bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemokines in Gestational Diabetes Mellitus
Authors: Liu Hongying , Liu Aizhong , Kaminga Atipatsa C. , McDonald Judy , Wen Shi Wu , Pan Xiongfeng
Published: February 2022

Background

Studies investigating chemokines in gestational diabetes mellitus (GDM) have yielded mixed results. The purpose of this meta-analysis was to explore whether concentrations of chemokines in patients with GDM differed from that of the controls.

Methods

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched Web of Science, Embase, Cochrane Library, and PubMed databases for articles, published in any language, on chemokines and GDM through August 1st, 2021. The difference in concentrations of chemokines between patients with GDM and controls was determined by a standardized mean difference (SMD) with a 95% confidence interval (CI), calculated in the meta-analysis of the eligible studies using a random-effects model with restricted maximum-likelihood estimator.

Results

Seventeen studies met the inclusion criteria for the meta-analysis. Altogether, they included nine different chemokines comparisons involving 5,158 participants (1,934 GDM patients and 3,224 controls). Results showed a significant increase of these chemokines (CCL2, CXCL1, CXCL8, CXCL9, and CXCL12) in the GDM patients compared with the controls. However, there was a significant decrease of the chemokines, CCL4, CCL11 and CXCL10, in the GDM patients compared with the controls. Moreover, subgroup analysis revealed a potential role of chemokines as biomarkers in relation to laboratory detection (different sample type and assay methods) and clinical characteristics of GDM patients (ethnicity and body mass index).

Conclusion

GDM is associated with several chemokines (CCL2, CCL4, CCL11, CXCL1, CXCL8, CXCL9, CXCL10 and CXCL12). Therefore, consideration of these chemokines as potential targets or biomarkers in the pathophysiology of GDM development is necessary. Notably, the information of subgroup analysis underscores the importance of exploring putative mechanisms underlying this association, in order to develop new individualized clinical and therapeutic strategies.
A Hidden Diversity in the Atlantic and the SE Pacific: Hamatipedidae n. fam. (Crustacea: Tanaidacea)
Authors: Gellert Marta , Bird Graham , Stȩpień Anna , Studzian Maciej , Błażewicz Magdalena
Published: February 2022

A new family of paratanaoidean Tanaidacea, the hamatipedids, formerly part of the Typhlotanaidae, is established to accommodate three genera (Hamatipedaand two new). Deep-sea hamatipedids collected from four sites in the Atlantic (Argentine and Guiana basins) and 14 sites from the Southeast coast of Australia were studied using a taxonomic approach combining morphological and morphometric data. Four new species ofHamatipedaand one of a new genus are described from different deep-sea areas of the Atlantic and Pacific oceans.Hamatipeda simaoriginally classified withinHamatipeda, is transferred to a new genus. We observed that several morphometric characters (i.e., length of the last two pereonites) in different life-stages of one of the newHamatipedaspecies (neuter, manca-2, and manca-3) are correlated with the total body length (TBL). Applying a morphometric approach, we aimed: (1) to identify those ontogenetic-dependent characters, and (2) to detect the characters, which can be used in discrimination of Hamatipedidae species, regardless their life-stage.
Gut Metagenome as a Potential Diagnostic and Predictive Biomarker in Slow Transit Constipation
Authors: Tian Hongliang , Ye Chen , Yang Bo , Cui Jiaqu , Zheng Zhijun , Wu Chunyan , Zhou Shailan , Lv Xiaoqiong , Qin Nan , Qin Huanlong , Li Ning , Chen Qiyi
Published: February 2022

Slow transit constipation (STC) is one of the most frequent gastrointestinal diagnoses. In this study, we conducted a quantitative metagenomics study in 118 Chinese individuals. These participants were divided into the discovery cohort of 50 patients with STC and 40 healthy controls as well as a validation cohort of 16 patients and 12 healthy controls. We found that the intestinal microbiome of patients with STC was significantly different from that of healthy individuals at the phylum, genus, and species level. Patients with STC had markedly higher levels of Alistipes and Eubacterium and lower abundance of multiple species belonging to the Roseburia genus. Patients with STC gene expression levels and the Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology pathway (such as fatty acid biosynthesis, butanoate metabolism, and methane metabolism pathways) enrichment were also substantially different from those of healthy controls. These microbiome and metabolite differences may be valuable biomarkers for STC. Our findings suggest that alteration of the microbiome may lead to constipation by changing the levels of microbial-derived metabolites in the gut. Above findings may help us in the development of microbial drugs.
Characteristics and Prognostic Value of Tertiary Lymphoid Organs in Membranous Nephropathy: A Retrospective Study
Authors: Wang Zu-feng , Cheng Yi-chun , Li Yue-Qiang , Liu Liu , Ge Shu-Wang , Xu Gang
Published: February 2022

Background

Tertiary lymphoid organs play an essential role in the inflammation of the kidney. The clinical association between TLOs and membranous nephropathy (MN) is not clear yet.

