bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Flow-Limiting Coronary Stenosis With PCS: A New Cost-Effective Index Derived From the Product of Corrected TIMI Frame Count and Percent Diameter Stenosis
Authors: Li Xinhao , Lyu Lijuan , Yang Wei , Pan Jichen , Dong Mei , Zhang Mei , Zhang Pengfei
Published: November 2021

Background: Identifying functional coronary stenosis with simple and cost-effective methods during invasive coronary angiography is still challenging. Corrected TIMI frame count (CTFC) is considered to be the frame count velocity of coronary blood flow. We aimed to propose a simple and cost-effective index based on CTFC and percent diameter stenosis (DS) to identify flow-limiting coronary stenosis. For this, a new index was put forward as the product of CTFC and DS (PCS). PCS can be regarded as the loss of coronary blood flow due to diameter stenosis.

Methods: DS, CTFC, PCS, and Fractional flow reserve (FFR) of 111 vessels in 84 patients with suspected coronary heart disease were measured. FFR ≤0.80 was defined as flow-limiting. Models involving CTFC, DS, and PCS were developed. Logistic regression was performed to evaluate the values on diagnosing flow-limiting stenosis.

Results: Vessels with flow-limiting coronary stenosis exhibited higher CTFC values than those without (28.56 vs. 21.64). The performance including the AUC (0.887), sensitivity (87.8%), and Youden index (0.678) for detecting flow-limiting stenosis was improved by adding the CTFC to the DS, while PCS had the largest positive predictive value (PPV) and diagnostic accuracy (DA) being 72.0 and 82.9%, respectively. For vessels with ≥50% lesions, PCS still had the best DA (80.9%), specificity (85.9%), and PPV (72.9%). At the same stenosis severity level, the AUC, Youden index and, DA of PCS were higher than those of CTFC.

Conclusions: PCS is simple and accurate to identify flow-limiting coronary stenosis, especially at vessels with moderate to severe stenosis.
An Investigation of Mathematics Anxiety and Academic Coping Strategies Among High School Students in Vietnam: A Cross-Sectional Study
Authors: Luu-Thi Huyen-Trang , Ngo-Thi Thuy-Trinh , Nguyen-Thi My-Tien , Thao-Ly Thanh , Nguyen-Duong Bao-Tran , Tran-Chi Vinh-Long
Published: November 2021

Increasing numbers of students around the world are suffering from mathematics anxiety. The main objective of this study is to investigate the relationship between mathematics anxiety and gender, grade, career choices, and academic achievement in Grade 10, 11, and 12 students. This study used the Revised Version of the Mathematics Anxiety Rating Scale to survey 1,548 high school students (570 males and 978 females) from high schools in Vietnam. A multivariate analysis of variance (MANOVA) test, Pearson correlation and multiple linear regression were used to analyze data. The results show that there are significant differences in the influence of grade, academic achievement, and students’ career choices on mathematics anxiety. Academic coping strategies, gender, grade, and career choices are significant predictors of mathematics anxiety. Grade 12 students have higher levels of mathematics anxiety than others. Students with high average mathematics scores (9.0–10.0) have higher levels of mathematics anxiety than students with lower scores. Besides, students choosing finance and economics or industrial engineering to pursue into higher education also experienced higher levels of mathematics anxiety than others. This study contributes to the general discussion about the nature of mathematics anxiety and the relationship between mathematics anxiety and academic achievement.
Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset
Authors: Rossetti Raffaella , Moleri Silvia , Guizzardi Fabiana , Gentilini Davide , Libera Laura , Marozzi Anna , Moretti Costanzo , Brancati Francesco , Bonomi Marco , Persani Luca
Published: November 2021

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.
Associations of Hypothyroxinemia With Risk of Preeclampsia–Eclampsia and Gestational Hypertension
Authors: Su Xiujuan , Liu Yang , Li Guohua , Liu Xiaosong , Huang Shijia , Duan Tao , Du Qiaoling
Published: November 2021

Objective

To investigate the association between hypothyroxinemia and the risk of preeclampsia–eclampsia and gestational hypertension.

Design

Historical cohort study.

Methods

The study included pregnant individuals who delivered live-born singletons and had at least one thyroid function assessment during pregnancy at a tertiary hospital. Hypothyroxinemia was defined as thyroid-stimulating hormone (TSH) levels within the normal reference range and free thyroxine (FT4) levels lower than the tenth percentile. Risk ratios (RRs) with 95% confidence intervals (95% CIs) for preeclampsia–eclampsia and gestational hypertension between women with and without a diagnosis of hypothyroxinemia during pregnancy were estimated using a generalized estimating equation model.

