bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytokinins: A Genetic Target for Increasing Yield Potential in the CRISPR Era
Authors: Mandal Sayanti , Ghorai Mimosa , Anand Uttpal , Roy Debleena , Kant Nishi , Mishra Tulika , Mane Abhijit Bhagwan , Jha Niraj Kumar , Lal Milan Kumar , Tiwari Rahul Kumar , Kumar Manoj , Radha  , Ghosh Arabinda , Bhattacharjee Rahul , Proćków Jarosław , Dey Abhijit
Published: April 2022

Over the last decade, remarkable progress has been made in our understanding the phytohormones, cytokinin’s (CKs) biosynthesis, perception, and signalling pathways. Additionally, it became apparent that interfering with any of these steps has a significant effect on all stages of plant growth and development. As a result of their complex regulatory and cross-talk interactions with other hormones and signalling networks, they influence and control a wide range of biological activities, from cellular to organismal levels. In agriculture, CKs are extensively used for yield improvement and management because of their wide-ranging effects on plant growth, development and physiology. One of the primary targets in this regard is cytokinin oxidase/dehydrogenase (CKO/CKX), which is encoded by CKX gene, which catalyses the irreversible degradation of cytokinin. The previous studies on various agronomically important crops indicated that plant breeders have targeted CKX directly. In recent years, prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been increasingly used in editing the CKO/CKX gene and phenomenal results have been achieved. This review provides an updated information on the applications of CRISPR-based gene-editing tools in manipulating cytokinin metabolism at the genetic level for yield improvement. Furthermore, we summarized the current developments of RNP-mediated DNA/transgene-free genomic editing of plants which would broaden the application of this technology. The current review will advance our understanding of cytokinins and their role in sustainably increase crop production through CRISPR/Cas genome editing tool.
Landscape of Peripheral Blood Mononuclear Cells and Soluble Factors in Severe COVID-19 Patients With Pulmonary Fibrosis Development
Authors: Wang Zhuolin , Zhang Yang , Yang Rirong , Wang Yujia , Guo Jiapei , Sun Ruya , Zhou Yuan , Su Li , Ge Qing , Feng Yingmei
Published: April 2022

Resulting from severe inflammation and cell destruction, COVID-19 patients could develop pulmonary fibrosis (PF), which remains in the convalescent stage. Nevertheless, how immune response participates in the pathogenesis of PF progression is not well defined. To investigate that question, 12 patients with severe COVID-19 were included in the study. Peripheral mononuclear cell (PBMC) samples were collected shortly after their admission and proceeded for single-cell RNA sequencing (scRNA-seq). After 14 days of discharge, the patients were revisited for chest CT scan. PF index (FI) was computed by AI-assisted CT images. Patients were categorized into FIhi and FIlo based on median of FI. By scRNA-seq analysis, our data demonstrated that frequency of CD4+ activated T cells and Treg cells were approximately 3-fold higher in FIhi patients compared with FIlo ones (p < 0.034 for all). By dissecting the differentially expressed genes, we found an overall downregulation of IFN-responsive genes (STAT1, IRF7, ISG15, ISG20, IFIs, and IFITMs) and S100s alarmins (S100A8, S100A9, S100A12, etc.) in all T-cell clusters, and cytotoxicity-related genes (GZMB, PRF1, and GNLY) in CTLs and γδ T cells in the FIhi cohort, compared with FIlo subjects. The GSEA analysis illustrated decreased expression of genes enriched in IFN signaling, innate immune response, adaptive immune response in T cells, NK cells, and monocytes in FIhi patients compared with FIlo ones. In conclusion, these data indicated that the attenuated IFN-responsive genes and their related signaling pathways could be critical for PF progression in COVID-19 patients.
Multi-Omics Analysis of the Prognosis and Biological Function for TRPV Channel Family in Clear Cell Renal Cell Carcinoma
Authors: Jiang Yuxiong , Han Dongxu , Zhao Yifan , Zhang Chen , Shi Xiujuan , Gu Wenyu
Published: April 2022

Background

The transient receptor potential vanilloid (TRPV) channels family, TRPV1-6, has been identified to profoundly affect a wide spectrum of pathological processes in various cancers. However, the biological function and prognostic value of TRPVs in clear cell renal cell carcinoma (ccRCC) are still largely unknown.

Methods

We obtained the gene expression data and clinical information of 539 ccRCC patients from The Cancer Genome Atlas (TCGA) database. A series of databases were used for data processing and visualization, including GEPIA, GeneMANIA, MethSurv, GSCA, TIMER, and starBase databases.

Results

The mRNA expression of TRPV2/3 was upregulated while the expression of TRPV5/6 was downregulated in ccRCC tumor tissues. TRPV family members in ccRCC were rarely mutated (nearly 7 frequencies). The ROC curve showed that TRPV2/5/6 had a high diagnostic ability in discriminating ccRCC from the control samples (AUC>0.9). Higher levels of TRPV3 expression were associated with poor prognosis of ccRCC patients, while higher expression of TRPV4 was associated with favorable prognosis. The expression of TRPV3 in normal and ccRCC tissues was validated by Immunohistochemistry, and its expression was remarkably related to high histologic grade and advanced stage. Besides, TRPV3 exhibit a reduction of DNA methylation level with tumor progression, and 12 CpGs of TRPV3 were associated with a significant prognosis. In addition, TRPV3 expression was significantly associated with the accumulation of several tumor-infiltrating immune cells, especially regulatory T cells. Furthermore, high levels of TRPV3 induced the expression of immune checkpoints such as LAG3, CTLA4, PDCD1, and TIGIT. Finally, we predicted a key SNHG3/AL513497.1-miR-10b-5p-TRPV3 axis linking to carcinogenesis and progression of ccRCC.