Methods

Consecutive patients with the histologically confirmed membranous nephropathy in Tongji Hospital from July 19, 2012, to September 26, 2019, were included in this study. TLOs in renal biopsy tissues were detected by periodic acid–Schiff-stained and immunohistochemistry. Logistic regression was performed to evaluate the correlations of TLOs and clinical features of patients with MN. Kaplan–Meier analysis was utilized to examine the relationship between TLOs and remission of proteinuria.

Results

A total of 442 patients with MN were included in this study, of which the average age was 46.4 years old, and 58.8% were male. Moreover, 33% of patients with MN had TLOs in this study. The median value of proteinuria among patients with MN with TLOs was 4.9 g/24 h, which was much greater than no-TLOs ones (3.2 g/24 h, p < 0.001). Moreover, the patients with TLOs had higher serum creatinine and lower serum albumin. The severity of clinical features among the patients with MN aggravated with the increase in the grade of TLOs. In addition, the patients who had TLOs were more likely to be positive of anti-phospholipase A2 receptor autoantibodies. Meanwhile, the patients without TLOs showed significantly higher complete remission and total remission of proteinuria.

Conclusion

In this study, we demonstrated that TLOs were common among patients with MN. Moreover, the patients with MN with TLOs showed a worse clinical manifestation and an outcome compared with the patients without TLOs.
The Aftermath of Tapering Tocilizumab After Achieving Treatment Target in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study
Authors: Park Jun Won , Kim Min Jung , Kim Hyoun-Ah , Kim Jin Hyun , Lee Eun Bong , Shin Kichul
Published: February 2022

Background

Although recent guidelines recommend that tapering of biologic disease-modifying anti-rheumatic drugs (bDMARDs) can be considered in patients with rheumatoid arthritis (RA), there has been little evidence supporting the strategy during the non-tumor necrosis factor inhibitor treatment. This study aims to investigate the effectiveness and safety of tapering tocilizumab (TCZ) dose in patients with RA who attain low disease activity (LDA) after TCZ therapy in a nationwide cohort.

Methods

Data were collected from a nationwide cohort of patients with RA receiving biologic disease-modifying anti-rheumatic drugs in South Korea (KOBIO-RA). This study included 350 patients who were treated with TCZ and achieved Clinical Disease Activity Index-low disease activity (CDAI)-LDA (CDAI ≤ 10) after 1 year of treatment. We performed longitudinal analysis considering clinical data measured at all 1-year intervals for the included patients using the generalized estimating equation. A total of 575 intervals were classified into two groups according to their dose quotient (DQ) of TCZ (tapering group vs. standard-dose group). The main outcome was maintaining CDAI-LDA in the following 1-year interval.

Results

Tapering TCZ dose strategy was used in 282 (49.0%) intervals with a mean (SD) DQ of 66.0 (15.5) %. Loss of CDAI-LDA occurred in 91 (15.1%) intervals. Multivariable GEE showed that the tapering group was associated with more frequent failure to sustain CDAI-LDA (adjusted OR [95% CI]: 0.57 [0.33–0.99]), which subsequently led to impaired functional status. The likelihood of achieving DAS28-deep remission (DAS28-ESR <1.98) was also significantly lower in the tapering group (adjusted OR 0.68 [0.46–0.99]). CDAI remission was achieved in only 69 (12.0%) of the total intervals, with no significant difference in the proportion of intervals achieving the target between the two groups. Incidence of adverse events was comparable in both groups except for hypercholesterolemia, which was lower in the tapering group.

Conclusions

Tapering TCZ dose after achieving LDA increases the risk of losing LDA without a significant merit in safety.
The Contribution of COL4A5 Splicing Variants to the Pathogenesis of X-Linked Alport Syndrome
Authors: Yamamura Tomohiko , Horinouchi Tomoko , Aoto Yuya , Lennon Rachel , Nozu Kandai
Published: February 2022