Results

A total of 59,463 women with live-born singletons were included in the analysis. Logistic regression models with restricted cubic spline suggested that there was a U-shaped association between FT4 levels and preeclampsia–eclampsia risk. Compared with euthyroid women, those with hypothyroxinemia had an increased risk of preeclampsia–eclampsia (RR = 1.16, 95% CI: 1.02–1.31), and the risk increased with the increasing severity of hypothyroxinemia (p for trend < 0.001). Moreover, persistent hypothyroxinemia from the first to second trimesters was associated with an increased risk of preeclampsia–eclampsia (RR = 1.37, 95% CI: 1.03–1.83), especially for women with severe hypothyroxinemia (RR = 1.70, 95% CI: 1.12–2.58). In contrast, there was no association between hypothyroxinemia and gestational hypertension.

Conclusion

Our study suggested that hypothyroxinemia was only associated with an increased risk of preeclampsia–eclampsia, especially in women with persistent hypothyroxinemia in the first half of pregnancy. Analyses of the associated risk of gestational hypertension with hypothyroxinemia were not significant.
Ecophysiological Vulnerability to Climate Change in Mexico City’s Urban Forest
Authors: Barradas Victor L. , Esperon-Rodriguez Manuel
Published: November 2021

Urban forests play an important role in regulating urban climate while providing multiple environmental services. These forests, however, are threatened by changes in climate, as plants are exposed not only to global climate change but also to urban climate, having an impact on physiological functions. Here, we selected two physiological variables (stomatal conductance and leaf water potential) and four environmental variables (air temperature, photosynthetically active radiation, vapor pressure deficit, and water availability) to compare and evaluate the ecophysiological vulnerability to climate change of 15 dominant tree species from Mexico City’s urban forest. The stomatal conductance response was evaluated using the boundary-line analysis, which allowed us to compare the stomatal response to changes in the environment among species. Our results showed differential species responses to the environmental variables and identified Buddleja cordata and Populus deltoides as the least and most vulnerable species, respectively. Air temperatures above 33°C and vapor pressure deficit above 3.5 kPa limited the stomatal function of all species. Stomatal conductance was more sensitive to changes in leaf water potential, followed by vapor pressure deficit, indicating that water is a key factor for tree species performance in Mexico City’s urban forest. Our findings can help to optimize species selection considering future climate change by identifying vulnerable and resilient species.
Increasing Hormonal Control of Skeletal Development: An Evolutionary Trend in Amphibians
Authors: Vassilieva Anna B. , Smirnov Sergei V.
Published: November 2021

The biphasic life history of amphibians includes metamorphosis, a complex developmental event that involves drastic changes in the morphology, physiology and biochemistry accompanying the transition from the larval to adult stage of development. Thyroid hormones (THs) are widely known to orchestrate this remodeling and, in particular, to mediate the development of the bony skeleton, which is a model system in evolutionary morphological studies of amphibians. Detailed experimental studies of the role of THs in the craniogenesis of diverse urodelan amphibians revealed that (i) these hormones affect both the timing and sequence of bone formation, (ii) TH involvement increases in parallel with the increase in divergence between larval and adult skull morphology, and (iii) among urodelans, TH-involvement in skull development changes from a minimum in basal salamanders (Hynobiidae) to the most pronounced in derived ones (Salamandridae and Plethodontidae). Given the increasing regulatory function of THs in urodelan evolution, we hypothesized a stronger involvement of THs in the control of skeletogenesis in anurans with their most complex and dramatic metamorphosis among all amphibians. Our experimental study of skeletal development in the hypo- and hyperthyroid yellow-bellied toad (Bombina variegata: Bombinatoridae) supports the greater involvement of THs in the mediation of all stages of anuran cranial and postcranial bones formation. Similar to urodelans,B. variegatadisplays enhancing TH involvement in the development of cranial bones that arise during larval ontogeny: while the hormonal impact on early larval ossifications is minimal, the skull bones forming during metamorphosis are strictly TH-inducible. However, in contrast to urodelans, all cranial bones, including the earliest to form, are TH-dependent inB. variegata; moreover, the development of all elements of the axial and limb skeleton is affected by THs. The more accentuated hormonal control of skeletogenesis inB. variegatademonstrates the advanced regulatory and inductive function of THs in the orchestration of anuran metamorphosis. Based on these findings, we discuss (i) changes in THs function in amphibian evolution and (ii) the role of THs in the evolution of life histories in amphibians.
Metabolic Imbalance Effect on Retinal Müller Glial Cells Reprogramming Capacity: Involvement of Histone Deacetylase SIRT6
Authors: Sanhueza Salas L Francisco , García-Venzor Alfredo , Beltramone Natalia , Capurro Claudia , Toiber Debra , Silberman Dafne Magalí
Published: November 2021

