster (SWAN, 48.6%; Pathways, 35.2%) characterized by low social and pain symptoms, a “high social-physical pain” cluster (SWAN, 17.9%; Pathways, 17.9%) characterized by high symptoms, and a “low social/high physical pain” cluster of women with high pain and compromised social functioning but otherwise low social symptoms (SWAN, 33.5%; Pathways, 46.9%). In meta-analysis, categorization into the high social-physical pain cluster was associated with elevated mortality (adjusted hazard ratio = 1.34, 95% confidence interval = 1.05–1.71, Q statistic = 0.782), compared with those in the low social-physical pain cluster.

Conclusions

In two cohorts of women, latent class analysis produced similar sets of social-physical pain clusters, with the same proportion having both high social and pain symptoms; women in this cluster had elevated mortality.
Plasmatic Coagulation Capacity Correlates With Inflammation and Abacavir Use During Chronic HIV Infection
Authors: van der Heijden Wouter A. , Wan Jun , Van de Wijer Lisa , Jaeger Martin , Netea Mihai G. , van der Ven Andre J. , de Groot Philip G. , Roest Mark , de Mast Quirijn
Published: January 2021

Background:

D-dimer concentrations in people living with HIV (PLHIV) on combination antiretroviral therapy (cART) are increased and have been linked to mortality. D-dimer is a biomarker of in vivo coagulation. In contrast to reports on D-dimer, data on coagulation capacity in PLHIV are conflicting. In this study, we assessed the effect of cART and inflammation on coagulation capacity.

Setting:

We explored coagulation capacity using calibrated thrombin generation (TG) and linked this to persistent inflammation and cART in a cross-sectional study including PLHIV with viral suppression and uninfected controls.

Methods:

We used multivariate analyses to identify independent factors influencing in vivo coagulation (D-dimer) and ex vivo coagulation capacity (TG).

Results:

Among 208 PLHIV, 94 (45%) were on an abacavir-containing regimen. D-dimer levels (219.1 vs 170.5 ng/mL, P = 0.001) and inflammatory makers (sCD14, sCD163, and high-sensitive C-reactive protein) were increased in PLHIV compared with those in controls (n = 56). PLHIV experienced lower TG (reflected by endogenous thrombin potential [ETP]) when compared with controls, after correction for age, sex, and antiretroviral therapy. Abacavir use was independently associated with increased ETP. Prothrombin concentrations were strongly associated with ETP and lower in PLHIV on a non–abacavir-containing regimen compared with those in controls, suggesting consumption as a possible mechanism for HIV-associated reduction in TG. D-dimer concentrations were associated with inflammation, but not TG.

Conclusions:

Abacavir use was associated with increased TG and could serve as an additional factor in the reported increase in thrombotic events during abacavir use. Increased exposure to triggers that propagate coagulation, such as inflammation, likely underlie increased D-dimer concentrations found in most PLHIV.
Interorganizational Collaboration in Emergency Cardiovascular Care
Authors: Langabeer James R. , Champagne-Langabeer Tiffany , Helton Jeffrey R. , Segrest Wendy , Kash Bita , DelliFraine Jami , Fowler Raymond
Published: January 2021

Background:

Interorganizational collaboration management theory contends that cooperation between distinct but related organizations can yield innovation and competitive advantage to the participating organization. Yet, it is unclear if a multi-institutional collaborative can improve quality outcomes across communities.

Methods:

We developed a large regional collaborative network of 15 hospitals and 24 emergency medical service agencies surrounding Dallas, Texas, and collected patient-level data on treatment times for acute myocardial infarctions. Using a pre-/posttest research design, we applied median tests of differences to explore outcome changes between groups and over the 6-year period, using data extracted from participating hospital electronic health records.

Results:

We analyzed temporal trends and changes in treatment times for 2302 patients with ST-elevation myocardial infarction between the pre- and posttest groups. We found a statistically significant 19-minute median reduction in the key outcome metric (total ischemic time, the time difference between the patient's first reported symptoms and the definitive opening of the artery). This represents a 10.8% community-wide improvement over time.

