bluuebunny/crossref_metadata_2025 huggingface dataset:
Holocene Paleoecology in the Neotropical Savannas of Northern South America (Llanos of the Orinoquia Ecoregion, Colombia and Venezuela): What Do We Know and on What Should We Focus in the Future?
Authors: Piraquive-Bermúdez Daniela , Behling Hermann
Published: March 2022

We provide an overview of the Holocene paleoecology of the Llanos ecoregion. A region that captured the attention of researchers for more than 200 years, as it exhibits a high heterogeneity in landscapes and vegetation, where savanna and forest mosaics exist. Located in an area influenced by the seasonal migration of the Intertropical Convergence Zone (ITCZ), it provides a unique area for understanding long-term dynamics of climate, vegetation and human history. Twelve locations have been paleoecologically studied, showing general vegetation and climate changes trends since the Last Glacial Maximum (LGM). During LGM savanna herbs were dominant, indicating dry climatic conditions. The transition of the Holocene was characterized by a slight increase in forest taxa, suggesting a transition to a wetter climate. Between ∼10,000 and 7,000 cal yr BP, grasslands were abundant, and few forest taxa, including Mauritia were also common but rare, pointing to a warm and humid climate. After ∼7,000 cal yr BP, the gallery forest started to expand, suggesting a change to a wetter climate. Mauritia palms increased markedly after 4,000–3,000 cal yr BP, possibly driven by higher mean annual precipitation and/or longer wet season. The start of human occupation remains unclear, but it has been linked to the time of expansion of Mauritia, a period in which fires, possibly of anthropogenic origin, were more frequent. To understand patterns of change in these ecosystems, it is necessary to improve the chronological control of the sediments in future studies and increase the resolution and proxies used to reconstruct their history.
Short Tandem Repeat Variation in the CNR1 Gene Associated With Analgesic Requirements of Opioids in Postoperative Pain Management
Authors: Kasai Shinya , Nishizawa Daisuke , Hasegawa Junko , Fukuda Ken-ichi , Ichinohe Tatsuya , Nagashima Makoto , Hayashida Masakazu , Ikeda Kazutaka
Published: March 2022

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the CNR1, GRIN2A, PENK, and PDYN genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the CNR1, GRIN2A, and PENK genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman’s rank correlation coefficient ρ = 0.199, p = 0.002, ρ = 0.174, p = 0.006, and ρ = 0.135, p = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery (ρ = −0.200, p = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery (ρ = 0.143, p = 0.023), respectively. The associations between STRs in the CNR1 gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm’s multiple-testing correction. These findings indicate that STRs in the CNR1 gene influence analgesia in the orofacial region.
Multi-Omics Analysis Reveals Aberrant Gut-Metabolome-Immune Network in Schizophrenia
Authors: Fan Yajuan , Gao Yuan , Ma Qingyan , Yang Zai , Zhao Binbin , He Xiaoyan , Yang Jian , Yan Bin , Gao Fengjie , Qian Li , Wang Wei , Zhu Feng , Ma Xiancang
Published: March 2022

Schizophrenia (SCZ) is associated with several immune dysfunctions, including elevated levels of pro-inflammatory cytokines. Microorganisms and their metabolites have been found to regulate the immune system, and that intestinal microbiota is significantly disturbed in schizophrenic patients. To systematically investigate aberrant gut-metabolome-immune network in schizophrenia, we performed an integrative analysis of intestinal microbiota, serum metabolome, and serum inflammatory cytokines in 63 SCZ patients and 57 healthy controls using a multi-omics strategy. Eighteen differentially abundant metabolite clusters were altered in patients displayed higher cytokine levels, with a significant increase in pro-inflammatory metabolites and a significant decrease in anti-inflammatory metabolites (such as oleic acid and linolenic acid). The bacterial co-abundance groups in the gut displayed more numerous and stronger correlations with circulating metabolites than with cytokines. By integrating these data, we identified that certain bacteria might affect inflammatory cytokines by modulating host metabolites, such as amino acids and fatty acids. A random forest model was constructed based on omics data, and seven serum metabolites significantly associated with cytokines and α-diversity of intestinal microbiota were able to accurately distinguish the cases from the controls with an area under the receiver operating characteristic curve of 0.99. Our results indicated aberrant gut-metabolome-immune network in SCZ and gut microbiota may influence immune responses by regulating host metabolic processes. These findings suggest a mechanism by which microbial-derived metabolites regulated inflammatory cytokines and insights into the diagnosis and treatment of mental disorders from the microbial-immune system in the future.
Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid
Authors: Iwamoto Yuichiro , Anno Takatoshi , Koyama Katsumasa , Kawasaki Fumiko , Kaku Kohei , Tomoda Koichi , Sugiyama Seiko , Aoyama Yumi , Kaneto Hideaki
Published: March 2022

