bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of Interventions Needed to Improve Maternal Healthcare Utilization: A Multinomial Analysis of the Inequity in Place of Childbirth in Afghanistan
Authors: Kim Christine , Erim Daniel , Natiq Kayhan , Salehi Ahmad Shah , Zeng Wu
Published: December 2020

Giving birth with a skilled birth attendant at a facility that provides emergency obstetric care services has better outcomes, but many women do not have access to these services in low- and middle-income countries. Individual, household, and societal factors influence women's decisions about place of birth. Factors influencing birthplace preference by type of provider and level of public facility are not well understood. Applying the Andersen Behavioral Model of healthcare services use, we explored the association between characteristics of women and their choice of childbirth location using a multinomial logistic regression, and conducted a scenario analysis to predict changes in the childbirth location by imposing various interventions. Most women gave birth at home (68.1%), while 15.1% gave birth at a public clinic, 12.1% at a public hospital, and 4.7% at a private facility. Women with higher levels of education, from households in the upper two wealth quintiles, and who had any antenatal care were more likely to give birth in public or private facilities than at home. A combination of multisector interventions had the strongest signals from the model for increasing the predicted probability of in-facility childbirths. This study enhances our understanding of factors associated with the use of public facilities and the private sector for childbirth in Afghanistan. Policymakers and healthcare providers should seek to improve equity in the delivery of health services. This study highlights the need for decisionmakers to consider a combination of multisector efforts (e.g., health, education, and social protection), to increase equitable use of maternal healthcare services.
Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects
Authors: Vita Gian Marco , De Simone Giovanna , Leboffe Loris , Montagnani Francesca , Mariotti Davide , Di Bella Stefano , Luzzati Roberto , Gori Andrea , Ascenzi Paolo , di Masi Alessandra
Published: December 2020

The pathogenicity of group AStreptococcus(GAS) is mediated by direct bacterial invasivity and toxin-associated damage. Among the extracellular products, the exotoxin streptolysin O (SLO) is produced by almost all GAS strains. SLO is a pore forming toxin (PFT) hemolitically active and extremely toxicin vivo. Recent evidence suggests that human serum albumin (HSA), the most abundant protein in plasma, is a player in the innate immunity “orchestra.” We previously demonstrated that HSA acts as a physiological buffer, partially neutralizingClostridioides difficiletoxins that reach the bloodstream after being produced in the colon. Here, we report thein vitroandex vivocapability of HSA to neutralize the cytotoxic and hemolytic effects of SLO. HSA binds SLO with high affinity at a non-conventional site located in domain II, which was previously reported to interact also withC. difficiletoxins. HSA:SLO recognition protects HEp-2 and A549 cells from cytotoxic effects and cell membrane permeabilization induced by SLO. Moreover, HSA inhibits the SLO-dependent hemolytic effect in red blood cells isolated from healthy human donors. The recognition of SLO by HSA may have a significant protective role in human serum and sustains the emerging hypothesis that HSA is an important constituent of the innate immunity system.
Methods to Detect MHC-Specific IgE in Mice and Men
Authors: Weijler Anna Marianne , Mucha Jasmin , Farkas Andreas Michael , Baranyi Ulrike , Pilat Nina , Cho Ara , Muckenhuber Moritz , Hopf Stefan , Wahrmann Markus , Linhart Birgit , Valenta Rudolf , Wekerle Thomas
Published: December 2020

Humoral immunity is a major barrier limiting long-term outcome after organ transplantation. Especially, the production of antibodies directed against donor HLA/MHC antigens (i.e. donor-specific antibodies (DSA)) leading to antibody-mediated rejection (ABMR) is considered to be a major factor negatively affecting allograft survival. DSAs of the IgG isotype are routinely measured in transplant patients. However, not all patients diagnosed with IgG-DSA develop ABMR events. Therefore, research in better understanding the mechanisms of ABMR is of great importance. We recently demonstrated the production of MHC-specific IgE upon allograft rejection in mice and in transplant patients. IgE is classically connected with allergy and is known to be important for the humoral defense against helminths and worms. However, its role in autoimmune diseases and cancer has been reported recently as well. The concentration of IgE in blood is extremely low compared to other antibody isotypes. Therefore, detection of MHC-specific IgE from serum requires methods of high sensitivity. Since MHC-specific IgG—typically present at much higher serum levels—develops as well, high specificity is also required of IgE detection methods. In the murine model we developed an enzyme linked immunosorbent assay (ELISA) using MHC monomers for measurement of MHC-specific IgE, allowing us to distinguish between specificities of antibodies against different class I and class II antigens. For measurement of functional activity of MHC-specific IgE in vitro, a release assay using a rat basophil cell line (RBL-2H3) was established. For functional analysis of MHC-specific IgE in vivo, a cutaneous hypersensitivity reaction assay was adapted for this purpose using MHC monomers. Humanized RBL-2H3 cells transfected with cDNA coding for the human-high affinity IgE receptor were used for functionality measurement of donor-specific IgE in sensitized transplant patients. For detection of HLA-specific IgE, a bead assay was adapted, using beads expressing single HLA antigens. The aim of this publication is to demonstrate currently established methods for the detection and characterization of MHC-specific IgE in the murine and human setting.
Short-Chain Fatty Acids: A Soldier Fighting Against Inflammation and Protecting From Tumorigenesis in People With Diabetes
Authors: Yang Qiyu , Ouyang Jing , Sun Fengjun , Yang Jiadan
Published: December 2020

