bluuebunny/crossref_metadata_2025 huggingface dataset:
Advances in the Regulation of Macrophage Polarization by Mesenchymal Stem Cells and Implications for ALI/ARDS Treatment
Authors: Liu Chang , Xiao Kun , Xie Lixin
Published: July 2022

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common condition with high mortality. ALI/ARDS is caused by multiple etiologies, and the main clinical manifestations are progressive dyspnea and intractable hypoxemia. Currently, supportive therapy is the main ALI/ARDS treatment, and there remains a lack of targeted and effective therapeutic strategies. Macrophages are important components of innate immunity. M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory and promote tissue repair. Mesenchymal stem cells (MSCs) are stem cells with broad application prospects in tissue regeneration due to their multi-directional differentiation potential along with their anti-inflammatory and paracrine properties. MSCs can regulate the balance of M1/M2 macrophage polarization to improve the prognosis of ALI/ARDS. In this paper, we review the mechanisms by which MSCs regulate macrophage polarization and the signaling pathways associated with polarization. This review is expected to provide new targets for the treatment of ALI/ARDS.
GARP as a Therapeutic Target for the Modulation of Regulatory T Cells in Cancer and Autoimmunity
Authors: Zimmer Niklas , Trzeciak Emily R. , Graefen Barbara , Satoh Kazuki , Tuettenberg Andrea
Published: July 2022

Regulatory T cells (Treg) play a critical role in immune homeostasis by suppressing several aspects of the immune response. Herein, Glycoprotein A repetitions predominant (GARP), the docking receptor for latent transforming growth factor (LTGF-β), which promotes its activation, plays a crucial role in maintaining Treg mediated immune tolerance. After activation, Treg uniquely express GARP on their surfaces. Due to its location and function, GARP may represent an important target for immunotherapeutic approaches, including the inhibition of Treg suppression in cancer or the enhancement of suppression in autoimmunity. In the present review, we will clarify the cellular and molecular regulation of GARP expression not only in human Treg but also in other cells present in the tumor microenvironment. We will also examine the overall roles of GARP in the regulation of the immune system. Furthermore, we will explore potential applications of GARP as a predictive and therapeutic biomarker as well as the targeting of GARP itself in immunotherapeutic approaches.
Immune Profiling in Gastric Cancer Reveals the Dynamic Landscape of Immune Signature Underlying Tumor Progression
Authors: Wei Yuhan , Zhang Jianwei , Fan Xueke , Zheng Zhi , Jiang Xiaoyue , Chen Dexi , Lu Yuting , Li Yingrui , Wang Miao , Hu Min , Du Qi , Yang Liuting , Li Hongzhong , Xiao Yi , Li Yongfu , Jin Jiangtao , Wang Deying , Yuan Xiangliang , Li Qin
Published: July 2022

The profiling of the tumor immune microenvironment (TIME) is critical for guiding immunotherapy strategies. However, how the composition of the immune landscape affects the tumor progression of gastric cancer (GC) is ill-defined. Here, we used mass cytometry to perform simultaneous in-depth immune profiling of the tumor, adjacent tissues, and blood cells from GC patients and revealed a unique GC tumor-immune signature, where CD8+ T cells were present at a lower frequency in tumor tissues compared to adjacent tissues, whereas regulatory T cells and tumor-associated macrophages (TAMs) were significantly increased, indicating strong suppressive TIME in GC. Incorporated with oncogenic genomic traits, we found that the unique immunophenotype was interactively shaped by a specific GC gene signature across tumor progression. Earlier-stage GC lesions with IFN signaling enrichment harbored significantly altered T-cell compartments while advanced GC featured by metabolism signaling activation was accumulated by TAMs. Interestingly, PD-1 expression on CD8+ T cells was relatively higher in earlier-stage GC patients, indicating that these patients may derive more benefits from PD-1 inhibitors. The dynamic properties of diverse immune cell types revealed by our study provide new dimensions to the immune landscape of GC and facilitate the development of novel immunotherapy strategies for GC patients.
Virulence-Associated Secretion in Mycobacterium abscessus
Authors: Bar-Oz Michal , Meir Michal , Barkan Daniel
Published: July 2022