Conclusions:

Interorganizational collaboration focused on quality improvement can impact population health across a community. This study provides a basis for broader understanding and participation by health care organizations in multi-institutional community change efforts.
Genetic Polymorphisms in Patients With Systemic Lupus Erythematosus and Jaccoud Arthropathy
Authors: Sousa Anna Paula Mota Duque , de Souza Costa Giselle Calasans , de Oliveira Costa Gustavo Nunes , Barbosa Lúcio Macedo , Grassi Maria Fernanda Rios , Monteiro Maria Eduarda Haerdy , dos Reis Mitermayer Galvão , Barreto Maurício Lima , Pedreira Ana Luisa , Ribeiro Daniel Sá , Lins Carolina Freitas , Galvão Verena , Santos Willer Gonçalves Dourado , Machicado Viviane , da Fonseca Emanuela Pimenta , Silva Carla Baleeiro Rodrigues , Santiago Mittermayer Barreto
Published: January 2021

Introduction

Jaccoud arthropathy (JA) is a nonerosive and deforming arthropathy experienced frequently by patients with systemic lupus erythematosus (SLE). Although genetic polymorphisms are associated with SLE development, the association between genetic polymorphisms and JA has not been studied to date. The main objective of this study was to evaluate an association between HLA, STAT4, IRF5, and BLK polymorphisms and the presence of JA in Brazilian individuals with SLE.

Methods

Patients were selected from a cohort of individuals with SLE followed at 2 rheumatology reference centers in Salvador, Bahia, Brazil. The JA diagnosis was based on clinical and radiological criteria. The participants were genotyped for rs9271100, rs7574865, rs10488631, and rs13277113 polymorphisms in the HLA, STAT4, IRF5, and BLK genes, respectively, using real-time polymerase chain reaction. The presence of JA was correlated with allele frequencies, and clinical and laboratory data.

Results

One hundred forty-four individuals with SLE (38 with JA and 106 with SLE without JA) were studied. The mean age of the patients was 45 ± 12 years; the majority were women and had brown skin. Patients with JA had a longer disease duration than patients without JA. Serositis and neuropsychiatric manifestations were more frequent in the JA population. The A allele of rs13277113 in the BLK gene was associated with the presence of JA.

Conclusions

The rs13277113 polymorphism in the BLK gene was found to be a possible genetic risk for JA development. However, further studies in larger populations should be performed to confirm this finding.
Physicians' Biological Drug Preference in Patients With Rheumatoid Arthritis and Spondyloarthritis With a History of Malignancy
Authors: Tekgoz Emre , Colak Seda , Yardimci Kubra G. , Kucuksahin Orhan , Cinar Muhammet , Yilmaz Sedat , Kasifoglu Timucin , Bes Cemal , Yagiz Burcu , Erden Abdulsamet , Kilic Levent , Kanitez Nilufer A. , Ertenli Ali I. , Coskun Belkis N. , Ediboglu Elif D. , Mercan Ridvan , Kiraz Sedat , Yazisiz Veli , Karadag Omer , Atagunduz Pamir , Kalyoncu Umut
Published: January 2021

Objective

Because of concerns about malignancy risks, using biological disease-modifying antirheumatic drugs (bDMARDs) in patients with a history of malignancy remains a challenging issue in rheumatology practice. This study aimed to investigate bDMARD preferences of physicians when treating of rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients with a history of malignancy.

Methods

The data for this cross-sectional study were gathered from the TReasure database using a date range of December 2017 and January 2020. Biological disease-modifying antirheumatic drug preferences were analyzed for 40 RA patients and 25 SpA patients with a history of malignancy.

Results

The most frequently prescribed bDMARD was rituximab, which was given to 28 RA patients (70%). For 25 patients (62.5%), the time between the diagnosis of malignancy and starting on a bDMARD regimen was less than 60 months, with a median interval of 43.5 months. Among SpA patients, the preferred bDMARDs were secukinumab and etanercept, which were each administered to 7 patients (28%). For 13 SpA patients (52%), the time between the diagnosis of malignancy and starting on bDMARDs was less than 60 months, with a median interval of 97 months.