Bullous pemphigoid (BP) is a rare autoimmune blistering disease, and the prevalence of type 2 diabetes mellitus (T2DM) is relatively high in subjects with BP. It is known that dipeptidyl peptidase-4 inhibitor (DPP-4i), one kind of antidiabetic drugs, can cause BP, although precise mechanism of DPP-4i-related BP remains unclear. In this report, we showed a case with appearance of various disease-specific antibodies after the onset of DPP-4i-related BP. Furthermore, various disease-specific antibodies became positive and showed high titers two years after the onset of DPP-4i-related BP and discontinuation of DPP-4i. These data showed that it is possible for immune tolerance to be broken after the onset of DPP-4i-related BP, and it may be important to check autoimmune antibodies in DPP-4i-related BP subjects even when BP symptoms are improved.
DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology
Authors: Zhao Jianan , Wei Kai , Chang Cen , Xu Lingxia , Jiang Ping , Guo Shicheng , Schrodi Steven J. , He Dongyi
Published: March 2022

Rheumatoid arthritis (RA) is an autoimmune disease that can cause joint damage and disability. Epigenetic variation, especially DNA methylation, has been shown to be involved in almost all the stages of the pathology of RA, from autoantibody production to various self-effector T cells and the defects of protective T cells that can lead to chronic inflammation and erosion of bones and joints. Given the critical role of T cells in the pathology of RA, the regulatory functions of DNA methylation in T cell biology remain unclear. In this review, we elaborate on the relationship between RA pathogenesis and DNA methylation in the context of different T cell populations. We summarize the relevant methylation events in T cell development, differentiation, and T cell-related genes in disease prediction and drug efficacy. Understanding the epigenetic regulation of T cells has the potential to profoundly translate preclinical results into clinical practice and provide a framework for the development of novel, individualized RA therapeutics.
A Systematic Review Demonstrates How Surrogate Populations Help Inform Conservation and Management of an Endangered Species—The Case of Cook Inlet, Alaska Belugas
Authors: Norman Stephanie A. , Dreiss Lindsay M. , Niederman Talia E. , Nalven Katharine B.
Published: March 2022

The genetically and geographically isolated Cook Inlet beluga whale (CIB) was listed as endangered under the Endangered Species Act in 2008 and a federal recovery plan was adopted in 2016. Despite these measures, the population has failed to make demonstrable progress toward recovery. Data and knowledge gaps exist, as well as high uncertainty in the recovery plan, regarding the impact and severity of identified threats on CIB health and recovery, particularly for threats driven by anthropogenic factors, and cumulative effects. These data deficiencies may hinder threat prioritization and conservation and management actions. Odontocete populations in similarly ecologically precarious situations may serve as research surrogates to help fill information gaps and guide future CIB research and conservation. Through a systematic review of CIB and selected surrogate species [St. Lawrence beluga (SLB), Hector’s dolphins (HD), and southern resident killer whales (SRKW)], we identify gaps associated with threats described and ranked in the CIB recovery plan. All threats identified by the National Marine Fisheries Services as “high”-concern to CIB recovery, except noise, are lower in publication volume compared to publications related to high concern threats in SLB and SRKW. “Medium” or “low” threats to CIB, such as prey reduction and contaminants, respectively, are identified as higher priority threats in surrogate populations. These topics have been more heavily researched for surrogates and suggests that synthesis of this work may help reduce uncertainty, to aid in informing management actions for CIB. Specifically, publishing volume suggests SLB and SRKW are valuable surrogates for understanding the impacts of noise, prey, and contaminants. Publishing volume is necessary to choose a surrogate, but is not sufficient. Surrogates were chosen based on physiological similarities to CIB as well as their comparable management situations. Therefore, these lower-ranked threats should be ranked more highly and researched specifically in regard to CIB. We use this review to offer management recommendations based on current CIB and surrogate literature regarding listed threats in the CIB recovery plan. Our analyses suggest that CIB may benefit from a revision to and elevation of some low and medium-concern threats such as contaminants, habitat degradation, and prey reduction.
Structure, Properties, and Modification of Polytrifluorochloroethylene: A Review
Authors: Zou Jiajia , Zhang Maocheng , Huang Mengqiu , Zhao Dan , Dai Yinhai
Published: March 2022

Polytrifluorochloroethylene (PCTFE) is one of the earliest synthesized and commercialized fluoroplastics. It shows ultralow dielectric constant and loss coupled with other excellent properties such as good water vapor permeation resistance, anti-corrosion, light transparency, creep resistance, and so forth, exhibiting great potential to break the bottleneck of the development of high-frequency communication field. Besides, PCTFE-based materials have already played an essential role in some high-tech fields, including chemical, medical, aerospace, and electrical industries. However, in terms of fundamental research, most of the reports concerning the chemical and physical structure of PCTFE came from the last century, but very few in recent years. Herein, the history of the development and the research progress of the structure, properties, and modification of PCTFE was introduced respectively and finally the perspective was proposed, aiming to provide guidance for the future research and application of PCTFE-based materials.
A Review of Roles of Uterine Artery Doppler in Pregnancy Complications
Authors: Tian Yingying , Yang Xiuhua
Published: March 2022