Non-tuberculous mycobacteria (NTM) are a heterogeneous group of originally environmental organi3sms, increasingly recognized as pathogens with rising prevalence worldwide. Knowledge of NTM’s mechanisms of virulence is lacking, as molecular research of these bacteria is challenging, sometimes more than that of M. tuberculosis (Mtb), and far less resources are allocated to their investigation. While some of the virulence mechanisms are common to several mycobacteria including Mtb, others NTM species-specific. Among NTMs, Mycobacterium abscessus (Mabs) causes some of the most severe and difficult to treat infections, especially chronic pulmonary infections. Mabs survives and proliferates intracellularly by circumventing host defenses, using multiple mechanisms, many of which remain poorly characterized. Some of these immune-evasion mechanisms are also found in Mtb, including phagosome pore formation, inhibition of phagosome maturation, cytokine response interference and apoptosis delay. While much is known of the role of Mtb-secreted effector molecules in mediating the manipulation of the host response, far less is known of the secreted effector molecules in Mabs. In this review, we briefly summarize the knowledge of secreted effectors in Mtb (such as ESX secretion, SecA2, TAT and others), and draw the parallel pathways in Mabs. We also describe pathways that are unique to Mabs, differentiating it from Mtb. This review will assist researchers interested in virulence-associated secretion in Mabs by providing the knowledge base and framework for their studies.
Efficacy and Safety of Drug-Eluting Beads Transarterial Chemoembolization Combining Immune Checkpoint Inhibitors in Unresectable Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis
Authors: Yang Xue-Gang , Sun Yan-Yuan , Li De-Shan , Xu Guo-Hui , Huang Xiao-Qi
Published: July 2022

Purpose

To assess the effectiveness and safety of drug-eluting beads transarterial chemoembolization plus immune checkpoint inhibitors (DEB-TACE+ICIs) versus chemotherapy (gemcitabine+cisplatin) for patients with unresectable intrahepatic cholangiocarcinoma (iCCA).

Materials and Methods

This retrospective study included unresectable iCCA patients treated with DEB-TACE+ICIs or chemotherapy between May, 2019 and August, 2021. The differences in tumor responses, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the 2 groups. Patient baseline characteristics, PFS, and OS were compared among 2 groups before and after propensity score-matching (PSM). Factors affecting PFS and OS were analyzed by Cox’s proportional hazards regression model.

Results

The study included 49 patients with unresectable iCCA patients, 20 in the DEB-TACE+ICIs group and 29 in the chemotherapy group. PSM analysis created 20 pairs of patients in 2 groups. The patients in the DEB-TACE+ICIs group had a higher objective response rate (55.0% vs. 20.0%, P=0.022), higher PFS (median, 7.2 vs. 5.7 months, P=0.036), and higher OS (median, 13.2 vs. 7.6 months, P=0.015) than those in the chemotherapy group. Multivariate analyses suggested that chemotherapy, tumor size >5cm, and multiple tumors were the independent risk factors for PFS and OS. The incidence of TRAEs was similar between the 2 groups.

Conclusion

Compared to chemotherapy, DEB-TACE plus ICIs improved survival and was well-tolerated in patients with unresectable iCCA.
Peripheral Helper T Cell Responses in Human Diseases
Authors: Yoshitomi Hiroyuki
Published: July 2022

A series of rheumatoid arthritis (RA) studies established a PD-1hiCXCR5-CD4+ T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key feature of Tph cells and may contribute to the formation of tertiary lymphoid structures (TLS) in inflamed tissues. In addition, Tph cells provide help to B cells in situ as efficiently as follicular helper T (Tfh) cells, and these features would implicate Tph cells in the pathogenesis of RA. Subsequent studies have revealed that Tph cells are involved in various human diseases such as autoimmune diseases, infectious diseases, and cancers. Although the analysis of human immunity has various limitations, accumulating evidence demonstrated the expansion of B cells with low somatic hypermutation and a link between TLS and immune functions in these diseases. We discuss about the emerging roles of the Tph cell and its relevant immune responses in peripheral tissues including B-cell expansion with atypical features.
Recent Insights Into the Role of Macrophages in Acute Gout
Authors: Liu Lei , Zhu Lingjiang , Liu Mengdan , Zhao Li , Yu Yiyun , Xue Yu , Shan Lizhen
Published: July 2022

Gout is a common type of inflammatory arthritis characterized by the presence of monosodium urate crystals (MSU) in the joints. Macrophages are believed to be involved in gout flares. It has long been recognized that resident macrophage and monocyte derived macrophages are distinct subsets and there have been attempts to investigate their roles in acute gout, respectively. Previous studies revealed that resident macrophages initiate and drive the inflammation, while monocyte derived macrophages differentiated into M1-like macrophages in response to MSU crystals. With the advancement of technologies, subpopulations of synovial resident macrophages have been defined with the characteristics more accurately described. Resident macrophages in the synovial lining layer showed an anti-inflammatory effect in rheumatoid arthritis, but specific Trpv4 depletion of them reduced MSU crystals induced murine arthritis. CD14+ monocytes in the synovial fluid from patients with gout exhibit phenotypes of anti-inflammatory as well as pro-inflammatory characteristics. Here, we review the main aspects of macrophages in the initiation and resolution of acute gout and try to clarify the specific role of each subpopulation. Building a reliable diagram of the effect of monocytes and macrophages during MSU crystals induced arthritis will bring us closer to targeting macrophages for improving the management of gout.
Effects of Land Use on the Soil Microbial Community in the Songnen Grassland of Northeast China
Authors: Liu Guofu , Bai Zhenjian , Cui Guowen , He Wenhua , Kongling Zelai , Ji Guoxu , Gong Hao , Li Dandan
Published: July 2022

