bluuebunny/crossref_metadata_2025 huggingface dataset:
EVALI Vaping Liquids Part 2: Mass Spectrometric Identification of Diluents and Additives
Authors: Ciolino Laura A. , Falconer Travis M. , Ranieri Tracy L. , Brueggemeyer Jana L. , Taylor Allison M. , Mohrhaus Angela S.
Published: October 2021

The vaping liquid additive vitamin E acetate (VEA) was strongly linked to the 2019 United States nationwide outbreak of pulmonary lung illness (EVALI) associated with e-cigarettes or vaping liquids. Our laboratory received over 1,000 vaping liquid products for identification of the vaping liquid additives, including hundreds of vaping products from EVALI patients. In this work, we present results obtained for the GC-MS identification of numerous vaping liquid additives in a large subset of ca. 300 Cannabis vaping liquids, including vitamin E acetate, medium chain triglycerides oil (MCT oil), polyethylene glycols, squalane, triethyl citrate, dipropylene glycol dibenzoate (DPG dibenzoate), pine rosin acids, pine rosin methyl esters, and sucrose acetate isobutyrate (SAIB). Confirmation of DPG dibenzoate and SAIB using LC-HRMS is also presented. GC-MS analysis for additives identified as the parent compounds was conducted after separation on a commercial 5% phenyl phase. GC-MS analysis for additives identified as the trimethylsilyl derivatives was conducted after separation on a commercial 35% silphenylene phase. LC-HRMS analysis was conducted using gradient elution with either C18 or phenyl-hexyl phases and determination of exact masses for the target compounds. In addition to providing rapid methods for the identification of vaping liquid additives, this work highlights the variety of Cannabis vaping liquid additives in current use.
Pd-Catalyzed Rearrangement Reaction of N-Tosylhydrazones Bearing Allyl Ethers Into Trans-Olefin-Substituted Sulfonylhydrazones
Authors: Chang Yaoyao , Fu Jianfang , Li Yingxue , Ding Rongcai , Liu Yue , Hu Jinxing
Published: October 2021

A novel and efficient rearrangement of N-tosylhydrazones bearing allyl ethers into trans-olefin-substituted sulfonylhydrazones is proposed. The reaction involves breakage of the C-O bond and formation of the C-N bond. The reaction can be extended to a wide range of substrates, and the target products can be synthesized smoothly, regardless of the presence of electron-donating and electron-withdrawing groups. The proposed strategy is a new direction in the field of rearrangement reactions.
Clinical Predictors of COVID-19 Severity and Mortality: A Perspective
Authors: Sharma Jitender , Rajput Roopali , Bhatia Manika , Arora Pooja , Sood Vikas
Published: October 2021

The COVID-19 pandemic has caused huge socio-economic losses and continues to threat humans worldwide. With more than 4.5 million deaths and more than 221 million confirmed COVID-19 cases, the impact on physical, mental, social and economic resources is immeasurable. During any novel disease outbreak, one of the primary requirements for effective mitigation is the knowledge of clinical manifestations of the disease. However, in absence of any unique identifying characteristics, diagnosis/prognosis becomes difficult. It intensifies misperception and leads to delay in containment of disease spread. Numerous clinical research studies, systematic reviews and meta-analyses have generated considerable data on the same. However, identification of some of the distinct clinical signs and symptoms, disease progression biomarkers and the risk factors leading to adverse COVID-19 outcomes warrant in-depth understanding. In view of this, we assessed 20 systematic reviews and meta-analyses with an intent to understand some of the potential independent predictors/biomarkers/risk factors of COVID-19 severity and mortality.
Gut Microbiota and Fecal Metabolites Associated With Neurocognitive Impairment in HIV-Infected Population
Authors: Dong Ruihua , Lin Haijiang , Chen Xiaoxiao , Shi Ruizi , Yuan Shiying , Li Jing , Zhu Bowen , Xu Xiaohui , Shen Weiwei , Wang Keran , Shu Xiao-Ou , Ding Ding , He Na
Published: October 2021

Gut microbiota dysbiosis has been associated with many neurological diseases. However, how microbiota composition and metabolism relate to neurocognitive impairment (NCI) in HIV-infected individuals is largely unknown. In this study, a total of 102 HIV infected participants were classified into two groups—those with NCI and those without—using the global deficit score (GDS). Fecal samples were collected from the participants for 16S rRNA gene sequencing and untargeted metabolomics. The plasma level of 25 hydroxy-vitamin D (25(OH)D) was also evaluated. Although α-diversity and β-diversity were comparable, the HIV patients with NCI were significantly different from those without NCI in terms of abundance of several gut microbiota. The decreased abundance of butyrate-producing bacteria (BPB) and increased abundance of Klebsiella were related with NCI and carotid intima-media thickness (CIMT). Significant differences in fecal metabolites were also found between individuals with versus without NCI, including increased bile acids and bioactive lipids, decreased vitamin D, terpenoids, and resolvin D1 in the NCI group. Furthermore, the perturbed metabolic profile was closely related to BPB and Klebsiella. In addition, a low level of vitamin D was associated with NCI and CIMT. Both fecal and plasma vitamin D were positively correlated with BPB. Our results show that BPB and Klebsiella and the associated metabolites are associated with NCI in people with HIV. In addition, vitamin D, both in feces and blood, was associated with NCI and BPB, suggesting a protective effect of vitamin D on NCI.
Structure-Based Primer Design Minimizes the Risk of PCR Failure Caused by SARS-CoV-2 Mutations
Authors: Dong Hongjie , Wang Shuai , Zhang Junmei , Zhang Kundi , Zhang Fengyu , Wang Hongwei , Xie Shiling , Hu Wei , Gu Lichuan
Published: October 2021