The invasion of trophoblasts into the uterine decidua and decidual vessels is critical for the formation of placenta. The defects of placentation are related to the etiologies of preeclampsia (PE), fetal growth restriction (FGR), and small-for-gestational age (SGA) neonates. It is possible to predict significant vascular events during pregnancy through uterine artery Doppler (UAD). From the implantation stage to the end of pregnancy, detecting changes in uterine and placental blood vessels can provide a favorable diagnostic instrument for pregnancy complications. This review aims to collect literature about the roles of UAD in pregnancy complications. We consider all relevant articles in English from January 1, 1983 to October 30, 2021. Predicting pregnancy complications in advance allows practitioners to carry out timely interventions to avoid or lessen the harm to mothers and neonates. Administering low-dose aspirin daily before 16 weeks of pregnancy can significantly reduce the incidence of pregnancy complications. From early pregnancy to late pregnancy, UAD can combine with other maternal factors, biochemical indicators, and fetal measurement data to identify high-risk population. The identification of high-risk groups can also lessen maternal mortality. Besides, through moderate risk stratification, stringent monitoring for high-risk pregnant women can be implemented, decreasing the incidence of adversities.
The Codon Usage Bias Analysis of Free-Living Ciliates’ Macronuclear Genomes and Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Vector Construction of Stylonychia lemnae
Authors: Wang Ying , Yao Lin , Fan Jinfeng , Zhao Xue , Zhang Qing , Chen Ying , Guo Changhong
Published: March 2022

Ciliates represent higher unicellular animals, and several species are also important model organisms for molecular biology research. Analyses of codon usage bias (CUB) of the macronuclear (MAC) genome in ciliates can not only promote a better understanding of the genetic mode and evolution history of these organisms but also help optimize codons to improve the gene editing efficiency of model ciliates. In this study, macronuclear genome sequences of nine free-living ciliates were analyzed with CodonW software to calculate the following indices: the guanine-cytosine content (GC); the frequency of the nucleotides U, C, A, and G at the third position of codons (U3s, C3s, A3s, G3s); the effective number of codons (ENC); the correlation between GC at the first and second positions (GC12); the frequency of the nucleotides G + C at the third position of synonymous codons (GC3s); the relative synonymous codon usage (RSCU). Parity rule 2 plot analysis, neutrality plot analysis, and correlation analysis were performed to explore the factors that influence codon preference. The results showed that the GC contents in nine ciliates’ MAC genomes were lower than 50% and appeared AT-rich. The base compositions of GC12 and GC3s are markedly distinct and the codon usage pattern and evolution of ciliates are affected by genetic mutation and natural selection. According to the synonymous codon analysis, the codons of most ciliates ended with A or U and eight codons were the general optimal codons of nine ciliates. A clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) expression vector of Stylonychia lemnae was constructed by optimizing the macronuclear genome codon and was successfully used to knock out the Adss gene. This is the first such extensive investigation of the MAC genome CUB of ciliates and the initial successful application of the CRISPR/Cas9 technique in free-living ciliates.
Spatio-Temporal Variation of Synechococcus Assemblages at DNA and cDNA Levels in the Tropical Estuarine and Coastal Waters
Authors: Wang Ting , Xia Xiaomin , Chen Jiawei , Liu Hongbin , Jing Hongmei
Published: March 2022

Synechococcusis a major contributor to global marine primary production. Here, its spatio-temporal variations in abundance and phylogenetic structure were studied at three stations of the South China Sea at both DNA and cDNA levels.Synechococcuscell abundance was lowest in March, but highest in October at two coastal stations. Its abundance was higher at the estuarine station, which reached a peak value of 1.36 × 105cells/ml in April, owing to the nitrogen nutrients discharged from the Sanya River. Gene and gene transcript abundances of fourSynechococcuslineages, clades II, III, VIII, and S5.3, were studied by quantitative PCR, which showed that clade II was the most abundant lineage at both DNA and cDNA levels. High-throughput sequencing revealed that, at the DNA level,Synechococcusassemblage was dominated by clade SY4 (a novel clade defined in this study), S5.2, and clade II in the coastal waters and was dominated by freshwater/S5.2Synechococcus, reaching a value up to 88.61% in June, in estuarine waters. Changes in salinity and nutrient concentration caused by seasonal monsoonal forcing and river discharge were the key determinants of the spatio-temporal variation inSynechococcusassemblages at the DNA level. In comparison, high dissimilation among samples at the same stations and in the same seasons leads to the imperceptible spatio-temporal variation pattern ofSynechococcusassemblages at the cDNA level. Furthermore, co-occurrence networks disclosed thatSynechococcuscommunity had closer and more complex internal interactions at the cDNA level. These discrepancies highlighted the necessity to studySynechococcusassemblages at both DNA and cDNA levels.
Machine Learning for Detecting Parkinson’s Disease by Resting-State Functional Magnetic Resonance Imaging: A Multicenter Radiomics Analysis
Authors: Shi Dafa , Zhang Haoran , Wang Guangsong , Wang Siyuan , Yao Xiang , Li Yanfei , Guo Qiu , Zheng Shuang , Ren Ke
Published: March 2022