X-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. Recent advances in genetic analysis and further understanding of genotype-phenotype correlations in affected male patients raises the importance of detecting splicing variants in COL4A5. Aberrant splicing of COL4A5 is caused not only by canonical splice site variants but also non-canonical splice site variants such as deep intronic changes or even substitutions in exons. Patients with splicing variants account for ~15% of all cases in XLAS. In addition, it has been shown that there is a significant difference in kidney survival depending on the aberrant splicing patterns of transcripts- in particular in-frame or out-of-frame nucleotide changes in transcripts. Therefore, cDNA analysis of patient mRNA is necessary to determine the impact of splice site variants and to confirm a diagnosis of XLAS and to predict the kidney prognosis. However, it is usually difficult to amplify COL4A5 transcripts extracted from peripheral blood leukocytes. For these cases, in vitro minigene assays or RNA sequence extracted from urine derived cells can confirm aberrant splicing patterns. Moreover, controlling aberrant splicing by nucleic acids or small molecular compounds in genetic diseases are attracting attention as a potential therapeutic strategy. Here, we review the frequency of splicing variants in COL4A5, the latest diagnostic strategies, and the prospects for new therapeutic approaches.
Helicobacter pylori-Mediated Oxidative Stress and Gastric Diseases: A Review
Authors: Han Lu , Shu Xu , Wang Jian
Published: February 2022

Gastric cancer is considered to be a type of gastrointestinal tumor and is mostly accompanied by Helicobacter pylori (HP) infection at the early stage. Hence, the long-term colonization of the gastric mucosa by HP as a causative factor for gastrointestinal diseases cannot be ignored. The virulence factors secreted by the bacterium activate the signaling pathway of oxidative stress and mediate chronic inflammatory response in the host cells. The virulence factors also thwart the antibacterial effect of neutrophils. Subsequently, DNA methylation is induced, which causes continuous cell proliferation and evolution toward low-grade-differentiated gastric cells. This process provides the pathological basis for the occurrence of progressive gastric cancer. Therefore, this review aims to summarize the oxidative stress response triggered by HP in the gastric mucosa and the subsequent signaling pathways. The findings are expected to help in the formulation of new targeted drugs for preventing the occurrence of early gastric cancer and its progression to middle and advanced cancer.
FOXM1/lncRNA TYMSOS/miR-214-3p–Mediated High Expression of NCAPG Correlates With Poor Prognosis and Cell Proliferation in Non–Small Cell Lung Carcinoma
Authors: Yuan Yixiao , Jiang Xiulin , Tang Lin , Wang Juan , Zhang Dahang , Cho William C. , Duan Lincan
Published: February 2022

Lung cancer is the most common cancer with high mortality. Increasing evidence has demonstrated that nonstructural maintenance of chromosomes condensin I complex subunit G (NCAPG) plays a crucial role in the progression of human cancers. However, the biological function and underlying mechanism of NCAPG in non–small cell lung cancer (NSCLC) are still unclear. Here, we utilized diverse public databases to analyze the expression of NCAPG in pan-cancer. We found that NCAPG was highly expressed in various human cancers, especially in NSCLC. NCAPG expression was significantly positively correlated with poor clinical-pathological features, poor prognosis, tumor mutational burden, DNA microsatellite instability, and immune cell infiltration in NSCLC. In addition, our results showed that depletion of NCAPG significantly inhibited NSCLC cell proliferation, migration, and self-renewal abilities, yet these could be reversed by adding microRNA (miRNA)-214-3p. Knockdown of long noncoding RNA (lncRNA) thymidylate synthetase opposite strand (TYMSOS) also inhibits the NSCLC cell proliferation, migration, and self-renewal abilities. In summary, our findings demonstrated that the crucial roles of the FOXM1/lncRNA-TYMSOS/miRNA-214-3p/NCAPG axis in NSCLC may shed light on how NCAPG may act as a therapeutic target for NSCLC.
Inteins as Drug Targets and Therapeutic Tools
Authors: Tharappel Anil Mathew , Li Zhong , Li Hongmin
Published: February 2022

Multidrug-resistant pathogens are of significant concern in recent years. Hence new antifungal and anti-bacterial drug targets are urgently needed before the situation goes beyond control. Inteins are polypeptides that self-splice from exteins without the need for cofactors or external energy, resulting in joining of extein fragments. Inteins are present in many organisms, including human pathogens such as Mycobacterium tuberculosis, Cryptococcus neoformans, C. gattii, and Aspergillus fumigatus. Because intein elements are not present in human genes, they are attractive drug targets to develop antifungals and antibiotics. Thus far, a few inhibitors of intein splicing have been reported. Metal-ions such as Zn2+ and Cu2+, and platinum-containing compound cisplatin inhibit intein splicing in M. tuberculosis and C. neoformans by binding to the active site cysteines. A small-molecule inhibitor 6G-318S and its derivative 6G-319S are found to inhibit intein splicing in C. neoformans and C. gattii with a MIC in nanomolar concentrations. Inteins have also been used in many other applications. Intein can be used in activating a protein inside a cell using small molecules. Moreover, split intein can be used to deliver large genes in experimental gene therapy and to kill selected species in a mixed population of microbes by taking advantage of the toxin-antitoxin system. Furthermore, split inteins are used in synthesizing cyclic peptides and in developing cell culture model to study infectious viruses including SARS-CoV-2 in the biosafety level (BSL) 2 facility. This mini-review discusses the recent research developments of inteins in drug discovery and therapeutic research.
Comparative Molecular Modelling of Capsular Polysaccharide Conformations in Streptococcus suis Serotypes 1, 2, 1/2 and 14 Identifies Common Epitopes for Antibody Binding
Authors: Kuttel Michelle M.
Published: February 2022