Conclusion

Our study may uncover TRPV channels–associated molecular mechanisms involved in the tumorigenesis and progression of ccRCC. TRPV family members might be diagnosed and prognostic markers and potential therapeutic targets for ccRCC patients.
Case Report: Invasive Cryptococcosis in French Guiana: Immune and Genetic Investigation in Six Non-HIV Patients
Authors: Goupil de Bouillé Jeanne , Epelboin Loïc , Henaff Fanny , Migaud Mélanie , Abboud Philippe , Blanchet Denis , Aznar Christine , Djossou Felix , Lortholary Olivier , Elenga Narcisse , Puel Anne , Lanternier Fanny , Demar Magalie
Published: April 2022

Objectives

We describe the clinical, mycological, immunological, and genetic characteristics of six HIV-negative patients presenting with invasive cryptococcosis.

Methods

Patients with cryptococcosis without any of the classical risk factors, such as HIV infection, followed at Cayenne Hospital, were prospectively included. An immunologic and genetic assessment was performed.

Results

Five male patients and one female patient, 5 adults and one child, were investigated. All presented a neuromeningeal localization.Cryptococcus neoformansvar.gattiiandC. neoformansvar.grubiiwere isolated in two and three patients, respectively, whereas one patient could not be investigated. Overall, we did not observe any global leukocyte defect. Two patients were found with high levels of circulating autoantibodies against Granulocyte macrophage-colony stimulating factor (GM-CSF), and none had detectable levels of autoantibodies against Interferon gamma (IFN-γ) Sequencing ofSTAT1exons and flanking regions performed for four patients was wild type.

Conclusion

To better understand cryptococcosis in patients with cryptococcosis but otherwise healthy, further explorations are needed with repeated immune checkups and strain virulence studies.
Impact of Adult Popillia japonica (Coleoptera: Scarabaeidae) Foliar Feeding Injury on Fruit Yield and Quality of a Temperate, Cold-Hardy Wine Grape, ‘Frontenac'
Authors: Ebbenga Dominique N. , Burkness Eric C. , Clark Matthew D. , Hutchison William D.
Published: April 2022

Popillia japonica(Newman), is a highly polyphagous, invasive species, first recorded in the U.S. in 1916, and detected in Minnesota in the late 1960s. Historically, research on this pest in the Midwest U.S. has focused primarily on ornamental and turf crops, with little attention placed on adult feeding damage to fruit crops. Recently, wine grape producers in the region noted substantial increases in defoliation fromP. japonicafeeding, confirming concerns for this perennial high value crop. To address these concerns, studies were conducted during the summers of 2020–2021 to understand the impact ofP. japonicafoliar feeding on the quality and yield of wine grapes. Trials utilized vines of the wine grape variety, ‘Frontenac.' In addition to open plots, whole vines were caged within fine mesh netting and infested withP. japonicaat 0, 25, 50, and 100 beetles per meter-row of vine. Beetles used for infestations were collected from natural field populations ofP. japonicaand left to feed until grapes were ready for harvest. During harvest, data collection included leaf samples for obtaining average percent defoliation, cluster weights, and berry subsamples for soluble solid content, pH, titratable acidity, and phenolic compound measurements. Results from these studies demonstrated that as beetle population density and defoliation per m-row increases, at-harvest measurements of quality parameters are significantly and negatively affected (P< 0.05) when compared with uninfested vines. The negative impacts to fruit quality exhibited in these studies will be important in the development of future management strategies forP. japonicain ‘Frontenac.'
The Beat Goes On: Humpback Whale Song Seasonality in Antarctic and South African Waters
Authors: Shabangu Fannie W. , Kowarski Katie A.
Published: April 2022

Little is known of the movements and seasonal occurrence of humpback whales (Megaptera novaeangliae) of South Africa and the Antarctic, populations once brought to near extinction by historic commercial whaling. We investigated the seasonal occurrence and diel-vocalizing pattern of humpback whale songs off the west coast of South Africa (migration route and opportunistic feeding ground) and the Maud Rise, Antarctica (feeding ground), using passive acoustic monitoring data collected between early 2014 and early 2017. Data were collected using acoustic autonomous recorders deployed 200-300 m below the sea surface in waters 855, 1,118 and 4,400 m deep. Acoustic data were manually analyzed for humpback whale vocalizations. While non-song calls were never identified, humpback whale songs were detected from June through December in South African waters, with a peak in percentage of acoustic occurrence around September/October in the austral spring. In Antarctic waters, songs were detected from March through May and in July (with a peak occurrence in April) where acoustic occurrence of humpback whales was negatively correlated to distance to the sea ice extent. Humpback whales were more vocally active at night than in the day at all recording sites. Detection range modelling indicates that humpback whale vocalizations could be detected as far as 18 and 45 km from recorders in South African and Antarctic waters, respectively. This study provides a multi-year description of the offshore acoustic occurrence of humpback whales off the west coast of South Africa and Maud Rise, Antarctica, regions that should continue to be monitored to understand these recovering populations.
Comparison of the Effectiveness of Various Drug Interventions to Prevent Etomidate-Induced Myoclonus: A Bayesian Network Meta-Analysis
Authors: Zhang Kang-Da , Wang Lin-Yu , Zhang Dan-Xu , Zhang Zhi-Hua , Wang Huan-Liang
Published: April 2022

Background

Myoclonic movement is a very common but undesirable phenomenon during the induction of general anesthesia using etomidate. Such movement may cause unnecessary problems. Currently, there is an increasing number of drugs for preventing etomidate-induced myoclonus (EM). However, direct comparisons of various drugs are lacking, and this interferes with clinical decision-making. Our network meta-analysis (NMA) aimed to compare the efficacy of different drugs for the prevention of moderate-to-severe general myoclonus.

