bluuebunny/crossref_metadata_2025 huggingface dataset:
ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways
Authors: de Almeida Arthur José Pontes Oliveira , de Oliveira Júlio César Pinheiro Lúcio , da Silva Pontes Larisse Virgolino , de Souza Júnior Javanyr Frederico , Gonçalves Tays Amanda Felisberto , Dantas Sabine Helena , de Almeida Feitosa Mathania Silva , Silva Antonia Oliveira , de Medeiros Isac Almeida
Published: October 2022

Reactive oxygen species (ROS) are bioproducts of cellular metabolism. There is a range of molecules with oxidizing properties known as ROS. Despite those molecules being implied negatively in aging and numerous diseases, their key role in cellular signaling is evident. ROS control several biological processes such as inflammation, proliferation, and cell death. The redox signaling underlying these cellular events is one characteristic of the new generation of scientists aimed at defining the role of ROS in the cellular environment. The control of redox potential, which includes the balance of the sources of ROS and the antioxidant system, implies an important target for understanding the cells’ fate derived from redox signaling. In this review, we summarized the chemical, the redox balance, the signaling, and the implications of ROS in biological aging.
In Vitro Mechanism of Action of Acanthospermum hispidum in Trypanosoma brucei
Authors: Dofuor Aboagye Kwarteng , Ademolue Temitayo Samson , Kuampah Karen Nana Akua , Ayertey Frederick , Gwira Theresa Manful
Published: October 2022

African trypanosomiasis is a major neglected tropical disease with significant health and economic concerns in sub-Saharan Africa. In the absence of vaccines for African trypanosomiasis, there is a consideration for alternative sources of chemotherapy. Acanthospermum hispidum DC (A. hispidum) is a herbal species of the Asteraceae family that is endowed with rich phytochemicals with unknown mechanisms of antitrypanosomal effects. This study aimed to investigate the cellular mechanisms of antitrypanosomal and antioxidant activities of A. hispidum against Trypanosoma brucei (T. brucei), a causative protozoan species of African trypanosomiasis. Fractions were prepared from the whole plant of A. hispidum through solvent partitioning by employing solvents of varying polarities (hexane, HEX; dichloromethane, DCM; ethyl acetate, EA; aqueous, AQ). The in vitro efficacies and mechanisms of antitrypanosomal activities of A. hispidum were investigated using a panel of cell biological approaches. GC-MS analysis was used to identify the major compounds with a possible contribution to the trypanocidal effects of A. hispidum. A. hispidum fractions displayed significant antitrypanosomal activities in terms of half-maximal effective concentrations (EC50) and selectivity indices (SI) (AH-HEX, EC50 = 2.4 μg/mL, SI = 35.1; AH-DCM, EC50 = 2.2 μg/mL, SI = 38.3; AH-EA, EC50 = 1.0 μg/mL, SI = 92.8; AH-AQ, EC50 = 2.0 μg/mL, SI = 43.8). Fluorescence microscopic analysis showed that at their EC50 values, the fractions of A. hispidum altered the cell morphology as well as the organization of the mitochondria, nucleus, and kinetoplast in T. brucei. At their maximum tested concentrations, the prepared fractions exhibited antioxidant absorbance intensities comparable to the reference antioxidant, Trolox, in contrast to the oxidant intensity of an animal antitrypanosomal drug, diminazene (Trolox, 0.11 A; diminazene, 0.65 A; AH-HEX, 0.20 A, AH-DCM, 0.20 A, AH-EA, 0.13 A, AH-AQ, 0.22 A). GC-MS analysis of the various fractions identified major compounds assignable to the group of alkaloids and esters or amides of aliphatic acids. The results provide useful pharmacological insights into the chemotherapeutic potential of A. hispidum toward drug discovery for African trypanosomiasis.
Blood Reference Intervals for Antillean Manatees (Trichechus manatus manatus) from Puerto Rico
Authors: Mignucci-Giannoni Antonio A. , Alsina-Guerrero Mayela M.
Published: October 2022

Antillean manatees (Trichechus manatus manatus) are endangered throughout the southwestern Gulf of Mexico, the Caribbean coast of Central and South America, the Greater Antilles, and the northeastern coast of South America to Brazil. Establishing blood reference intervals is essential as a tool in classifying health status, diagnosing, establishing treatment regimens, and monitoring the progress of a disease in rescued manatees. We collected blood samples from 44 free-ranging and 26 rescued manatees from Puerto Rico between 1992 and 2020 for hematology and blood chemistry analysis. We obtained values for white blood cell count and red blood cell count, hemoglobin, hematocrit, platelet, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, and red cell distribution width. A manual leukocyte differential allowed for the evaluation of different cell types. In addition, we performed a comprehensive metabolic panel on serum samples. These analytes were grouped based on six physiologic processes: liver-associated enzymes and pigments; muscle-associated enzymes; kidney-associated compounds and products; sugars, lipids, and pancreatic-associated enzymes; proteins; and electrolytes. For every parameter, summary statistics of values were calculated on all the samples. Reference ranges were determined as ±1 standard deviation around the mean. An unpaired two-sample T-test was done comparing males versus females and adults versus calves for any significant differences (

p
≤
0.05

). We establish the reference intervals of hematology and blood chemistry for the population of Antillean manatees in Puerto Rico and compare them with those established for manatees from Belize, Brazil, Florida, Guyana, and Mexico.
ZNF521 Is Correlated with Tumor Immune Cell Infiltration and Act as a Valuable Prognostic Biomarker in Gastric Cancer
Authors: Li Li , Liu Zheng-Hui , Wang Hui-Ju , Wang Lei , Ru Guo-Qing , Wang Yuan-Yu
Published: October 2022