Streptococcus suis is an encapsulated, commensal, potentially pathogenic bacterium that infects swine globally and causes sporadic life-threatening zoonotic septicemia and meningitis infections in humans. The capsular polysaccharide is a primary virulence factor for S. suis. As S. suis serotype 2 is the most prevalent serotype globally, the serotype 2 CPS is the primary target of current efforts to develop an effective glycoconjugate veterinary vaccine against S. suis. Possible cross-protection with related serotypes would broaden the coverage of a vaccine. The CPS in serotypes 2 and 1/2 differ at a single residue (Gal versus GalNAc), and both are similar to serotypes 1 and 14: all contain a terminal sialic acid on a side chain. However, despite this similarity, there is complex pattern of cross-protection for these serotypes, with varying estimations of the importance of sialic acid in a protective epitope. Further, a pentasaccharide without the terminal sialic acid has been identified as minimal epitope for serotype 2. Here we use molecular simulation to model the molecule conformations of the CPS in serotypes 2, 1/2, 1 and 14, as well as three vaccine candidate oligosaccharides. The common epitopes we identify assist in rationalizing the apparently contradictory immunological data and provide a basis for rational design of S. suis vaccines in the future.
Stereopsis and Eye Movement Abnormalities in Parkinson’s Disease and Their Clinical Implications
Authors: Ba Fang , Sang Tina T. , He Wenjing , Fatehi Jaleh , Mostofi Emanuel , Zheng Bin
Published: February 2022

Background

Parkinson’s disease (PD) is not exclusively a motor disorder. Among non-motor features, patients with PD possess sensory visual dysfunctions. Depth perception and oculomotor deficits can significantly impact patients’ motor performance. Stereopsis and eye behavioral study using 3D stimuli may help determine their implications in disease status.

Objective

The objective of this study is to investigate stereopsis and eye movement abnormalities in PD with reliable tools and their correlation with indicators of PD severity. We hypothesize that patients with PD exhibit different eye behaviors and that these differences may correlate to the severity of motor symptoms and cognitive status.

Methods

Control and PD participants were first evaluated for visual acuity, visual field, contrast acuity, and stereo perception with 2D and Titmus stereotests, followed by the assessment with a 3D active shutter system. Eye movement behaviors were assessed by a Tobii X2-60 eye tracker.

Results

Screening visual tests did not reveal any differences between the PD and control groups. With the 3D active shutter system, the PD group demonstrated significantly worse stereopsis. The preserved cognitive function was correlated to a more intact stereo function. Patients with PD had longer visual response times, with a higher number of fixations and bigger saccade amplitude, suggesting fixation stabilization difficulties. Such changes showed a positive correlation with the severity of motor symptoms and a negative correlation with normal cognitive status.

Conclusion

We assessed stereopsis with a 3D active shutter system and oculomotor behaviors with the Tobii eye tracker. Patients with PD exhibit poorer stereopsis and impaired oculomotor behaviors during response time. These deficits were correlated with PD motor and cognitive status. The visual parameters may potentially serve as the clinical biomarkers for PD.
Fecal Implants From AppNL–G–F and AppNL–G–F/E4 Donor Mice Sufficient to Induce Behavioral Phenotypes in Germ-Free Mice
Authors: Kundu Payel , Stagaman Keaton , Kasschau Kristin , Holden Sarah , Shulzhenko Natalia , Sharpton Thomas J. , Raber Jacob
Published: February 2022