Converging evidences showed that people with diabetes mellitus (DM) have significantly higher risk for different cancers, of which the exact mechanism underlying the association has not been fully realized. Short-chain fatty acids (SCFAs), the fermentation products of the intestinal microbiota, are an essential source for energy supply in gut epithelial cells. They have been reported to improve intestinal barrier integrity, prevent microbial translocation, and further dampen inflammation. Gut dysbiosis and reduction in SCFA-producing bacteria as well as SCFAs production in the intestine are commonly seen in metabolic disorders including DM and obesity. Moreover, inflammation can contribute to tumor initiation and progression through multiple pathways, such as enhancing DNA damage, accumulating mutations in tumor suppressor genes Tp53, and activating nuclear factor-kappa B (NF-κB) signaling pathways. Based on these facts, we hypothesize that lower levels of microbial SCFAs resulted from gut dysbiosis in diabetic individuals, enhance microbial translocation, and increase the inflammatory responses, inducing tumorigenesis ulteriorly. To this end, we will discuss protective properties of microbial SCFAs and explore the pivotal roles SCFAs played in the link of DM with cancer, so as to take early precautions to reduce the risk of cancer in patients with DM.
Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review
Authors: Suárez Lina J. , Garzón Hernan , Arboleda Silie , Rodríguez Adriana
Published: December 2020

The current paradigm of onset and progression of periodontitis includes oral dysbiosis directed by inflammophilic bacteria, leading to altered resolution of inflammation and lack of regulation of the inflammatory responses. In the construction of explanatory models of the etiopathogenesis of periodontal disease, autoimmune mechanisms were among the first to be explored and historically, for more than five decades, they have been described in an isolated manner as part of the tissue damage process observed in periodontitis, however direct participation of these mechanisms in the tissue damage is still controversial. Autoimmunity is affected by genetic and environmental factors, leading to an imbalance between the effector and regulatory responses, mostly associated with failed resolution mechanisms. However, dysbiosis/infection and chronic inflammation could trigger autoimmunity by several mechanisms including bystander activation, dysregulation of toll-like receptors, amplification of autoimmunity by cytokines, epitope spreading, autoantigens complementarity, autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, and activation or inhibition of receptors related to autoimmunity by microorganisms. Even though autoreactivity in periodontitis is biologically plausible, the associated mechanisms could be related to non-pathologic responses which could even explain non-recognized physiological functions. In this review we shall discuss from a descriptive point of view, the autoimmune mechanisms related to periodontitis physio-pathogenesis and the participation of oral dysbiosis on local periodontal autoimmune responses as well as on different systemic inflammatory diseases.
An Immune-Related Signature for Predicting the Prognosis of Lower-Grade Gliomas
Authors: Zhang Hongbo , Li Xuesong , Li Yuntao , Chen Baodong , Zong Zhitao , Shen Liang
Published: December 2020

Background

Lower-grade gliomas (LGGs) have more favorable outcomes than glioblastomas; however, LGGs often progress to process glioblastomas within a few years. Numerous studies have proven that the tumor microenvironment (TME) is correlated with the prognosis of glioma.

Methods

LGG RNA-Sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were extracted and then divided into training and testing cohorts, respectively. Immune-related differentially expressed genes (DEGs) were screened to establish a prognostic signature by a multivariate Cox proportional hazards regression model. The immune-related risk score and clinical information, such as age, sex, World Health Organization (WHO) grade, and isocitrate dehydrogenase 1 (IDH1) mutation, were used to independently validate and develop a prognostic nomogram. GO and KEGG pathway analyses to DEGs between immune-related high-risk and low-risk groups were performed.

Results

Sixteen immune-related genes were screened for establishing a prognostic signature. The risk score had a negative correlation with prognosis, with an area under the receiver operating characteristic (ROC) curve of 0.941. The risk score, age, grade, and IDH1 mutation were identified as independent prognostic factors in patients with LGGs. The hazard ratios (HRs) of the high-risk score were 5.247 [95% confidence interval (CI) = 3.060–8.996] in the multivariate analysis. A prognostic nomogram of 1-, 3-, and 5-year survival was established and validated internally and externally. Go and KEGG pathway analyses implied that immune-related biological function and pathways were involved in the TME.