Aim. To explore the correlations between the expression of zinc finger protein 521 (ZNF521) with immune invasion and prognosis of gastric cancer. Methods. Expression of ZNF521 was examined by immunohistochemistry in gastric cancer cases. Kaplan–Meier plotter was used to determine the relationships between ZNF521 and prognosis. TIMER and GEPIA were used to analyze the correlation between ZNF521 expression and gene markers of immune cell infiltration. Results. The expression of ZNF521 was up-regulated in gastric cancer samples. Kaplan–Meier analysis indicated that higher expression of ZNF521 was associated with poor prognosis. The expression of ZNF521 was correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells in gastric cancer, which also correlated with diverse immune marker sets. Conclusions. ZNF521 is correlated significantly with immune cell infiltration and is a valuable biomarker for prognosis in gastric cancer.
Analysis of Trends in Demographic Distribution of Dental Workforce in the Kingdom of Saudi Arabia
Authors: Alqahtani Abdullah Saad , Alqhtani Nasser Raqe , Gufran Khalid , Aljulayfi Ibrahim Saleh , Alateek Abdulaziz M. , Alotni Soltan Ibrahim , Aljarad Anas J. , Alhamdi Albatool A. , Alotaibi Yasser Khaled
Published: October 2022

Dental professionals are playing an imperative role in the healthcare system. It is important to distribute the dental workforce across the country. Therefore, this study aimed at analyzing the recent distribution of the dental workforce in the Kingdom of Saudi Arabia (KSA) and determining the current dentist-to-population ratio in the KSA. This is a cross-sectional study focused on the dental workforces working in the KSA between 2015 and 2020. Complete data of dentists working in the KSA with different professional ranks were obtained. The data were stratified by gender, professional rank (Saudi and non-Saudi), area of working (13 provinces in the KSA), and sector of working (public and private). A complete list of all dental universities was obtained to identify the increasing number of dental institutes at this current moment. In addition, the dentist-to-population ratio was also evaluated based on the current inhabitant in the KSA and the total dental surgeons. There are a total of 27181 dental surgeons and 8022 dental auxiliaries registered in different specialties as of 2020. Saudi citizens are holding the majority of the posts in both dentist and dental auxiliary categories. The percentage of males and female is slightly higher in dentists and dental auxiliaries, respectively. It also indicated that where most of the dental personnel work in the private sector, dental auxiliaries work in the public sector. Moreover, the highest number of dental workforces is identified in the Riyadh region among all the 13 provinces. Based on the databases, the current dentist-to-population ratio is 1 : 1288.16. In conclusion, the number of dental professionals is ample; however, rural areas lack specialists. Saudi dentists are progressively replacing foreign dentists in different professional ranks working in the KSA.
Fibroblast Common Serum Response Signature-Related Classification Affects the Tumour Microenvironment and Predicts Prognosis in Bladder Cancer
Authors: Yang Xiangchou , Zhou Yangyang , Huang Linjing , Lin Shang , Ye Haihao , Shan Yujuan
Published: October 2022

Abnormal oncogenic signatures provide important clues regarding cancer prognosis and treatment. We analysed the variations in 189 oncogenic signature gene sets between normal and tumourous tissues from The Cancer Genome Atlas (TCGA) and found that the “CSR_LATE_UP” signature was the most upregulated oncogenic signature gene set in bladder cancer. Next, we developed a common serum response (CSR) risk score (CRS) model based on fibroblast CSR genes and systematically analysed the correlations of these genes or the CRSs with survival, previously reported molecular subtypes, clinicopathological features, cancer signalling pathways, chemotherapeutic responses, and the tumour microenvironment using TCGA and validation cohorts. The CRS could predict the malignant phenotype, chemotherapeutic efficacy, immune invasion, and disease prognosis. Inflammatory signalling pathways (e.g., inflammatory response, TNFA signalling via NFƘB, IFNα response, and IL2-STAT5 signalling) were markedly upregulated in patients with high CRS. Notably, the CSR-related gene ANLN was positively correlated with CD8+ immune cell infiltration, PD-L1 expression, and sensitivity to PD-L1 inhibitors and could thus provide guidance for clinical immunotherapy. This study highlights the crucial role of the CSR signature in bladder cancer and provides a CRS model for accurate predictions of the disease prognosis and chemotherapy and immunotherapy responses.
Frequency of CYP2B6 Alleles in Major Iranian Ethnicities, Affecting Response to Efavirenz
Authors: Mardi Parham , Tavakoli-Far Bahareh , Sheibani Nia Samira , Jazayeri Roshanak , Houshmand Massoud
Published: October 2022