Land use change obviously changes the plant community composition and soil properties of grasslands and thus affects multiple functions and services of grassland ecosystems. However, the response mechanisms of soil microorganisms, key drivers of the nutrient cycle and other soil functions during changes in grassland use type and associated vegetation are not well understood. In this study, Illumina high-throughput sequencing was used to analyze the changes in the soil microbial community structure of four grassland use types: exclosure (EL), mowed land (ML), grazed land (GL), and farmland (FL) in the Songnen Plain of Northeast China. The results showed that the FL and EL had significantly higher soil total nitrogen (TN) and lower soil electrical conductivity (EC) and pH than GL and ML. In contrast, the GL and ML had higher soil bulk density (BD) and organic matter, respectively, than the other land use types. In addition, the values of the Shannon diversity and Pielou’s evenness indexes were highest in the EL of all the land use types. Based on the high-throughput sequencing results, we observed high levels of α diversity in the FL for both bacteria and fungi. A structural equation model (SEM) revealed that pH and EC had a direct and positive effect on the bacterial community structure and composition. In addition, plant taxonomic diversity (according to the Shannon diversity and Pielou’s evenness indexes) indirectly affected the bacterial community composition via soil pH and EC. Notably, fungal composition was directly and positively correlated with soil nutrients and the value of Pielou’s evenness index changed with land use type. In conclusion, soil properties and/or plant diversity might drive the changes in the soil microbial community structure and composition in different grassland use types.
High Prevalence and Overexpression of Fosfomycin-Resistant Gene fosX in Enterococcus faecium From China
Authors: Xin Ling , Xu Xiaogang , Shi Qingyu , Han Renru , Wang Jue , Guo Yan , Hu Fupin
Published: July 2022

Enterococci are one of the main causes of gastrointestinal tract infections in the healthcare system and can develop resistance to fosfomycin through plasmid or chromosomally encoded fosfomycin resistance genes. To investigate the mechanisms of fosfomycin resistance, a total of 4,414 clinical isolates of non-replicated clinical enterococci collected from 62 hospitals in 26 provinces or cities in China were tested. Antibiotic susceptibility testing, detection of fosfomycin resistance genes, and cloning of the fosX gene were done. The PFGE, MLST, qRT-PCR, and next genome sequencing were carried out. The results revealed that the fosfomycin-resistant rate of enterococci was 3.5% (153/4,414), and the major resistance mechanism was fosX (101/153) and fosB (52/153) genes. The fosX gene could increase 4- fold fosfomycin MIC in Enterococcus faecium BM4105RF transformants, and the results of PFGE showed the 101 E. faecium carrying fosX were grouped into 48 pulse types. The multilocus sequence typing identified ST555 as the vast majority of STs, mostly distributed in Shanghai, China. Furthermore, the fosX gene expression was strongly related to the fosfomycin-resistant levels of enterococci. The present study was the first to describe the high prevalence presence of the fosX gene in E. faecium from China.
Enhancement of Rubella Virus Infection in Immortalized Human First-Trimester Trophoblasts Under Low-Glucose Stress Conditions
Authors: Trinh Quang Duy , Takada Kazuhide , Pham Ngan Thi Kim , Takano Chika , Namiki Takahiro , Ikuta Ryo , Hayashida Shingo , Okitsu Shoko , Ushijima Hiroshi , Komine-Aizawa Shihoko , Hayakawa Satoshi
Published: July 2022

Rubella virus (RuV) infections in pregnant women, especially first-trimester infections, can lead to congenital rubella syndrome (CRS). However, the mechanisms of fetal RuV infection are not completely understood, and it is not observed in every pregnant woman infected with RuV. As gestational diabetes mellitus is a risk factor for congenital viral infections, we investigated the possible roles of hypoglycemia-related endoplasmic reticulum (ER) stress as a key factor for vertical RuV infection using immortalized human first-trimester trophoblasts. Low-glucose stress was induced prior to RuV infection by culturing HTR-8/SVneo and Swan.71 cells in low-glucose (LG) medium for 24 h or high-glucose medium for 6 h and then LG medium for an additional 18 h. Clinically isolated RuV was inoculated at a multiplicity of infection of 5 to 10. The intracellular localization of the RuV capsid protein was investigated 24 to 48 h post-infection (pi) with flow cytometry (FCM) analysis and fluorescence microscopy. Viral progeny production was monitored by FCM analysis. Increases in RuV infection in LG-induced ER-stressed trophoblasts were observed. No significant increase in apoptosis of RuV-infected cells was noted at days 2 and 5 pi, and substantial viral progeny production was observed until day 5 pi. An approximate fivefold increase in viral binding was noted for the LG-stressed cells. Although the detailed mechanisms underlying viral entry into LG-stressed cells are not known and require further investigation, these findings suggest that a certain degree of LG stress in early pregnancy may facilitate infection and cause CRS.
Diversity and Ecophysiology of the Genus OLB8 and Other Abundant Uncultured Saprospiraceae Genera in Global Wastewater Treatment Systems
Authors: Kondrotaite Zivile , Valk Laura C. , Petriglieri Francesca , Singleton Caitlin , Nierychlo Marta , Dueholm Morten K. D. , Nielsen Per H.
Published: July 2022