Conclusion

The immune-related prognostic signature and the prognostic nomogram could accurately predict survival.
The Impact of the COVID-19 Epidemic on Orthodontic Patients in China: An Analysis of Posts on Weibo
Authors: Guo Feiyang , Tang Bojun , Qin Danchen , Zhao Tingting , Su Yu-xiong , McGrath Colman , Hua Fang , He Hong
Published: December 2020

Background: During the COVID-19 pandemic, many dental care services including orthodontic practice were suspended. Orthodontic patients turned to social media platforms to communicate, share experiences, and look for solutions. Our study aimed to investigate the attitudes and perspectives of orthodontic patients during the COVID-19 epidemic in China by analyzing orthodontics-related posts on Sina Weibo (a Chinese counterpart of Twitter).

Materials and Methods: Potentially eligible posts on Sina Weibo platform were collected between December 30, 2019, and April 18, 2020. Posts related to both orthodontics and COVID-19 were included and then coded and classified into specific appliances and themes. Geographic and temporal distributions of the included posts were analyzed. In addition, time-lagged cross correlation was performed to explore the association between the number of daily posts and daily new COVID-19 cases/deaths in China. Chi-square tests were employed to compare the differences between fixed appliances and aligners in problems/difficulties and feelings during the epidemic.

Results: Of the 28,911 posts identified, 4,484 were included in the analysis. The most frequently mentioned themes were appointments (n = 2,621, 58.5%), negative feelings (n = 2,189, 48.8%), and problems/difficulties (n = 1,155, 25.8%). A majority of posts were tweeted in regions with high levels of economic development and population density in eastern China and from February to March. The number of daily posts had a significantly positive correlation with daily new COVID-19 cases/deaths in China (P < 0.05). Compared with clear aligners, patients with fixed appliances reported more problems/difficulties (P < 0.001) and negative feelings (P < 0.001), but fewer positive feelings (P < 0.001).

Conclusions: The analysis of Weibo posts provided a timely understanding of the impact of COVID-19 on orthodontic patients. Delayed appointments were their greatest concern, and negative feelings and untreated orthodontic problems increased during the suspension of dental care services. However, patients with clear aligners reported fewer negative feelings and problems than those with fixed appliances. The findings highlighted the need to consider both treatment- and psychology-related issues of orthodontic patients and how to handle them appropriately during the epidemic.
Potential of Lactic Acid Bacteria Isolated From Different Forages as Silage Inoculants for Improving Fermentation Quality and Aerobic Stability
Authors: Puntillo Melisa , Gaggiotti Mónica , Oteiza Juan Martín , Binetti Ana , Massera Ariel , Vinderola Gabriel
Published: December 2020

We aimed at isolating lactic acid bacteria (LAB) from different plant materials to study their crossed-fermentation capacity in silos and to find strains able to confer enhanced aerobic stability to silage. A total of 129 LAB isolates were obtained from lucerne (alfalfa), maize, sorghum, ryegrass, rice, barley, canola, Gatton panic, Melilotus albus, soy, white clover, wheat, sunflower, oat, and moha. Four Lactiplantibacillus plantarum subsp. plantarum strains (isolated from oat, lucerne, sorghum, or maize) were selected for their growth capacity. Identity (16S sequencing) and diversity (RAPD-PCR) were confirmed. Fermentative capacity (inoculated at 104, 105, 106, 107 CFU/g) was studied in maize silage and their cross-fermentation capacity was assessed in oat, lucerne, sorghum, and maize. Heterofermentative strains with the highest acetic acid production capacity conferred higher aerobic stability to maize silages. Regardless the source of isolation, L. plantarum strains, inoculated at a rate of 106 CFU/g, were effective to produce silage from different plant materials. From more than 100 isolates obtained, the application of a succession of experiments allowed us to narrow down the number of potential candidates of silage inoculants to two strains. Based on the studies made, L. plantarum LpM15 and Limosilactobacillus fermentum LfM1 showed potential to be used as inoculants, however further studies are needed to determine their performance when inoculated together. The former because it positively influenced different quality parameters in oat, lucerne, sorghum, and maize silage, and the latter because of its capacity to confer enhanced aerobic stability to maize silage. The rest of the strains constitute a valuable collection of autochthonous strains that will be further studied in the future for new applications in animal or human foods.
Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis
Authors: Putra Marson , Puttachary Sreekanth , Liu Guanghao , Lee Gloria , Thippeswamy Thimmasettappa
Published: December 2020

Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation offynortauappears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO (fyn−/−), tau KO (tau−/−), double knockout (DKO) (fyn−/−/tau−/−), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of thetau−/−and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.
The Relationship Between Penumbral Tissue and Blood-Brain Barrier Disruption in Acute Stroke Patients Presenting in an Extended Time Window
Authors: Heidari Parisa , Blayney Sarah , Butler Jarrhett , Hitomi Emi , Luby Marie , Leigh Richard
Published: December 2020

Background: Penumbral brain tissue identified with multimodal imaging can be salvaged with reperfusion in an extended time window. The risk of severe hemorrhagic complications after reperfusion therapy increases with worsening disruption of the blood-brain barrier (BBB). The relationship between penumbral tissue and BBB disruption has not been previously studied.