Introduction. Efavirenz is an antihuman immunodeficiency virus (HIV) drug metabolized by cytochrome P450 2B6 (CYP2B6) enzyme. Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. Polymorphisms of this gene play a crucial role in the metabolism of drugs such as Efavirenz. This study aims to evaluate the frequency of three clinically significant CYP2B6 polymorphisms (CYP2B6

∗

6 (516G > T), CYP2B6

∗

4 (785A > G), and CYP2B6

∗

5 (1459C > T)) in three major Iranian ethnicities. Methods. One hundred forty-seven participants from three main Iranian ethnicities were included in this study. After DNA extraction, CYP2B6

∗

6 (516G > T), CYP2B6

∗

4 (785A > G), and CYP2B6

∗

5 (1459C > T) were genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Results. The frequency of the mutated allele in the Iranian population for CYP2B6

∗

6 (516G > T) was 41.50 (95% CI: 35.81, 47.36), which was significantly lower than in Kurds (59.62, 95% CI: 45.10, 72.99). Similarly, Kurds had a higher frequency of mutated allele of CYP2B6

∗

5 (1459C > T) (46.15%, 95% CI: 32.23, 60.53) than in Iranians (24.49%, 95% CI: 19.68, 29.82). The frequency of A and G alleles of CYP2B6

∗

4 (785A > G) was 62.59% (95% CI: 56.78, 68.13) and 37.41 (95% CI: 31.87, 43.22), respectively. Conclusion. Kurds are at higher risk of adverse drug reactions (ADRs) and insufficient anti-HIV response compared to other Iranians.
Kai-Xin-San Protects Depression Mice Against CORT-Induced Neuronal Injury by Inhibiting Microglia Activation and Oxidative Stress
Authors: Bai Guiqin , Jing Shangwen , Cao Huimin , Qiao Yiqi , Chen Gongchan , Duan Lining , Yang Yuna , Li Min , Li Weirong , Chang Xiang , Yang Cong , Wang Qi
Published: October 2022

Objective. Traditional Chinese medicine formula Kai-Xin-San (KXS) is used to treat psychiatric disorders, especially in anxiety and depression. However, the precise molecular mechanism of action remains unclear. In this study, we investigated the antidepressant effect of KXS on inhibiting inflammation and oxidative stress in corticosterone (CORT)-induced depression. Methods. The therapeutic efficacy of KXS was evaluated in a mouse model of depression induced by CORT. Behavioral tests were conducted to evaluate the effectiveness of KXS in treating depressive-like behavior. Nissl staining and β-galactosidase staining were used to assess the effects of KXS on neuronal injury in depressed mice. To screen key potential therapeutic targets of KXS, transcriptome sequences and data analysis were performed. Then, Iba1 immunofluorescence staining and their relative inflammatory factors mRNA expression were conducted to assess the effect of KXS in inhibiting microglial inflammation activation response. Concurrently, the measurement of 4-Hydroxynonenal (4-HNE) immunohistochemistry staining, malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were performed to evaluate the effect of KXS on anti-oxidative stress of depression in vivo. Besides, nitric oxide (NO), relative inflammatory factors mRNA expression, JC-1 staining, and ROS were used to evaluate the effect of KXS by lipopolysaccharide (LPS)/interferon-gamma (IFNγ)-induced BV2 cells. Results. KXS significantly relieved the depressive-like symptoms induced by CORT, as well as ameliorating the neuronal damage, which decreased microglia inflammatory activation response of IL-1β, IL-6, and tumor necrosis factor α (TNFα) in vivo or in vitro too. Transcriptome Sequencing and Data Analysis showed that KXS mainly by regulating immune system and transduction pathways decreased CORT-induced depression in mice. And showed that there were 19 Principal components and 10 genes in the main regulatory position with the strongest correlation in depression mice. Meanwhile, KXS effectively decreased senescence, the expression of 4-HNE, MDA content, and the production of ROS, while increasing the SOD activity in CORT-induced mice. Besides, KXS significantly reversed the mitochondrial membrane potential loss and excessive ROS production in LPS/IFNγ-induced BV2 cells. Conclusion. Our research suggested that KXS might protect depressed mice against CORT-induced neuronal injury by inhibiting microglia activation and oxidative stress.
Effects of Lycium Barbarum Polysaccharides on the Metabolism of Dendritic Cells: An In Vitro Study
Authors: Zhang Baochen , Chen Kengyu , Liu Li , Li Xiuyun , Wu Enhui , Han Liang , Shi Zhongfeng , Deng Xiangliang
Published: October 2022