Methods

Using several biomedical databases, randomized controlled trials (RCTs) published in English from inception to August 22, 2021 were searched. Among the various interventions, we selected nine types of intervention drugs (dexmedetomidine, etomidate, lidocaine, NMDA receptor antagonist, κ opioid receptor agonist, μ opioid receptor agonist, muscle relaxant, gabapentin, and midazolam) for comparison, according to the number of studies. Bayesian NMA was performed using STATA16 and R softwares. The relative risk of EM was assessed using risk ratios (RRs) and the corresponding 95% confidence intervals (CI).

Results

A total of 31 RCTs (3209 patients) were included. NMA results showed that, compared with a placebo, etomidate (RR 4.0, 95%CI 2.1–7.8), κ opioid receptor agonist (RR 2.9, 95%CI 1.9–4.6), μ opioid receptor agonist (RR 3.1, 95%CI 2.3–4.3), NMDA receptor antagonist (RR 1.7, 95%CI 1.0–2.8), dexmedetomidine (RR 2.4, 95%CI 1.5–3.9), lidocaine (RR 2.1, 95%CI 1.2–3.9), and midazolam (RR 2.2, 95%CI 1.5–3.2) can significantly reduce the risk of EM. In contrast, the effects of muscle relaxants (RR 2.1, 95%CI 0.81–5.3) and gabapentin (RR 2.8, 95%CI 0.92–9.3) were inconclusive. Further subgroup analyses showed that preoperative low-dose etomidate, μ-opioid receptor agonist, and κ-opioid receptor agonist were significantly better than other interventions in the prevention of moderate to severe EM.

Conclusion

Preoperative use of small doses of etomidate or opioids may be the most effective way to avoid EM, especially moderate and severe EM, which makes anesthesia induction safer, more stable, and aligns better with the requirements of comfortable medicine.

Systematic Review Registration

[https://www.crd.york.ac.uk/prospero/], [CRD4202127706].
Research Trends and Hotspots on Herpes Zoster: A 10-Year Bibliometric Analysis (2012–2021)
Authors: Zhang Jian , Han Xu , Su Diansan , Gu Xiyao , Yu Weifeng
Published: April 2022

Purpose

Herpes zoster infection, with its considerable burden to individuals and society, remains a challenge around the world. However, to the knowledge of the authors, little bibliometric quantitative or qualitative analysis has been carried out to evaluate herpes zoster research. This study aimed to use a bibliometric analysis to evaluate current publication trends and hotspots on herpes zoster research worldwide, in order to advance research in this field.

Methods

Relevant publications from January 2012 to December 2021 were collected from the Web of Science Core Collection database. Citespace (V5.8.R3) was used to analyze the research points, including publication countries, institutions and authors, cited author, cited reference and their clustering, and keyword co-occurrence, and burst keyword to acquire research trends and hotspots.

Results

A total of 9,259 publications were obtained, with a steady increase in the number of annual publications during the decade. Articles were the main type of publication. The United States is the leading country in this research, and the University of Colorado has the highest influence in this field. Oxman is the most representative author, with a main research interest in herpes zoster vaccines. The top five cited authors' publications focused on herpes zoster vaccines, molecular mechanisms, and postherpetic neuralgia. A co-citation map resulted 19 main clusters, and revealed that vaccines, postherpetic neuralgia, treatments, varicella zoster virus and its mechanisms, and epidemiology of herpes zoster were the current research focus after clustering co-cited publications. Human herpesviruses, antiviral prophylaxis, rheumatoid arthritis, recombinant zoster vaccine, varicella vaccination and postherpetic neuralgia were the top clusters after co-occurrence keywords analysis. Moreover, burst keywords detection showed that the subunit vaccine was the new hotspot in the field of herpes zoster.

Conclusion

This bibliometric study defined the overall prospects in the field of herpes zoster and provided valuable instruction for the ongoing research. The keyword “subunit vaccine” indicated that a vaccine for herpes zoster prevention was the hotspot. Efforts to prevent varicella zoster virus infection will be essential to improve herpes zoster outcomes.
The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis
Authors: Dörr Katharina , Kammer Michael , Reindl-Schwaighofer Roman , Lorenz Matthias , Marculescu Rodrig , Poglitsch Marko , Beitzke Dietrich , Oberbauer Rainer
Published: April 2022