Retinal Müller glial cells (MGs) are among the first to demonstrate metabolic changes during retinal disease and are a potential source of regenerative cells. In response to a harmful stimulus, they can dedifferentiate acquiring neural stem cells properties, proliferate and migrate to the damaged retinal layer and differentiate into lost neurons. However, it is not yet known how this reprogramming process is regulated in mammals. Since glucose and oxygen are important regulatory elements that may help directing stem cell fate, we aimed to study the effect of glucose variations and oxidative stress in Müller cells reprogramming capacity and analyze the participation the histone deacetylase SIRT6, as an epigenetic modulator of this process. We found that the combination of high glucose and oxidative stress induced a decrease in the levels of the marker glutamine synthetase, and an increase in the migration capacity of the cells suggesting that these experimental conditions could induce some degree of dedifferentiation and favor the migration ability. High glucose induced an increase in the levels of the pluripotent factor SOX9 and a decrease in SIRT6 levels accompanied by the increase in the acetylation levels of H3K9. Inhibiting SIRT6 expression by siRNA rendered an increase in SOX9 levels. We also determined SOX9 levels in retinas from mice with a conditional deletion of SIRT6 in the CNS. To further understand the mechanisms that regulate MGs response under metabolic impaired conditions, we evaluated the gene expression profile and performed Gene Ontology enrichment analysis of Müller cells from a murine model of Diabetes. We found several differentially expressed genes and observed that the transcriptomic change involved the enrichment of genes associated with glucose metabolism, cell migration, development and pluripotency. We found that many functional categories affected in cells of diabetic animals were directly related to SIRT6 function. Transcription factors enrichment analysis allowed us to predict several factors, including SOX9, that may be involved in the modulation of the differential expression program observed in diabetic MGs. Our results underline the heterogeneity of Müller cells response and the challenge that the study of metabolic impairment in vivo represents.
Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability
Authors: Payliss Brandon J. , Patel Ayushi , Sheppard Anneka C. , Wyatt Haley D. M.
Published: November 2021

All organisms depend on the ability of cells to accurately duplicate and segregate DNA into progeny. However, DNA is frequently damaged by factors in the environment and from within cells. One of the most dangerous lesions is a DNA double-strand break. Unrepaired breaks are a major driving force for genome instability. Cells contain sophisticated DNA repair networks to counteract the harmful effects of genotoxic agents, thus safeguarding genome integrity. Homologous recombination is a high-fidelity, template-dependent DNA repair pathway essential for the accurate repair of DNA nicks, gaps and double-strand breaks. Accurate homologous recombination depends on the ability of cells to remove branched DNA structures that form during repair, which is achieved through the opposing actions of helicases and structure-selective endonucleases. This review focuses on a structure-selective endonuclease called SLX1-SLX4 and the macromolecular endonuclease complexes that assemble on the SLX4 scaffold. First, we discuss recent developments that illuminate the structure and biochemical properties of this somewhat atypical structure-selective endonuclease. We then summarize the multifaceted roles that are fulfilled by human SLX1-SLX4 and its associated endonucleases in homologous recombination and genome stability. Finally, we discuss recent work on SLX4-binding proteins that may represent integral components of these macromolecular nuclease complexes, emphasizing the structure and function of a protein called SLX4IP.
Case Report: Complete Response to Nivolumab in a Patient With Programmed Cell Death 1 Ligand 1-Positive and Multiple Gene-Driven Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor-Resistant Lung Adenocarcinoma
Authors: Dong Wen , Lei Pengfei , Liu Xin , Li Qin , Cheng Xiangyang
Published: November 2021

Multiple gene-driven programmed cell death 1 ligand 1 (PD-L1)-expressing non-small-cell lung cancer (NSCLC) is very rare. Previous studies have shown that patients with NSCLC with anaplastic lymphoma kinase (ALK) gene rearrangement rarely benefit from PD-L1 inhibitors. Besides the secondary mutations in ALK gene, other mechanisms might contribute to tumor resistance to ALK tyrosine kinase inhibitors (ALK-TKIs). Herein, we present a case of PD-L1-overexpressing lung adenocarcinoma that harbors both EML4-ALK gene rearrangement and BRAF mutation. In particular, a second molecular analysis after resistance to first- and second-generation ALK-TKIs revealed a high PD-L1 expression and tumor mutation burden. Therefore, treatment with nivolumab monotherapy, an anti-PD-1 inhibitor, was started and the patient achieved complete remission. This case report suggested that PD-1 inhibitors might be an effective treatment option for patients with multiple gene-driven PD-L1-expressing NSCLC harboring ALK gene rearrangement.
Physical Exercise Promotes a Reduction in Cardiac Fibrosis in the Chronic Indeterminate Form of Experimental Chagas Disease
Authors: Pedra-Rezende Yasmin , Barbosa Juliana M. C. , Bombaça Ana Cristina S. , Dantas-Pereira Luiza , Gibaldi Daniel , Vilar-Pereira Glaucia , dos Santos Hílton Antônio Mata , Ramos Isalira Peroba , Silva-Gomes Natália Lins , Moreira Otacilio C. , Lannes-Vieira Joseli , Menna-Barreto Rubem F. S.
Published: November 2021