Targeting dendritic cells (DCs) metabolism-related pathways and in-situ activation of DCs have become a new trend in DC-based immunotherapy. Studies have shown that Lycium barbarum polysaccharide can promote DCs function. This study is aimed at exploring the mechanism of LBP affecting DCs function from the perspective of metabolomics. MTT method was used to detect the activity of DC2.4 cells. ELISA kit method was used to detect the contents of IL-6, IL-12, and TNF-α in the supernatant of cells. Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to detect general changes in DC2.4 cell metabolism. And then multidistance covariates and bioinformatics, partial least squares-discriminant analysis (PLS-DA) were used to analyze differential metabolites. Finally, metabolic pathway analysis was performed by MetaboAnalyst v5.0. The results showed that LBP had no significant inhibitory effect on the activity of DC2.4 cells at the experimental dose of 50-200 μg/ml. LBP (100 μg/ml) could significantly stimulate DC2.4 cells to secrete IL-6, TNF-α, and IL-12. Moreover, 20 differential metabolites could be identified, including betaine, hypoxanthine, L-carnitine, 5’-methylthioadenosine, orotic acid, sphingomyelin, and L-glutamine. These metabolites were involved 28 metabolic pathways and the top 5 metabolic pathways were aspartate metabolism, pyrimidine metabolism, phenylacetate metabolism, methionine metabolism, and fatty acid metabolism. These results suggest that the effect of LBP on DCs function is related to the regulation of cell metabolism.
Analysis of Individuals’ Acceptance and Influencing Factors for Young Users of Autonomous Vehicles Using the Hybrid Choice Model
Authors: Wan Ming , Liu Qingmei , Yan Lixin , Peng Liqun , Yu Xujin , Wan Ping
Published: October 2022

Autonomous vehicles (AVs) are a vital direction for intelligent transportation; nevertheless, the current research is insufficient, and the aspects and mechanisms that influence individuals’ adoption of AVs require additional investigation. This study examines the acceptance of the popularity of AVs from three perspectives: personal-psychological attributes, travel characteristics attributes, and latent variables. The descriptive statistical analysis revealed that the acceptance rate of AVs was 54.6% based on 304 valid questionnaires received through online questionnaires. And the proportion of the 18∼50 group in the article reached 92.8%; thus, this study takes the young group as the object to investigate the acceptance of AVs. A quantitative analysis of each factor’s impact on the acceptability of AVs was conducted using the hybrid choice model (HCM), which was utilized to observe the link between latent variables. Results from parameter estimates demonstrate that the HCM’s fitting impact when latent factors are taken into account is superior to that when latent variables are not taken into account. When latent variables are taken into account, the associated goodness ratio coefficient rises by 0.2337 to 0.2898, which is greater than the model as a whole. The three factors with the highest impact on AV acceptability among the five latent variables were attitude toward use, sense of use gain, and perceived trust, with matching z-test values of 2.42, 2.44, and 2.12, respectively. The development and marketing of AVs by pertinent businesses and government agencies would benefit greatly from this research as a source of reference.
Identifying Key Risk Factors in Air Traffic Controller Workload by SEIR Model
Authors: Heng Yuming , Wu Minggong , Wen Xiangxi
Published: October 2022

To address the controller workload with the forecast, the capacity of the air traffic management system is effectively enhanced. It should be based on a specific analysis of the controller workload. In the current controller workload studies, there is no clear means to analyze the process of controller workload development propagation. In this paper, we propose a new method for analyzing the factors influencing the controller workload. This method takes into account the influence of various situations in the actual work of controllers and objectively quantifies the complexity of work conditions. A complex network is constructed by treating various factors as nodes and the complexity relationships between these nodes as edges. The complexity network was then tested using the contagion model. The sum of the number of times of infecting other nodes and being infected in the detection result was defined as the infection capacity of the nodes, and the point with the strongest infection capacity was controlled and analyzed. The results show that the point with the strongest infection capacity is the key factor for the development of controller workload generation. In addition, the analysis of the key factors using a backpropagation neural network shows that the prediction of the controller workload can be made by the key factors. It will provide a new effective method to control controller workload and improve air traffic control capability.
The Credit Risk Contagion Mechanism of Financial Guarantee Network: An Application of the SEIR‐Epidemic Model
Authors: Ma Guojian , Ding Juan , Lv Youqing
Published: October 2022

Financing guarantee is an important means and key link to solve the financing difficulties of small‐ and medium‐size enterprises (SMEs). However, while financial guarantees alleviate the financing difficulties of SMEs, the complex guarantee relationships also constitute a new channel for credit risk contagion in the financial guarantee network. In this paper, we construct a model of credit risk contagion process of guarantee network based on SEIR and analyse the equilibrium point and stability of the model. Then, we find the threshold value of risk contagion and further simulate the SEIR model dynamically to analyse the influence of each parameter of the model. The results show that the risk of the financing guarantee network begins to be widely contagious only when risk contagion threshold is greater than 1, and the conversion rate of exposed enterprises, removal rate of infected enterprises, nodal enterprises degree, and risk contagion rate have significant effects on the changes of individual density of susceptible, exposed, infected, and recovered enterprises. Combining the above findings, it is of great theoretical and practical significance to propose relevant countermeasures for credit risk control of financial guarantee network.
Toxicity of Usnic Acid: A Narrative Review
Authors: Croce Nicoletta , Pitaro Michele , Gallo Valentina , Antonini Giovanni
Published: October 2022

