bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between the Gut Microbiome-Immune System-Brain Axis and Major Depressive Disorder
Authors: Foster Jane A. , Baker Glen B. , Dursun Serdar M.
Published: September 2021

Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.
A Case Report of Pulsed Radiofrequency Plus Suboccipital Injection of the Greater Occipital Nerve: An Easier Target for Treatment of Cluster Headache
Authors: Belgrado Enrico , Surcinelli Andrea , Gigli Gian Luigi , Pellitteri Gaia , Dalla Torre Chiara , Valente Mariarosaria
Published: September 2021

Introduction: In cluster headache, the efficacy of suboccipital steroid injection is notable within a few days, although few data are available about the duration of efficacy. A combination treatment, consisting of suboccipital steroid injection plus pulsed radiofrequency, could potentially lead to long-term benefit. Evidence about pulsed radiofrequency of the greater occipital nerve is lacking.

Patients and Methods: We retrospectively describe a series of four cluster headache patients treated with suboccipital steroid injection plus pulsed radiofrequency of the greater occipital nerve.

Results: All patients achieved a 50% reduction in attack frequency in the 7 days after the first treatment. Moreover, a long pain-free remission period up to 15 months was noted.

Conclusion: Suboccipital steroid injection plus pulsed radiofrequency of the greater occipital nerve might have both acute and prophylactic effects in cluster headache. The greater occipital nerve is more accessible to pulsed radiofrequency than other targets.
Severity of Downgaze Palsy in the Context of Disease Duration Could Estimate Survival Duration in Patients With Progressive Supranuclear Palsy
Authors: Xie Tao , Yuen Carlen A. , Kang Wenjun , Padmanaban Mahesh , Hain Timothy C. , Nichols Jeffrey
Published: September 2021

It is an unmet need to estimate survival duration for patients with progressive supranuclear palsy (PSP). The objective of this study was to identify factors associated with the survival duration in patients with PSP. We followed up 23 patients with probable PSP-RS (Richardson syndrome) or PSP-P (parkinsonism) in our PSP center until death from 2011 to 2019. We prospectively and quantitatively rated their downgaze palsy whenever first noticed in our clinic. This was utilized along with the disease duration, motor function, medication use for parkinsonism, sex, age at onset of PSP, comorbid pulmonary and cardiovascular diseases, and the total survival duration from the onset of PSP to death for prediction analysis. A well-fitted linear regression model and a multivariant Cox model were applied to identify predicting factors for total survival duration. All patients had the specific hummingbird sign on brain MRI for PSP when downgaze palsy was documented. We found that the severity of downgaze palsy and the disease duration at the assessment were consistently correlated with the total survival duration in both models. The total survival duration could be further estimated by a formed regression equation. We conclude that severity and time to develop downgaze palsy could help to estimate the total survival duration in patients with probable PSP-RS and PSP-P, the major forms of PSP, which has significant clinical applications in clinical counseling and trial enrollment.
Teaching the Science in Neuroscience to Protect From Neuromyths: From Courses to Fieldwork
Authors: Carboni Alejandra , Maiche Alejandro , Valle-Lisboa Juan C.
Published: September 2021

In recent decades, Cognitive Neuroscience has evolved from a rather arcane field trying to understand how the brain supports mental activities, to one that contributes to public policies. In this article, we focus on the contributions from Cognitive Neuroscience to Education. This line of research has produced a great deal of information that can potentially help in the transformation of Education, promoting interventions that help in several domains including literacy and math learning, social skills and science. The growth of the Neurosciences has also created a public demand for knowledge and a market for neuro-products to fulfill these demands, through books, booklets, courses, apps and websites. These products are not always based on scientific findings and coupled to the complexities of the scientific theories and evidence, have led to the propagation of misconceptions and the perpetuation of neuromyths. This is particularly harmful for educators because these misconceptions might make them abandon useful practices in favor of others not sustained by evidence. In order to bridge the gap between Education and Neuroscience, we have been conducting, since 2013, a set of activities that put educators and scientists to work together in research projects. The participation goes from discussing the research results of our projects to being part and deciding aspects of the field interventions. Another strategy consists of a course centered around the applications of Neuroscience to Education and their empirical and theoretical bases. These two strategies have to be compared to popularization efforts that just present Neuroscientific results. We show that the more the educators are involved in the discussion of the methodological bases of Neuroscientific knowledge, be it in the course or as part of a stay, the better they manage the underlying concepts. We argue that this is due to the understanding of scientific principles, which leads to a more profound comprehension of what the evidence can and cannot support, thus shielding teachers from the false allure of some commercial neuro-products. We discuss the three approaches and present our efforts to determine whether they lead to a strong understanding of the conceptual and empirical base of Neuroscience.
Standard Tone Stability as a Manipulation of Precision in the Oddball Paradigm: Modulation of Prediction Error Responses to Fixed-Probability Deviants
Authors: SanMiguel Iria , Costa-Faidella Jordi , Lugo Zulay R. , Vilella Elisabet , Escera Carles
Published: September 2021