Parkinson’s disease (PD) is one of the most common progressive degenerative diseases, and its diagnosis is challenging on clinical grounds. Clinically, effective and quantifiable biomarkers to detect PD are urgently needed. In our study, we analyzed data from two centers, the primary set was used to train the model, and the independent external validation set was used to validate our model. We applied amplitude of low-frequency fluctuation (ALFF)-based radiomics method to extract radiomics features (including first- and high-order features). Subsequently, t-test and least absolute shrinkage and selection operator (LASSO) were harnessed for feature selection and data dimensionality reduction, and grid search method and nested 10-fold cross-validation were applied to determine the optimal hyper-parameter λ of LASSO and evaluate the performance of the model, in which a support vector machine was used to construct the classification model to classify patients with PD and healthy controls (HCs). We found that our model achieved good performance [accuracy = 81.45% and area under the curve (AUC) = 0.850] in the primary set and good generalization in the external validation set (accuracy = 67.44% and AUC = 0.667). Most of the discriminative features were high-order radiomics features, and the identified brain regions were mainly located in the sensorimotor network and lateral parietal cortex. Our study indicated that our proposed method can effectively classify patients with PD and HCs, ALFF-based radiomics features that might be potential biomarkers of PD, and provided further support for the pathological mechanism of PD, that is, PD may be related to abnormal brain activity in the sensorimotor network and lateral parietal cortex.
A Dynamic 3D Aggregate-Based System for the Successful Expansion and Neural Induction of Human Pluripotent Stem Cells
Authors: Miranda Cláudia C. , Akenhead Michael L. , Silva Teresa P. , Derr Michael A. , Vemuri Mohan C. , Cabral Joaquim M. S. , Fernandes Tiago G.
Published: March 2022

The demand for large cell numbers for cellular therapies and drug screening applications requires the development of scalable platforms capable of generating high-quality populations of tissue-specific cells derived from human pluripotent stem cells (hPSCs). Here, we studied the ability of Gibco StemScale PSC Suspension Medium to promote the efficient expansion of hPSC cultures as aggregates grown in suspension. We tested human induced pluripotent stem cell (hiPSC) growth in 6-well plates (on orbital shaker platforms) and single-use vertical-wheel bioreactors for a total of three consecutive passages. Up to a 9-fold increase in cell number was observed over 5 days per passage, with a cumulative fold change up to 600 in 15 days. Additionally, we compared neural induction of hiPSCs by using a dual SMAD inhibition protocol with a commercially available neural induction medium, which can potentially yield more than a 30-fold change, including neural progenitor induction and expansion. This system can also be adapted toward the generation of floor plate progenitors, which yields up to an 80-fold change in cell number and generates FOXA2-positive populations. In summary, we developed platforms for hiPSC expansion and neural induction into different brain regions that provide scalability toward producing clinically relevant cell numbers.
Quantification of Kuramoto Coupling Between Intrinsic Brain Networks Applied to fMRI Data in Major Depressive Disorder
Authors: Bauer Lena G. , Hirsch Fabian , Jones Corey , Hollander Matthew , Grohs Philipp , Anand Amit , Plant Claudia , Wohlschläger Afra
Published: March 2022

Organized patterns of system-wide neural activity adapt fluently within the brain to adjust behavioral performance to environmental demands. In major depressive disorder (MD), markedly different co-activation patterns across the brain emerge from a rather similar structural substrate. Despite the application of advanced methods to describe the functional architecture, e.g., between intrinsic brain networks (IBNs), the underlying mechanisms mediating these differences remain elusive. Here we propose a novel complementary approach for quantifying the functional relations between IBNs based on the Kuramoto model. We directly estimate the Kuramoto coupling parameters (K) from IBN time courses derived from empirical fMRI data in 24 MD patients and 24 healthy controls. We find a large pattern with a significant number of Ks depending on the disease severity score Hamilton D, as assessed by permutation testing. We successfully reproduced the dependency in an independent test data set of 44 MD patients and 37 healthy controls. Comparing the results to functional connectivity from partial correlations (FC), to phase synchrony (PS) as well as to first order auto-regressive measures (AR) between the same IBNs did not show similar correlations. In subsequent validation experiments with artificial data we find that a ground truth of parametric dependencies on artificial regressors can be recovered. The results indicate that the calculation of Ks can be a useful addition to standard methods of quantifying the brain's functional architecture.
Sex-Differences in Oral Anticoagulant-Related Intracerebral Hemorrhage
Authors: Grundtvig Josefine , Ovesen Christian , Steiner Thorsten , Carcel Cheryl , Gaist David , Christensen Louisa , Marstrand Jacob , Meden Per , Rosenbaum Sverre , Iversen Helle K. , Kruuse Christina , Christensen Thomas , Ægidius Karen , Havsteen Inger , Christensen Hanne
Published: March 2022

Introduction and Aim

Data remain limited on sex-differences in patients with oral anticoagulant (OAC)-related intracerebral hemorrhage (ICH). We aim to explore similarities and differences in risk factors, acute presentation, treatments, and outcome in men and women admitted with OAC-related ICH.

Method

This study was a retrospective observational study based on 401 consecutive patients with OAC-related ICH admitted within 24 h of symptom onset. The study was registered on osf.io. We performed logarithmic regression and cox-regression adjusting for age, hematoma volume, Charlson Comorbidity Index (CCI), and pre-stroke modified Ranking Scale (mRS). Gender and age were excluded from CHA2DS2-VASc and CCI was not adjusted for age.