The gut microbiome and the gut brain axis are potential determinants of Alzheimer’s disease (AD) etiology or severity and gut microbiota might coordinate with the gut-brain axis to regulate behavioral phenotypes in AD mouse models. Using 6-month-old human amyloid precursor protein (hAPP) knock-in (KI) mice, which contain the Swedish and Iberian mutations [APP NL-F (AppNL–F)] or the Arctic mutation as third mutation [APP NL-G-F (AppNL–G–F)], behavioral and cognitive performance is associated with the gut microbiome and APP genotype modulates this association. In this study, we determined the feasibility of behavioral testing of mice in a biosafety cabinet and whether stool from 6-month-old AppNL–G–F mice or AppNL–G–F crossed with human apoE4 targeted replacement mice is sufficient to induce behavioral phenotypes in 4-5 month-old germ-free C57BL/6J mice 4 weeks following inoculation. We also compared the behavioral phenotypes of the recipient mice with that of the donor mice. Finally, we assessed cortical Aβ levels and analyzed the gut microbiome in the recipient mice. These results show that it is feasible to behaviorally test germ-free mice inside a biosafety cabinet. However, the host genotype was critical in modulating the pattern of induced behavioral phenotypes as compared to those seen in the genotype- and sex-match donor mice. Male mice that received stool from AppNL–G–F and AppNL–G–F/E4 donor genotypes tended to have lower body weight as compared to wild type, an effect not observed among donor mice. Additionally, AppNL–G–F/E4 recipient males, but not females, showed impaired object recognition. Insoluble Aβ40 levels were detected in AppNL–G–F and AppNL–G–F/E4 recipient mice. Recipients of AppNL–G–F, but not AppNL–G–F/E4, donor mice carried cortical insoluble Aβ40 levels that positively correlated with activity levels on the first and second day of open field testing. For recipient mice, the interaction between donor genotype and several behavioral scores predicted gut microbiome alpha-diversity. Similarly, two behavioral performance scores predicted microbiome composition in recipient mice, but this association was dependent on the donor genotype. These data suggest that genotypes of the donor and recipient might need to be considered for developing novel therapeutic strategies targeting the gut microbiome in AD and other neurodegenerative disorders.
Topological Abnormalities of Pallido-Thalamo-Cortical Circuit in Functional Brain Network of Patients With Nonchemotherapy With Non-small Cell Lung Cancer
Authors: Liu Siwen , Yin Na , Li Chenchen , Li Xiaoyou , Ni Jie , Pan Xuan , Ma Rong , Wu Jianzhong , Feng Jifeng , Shen Bo
Published: February 2022

Introduction

Some previous studies in patients with lung cancer have mainly focused on exploring the cognitive dysfunction and deficits of brain function associated with chemotherapy. However, little is known about functional brain alterations that might occur prior to chemotherapy. Therefore, this study aimed to evaluate brain functional changes in patients with nonchemotherapy before chemotherapy with non-small cell lung cancer (NSCLC).

Methods

Resting-state functional MRI data of 35 patients with NSCLC and 46 matched healthy controls (HCs) were acquired to construct functional brain networks. Graph theoretical analysis was then applied to investigate the differences of the network and nodal measures between groups. Finally, the receiver operating characteristic (ROC) curve analysis was performed to distinguish between NSCLC and HC.

Results

Decreased nodal strength was found in the left inferior frontal gyrus (opercular part), inferior frontal gyrus (triangular part), inferior occipital gyrus, and right inferior frontal gyrus (triangular part) of patients with NSCLC while increased nodal strength was found in the right pallidum and thalamus. NSCLC also showed decreased nodal betweenness in the right superior occipital gyrus. Different hub regions distribution was found between groups, however, no hub regions showed group differences in the nodal measures. Furthermore, the ROC curve analysis showed good performance in distinguishing NSCLC from HC.

Conclusion

These results suggested that topological abnormalities of pallido-thalamo-cortical circuit in functional brain network might be related to NSCLC prior to chemotherapy, which provided new insights concerning the pathophysiological mechanisms of NSCLC and could serve as promising biological markers for the identification of patients with NSCLC.
Synthetic Spatial Foraging With Active Inference in a Geocaching Task
Authors: Neacsu Victorita , Convertino Laura , Friston Karl J.
Published: February 2022

Humans are highly proficient in learning about the environments in which they operate. They form flexible spatial representations of their surroundings that can be leveraged with ease during spatial foraging and navigation. To capture these abilities, we present a deep Active Inference model of goal-directed behavior, and the accompanying belief updating. Active Inference rests upon optimizing Bayesian beliefs to maximize model evidence or marginal likelihood. Bayesian beliefs are probability distributions over the causes of observable outcomes. These causes include an agent’s actions, which enables one to treat planning as inference. We use simulations of a geocaching task to elucidate the belief updating—that underwrites spatial foraging—and the associated behavioral and neurophysiological responses. In a geocaching task, the aim is to find hidden objects in the environment using spatial coordinates. Here, synthetic agents learn about the environment via inference and learning (e.g., learning about the likelihoods of outcomes given latent states) to reach a target location, and then forage locally to discover the hidden object that offers clues for the next location.
Imaging of Reactive Astrogliosis by Positron Emission Tomography
Authors: Harada Ryuichi , Furumoto Shozo , Kudo Yukitsuka , Yanai Kazuhiko , Villemagne Victor L. , Okamura Nobuyuki
Published: February 2022