Fibroblast growth factor 23 (FGF23) is elevated in patients with chronic kidney disease and contributes to left ventricular hypertrophy (LVH). The aim of the analysis was to determine whether this effect is mediated by the renin-angiotensin-aldosterone system (RAAS) in hemodialysis. Serum samples from 62 randomized hemodialysis patients with LVH were analyzed for plasma renin activity (PRA-S), angiotensin II (AngII), and metabolites, angiotensin-converting enzyme-2 (ACE2) and aldosterone using a high throughput mass spectrometry assay. Compared to healthy individuals, levels of the RAAS parameters PRA-S, AngII and aldosterone were generally lower [median (IQR) PRA-S 130 (46–269) vs. 196 (98, 238) pmol/L; AngII 70 (28–157) vs. 137 (76, 201) pmol/L; Aldosterone 130 (54, 278) vs. 196 (98, 238) pmol/L]. We did not find an indication that the effect of FGF23 on LVH was mediated by RAAS parameters, with all estimated indirect effects virtually zero. Furthermore, FGF23 was not associated with RAAS parameter levels throughout the study. While there was a clear association between FGF23 levels and left ventricular mass index (LVMI) at the end of the study and in the FGF23 fold change and LVMI change analysis, no association between RAAS and LVMI was observed. Serum concentrations of PRA-S, AngII, and aldosterone were below the ranges measured in healthy controls suggesting that RAAS is not systemically activated in hemodialysis patients. The effect of FGF23 on LVMI was not mediated by systemic RAAS activity. These findings challenge the current paradigm of LVH progression and treatment with RAAS blockers in dialysis.

Clinical Trial Registration

[https://clinicaltrials.gov/ct2/show/NCT03182699], identifier [NCT03182699].
Petasites for Migraine Prevention: New Data on Mode of Action, Pharmacology and Safety. A Narrative Review
Authors: Borlak Jürgen , Diener Hans-Christoph , Kleeberg-Hartmann Johanna , Messlinger Karl , Silberstein Stephen
Published: April 2022

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45–90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.
Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice
Authors: Yang Xiaofan , Yin Hongqiang , Wang Xiaojing , Sun Yueqing , Bian Xianli , Zhang Gaorui , Li Anning , Cao Aihua , Li Baomin , Ebrahimi-Fakhari Darius , Yang Zhuo , Meisler Miriam H. , Liu Qiji
Published: April 2022

Mutations in the SCN8A gene encoding the voltage-gated sodium channel α-subunit Nav1. 6 have been reported in individuals with epilepsy, intellectual disability and features of autism spectrum disorder. SCN8A is widely expressed in the central nervous system, including the cerebellum. Cerebellar dysfunction has been implicated in autism spectrum disorder. We investigated conditional Scn8a knockout mice under C57BL/6J strain background that specifically lack Scn8a expression in cerebellar Purkinje cells (Scn8aflox/flox, L7Cre+ mice). Cerebellar morphology was analyzed by immunohistochemistry and MR imaging. Mice were subjected to a battery of behavioral tests including the accelerating rotarod, open field, elevated plus maze, light-dark transition box, three chambers, male-female interaction, social olfaction, and water T-maze tests. Patch clamp recordings were used to evaluate evoked action potentials in Purkinje cells. Behavioral phenotyping demonstrated that Scn8aflox/flox, L7Cre+ mice have impaired social interaction, motor learning and reversal learning as well as increased repetitive behavior and anxiety-like behaviors. By 5 months of age, Scn8aflox/flox, L7Cre+ mice began to exhibit cerebellar Purkinje cell loss and reduced molecular thickness. At 9 months of age, Scn8aflox/flox, L7Cre+ mice exhibited decreased cerebellar size and a reduced number of cerebellar Purkinje cells more profoundly, with evidence of additional neurodegeneration in the molecular layer and deep cerebellar nuclei. Purkinje cells in Scn8aflox/flox, L7Cre+ mice exhibited reduced repetitive firing. Taken together, our experiments indicated that loss of Scn8a expression in cerebellar Purkinje cells leads to cerebellar degeneration and several ASD-related behaviors. Our study demonstrated the specific contribution of loss of Scn8a in cerebellar Purkinje cells to behavioral deficits characteristic of ASD. However, it should be noted that our observed effects reported here are specific to the C57BL/6 genome type.
Dietary Acid Load but Not Mediterranean Diet Adherence Score Is Associated With Metabolic and Cardiovascular Health State: A Population Observational Study From Northern Italy
Authors: Sanz Juana Maria , Sergi Domenico , Colombari Simona , Capatti Eleonora , Situlin Roberta , Biolo Gianni , Di Girolamo Filippo Giorgio , Lazzer Stefano , Šimunič Boštjan , Pišot Rado , Passaro Angelina
Published: April 2022