Methods: Stroke patients presenting in an extended time window without a large vessel occlusion who underwent diffusion-perfusion MRI within 24 h of last-seen-normal were included. The volume of penumbral tissue was calculated using mismatch on MRI. Mean permeability derangement (MPD) of the BBB was measured within the ischemic lesion. A target profile (TP) for treatment was defined based on the EXTEND trial.

Results: 222 patients were included with a median age of 73 and 55% women. The median NIHSS was 6, the mean core volume was 14 ml, the mean ischemic volume was 47 mL and the mean mismatch volume was 33 mL. Higher MPD was significantly associated with less mismatch volume (p = 0.001). A target profile was associated with lower MPD (OR 0.97; CI 0.96:0.99; p < 0.001). Of the 105 patients who had a TP, 31 (30%) had a MPD > 20% suggesting an increased risk of hemorrhage. Thus, 33% (74/222) of patients had a favorable profile for benefit and safety.

Conclusions: Patients presenting in an extended time window with a favorable penumbral profile for treatment have less severe BBB disruption. Up to a third of patients who currently go untreated could be considered for enrollment in a clinical trial of thrombolysis in an extended time window.
Pre-operative Neurocognitive Function Was More Susceptible to Decline in Isocitrate Dehydrogenase Wild-Type Subgroups of Lower-Grade Glioma Patients
Authors: Zhang Zhe , Jin Zeping , Yang Xiaojie , Zhang Liang , Zhang Yang , Liu Dayuan , Chi Xiaohan , Hao Shuyu , Feng Jie , Ji Nan
Published: December 2020

Background: Neuropsychological deficits frequently occur in diffuse lower-grade glioma (DLGG) patients, but their relationship with molecular subgroups based on the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) is unclear.

Methods: All patients enrolled for this study were divided into different subgroups according to the molecular-integrated 2016 CNS WHO and morphology-centric 2007 CNS WHO to compare their neurocognitive function (NCF) dysfunction. Univariate and multivariate analyses were used to assess the independent factors for NCF decline. The performance of NCF changes for discrimination of IDH and 1p19q status was evaluated by receiver operating characteristic (ROC).

Results: There was no significant difference in the clinical characteristics among the molecular and morphologic subgroups. In the molecular subgroups, significant differences in NCF alterations were found in terms of attention function, working memory and executive function in grade II glioma patients; in addition to these changes in NCF, memory function and abstract thinking were also significantly different in grade III glioma patients. The pairwise comparison further confirmed that patients with astrocytoma (A)/anaplastic astrocytoma (AA) with isocitrate dehydrogenase wild-type (IDHwt) glioma were more susceptible to severe cognitive decline in terms of the NCF performance described above. For the morphologic subgroups, only working memory was significantly different in grade III glioma patients. The distribution proportion was significantly different among each subgroup of DLGG (grade II, P = 0.001; grade III, P = 0.002). The proportion of extensive NCF decline (≥5 tests) was 4, 12, and 50% in the IDH mutant oligodendroglioma (IDHm-O), IDHm-A, and IDHwt-A subgroups, and this proportion was 33, 60, and 93% in the IDHm-AO, IDHm-AA, and IDHwt-AA subgroups, respectively. In multivariate regression analysis, molecular types were independent factors for NCF alterations after adjusted the factors of tumor and demographics (p < 0.05). ROC curves suggested combined NCF tests model showed an advantage in the differentiation of IDH status.