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques and tau tangles in Alzheimer’s disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aβ plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with Aβ and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [18F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [18F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [18F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [18F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers.
Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation
Authors: Chilton Floyd H. , Manichaikul Ani , Yang Chaojie , O'Connor Timothy D. , Johnstone Laurel M. , Blomquist Sarah , Schembre Susan M. , Sergeant Susan , Zec Manja , Tsai Michael Y. , Rich Stephen S. , Bridgewater Susan J. , Mathias Rasika A. , Hallmark Brian
Published: February 2022

Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS “derived” haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an “ancestral” haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.
Zinc Intakes and Health Outcomes: An Umbrella Review
Authors: Li Jin , Cao Dehong , Huang Yin , Chen Bo , Chen Zeyu , Wang Ruyi , Dong Qiang , Wei Qiang , Liu Liangren
Published: February 2022

It is widely accepted that the zinc element is crucial in human beings. Zinc has gained more attention during the COVID-19 pandemic due to its utilization for the treatment and prevention of respiratory tract infections. However, some studies also pointed out that zinc intake might cause unwanted side effects and even be dangerous when overdosed. To reveal the relationship between zinc intake and health outcomes, we performed an umbrella review from human studies. In total, the umbrella review included 43 articles and identified 11 outcomes for dietary zinc intake and 86 outcomes for supplementary zinc intake. Dietary zinc intake in the highest dose would decrease the risk of overall and specific digestive tract cancers, depression, and type 2 diabetes mellitus (T2DM) in adults. Supplementary zinc consumption in adults was linked to an improvement of depression, antioxidant capacity and sperm quality, higher serum zinc concentration, and lower concentration of inflammatory markers. Zinc supplementation in children would reduce the incidence of diarrhea and pneumonia, improve zinc deficiency and boost growth. However, zinc might not decrease all-cause mortality in adults or the in-hospital mortality of COVID-19. And better maternal and neonatal outcomes may not derive from pregnant women who consumed higher or lower doses of zinc supplementation (>20 mg/day and <20 mg/day, respectively). Dose-response analyses revealed that a daily 5 mg increment of zinc would lower the risk of colorectal and esophageal cancer, whereas a large dose of zinc supplementation (daily 100 mg) showed no benefit in reducing prostate cancer risk.
Transforming Growth Factor-Beta-Regulated LncRNA-MUF Promotes Invasion by Modulating the miR-34a Snail1 Axis in Glioblastoma Multiforme
Authors: Shree Bakhya , Tripathi Shraddha , Sharma Vivek
Published: February 2022

Transforming growth factor beta (TGF-β)-regulated long-non-coding RNAs (lncRNAs) modulate several aspects of tumor development such as proliferation, invasion, metastasis, epithelial to mesenchymal transition (EMT), and drug resistance in various cancers, including Glioblastoma multiforme (GBM). We identified several novel differentially expressed lncRNAs upon TGF-β treatment in glioma cells using genome-wide microarray screening. We show that TGF-β induces lncRNA-MUF in glioma cells, and its expression is significantly upregulated in glioma tissues and is associated with poor overall survival of GBM patients. Knockdown of lncRNA-MUF reduces proliferation, migration, and invasion in glioma cells and sensitizes them to temozolomide (TMZ)-induced apoptosis. In addition, lncRNA-MUF downregulation impairs TGF-β-induced smad2/3 phosphorylation. In line with its role in regulating invasion, lncRNA-MUF functions as a competing endogenous RNA (ceRNA) for miR-34a and promotes Snail1 expression. Collectively, our findings suggest lncRNA-MUF as an attractive therapeutic target for GBM.
Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis
Authors: Xiao Qiaoling , Lei Li , Ren Jun , Peng Meixi , Jing Yipei , Jiang Xueke , Huang Junpeng , Tao Yonghong , Lin Can , Yang Jing , Sun Minghui , Tang Lisha , Wei Xingyu , Yang Zailin , Zhang Ling
Published: February 2022

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.
ANXA2P2: A Potential Immunological and Prognostic Signature in Ovarian Serous Cystadenocarcinoma via Pan-Carcinoma Synthesis
Authors: Zhang Yanna , Du Ting , Chen Xiancheng
Published: February 2022

Background

Although the effect of pseudogene ANXA2P2 on some tumors has been reported in a few literatures, the therapeutic potential and prognostic value of ANXA2P2 in ovarian serous cystadenocarcinoma (OV) have not been elucidated.

Methods

The correlation for ANXA2P2 expression patterns to prognostic characteristics, tumor immune microenvironment, immune cell infiltration level, tumor mutation burden (TMB), tumor microsatellite instability (MSI), drug sensitivity, and pathway function enrichment were investigated in pan-carcinoma via TCGA and GTEx databases. Subsequently, the role of ANXA2P2 expression levels in the pathway enrichments and prognosis prediction in OV were further explored using weighted correlation network analysis (WGCNA) analysis, gene mutation analysis, and risk-independent prognostic analysis.