The Saprospiraceae family within the phylum Bacteroidota is commonly present and highly abundant in wastewater treatment plants (WWTPs) worldwide, but little is known about its role. In this study, we used MiDAS 4 global survey with samples from 30 countries to analyze the abundance and distribution of members of Saprospiraceae. Phylogenomics were used to delineate five new genera from a set of 31 high-quality metagenome-assembled genomes from Danish WWTPs. Newly designed probes for fluorescence in situ hybridization (FISH) revealed rod-shaped morphologies for all genera analyzed, including OLB8, present mostly inside the activated sludge flocs. The genomes revealed potential metabolic capabilities for the degradation of polysaccharides, proteins, and other complex molecules; partial denitrification; and storage of intracellular polymers (glycogen, polyphosphate, and polyhydroxyalkanoates). FISH in combination with Raman microspectroscopy confirmed the presence of intracellular glycogen in Candidatus Brachybacter, Candidatus Parvibacillus calidus (both from the former genus OLB8), and Candidatus Opimibacter, and the presence of polyhydroxyalkanoates in Candidatus Defluviibacterium haderslevense and Candidatus Vicinibacter. These results provide the first overview of the most abundant novel Saprospiraceae genera present in WWTPs across the world and their potential involvement in nutrient removal and the degradation of macromolecules.
Practical Qualitative Evaluation and Screening of Potential Biomarkers for Different Parts of Wolfiporia cocos Using Machine Learning and Network Pharmacology
Authors: Li Lian , Zuo ZhiTian , Wang YuanZhong
Published: July 2022

Wolfiporia cocos is a widely used traditional Chinese medicine and dietary supplement. Artificial intelligence algorithms use different types of data based on the different strategies to complete multiple tasks such as search and discrimination, which has become a trend to be suitable for solving massive data analysis problems faced in network pharmacology research. In this study, we attempted to screen the potential biomarkers in different parts of W. cocos from the perspective of measurability and effectiveness based on fingerprint, machine learning, and network pharmacology. Based on the conclusions drawn from the results, we noted the following: (1) exploratory analysis results showed that differences between different parts were greater than those between different regions, and the partial least squares discriminant analysis and residual network models were excellent to identify Poria and Poriae cutis based on Fourier transform near-infrared spectroscopy spectra; (2) from the perspective of effectiveness, the results of network pharmacology showed that 11 components such as dehydropachymic acid and 16α-hydroxydehydrotrametenolic acid, and so on had high connectivity in the “component-target-pathway” network and were the main active components. (3) From a measurability perspective, through orthogonal partial least squares discriminant analysis and the variable importance projection > 1, it was confirmed that three components, namely, dehydrotrametenolic acid, poricoic acid A, and pachymic acid, were the main potential biomarkers based on high-performance liquid chromatography. (4) The content of the three components in Poria was significantly higher than that in Poriae cutis. (5) The integrated analysis showed that dehydrotrametenolic acid, poricoic acid A, and pachymic acid were the potential biomarkers for Poria and Poriae cutis. Overall, this approach provided a novel strategy to explore potential biomarkers with an explanation for the clinical application and reasonable development and utilization in Poria and Poriae cutis.
An Abundant and Diverse New Family of Electron Bifurcating Enzymes With a Non-canonical Catalytic Mechanism
Authors: Schut Gerrit J. , Haja Dominik K. , Feng Xiang , Poole Farris L. , Li Huilin , Adams Michael W. W.
Published: July 2022