Conclusions

The observed bDMARD preferences may be related to the therapeutic effects of rituximab on lymphoproliferative malignancies, the protective effects of secukinumab on tumor progression, and the short half-life of etanercept. Biological disease-modifying antirheumatic drugs should be used in RA and SpA patients with malignancy in case of high inflammatory activity.
Metastatic Adamantinoma of the Femur on FDG PET/CT
Authors: Martineau Patrick , Bloise Ingrid , Gowdy Claire , Worsley Daniel
Published: January 2021

Adamantinomas are rare malignant primary bone tumors, which typically arise in young patients, are generally low-grade tumors, and classically arise from the anterior tibial diaphysis. We present the case of a 70-year-old woman who underwent repeat imaging with FDG PET for a pathologically proven case of femoral adamantinoma who experienced a relatively rapid development of metastatic disease with an atypical distribution of lesions.
Impact of a Long Linear Staplers on the Incidence of Stricture after Triangulating Esophagogastric Anastomosis
Authors: Toyota Satoshi , Kimura Yasue , Jogo Tomoko , Hu Qingjiang , Hokonohara Kentaro , Nakanishi Ryota , Hisamatsu Yuichi , Ando Koji , Oki Eiji , Mori Masaki
Published: January 2021

Background:

Various techniques have been reported for esophagogastric anastomosis to prevent anastomotic leakage. Recently, not only postoperative anastomotic leakage but also anastomotic stricture is considered important because stricture contributes to the patient’s postoperative quality of life. However, the best procedure for anastomosis has not been established.

Materials and Methods:

The authors divided 101 patients with thoracic or abdominal esophageal cancer who underwent cervical triangulating esophagogastric anastomosis using a linear stapler between May 2017 and May 2020 into 2 groups: surgery with a short (45 mm) linear stapler (SS group, n=59) or a long (60 mm) stapler (LS group, n=42). The frequencies of anastomotic leakage and stricture were compared between the 2 groups.

Results:

The incidence of anastomotic leakage and stricture without leakage were significantly lower in the LS versus SS group (respectively: leakage: 15% vs. 0%, P=0.01; stricture: 36% vs. 7%, P=0.01). A short linear stapler and anastomotic leakage were independent risk factors for anastomotic stricture in the multivariate analysis (short stapler: odds ratio, 3.27; 95% confidence interval, 1.08-9.9; P=0.03; anastomotic leakage: odds ratio, 2.78; 95% confidence interval, 1.02-8.5; P=0.04).

Conclusion:

A long linear stapler is preferable for cervical triangulating esophagogastric anastomosis.
Genetic neuroimaging of bipolar disorder: a systematic 2017–2020 update
Authors: Janiri Delfina , Kotzalidis Georgios D. , di Luzio Michelangelo , Giuseppin Giulia , Simonetti Alessio , Janiri Luigi , Sani Gabriele
Published: January 2021

There is evidence of genetic polymorphism influences on brain structure and function, genetic risk in bipolar disorder (BD), and neuroimaging correlates of BD. How genetic influences related to BD could be reflected on brain changes in BD has been efficiently reviewed in a 2017 systematic review. We aimed to confirm and extend these findings through a Preferred Reporting Items for Systematic reviews and Meta-Analyses-based systematic review. Our study allowed us to conclude that there is no replicated finding in the timeframe considered. We were also unable to further confirm prior results of the BDNF gene polymorphisms to affect brain structure and function in BD. The most consistent finding is an influence of the CACNA1C rs1006737 polymorphism in brain connectivity and grey matter structure and function. There was a tendency of undersized studies to obtain positive results and large, genome-wide polygenic risk studies to find negative results in BD. The neuroimaging genetics in BD field is rapidly expanding.
CO2 treatment and co-treatment with ClO2
improves quality of ‘Dotaerang’ tomato during
storage
Authors: Yang Haejo , Beak Dong Ryeol , Park Me Hea
Published: January 2021