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected tropical disease and a health problem in Latin America. Etiological treatment has limited effectiveness in chronic CD; thus, new therapeutic strategies are required. The practice of physical exercises has been widely advocated to improve the quality of life of CD patients. The most frequent clinical CD manifestation is the chronic indeterminate form (CIF), and the effect of physical exercises on disease progression remains unknown. Here, in a CIF model, we aimed to evaluate the effect of physical exercises on cardiac histological, parasitological, mitochondrial, and oxidative metabolism, electro and echocardiographic profiles, and immunological features. To establish a CIF model, BALB/c and C57BL/6 mice were infected with 100 and 500 trypomastigotes of the Y T. cruzi strain. At 120 days postinfection (dpi), all mouse groups showed normal PR and corrected QT intervals and QRS complexes. Compared to BALB/c mice, C57BL/6 mice showed a lower parasitemia peak, mortality rate, and less intense myocarditis. Thus, C57BL/6 mice infected with 500 parasites were used for subsequent analyses. At 120 dpi, a decrease in cardiac mitochondrial oxygen consumption and an increase in reactive oxygen species (ROS) were detected. When we increased the number of analyzed mice, a reduced heart rate and slightly prolonged corrected QT intervals were detected, at 120 and 150 dpi, which were then normalized at 180 dpi, thus characterizing the CIF. Y-infected mice were subjected to an exercise program on a treadmill for 4 weeks (from 150 to 180 dpi), five times per week in a 30–60-min daily training session. At 180 dpi, no alterations were detected in cardiac mitochondrial and oxidative metabolism, which were not affected by physical exercises, although ROS production increased. At 120 and 180 dpi, comparing infected and non-infected mice, no differences were observed in the levels of plasma cytokines, indicating that a crucial biomarker of the systemic inflammatory profile was absent and not affected by exercise. Compared with sedentary mice, trained Y-infected mice showed similar parasite loads and inflammatory cells but reduced cardiac fibrosis. Therefore, our data show that physical exercises promote beneficial changes that may prevent CD progression.
Monocytes, Macrophages, and Their Potential Niches in Synovial Joints – Therapeutic Targets in Post-Traumatic Osteoarthritis?
Authors: Haubruck Patrick , Pinto Marlene Magalhaes , Moradi Babak , Little Christopher B. , Gentek Rebecca
Published: November 2021

Synovial joints are complex structures that enable normal locomotion. Following injury, they undergo a series of changes, including a prevalent inflammatory response. This increases the risk for development of osteoarthritis (OA), the most common joint disorder. In healthy joints, macrophages are the predominant immune cells. They regulate bone turnover, constantly scavenge debris from the joint cavity and, together with synovial fibroblasts, form a protective barrier. Macrophages thus work in concert with the non-hematopoietic stroma. In turn, the stroma provides a scaffold as well as molecular signals for macrophage survival and functional imprinting: “a macrophage niche”. These intricate cellular interactions are susceptible to perturbations like those induced by joint injury. With this review, we explore how the concepts of local tissue niches apply to synovial joints. We introduce the joint micro-anatomy and cellular players, and discuss their potential interactions in healthy joints, with an emphasis on molecular cues underlying their crosstalk and relevance to joint functionality. We then consider how these interactions are perturbed by joint injury and how they may contribute to OA pathogenesis. We conclude by discussing how understanding these changes might help identify novel therapeutic avenues with the potential of restoring joint function and reducing post-traumatic OA risk.
Implementing Logic Gates for Safer Immunotherapy of Cancer
Authors: Savanur Mohammed Azharuddin , Weinstein-Marom Hadas , Gross Gideon
Published: November 2021

Targeting solid tumors with absolute precision is a long-standing challenge in cancer immunotherapy. The identification of antigens, which are expressed by a large fraction of tumors of a given type and, preferably, across various types, but not by normal cells, holds the key to developing safe, off-the-shelf immunotherapies. Although the quest for widely shared, strictly tumor-specific antigens has been the focus of tremendous effort, only few such candidates have been implicated. Almost all antigens that are currently explored as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR)-T cell therapy are also expressed by healthy cells and the risk of on-target off-tumor toxicity has remained a major concern. Recent studies suggest that this risk could be obviated by targeting instead combinations of two or more antigens, which are co-expressed by tumor but not normal cells and, as such, are tumor-specific. Moreover, the expression of a shared tumor antigen along with the lack of a second antigen that is expressed by normal tissues can also be exploited for precise recognition. Additional cues, antigenic or non-antigenic ones, which characterize the tumor microenvironment, could be harnessed to further increase precision. This review focuses on attempts to define the targetable signatures of tumors and assesses different strategies employing advanced synthetic biology for translating such information into safer modes of immunotherapy, implementing the principles of Boolean logic gates.
Influence of Welding Process on Microstructure and Properties of Laser Welding of SiCp/6061 Al Matrix Composite
Authors: Li Hongliang , Cao Hongyang , Zhu Qiang , Lu Yunbin , Wang Zeyu , Zhao Wentao , Xia Hongbo
Published: November 2021