Diet plays a pivotal role in shaping the trajectory of chronic diseases. In this regard, the Mediterranean diet has been widely shown to exert beneficial effects on cardiometabolic health. On the contrary, the Western diet, which has also been reported to be an acidogenic dietary pattern, elicits detrimental effects on both metabolic and cardiovascular (CV) health. However, the role of dietary acid load (DAL) as a predictor of cardiometabolic prognosis remains to be elucidated. Thus, this study aims to compare Mediterranean diet adherence (MDA) and DAL focusing on their relationship with metabolic and CV prognosis. A total of 448 individuals aged 55–80 years were grouped depending on their MDA, assessed using food frequency questionnaires, or DAL, evaluated using potential renal load acid (PRAL) and net-endogenous acid production (NEAP). Study participants underwent anthropometric and biochemical measurements. The metabolic syndrome (MetS) prevalence was evaluated according to the National Cholesterol Education Program-Adult Treatment Panel III. Finally, the CV risk was evaluated using three independent algorithms: atherosclerotic cardiovascular disease (ASCVD), European Systematic COronary Risk Evaluation (SCORE), and Cuore risk scores. Mediterranean diet adherence was negatively associated with PRAL and NEAP. Individuals in the higher MDA tertile group had higher HDL cholesterol as well as lower homeostasis model assessment index (HOMA-IR) and fat mass relative to the lowest MDA tertile. However, in the high-MDA tertile group, there was neither a significantly lower MetS prevalence nor CV risk. Instead, both the MetS prevalence and CV risk were higher in individuals in the higher acid PRAL quartile relative to the lower alkaline PRAL quartile. Dietary acid load, especially assessed using PRAL but not MDA, was associated with indices of metabolic and CV prognosis. Thus, DAL assessed by 24-h dietary recalls may represent a better predictor of cardiometabolic health if compared to MDA evaluated using food frequency questionnaires.
The Relationship Between Fat-Free Mass and Glucose Metabolism in Children and Adolescents: A Systematic Review and Meta-Analysis
Authors: Wu Lijun , Chen Fangfang , Liu Junting , Hou Dongqing , Li Tao , Chen Yiren , Liao Zijun
Published: April 2022

Purpose

To assess the relationship between fat-free mass (FFM) and glucose metabolism in children 0–18 years of age.

Methods

We performed a systematic review of the literature on Medline/PubMed, SinoMed, Embase, and the Cochrane Library using the PRISMA 2020 guidelines to 12 October 2021; this encompassed observational studies in which the relationship between FFM and glucose metabolism was assessed. Correlation coefficient (r), regression coefficient (β), and odds ratio (OR) values in the studies were extracted and recorded as the primary data. “Agency for Healthcare Research and Quality” quality-assessment forms recommended for cross-sectional/prevalence studies were applied to evaluate the quality of the selected studies, and we executed R software to combine the pooled data.

Results

We included eight studies comprising 13,282 individuals, five of which involved the assessment of the relationship between FFM and blood glucose, and four on the relationship between FFM and insulin resistance (IR). Our results showed that FFM was significantly associated with fasting plasma insulin levels (r = 0.34, 95% CI: 0.30–0.39, P < 0.001). Due to high heterogeneity or insufficient quantity of data, the studies of the relationship between FFM and fasting plasma glucose, HOMA-IR, or HbA1c were not congruent, and were therefore not suitable for meta-analysis.

Conclusion

Our results indicated that FFM was significantly associated with fasting plasma insulin levels. As far as we have determined, this is the first-ever systematic review and meta-analysis of the associations between FFM and glucose metabolism in children and adolescents; and our results thus provide novel information to fill a gap in the literature in this area.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020150320, PROSPERO CRD42020150320.
HMGB1 in Pediatric COVID-19 Infection and MIS-C: A Pilot Study
Authors: Petrarca Laura , Manganelli Valeria , Nenna Raffaella , Frassanito Antonella , Ben David Shira , Mancino Enrica , Garofalo Tina , Sorice Maurizio , Misasi Roberta , Midulla Fabio
Published: April 2022

Objective

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, a novel syndrome known as a multisystem inflammatory syndrome in children (MIS-C) was reported in previously healthy children. A possible pro-inflammatory molecule, high-mobility group box 1 (HMGB1), may be assumed to play an important role in the pathogenesis and clinical presentation of MIS-C. We described the clinical picture of patients with MIS-C and we also aimed to test and compare HMGB1 serum levels of MIS-C patients with those of patients with previous SARS-CoV2 infection and healthy children.

Study design

We determined HMGB1 levels by Western blot in 46 patients and divided them into three groups, namely, five patients with MIS-C (median age: 8.36 years), 20 children with a history of SARS-CoV-2 infection (median age: 10.45 years), and 21 healthy children (controls) (median age: 4.84 years), without evidence of respiratory infection in the last 3 months.

Results

The median level of HMGB1 in the serum of five patients with MIS-C was found to be significantly higher compared with both patients with a recent history of COVID-19 (1,151.38 vs. 545.90 densitometric units (DU), p = 0.001) and control (1,151.38 vs. 320.33 DU, p = 0.001) groups. The HMGB1 level in MIS-C patients with coronary involvement had a slightly higher value with respect to patients without coronary dilatation (1,225.36 vs. 1,030.49 DU, p = 0.248). In two of the five children with MIS-C that performed a follow-up, the HMGB1 value decreased to levels that were superimposable to the ones of the control group.

Conclusion

The significantly high level of HMGB1 protein found in the serum of COVID-19 and patients with MIS-C supports its involvement in inflammatory manifestations, suggesting HMGB1 as a potential biomarker and therapeutic target in patients with severe illness.
Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning
Authors: Yang Yujia , Yi Xu , Cai Yue , Zhang Yuan , Xu Zhiqiang
Published: April 2022

Objective: Experimental and clinical evidence suggests that atherosclerosis is a chronic inflammatory disease. Our study was conducted for uncovering the roles of immune-associated genes during atherosclerotic plaque progression.