Conclusions: NCF alteration is closely related to molecular-integrated subgroups with varying degrees and frequencies in DLGG. Patients with IDHwt gliomas are more susceptible to suffer from severe and extensive NCF decline than other subgroups.
Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?
Authors: Negron Austin , Stüve Olaf , Forsthuber Thomas G.
Published: December 2020

While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.
PASS: A Multimodal Database of Physical Activity and Stress for Mobile Passive Body/ Brain-Computer Interface Research
Authors: Parent Mark , Albuquerque Isabela , Tiwari Abhishek , Cassani Raymundo , Gagnon Jean-François , Lafond Daniel , Tremblay Sébastien , Falk Tiago H.
Published: December 2020

With the burgeoning of wearable devices and passive body/brain-computer interfaces (B/BCIs), automated stress monitoring in everyday settings has gained significant attention recently, with applications ranging from serious games to clinical monitoring. With mobile users, however, challenges arise due to other overlapping (and potentially confounding) physiological responses (e.g., due to physical activity) that may mask the effects of stress, as well as movement artifacts that can be introduced in the measured signals. For example, the classical increase in heart rate can no longer be attributed solely to stress and could be caused by the activity itself. This makes the development of mobile passive B/BCIs challenging. In this paper, we introduce PASS, a multimodal database ofPhysicalActivity andStresScollected from 48 participants. Participants performed tasks of varying stress levels at three different activity levels and provided quantitative ratings of their perceived stress and fatigue levels. To manipulate stress, two video games (i.e., a calm exploration game and a survival game) were used. Peripheral physical activity (electrocardiography, electrodermal activity, breathing, skin temperature) as well as cerebral activity (electroencephalography) were measured throughout the experiment. A complete description of the experimental protocol is provided and preliminary analyses are performed to investigate the physiological reactions to stress in the presence of physical activity. The PASS database, including raw data and subjective ratings has been made available to the research community athttp://musaelab.ca/pass-database/. It is hoped that this database will help advance mobile passive B/BCIs for use in everyday settings.
Iron Metabolism and Ferroptosis in Epilepsy
Authors: Chen Shuang , Chen Yongmin , Zhang Yukang , Kuang Xi , Liu Yan , Guo Meiwen , Ma Lin , Zhang Daqi , Li Qifu
Published: December 2020

Epilepsy is a disease characterized by recurrent, episodic, and transient central nervous system (CNS) dysfunction resulting from an excessive synchronous discharge of brain neurons. It is characterized by diverse etiology, complex pathogenesis, and difficult treatment. In addition, most epileptic patients exhibit social cognitive impairment and psychological impairment. Iron is an essential trace element for human growth and development and is also involved in a variety of redox reactions in organisms. However, abnormal iron metabolism is associated with several neurological disorders, including hemorrhagic post-stroke epilepsy and post-traumatic epilepsy (PTE). Moreover, ferroptosis is also considered a new form of regulation of cell death, which is attributed to severe lipid peroxidation caused by the production of reactive oxygen species (ROS) and iron overload found in various neurological diseases, including epilepsy. Therefore, this review summarizes the study on iron metabolism and ferroptosis in epilepsy, in order to elucidate the correlation between iron and epilepsy. It also provides a novel method for the treatment, prevention, and research of epilepsy, to control epileptic seizures and reduce nerve injury after the epileptic seizure.
Cow's Milk and Dairy Consumption: Is There Now Consensus for Cardiometabolic Health?
Authors: Poppitt Sally D.
Published: December 2020

Cow's milk and dairy products derived from this complex food source have long been proposed as beneficial to human health, yet underlying clinical evidence of direct benefit continues to raise controversy. Limited evidence supports positive cardiometabolic effects of a number of dairy macro- and micronutrient components including whey protein and casein, unsaturated fats, milk fat globule membrane (MFGM) and polar phospholipids, vitamin D and calcium, in addition to non-bovine components including bacterial and yeast probiotics. More controversial remain lipid components trans fats, including trans vaccenic acid, trans palmitoleic acid, and conjugated cis trans linoleic acid (CLA), plus medium-chain and odd-chain dairy fats. New evidence is rapidly identifying multiple pathways by which these dairy nutrients may effect health. Processing, including fermentation and homogenization, may also have positive effects. Conversely, the high saturated fat content of dairy has long raised concern, aligned with international guidelines to minimize dietary intake of animal-origin saturated fatty acids (SFA) to achieve better cardiometabolic health. However, led in part by observational studies and meta-analyses showing dairy to have no or even an inverse association with cardiometabolic health, evidence from randomized controlled trials (RCTs) has been scrutinized over the last 5 years, and focus on low-fat dairy has been challenged. Recent evidence supports the hypothesis that adverse effects of SFAs on metabolic health may be ameliorated when these fats are consumed within a complex matrix such as milk, cheese or yogurt, and that dairy food categories may influence outcomes as much as total fat content. For example, yogurt and high-fat, high-SFA cheese have a negative association with risk of type 2 diabetes (T2D) in many, not all, published trials. However, large sample dairy RCTs of long duration with CVD or T2D incidence as primary endpoints are lacking. This is a clear research gap, with these clinical studies required if a causative link between dairy and improved cardiometabolic health is to be confirmed and in turn promoted through dietary guidelines. Current advisories from national guidance groups such as American Heart Association (AHA) and European Society of Cardiology (ESC) continue to promote consumption of low-fat dairy products, whilst liquid milk and yogurt remain part of nutrition guidelines from joint American Diabetes Association (ADA)/European Association for Study of Diabetes (EASD) reports, and as part of a “no-one-size-fits-all” answer to diet and T2D by the ADA in their most recent 2019 Consensus Report.
Repurposing Individualized Nutritional Intervention as a Therapeutic Component to Prevent the Adverse Effects of Radiotherapy in Patients With Cervical Cancer
Authors: Medina-Jiménez Ana Karen , Monroy-Torres Rebeca
Published: December 2020