The coronavirus disease 2019 (COVID-19) has caused and is still causing tremendous damage to the global economy and human health. Qualitative reverse transcription-PCR (RT-qPCR) is the golden standard for COVID-19 test. However, the SARS-CoV-2 variants may not only make vaccine less effective but also evade RT-qPCR test. Here we suggest an innovative primer design strategy for the RT-qPCR test of SARS-CoV-2. The principle is that the primers should be designed based on both the nucleic acid sequence and the structure of the protein encoded. The three nucleotides closest to the 3′ end of the primer should be the codon which encodes the tryptophan in the structure core. Based on this principle, we designed a pair of primers targeting the nucleocapsid (N) gene. Since tryptophan is encoded by only one codon, any mutation that occurs at this position would change the amino acid residue, resulting in an unstable N protein. This means that this kind of SARS-CoV-2 variant could not survive. In addition, both our data and previous reports all indicate that the mutations occurring at other places in the primers do not significantly affect the RT-qPCR result. Consequently, no SARS-CoV-2 variant can escape detection by the RT-qPCR kit containing the primers designed based on our strategy.
Vibrio neptunius Produces Piscibactin and Amphibactin and Both Siderophores Contribute Significantly to Virulence for Clams
Authors: Galvis Fabián , Ageitos Lucía , Rodríguez Jaime , Jiménez Carlos , Barja Juan L. , Lemos Manuel L. , Balado Miguel
Published: October 2021

Vibrio neptunius is an inhabitant of mollusc microbiota and an opportunistic pathogen causing disease outbreaks in marine bivalve mollusc species including oysters and clams. Virulence of mollusc pathogenic vibrios is mainly associated with the production of extracellular products. However, siderophore production is a common feature in pathogenic marine bacteria but its role in fitness and virulence of mollusc pathogens remains unknown. We previously found that V. neptunius produces amphibactin, one of the most abundant siderophores in marine microbes. In this work, synthesis of the siderophore piscibactin was identified as the second siderophore produced by V. neptunius. Single and double mutants in biosynthetic genes of each siderophore system, piscibactin and amphibactin, were constructed in V. neptunius and their role in growth ability and virulence was characterized. Although the High Pathogenicity Island encoding piscibactin is a major virulence factor in vibrios pathogenic for fish, the V. neptunius wild type did not cause mortality in turbot. The results showed that amphibactin contributes more than piscibactin to bacterial fitness in vitro. However, infection challenges showed that each siderophore system contributes equally to virulence for molluscs. The V. neptunius strain unable to produce any siderophore was severely impaired to cause vibriosis in clams. Although the inactivation of one of the two siderophore systems (either amphibactin or piscibactin) significantly reduced virulence compared to the wild type strain, the ability to produce both siderophores simultaneously maximised the degree of virulence. Evaluation of the gene expression pattern of each siderophore system showed that they are simultaneously expressed when V. neptunius is cultivated under low iron availability in vitro and ex vivo. Finally, the analysis of the distribution of siderophore systems in genomes of Vibrio spp. pathogenic for molluscs showed that the gene clusters encoding amphibactin and piscibactin are widespread in the Coralliilyticus clade. Thus, siderophore production would constitute a key virulence factor for bivalve molluscs pathogenic vibrios.
Piscirickettsia salmonis Produces a N-Acetyl-L-Homoserine Lactone as a Bacterial Quorum Sensing System-Related Molecule
Authors: Ruiz Pamela , Sepulveda Daniela , Vidal José Miguel , Romero Romina , Contreras David , Barros Javier , Carrasco Carlos , Ruiz-Tagle Nathaly , Romero Alex , Urrutia Homero , Oliver Cristian
Published: October 2021

Piscirickettsia salmonis is the etiological agent of piscirickettsiosis, the most prevalent disease in salmonid species in Chilean salmonids farms. Many bacteria produce N-acyl-homoserine lactones (AHLs) as a quorum-sensing signal molecule to regulate gene expression in a cell density-dependent manner, and thus modulate physiological characteristics and several bacterial mechanisms. In this study, a fluorescent biosensor system method and gas chromatography-tandem mass spectrometry (GC/MS) were combined to detect AHLs produced by P. salmonis. These analyses revealed an emitted fluorescence signal when the biosensor P. putida EL106 (RPL4cep) was co-cultured with both, P. salmonis LF-89 type strain and an EM-90-like strain Ps007, respectively. Furthermore, the production of an AHL-type molecule was confirmed by GC/MS by both P. salmonis strains, which identified the presence of a N-acetyl-L-homoserine Lactone in the supernatant extract. However, It is suggested that an alternate pathway could synthesizes AHLs, which should be address in future experiments in order to elucidate this important bacterial process. To the best of our knowledge, the present report is the first to describe the type of AHLs produced by P. salmonis.
Case Report: A Rare Case of a Ventricular Perivascular Epithelioid Cell Tumor With Histologic Characteristics That Resembled a Primary Cardiac Rhabdomyoma
Authors: Cossío-Aranda Jorge , Aranda-Frausto Alberto , Berarducci Joaquin , Espinola-Zavaleta Nilda , González-Melchor Laila , Vázquez-Antona Clara , Meléndez-Ramirez Gabriela , Armenta-Moreno Javier Ivan , Keirns Candace
Published: October 2021