Electrophysiological sensory deviance detection signals, such as the mismatch negativity (MMN), have been interpreted from the predictive coding framework as manifestations of prediction error (PE). From a frequentist perspective of the classic oddball paradigm, deviant stimuli are unexpected because of their low probability. However, the amount of PE elicited by a stimulus can be dissociated from its probability of occurrence: when the observer cannot make confident predictions, any event holds little surprise value, no matter how improbable. Here we tested the hypothesis that the magnitude of the neural response elicited to an improbable sound (D) would scale with the precision of the prediction derived from the repetition of another sound (S), by manipulating repetition stability. We recorded the Electroencephalogram (EEG) from 20 participants while passively listening to 4 types of isochronous pure tone sequences differing in the probability of the S tone (880 Hz) while holding constant the probability of the D tone [1,046 Hz; p(D) = 1/11]: Oddball [p(S) = 10/11]; High confidence (7/11); Low confidence (4/11); and Random (1/11). Tones of 9 different frequencies were equiprobably presented as fillers [p(S) + p(D) + p(F) = 1]. Using a mass-univariate non-parametric, cluster-based correlation analysis controlling for multiple comparisons, we found that the amplitude of the deviant-elicited ERP became more negative with increasing S probability, in a time-electrode window consistent with the MMN (ca. 120–200 ms; frontal), suggesting that the strength of a PE elicited to an improbable event indeed increases with the precision of the predictive model.
hnRNP A1B, a Splice Variant of HNRNPA1, Is Spatially and Temporally Regulated
Authors: Gagné Myriam , Deshaies Jade-Emmanuelle , Sidibé Hadjara , Benchaar Yousri , Arbour Danielle , Dubinski Alicia , Litt Gurleen , Peyrard Sarah , Robitaille Richard , Sephton Chantelle F. , Vande Velde Christine
Published: September 2021

RNA binding proteins (RBPs) play a key role in cellular growth, homoeostasis and survival and are tightly regulated. A deep understanding of their spatiotemporal regulation is needed to understand their contribution to physiology and pathology. Here, we have characterized the spatiotemporal expression pattern of hnRNP A1 and its splice variant hnRNP A1B in mice. We have found that hnRNP A1B expression is more restricted to the CNS compared to hnRNP A1, and that it can form an SDS-resistant dimer in the CNS. Also, hnRNP A1B expression becomes progressively restricted to motor neurons in the ventral horn of the spinal cord, compared to hnRNP A1 which is more broadly expressed. We also demonstrate that hnRNP A1B is present in neuronal processes, while hnRNP A1 is absent. This finding supports a hypothesis that hnRNP A1B may have a cytosolic function in neurons that is not shared with hnRNP A1. Our results demonstrate that both isoforms are differentially expressed across tissues and have distinct localization profiles, suggesting that the two isoforms may have specific subcellular functions that can uniquely contribute to disease progression.
Identification of DNA Methylation Changes That Predict Onset of Post-traumatic Stress Disorder and Depression Following Physical Trauma
Authors: Martin Carina A. , Vorn Rany , Schrieber Martin , Lai Chen , Yun Sijung , Kim Hyung-Suk , Gill Jessica
Published: September 2021

Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly experienced after exposure to highly stressful events, including physical trauma, yet, biological predictors remain elusive. Methylation of DNA may provide key insights, as it likely is reflective of factors that may increase the risk in trauma patients, as DNA methylation is altered by previous stressors. Here, we compared DNA methylation patterns using bisulfite sequencing in patients with a physical trauma that required more than a 24-h hospitalization (n = 33). We then compared DNA methylation in patients who developed and compared the following groups (1) PTSD and MDD; n = 12), (2) MDD (patients with MDD only; n = 12), and (3) control (patients who did not have PTSD or MDD; n = 9), determined by the PTSD Checklist (PCL-5) and Quick Inventory of Depressive Symptomatology (QIDS) at 6-months follow-up. We identified 17 genes with hypermethylated cytosine sites and 2 genes with hypomethylated sites in comparison between PTSD and control group. In comparison between MDD and control group, we identified 12 genes with hypermethylated cytosine sites and 6 genes with hypomethylated sites. Demethylation of these genes altered the CREB signaling pathway in neurons and may represent a promising therapeutic development target for PTSD and MDD. Our findings suggest that epigenetic changes in these gene regions potentially relate to the onset and symptomology of PTSD and MDD and could be used as potential biomarkers in predicting the onset of PTSD or MDD following traumatic events.
Interruption of Endolysosomal Trafficking After Focal Brain Ischemia
Authors: Hu Kurt , Gaire Bhakta Prasad , Subedi Lalita , Arya Awadhesh , Teramoto Hironori , Liu Chunli , Hu Bingren
Published: September 2021