Worldwide, cervical cancer was the fourth leading cause of cancer death among women, while in Mexico was the second cause (5.28%). Cancer patients receiving chemotherapy and radiotherapy have a high risk of malnutrition secondary to the disease and treatment, affects the patient’s overall, with adverse effects on gastrointestinal symptoms. These use affects the medical therapy. The aim of the present study was to evaluate the benefits on individualized nutritional therapy on decrease weight loss and gastrointestinal adverse effects and to consider these outcomes in pharmacology research, especially in repurposing drugs. We conducted a longitudinal design with two comparation groups with medical diagnosis of cervical cancer and received radiotherapy weekly, 1) the intervention group (nutritional intervention and counseling -INC-) with 20 participants and 2) control group (retrospective cohort -CG-) with 9 participants. Weekly body composition, dietary intake, adverse effects (gastrointestinal symptoms), glucose, hemoglobin, and blood pressure were analyzed during 4 to 5 weeks. Both groups had weight loss weekly (p = 0.013 and p = 0.043 respectively) but the CG vs INC presented loss fat-free mass ≥500g in 67 and of 37% respectively. By the end of the intervention a 25% of the INC group had <10 g/dL of hemoglobin vs 60% for the CG. To compare the dietary intake of vitamins (A and folic acid), fiber (p = 0.006), iron (p = 0.03) and energy (mainly carbohydrates) (p = 0.04) were according to the recommendations in INC group (p>0.05). The number needed to treat was 4 (95% CI, 2 to 13). The nutritional intervention and counseling weekly during radiotherapy in cervical cancer to maintain/improve muscle mass, hemoglobin, and dietary intake above 70% of the recommendations for INC group compared to the evidence. Adequate nutritional status was maintained and decrease the rate of complications, mainly gastrointestinal symptoms, in INC group. The efficacy of drug repurposing can improve through individualized nutritional therapy for preventing adverse effects of radiotherapy in patients with cervical cancer.
The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives
Authors: Wang Wenjun , Bai Ling , Li Wei , Cui Jiuwei
Published: December 2020

Lipid metabolism reprograming, as a hallmark of malignancy, has received renewed interest in recent years in such areas as energy sources, cell membrane components, and signaling molecules involved in the rapid tumor growth and the adaptation to the tumor microenvironment. Lipid metabolism deregulation in cancer involves multiple aspects, including an increased lipid uptake, endogenous de novo fatty acid synthesis, fatty acid oxidation, and cholesterol accumulation, thereby promoting tumor growth and progression. Recent advances in the understanding of specific metabolic alterations in cancer reveal novel pathogenesis mechanisms and a growing number of drugs targeting lipid metabolism have been applied in anti-tumor therapy. Thus, this review discusses the lipid metabolic landscape of cancers and the interplay with oncogenic signaling, and summarizes potential therapeutic targets to improve the therapeutic efficiency in cancer patients, in order to provide more reference and thinking for the treatment of lipid metabolism of cancer patients.
The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer
Authors: Shi Yi , Riese David J. , Shen Jianzhong
Published: December 2020

Chemokines are a family of small, secreted cytokines which regulate a variety of cell functions. The C-X-C motif chemokine ligand 12 (CXCL12) binds to C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7). The interaction of CXCL12 and its receptors subsequently induces downstream signaling pathways with broad effects on chemotaxis, cell proliferation, migration, and gene expression. Accumulating evidence suggests that the CXCL12/CXCR4/CXCR7 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, and tumor microenvironment. In addition, this chemokine axis promotes chemoresistance in cancer therapy via complex crosstalk with other pathways. Multiple small molecules targeting CXCR4/CXCR7 have been developed and used for preclinical and clinical cancer treatment. In this review, we describe the roles of the CXCL12/CXCR4/CXCR7 axis in cancer progression and summarize strategies to develop novel targeted cancer therapies.
Taohong Siwu Decoction Ameliorates Ischemic Stroke Injury Via Suppressing Pyroptosis
Authors: Wang Mengmeng , Liu Zhuqing , Hu Shoushan , Duan Xianchun , Zhang Yanyan , Peng Can , Peng Daiyin , Han Lan
Published: December 2020

Objective: Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis, and it has a good therapeutic effect on ischemic stroke. We sought to explore the therapeutic effects of THSWD on pyroptosis in rats with middle cerebral artery occlusion-reperfusion (MCAO/R).