We present the case of a young male patient with an initial diagnosis of a rhabdomyoma that was surgically treated at a different hospital when he was 17. After a 2-year disease-free period, the patient presented another intra-cardiac mass. He refused surgical treatment and died 5 years later. Post-mortem immunochemistry studies of both tumors led to the diagnosis of a primary malignant cardiac PEComa with histopathologic characteristics that resembled a rhabdomyoma with abundant “spider cells.”
External Counterpulsation Improves Angiogenesis by Preserving Vascular Endothelial Growth Factor-A and Vascular Endothelial Growth Factor Receptor-2 but Not Regulating MicroRNA-92a Expression in Patients With Refractory Angina
Authors: Ambari Ade Meidian , Lilihata Gracia , Zuhri Ervan , Ekawati Elok , Wijaya Shoma Adhi , Dwiputra Bambang , Sukmawan Renan , Radi Basuni , Haryana Sofia Mubarika , Adiarto Suko , Hanafy Dicky A. , Zamroni Dian , Elen Elen , Mangkuanom Arwin S. , Santoso Anwar
Published: October 2021

Objective: External counterpulsation (ECP) provides long-term benefits of improved anginal frequency and exercise tolerance in patients with refractory angina (RA). This is postulated as a result of improved angiogenesis and endothelial function through an increase in shear stress. Angiogenesis is mainly represented by vascular endothelial growth factor-A (VEGF-A) and its receptor, vascular endothelial growth factor receptor-2 (VEGFR-2). The microRNA-92a (miR-92a) is a flow-sensitive miRNA that regulates atherosclerosis and angiogenesis in response to shear stress. Thus, ECP beneficial effect might be achieved through interaction between VEGF-A, VEGFR-2, and miR-92a. This study aims to evaluate the ECP effect on VEGF-A, VEGFR-2, and miR-92a in patients with RA in a sham-controlled manner.

Methods: This was a randomized sham-controlled trial, enrolling 50 patients with RA who have coronary artery disease (CAD). Participants were randomized (1:1 ratio) to 35 sessions of either ECP (n = 25) or sham (n = 25), each session lasting for 1 h. Plasma levels of VEGF-A and VEGFR-2 were assayed by the ELISA technique. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to measure miR-92a circulating levels in plasma.

Result: External counterpulsation significantly preserved VEGF-A and VEGFR-2 level compared to sham [ΔVEGF-A: 1 (−139 to 160) vs.−136 (−237 to 67) pg/ml, p = 0.026; ΔVEGFR-2: −171(-844 to +1,166) vs. −517(−1,549 to +1,407) pg/ml, p = 0.021, respectively]. Circulating miR-92a increased significantly in ECP [5.1 (4.2–6.4) to 5.9 (4.8–6.4), p < 0.001] and sham [5.2 (4.1–9.4) to 5.6 (4.8–6.3), p = 0.008] post-intervention. The fold changes tended to be higher in ECP group, although was not statistically different from sham [fold changes ECP = 4.6 (0.3–36.5) vs. sham 2.8 (0–15), p = 0.33)].

Conclusion: External counterpulsation improved angiogenesis by preserving VEGF-A and VEGFR-2 levels. Both ECP and sham increased miR-92a significantly, yet the changes were not different between the two groups. (Study registered on www.clinicaltrials.gov, no: NCT03991871, August 8, 2019, and received a grant from the National Health Research and Development of Ministry of Health of Indonesia, No: HK.02.02/I/27/2020).
Automated Analysis of the US Drought Monitor Maps With Machine Learning and Multiple Drought Indicators
Authors: Hatami Bahman Beiglou Pouyan , Luo Lifeng , Tan Pang-Ning , Pei Lisi
Published: October 2021

The US Drought Monitor (USDM) is a hallmark in real time drought monitoring and assessment as it was developed by multiple agencies to provide an accurate and timely assessment of drought conditions in the US on a weekly basis. The map is built based on multiple physical indicators as well as reported observations from local contributors before human analysts combine the information and produce the drought map using their best judgement. Since human subjectivity is included in the production of the USDM maps, it is not an entirely clear quantitative procedure for other entities to reproduce the maps. In this study, we developed a framework to automatically generate the maps through a machine learning approach by predicting the drought categories across the domain of study. A persistence model served as the baseline model for comparison in the framework. Three machine learning algorithms, logistic regression, random forests, and support vector machines, with four different groups of input data, which formed an overall of 12 different configurations, were used for the prediction of drought categories. Finally, all the configurations were evaluated against the baseline model to select the best performing option. The results showed that our proposed framework could reproduce the drought maps to a near-perfect level with the support vector machines algorithm and the group 4 data. The rest of the findings of this study can be highlighted as: 1) employing the past week drought data as a predictor in the models played an important role in achieving high prediction scores, 2) the nonlinear models, random forest, and support vector machines had a better overall performance compared to the logistic regression models, and 3) with borrowing the neighboring grid cells information, we could compensate the lack of training data in the grid cells with insufficient historical USDM data particularly for extreme and exceptional drought conditions.
Secondary Immunodeficiency in Hematological Malignancies: Focus on Multiple Myeloma and Chronic Lymphocytic Leukemia
Authors: Allegra Alessandro , Tonacci Alessandro , Musolino Caterina , Pioggia Giovanni , Gangemi Sebastiano
Published: October 2021