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.
Barley Melanoidins: Key Dietary Compounds With Potential Health Benefits
Authors: Sharma Jitendra Kumar , Sihmar Monika , Santal Anita Rani , Prager Louis , Carbonero Franck , Singh Nater Pal
Published: September 2021

This paper is a review of the potential health benefits of barley melanoidins. Food melanoidins are still rather understudied, despite their potential antioxidant, antimicrobial, and prebiotic properties. Free radicals are villainous substances in humans produced as metabolic byproducts and causing cancers and cardiovascular diseases, and the melanoidins alleviate the effects of these free radicals. Malt is produced from cereal grains such as barley, wheat, and maize, and barley is predominantly used in beer production. Beer (alcoholic and non-alcoholic) is a widely consumed beverage worldwide and a good source of dietary melanoidins, which enhance the beers' flavor, texture, and sensorial properties. Melanoidins, the final products of the Maillard reaction, are produced at different stages during the brewing process. Beer melanoidins protect the cells from oxidative damage of DNA. The high reducing capacity of melanoidins can induce hydroxyl radicals from H2O2 in the presence of ferric ion (Fe3+). Melanoidins inhibit lipid peroxidation during digestion due to their chelating metal property. However, lower digestibility of melanoidins leads to less availability to the organisms but is considered to function as dietary fiber that can be metabolized by the lower gut microbiota and possibly incur prebiotic properties. Melanoidins promote the growth of Lactobacilli and Bifidobacteria in the gastrointestinal tract, preventing the colonization of potential pathogens. Barley is already popular through beer production and increasingly as a functional food. Considering this economic and industrial importance, more research to explore the chemical properties of barley melanoidins and corresponding health benefits as barley is warranted.
25(OH)D Levels in Infancy Is Associated With Celiac Disease Autoimmunity in At-Risk Children: A Case–Control Study
Authors: Andrén Aronsson Carin , Liu Xiang , Norris Jill M. , Uusitalo Ulla , Butterworth Martha D. , Koletzko Sibylle , Virtanen Suvi M. , Erlund Iris , Kurppa Kalle , Hagopian William A. , Rewers Marian J. , She Jin-Xiong , Toppari Jorma , Ziegler Anette-G. , Akolkar Beena , Krischer Jeffrey P. , Agardh Daniel
Published: September 2021

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children.

Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case–control study. In total, 281 case–control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA.

Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95–1.04) or childhood (OR 1.02, 95% CI 0.97–1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations <30 nmol/L (OR 2.23, 95% CI 1.29, 3.84) and >75 nmol/L (OR 2.10, 95% CI 1.28–3.44) in early infancy, as compared with 50–75 nmol/L.

Conclusion: This study indicates that 25(OH)D concentrations <30 nmol/L and >75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset.
Identification of Key Genes Related to CD8+ T-Cell Infiltration as Prognostic Biomarkers for Lung Adenocarcinoma
Authors: Du Minjun , Liang Yicheng , Liu Zixu , Li Xingkai , Liang Mei , Zhou Boxuan , Gao Yushun
Published: September 2021

Background

CD8+ T cells are one of the central effector cells in the immune microenvironment. CD8+ T cells play a vital role in the development and progression of lung adenocarcinoma (LUAD). This study aimed to explore the key genes related to CD8+ T-cell infiltration in LUAD and to develop a novel prognosis model based on these genes.

Methods

With the use of the LUAD dataset from The Cancer Genome Atlas (TCGA), the differentially expressed genes (DEGs) were analyzed, and a co-expression network was constructed by weighted gene co-expression network analysis (WGCNA). Combined with the CIBERSORT algorithm, the gene module in WGCNA, which was the most significantly correlated with CD8+ T cells, was selected for the subsequent analyses. Key genes were then identified by co-expression network analysis, protein–protein interactions network analysis, and least absolute shrinkage and selection operator (Lasso)-penalized Cox regression analysis. A risk assessment model was built based on these key genes and then validated by the dataset from the Gene Expression Omnibus (GEO) database and multiple fluorescence in situ hybridization experiments of a tissue microarray.

Results

Five key genes (MZT2A, ALG3, ATIC, GPI, and GAPDH) related to prognosis and CD8+ T-cell infiltration were identified, and a risk assessment model was established based on them. We found that the risk score could well predict the prognosis of LUAD, and the risk score was negatively related to CD8+ T-cell infiltration and correlated with the advanced tumor stage. The results of the GEO database and tissue microarray were consistent with those of TCGA. Furthermore, the risk score was higher significantly in tumor tissues than in adjacent lung tissues and was correlated with the advanced tumor stage.