Usnic acid (UA) is a dibenzofuran derivative naturally present in lichens, organisms resulting from the symbiosis between a fungus and a cyanobacterium, or an alga. UA shows antimicrobial, antitumor, antioxidant, analgesic, anti-inflammatory as well as UV-protective activities. Its use as pharmacological agent is widely described in traditional medicine, and in the past few years, the product has been marketed as a food supplement for the induction of weight loss. However, the development of severe hepatotoxicity in a limited number of subjects prompted the FDA to issue a warning letter, which led to the withdrawal of the product from the market in November 2001. Data published in literature on UA toxicology, genotoxicity, mutagenesis, and teratogenicity have been reviewed, as well as the case reports of subjects who developed hepatotoxicity following oral administration of UA as a slimming agent. Finally, we reviewed the most recent studies on the topical use of UA, as well as studies aimed at improving UA pharmacologic activity and reducing toxicity. Indeed, advancements in this field of research could open the possibility to reintroduce the use of UA as therapeutical agent.
Coarse-Grained Load Balancing with Traffic-Aware Marking in Data Center Networks
Authors: Huang Ran , Zhang Jingliang , Hu Yuanzhen , Zou Shaojun , Luan Xidao , Hu Jinbin , Ruan Chang , Zhang Tao
Published: October 2022

In the data center environment, meeting the dissimilar requirements of transmission performance for long and short data flows is crucial for guaranteeing the data center service quality. It is well known that optimizing the network transmission performance is the key. Abundant research studies have reported that designing an effective load-balancing scheme can boost the network performance by enhancing the path utilization of multirooted data center networks. Unfortunately, the existing data center load-balancing schemes fail to provide satisfying flow-level transmission performance since they choose to ignore the constant changing path status and blindly assign paths to data flows regardless of their different performance requirements. In order to solve these issues, we propose a data center load-balancing scheme called TAM to meet the performance requirements of long and short flows simultaneously. In detail, TAM leverages the traffic-aware ECN marking mechanism to force long flows to proactively maintain the switch queue length at a low level and release bandwidth to short flows when they compete for the bottleneck link. On the contrary, TAM carries out the coarse-grained routing or rerouting for short and long flows, respectively, in real time by perceiving the path status. In this way, the short flows achieve low delay transmission while the long flows obtain high throughput. The simulation results based on NS2 tests show that TAM achieves up to 60% lower FCTs for short flows and a 40% improvement in goodput for long flows.
A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia
Authors: Zhou Fengbiao , Aroua Nesrine , Liu Yi , Rohde Christian , Cheng Jingdong , Wirth Anna-Katharina , Fijalkowska Daria , Göllner Stefanie , Lotze Michelle , Yun Haiyang , Yu Xiaobing , Pabst Caroline , Sauer Tim , Oellerich Thomas , Serve Hubert , Röllig Christoph , Bornhäuser Martin , Thiede Christian , Baldus Claudia , Frye Michaela , Raffel Simon , Krijgsveld Jeroen , Jeremias Irmela , Beckmann Roland , Trumpp Andreas , Müller-Tidow Carsten
Published: October 2022

The development and regulation of malignant self-renewal remain unresolved issues. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2′-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2′-O-methylation landscape of 94 patients with acute myeloid leukemia (AML) revealed dynamic 2′-O-methylation specifically at exterior sites of ribosomes. The rRNA 2′-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of the 2′-O-methyltransferase fibrillarin (FBL) induced an AML stem cell phenotype and enabled engraftment of non-LSC leukemia cells in NSG mice. Enhanced 2′-O-methylation redirected the ribosome translation program toward amino acid transporter mRNAs enriched in optimal codons and subsequently increased intracellular amino acid levels. Methylation at the single site 18S-guanosine 1447 was instrumental for LSC activity. Collectively, our work demonstrates that dynamic 2′-O-methylation at specific sites on rRNAs shifts translational preferences and controls AML LSC self-renewal.

Significance:

We establish the complete rRNA 2′-O-methylation landscape in human AML. Plasticity of rRNA 2′-O-methylation shifts protein translation toward an LSC phenotype. This dynamic process constitutes a novel concept of how cancers reprogram cell fate and function.

This article is highlighted in the In This Issue feature, p. 247
Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety
Authors: Vitanza Nicholas A. , Wilson Ashley L. , Huang Wenjun , Seidel Kristy , Brown Christopher , Gustafson Joshua A. , Yokoyama Jason K. , Johnson Adam J. , Baxter Blake A. , Koning Ryan W. , Reid Aquene N. , Meechan Michael , Biery Matthew C. , Myers Carrie , Rawlings-Rhea Stephanie D. , Albert Catherine M. , Browd Samuel R. , Hauptman Jason S. , Lee Amy , Ojemann Jeffrey G. , Berens Michael E. , Dun Matthew D. , Foster Jessica B. , Crotty Erin E. , Leary Sarah E.S. , Cole Bonnie L. , Perez Francisco A. , Wright Jason N. , Orentas Rimas J. , Chour Tony , Newell Evan W. , Whiteaker Jeffrey R. , Zhao Lei , Paulovich Amanda G. , Pinto Navin , Gust Juliane , Gardner Rebecca A. , Jensen Michael C. , Park Julie R.
Published: October 2022

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.