Results

A total of 226 men and 175 women were identified. More men were pre-treated with vitamin K-antagonists (73.5% men vs. 60.6% women) and more women with non-vitamin K-antagonist oral anticoagulants (26.5% men vs. 39.4% women), p = 0.009. Women were older (mean age 81.9 vs. 76.9 years, p < 0.001). CHA2DS2-VASc and CCI were similar in men and women.

Hematoma volumes (22.1 ml in men and 19.1 ml in women) and National Institute of Health Stroke Scale (NIHSS) scores (13 vs. 13) were not statistically different, while median Glasgow Coma Scale (GCS) was lower in women, (14 [8;15] vs. 14 [10;15] p = 0.003).

Women's probability of receiving reversal agents was significantly lower (adjusted odds ratio [aOR] = 0.52, p = 0.007) but not for surgical clot removal (aOR = 0.56, p = 0.25). Women had higher odds of receiving do-not-resuscitate (DNR) orders within a week (aOR = 1.67, p = 0.04). There were no sex-differences in neurological deterioration (aOR = 1.48, p = 0.10), ability to walk at 3 months (aOR = 0.69, p = 0.21) or 1-year mortality (adjusted hazard ratio = 1.18, p = 0.27).

Conclusion

Significant sex-differences were observed in age, risk factors, access to treatment, and DNRs while no significant differences were observed in comorbidity burden, stroke severity, or hematoma volume. Outcomes, such as adjusted mortality, ability to walk, and neurological deterioration, were comparable. This study supports the presence of sex-differences in risk factors and care but not in presentation and outcomes.
A Fully Adapted Headstage With Custom Electrode Arrays Designed for Electrophysiological Experiments
Authors: Mourão Flávio Afonso Gonçalves , Guarnieri Leonardo de Oliveira , Amaral Júnior Paulo Aparecido , Carvalho Vinícius Rezende , Mendes Eduardo Mazoni Andrade Marçal , Moraes Márcio Flávio Dutra
Published: March 2022

Electrophysiological recordings lead amongst the techniques that aim to investigate the dynamics of neural activity sampled from large neural ensembles. However, the financial costs associated with the state-of-the-art technology used to manufacture probes and multi-channel recording systems make these experiments virtually inaccessible to small laboratories, especially if located in developing countries. Here, we describe a new method for implanting several tungsten electrode arrays, widely distributed over the brain. Moreover, we designed a headstage system, using the Intan® RHD2000 chipset, associated with a connector (replacing the expensive commercial Omnetics connector), that allows the usage of disposable and inexpensive cranial implants. Our results showed high-quality multichannel recording in freely moving animals (detecting local field, evoked responses and unit activities) and robust mechanical connections ensuring long-term continuous recordings. Our project represents an open source and inexpensive alternative to develop customized extracellular records from multiple brain regions.
SNCA rs3910105 Is Associated With Development of Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s Disease
Authors: Yang Nan-nan , Sang Shu-shan , Peng Tao , lu Hong
Published: March 2022

Background and Purpose

Rapid eye movement (REM) Rapid eye movement sleep behavior disorder (RBD) is a common non-motor symptom of PD. However, the association between the SNCA rs3910105 genotype and RBD in Parkinson’s disease (PD) remains unclear.

Methods

This study used Parkinson’s Progression Markers Initiative (PPMI) data and included 270 patients with newly diagnosed PD without RBD who were divided into SNCA rs3910105 C carriers (CC+CT; n = 187) and TT carriers (n = 83). They were followed up for 5 years to identify the development of RBD. To investigate the influence of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) and β-amyloid 1–42 (Aβ42) in the association between rs3910105 and RBD, the patients were additionally classified into “high-level” and “low-level” groups using cutoff values for CSF α-syn and Aβ42 levels.

Results

At baseline, the rs3910105 C allele group had lower CSF α-syn and Aβ42 levels than the TT group. During the 5.0-year follow-up, the rs3910105 C allele group had a higher incidence of RBD than the TT group. In the subgroup analyses, the effect of the rs3910105 C allele was not found in the “low-level” group. However, in the “high-level” group, the rs3910105 C allele independently increased the risk of RBD.

Conclusion

The SNCA rs3910105 C allele might be a novel genetic risk factor for RBD development in PD, α-syn pathways might have a role in this association and more basic research would be needed to elucidate the mechanism in the future.
The Difficult Decision Not to Prescribe Artificial Nutrition by Health Professionals and Family: Bioethical Aspects
Authors: Pereira Andrea Z. , da Cunha Selma Freire de Carvalho , Grunspun Henrique , Bueno Marco Aurelio Scarpinella
Published: March 2022

Introduction

Bioethics and nutrition are essential issues in end of life, advanced dementia, life-sustaining therapies, permanent vegetative status, and unacceptably minimal quality of life. Even though artificially administered nutrition (AAN), for this type of health condition, does not improve quality of life and extension of life, and there is evidence of complications (pulmonary and gastrointestinal), it has been used frequently. It had been easier considering cardiopulmonary resuscitation as an ineffective treatment than AAN for a healthy team and/or family. For this reason, many times, this issue has been forgotten.

Objectives

This study aimed to discuss bioethical principles and AAN in the involved patients.