Conclusions

This study may provide a novel risk assessment model for prognosis prediction and a new perspective to explore the mechanism of tumor immune microenvironment related to CD8+ T-cell infiltration in LUAD.
The Landscape of Immune Cells Indicates Prognosis and Applicability of Checkpoint Therapy in Hepatocellular Carcinoma
Authors: Huang Jiacheng , Zhang Lele , Chen Jianxiang , Wan Dalong , Zhou Lin , Zheng Shusen , Qiao Yiting
Published: September 2021

Background

Tumor-infiltrating immune cells are important components of tumor microenvironment (TME), and their composition reflects the confrontation between host immune system and tumor cells. However, the relationship between the composition of infiltrating immune cells, prognosis, and the applicability of anti-PD-1/PD-L1 therapy in hepatocellular carcinoma (HCC) needs systematic examination.

Methods

Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was applied to evaluate the infiltration of immune cells based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) cohort. Diagnostic and prognostic models were constructed based on immune cells, and the models were validated by two external cohorts. The relationship between immune cells and PD-L1 was evaluated by Spearman correlation, and the finding was validated in our in-house HCC sample.

Result

Patients in TCGA LIHC cohort were classified into six subtypes with different prognosis based on the proportion of tumor-infiltrating immune cells simulated via CIBERSORT. Among 22 types of immune cells, intratumoral PD-L1 mRNA level exhibited linear relationship with the fraction of five types of immune cells (M1 macrophages, plasma cells, CD8+ T cells, resting mast cells, and regulatory T cells), and M1 macrophages showed the strongest relevance (R = 0.26, p < 0.001). Immunohistochemistry of our in-house HCC specimens verified this conclusion. Moreover, intratumoral mRNA levels of M1 macrophage-associated cytokines were positively correlated with PD-L1 level.

Conclusions

Our study demonstrated that the prognosis of HCC patients was associated with the pattern of infiltrating immune cells in TME, and macrophage-associated cytokines might be a potential non-invasive marker for predicting the PD-L1 level for HCC patients.
Addition of Plasma Myeloperoxidase and Trimethylamine N-Oxide to the GRACE Score Improves Prediction of Near-Term Major Adverse Cardiovascular Events in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Tan Yu , Zhou Jinying , Yang Shujun , Li Jiannan , Zhao Hanjun , Song Li , Yan Hongbing
Published: September 2021

Background: The Global Registry of Acute Coronary Events (GRACE) risk score (GRS) is an established powerful model in predicting prognosis of patients with acute coronary syndrome. However, it does not contain pathophysiological biomarkers. Myeloperoxidase (MPO) and trimethylamine N-oxide (TMAO) are novel biomarkers of different pathophysiological processes of acute myocardial infarction, and each of them predicts risk of adverse clinical outcomes. We aimed to investigate whether the addition of MPO and TMAO could improve a GRS-based prediction model in patients with ST-segment elevation myocardial infarction (STEMI).

Methods: A prospective cohort of 444 consecutive patients with STEMI who underwent primary percutaneous coronary intervention were enrolled in this study. Plasma levels of MPO and TMAO were measured using samples collected before the interventional procedure. GRS at admission was calculated. Death and nonfatal myocardial infarction were recorded as major adverse cardiac events (MACEs). Kaplan–Meier survival analysis with Cox proportional-hazards regression was used to identify predictive values of MPO and TMAO. Area under the receiver-operator characteristic curve (AUC) and net reclassification improvement (NRI) were calculated to evaluate the increment of predictive value for the combination of MPO and TMAO with GRS in predicting adverse clinical outcomes.

Results: During 6 months follow-up, 27 patients suffered MACEs. Both MPO (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.11–5.87; p < 0.05) and TMAO (HR: 4.50, 95% CI: 1.78–11.40, p < 0.01) predicted MACEs at 6 months. The AUC for MPO, TMAO, GRS, and their combination in predicting risk of MACEs at 6 months is 0.642, 0.692, 0.736, and 0.760, respectively. The addition of MPO and TMAO significantly improved the net reclassification of GRS for predicting MACEs at 6 months (NRI: 0.42, p = 0.032).