Significance:

This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF.

This article is highlighted in the In This Issue feature, p. 1
Impacto de la covid-19 en estudiantes de preparatoria en comunidades rurales, México
Authors: Ruiz-Ramírez Rosalva , García-Cué José Luis , Estrada-Castro Karyme Elizabeth , Zapata-Martelo Emma , Ruiz-Martínez Fortunato
Published: October 2022

(analytical)The educational process shifted from schools to the home for Mexicans as a result of COVID-19. The objective was to analyze the economic, family and academic impact of COVID-19 among students from rural communities attending high school in Sinaloa. The methodology used for the study was the quantitative. The statistical sample size was 222 students from the Universidad Autónoma de Sinaloa, in México, who respond to an online questionnaire. The data was analyzed using descriptive statistics and correlational analysis. The results showed three types of problems: economic issues due to lack of income to buy the technological items required for online learning; family problems, specifically the lack of support provided by parents to help children with distance education; and academic difficulties, because there was little training provided to students on the use of technology. The authors concluded that COVID-19 caused difficulties and highlighted the existence of a digital divide, social inequality and educational lag.
Keywords: Distance education; digital divide; learning difficulties; school dropouts.
Mortality inequalities measured by socioeconomic indicators in Brazil: a scoping review
Authors: Ichihara Maria Yury , Ferreira Andrêa J.F. , Teixeira Camila S. S. , Alves Flávia Jôse O. , Rocha Aline Santos , Diógenes Victor Hugo Dias , Ramos Dandara Oliveira , Pinto Júnior Elzo Pereira , Flores-Ortiz Renzo , Rameh Leila , Costa Lilia Carolina C. da , Gonzaga Marcos Roberto , Lima Everton E. C. , Dundas Ruth , Leyland Alastair , Barreto Maurício L.
Published: October 2022

OBJECTIVE Summarize the literature on the relationship between composite socioeconomic indicators and mortality in different geographical areas of Brazil. METHODS This scoping review included articles published between January 1, 2000, and August 31, 2020, retrieved by means of a bibliographic search carried out in the Medline, Scopus, Web of Science, and Lilacs databases. Studies reporting on the association between composite socioeconomic indicators and all-cause, or specific cause of death in any age group in different geographical areas were selected. The review summarized the measures constructed, their associations with the outcomes, and potential study limitations. RESULTS Of the 77 full texts that met the inclusion criteria, the study reviewed 24. The area level of composite socioeconomic indicators analyzed comprised municipalities (n = 6), districts (n = 5), census tracts (n = 4), state (n = 2), country (n = 2), and other areas (n = 5). Six studies used composite socioeconomic indicators such as the Human Development Index, Gross Domestic Product, and the Gini Index; the remaining 18 papers created their own socioeconomic measures based on sociodemographic and health indicators. Socioeconomic status was inversely associated with higher rates of all-cause mortality, external cause mortality, suicide, homicide, fetal and infant mortality, respiratory and circulatory diseases, stroke, infectious and parasitic diseases, malnutrition, gastroenteritis, and oropharyngeal cancer. Higher mortality rates due to colorectal cancer, leukemia, a general group of neoplasms, traffic accident, and suicide, in turn, were observed in less deprived areas and/or those with more significant socioeconomic development. Underreporting of death and differences in mortality coverage in Brazilian areas were cited as the main limitation. CONCLUSIONS Studies analyzed mortality inequalities in different geographical areas by means of composite socioeconomic indicators, showing that the association directions vary according to the mortality outcome. But studies on all-cause mortality and at the census tract level remain scarce. The results may guide the development of new composite socioeconomic indicators for use in mortality inequality analysis.
Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9
Authors: Bai Congxia , Su Ming , Zhang Yaohua , Lin Yahui , Sun Yingying , Song Li , Xiao Ning , Xu Haochen , Wen Hongyan , Zhang Meng , Ping Jiedan , Liu Jing , Hui Rutai , Li Hao , Chen Jingzhou
Published: October 2022

Background:

Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms.

Methods:

Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay.
Ovgp1
transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein–protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays.

Results:

We found a hypomethylated site at cg20823859 in the promoter region of
OVGP1
and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In
Ovgp1
transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II–induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling.

Conclusions:

Hypomethylation at cg20823859 in the promoter region of
OVGP1
is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.
Temperature Control After In-Hospital Cardiac Arrest: A Randomized Clinical Trial
Authors: Wolfrum Sebastian , Roedl Kevin , Hanebutte Alexia , Pfeifer Rüdiger , Kurowski Volkhard , Riessen Reimer , Daubmann Anne , Braune Stephan , Söffker Gerold , Bibiza-Freiwald Eric , Wegscheider Karl , Schunkert Heribert , Thiele Holger , Kluge Stefan ,   for the Hypothermia After In-Hospital Cardiac Arrest Study Group
Published: October 2022

Background:

This study was conducted to determine the effect of hypothermic temperature control after in-hospital cardiac arrest (IHCA) on mortality and functional outcome as compared with normothermia.