Direct laser welding, laser welding with Ti interlayer, and ultrasonic-assisted laser welding with Ti interlayer were used to join SiCp/6061 Al matrix composites. Microstructural evolutions, compositional distributions and tensile strengths under three processes were compared and analyzed. The experimental results showed that ultrasonic-assisted laser welding with Ti interlayer can obtain joints with good continuity and without obvious defects. Due to combined effects of Ti interlayer and ultrasonic, formation of brittle Al4C3 phase was greatly suppressed and fine TiC precipitates were also uniformly distributed in weld metal. The strength shown by the welded joints could reach up to 77.2% of the strength of the base material. Because of the internal defects (voids and pores) and the generated large numbers of brittle phases of Al4C3 in weld metal, the joint strength shown by the other two techniques, direct laser welding and laser welding with Ti interlayer, only reached 49.4 and 64.8% of the base material strength, respectively.
Does a Starting Positive End-Expiratory Pressure of 8 cmH2O Decrease the Probability of a Ventilator-Associated Event?
Authors: Barnett William R. , Maqsood Aadil , Kesireddy Nithin , Khokher Waleed , Holtzapple Zachary , Safi Fadi A. , Assaly Ragheb
Published: November 2021

Introduction: Ventilator-associated events (VAEs) are objective measures as defined by the Centers for Disease Control and Prevention (CDC). To reduce VAEs, some hospitals have started patients on higher baseline positive end-expiratory pressure (PEEP) to avoid triggering VAE criteria due to respiratory fluctuations.

Methods: At our institution, VAEs were gathered from January 2014 through December 2019. Using the CDC-defined classifications, VAEs were split into two groups to separate patients with hypoxemia only (VAC) and those with hypoxemia and evidence of inflammation or infection (IVAC-plus). We used the geometric distribution to calculate the daily event probability before and after the protocol implementation. A probability threshold was used to determine if the days between events was exceeded during the post-protocol period.

Results: A total of 306 VAEs were collected over the study period. Of those, 155 were VACs and 107 were IVAC-plus events during the pre-protocol period. After implementing the protocol, 24 VACs and 20 IVAC-plus events were reported. There was a non-significant decrease in daily event probabilities in both the VAC and IVAC-plus groups (0.083 vs. 0.068 and 0.057 vs. 0.039, respectively).

Conclusion: We concluded a starting PEEP of 8 cmH2O is unlikely to be an effective intervention at reducing the probability of a VAE. Until specific guidelines by the CDC are established, hospitals should consider alternative methods to reduce VAEs.
Mathematical Models of Plasmid Population Dynamics
Authors: Hernández-Beltrán José Carlos Ramón , San Millán Alvaro , Fuentes-Hernández Ayari , Peña-Miller Rafael
Published: November 2021

With plasmid-mediated antibiotic resistance thriving and threatening to become a serious public health problem, it is paramount to increase our understanding of the forces that enable the spread and maintenance of drug resistance genes encoded in mobile genetic elements. The relevance of plasmids as vehicles for the dissemination of antibiotic resistance genes, in addition to the extensive use of plasmid-derived vectors for biotechnological and industrial purposes, has promoted the in-depth study of the molecular mechanisms controlling multiple aspects of a plasmids’ life cycle. This body of experimental work has been paralleled by the development of a wealth of mathematical models aimed at understanding the interplay between transmission, replication, and segregation, as well as their consequences in the ecological and evolutionary dynamics of plasmid-bearing bacterial populations. In this review, we discuss theoretical models of plasmid dynamics that span from the molecular mechanisms of plasmid partition and copy-number control occurring at a cellular level, to their consequences in the population dynamics of complex microbial communities. We conclude by discussing future directions for this exciting research topic.
Glycan Biosynthesis Ability of Gut Microbiota Increased in Primary Hypertension Patients Taking Antihypertension Medications and Potentially Promoted by Macrophage-Adenosine Monophosphate-Activated Protein Kinase
Authors: Zheng Shuai , Piao Chunmei , Liu Yan , Liu Xuxia , Liu Tingting , Zhang Xiaoping , Ren Jingyuan , Liu Yulei , Zhu Baoli , Du Jie
Published: November 2021