Conclusion: Plasma MPO and TMAO each predict near-term risk of adverse outcomes in patients with STEMI. Furthermore, the combination of MPO and TMAO with GRS enables more accurate prediction of cardiovascular events compared with GRS alone.
Risk of Cardiovascular Events and Medical Cost of Dapagliflozin and Dipeptidyl Peptidase-4 Inhibitors
Authors: Seong Jong-Mi , Kim Jong Joo , Kim Hae Jin , Sohn Hyun Soon
Published: September 2021

This study compared dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, and dipeptidyl peptidase-4 inhibitors (DPP-4i) with regard to cardiovascular (CV) event incidence and direct medical costs during type 2 diabetes treatment. A retrospective cohort study was conducted using national health insurance claims data from September 1, 2014, to June 30, 2018, of patients in Korea. Patients who were prescribed dapagliflozin and DPP-4i for the first time were included. The primary outcome was the incidence of a composite of major adverse CV events (MACEs)—nonfatal myocardial infarction, nonfatal stroke, or in-hospital CV death. Proportional hazard models after propensity score weighting were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) for MACE in the dapagliflozin and DPP-4i groups. A decision analytic model was used to compare direct medical costs between the two treatment groups from a healthcare provider’s perspective. Of the 260,336 patients in the cohort, 23,147 and 237,189 received dapagliflozin and DPP-4i, respectively. During the follow-up, 184 patients receiving dapagliflozin and 3,674 receiving DPP-4i (incidence, 6.47 and 11.33 events/1,000 person-years, respectively) had MACE. The adjusted HR of MACE for dapagliflozin compared with that for DPP-4i was 0.69 (95% CI 0.57–0.83). The corresponding HRs were consistent among patients with and without underlying CV disease. The estimated direct medical cost appeared to be lower by $68,452 in the dapagliflozin group than that in the DPP-4i group for 3 years, in 1,000 hypothetical patients. In this population-based cohort study, the use of dapagliflozin instead of DPP-4i was associated with a reduced risk of MACE, which subsequently reduced direct medical costs. These data provide valuable information to patients, practitioners, and authorities regarding the risk of CV events associated with dapagliflozin versus DPP-4i use in clinical practice.
Understanding Fatal and Non-Fatal Drug Overdose Risk Factors: Overdose Risk Questionnaire Pilot Study—Validation
Authors: Doggui Radhouene , Adib Keyrellous , Baldacchino Alex
Published: September 2021

Background: Drug overdoses (fatal and non-fatal) are among the leading causes of death in population with substance use disorders. The aim of the current study was to identify risk factors for fatal and non-fatal drug overdose for predominantly opioid-dependent treatment–seeking population.

Methods: Data were collected from 640 adult patients using a self-reported 25-item Overdose Risk (OdRi) questionnaire pertaining to drug use and identified related domains. The exploratory factor analysis (EFA) was primarily used to improve the interpretability of this questionnaire. Two sets of EFA were conducted; in the first set of analysis, all items were included, while in the second set, items related to the experience of overdose were removed. Logistic regression was used for the assessment of latent factors’ association with both fatal and non-fatal overdoses.

Results: EFA suggested a three-factor solution accounting for 75 and 97% of the variance for items treated in the first and second sets of analysis, respectively. Factor 1 was common for both sets of EFA analysis, containing six items (Cronbach’s α = 0.70) focusing around “illicit drug use and lack of treatment.” In the first set of analysis, Factors 2 (Cronbach’s α = 0.60) and 3 (Cronbach’s α = 0.34) were focusing around “mental health and emotional trauma” and “chronic drug use and frequent overdose” domains, respectively. The increase of Factor 2 was found to be a risk factor for fatal drug overdose (adjusted coefficient = 1.94, p = 0.038). In the second set of analysis, Factors 2 (Cronbach’s α = 0.65) and 3 (Cronbach’s α = 0.59) as well as Factor 1 were found to be risk factors for non-fatal drug overdose ever occurring. Only Factors 1 and 3 were positively associated with non-fatal overdose (one in a past year).

Conclusion: The OdRi tool developed here could be helpful for clinical studies for the overdose risk assessment. However, integrating validated tools for mental health can probably help refining the accuracy of latent variables and the questionnaire’s consistency. Mental health and life stress appear as important predictors of both fatal and non-fatal overdoses.
Biochemical and Proteomic Characterization, and Pharmacological Insights of Indian Red Scorpion Venom Toxins
Authors: Das Bhabana , Saviola Anthony J. , Mukherjee Ashis K.
Published: September 2021