Methods: Gene expression profiling of GSE28829, GSE43292, GSE41571, and GSE120521 datasets was retrieved from the GEO database. Three machine learning algorithms, least absolute shrinkage, and selection operator (LASSO), random forest, and support vector machine–recursive feature elimination (SVM-RFE) were utilized for screening characteristic genes among atherosclerotic plaque progression- and immune-associated genes. ROC curves were generated for estimating the diagnostic efficacy. Immune cell infiltrations were estimated via ssGSEA, and immune checkpoints were quantified. CMap analysis was implemented to screen potential small-molecule compounds. Atherosclerotic plaque specimens were classified using a consensus clustering approach.

Results: Seven characteristic genes (TNFSF13B, CCL5, CCL19, ITGAL, CD14, GZMB, and BTK) were identified, which enabled the prediction of progression of atherosclerotic plaques. Higher immune cell infiltrations and immune checkpoint expressions were found in advanced-stage than in early-stage atherosclerotic plaques and were positively linked to characteristic genes. Patients could clinically benefit from the characteristic gene-based nomogram. Several small molecular compounds were predicted based on the characteristic genes. Two subtypes, namely, C1 immune subtype and C2 non-immune subtype, were classified across atherosclerotic plaques. The characteristic genes presented higher expression in C1 than in C2 subtypes.

Conclusion: Our findings provide several promising atherosclerotic plaque progression- and immune-associated genes as well as immune subtypes, which might enable to assist the design of more accurately tailored cardiovascular immunotherapy.
Immune Checkpoint Inhibitors in Peripheral T-Cell Lymphoma
Authors: Chen Xi , Wu Wanchun , Wei Wenwen , Zou Liqun
Published: April 2022

Peripheral T-cell lymphomas (PTCLs) are highly heterogeneous and present significant treatment challenges. Immune checkpoint therapies, such as PD-1 and CTLA-4 inhibitors, have significantly changed the clinical management paradigm of tumors. The roles of immune checkpoints in PTCL and related agents have been actively explored over recent years. PD-1 and PD-L1 expression is detectable in both PTCL and immune cells within the tumor microenvironment and forms the basis for the exploration of antibodies targeting these proteins. Such antibodies are currently being investigated in clinical trials to guide individualized therapy. PD-1/PD-L1 inhibitors alone and in combination with chemotherapy, radiotherapy, or targeted therapy have shown broad clinical efficacy and improved the survival of cancer patients. Studies of other immune checkpoint proteins, such as CTLA-4, TIM-3, LAG-3, and TIGIT, are likely to provide potential novel targets for immunotherapy. Here, we review the role of and recent advances in immune checkpoint blockade in common subtypes of PTCL, focusing on the anti-tumor immune responses to PD-1/PD-L1 blockers.
A Potent Antibiotic Combination of Linezolid and Polymycin B Nonapeptide Against Klebsiella pneumoniae Infection In Vitro and In Vivo
Authors: Huang Ting , Lv Zheng , Lin Jiafu , Zhao Kelei , Zhai Longfei , Wang Xinrong , Chu Yiwen
Published: April 2022

The emergence of antibiotic resistant Gram-negative bacteria such as Klebsiella pneumoniae (KP) is becoming a major public health threat and imposing a financial burden worldwide. A serious lack of new drugs under development is undermining efforts to fight them. In this study, we report a potent combination of linezolid and polymyxin B nonapeptide PBNP (LP) against KP infection in vitro and in vivo. The checkerboard test and the time-kill assay were performed to detect the antibacterial activity of LP against KP in vitro. And the Caenorhabditis elegans (C. elegans) was used as infection model to evaluate the protective effect of LP against KP infection in vivo. The LP combination showed significantly synergistic activity and antibacterial effects against KP, while linezolid and PBNP as monotherapies revealed no dramatically antibacterial activity against the KP strains. Additionally, we found that the LP treatment altered the biofilm production and morphology of KP. Furthermore, the LP treatments significantly protected C. elegans from KP infection. In conclusion, this study indicated that the LP combination exhibited significantly synergistic activity against KP and PBNP can be used as a potential activity enhancer. More importantly, this strategy provided the improvement of antibacterial activity spectrum of agents like linezolid and represented a potent alternative to overcome antibiotic resistance in the future.
A Comprehensive Review on the Chemical Properties, Plant Sources, Pharmacological Activities, Pharmacokinetic and Toxicological Characteristics of Tetrahydropalmatine
Authors: Du Qinyun , Meng Xianli , Wang Shaohui
Published: April 2022

Tetrahydropalmatine (THP), a tetrahydroproberine isoquinoline alkaloid, is widely present in some botanical drugs, such as Stephania epigaea H.S. Lo (Menispermaceae; Radix stephaniae epigaeae), Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T. Wang ex Z.Y. Su and C.Y. Wu (Papaveraceae; Corydalis rhizoma), and Phellodendron chinense C.K.Schneid (Berberidaceae; Phellodendri chinensis cortex). THP has attracted considerable attention because of its diverse pharmacological activities. In this review, the chemical properties, plant sources, pharmacological activities, pharmacokinetic and toxicological characteristics of THP were systematically summarized for the first time. The results indicated that THP mainly existed in Papaveraceae and Menispermaceae families. Its pharmacological activities include anti-addiction, anti-inflammatory, analgesic, neuroprotective, and antitumor effects. Pharmacokinetic studies showed that THP was inadequately absorbed in the intestine and had rapid clearance and low bioavailability in vivo, as well as self-microemulsifying drug delivery systems, which could increase the absorption level and absorption rate of THP and improve its bioavailability. In addition, THP may have potential cardiac and neurological toxicity, but toxicity studies of THP are limited, especially its long-duration and acute toxicity tests. In summary, THP, as a natural alkaloid, has application prospects and potential development value, which is promising to be a novel drug for the treatment of pain, inflammation, and other related diseases. Further research on its potential target, molecular mechanism, toxicity, and oral utilization should need to be strengthened in the future.
The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke
Authors: Li Fan , Kang Xiaokui , Xin Wenqiang , Li Xin
Published: April 2022