Secondary immunodeficiency is reported in most patients with hematological malignancies such as chronic lymphocytic leukemia and multiple myeloma. The aim of our review was to evaluate the existing literature data on patients with hematological malignancies, with regard to the effect of immunodeficiency on the outcome, the clinical and therapeutic approach, and on the onset of noninfectious complications, including thrombosis, pleural effusion, and orofacial complications. Immunodeficiency in these patients has an intense impact on their risk of infection, in turn increasing morbidity and mortality even years after treatment completion. However, these patients with increased risk of severe infectious diseases could be treated with adequate vaccination coverage, but the vaccines’ administration can be associated with a decreased immune response and an augmented risk of adverse reactions. Probably, immunogenicity of the inactivated is analogous to that of healthy subjects at the moment of vaccination, but it undertakes a gradual weakening over time. However, the dispensation of live attenuated viral vaccines is controversial because of the risk of the activation of vaccine viruses. A particular immunization schedule should be employed according to the clinical and immunological condition of each of these patients to guarantee a constant immune response without any risks to the patients’ health.
Brain Distribution of 10 cart Transcripts and Their Response to 4 Days of Fasting in Atlantic Salmon (Salmo salar L.)
Authors: Kalananthan Tharmini , Gomes Ana S. , Lai Floriana , Tolås Ingvill , Jordal Ann-Elise O. , Norland Sissel , Murashita Koji , Rønnestad Ivar
Published: October 2021

Cocaine- and amphetamine-regulated transcript (CART) has been known to be involved in feeding and energy balance in mammals, acting as an anorexigenic neuropeptide in hypothalamus. In Atlantic salmon, little is known about Cart brain localization and its function. In this study, in silico analysis revealed the existence of 10 cart paralogs, here named cart1a, 1b1, 1b2, 2a, 2b1, 2b2, 3a1, 3a2, 3b, and 4. The Atlantic salmon Cart sequences shared from 19 to 50% of identity with the human homolog and between 25 and 90% of sequence identity among paralogs, except for Cart4 which only shared 18–23% of identity. We further explored cart mRNA expressions in 8 brain regions (Olfactory Bulb-OB, Telencephalon-TEL, Midbrain-MB, Cerebellum-CE, Hypothalamus-HYP, Saccus vasculosus-SV, Pituitary-PT, and Brain Stem-BS) of Atlantic salmon smolt under 4 days of fasting and continuous fed conditions. The cart paralogs analyzed were widely distributed among the brain regions and OB, TEL, HYP, MB, and BS seemed to be the major sites of expression. The expression of cart1a and 1b showed quite similar pattern in MB, HYP, and BS. The expression of cart2a had the highest in MB followed by HYP and TEL. The cart3a transcript was widely distributed in rostrocaudal regions of brain except in OB and SV whereas cart3b was predominantly expressed in BS followed by MB. Expression of cart4 was high in HYP followed by TEL. With regards to effect of feeding status the Atlantic salmon cart2b, which is the most abundant among the paralogs, was upregulated after 4 days of fasting in OB, MB, and HYP compared to fed group. This may suggest an unexpected, but possible orexigenic role of cart2b in Atlantic salmon or a fasting induced stress effect. No other significant effect was observed. Collectively, the differential expressions of the cart paralogs in different brain regions suggest that they may have roles in regional integration of appetite signals and are possibly involved in regulating other brain functions in Atlantic salmon. The fact that salmon has 10 cart paralogs, while mammalians only one, opens interesting perspectives for comparative research on evolutionary adaptations of gene function in the control of appetite and energy homeostasis.
Environmental Risk Factors for Endometriosis: An Umbrella Review of a Meta-Analysis of 354 Observational Studies With Over 5 Million Populations
Authors: Zhang Ye , Ma Ning-Ye
Published: October 2021

Background: The association between a diverse array of environmental risk factors and the risk of endometriosis is contradictory.

Objective: To summarize the evidence of associations between environmental risk factors and the risk of endometriosis.

Methods: Databases such as PubMed, EMBASE, Web of Science, and ClinicalTrial.gov were systematically searched in June 2020. Meta-analyses of observational studies investigated any environmental exposure (non-genetic) and endometriosis risk. For each article, we estimated the summary effect size, 95% CIs, and the 95% prediction interval (PI). We also estimated the between-study heterogeneity expressed by I2, evidence for small-study effects, and evidence of excess significance bias.

Results: About 12 eligible articles (featuring 143,422 cases and 5,112,967 participants) yielded data on 40 unique environmental risk factors, including life styles (n = 16), reproductive factors (n = 3), early life factors (n = 4), and a range of other risk factors [e.g., phthalate metabolites, endocrine-disrupting chemicals, and body mass index (BMI)]. About 25 of these 40 associations (62.5%) were statistically significant (p < 0.05) under random-effects models. Evidence for an association was indicated for alcohol intake [relative risk (RR): 1.25; 95% CI: 1.11–1.41] and the exposure to endocrine disruptor chemicals (EDCs) (RR: 1.41; 95% CI: 1.23–1.60) while 15 associations presented only weak evidence.