The Indian red scorpion (Mesobuthus tamulus) is one of the world’s deadliest scorpions, with stings representing a life-threatening medical emergency. This species is distributed throughout the Indian sub-continent, including eastern Pakistan, eastern Nepal, and Sri Lanka. In India, Indian red scorpions are broadly distributed in western Maharashtra, Saurashtra, Kerala, Andhra Pradesh, Tamil Nadu, and Karnataka; however, fatal envenomations have been recorded primarily in the Konkan region of Maharashtra. The Indian red scorpion venom proteome comprises 110 proteins belonging to 13 venom protein families. The significant pharmacological activity is predominantly caused by the low molecular mass non-enzymatic Na+ and K+ ion channel toxins. Other minor toxins comprise 15.6% of the total venom proteome. Indian red scorpion stings induce the release of catecholamine, which leads to pathophysiological abnormalities in the victim. A strong correlation has been observed between venom proteome composition and local (swelling, redness, heat, and regional lymph node involvement) and systemic (tachycardia, mydriasis, hyperglycemia, hypertension, toxic myocarditis, cardiac failure, and pulmonary edema) manifestations. Immediate administration of antivenom is the preferred treatment for Indian red scorpion stings. However, scorpion-specific antivenoms have exhibited poor immunorecognition and neutralization of the low molecular mass toxins. The proteomic analysis also suggests that Indian red scorpion venom is a rich source of pharmacologically active molecules that may be envisaged as drug prototypes. The following review summarizes the progress made towards understanding the venom proteome of the Indian red scorpion and addresses the current understanding of the pathophysiology associated with its sting.
Effects of Radix Scrophulariae on Hyperthyroidism Assessed by Metabonomics and Network Pharmacology
Authors: Zhang Ning , Lu Fang , Li Zihui , Zhao Hongwei , Pang Mu , Ye Tao , Wang Xijun , Liu Shumin
Published: September 2021

Radix Scrophulariae (Chinese name: Xuanshen), a traditional Chinese herb, is used for the treatment of hyperthyroidism, and in this study, its mechanisms were evaluated by metabonomics and system pharmacology. To study the anti-hyperthyroidism effects of R. Scrophulariae, a male SD rat (180–220 g) model of hyperthyroidism induced by Euthyrox was used. Thirty rats were randomly distributed into three groups: the Model group, the R. Scrophulariae treatment group (RS group) and the healthy Control group. Using the UHPLC/Q-TOF-MS metabolomics approach, 44 metabolites were found to be profoundly altered in the model group, and the levels of these biomarkers were significantly decreased after treatment with R. Scrophulariae. Forty-four metabolites and 13 signaling pathways related to R. Scrophulariae, including the biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis and sphingolipid metabolism, were explored, and linoleic acid metabolism and sphingolipid metabolism were identified as the most relevant metabolic pathways. In addition, the system pharmacology paradigm revealed that R. Scrophulariae contains 83 active ingredients and is related to 795 genes, and 804 disease genes are related to hyperthyroidism. The construction of the R. Scrophulariaceae-chemical composition-target-hyperthyroidism network identified a total of 112 intersection genes. The enriched gene targets were analyzed, and five pathways were found to be enriched. Among them pathways, the HIF signaling pathway had the highest enrichment score, which indicated that this pathway might be the main signaling pathway related to the treatment of hyperthyroidism by R. Scrophulariae.The integrated approach involving metabolomics and network pharmacology revealed that R. Scrophulariae might play a role in the treatment of hyperthyroidism by regulating the “IL6-APOA1-cholesterol” pathway and disturbing the HIF signaling pathway. The results demonstrate that the combination of metabolomics and network pharmacology could be used to reflect the effects of R. Scrophulariae on the biological network and metabolic state of hyperthyroidism and to evaluate the drug efficacy of R. Scrophulariaceae and its related mechanisms.
Genistein Inhibits the Pathogenesis of Aeromonas hydrophila by Disrupting Quorum Sensing Mediated Biofilm Formation and Aerolysin Production
Authors: Dong Jing , Zhang Defu , Li Jianrong , Liu Yongtao , Zhou Shun , Yang Yibin , Xu Ning , Yang Qiuhong , Ai Xiaohui
Published: September 2021

Aeromonas hydrophila is an opportunistic pathogen that is responsible for a variety of infectious diseases both in human and animals, particularly aquatic animals. Moreover, the pathogen has become a foodborne pathogen by transmitting from seafood to human. The abuse of antibiotics in aquaculture results in the emergence of antibiotic resistance and treatment failure. Therefore, novel approaches are urgently needed for managing resistant A. hydrophila associated infections. Aerolysin, an essential virulence factor of pathogenic A. hydrophila strain, has been identified as target developing novel drugs against pathogenesis of A. hydrophila. In the present study, genistein, without anti-A. hydrophila activity, was identified that could decrease the production of aerolysin and biofilm formation at a dose-dependent manner. Transcription of aerolysin encoding gene aerA and quorum sensing related genes ahyI and ahyR was significantly down-regulated when co-cultured with genistein. Cell viability studies demonstrated that genistein could significantly improve aerolysin mediated A549 cell injury. Furthermore, genistein could provide a remarkable protection to channel catfish infected with A. hydrophila. These findings indicate that targeting quorum sensing and virulence can be a useful approach developing drugs against A. hydrophila infections in aquaculture. Moreover, genistein can be chosen as a promising candidate in developing drugs against A. hydrophila.
Pharmacy Compounded Medicines for Patients With Rare Diseases: Lessons Learned From Chenodeoxycholic Acid and Cholic Acid
Authors: Polak Yasmin , Jacobs Bart A. W. , Kemper E. Marleen
Published: September 2021