Methods:

An investigator initiated, open-label, blinded-outcome-assessor, multicenter, randomized controlled trial comparing hypothermic temperature control (32-34°C) for 24 h with normothermia after IHCA in 11 hospitals in Germany. The primary endpoint was all-cause mortality after 180 days. Secondary end points included in-hospital mortality and favorable functional outcome using the Cerebral Performance Category scale after 180 days. A Cerebral Performance Category score of 1 or 2 was defined as a favorable functional outcome.

Results:

A total of 1055 patients were screened for eligibility and 249 patients were randomized: 126 were assigned to hypothermic temperature control and 123 to normothermia. The mean age of the cohort was 72.6±10.4 years, 64% (152 of 236) were male, 73% (166 of 227) of cardiac arrests were witnessed, 25% (57 of 231) had an initial shockable rhythm, and time to return of spontaneous circulation was 16.4±10.5 minutes. Target temperature was reached within 4.2±2.8 hours after randomization in the hypothermic group and temperature was controlled for 48 hours at 37.0°±0.9°C in the normothermia group. Mortality by day 180 was 72.5% (87 of 120) in hypothermic temperature control arm, compared with 71.2% (84 of 118) in the normothermia group (relative risk, 1.03 [95% CI, 0.79–1.40];
P
=0.822). In-hospital mortality was 62.5% (75 of 120) in the hypothermic temperature control as compared with 57.6% (68 of 118) in the normothermia group (relative risk, 1.11 [95% CI, 0.86–1.46,
P
=0.443). Favorable functional outcome (Cerebral Performance Category 1 or 2) by day 180 was 22.5% (27 of 120) in the hypothermic temperature control, compared with 23.7% (28 of 118) in the normothermia group (relative risk, 1.04 [95% CI, 0.78–1.44];
P
=0.822). The study was prematurely terminated because of futility.

Conclusions:

Hypothermic temperature control as compared with normothermia did not improve survival nor functional outcome at day 180 in patients presenting with coma after IHCA. The HACA in-hospital trial (Hypothermia After Cardiac Arrest in-hospital) was underpowered and may have failed to detect clinically important differences between hypothermic temperature control and normothermia.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT00457431.
Peripartum and Long-Term Maternal Cardiovascular Health After Preeclampsia
Authors: Giorgione Veronica , Jansen Gwyneth , Kitt Jamie , Ghossein-Doha Chahinda , Leeson Paul , Thilaganathan Basky
Published: October 2022

There is widespread acceptance of the increased prevalence of cardiovascular diseases occurring within 1 to 2 decades in women following a preeclamptic pregnancy. More recent evidence suggests that the deranged biochemical and echocardiographic findings in women do not resolve in the majority of preeclamptic women following giving birth. Many women continue to be hypertensive in the immediate postnatal period with some exhibiting occult signs of cardiac dysfunction. There is now promising evidence that with close monitoring and effective control of blood pressure control in the immediate postnatal period, women may have persistently lower blood pressures many years after stopping their medication. This review highlights the evidence that delivering effective medical care in the fourth trimester of pregnancy can improve the long-term cardiovascular health after a preeclamptic birth.
Peripheral Immune Cell Composition is Altered in Women Before and After a Hypertension Diagnosis
Authors: Kresovich Jacob K. , Xu Zongli , O’Brien Katie M. , Parks Christine G. , Weinberg Clarice R. , Sandler Dale P. , Taylor Jack A.
Published: October 2022

Background:

The development and consequences of hypertension involve multiple biological systems that may include changes in immune profiles. Whether hypertension is related to peripheral immune cell composition has not been examined in large human cohorts.

Methods:

We estimated circulating proportions of 12 leukocyte subsets from the lymphoid and myeloid lineages by deconvolving cell-type-specific DNA methylation data from 4124 women. Hypertension status at baseline was defined by current use of antihypertensive medication and blood pressure measurements while new incident cases were identified during follow-up via annual health questionnaires.

Results:

Among hypertension-free women at baseline, higher B cell and lower naïve CD4+ helper T cell proportions were associated with subsequent increased hazard of hypertension incidence (B cells; adjusted HR: 1.17 [95% CI: 1.02–1.35];
P
=0.03; naïve CD4+ T cell, adjusted HR: 0.88 [95% CI: 0.78–0.99];
P
=0.04). Blood pressure measurements at baseline were similarly positively associated with B cells and inversely associated with naïve CD4+ helper T cells. Compared to normotensive women, women with hypertension had higher circulating proportions of neutrophils (adjusted odds ratio: 1.18 [95% CI: 1.07–1.31];
P
=0.001) and lower proportions of CD4+ helper T cells (adjusted odds ratio: 0.90 [95% CI: 0.81–1.00]
P
=0.05), natural killers (adjusted odds ratio: 0.82 [95% CI: 0.74–0.91];
P
<0.001), and B cells (adjusted odds ratio: 0.84 [95% CI: 0.74–0.96];
P
=0.01).