Conclusions: Our analyses showed that alcohol intake and exposure to endocrine-disrupting chemicals may be potential risk factors for endometriosis and supported by suggestive epidemiological evidence. However, it was evident that there was substantial heterogeneity and/or bias between the different studies featured in various meta-analyses included in this review; therefore, the outcomes of our analysis should be interpreted cautiously.
Identification of Five Quality Needs for Rheumatology (Text Analysis and Literature Review)
Authors: Pallua Johannes , Schirmer Michael
Published: October 2021

Background: While the use of the term “quality” in industry relates to the basic idea of making processes measurable and standardizing processes, medicine focuses on achieving health goals that go far beyond the mere implementation of diagnostic and therapeutic processes. However, the quality management systems used are often simple, self-created concepts that concentrate on administrative processes without considering the quality of the results, which is essential for the patient. For several rheumatic diseases, both outcome and treatment goals have been defined. This work summarizes current mainstreams of strategies with published quality efforts in rheumatology.

Methods: PubMed, Cochrane Library, and Web of Science were used to search for studies, and additional manual searches were carried out. Screening and content evaluation were carried out using the PRISMA-P 2015 checklist. After duplicate search in the Endnote reference management software (version X9.1), the software Rayyan QCRI (https://rayyan.qcri.org) was applied to check for pre-defined inclusion and exclusion criteria. Abstracts and full texts were screened and rated using Voyant Tools (https://voyant-tools.org/). Key issues were identified using the collocate analysis.

Results: The number of selected publications was small but specific (14 relevant correlations with coefficients >0.8). Using trend analysis, 15 publications with relative frequency of keywords >0.0125 were used for content analysis, revealing 5 quality needs. The treat to target (T2T) initiative was identified as fundamental paradigm. Outcome parameters required for T2T also allow quality assessments in routine clinical work. Quality care by multidisciplinary teams also focusing on polypharmacy and other quality aspects become essential, A global software platform to assess quality aspects is missing. Such an approach requires reporting of multiple outcome parameters according to evidence-based clinical guidelines and recommendations for the different rheumatic diseases. All health aspects defined by the WHO (physical, mental, and social health) have to be integrated into the management of rheumatic patients.

Conclusion: For the future, quality projects need goals defined by T2T based initiatives in routine clinical work, secondary quality goals include multidisciplinary cooperation and reduction of polypharmacy. Quality indicators and standards in different health systems will provide new information to optimize patients' care in different health systems.
Model-Free or Not?
Authors: Zumpfe Kai , Smith Albert A.
Published: October 2021

Relaxation in nuclear magnetic resonance is a powerful method for obtaining spatially resolved, timescale-specific dynamics information about molecular systems. However, dynamics in biomolecular systems are generally too complex to be fully characterized based on NMR data alone. This is a familiar problem, addressed by the Lipari-Szabo model-free analysis, a method that captures the full information content of NMR relaxation data in case all internal motion of a molecule in solution is sufficiently fast. We investigate model-free analysis, as well as several other approaches, and find that model-free, spectral density mapping, LeMaster’s approach, and ourdetectoranalysis form a class of analysis methods, for which behavior of the fitted parameters has a well-defined relationship to the distribution of correlation times of motion, independent of the specific form of that distribution. In a sense, they are all “model-free.” Of these methods, only detectors are generally applicable to solid-state NMR relaxation data. We further discuss how detectors may be used for comparison of experimental data to data extracted from molecular dynamics simulation, and how simulation may be used to extract details of the dynamics that are not accessible via NMR, where detector analysis can be used to connect those details to experiments. We expect that combined methodology can eventually provide enough insight into complex dynamics to provide highly accurate models of motion, thus lending deeper insight into the nature of biomolecular dynamics.
Higher-Order Thalamic Encoding of Somatosensory Patterns and Bilateral Events
Authors: Castejon Carlos , Martin-Cortecero Jesus , Nuñez Angel
Published: October 2021

The function of the higher-order sensory thalamus remains unclear. Here, the posterior medial (POm) nucleus of the thalamus was examined byin vivoextracellular recordings in anesthetized rats across a variety of contralateral, ipsilateral, and bilateral whisker sensory patterns. We found that POm was highly sensitive to multiwhisker stimuli involving diverse spatiotemporal interactions. Accurate increases in POm activity were produced during the overlapping time between spatial signals reflecting changes in the spatiotemporal structure of sensory patterns. In addition, our results showed for first time that POm was also able to respond to tactile stimulation of ipsilateral whiskers. This finding challenges the notion that the somatosensory thalamus only computes unilateral stimuli. We found that POm also integrates signals from both whisker pads and described how this integration is generated. Our results showed that ipsilateral activity reached one POm indirectly from the other POm and demonstrated a transmission of sensory activity between both nuclei through a functional POm-POm loop formed by thalamocortical, interhemispheric, and corticothalamic projections. The implication of different cortical areas was investigated revealing that S1 plays a central role in this POm-POm loop. Accordingly, the subcortical and cortical inputs allow POm but not the ventral posteromedial thalamic nucleus (VPM) to have sensory information from both sides of the body. This finding is in agreement with the higher-order nature of POm and can be considered to functionally differentiate and classify these thalamic nuclei. A possible functional role of these higher-order thalamic patterns of integrated activity in brain function is discussed.
Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder
Authors: Garrett Melanie E. , Qin Xue Jun , Mehta Divya , Dennis Michelle F. , Marx Christine E. , Grant Gerald A. ,   VA Mid-Atlantic MIRECC Workgroup,   PTSD Initiative,   Injury and Traumatic Stress (INTRuST) Clinical Consortium,   Psychiatric Genomics Consortium PTSD Group, Stein Murray B. , Kimbrel Nathan A. , Beckham Jean C. , Hauser Michael A. , Ashley-Koch Allison E.
Published: October 2021