Results

ANXA2P2 was frequently overexpressed in a variety of tumors compared with normal tissues. The correlation analysis for prognostic characteristics, tumor immune microenvironment, immune cell infiltration level, TMB, MSI, drug sensitivity, and pathway function enrichment revealed that ANXA2P2 expression patterns might deal a significant impact on the pathogenesis, development, and prognosis of various tumors. Then, GSVA, GSEA, WGCNA, gene mutation, and independent prognostic analysis for OV have indicated that high expression in ANXA2P2 could be mostly enriched in TNF-α signaling-via-NF-κB, epithelial-mesenchymal transition, apical junction, IL-6-JAK STAT3 signaling, etc., which were also proved to act as crucial factors on tumorigenesis, development, invasion, and metastasis. The mutation of TP53 (94%), TTN (24%), and CSMD3 (9%) in the biological process of tumor had been confirmed by relevant studies. Finally, the independent prognostic analysis demonstrated that ANXA2P2 expression in OV contributes greatly to the dependability of 3- and 5-year survival prediction.

Conclusion

In summary, our findings might provide a helpful foundation for prospective explorative researches, afford new strategies for the clinical treatment, deal prognosis prediction, and give new hope for OV patients.
Impact of Low-Burden TP53 Mutations in the Management of CLL
Authors: Lazarian Gregory , Cymbalista Florence , Baran-Marszak Fanny
Published: February 2022

In chronic lymphocytic leukemia (CLL), TP53 abnormalities are associated with reduced survival and resistance to chemoimmunotherapy (CIT). The recommended threshold to clinically report TP53 mutations is a matter of debate given that next-generation sequencing technologies can detect mutations with a limit of detection of approximately 1% with high confidence. However, the clinical impact of low-burden TP53 mutations with a variant allele frequency (VAF) of less than 10% remains unclear. Longitudinal analysis before and after fludarabine based on NGS sequencing demonstrated that low-burden TP53 mutations were present before the onset of treatment and expanded at relapse to become the predominant clone. Most studies evaluating the prognostic or predictive impact of low-burden TP53 mutations in untreated patients show that low-burden TP53 mutations have the same unfavorable prognostic impact as clonal defects. Moreover, studies designed to assess the predictive impact of low-burden TP53 mutations showed that TP53 mutations, irrespective of mutation burden, have an inferior impact on overall survival for CIT-treated patients. As low-burden and high-burden TP53 mutations have comparable clinical impacts, redefining the VAF threshold may have important implications for the clinical management of CLL.
Perioperative Low Dose Dexmedetomidine and Its Effect on the Visibility of the Surgical Field for Middle Ear Microsurgery: A Randomised Controlled Trial
Authors: Wu Jinhong , Han Yuan , Lu Yu , Zhuang Yan , Li Wenxian , Jia Ji’e
Published: February 2022

Background and Purpose: There are many benefits of administering dexmedetomidine perioperatively. The pharmacokinetics (PK) and pharmacodynamics (PD) of intravenous, intranasal and oral dexmedetomidine that was administered before anesthesia were compared in this study, and the effects of dexmedetomidine on the surgical field visibility in tympanoplasty was evaluated.

Methods: A single-blind, randomized controlled trial was conducted in a university-affiliated hospital where 45 patients who underwent tympanoplasty under general anesthesia were randomly allocated into three groups. Dexmedetomidine was administered by intravenous infusion at 0.8 μg.kg−1 for 10 min, intranasal instillation at a drop rate of 1 μg.kg−1 and oral intake at 4 μg.kg−1 ten minutes before the induction of anesthesia. The PK and PD of dexmedetomidine after a single low dose administration and its effect on the surgical field in tympanoplasty were analysed.

Results: A plasma concentration of dexmedetomidine of 220 pg/ml was achieved immediately after intravenous infusion and at 13.2 and 70.3 min for intranasal and oral administration, respectively. Dexmedetomidine decreased the heart rate (HR) and mean arterial pressure (MAP) in all three groups, although these values remained higher in the oral dexmedetomidine group at all eight time points. Intravenous dexmedetomidine provided the best visualization of the surgical field for opening of the tympanic sinus, 30 min after the start of the infusion (p < 0.05). Intranasal dexmedetomidine provided a significantly better visual field than oral dexmedetomidine for the repair of a tympanic membrane perforation using the fascia temporal muscle (p < 0.05).

Conclusion: A single low dose of dexmedetomidine administered intravenously or intranasally could decrease HR and MAP, improve surgical field visibility and be appropriate for deliberate hypotension for surgical procedures of 1–2 h in length.