Microorganisms utilize electron bifurcating enzymes in metabolic pathways to carry out thermodynamically unfavorable reactions. Bifurcating FeFe-hydrogenases (HydABC) reversibly oxidize NADH (E′∼−280 mV, under physiological conditions) and reduce protons to H2 gas (E°′−414 mV) by coupling this endergonic reaction to the exergonic reduction of protons by reduced ferredoxin (Fd) (E′∼−500 mV). We show here that HydABC homologs are surprisingly ubiquitous in the microbial world and are represented by 57 phylogenetically distinct clades but only about half are FeFe-hydrogenases. The others have replaced the hydrogenase domain with another oxidoreductase domain or they contain additional subunits, both of which enable various third reactions to be reversibly coupled to NAD+ and Fd reduction. We hypothesize that all of these enzymes carry out electron bifurcation and that their third substrates can include hydrogen peroxide, pyruvate, carbon monoxide, aldehydes, aryl-CoA thioesters, NADP+, cofactor F420, formate, and quinones, as well as many yet to be discovered. Some of the enzymes are proposed to be integral membrane-bound proton-translocating complexes. These different functionalities are associated with phylogenetically distinct clades and in many cases with specific microbial phyla. We propose that this new and abundant class of electron bifurcating enzyme be referred to as the Bfu family whose defining feature is a conserved bifurcating BfuBC core. This core contains FMN and six iron sulfur clusters and it interacts directly with ferredoxin (Fd) and NAD(H). Electrons to or from the third substrate are fed into the BfuBC core via BfuA. The other three known families of electron bifurcating enzyme (abbreviated as Nfn, EtfAB, and HdrA) contain a special FAD that bifurcates electrons to high and low potential pathways. The Bfu family are proposed to use a different electron bifurcation mechanism that involves a combination of FMN and three adjacent iron sulfur clusters, including a novel [2Fe-2S] cluster with pentacoordinate and partial non-Cys coordination. The absolute conservation of the redox cofactors of BfuBC in all members of the Bfu enzyme family indicate they have the same non-canonical mechanism to bifurcate electrons. A hypothetical catalytic mechanism is proposed as a basis for future spectroscopic analyses of Bfu family members.
The Clinical View on Streptococcus anginosus Group – Opportunistic Pathogens Coming Out of Hiding
Authors: Pilarczyk-Zurek Magdalena , Sitkiewicz Izabela , Koziel Joanna
Published: July 2022

Three distinct streptococcal species:Streptococcus anginosus, Streptococcus intermedius, andStreptococcus constellatus, belonging to theStreptococcus anginosusgroup (SAG), also known asStreptococcus millerigroup, have been attracting clinicians and microbiologists, not only as oral commensals but also as opportunistic pathogens. For years they have been simply classified as so called viridans streptococci, and distinct species were not associated with particular clinical manifestations. Therefore, description of SAG members are clearly underrepresented in the literature, compared to other medically relevant streptococci. However, the increasing number of reports of life-threatening infections caused by SAG indicates their emerging pathogenicity. The improved clinical data generated with the application of modern molecular diagnostic techniques allow for precise identification of individual species belonging to SAG. This review summarizes clinical reports on SAG infections and systematizes data on the occurrence of individual species at the site of infection. We also discuss the issue of proper microbiological diagnostics, which is crucial for further clinical treatment.
A Multi-Scale Approach to Model K+ Permeation Through the KcsA Channel
Authors: Horng T. L. , Chen R. S. , Leonardi M. V. , Franciolini F. , Catacuzzeno L.
Published: July 2022

K+ channels allow a very efficient passage of K+ ions through the membrane while excluding Na+ ions, and these properties are essential for life. The 3D structure of the KcsA K+ channel, solved more than 20 years ago, allows to address many relevant aspects of K+ permeation and selectivity mechanisms at the molecular level. Recent crystallographic data and molecular dynamics (MD) studies suggest that no water is normally present inside the selectivity filter (SF), which can instead accommodate four adjacent K+ ions. Using a multi-scale approach, whereby information taken from a low-level simulation approach is used to feed a high-level model, we studied the mechanism of K+ permeation through KcsA channels. More specifically, we used MD to find stable ion configurations under physiological conditions. They were characterized by two adjacent K+ ions occupying the more central positions of the SF (sites S2 and S3), while the other two K+ ions could be found at the external and internal entrances to the SF. Sites S1 and S4 were instead not occupied by K+. A continuum Bikerman–Poisson–Boltzmann model that takes into account the volume of the ions and their dehydration when entering the SF fully confirmed the MD results, showing peaks of K+ occupancy at S2, S3, and the external and internal entrances, with S1 and S4 sites being virtually never occupied by K+. Inspired by the newly found ion configuration in the SF at equilibrium, we developed a simple kinetic permeation model which, fed with kinetic rate constants assessed from molecular meta-dynamics, reproduced the main permeation properties of the KcsA channel found experimentally, including sublinear current-voltage and saturating conductance-concentration relationships. This good agreement with the experimental data also implies that the ion configuration in the SF we identified at equilibrium would also be a key configuration during permeation.
Neuroprotective Effects of Estrogen Through BDNF-Transient Receptor Potential Channels 6 Signaling Pathway in the Hippocampus in a Rat Model of Perimenopausal Depression
Authors: Song Qiaoli , Huang Weiming , Ye Wenbin , Yan Huan , Wang Liting , Yang Yan , Cheng Xi , Zhang Weiqiang , Zheng Jie , He Ping , He Yaojuan , Fang Dajun , Han Xinjia
Published: July 2022