Discussion

The AAN has been an essential source of ethical concern and controversy. There is a conceptual doubt about AAN be or not be a medical treatment. It would be a form of nourishment, which constitutes primary care. These principles should be used to guide the decision-making of healthcare professionals in collaboration with patients and their surrogates.

Conclusions

This difficult decision about whether or not to prescribe AAN in patients with a poor prognosis and without benefits should be based on discussions with the bioethics committee, encouraging the use of advanced directives, education, and support for the patient, family, and health team, in addition to the establishment of effective protocols on the subject. All of this would benefit the most important person in this process, the patient.
Bacillus velezensis A2 Inhibited the Cecal Inflammation Induced by Zearalenone by Regulating Intestinal Flora and Short-Chain Fatty Acids
Authors: Cai Jing , Wang Nan , Chen Jia , Wu Aibo , Nepovimova Eugenie , Valis Martin , Long Miao , Wu Wenda , Kuca Kamil
Published: March 2022

Zearalenone (ZEA) as an estrogen-like mycotoxin can cause the inflammatory injury of the cecum. How to reduce the harm that ZEA causes to humans and animals is a current concern for researchers. In this study, we aimed to ascertain whether Bacillus velezensis A2 (A2) could alleviate injury caused by ZEA by regulating the intestinal flora and the content of short chain fatty acids in the cecum among mice. Our results showed that Bacillus velezensis A2 improved the fold height, myometrial thickness, and crypt depth of the cecum induced by ZEA. Enzyme-linked immunosorbent assay and Western blotting results showed that A2 could decrease the ZEA-induced increase in expression levels of IL-2, IL-6, IFN-γ, TNF-α, and FC. Studies also showed that A2 increased the content of SCFA in the cecum which was decreased by ZEA. The microbial communities in the cecum were changed when given ZEA or A2. A2 was found to greatly reduce the ZEN-induced increase in the relative abundance of p_Actinobacteria, p_Protebacteria, o_Coriobacteriales, g_Anaerotruncus, g_Pseudoflavonifractor, g_Lachnoclostridium, g_Enterorhabdus, and f_Oscillospiraceae, and increase the ZEN-induced decrease in the relative abundance of f_Coriobacteriales. Results indicated that Bacillus velezensis A2 can largely ameliorate the intestinal inflammatory injury induced by ZEA in mice by regulating the microflora and short chain fatty acids content.
Association Between Consumption of Fermented Food and Food-Derived Prebiotics With Cognitive Performance, Depressive, and Anxiety Symptoms in Psychiatrically Healthy Medical Students Under Psychological Stress: A Prospective Cohort Study
Authors: Karbownik Michał Seweryn , Mokros Łukasz , Dobielska Maria , Kowalczyk Mateusz , Kowalczyk Edward
Published: March 2022

Background

Gut microbiota-based therapeutic strategies, such as probiotic and prebiotic preparations, may benefit mental health. However, commonly consumed fermented and prebiotic-containing foods have not been well-tested. The aim of the present study was to determine whether consumption of fermented food and food-derived prebiotics is associated with cognitive performance, depressive, and anxiety symptoms in psychiatrically healthy medical students under psychological stress.

Methods

The study protocol with data analysis plan was prospectively registered. Food consumption was evaluated with a 7-day dietary record. Cognitive performance was modeled with academic examination performance in relation to subject knowledge. Pre-exam depressive and anxiety symptoms were assessed with the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7, respectively.

Results

In total, 372 medical students (22.7 ± 1.1 years of age, 66% female) completed the study. No relationship was observed between cognitive performance under stress and either fermented food (adjusted β 0.02, 95% CI −0.07–0.11, p = 0.63) or food-derived prebiotics consumption (adjusted β −0.00, 95% CI −0.09–0.09, p = 0.99). High intake of fermented food was associated with more severe depressive (adjusted β 0.11, 95% CI 0.01–0.20, p = 0.032) and anxiety symptoms under stress (adjusted β 0.13, 95% CI 0.04–0.22, p = 0.0065); however, no such link was observed for food-derived prebiotics (adjusted β 0.03, 95% CI −0.07–0.13, p = 0.50 and −0.01, 95% CI −0.11–0.08, p = 0.83, for depression and anxiety, respectively).

Conclusions

Under psychological stress in medical students, consumption of fermented food and food-derived prebiotics appears to be not associated with cognitive performance. High intake of fermented food, but not food-derived prebiotics, may be associated with severity of depressive and anxiety symptoms. The safety of fermented food in this regard therefore requires further clarification.
Prognostic Impact of Pattern of Mandibular Involvement in Gingivo-Buccal Complex Squamous Cell Carcinomas: Marrow and Mandibular Canal Staging System
Authors: Mahajan Abhishek , Dhone Navnath , Vaish Richa , Singhania Ankita , Malik Akshat , Prabhash Kumar , Ahuja Ankita , Sable Nilesh , Chaturvedi Pankaj , Noronha Vanita , Gosh Laskar Sarbani , Agarwal Ujjwal , Shukla Shreya , Pantvaidya Gouri , Pai Prathamesh , Bhattacharjee Atanu , Patil Vijay , Patil Asawari , Bal Munita , Rane Swapnil , Thiagarajan Shivakumar , D’ Cruz Anil
Published: March 2022

Purpose

To study the pattern of mandibular involvement and its impact on oncologic outcomes in patients with gingivo-buccal complex squamous cell carcinoma (GBC-SCC) and propose a staging system based on the pattern of bone involvement (MMC: Marrow and mandibular canal staging system) and compare its performance with the 8th edition of the American Joint Committee on Cancer (AJCC8).