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that can develop following exposure to traumatic events. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has collected over 20,000 multi-ethnic PTSD cases and controls and has identified both genetic and epigenetic factors associated with PTSD risk. To further investigate biological correlates of PTSD risk, we examined three PGC-PTSD cohorts comprising 977 subjects to identify differentially expressed genes among PTSD cases and controls. Whole blood gene expression was quantified with the HumanHT-12 v4 Expression BeadChip for 726 OEF/OIF veterans from the Veterans Affairs (VA) Mental Illness Research Education and Clinical Center (MIRECC), 155 samples from the Injury and Traumatic Stress (INTRuST) Clinical Consortium, and 96 Australian Vietnam War veterans. Differential gene expression analysis was performed in each cohort separately followed by meta-analysis. In the largest cohort, we performed co-expression analysis to identify modules of genes that are associated with PTSD and MDD. We then conducted expression quantitative trait loci (eQTL) analysis and assessed the presence of eQTL interactions involving PTSD and major depressive disorder (MDD). Finally, we utilized PTSD and MDD GWAS summary statistics to identify regions that colocalize with eQTLs. Although not surpassing correction for multiple testing, the most differentially expressed genes in meta-analysis were interleukin-1 beta (IL1B), a pro-inflammatory cytokine previously associated with PTSD, and integrin-linked kinase (ILK), which is highly expressed in brain and can rescue dysregulated hippocampal neurogenesis and memory deficits. Pathway analysis revealed enrichment of toll-like receptor (TLR) and interleukin-1 receptor genes, which are integral to cellular innate immune response. Co-expression analysis identified four modules of genes associated with PTSD, two of which are also associated with MDD, demonstrating common biological pathways underlying the two conditions. Lastly, we identified four genes (UBA7, HLA-F, HSPA1B, and RERE) with high probability of a shared causal eQTL variant with PTSD and/or MDD GWAS variants, thereby providing a potential mechanism by which the GWAS variant contributes to disease risk. In summary, we provide additional evidence for genes and pathways previously reported and identified plausible novel candidates for PTSD. These data provide further insight into genetic factors and pathways involved in PTSD, as well as potential regions of pleiotropy between PTSD and MDD.
Expression and Physiology of Voltage-Gated Sodium Channels in Developing Human Inner Ear
Authors: Quinn Rikki K. , Drury Hannah R. , Cresswell Ethan T. , Tadros Melissa A. , Nayagam Bryony A. , Callister Robert J. , Brichta Alan M. , Lim Rebecca
Published: October 2021

Sodium channel expression in inner ear afferents is essential for the transmission of vestibular and auditory information to the central nervous system. During development, however, there is also a transient expression of Na+ channels in vestibular and auditory hair cells. Using qPCR analysis, we describe the expression of four Na+ channel genes, SCN5A (Nav1.5), SCN8A (Nav1.6), SCN9A (Nav1.7), and SCN10A (Nav1.8) in the human fetal cristae ampullares, utricle, and base, middle, and apex of the cochlea. Our data show distinct patterns of Na+ channel gene expression with age and between these inner ear organs. In the utricle, there was a general trend toward fold-change increases in expression of SCN8A, SCN9A, and SCN10A with age, while the crista exhibited fold-change increases in SCN5A and SCN8A and fold-change decreases in SCN9A and SCN10A. Fold-change differences of each gene in the cochlea were more complex and likely related to distinct patterns of expression based on tonotopy. Generally, the relative expression of SCN genes in the cochlea was greater than that in utricle and cristae ampullares. We also recorded Na+ currents from developing human vestibular hair cells aged 10–11 weeks gestation (WG), 12–13 WG, and 14+ WG and found there is a decrease in the number of vestibular hair cells that exhibit Na+ currents with increasing gestational age. Na+ current properties and responses to the application of tetrodotoxin (TTX; 1 μM) in human fetal vestibular hair cells are consistent with those recorded in other species during embryonic and postnatal development. Both TTX-sensitive and TTX-resistant currents are present in human fetal vestibular hair cells. These results provide a timeline of sodium channel gene expression in inner ear neuroepithelium and the physiological characterization of Na+ currents in human fetal vestibular neuroepithelium. Understanding the normal developmental timeline of ion channel gene expression and when cells express functional ion channels is essential information for regenerative technologies.
Dietary Management for Faecal Microbiota Transplant: An International Survey of Clinical and Research Practice, Knowledge and Attitudes
Authors: Clancy Annabel K. , Gunaratne Anoja W. , Borody Thomas J.
Published: October 2021