Pink-colored tomatoes have higher sugar content than the red-colored tomatoes;
however, they are more prone to fruit cracking during cultivation and
transportation owing to their lower firmness. Short-term high CO2 and
ClO2 gas treatments were used to prevent chilling injury and
reduce decay incidence during the cold storage of tomato
‘Dotaerang’ fruits (Solanum lycopersicum Mill.
cv. Dotaerang). Harvested tomatoes were treated with 30% CO2,
60% CO2, and 30% CO2 combined with 10 ppm
ClO2 (mixed with ambient air) for 3 h, and then stored at
4°C and 20°C. Fruit quality was assessed after storage at
4°C for 14 days and/or transferred to 20°C for 3 days (14+3
days), and 20°C for 13 days. Cold storage and CO2 treatment
inhibited the softening process and delayed fruit surface color development and
lycopene accumulation in tomatoes (‘Dotaerang’). A high positive
correlation was found between the a* value and lycopene content of
tomatoes during storage. The chilling injury index was confirmed to be reduced
by cold storage and 30% CO2 treatment. In particular, the
30% CO2 combined with 10 ppm ClO2 treatment was
highly effective in preventing the decay of tomatoes during long-term cold
storage after harvest. These results suggest that pre-storage high
CO2 and/or ClO2 treatment and low-temperature storage
can effectively extend the shelf life and improve the quality of pink-colored
tomato ‘Dotaerang’ fruits.
Diversity of Bacillus groups isolated from
fermented soybean foods (‘Doenjang’ and
‘Kanjang’) and their fermentation characteristics of
‘Cheonggukjang’
Authors: Hwang Chung Eun , Cho Kye Man , Joo Ok Soo
Published: January 2021

In this study, Bacillus strains were isolated from Korean
traditional fermented foods, ‘Doenjang’ and
‘Kanjang’, and the fermentative properties of
‘Cheonggukjang’ prepared using these strains were analyzed. During
the fermentation of ‘Chenoggukjang’, viable cell count, average
β-glycosidase activity, and ammonia level were calculated as 9.49-13.13
log CFU/mL, 22.15 unit/g, and 77.52-273.63 mg/100 g, respectively.
γ-aminobutyric acid (GABA) content was highest when using B.
subtilis MGD07 (81.33 mg/100 g), whereas it was lowest when using
B. cytotoxicus MGD01 (12.56 mg/100 g). Moreover, the
presence of β-glycoside forms such as daidzin and genistin, decreased
during fermentation, which corresponed to the increase in aglycone forms
including daidzein and genistein, observed after fermentation. Additionally, the
content of daidzein (249.78 μg/g), glycitein (39.23 μg/g), and
genistein (23.61 μg/g) was highest in ‘Cheonggukjang’
prepared using B. licheniformis MGD05 isolated from
‘Doenjang’. Conversely, the total aglycone content was highest
(305.55 μg/g) in ‘Cheonggukjang’ prepared using B.
subtilis MGK04 isolated from ‘Kanjang’. In addition,
the total polyphenol content and antioxidant activity, such as DPPH and ABTS
radical scavenging, were higher in all ‘Cheonggukjang’ extracts
than in steamed soybeans. In particular, B. amyloliquefaciens
MGD02 and B. subtilis MGK02 produced low levels of ammonia and
exhibited enhanced functional components (GABA and non-glycoside
isoflavones).
Anti-allergic effects of onion, apple, cucumber, ginger, and
broccoli mixtures and their bioactive compounds in RBL-2H3
cells
Authors: Chung Mi Ja , Lee Sanghyun , Kim Deok Soon
Published: January 2021

We investigated the anti-allergic effects of onion, apple, cucumber, ginger, and
broccoli mixtures and their bioactive compounds on immunoglobulin E
(IgE)-antigen complex-mediated allergic responses in rat basophilic leukemia
(RBL)-2H3 cells. Cell viability, formation of reactive oxygen species (ROS),
β-hexosaminidase release, and cytokine production
were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide assay, 2,7-dichlorofluorescein diacetate assay,
β-hexosaminidase assay, and enzyme-linked
immunosorbent assay, respectively. Ethanol extracts of onion, apple, cucumber,
ginger, and broccoli inhibited the release of
β-hexosaminidase in IgE-antigen complex-stimulated
RBL-2H3 cells. Plant mixtures (1, 2, and 3) containing different ratios of
onion, apple, cucumber, ginger, and broccoli were prepared. The extracts of
these mixtures also inhibited the release of IgE-antigen complex-stimulated
β-hexosaminidase. High-performance liquid
chromatography identified that the main bioactive compounds constituting these
extracts were fisetin (Fis), kaempferol (Kae), isoquercitrin and spiraeoside.
Fis and Kae dose-dependently inhibited the increase in ROS and
β-hexosaminidase levels in IgE-antigen
complex-stimulated RBL-2H3 cells. Additionally, Fis and Kae significantly
attenuated the production of IgE-mediated pro-inflammatory cytokines, such as
interleukin (IL)-4, IL-13, and tumor necrosis factor-alpha. Therefore, mixtures
containing Fis and Kae may be used to develop anti-allergic functional
foods.
Effect of red chicory extract on scopolamine-induced memory
impairment in mice
Authors: Yun So Won , Baek Seung Yeon , Kim Mee Ree
Published: January 2021