Conclusions:

These observations suggest that shifts in lymphocyte subsets occur before hypertension development, followed by later changes to neutrophils and additional lymphocytes.
Metabolome-Wide Association Study of Cord Blood Metabolites With Blood Pressure in Childhood and Adolescence
Authors: Zhang Mingyu , Brady Tammy M. , Buckley Jessie P. , Appel Lawrence J. , Hong Xiumei , Wang Guoying , Liang Liming , Wang Xiaobin , Mueller Noel T.
Published: October 2022

Background:

No studies have examined whether the cord blood metabolome—a reflection of in utero metabolism—influences blood pressure (BP) in children.

Objectives:

To examine prospective associations of cord blood metabolites with systolic BP (SBP), diastolic BP (DBP), and risk of elevated BP in childhood and adolescence.

Methods:

In the Boston Birth Cohort, we measured metabolites in cord blood plasma, and SBP and DBP at clinic visits between 3 and 18 years. We examined associations of cord metabolites with SBP and DBP percentiles using linear mixed models and with elevated BP using mixed-effects Poisson regression.

Results:

Our study included 902 mother-child dyads (60% Black, 23% Hispanic, 45% female). Children were followed for a median of 9.2 (interquartile range, 6.7–11.7) years, and the median number of BP observations per child was 7 (interquartile range, 4–11). After false discovery rate correction, 3 metabolites were associated with SBP, 96 with DBP, and 24 with elevated BP; 2 metabolites (1-methylnicotinamide, dimethylguanidino valeric acid) were associated with all 3 outcomes, and 21 metabolites were associated with both DBP and elevated BP. After multivariable adjustment, 48 metabolites remained significantly associated with DBP. Metabolites that showed the strongest associations with SBP, DBP, and elevated BP included nucleotides (eg, xanthosine, hypoxanthine, xanthine) and acylcarnitines (eg, C6 and C7 carnitines), which represent fatty acid oxidation and purine metabolism pathways.

Conclusions:

In our urban and predominantly racial/ethnic minority cohort, we provide evidence that metabolomic alterations in utero, in particular, acylcarnitine- and purine-metabolism metabolites, may be involved in the early life origins of hypertension.
Rush hour: arboreal mammal activity patterns in natural canopy bridges in the Peruvian Amazon
Authors: Gregory Tremaine , Carrasco-Rueda Farah , Balbuena Diego , Kolowski Joseph
Published: October 2022

Canopy bridges are an increasingly popular method to mitigate linear infrastructure fragmentation impacts, but little is known about when, over the course of the day and night, they are used. Natural canopy bridges monitored with camera traps provide an excellent source of information on community-wide arboreal mammal activity patterns, which are otherwise challenging to document. Natural bridges represent a hotspot of activity, being bottleneck crossing points over linear infrastructure, and cameras provide 24-hour monitoring capability. We monitored 20 natural canopy bridges over pipeline clearings distributed at two sites in the Peruvian Amazon for over a year using camera traps. Across 11 492 camera trap nights, we recorded 5165 events of 27 arboreal mammal species and used these events to describe both overall mammal activity in natural canopy bridges and activity patterns for the most frequently registered species: Aotus nigriceps, Potos flavus, Bassaricyon alleni, Caluromys lanatus, Coendou ichillus, and Sapajus apella. The long duration of our study allowed us to investigate potential changes in activity patterns resulting from seasonality and disturbance associated with pipeline construction, and the inclusion of two study sites allowed comparisons between them. We found substantially more mammalian activity in bridges during the night (87.4%) than the day, with only one of the most frequently registered species being diurnal (S. apella). Changes in activity between disturbance phases and seasons were only apparent for C. ichillus, and comparisons across species revealed differences in activity peaks, such as a unique peak early in the night for A. nigriceps. Our data provide some of the first substantial activity information for the species evaluated and help elucidate temporal patterns of canopy bridge usage to be expected for arboreal Neotropical wildlife. Knowing when to expect bridge use helps both guide the design of mitigation plans for future projects that include natural and artificial canopy bridges and identify the best monitoring methods. Given the high rate of nocturnal activity we observed, we recommend mitigation plans consider limiting human activity on linear infrastructure at night, if possible, and consider the requirements of nocturnal species in bridge designs. We also recommend camera trapping for monitoring.
Religions by Continent
Authors: Johnson Todd M. , Crossing Peter F.
Published: October 2022

To supplement our global assessment of 18 religions in a previous article in this issue of the journal, here we offer analysis of religious affiliation by the globe and six continents: Africa, Asia, Europe, Latin America, Northern America, and Oceania. Estimates of religious affiliation are made for four dates, 1970, 2000, 2022, and projections for 2030. We also contrast growth in two 30-year periods, 1970–2000 and 2000–2030. These global and continental tables are based on country data (World Religion Database). United Nations regional tables (e.g., Western Africa) can also be constructed from the country data.
The World by Religion
Authors: Johnson Todd M. , Crossing Peter F.
Published: October 2022

The following article represents the results of analysis of data on religion for all of the countries of the world which appear in the World Religion Database (Johnson and Grim 2022). The data contained are collected at the national level from a number of sources including censuses, surveys, polls, religious communities, scholars, and others.