Faecal microbiota transplantation (FMT) involves homogenisation and infusion of stool from a healthy, highly screened individual into the bowel of an unwell recipient. Dietary intake is an important modulator of the gut microbiota. Currently there are no clinical practice recommendations available to provide patients or stool donors with dietary advice for FMT. This study aimed to conduct an international survey to examine health professionals and researchers' attitudes, knowledge and current practice recommendations for diet in patients undergoing FMT. An online, cross-sectional, international survey comprising of health professionals and researchers managing patients undergoing treatment with FMT was conducted between July-October 2020. Purposeful and snowball sampling techniques were employed to identify eligible participants who were sent an email invitation and two email reminders with a link to participate in the electronic survey. The survey comprised 21 questions covering demographics, current practice, beliefs and future directions regarding FMT and diet. Closed responses were calculated as proportions of total responses. Open-ended responses were systematically categorised. Common themes were identified from recurring categories. Fifty-eight (M 60%) participants from 14 countries completed the survey. Participants were gastroenterologists (55%), with 1-5 years' experience working in FMT (48%) and treating up to ten patients with FMT per month (74%). Participants agreed that diet was an important consideration for FMT recipients and stool donors (both 71%), and that it would affect the outcomes of FMT. However, they did not feel confident in providing dietary advice to patients, nor that there was sufficient evidence to provide dietary advice and this was reflected in their practice. Future research must collect information on the dietary intake of patients and donors to better understand the relationship between diet and FMT outcomes. In clinical practice, promotion of healthy eating guidelines aligns with current practice and literature.
Analysis of Cow-Calf Microbiome Transfer Routes and Microbiome Diversity in the Newborn Holstein Dairy Calf Hindgut
Authors: Zhu Huan , Yang Minna , Loor Juan J. , Elolimy Ahmed , Li Lingyan , Xu Chuang , Wang Weidong , Yin Shuxin , Qu Yongli
Published: October 2021

Hindgut microorganisms in newborn calves play an important role in the development of immunity and metabolism, and optimization of performance. However, knowledge of the extent to which microbiome colonization of the calf intestine is dependent on maternal characteristics is limited. In this study, placenta, umbilical cord, amniotic fluid, colostrum, cow feces, and calf meconium samples were collected from 6 Holstein cow-calf pairs. Microbial composition was analyzed by 16S rRNA gene high-throughput sequencing, and maternal transfer characteristics assessed using SourceTracker based on Gibbs sampling to fit the joint distribution using the mean proportions of each sample with meconium as the “sink” and other sample types as different “sources.” Alpha and beta diversity analyses revealed sample type-specific microbiome features: microbial composition of the placenta, umbilical cord, amniotic fluid, colostrum, and calf feces were similar, but differed from cow feces (p < 0.05). Compared with profiles of meconium vs. placenta, meconium vs. umbilical cord, and meconium vs. colostrum, differences between the meconium and amniotic fluid were most obvious. SourceTracker analysis revealed that 23.8 ± 2.21% of the meconium OTUs matched those of umbilical cord samples, followed by the meconium-placenta pair (15.57 ± 2.2%), meconium-colostrum pair (14.4 ± 1.9%), and meconium-amniotic fluid pair (11.2 ± 1.7%). The matching ratio between meconium and cow feces was the smallest (10.5 ± 1%). Overall, our data indicated that the composition of the meconium microflora was similar compared with multiple maternal sites including umbilical cord, placenta, colostrum, and amniotic fluid. The umbilical cord microflora seemed to contribute the most to colonization of the fecal microflora of calves. Bacteria with digestive functions such as cellulose decomposition and rumen fermentation were mainly transmitted during the maternal transfer process.
Computational Recognition and Clinical Verification of TGF-β-Derived miRNA Signature With Potential Implications in Prognosis and Immunotherapy of Intrahepatic Cholangiocarcinoma
Authors: Liu Zaoqu , Weng Siyuan , Xu Hui , Wang Libo , Liu Long , Zhang Yuyuan , Guo ChunGuang , Dang Qin , Xing Zhe , Lu Taoyuan , Han Xinwei
Published: October 2021

MicroRNAs (miRNAs) were recently implicated in modifying the transforming growth factor β (TGF-β) signaling in multiple cancers. However, TGF-β-derived miRNAs and their potential clinical significance remain largely unexplored in intrahepatic cholangiocarcinoma (ICC). In this study, we proposed an integrated framework that enables the identification of TGF-β-derived miRNAs in ICC (termed “TGFmitor”). A total of 36 TGF-β-derived miRNAs were identified, of which nine significantly correlated with overall survival (OS) and aberrantly expressed in ICC. According to these miRNAs, we discovered and validated a TGF-β associated miRNA signature (TAMIS) in GSE53870 (n =63) and TCGA-CHOL (n =32). To further confirm the clinical interpretation of TAMIS, another validation based on qRT-PCR results from 181 ICC tissues was performed. TAMIS was proven to be an independent risk indicator for both OS and relapse-free survival (RFS). TAMIS also displayed robust performance in three cohorts, with satisfactory AUCs and C-index. Besides, patients with low TAMIS were characterized by superior levels of CD8+ T cells infiltration and PD-L1 expression, while patients with high TAMIS possessed enhanced CMTM6 expression. Kaplan-Meier analysis suggested CMTM6 could further stratify TAMIS. The TAMIShighCMTM6high subtype had the worst prognosis and lowest levels of CD8A and PD-L1 expression relative to the other subtypes, indicating this subtype might behave as “super-cold” tumors. Notably, the improved discrimination was observed when CMTM6 was combined with TAMIS. Overall, our signature could serve as a powerful tool to help improve prognostic management and immunotherapies of ICC patients.
Identification of Immune-Cell-Related Prognostic Biomarkers of Esophageal Squamous Cell Carcinoma Based on Tumor Microenvironment
Authors: Cui Yiyao , Hou Ruiqin , Lv Xiaoshuo , Wang Feng , Yu Zhaoyan , Cui Yong
Published: October 2021

Background

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal cancers in the world. The 5-year survival rate of ESCC is <30%. However, few biomarkers can accurately predict the prognosis of patients with ESCC. We aimed to identify potential survival-associated biomarkers for ESCC to improve its poor prognosis.