Patients with rare diseases are often confronted with the fact that effective medicines are unavailable or simply not being developed. This situation jeopardizes the health of a large population of vulnerable patients with rare diseases. Pharmacy compounded formulations can provide a safe alternative when authorized treatments are unavailable or unsuitable. Practical guidelines on how to develop and implement pharmacy compounded formulations for patients with rare diseases are limited. The aim of this article is to provide guidance for when and how to apply pharmacy compounded formulations for patients with rare diseases. This is illustrated with two challenging examples: the development and implementation of pharmacy compounding of 1) chenodeoxycholic acid (CDCA) capsules for patients with cerebrotendinous xanthomatosis (CTX) and 2) cholic acid (CA) capsules for patients with rare bile acid synthesis defects (BASD). All critical steps of the development of CDCA and CA capsules are explained and summarized in a practical guideline.
Methods: Of Stream Functions and Thin Wires: An Intuitive Approach to Gradient Coil Design
Authors: Littin Sebastian , Jia Feng , Amrein Philipp , Zaitsev Maxim
Published: September 2021

The design of gradient coils is sometimes perceived as complex and counterintuitive. However, a current density is connected to a stream function in fact by a simple relation. Here we present an intuitive open source code collection to derive stream functions from current densities on simple surface geometries. Discrete thin wires, oriented orthogonally to the main magnetic field direction are used to describe a surface current density. An inverse problem is solved and stream functions are derived to find coil designs in the current and stream function domains. The flexibility of the design method is demonstrated by deriving gradient coil designs on several different surface topologies. This collection is primarily intended for teaching, as well as for demonstrating all gradient coil design steps with openly available software tools.
Optical Coherence Tomography for Three-Dimensional Imaging in the Biomedical Field: A Review
Authors: Zheng Shu , Bai Yanru , Xu Zihao , Liu Pengfei , Ni Guangjian
Published: September 2021

Optical coherence tomography (OCT) has become a novel approach to noninvasive imaging in the past three decades, bringing a significant potential to biological research and medical biopsy in situ, particularly in three-dimensional (3D) in vivo conditions. Specifically, OCT systems using broad bandwidth sources, mainly centered at near-infrared-II, allow significantly higher imaging depth, as well as maintain a high-resolution and better signal-to-noise ratio than the traditional microscope, which avoids the scattering blur and thus obtains more details from delicate biological structures not just limited to the surface. Furthermore, OCT systems combined the spectrometer with novel light sources, such as multiplexed superluminescent diodes or ultra-broadband supercontinuum laser sources, to obtain sub-micron resolution imaging with high-speed achieve widespread clinical applications. Besides improving OCT performance, the functional extensions of OCT with other designs and instrumentations, taking polarization state or birefringence into account, have further improved OCT properties and functions. We summarized the conventional principle of OCT systems, including time-domain OCT, Fourier-domain OCT, and several typical OCT extensions, compared their different components and properties, and analyzed factors that affect OCT performance. We also reviewed current applications of OCT in the biomedical field, especially in hearing science, discussed existing limitations and challenges, and looked forward to future development, which may provide a guideline for those with 3D in vivo imaging desires.
Abiotic Stress-Induced Actin-Depolymerizing Factor 3 From Deschampsia antarctica Enhanced Cold Tolerance When Constitutively Expressed in Rice
Authors: Byun Mi Young , Cui Li Hua , Lee Andosung , Oh Hyung Geun , Yoo Yo-Han , Lee Jungeun , Kim Woo Taek , Lee Hyoungseok
Published: September 2021

The Antarctic flowering plant Deschampsia antarctica is highly sensitive to climate change and has shown rapid population increases during regional warming of the Antarctic Peninsula. Several studies have examined the physiological and biochemical changes related to environmental stress tolerance that allow D. antarctica to colonize harsh Antarctic environments; however, the molecular mechanisms of its responses to environmental changes remain poorly understood. To elucidate the survival strategies of D. antarctica in Antarctic environments, we investigated the functions of actin depolymerizing factor (ADF) in this species. We identified eight ADF genes in the transcriptome that were clustered into five subgroups by phylogenetic analysis. DaADF3, which belongs to a monocot-specific clade together with cold-responsive ADF in wheat, showed significant transcriptional induction in response to dehydration and cold, as well as under Antarctic field conditions. Multiple drought and low-temperature responsive elements were identified as possible binding sites of C-repeat-binding factors in the promoter region of DaADF3, indicating a close relationship between DaADF3 transcription control and abiotic stress responses. To investigate the functions of DaADF3 related to abiotic stresses in vivo, we generated transgenic rice plants overexpressing DaADF3. These transgenic plants showed greater tolerance to low-temperature stress than the wild-type in terms of survival rate, leaf chlorophyll content, and electrolyte leakage, accompanied by changes in actin filament organization in the root tips. Together, our results imply that DaADF3 played an important role in the enhancement of cold tolerance in transgenic rice plants and in the adaptation of D. antarctica to its extreme environment.
The Complementary Roles of Chloroplast Cyclic Electron Transport and Mitochondrial Alternative Oxidase to Ensure Photosynthetic Performance
Authors: Chadee Avesh , Alber Nicole A. , Dahal Keshav , Vanlerberghe Greg C.
Published: September 2021