Methods

This retrospective observational study included treatment-naïve GBC-SCC patients who underwent preoperative computed tomography (CT) imaging between January 1, 2012, and March 31, 2016, at a tertiary care cancer center. Patients with T4b disease with high infratemporal fossa involvement, maxillary erosion, and follow-up of less than a year were excluded. The chi-square or Fisher’s exact test was used for descriptive analysis. Kaplan–Meier estimate and log-rank test were performed for survival analysis. Multivariate analysis was done using Cox regression analysis after making adjustments for other prognostic factors. p-Value <0.05 was considered as significant. Based upon the survival analysis with different patterns of bone invasion, a new staging system was proposed “MMC: Marrow and mandibular canal staging system”. “Akaike information criterion” (AIC) was used to study the relative fitted model of the various staging (TNM staging—AJCC8) with respect to survival parameters.

Results

A total of 1,200 patients were screened; 303 patients were included in the study. On radiology review, mandibular bone was involved in 62% of patients. The pattern of bone involvement was as follows: deep cortical bone erosion (DCBE) in 23%, marrow in 34%, and marrow with the mandibular canal in 43% of patients. Patients with DCBE and no bone involvement (including superficial cortical) had similar survival [disease-free survival (DFS) and locoregional recurrence-free survival (LRRFS)], and this was significantly better than those with marrow with or without mandibular canal involvement (for both DFS and LRRFS). Patients with DCBE were staged using the MMC, and when compared with the AJCC8, the MMC system was better for the prediction of survival outcomes, as AIC values were lower compared with those of the AJCC8. There was a significant association (p = 0.013) between the type of bone involvement and the pattern of recurrence.

Conclusions

For GBC-SCC, only marrow with or without mandibular canal involvement is associated with poorer survival outcomes. As compared with the AJCC8, the proposed Mahajan et al. MMC staging system downstages DCBE correlates better with survival outcomes.
CAF-Associated Paracrine Signaling Worsens Outcome and Potentially Contributes to Chemoresistance in Epithelial Ovarian Cancer
Authors: Wessolly Michael , Mairinger Elena , Borchert Sabrina , Bankfalvi Agnes , Mach Pawel , Schmid Kurt Werner , Kimmig Rainer , Buderath Paul , Mairinger Fabian Dominik
Published: March 2022

Background

High-grade serous ovarian cancer (HGSOC) is the predominant and deadliest form of ovarian cancer. Some of its histological subtypes can be distinguished by frequent occurrence of cancer-associated myofibroblasts (CAFs) and desmoplastic stroma reaction (DSR). In this study, we want to explore the relationship between therapy outcome and the activity of CAF-associated signaling pathways in a homogeneous HGSOC patient collective. Furthermore, we want to validate these findings in a general Epithelial ovarian cancer (EOC) cohort.

Methods

The investigation cohort consists of 24 HGSOC patients. All of them were treated with platinum-based components and clinical follow-up was available. The validation cohort was comprised of 303 patients. Sequencing data (whole transcriptome) and clinical data were extracted from The Cancer Genome Atlas (TCGA). RNA of HGSOC patients was isolated using a Maxwell RSC instrument and the appropriate RNA isolation kit. For digital expression analysis a custom-designed gene panel was employed. All genes were linked to various DSR- and CAF- associated pathways. Expression analysis was performed on the NanoString nCounter platform. Finally, data were explored using the R programming environment (v. 4.0.3).

Result

In total, 15 CAF-associated genes were associated with patients’ survival. More specifically, 6 genes (MMP13, CGA, EPHA3, PSMD9, PITX2, PHLPP1) were linked to poor therapy outcome. Though a variety of different pathways appeared to be associated with therapy failure, many were related to CAF paracrine signaling, including MAPK, Ras and TGF-β pathways. Similar results were obtained from the validation cohort.

Discussion

In this study, we could successfully link CAF-associated pathways, as shown by increased Ras, MAPK and PI3K-Akt signaling to therapy failure (chemotherapy) in HGSOC and EOCs in general. As platinum-based chemotherapy has been the state-of-the-art therapy to treat HGSOC for decades, it is necessary to unveil the reasons behind resistance developments and poor outcome. In this work, CAF-associated signaling is shown to compromise therapy response. In the validation cohort, CAF-associated signaling is also associated with therapy failure in general EOC, possibly hinting towards a conserved mechanism. Therefore, it may be helpful to stratify HGSOC patients for CAF activity and consider alternative treatment options.
Correlation Between Components of Malnutrition Diagnosed by Global Leadership Initiative on Malnutrition Criteria and the Clinical Outcomes in Gastric Cancer Patients: A Propensity Score Matching Analysis
Authors: Xu Li-Bin , Mei Ting-Ting , Cai Yi-Qi , Chen Wen-Jing , Zheng Si-Xin , Wang Liang , Chen Xiao-Dong , Huang Yun-Shi
Published: March 2022

Objective

Malnutrition is recognized as a risk factor for poor outcome in patients with gastric cancer (GC). In 2018, the Global Leadership Initiative on Malnutrition (GLIM) published standardized criteria for the diagnosis of malnutrition. Our aim was to investigate whether any of the components of the GLIM diagnostic criteria were related to worse clinical outcomes in patients with GC.