Neurons and neurogliocytes (oligodendrocytes, astrocytes, and microglia) are essential for maintaining homeostasis of the microenvironment in the central nervous system (CNS). These cells have been shown to support cell-cell communication via multiple mechanisms, most recently by the release of extracellular vesicles (EVs). Since EVs carry a variety of cargoes of nucleic acids, lipids, and proteins and mediate intercellular communication, they have been the hotspot of diagnosis and treatment. The mechanisms underlying CNS disorders include angiogenesis, autophagy, apoptosis, cell death, and inflammation, and cell-EVs have been revealed to be involved in these pathological processes. Ischemic stroke is one of the most common causes of death and disability worldwide. It results in serious neurological and physical dysfunction and even leads to heavy economic and social burdens. Although a large number of researchers have reported that EVs derived from these cells play a vital role in regulating multiple pathological mechanisms in ischemic stroke, the specific interactional relationships and mechanisms between specific cell-EVs and stroke treatment have not been clearly described. This review aims to summarize the therapeutic effects and mechanisms of action of specific cell-EVs on ischemia. Additionally, this study emphasizes that these EVs are involved in stroke treatment by inhibiting and activating various signaling pathways such as ncRNAs, TGF-β1, and NF-κB.
Performance and Robustness Testing of a Non-Invasive Mapping System for Ventricular Arrhythmias
Authors: Lesina Krista , Szili-Torok Tamas , Peters Emile , de Wit André , Wijchers Sip A. , Bhagwandien Rohit E. , Yap Sing-Chien , Hirsch Alexander , Hoogendijk Mark G.
Published: April 2022

Background: The clinical value of non-invasive mapping system depends on its accuracy under common variations of the inputs. The View Into Ventricular Onset (VIVO) system matches simulated QRS complexes of a patient-specific anatomical model with a 12-lead ECG to estimate the origin of ventricular arrhythmias. We aim to test the performance of the VIVO system and its sensitivity to changes in the anatomical model, time marker placement to demarcate the QRS complex and body position.

Methods: Non-invasive activation maps of idiopathic premature ventricular complexes (PVCs) using a patient-specific or generic anatomical model were matched with the location during electrophysiological studies. Activation maps were analyzed before and after systematically changing the time marker placement. Morphologically identical PVCs recorded in supine and sitting position were compared in a subgroup.

Results: Non-invasive activation maps of 48 patients (age 51 ± 14 years, 28 female) were analyzed. The origin of the PVCs as determined by VIVO system matched with the clinical localization in 36/48 (75%) patients. Mismatches were more common for PVCs of left than right ventricular origin [11/27 (41%) vs. 1/21 (5%) of cases, p < 0.01]. The first 32 cases were analyzed for robustness testing of the VIVO system. Changing the patient-specific vs. the generic anatomical model reduced the accuracy from 23/32 (72%) to 15/32 (47%), p < 0.05. Time marker placement in the QRS complex (delayed onset or advanced end marker) or in the ST-segment (delaying the QRS complex end marker) resulted in progressive shifts in origins of PVCs. Altered body positions did not change the predicted origin of PVCs in most patients [clinically unchanged 11/15 (73%)].

Conclusion: VIVO activation mapping is sensitive to changes in the anatomical model and time marker placement but less to altered body position.
On the Reflexive KENDİ in Turkish Sign Language
Authors: Kayabaşı Demet , Abner Natasha
Published: April 2022

Linguistic analysis is improved when it includes language beyond the spoken modality. This paper uses sign language data to explore and advance cross-linguistic typologies of reflexives, constructions expressing that co-arguments of a predicate are also co-referent. In doing so, we also demonstrate that the lexical item KENDİ in Turkish Sign Language (henceforth, TİD) can function as a traditional reflexive, in addition to its previously documented emphatic functions. We further show that KENDİ is a DP-type reflexive, which helps to explain the emphatic usages of KENDİ that have been the focus of previous research. We end by outlining a plan for future research that can further probe and unify the superficially distinct functions of KENDİ and the typology of anaphoricity across modalities. Data for the present research comes from recently conducted fieldwork interviews with two signers of the İstanbul dialect of TİD, both of whom have been exposed to TİD since birth.
Examining the Relation Between Practicing Meditation and Having Peak Experiences and Lucid Dreams. A Cross-Sectional Study
Authors: Garcia-Campayo Javier , Hijar-Aguinaga Rinchen , Barceló-Soler Alberto , Fernández-Martínez Selene , Aristegui Roberto , Pérez-Aranda Adrián
Published: April 2022