Methods: MCAO/R model of rats were established by suture-occluded method. MCAO/R rats were randomly divided into five groups, which were model group, nimodipine group, THSWD high, medium and low dose group (18, 9, and 4.5 g/kg, respectively), rats of sham group without thread embolus. All rats were treated by intragastric administration for 7 days. We detected the level of inflammatory factors. NLRP3 and Caspase-1 were detected by immunofluorescence. Western blot was used to detect NLRP3, Caspase-1, ASC, and GSDMD in penumbra. Also, the expression of TXNIP, HMGB1, toll-like receptors (TLR4), NF-κB, and MAPK were detected.

Results: THSWD treatment improved the behavioral function and brain pathological damage. These results showed that the levels of TNF-α, TGF-β, IL-2, IL-6, IL-1β, and IL-18 were significantly reduced in THSWD treatment groups. THSWD could significantly decrease the expression levels of NLRP3, Caspase-1, Caspase-1 p10, ASC, TXNIP, GSDMD, HMGB1, TLR4/NFκB, p38 MAPK, and JNK in penumbra.

Conclusion: Our results showed that THSWD could reduce the activation level of NLRP3 inflammatory corpuscle, down-regulate GSDMD, and inhibit pyroptosis in MCAO/R rats. These may be affected by inhibiting HMGB1/TLR4/NFκB, MAPK signaling pathways.
Clinical Relevance of the Anti-inflammatory Effects of Roflumilast on Human Bronchus: Potentiation by a Long-Acting Beta-2-Agonist
Authors: Salvator Hélène , Buenestado Amparo , Brollo Marion , Naline Emmanuel , Victoni Tatiana , Longchamp Elisabeth , Tenor Hermann , Grassin-Delyle Stanislas , Devillier Philippe
Published: December 2020

Background: Roflumilast is an option for treating patients with severe COPD and frequent exacerbations despite optimal therapy with inhaled drugs. The present study focused on whether the phosphodiesterase (PDE) 4 inhibitor roflumilast and its active metabolite roflumilast N-oxide affect the release of tumor necrosis factor (TNF)-α and chemokines by lipopolysaccharide (LPS)-stimulated human bronchial explants. We also investigated the interactions between roflumilast, roflumilast N-oxide and the β2-agonist formoterol with regard to cytokine release by the bronchial preparations.

Methods: Bronchial explants from resected lungs were incubated with roflumilast, roflumilast N-oxide and/or formoterol and then stimulated with LPS. An ELISA was used to measure levels of TNF-α and chemokines in the culture supernatants.

Results: At a clinically relevant concentration (1 nM), roflumilast N-oxide and roflumilast consistently reduced the release of TNF-α, CCL2, CCL3, CCL4, CCL5 and CXCL9 (but not CXCL1, CXCL5, CXCL8 and IL-6) from human bronchial explants. Formoterol alone decreased the release of TNF-α, CCL2, and CCL3. The combination of formoterol with roflumilast (1 nM) was more potent than roflumilast alone for inhibiting the LPS-induced release of TNF-α, CCL2, CCL3, CCL4, and CXCL9 by the bronchial explants.

Conclusions: At a clinically relevant concentration, roflumilast N-oxide and its parent compound, roflumilast, reduced the LPS-induced production of TNF-α and chemokines involved in monocyte and T-cell recruitment but did not alter the release of chemokines involved in neutrophil recruitment. The combination of formoterol with roflumilast enhanced the individual drugs’ anti-inflammatory effects.
Panacis Quinquefolii Radix: A Review of the Botany, Phytochemistry, Quality Control, Pharmacology, Toxicology and Industrial Applications Research Progress
Authors: Yang Liu , Hou Ajiao , Zhang Jiaxu , Wang Song , Man Wenjing , Yu Huan , Zheng Senwang , Wang Xuejiao , Liu Songtao , Jiang Hai
Published: December 2020