Estradiol (E2) has been proven to be effective in treating perimenopausal depression (PD); however, the downstream signaling pathways have not been fully elucidated. Transient receptor potential channels 6 (TRPC6) plays a vital role in promoting neuronal development and the formation of excitatory synapses. At present, we found that the serum levels of E2 and brain-derived neurotrophic factor (BDNF) declined significantly in the women with PD compared to perimenopausal women, which was accompanied by a clear reduction in TRPC6 levels. To further reveal the effects of TRPC6 on neuronal survival and excitability, the PD-like rat model was established by the total removal of left ovary and 80% removal of right ovary followed by 21 days of the chronic unpredictable mild stress. Intragastric administration of E2 (2 mg/kg), intraperitoneal injection of BDNF/TrB signaling pathway inhibitor (K252a, 100 μg/kg) and TRPC6 agonist (OAG, 0.6 mg/kg), and intracerebroventricular infusion of anti-BDNF antibody for blocking BDNF (0.5 μg/24 μl/rat) daily for 21 days were conducted. The levels of BDNF and TRPC6 in rat serum were lower in PD rats compared to the control rats; the depression-like behavior was induced, the neuronal death rate in the hippocampus increased, and the thickness of postsynaptic density (PSD) and the number of asymmetric synapses decreased significantly in the PD group. E2 treatment greatly upregulated the serum levels of BDNF and TRPC6, the neuronal excitability indicated by an elevation in the PSD thickness and the numbers of asymmetric synapses, and these actions were reversed by K252a; co-administration of TRPC6 agonist and K252a improved neuronal degeneration and increased the neuronal excitability induced in the E2-treated PD rats. K252a or anti-BDNF antibody inhibited the increased neuronal BDNF and TRPC6 expression in E2-treated PD rats; co-treatment of TRPC6 agonist and anti-BDNF antibody reduced neuronal death and increased the BDNF and TRPC6 expression in the hippocampal CA1 neurons in the E2-treated PD rats. These results suggest that the neuroprotective role of E2 in PD is closely related to enhance the activity of BDNF/TRPC6 pathway and is helpful to provide new prevention and strategies.
Cognition Meets Gait: Where and How Mind and Body Weave Each Other in a Computational Psychometrics Approach in Aging
Authors: Bruni Francesca , Borghesi Francesca , Mancuso Valentina , Riva Giuseppe , Stramba-Badiale Marco , Pedroli Elisa , Cipresso Pietro
Published: July 2022

Aging may be associated with conditions characterized by motor and cognitive alterations, which could have a detrimental impact on daily life. Although motors and cognitive aspects have always been treated as separate entities, recent literature highlights their relationship, stressing a strong association between locomotion and executive functions. Thus, designing interventions targeting the risks deriving from both components’ impairments is crucial: the dual-task represents a starting point. Although its role in targeting and decreasing difficulties in aging is well known, most interventions are focused on a single domain, proposing a vertical model in which patients emerge only for a single aspect per time during assessment and rehabilitation. In this perspective, we propose a view of the individual as a whole between mind and body, suggesting a multicomponent and multidomain approach that could integrate different domains at the same time retracing lifelike situations. Virtual Reality, thanks to the possibility to develop daily environments with engaging challenges for patients, as well as to manage different devices to collect multiple data, provides the optimal scenario in which the integration could occur. Artificial Intelligence, otherwise, offers the best methodologies to integrate a great amount of various data to create a predictive model and identify appropriate and individualized interventions. Based on these assumptions the present perspective aims to propose the development of a new approach to an integrated, multimethod, multidimensional training in order to enhance cognition and physical aspects based on behavioral data, incorporating consolidated technologies in an innovative approach to neurology.
Characterizing and TRAPing a Social Stress-Activated Neuronal Ensemble in the Ventral Tegmental Area
Authors: Koutlas Ioannis , Linders Louisa E. , van der Starre Stef E. , Wolterink-Donselaar Inge G. , Adan Roger A. H. , Meye Frank J.
Published: July 2022