Increasing evidences suggest that the gut microbiota have their contributions to the hypertension, but the metagenomic characteristics and potential regulating mechanisms in primary hypertension patients taking antihypertension drugs are not clear yet. We carried out a metagenomic analysis in 30 primary hypertension patients taking antihypertension medications and eight healthy adults without any medication. We found that bacterial strains from species, such as Bacteroides fragilis, Bacteroides vulgatus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus vestibularis, were highly increased in patients; and these strains were reported to generate glycan, short-chain fatty acid (SCFA) and trimethylamine (TMA) or be opportunistic pathogens. Meanwhile, Dorea longicatena, Eubacterium hallii, Clostridium leptum, Faecalibacterium prausnitzii, and some other strains were greatly decreased in the patient group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that ortholog groups and pathways related to glycan biosynthesis and multidrug resistance were significantly increased in the patient group, and some of the hub genes related to N-glycan biosynthesis were increased in the patient group, while those related to TMA precursor metabolism and amino acid metabolism both increased and decreased in the patient group. Metabolites tested by untargeted liquid chromatography–mass spectrometry (LC-MS) proved the decrease of acetic acid, choline, betaine, and several amino acids in patients’ fecal samples. Moreover, meta-analysis of recent studies found that almost all patients were taking at least one kind of drugs that were reported to regulate adenosine monophosphate-activated protein kinase (AMPK) pathway, so we further investigated if AMPK regulated the metagenomic changes by using angiotensin II-induced mouse hypertensive model on wild-type and macrophage-specific AMPK-knockout mice. We found that the changes in E. coli and Dorea and glycan biosynthesis-related orthologs and pathways were similar in our cohort and hypertensive wild-type mice but reversed after AMPK knockout. These results suggest that the gut microbiota-derived glycan, SCFA, TMA, and some other metabolites change in medication-taking primary hypertension patients and that medications might promote gut microbiota glycan biosynthesis through activating macrophage-AMPK.
Microbial Transformation of Chlordecone and Two Transformation Products Formed During in situ Chemical Reduction
Authors: Hellal Jennifer , Saaidi Pierre-Loïc , Bristeau Sébastien , Crampon Marc , Muselet Delphine , Della-Negra Oriane , Mauffret Aourell , Mouvet Christophe , Joulian Catherine
Published: November 2021

Chlordecone (CLD) is a very persistent synthetic organochlorine pesticide found in the French West Indies. Recently published work has demonstrated the potential of zero-valent iron to dechlorinate CLD by in situ chemical reduction (ISCR) in soils under water-saturated conditions, forming mono- to penta-dechlorinated CLD transformation products. These transformation products are more mobile than CLD and less toxic; however, nothing is known about their further degradation, although increasing evidence of CLD biodegradation by bacteria is being found. The present study began with the enrichment from wastewater sludge of a CLD-transforming community which was then inoculated into fresh media in the presence of either CLD or two of the main ISCR transformation products, 10-monohydroCLD (-1Cl-CLD) and tri-hydroCLD (-3Cl-CLD). Carried out in triplicate batches and incubated at 38°C under anoxic conditions and in the dark, the cultures were sampled regularly during 3 months and analyzed for CLD, -1Cl-CLD, -3Cl-CLD, and possible transformation products by gas chromatography coupled to mass spectrometry. All batches showed a decrease in the amended substrates (CLD or hydroCLD). CLD degradation occurred with concomitant formation of a nine-carbon compound (pentachloroindene) and two sulfur-containing transformation products (chlordecthiol, CLD-SH; methyl chlordecsulfide, CLD-SCH3), demonstrating competing transformation pathways. In contrast, -1Cl-CLD and -3Cl-CLD only underwent a sequential reductive sulfidation/S-methylation process resulting in -1Cl-CLD-SH and -1Cl-CLD-SCH3 on the one hand, and -3Cl-CLD-SH, -3Cl-CLD-SCH3 on the other hand. Some sulfur-containing transformation products have been reported previously with single bacterial strains, but never in the presence of a complex microbial community. At the end of the experiment, bacterial and archaeal populations were investigated by 16S rRNA gene amplicon sequencing. The observed diversity was mostly similar in the CLD and -1Cl-CLD conditions to the inoculum with a dominant archaea genus, Methanobacterium, and four OTU affiliated to bacteria, identified at the family (Spirochaetaceae) or genus level (Desulfovibrio, Aminobacterium, and Soehngenia). On the other hand, in the -3Cl-CLD condition, although the same OTU were found, Clostridium sensu stricto 7, Candidatus Cloacimonas, and Proteiniphilum were also present at > 2% sequences. Presence of methanogens and sulfate-reducing bacteria could contribute to sulfidation and S-methylation biotransformations. Overall, these results contribute to increasing our knowledge on the biodegradability of CLD and its transformation products, helping to progress toward effective remediation solutions.
An Ultrafast One-Step Quantitative Reverse Transcription–Polymerase Chain Reaction Assay for Detection of SARS-CoV-2
Authors: Milosevic Jadranka , Lu Mengrou , Greene Wallace , He Hong-Zhang , Zheng Si-Yang
Published: November 2021