We investigated the protective effects and mechanisms of red chicory extract
(RCE) on scopolamine-induced memory impairment in mice. Antioxidant effects were
investigated by measuring DPPH radical scavenging activity, and cell viability
and intracellular ROS levels were examined by inducing cytotoxicity with
L-glutamate in HT-22 cells. In addition, mice were administered orally with RCE
(150 and 300 mg/kg). Memory was evaluated using Morris water maze (MWZ) and
passive avoidance tests. Administration of SRCE 150 kg/mg significantly
increased escape latency time (p<0.05) that was shortened by scopolamine.
It further increased platform crossing numbers after 7 days of training in MWZ
tests (p<0.05), which were significantly shortened by scopolamine, and
prolonged latency (p<0.01) in passive avoidance tests. Biochemical
findings showed significantly increased total glutathione (GSH) (p<0.05),
glutathione S-transferase (GST) (p<0.01), and glutathione peroxidase
(GPx) (p<0.01) in the mice administered RCE 150 mg/kg compared with the
scopolamine-induced positive control. Glutathione reductase (GR) did not
significantly differ between the RCE 300 mg/kg and scopolamine-induced groups
(p<0.05). These results suggested that RCE has antioxidant activity and
enhances scopolamine-induced cognitive impairment by attenuating oxidative
stress.
TXN, a Xanthohumol Derivative, Attenuates High-Fat Diet Induced Hepatic Steatosis by Antagonizing PPARγ
Authors: Zhang Yang , Bobe Gerd , Miranda Cristobal L. , Lowry Malcolm B. , Hsu Victor L. , Löhr Christiane V. , Wong Carmen P. , Jump Donald B. , Robinson Matthew M. , Sharpton Thomas J. , Maier Claudia S. , Stevens Jan F. , Gombart Adrian F.
Published: January 2021

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN) attenuates high-fat diet (HFD) induced obesity and metabolic syndrome in C57BL/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated TXN might antagonize lipogenic PPARγ actionsin vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A PPARγ competitive binding assay showed XN and TXN bind to PPARγ with an IC50similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.
Diverse functions associate with trans-species polymorphisms in humans
Authors: Velázquez-Arcelay Keila , Benton Mary Lauren , Capra John A.
Published: January 2021

Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. We integrated diverse genomic annotations to explore the functions of 125 previously identified non-coding TSPs that are likely under LTBS since the common ancestor of humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. The diversity of traits associated with non-coding human TSPs suggest that functions beyond the immune system are often subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.

Significance statement

Most genetic variants present in human populations are young (<100,000 years old); however, a few hundred are millions of years old with origins before the divergence of humans and chimpanzees. These trans-species polymorphisms (TSPs) were likely maintained by balancing selection—evolutionary pressure to maintain genetic diversity at a locus. However, the functions driving this selection, especially for non-coding TSPs, are largely unknown. We integrate genome-wide annotation strategies to demonstrate TSP associations with immune system function, behavior (addition, cognition, risky behavior), uric acid metabolism, and many other phenotypes. These results substantially expand our understanding of functions TSPs and suggest a substantial role for balancing selection beyond the immune system.
Effects of transcranial alternating current stimulation on spiking activity in computational models of single neocortical neurons
Authors: Tran Harry , Shirinpour Sina , Opitz Alexander
Published: January 2021