Social stress is a major contributor to neuropsychiatric issues such as depression, substance abuse and eating disorders. The ventral tegmental area (VTA) is involved in the effects of stress on cognitive and emotional processes perturbed in these disorders. However, the VTA is a cellularly heterogeneous brain area and it remains unclear which of its neuronal populations make up the social stress-sensitive ensemble. The current study characterizes the molecular, topographical and functional properties of VTA social stress-activated cells. First, we used immunohistochemical analysis of Fos protein, a marker of recent increased neuronal activity, to show that acute social stress activates a mainly neuronal ensemble in the VTA (VTASocial stress neurons). Topographical analysis showed that this ensemble, which comprises ∼11% of all VTA neurons, occurs across VTA subregions. Further analysis showed that approximately half of the VTASocial stress neurons express the dopamine synthesis rate-limiting enzyme tyrosine hydroxylase (TH). In a minority of cases this occurred with coexpression of vesicular glutamate transporter 2 (Vglut2). Also part of the ensemble were VTA cells expressing just Vglut2 without TH, and cells expressing the vesicular GABA transporter (VGAT) without TH. Next, using targeted recombination in active populations (TRAP2), we showed that VTASocial stress neurons can be permanently tagged and made tractable for future functional investigations. Using a combination of TRAP2 and patch-clamp electrophysiology we demonstrate that VTASocial stress neurons exhibit higher excitability than their non-TRAPed neighbor cells. Overall, this study shows that acute social stress activates an ensemble of neurons throughout the VTA, comprising distinct molecular identities, and with specific electrophysiological features. It also identifies TRAP2 as a tool to make this ensemble tractable for future functional studies.
UAV Based Indoor Localization and Objection Detection
Authors: Zhou Yimin , Yu Zhixiong , Ma Zhuang
Published: July 2022

This article targets fast indoor positioning and 3D target detection for unmanned aerial vehicle (UAV) real-time task implementation. With the combined direct method and feature method, a method is proposed for fast and accurate position estimation of the UAV. The camera pose is estimated by the visual odometer via the photometric error between the frames. Then the ORB features can be extended from the keyframes for the map consistency improvement by Bundle Adjustment with local and global optimization. A depth filter is also applied to assist the convergence of the map points with depth information updates from multiple frames. Moreover, the convolutional neural network is used to detect the specific target in an unknown space, while YOLOv3 is applied to obtain the semantic information of the target in the images. Thus, the spatial map points of the feature in the keyframes can be associated with the target detection box, while the statistical outlier filter can be simultaneously applied to eliminate the noise points. Experiments with public dataset, and field experiments on the established UAV platform in indoor environments have been carried out for visual based fast localization and object detection in real-time for the efficacy verification of the proposed method.
Progranulin Preserves Autophagy Flux and Mitochondrial Function in Rat Cortical Neurons Under High Glucose Stress
Authors: Dedert Cass , Mishra Vandana , Aggarwal Geetika , Nguyen Andrew D. , Xu Fenglian
Published: July 2022

Chronic hyperglycemia in type II diabetes results in impaired autophagy function, accumulation of protein aggregates, and neurodegeneration. However, little is known about how to preserve autophagy function under hyperglycemic conditions. In this study, we tested whether progranulin (PGRN), a neurotrophic factor required for proper lysosome function, can restore autophagy function in neurons under high-glucose stress. We cultured primary cortical neurons derived from E18 Sprague-Dawley rat pups to maturity at 10 days in vitro (DIV) before incubation in high glucose medium and PGRN for 24-72 h before testing for autophagy flux, protein turnover, and mitochondrial function. We found that although PGRN by itself did not upregulate autophagy, it attenuated impairments in autophagy seen under high-glucose conditions. Additionally, buildup of the autophagosome marker light chain 3B (LC3B) and lysosome marker lysosome-associated membrane protein 2A (LAMP2A) changed in both neurons and astrocytes, indicating a possible role for glia in autophagy flux. Protein turnover, assessed by remaining advanced glycation end-product levels after a 6-h incubation, was preserved with PGRN treatment. Mitochondrial activity differed by complex, although PGRN appeared to increase overall activity in high glucose. We also found that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3β (GSK3β), kinases implicated in autophagy function, increased with PGRN treatment under stress. Together, our data suggest that PGRN prevents hyperglycemia-induced decreases in autophagy by increasing autophagy flux via increased ERK1/2 kinase activity in primary rat cortical neurons.
Performance of Machine Learning for Tissue Outcome Prediction in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
Authors: Wang Xinrui , Fan Yiming , Zhang Nan , Li Jing , Duan Yang , Yang Benqiang
Published: July 2022