Chloroplasts use light energy and a linear electron transport (LET) pathway for the coupled generation of NADPH and ATP. It is widely accepted that the production ratio of ATP to NADPH is usually less than required to fulfill the energetic needs of the chloroplast. Left uncorrected, this would quickly result in an over-reduction of the stromal pyridine nucleotide pool (i.e., high NADPH/NADP+ ratio) and under-energization of the stromal adenine nucleotide pool (i.e., low ATP/ADP ratio). These imbalances could cause metabolic bottlenecks, as well as increased generation of damaging reactive oxygen species. Chloroplast cyclic electron transport (CET) and the chloroplast malate valve could each act to prevent stromal over-reduction, albeit in distinct ways. CET avoids the NADPH production associated with LET, while the malate valve consumes the NADPH associated with LET. CET could operate by one of two different pathways, depending upon the chloroplast ATP demand. The NADH dehydrogenase-like pathway yields a higher ATP return per electron flux than the pathway involving PROTON GRADIENT REGULATION5 (PGR5) and PGR5-LIKE PHOTOSYNTHETIC PHENOTYPE1 (PGRL1). Similarly, the malate valve could couple with one of two different mitochondrial electron transport pathways, depending upon the cytosolic ATP demand. The cytochrome pathway yields a higher ATP return per electron flux than the alternative oxidase (AOX) pathway. In both Arabidopsis thaliana and Chlamydomonas reinhardtii, PGR5/PGRL1 pathway mutants have increased amounts of AOX, suggesting complementary roles for these two lesser-ATP yielding mechanisms of preventing stromal over-reduction. These two pathways may become most relevant under environmental stress conditions that lower the ATP demands for carbon fixation and carbohydrate export.
Perspective on Sub-national Governance of Crossborder Regions: Democratic Governance in Anti-democratic Times?
Authors: Svensson Sara
Published: September 2021

In the past decades, subnational cooperation between municipalities and regions has become more common all over the world. In Europe and its neighborhood this tendency has been especially visible, much due to policy advocacy and technical assistance by regional intergovernmental organizations such as the Council of Europe, the European Union and the Organization for Security and Cooperation in Europe. This development accelerated in the 1990s in tandem with the transition and democratization processes that started after the fall of the Soviet Union. However, in many places democratization has stopped or started to reverse, leading to backsliding away from democracy. While democracy has always been different in crossborder regions due to the special status of their governance arrangements, this new development accentuates a need for new tools to understand the implications of various threats to democracy for the future of crossborder cooperation. This Perspective article provides an overview of the literature on participatory governance and democracy with relation to border regions, and suggests some mechanisms whereby current backsliding developments might harm sub-national cross-border democracy and a way by which current indexes of democracy at the national level could be adapted to the “messy” spaces of cross-border regional governance. This allows the Perspective article to be useful to both further research in the area and policy practitioners. Empirical examples from Central and Eastern Europe, are used as illustrations.
Does Self-Reassurance Reduce Neural and Self-Report Reactivity to Negative Life Events?
Authors: Kim Jeffrey J. , Doty James R. , Cunnington Ross , Kirby James N.
Published: September 2021

Whilst research has shown how self-criticism may increase both neural and self-report markers of negative emotion, less well-known is how self-reassurance—a compassionately-motivated cognitive self-relating style—may regulate negative emotion. Using fMRI, we invited participants to engage in self-criticism and self-reassurance toward written descriptions of negative life events (mistakes, setbacks, failures). Our results identify that neural markers of negative emotion and self-report markers of trial intensity during fMRI are down-regulated under conditions of self-reassurance, relative to self-criticism. Future work to control for autobiographical memory during this fMRI task is needed, as are controls for how well participants can engage in both thinking styles, to explore how memory/task engagement can contribute to self-reassurance and self-criticism. Engagement in self-reassurance can reduce the “sting” of negative life-events, both neural and self-report, which holds important implications for therapy.