We developed an ultrafast one-step RT-qPCR assay for SARS-CoV-2 detection, which can be completed in only 30 min on benchtop Bio-Rad CFX96. The assay significantly reduces the running time of conventional RT-qPCR: reduced RT step from 10 to 1 min, and reduced the PCR cycle of denaturation from 10 to 1 s and extension from 30 to 1 s. A cohort of 60 nasopharyngeal swab samples testing showed that the assay had a clinical sensitivity of 100% and a clinical specificity of 100%.
Antimicrobial Use and Susceptibility of Indicator Escherichia coli in Finnish Integrated Pork Production
Authors: Sali Virpi , Nykäsenoja Suvi , Heikinheimo Annamari , Hälli Outi , Tirkkonen Taneli , Heinonen Mari
Published: November 2021

In pigs, antimicrobial use (AMU) practices vary at different production phases between herds and between countries. Antimicrobial resistance (AMR) development is linked to AMU but recognized as a multi-factorial issue, and thus, any information increasing knowledge of AMU and AMR relationships is valuable. We described AMU and screened the carriage of different AMR phenotypes of indicatorEscherichia coliin 25 selected Finnish piglet-producing and finishing herds that formed nine birth-to-slaughter production lines. Moreover, we studied associations between AMU and AMR in both herd types and throughout the production line. Treatment records were obtained from the national Sikava register for 1year, and AMU was quantified as mg/PCU (population correction unit) and TIs (treatment incidences). For phenotypic antimicrobial susceptibility testing, ten pen-level pooled feces samples (n=250) in each herd were collected from one room representing the oldest weaned piglets or the oldest finishing pigs. Majority of the medications (96.8%) was administered parenterally, and penicillin was the predominant antimicrobial in every herd. More different antimicrobial substances were used in piglet-producing than in finishing herds (median 5 and 1, respectively,p<0.001). As mg/PCU, sows had the highest AMU and suckling piglets had the highest TIs, whereas finishing pigs were the least treated age group. The proportion of susceptible indicatorE. coliisolates of all studied isolates was 59.6%. Resistance was found most commonly against tetracycline, sulfamethoxazole, trimethoprim, and ampicillin, and multi-resistant (MR) isolates (46.5% of all resistant isolates) were resistant to a maximum of four different antimicrobials. Quinolone resistance was rare, and no resistance against 3rd-generation cephalosporins, meropenem, azithromycin, colistin, gentamicin, or tigecycline was detected. The main associations between AMU and AMR were found at antimicrobial group level when use was compared with the presence of AMR phenotypes. The proportion of resistant isolates was not associated with AMU, and herd size was not associated with either AMU or AMR. We suggest that the use of narrow-spectrum beta-lactams as a primary treatment option and lack of wide application of oral group medications potentially favors a good resistance pattern in integrated pork production.
A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data
Authors: Pagano Gennaro , Boess Frank G. , Taylor Kirsten I. , Ricci Benedicte , Mollenhauer Brit , Poewe Werner , Boulay Anne , Anzures-Cabrera Judith , Vogt Annamarie , Marchesi Maddalena , Post Anke , Nikolcheva Tania , Kinney Gene G. , Zago Wagner M. , Ness Daniel K. , Svoboda Hanno , Britschgi Markus , Ostrowitzki Susanne , Simuni Tanya , Marek Kenneth , Koller Martin , Sevigny Jeff , Doody Rachelle , Fontoura Paulo , Umbricht Daniel , Bonni Azad ,   PASADENA Investigators,   Prasinezumab Study Group
Published: November 2021

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.

Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.

Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.

Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).

Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.

Trial Registration: NCT03100149.
Fixel-Based Analysis and Free Water Corrected DTI Evaluation of HIV-Associated Neurocognitive Disorders
Authors: Finkelstein Alan , Faiyaz Abrar , Weber Miriam T. , Qiu Xing , Uddin Md Nasir , Zhong Jianhui , Schifitto Giovanni
Published: November 2021

Background: White matter (WM) damage is a consistent finding in HIV-infected (HIV+) individuals. Previous studies have evaluated WM fiber tract-specific brain regions in HIV-associated neurocognitive disorders (HAND) using diffusion tensor imaging (DTI). However, DTI might lack an accurate biological interpretation, and the technique suffers from several limitations. Fixel-based analysis (FBA) and free water corrected DTI (fwcDTI) have recently emerged as useful techniques to quantify abnormalities in WM. Here, we sought to evaluate FBA and fwcDTI metrics between HIV+ and healthy controls (HIV−) individuals. Using machine learning classifiers, we compared the specificity of both FBA and fwcDTI metrics in their ability to distinguish between individuals with and without cognitive impairment in HIV+ individuals.