Trial registration: Clinicaltrials.gov identifier: NCT03800641.
Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling
Authors: Jackson-Patel Victoria , Liu Emily , Bull Matthew R. , Ashoorzadeh Amir , Bogle Gib , Wolfram Anna , Hicks Kevin O. , Smaill Jeff B. , Patterson Adam V.
Published: February 2022

Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a “bystander effect”. In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling. The approach employs a number of experimental model systems to define parameters for the cellular uptake, metabolism and diffusion of both the prodrug and its metabolites. The model predicts rapid uptake of CP-506 to high intracellular concentrations with its long plasma half-life driving tissue diffusion to a penetration depth of 190 µm, deep within hypoxic activating regions. While bioreductive metabolism is restricted to regions of severe pathological hypoxia (<1 µM O2), its active metabolites show substantial bystander potential with release from the cell of origin into the extracellular space. Model predictions of bystander efficiency were validated using spheroid co-cultures, where the clonogenic killing of metabolically defective “target” cells increased with the proportion of metabolically competent “activator” cells. Our simulations predict a striking bystander efficiency at tissue-like densities with the bis-chloro-mustard amine metabolite (CP-506M-Cl2) identified as a major diffusible metabolite. Overall, this study shows that CP-506 has favourable pharmacological properties in tumour tissue and supports its ongoing development for use in the treatment of patients with advanced solid malignancies.
Transgenerational Sex-dependent Disruption of Dopamine Function Induced by Maternal Immune Activation
Authors: Santoni Michele , Frau Roberto , Pistis Marco
Published: February 2022

Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by in vivo electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors’ polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.
Birth, Annexation, and Squeezing of Cities in a Prefecture: Can the Ranking of Competitive Areas of Municipalities Obey the Authentic Power Law?
Authors: Hayata Kazuya
Published: February 2022

As the first step for revealing potential rules inherent in cities that are closely squeezed in a sectioned domain, municipalities in the entire prefecture in Japan are considered and their distributions of the areas are analyzed in details according to a rank-size procedure. Computed results suggest that among the population, area, and population density, the last becomes the most important factor in finding the rank-size rule. Indeed, of the 47 Japanese prefectures the Metropolis of Tokyo and Fukuoka Prefecture exhibit the most typical rank-size rules, where the former possesses the exceptionally high population density as well as urbanized rate. The underlying mechanism of the rule can be supported by a toy model with a tournament game using a sequence of random numbers, where teams (municipalities) are highly competitive in gaining the final wins (broadest territory). A stability analysis implying perturbations due to global warming allows one to confirm unexpected robustness of the rank-size relation. Finally, the authenticity of the log-log relation in the rank-area data of Tokyo Metropolis is tested statistically.
Analysis of the Complete Plastomes of 31 Species of Hoya Group: Insights Into Their Comparative Genomics and Phylogenetic Relationships
Authors: Odago Wyclif Ochieng , Waswa Emmanuel Nyongesa , Nanjala Consolata , Mutinda Elizabeth Syowai , Wanga Vincent Okelo , Mkala Elijah Mbandi , Oulo Millicent Akinyi , Wang Yan , Zhang Cai-Fei , Hu Guang-Wan , Wang Qing-Feng
Published: February 2022

Hoya is a genus in Apocynaceae-Asclepiadoideae, known for its showy wax flowers, making it a popular ornamental plant. However, phylogenetic relationships among most Hoya species are not yet fully resolved. In this study, we sequenced 31 plastomes of Hoya group species using genome skimming data and carried out multiple analyses to understand genome variation to resolve the phylogenetic positions of some newly sequenced Chinese endemic species. We also screened possible hotspots, trnT-trnL-trnF, psba-trnH, and trnG-UCC, ndhF, ycf1, matK, rps16, and accD genes that could be used as molecular markers for DNA barcoding and species identification. Using maximum likelihood (ML) and Bayesian Inference (BI), a species phylogeny was constructed. The newly assembled plastomes genomes showed the quasi-tripartite structure characteristic for Hoya and Dischidia with a reduced small single copy (SSC) and extremely enlarged inverted repeats (IR). The lengths ranged from 175,404 bp in Hoya lacunosa to 179,069 bp in H. ariadna. The large single copy (LSC) regions ranged from 80,795 bp (Hoya liangii) to 92,072 bp (Hoya_sp2_ZCF6006). The massively expanded IR regions were relatively conserved in length, with the small single-copy region reduced to a single gene, ndhF. We identified 235 long dispersed repeats (LDRs) and ten highly divergent hotspots in the 31 Hoya plastomes, which can be used as DNA barcodes for species identification. The phylogeny supports Clemensiella as a distinct genus. Hoya ignorata is resolved as a relative to Clade VI species. This study discloses the advantages of using Plastome genome data to study phylogenetic relationships.