Methods

This study analyzed patients with GC who underwent radical gastrectomy in our hospital between 2014 and 2019. A preoperative nutritional assessment was performed for each patient. Matching was based on the presence of three GLIM components: high weight loss (WL), low body mass index (BMI), and low skeletal muscle index (SMI).

Results

The analysis included 1,188 patients, including 241 (20.3%) with high WL, 156 (13.1%) with low BMI, and 355 (29.9%) with low SMI. Before matching, patients who met the GLIM component criteria were mostly associated with older age, low nutritional reserves, and late tumor progression. After matching, the clinical characteristics of the three cohorts were balanced. In the matched queue, the survival prognosis of the high WL group was worse than that of the non-WL group, and the postoperative complication rate was higher in the low SMI group than in the normal SMI group (P <0.05). In addition, the clinical outcomes in the low and normal BMI groups were similar (P >0.05).

Conclusion

Of the GLIM criteria, high WL and low SMI may be associated with poor clinical outcomes in patients with GC, while a low BMI may not be associated with outcome.
USP30: Structure, Emerging Physiological Role, and Target Inhibition
Authors: Wang Feng , Gao Yu , Zhou Lihui , Chen Junhao , Xie Zhiyan , Ye Zifan , Wang Yanfeng
Published: March 2022

Ubiquitin-specific protease 30 (USP30) is a deubiquitinating enzyme (DUB) belonging to the USP subfamily, which was found localized in the mitochondrial outer membrane and peroxisomes owing to its unique transmembrane domain. Structural study revealed that USP30 employed a unique catalytic triad and molecular architecture to preferentially cleave the Lys6 linked ubiquitin chains. USP30 plays an essential role in several cellular events, such as the PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKβ–USP30–ACLY-regulated lipogenesis/tumorigenesis, and is tightly regulated by post-translational modification including phosphorylation and mono-ubiquitination. Dysregulation of USP30 is associated with a range of physiological disorders, such as neurodegenerative disease, hepatocellular carcinoma, pulmonary disorders, and peroxisome biogenesis disorders. Nowadays, scientists and many biopharmaceutical companies are making much effort to explore USP30 inhibitors including natural compounds, phenylalanine derivatives, N-cyano pyrrolidines, benzosulphonamide, and other compounds. For the treatment of pulmonary disorders, the study in Mission Therapeutics of USP30 inhibitor is already in the pre-clinical stage. In this review, we will summarize the current knowledge of the structure, regulation, emerging physiological role, and target inhibition of USP30, hoping to prompt further investigation and understanding of it.
The Circ-CYP24A1-miR-224-PRLR Axis Impairs Cell Proliferation and Apoptosis in Recurrent Miscarriage
Authors: Su Yan , Xu Jiani , Gao Rufei , Liu Xiaoli , Liu Taihang , Li Cong , Ding Yubin , Chen Xuemei , He Junlin , Liu Xueqing , Li Chunli , Qi Hongbo , Wang Yingxiong
Published: March 2022

Aim

Recurrent miscarriage (RM) is associated with numerous clinical factors. However, some RM occurred without specific factors. It has been revealed that some molecules such as hormones, miRNAs, and transcription factors are involved in RM by regulating proliferation, apoptosis, etc. However, the mechanism of RM has yet to be identified clearly. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that often act as sponges for miRNAs or binds to proteins involved in biological processes. However, the functional role of circRNAs in the uterine decidua of patients with early RM is still unclear. In this study, we aimed to investigate the mechanisms of circ-CYP24A1 in RM.

Methods

The Dual-Luciferase Activity Assay was designed to analyze the bonding between circ-CYP24A1 and miR-224, and miR-224 and prolactin receptor (PRLR) mRNA 3′UTR. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to observe the expression of circ-CYP24A1 and PRLR in the decidua. Rescue experiments were performed to investigate the regulating effects of circ-CYP24A1, miR-224, and PRLR. Western blotting was conducted to test the expression level of PRLR. The proliferation and apoptosis-related markers in Ishikawa cells were analyzed using CCK8, immunofluorescence staining, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay.

Results

In this study, based on the microarray analysis data, we identified a high level of circ-CYP24A1 and PRLR in the decidua of patients with early RM. Based on the bioinformatics prediction, the binding relationship between circ-CYP24A1 and miR-224, as well as miR-224 and PRLR, were verified. Functional experiments demonstrated that circ-CYP24A1 regulated proliferation and apoptosis by binding to and inhibiting miR-224, resulting in increased PRLR expression. Taken together, this study provides new insights into the mechanism of RM.

Conclusion

In this study, we found that circ-CYP24A1 plays a role in RM by impairing the balance of cell proliferation and apoptosis by sponging miR-224, thereby regulating PRLR.