Methods: Forty-two HIV+ and 52 HIV– participants underwent MRI exam, clinical, and neuropsychological assessments. FBA metrics included fiber density (FD), fiber bundle cross section (FC), and fiber density and cross section (FDC). We also obtained fwcDTI metrics such as fractional anisotropy (FAT) and mean diffusivity (MDT). Tract-based spatial statistics (TBSS) was performed on FAT and MDT. We evaluated the correlations between MRI metrics with cognitive performance and blood markers, such as neurofilament light chain (NfL), and Tau protein. Four different binary classifiers were used to show the specificity of the MRI metrics for classifying cognitive impairment in HIV+ individuals.

Results: Whole-brain FBA showed significant reductions (up to 15%) in various fiber bundles, specifically the cerebral peduncle, posterior limb of internal capsule, middle cerebellar peduncle, and superior corona radiata. TBSS of fwcDTI metrics revealed decreased FAT in HIV+ individuals compared to HIV– individuals in areas consistent with those observed in FBA, but these were not significant. Machine learning classifiers were consistently better able to distinguish between cognitively normal patients and those with cognitive impairment when using fixel-based metrics as input features as compared to fwcDTI metrics.

Conclusion: Our findings lend support that FBA may serve as a potential in vivo biomarker for evaluating and monitoring axonal degeneration in HIV+ patients at risk for neurocognitive impairment.
Model-Based Prediction of Operation Consequences When Driving a Car to Compensate for a Partially Restricted Visual Field by A-Pillars
Authors: Ueda Sayako , Sato Toshihisa , Kumada Takatsune
Published: November 2021

The partial restriction of a driver’s visual field by the physical structure of the car (e.g., the A-pillar) can lead to unsafe situations where steering performance is degraded. Drivers require both environmental information and visual feedback regarding operation consequences. When driving with a partially restricted visual field, and thus restricted visual feedback, drivers may predict operation consequences using a previously acquired internal model of a car. To investigate this hypothesis, we conducted a tracking and driving task in which visual information was restricted to varying degrees. In the tracking task, participants tracked a moving target on a computer screen with visible and invisible cursors. In the driving task, they drove a real car with or without the ability to see the distant parts of a visual field. Consequently, we found that the decrease in tracking performance induced by visual feedback restriction predicted the decrease in steering smoothness induced by visual field restriction, suggesting that model-based prediction was used in both tasks. These findings indicate that laboratory-based task performance can be used to identify drivers with low model-based prediction ability whose driving behavior is less optimal in restricted vision scenarios, even before they obtain a driver’s license. However, further studies are required to examine the underlying neural mechanisms and to establish the generalizability of these findings to more realistic settings.
SSTDP: Supervised Spike Timing Dependent Plasticity for Efficient Spiking Neural Network Training
Authors: Liu Fangxin , Zhao Wenbo , Chen Yongbiao , Wang Zongwu , Yang Tao , Jiang Li
Published: November 2021

Spiking Neural Networks (SNNs) are a pathway that could potentially empower low-power event-driven neuromorphic hardware due to their spatio-temporal information processing capability and high biological plausibility. Although SNNs are currently more efficient than artificial neural networks (ANNs), they are not as accurate as ANNs. Error backpropagation is the most common method for directly training neural networks, promoting the prosperity of ANNs in various deep learning fields. However, since the signals transmitted in the SNN are non-differentiable discrete binary spike events, the activation function in the form of spikes presents difficulties for the gradient-based optimization algorithms to be directly applied in SNNs, leading to a performance gap (i.e., accuracy and latency) between SNNs and ANNs. This paper introduces a new learning algorithm, called SSTDP, which bridges the gap between backpropagation (BP)-based learning and spike-time-dependent plasticity (STDP)-based learning to train SNNs efficiently. The scheme incorporates the global optimization process from BP and the efficient weight update derived from STDP. It not only avoids the non-differentiable derivation in the BP process but also utilizes the local feature extraction property of STDP. Consequently, our method can lower the possibility of vanishing spikes in BP training and reduce the number of time steps to reduce network latency. In SSTDP, we employ temporal-based coding and use Integrate-and-Fire (IF) neuron as the neuron model to provide considerable computational benefits. Our experiments show the effectiveness of the proposed SSTDP learning algorithm on the SNN by achieving the best classification accuracy 99.3% on the Caltech 101 dataset, 98.1% on the MNIST dataset, and 91.3% on the CIFAR-10 dataset compared to other SNNs trained with other learning methods. It also surpasses the best inference accuracy of the directly trained SNN with 25~32× less inference latency. Moreover, we analyze event-based computations to demonstrate the efficacy of the SNN for inference operation in the spiking domain, and SSTDP methods can achieve 1.3~37.7× fewer addition operations per inference. The code is available at:https://github.com/MXHX7199/SNN-SSTDP.