The aim of this study was to compare meditators and non-meditators in terms of their tendency to have peak experiences and their dream lucidity, while examining the associations between these outcomes and some related variables such as non-dual awareness, mindfulness facets and absorption. In this cross-sectional study, 237 participants from general Spanish population completed an online survey that included ad hoc questions related to the study aim, along with the Five Facet Mindfulness Questionnaire (FFMQ), the Non-dual Embodiment Thematic Inventory (NETI), the Tellegen Absorption Scale (TAS) and the Lucidity and Consciousness in Dreams Scale (LUCID). Of the total, 110 participants were identified as meditators and 127 as non-meditators. More than half of the sample (58.2%) reported having experienced at least one peak experience in their life; these showed no differences in the number, intensity, or self-inducing ability of these experiences between both groups but were significantly more common among meditators (71.8% vs. 46.8%; p < 0.001), who also presented higher scores in most of the questionnaires, except for some LUCID subscales. Regression models demonstrated that being a meditator was a significant predictor of having had a peak experience, but not of LUCID scores. These results, which need to be interpreted considering the study limitations, support the potential of meditation to facilitate having peak experiences, while its impact on lucid dreams remains unclear.
Similarities and Differences in Brain Activation Between Patients With Schizophrenia and Obsessive-Compulsive Disorder: A Near-Infrared Spectroscopy Study
Authors: Fu Xiaoyu , Quan Wenxiang , Liu Lijun , Li Tian , Dong Wentian , Wang Jiuju , Tian Ju , Yan Jun , Liao Jinmin
Published: April 2022

Schizophrenia (SZ) and obsessive-compulsive disorder (OCD) share several epidemiological and clinical features, but the neurobiological substrates shared by these two diseases remain unclear. This study aimed to explore the similarities and differences in brain function between them using near-infrared spectroscopy (NIRS). Eventually, 130 SZ patients, 70 OCD and 75 normal controls (NCs) were enrolled. A 52-channel NIRS instrument was used to detect the concentration changes in oxygenated hemoglobin ([oxy-Hb]) during the verbal fluency task. Ten regions of interests (ROIs) were defined: the bilateral dorsolateral prefrontal cortex (DLPFC), frontopolar cortex (FPC), orbitofrontal cortex (OFC), inferior prefrontal gyrus (IFG) and temporal gyrus (TG). Through two different analysis strategies based on channels or ROIs, we compared the [oxy-Hb] changes in three groups by one-way analysis of variance (ANOVA) and post-hoc tests. Across 52 channels, compared to the NC group, both SZ and OCD groups exhibited reduced activity in 17 channels, including left FPC, left DLPFC, bilateral OFC, IFG, middle TG, supplementary motor cortex and Broca’s area, while SZ showed lower activity in channel 35 (right OFC) than OCD patients. Across all ROIs, compared to the NC group, both SZ and OCD groups showed reduced activity in 7 ROIs, including left FPC, bilateral OFC, IFG and TG, while SZ showed lower activity in the right OFC than OCD group, which were almost consistent with the results based on channels. This study suggests SZ and OCD present with some similar neuropathological changes, while SZ shows more severe impairment in the right OFC than OCD.
Early Screening for Diabetic Retinopathy in Newly Diagnosed Type 2 Diabetes and Its Effectiveness in Terms of Morbidity and Clinical Treatment: A Nationwide Population-Based Cohort
Authors: Chung Yu-Chien , Xu Ting , Tung Tao-Hsin , Chen Mingchih , Chen Pei-En
Published: April 2022

Purpose

To characterize the association between the frequency of screening for diabetic retinopathy (DR) and the detection of DR in patients with newly diagnosed type 2 diabetes mellitus (T2DM).

Methods

This nationwide population-based cohort study used data from the National Health Insurance Research Database to identify adult patients who were newly diagnosed with T2DM between 2000 and 2004. Data from their follow-up Diabetic retinopathy (DR) treatments over the next 10 years following diagnosis were also analyzed.

Results

The 41,522 subjects were respectively assigned to a periodic screening group (n = 3850) and nonperiodic screening group (n = 37,672). Significant differences were observed between the two groups in terms of age, Charlson Comorbidity Index (CCI), sex, DR treatment, and the prevalence of DR. The association between periodic screening and DR treatment, only the elderly, female, and patient with severe CCI status showed the significance in the further stratified analysis.

Conclusion

Periodic screening (annual or biannual screening in the first 5 years) was more effective than nonperiodic screening in detecting instances of DR in the middle-to-advanced aged group but not among younger patients. Screening pattern did not have a significant effect on the likelihood of DR-related treatment during the 5-year follow-up. It appears that a tight screening schedule for the first 5 years after diagnosis with diabetes is not necessary.
Developments in Deep Brain Stimulators for Successful Aging Towards Smart Devices—An Overview
Authors: Silverio Angelito A. , Silverio Lean Angelo A.
Published: April 2022

This work provides an overview of the present state-of-the-art in the development of deep brain Deep Brain Stimulation (DBS) and how such devices alleviate motor and cognitive disorders for a successful aging. This work reviews chronic diseases that are addressable via DBS, reporting also the treatment efficacies. The underlying mechanism for DBS is also reported. A discussion on hardware developments focusing on DBS control paradigms is included specifically the open- and closed-loop “smart” control implementations. Furthermore, developments towards a “smart” DBS, while considering the design challenges, current state of the art, and constraints, are also presented. This work also showcased different methods, using ambient energy scavenging, that offer alternative solutions to prolong the battery life of the DBS device. These are geared towards a low maintenance, semi-autonomous, and less disruptive device to be used by the elderly patient suffering from motor and cognitive disorders.