Neural oscillations are a key mechanism for information transfer in brain circuits. Rhythmic fluctuations of local field potentials control spike timing through cyclic membrane de- and hyperpolarization. Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation method which can directly interact with brain oscillatory activity by imposing an oscillating electric field on neurons. Despite its increasing use, the basic mechanisms of tACS are still not fully understood. Here, we investigate in a computational study the effects of tACS on morphologically realistic neurons with ongoing spiking activity. We characterize the membrane polarization as a function of electric field strength and subsequent effects on spiking activity in a set of 25 neurons from different neocortical layers. We find that tACS does not affect the firing rate of investigated neurons for electric field strengths applicable to human studies. However, we find that the applied electric fields entrain the spiking activity of large pyramidal neurons at < 1mV/mm field strengths. Our model results are in line with recent experimental studies and can provide a mechanistic framework to understand the effects of oscillating electric fields on single neuron activity. They highlight the importance of neuron morphology in responsiveness to electrical stimulation and suggest that large pyramidal neurons are most likely the prime target for tACS.
Human-genome gut-microbiome interaction in Parkinson’s disease
Authors: Wallen Zachary D. , Stone William J. , Factor Stewart A. , Molho Eric , Zabetian Cyrus P. , Standaert David G. , Payami Haydeh
Published: January 2021

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson’s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we show that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha-synuclein locus, and that the variants responsible modulate alpha-synuclein expression. This is the first demonstration of interaction between genetic factors in the human genome and the dysbiosis of gut microbiome in PD.
IMPAIRED OLFACTORY NETWORK FUNCTIONAL CONNECTIVITY IN PARKINSON’S DISEASE: A NOVEL MARKER FOR DISEASE PROGRESSION
Authors: Karunanayaka Prasanna , Lu Jiaming , Lewis Mechelle M. , Elyan Rommy , Yang Qing X. , Eslinger Paul J. , Huang Xuemei
Published: January 2021

Objective

Determine the neural basis of olfactory impairment in akinetic-rigid (PDAR) and tremor predominant (PDT) Parkinson’s disease subtypes.

Methods

We combined resting-state fMRI (rs-fMRI) with seed based functional connectivity (FC) in order to delineate the olfactory network’s functional connectivity (ON FC) between PDARand PDTpatients. We then contrasted their ON FC patterns with cognitively normal (CN) subjects. All three groups were closely matched in age, demographic variables, and adjusted for relative cognitive performance. Olfactory function was measured using the University of Pennsylvania Smell Identification Test (UPSIT).

Results

UPSIT scores were lower in akinetic-rigid vs tremor subtypes; ON FC values were lower in PDARcompared to PDTand CN, and followed the trend observed in UPSIT scores. UPSIT scores and ON FC values were significantly correlated, reflecting the effects of PD pathologies.

Conclusions

The results show that olfactory function differs between PDARand PDTsuggesting a correlation between PD-related motor symptoms and olfactory deficits. ON FC differences accounts for the impaired olfactory functions observed between PDARand PDT. PDARis known to have worse clinical outcomes and faster cognitive decline compared to PDT; therefore, PD-related olfactory dysfunction may serve as a novel metric for enhancing PD prognosis.
Sharpened and mechanically durable carbon fiber electrode arrays for neural interfacing
Authors: Welle Elissa J. , Woods Joshua E. , Jiman Ahmad A. , Richie Julianna M. , Bottorff Elizabeth C. , Ouyang Zhonghua , Seymour John P. , Patel Paras R. , Bruns Tim M. , Chestek Cynthia A.
Published: January 2021

Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers were sharpened using a reproducible blowtorch method that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 ± 33.5 degree tip angle with 146.8 ± 17.7 μm exposed carbon. Silicone-embedded carbon fiber arrays were durable with 87.5% of fibers remaining after 50,000 passes. Observable neural clusters were recorded using sharpened carbon fiber electrodes from rat CVN (41.8 μVpp), feline DRG (101.1 μVpp), and rat brain (80.7 μVpp). Recordings from the feline DRG included physiologically-relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recording device. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems.
Insights into animal septins using recombinant human septin octamers with distinct SEPT9 isoforms
Authors: Iv Francois , Martins Carla Silva , Castro-Linares Gerard , Taveneau Cyntia , Barbier Pascale , Verdier-Pinard Pascal , Camoin Luc , Audebert Stéphane , Tsai Feng-Ching , Ramond Laurie , Llewellyn Alex , Belhabib Mayssa , Nakazawa Koyomi , Cicco Aurélie Di , Vincentelli Renaud , Wenger Jerome , Cabantous Stéphanie , Koenderink Gijsje H. , Bertin Aurélie , Mavrakis Manos
Published: January 2021