On January 2, 2020, The National Health Commission and the State Administration for Market Regulation listed Panacis Quinquefolii Radix (PQR) as a medicinal and food homologous product. PQR is the dry root of Panax quinquefolium L., which has the functions of replenishing qi and nourishing Yin, clearing heat and producing body fluid. It is often used for qi deficiency and Yin deficiency, heat exhaustion, asthma and phlegm, dry mouth and pharynx. PQR is sweet, slightly bitter and cool in nature, and enter the heart, lung and kidney meridian exerts the remedial and hygienical effect. At present, active components such as saponins, flavonoids, fatty acids, polyalkynes, volatile oils and other nutrients such as amino acids, carbohydrates, vitamins and trace elements have been isolated from PQR. Modern pharmacological studies have shown that PQR has the effects of hypoglycemic, antihypertensive, anti fatigue, anti-oxidation, anti-tumor, immunomodulatory, neuroprotective and so on. In addition, PQR is recognized as a health care product to strengthen the body and dispel diseases. It is not only the raw material of Traditional Chinese medicine preparations, but also the treasure of dietary therapy and herbal cuisine. This study not only reviewed the botany, phytochemistry and pharmacology of PQR, but also summarized its quality control, toxicity and industrial applications for the first time. This paper not only summarizes the development status of PQR, but also analyzes the shortcomings of the current research on PQR, and puts forward the corresponding solutions, in order to provide reference for future scholars to study PQR.
Identification of Pathways and Key Genes in Venous Remodeling After Arteriovenous Fistula by Bioinformatics Analysis
Authors: Jie Kong , Feng Wang , Boxiang Zhao , Maofeng Gong , Jianbin Zhang , Zhaoxuan Lu , Yangyi Zhou , Liang Chen , Haobo Su , Wensheng Lou , Guoping Chen , Jianping Gu , Xu He , Jianyan Wen
Published: December 2020

The arteriovenous fistula (AVF) is the first choice for vascular access for hemodialysis of renal failure patients. Venous remodeling after exposure to high fistula flow is important for AVF to mature but the mechanism underlying remodeling is still unknown. The objective of this study is to identify the molecular mechanisms that contribute to venous remodeling after AVF. To screen and identify the differentially expressed genes (DEGs) that may involve venous remodeling after AVF, we used bioinformatics to download the public microarray data (GSE39488) from the Gene Expression Omnibus (GEO) and screen for DEGs. We then performed gene ontology (GO) function analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA) for the functional annotation of DEGs. The protein-protein interaction (PPI) network was constructed and the hub genes were carried out. Finally, we harvested 12 normal vein samples and 12 AVF vein samples which were used to confirm the expressions of the hub genes by immunohistochemistry. A total of 45 DEGs were detected, including 32 upregulated and 13 downregulated DEGs. The biological process (BP) of the GO analysis were enriched in the extrinsic apoptotic signaling pathway, cGMP-mediated pathway signaling, and molting cycle. The KEGG pathway analysis showed that the upregulated DEGs were enriched in glycosaminoglycan biosynthesis and purine metabolism, while the downregulated DEGs were mainly enriched in pathways of glycosaminoglycan biosynthesis, antifolate resistance, and ABC transporters. The GSEA analysis result showed that the top three involved pathways were oxidative phosphorylation, TNFA signaling via NF-K B, and the inflammatory response. The PPI was constructed and the hub genes found through the method of DMNC showed that INHBA and NR4A2 might play an important role in venous remodeling after AVF. The integrated optical density (DOI) examined by immunohistochemistry staining showed that the expression of both INHBA and NR4A2 increased in AVF compared to the control group. Our research contributes to the understanding of the molecular mechanism of venous remodeling after exposure to high fistula flow, which may be useful in treating AVF failure.
Genome-Wide Association Study to Identify Candidate Loci for Biomass Formation Under Water Deficit in Perennial Ryegrass
Authors: Jaškūnė Kristina , Aleliūnas Andrius , Statkevičiūtė Gražina , Kemešytė Vilma , Studer Bruno , Yates Steven
Published: December 2020

Global warming is predicted to impact many agricultural areas, which will suffer from reduced water availability. Due to precipitation changes, mild summer droughts are expected to become more frequent, even in temperate regions. For perennial ryegrass (Lolium perenneL.), an important forage grass of thePoaceaefamily, leaf growth is a crucial factor determining biomass accumulation and hence forage yield. Although leaf elongation has been shown to be temperature-dependent under normal conditions, the genetic regulation of leaf growth under water deficit in perennial ryegrass is poorly understood. Herein, we evaluated the response to water deprivation in a diverse panel of perennial ryegrass genotypes, employing a high-precision phenotyping platform. The study revealed phenotypic variation for growth-related traits and significant (P< 0.05) differences in leaf growth under normal conditions within the subgroups of turf and forage type cultivars. The phenotypic data was combined with genotypic variants identified using genotyping-by-sequencing to conduct a genome-wide association study (GWAS). Using GWAS, we identified DNA polymorphisms significantly associated with leaf growth reduction under water deprivation. These polymorphisms were adjacent to genes predicted to encode for phytochrome B and a MYB41 transcription factor. The result obtained in the present study will increase our understanding on the complex molecular mechanisms involved in plant growth under water deficit. Moreover, the single nucleotide polymorphism (SNP) markers identified will serve as a valuable resource in future breeding programs to select for enhanced biomass formation under mild summer drought conditions.