Methods

ImmuneAI analysis was first used to access the immune cell abundance of ESCC. Then, ESTIMATE analysis was performed to explore the tumor microenvironment (TME), and differential analysis was used for the selection of immune-related differentially expressed genes (DEGs). Weighted gene coexpression network analysis (WGCNA) was used for selecting the candidate DEGs. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to build the immune-cell-associated prognostic model (ICPM). Kaplan–Meier curve of survival analysis was performed to evaluate the efficacy of the ICPM.

Results

Based on the ESTIMATE and ImmuneAI analysis, we obtained 24 immune cells’ abundance. Next, we identified six coexpression module that was associated with the abundance. Then, LASSO regression models were constructed by selecting the genes in the module that is most relevant to immune cells. Two test dataset was used to testify the model, and we finally, obtained a seven-genes survival model that performed an excellent prognostic efficacy.

Conclusion

In the current study, we filtered seven key genes that may be potential prognostic biomarkers of ESCC, and they may be used as new factors to improve the prognosis of cancer.
Clinical Characteristics and Inflammatory Immune Responses in COVID-19 Patients With Hypertension: A Retrospective Study
Authors: Wu Chaoran , Qu Guangbo , Wang Lei , Cao Shiyu , Xia Dandan , Wang Baolong , Fan Xiaoyun , Wang Changhui
Published: October 2021

Coronavirus disease (COVID-19) patients with cardiovascular and metabolic disorders have been found to have a high risk of developing severe conditions with high mortality, further affecting the prognosis of COVID-19. However, the effect of hypertension and angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) agents on the clinical characteristics and inflammatory immune responses in COVID-19 patients is still undefined. In this study, 90 COVID-19 patients were divided into hypertension and nonhypertension groups. The hypertension group was divided into well-controlled and poorly controlled subgroups based on blood pressure levels; moreover, hypertensive patients were also divided into ACEI/ARB and non-ACEI/ARB subgroups according to the administration of ACEI/ARB antihypertensive agents. The clinical characteristics of and inflammatory immune biomarker levels in the different groups of COVID-19 patients were compared, and the association between the combined effect of hypertension with ACEI/ARB antihypertensive agents and the severity of COVID-19 was examined. The results showed that the levels of aminotransferase (AST) and hs-cTnI were higher in the hypertension group compared with the nonhypertension group. The long-term use of ACEI/ARB agents in patients had statistically significantly lower AST, low-density lipoprotein cholesterol (LDL-C), and oxygen uptake and lower white cell count, neutrophil count, and levels of CD4, CD8, CRP, and PCT but without statistical significance. In addition, compared with COVID-19 patients without hypertension, hypertensive patients without the use of ACEI/ARB had a higher risk of developing severity of COVID-19 (for poorly controlled patients: OR = 3.97, 95% CI = 1.03–15.30; for well-controlled patients: OR = 6.48, 95% CI = 1.77–23.81). Hypertension could cause organ damage in COVID-19 patients, but the long-term use of ACEI/ARB agents may be beneficial to alleviate this injury.
Mitochondrial BKCa Mediates the Protective Effect of Low-Dose Ethanol Preconditioning on Oxygen-Glucose Deprivation and Reperfusion-Induced Neuronal Apoptosis
Authors: Su Fang , Yang Huajun , Guo Anchen , Qu Zhengyi , Wu Jianping , Wang Qun
Published: October 2021

Ischemia-reperfusion (I/R) injury contributes to the morbidity and mortality of ischemic strokes. As an in vitro model, oxygen-glucose deprivation and reperfusion (OGD/R) exposure induces neuronal injury. Low-dose ethanol preconditioning (EtOH-PC) was reported to alleviate neuronal apoptosis during OGD/R. However, whether the mitochondrial BKCa (mitoBKCa) channel is involved in the neuroprotective effect of EtOH-PC during OGD/R is not clearly defined. This study attempts to explore the mediation of the mitoBKCa channel in the neuroprotective effect of EtOH-PC on OGD/R-induced neuronal apoptosis and the underlying mechanisms. OGD/R model was established using primary cortical neurons that were preincubated with ethanol. Subsequently, the cell viability was measured by CCK-8 assay, and the apoptotic cells were determined by TUNEL assay. Annexin V/7-AAD staining and mitochondrial membrane potential using JC-10 were detected by flow cytometry. Western blot analysis was performed to check the apoptosis-related proteins. In the mixed primary culture, 95% neurofilament-positive cells were cortical neurons. Low-dose EtOH-PC (10 mmol/L) for 24 h significantly attenuated the OGD2h/R24h-induced neuronal apoptosis through activating the BKCa channel. Further investigations suggested that ethanol pretreatment increased the mitochondrial membrane potential (MMP) and downregulated the production of cleaved caspase 3 in OGD/R-injured neurons by activating the mitoBKCa channel. Low-dose ethanol pretreatment significantly attenuated the OGD/R-induced neuronal apoptosis mediated by the mitoBKCa channel which modulated the mitochondrial function by impeding the uncontrolled opening of mitochondrial permeability transition pore (MPTP).