Septin GTP-binding proteins contribute essential biological functions that range from the establishment of cell polarity to animal tissue morphogenesis. Human septins in cells form hetero-octameric septin complexes containing the ubiquitously expressed SEPT9. Despite the established role of SEPT9 in mammalian development and human pathophysiology, biochemical and biophysical studies have relied on monomeric SEPT9 thus not recapitulating its native assembly into hetero-octameric complexes. We established a protocol that enabled the first-time isolation of recombinant human septin octamers containing distinct SEPT9 isoforms. A combination of biochemical and biophysical assays confirmed the octameric nature of the isolated complexes in solution. Reconstitution studies showed that octamers with either a long or a short SEPT9 isoform form filament assemblies, and can directly bind and cross-link actin filaments, raising the possibility that septin-decorated actin structures in cells reflect direct actin-septin interactions. Recombinant SEPT9-containing octamers will make it possible to design cell-free assays to dissect the complex interactions of septins with cell membranes and the actin/microtubule cytoskeleton.

Human septins in cells form hetero-octameric complexes containing the ubiquitously expressed SEPT9. Iv et al. describe the first-time isolation of recombinant human septin octamers with distinct SEPT9 isoforms. Reconstitution studies show that octamers with either a long or a short SEPT9 isoform form higher-order filament assemblies and directly bind and cross-link actin filaments.
RNAi screening reveals requirement for PDGFRβ in JEV infection
Authors: Zhou Minmin , Wang Shaobo , Guo Jiao , Liu Yang , Cao Junyuan , Lan Xiaohao , Jia Xiaoying , Zhang Bo , Xiao Gengfu , Wang Wei
Published: January 2021

Mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide and is associated with high morbidity and mortality. To identify potential host therapeutic targets, a high-throughput receptor tyrosine kinase small interfering RNA library screening was performed with recombinant JEV particles. Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a hit after two rounds of screening. Knockdown ofPDGFRβblocked JEV infection, and trans-complementation of PDGFRβ could partly restore its infectivity. The PDGFRβ inhibitor imatinib, which has been approved for the treatment of malignant metastatic cancer, protected mice against JEV-induced lethality by decreasing the viral load in the brain, while abrogating the histopathological changes associated with JEV infection. These findings demonstrated that PDGFRβ is important in viral infection and provided evidence for the potential to develop imatinib as a therapeutic intervention against JEV infection.
Detection of SARS-CoV-2 infection by rapid antigen test in comparison with RT-PCR in a public setting
Authors: Jakobsen Kathrine Kronberg , Jensen Jakob Schmidt , Todsen Tobias , Lippert Freddy , Martel Cyril Jean-Marie , Klokker Mads , von Buchwald Christian
Published: January 2021

Background

Rapid and accurate detection of SARS-CoV-2 infection is essential in limiting the spread of infection during the ongoing COVID-19 pandemic. The aim of this study was to determine the accuracy of the STANDARD Q COVID-19 Ag test (SD BIOSENSOR) by comparison with RT-PCR in a public setting.

Method

Individuals aged 18 years or older who had booked an appointment for a RT-PCR test on December 26-31, 2020 at a public test center in Copenhagen, Denmark, were invited to participate. An oropharyngeal swab was collected for RT-PCR analysis, immediately followed by a nasopharyngeal swab examined by the STANDARD Q COVID-19 Ag test (SD BIOSENSOR). Sensitivity, specificity, positive and negative predictive values of the antigen test were calculated with test results from RT-PCR as reference.

Results

Overall, 4697 individuals were included (female n=2456, 53.3%; mean age: 44.7 years, SD: 16.9 years); 196 individuals were tested twice or more. Among 4811 paired conclusive test results from the RT-PCR and antigen tests, 221 (4.6%) RT-PCR tests were positive. The overall sensitivity and specificity of the antigen test were 69.7% and 99.5%, the positive and negative predictive values were 87.0% and 98.5%. Ct values were significantly higher among individuals with false negative antigen tests compared to true positives.

Conclusion

The sensitivity, specificity, and predictive values found indicate that the STANDARD Q COVID-19 Ag is a good supplement to RT-PCR testing.
Adult porcine (Sus scrofa) derived inner ear cells possessing multipotent stem/progenitor cell characteristics inin vitrocultures
Authors: Wijesinghe Printha , Sastry Anand , Hui Elizabeth , Cogan Tristan A. , Zheng Boyuan , Ho Germain , Kakal Juzer , Nunez Desmond A.
Published: January 2021

The human inner ear compared with that of other mammalian species is very complex. Although the mouse’s cochlea is frequently studied the mouse’s inner ear continues to develop postnatally whilst the human inner ear is fully developed by the third month of gestation which leads one to question the applicability of findings based on research on mice to human regenerative therapies. Here, we report a novelin vitroculture of adult porcine (Sus scrofa) inner ear cells developed from post-mortem labyrinth specimens. Anatomical findings based on maximal transverse and vertical axial diameters and the length of the cochlear duct suggest that the pig’s cochlea is similar to the human cochlea.In vitrocultures of porcine cochlear and vestibular cells showed the persistence of both inner ear hair cell (HC), supporting cell (SC) and stem/progenitor cell characteristics across passages up to 6 based on scanning electron microscopy, fluorescence immunocytochemistry and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Our findings showed that porcine cochlear and vestibular epithelia maintained multipotent stem/progenitor cell populations into adulthood although their regenerative capacities differed across the passages. The development of a viable and reproducible method to culture porcine inner ear cells provides an important investigative tool that can be utilized to study and evaluate the pathophysiological causes and cellular consequences of human inner ear disorders.
Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease
Authors: De Gasparo Raoul , Pedotti Mattia , Simonelli Luca , Nickl Petr , Muecksch Frauke , Cassaniti Irene , Percivalle Elena , Lorenzi Julio C. C. , Mazzola Federica , Magrì Davide , Michalcikova Tereza , Haviernik Jan , Honig Vaclav , Mrazkova Blanka , Polakova Natalie , Fortova Andrea , Tureckova Jolana , Iatsiuk Veronika , Girolamo Salvatore Di , Palus Martin , Zudova Dagmar , Bednar Petr , Bukova Ivana , Bianchini Filippo , Mehn Dora , Nencka Radim , Strakova Petra , Pavlis Oto , Rozman Jan , Gioria Sabrina , Camilla Sammartino Josè , Giardina Federica , Gaiarsa Stefano , Hammarström Qiang Pan , Barnes Christopher O. , Bjorkman Pamela J. , Calzolai Luigi , Piralla Antonio , Baldanti Fausto , Nussenzweig Michel C. , Bieniasz Paul D. , Hatziioannou Theodora , Prochazka Jan , Sedlacek Radislav , Robbiani Davide F. , Ruzek Daniel , Varani Luca
Published: January 2021

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19)1,2. We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C1353. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.
Systemic administration of anti-CD20 indirectly reduces B cells in the inflamed meninges in a chronic model of central nervous system autoimmunity
Authors: Tesfagiorgis Yodit , Craig Heather C , Parham Kate A , Kerfoot Steven M
Published: January 2021

Anti-CD20 B cell depleting therapies have demonstrated that B cells are important drivers of disease progress in Multiple Sclerosis, although the pathogenic mechanisms are not well understood. A population of B cells accumulates in the inflamed meninges in MS and also some chronic animal models of disease, typically adjacent to demyelinating lesions. The role of these meningeal B cells in disease is not known, nor is their susceptibility to anti-CD20 therapy. Here, we administered anti-CD20 to 2D2 IgHMOGspontaneous experimental autoimmune encephalomyelitis mice in the chronic phase of disease, after the establishment of meningeal B cell clusters. Compared to the circulation, lymph nodes, and spleen, B cell depletion from the CNS was delayed and not evident until 7d post administration of anti-CD20. Further, we did not find evidence that anti-CD20 accessed meningeal B cells directly, but rather that depletion was indirect and the result of ongoing turnover of the meningeal population and elimination of the peripheral pool from which it is sustained. The reduction of B cell numbers in the CNS coincided with less demyelination of the spinal cord white matter and also, surprisingly, an increase in the number of T cells recruited to the meninges but not parenchyma.