Machine learning (ML) has been proposed for lesion segmentation in acute ischemic stroke (AIS). This study aimed to provide a systematic review and meta-analysis of the overall performance of current ML algorithms for final infarct prediction from baseline imaging. We made a comprehensive literature search on eligible studies developing ML models for core infarcted tissue estimation on admission CT or MRI in AIS patients. Eleven studies meeting the inclusion criteria were included in the quantitative analysis. Study characteristics, model methodology, and predictive performance of the included studies were extracted. A meta-analysis was conducted on the dice similarity coefficient (DSC) score by using a random-effects model to assess the overall predictive performance. Study heterogeneity was assessed by Cochrane Q and Higgins I2 tests. The pooled DSC score of the included ML models was 0.50 (95% CI 0.39–0.61), with high heterogeneity observed across studies (I2 96.5%, p < 0.001). Sensitivity analyses using the one-study removed method showed the adjusted overall DSC score ranged from 0.47 to 0.52. Subgroup analyses indicated that the DL-based models outperformed the conventional ML classifiers with the best performance observed in DL algorithms combined with CT data. Despite the presence of heterogeneity, current ML-based approaches for final infarct prediction showed moderate but promising performance. Before well integrated into clinical stroke workflow, future investigations are suggested to train ML models on large-scale, multi-vendor data, validate on external cohorts and adopt formalized reporting standards for improving model accuracy and robustness.
Association of Serum Interleukin-8 and Serum Amyloid A With Anxiety Symptoms in Patients With Cerebral Small Vessel Disease
Authors: Shan Li-Li , Wang Yi-Lin , Qiao Tian-Ci , Bian Yue-Feng , Huo Ya-Jing , Guo Cen , Liu Qian-Yun , Yang Zi-Dong , Li Ze-Zhi , Liu Ming-Yuan , Han Yan
Published: July 2022

Objective

Cerebral small vessel disease (CSVD) is a clinical syndrome caused by pathological changes in small vessels. Anxiety is a common symptom of CSVD. Previous studies have reported the association between inflammatory factors and anxiety in other diseases, but this association in patients with CSVD remains uncovered. Our study aimed to investigate whether serum inflammatory factors correlated with anxiety in patients with CSVD.

Methods

A total of 245 CSVD patients confirmed using brain magnetic resonance imaging (MRI) were recruited from December 2019 to December 2021. Hamilton Anxiety Rating Scale (HAMA) was used to assess the anxiety symptoms of CSVD patients. Patients with HAMA scores ≥7 were considered to have anxiety symptoms. The serum levels of interleukin-1β (IL-1β), IL-2R, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), serum amyloid A (SAA), C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP) and erythrocyte sedimentation rate (ESR) were detected. We compared levels of inflammatory factors between the anxiety and non-anxiety groups. Logistic regression analyses examined the correlation between inflammatory factors and anxiety symptoms. We further performed a gender subgroup analysis to investigate whether this association differed by gender.

Results

In the fully adjusted multivariate logistic regression analysis model, we found that lower levels of IL-8 were linked to a higher risk of anxiety symptoms. Moreover, higher levels of SAA were linked to a lower risk of anxiety symptoms. Our study identified sex-specific effects, and the correlation between IL-8 and anxiety symptoms remained significant among males, while the correlation between SAA and anxiety symptoms remained significant among females.

Conclusions

In this study, we found a suggestive association between IL-8, SAA, and anxiety symptoms in CSVD participants. Furthermore, IL-8 and SAA may have a sex-specific relationship with anxiety symptoms.
Transient Motion Classification Through Turbid Volumes via Parallelized Single-Photon Detection and Deep Contrastive Embedding
Authors: Xu Shiqi , Liu Wenhui , Yang Xi , Jönsson Joakim , Qian Ruobing , McKee Paul , Kim Kanghyun , Konda Pavan Chandra , Zhou Kevin C. , Kreiß Lucas , Wang Haoqian , Berrocal Edouard , Huettel Scott A. , Horstmeyer Roarke
Published: July 2022

Fast noninvasive probing of spatially varying decorrelating events, such as cerebral blood flow beneath the human skull, is an essential task in various scientific and clinical settings. One of the primary optical techniques used is diffuse correlation spectroscopy (DCS), whose classical implementation uses a single or few single-photon detectors, resulting in poor spatial localization accuracy and relatively low temporal resolution. Here, we propose a technique termed ClassifyingRapid decorrelationEvents viaParallelized single photon dEtection (CREPE), a new form of DCS that can probe and classify different decorrelating movements hidden underneath turbid volume with high sensitivity using parallelized speckle detection from a 32 × 32 pixel SPAD array. We evaluate our setup by classifying different spatiotemporal-decorrelating patterns hidden beneath a 5 mm tissue-like phantom made with rapidly decorrelating dynamic scattering media. Twelve multi-mode fibers are used to collect scattered light from different positions on the surface of the tissue phantom. To validate our setup, we generate perturbed decorrelation patterns by both a digital micromirror device (DMD) modulated at multi-kilo-hertz rates, as well as a vessel phantom containing flowing fluid. Along with a deep contrastive learning algorithm that outperforms classic unsupervised learning methods, we demonstrate our approach can accurately detect and classify different transient decorrelation events (happening in 0.1–0.4 s) underneath turbid scattering media, without any data labeling. This has the potential to be applied to non-invasively monitor deep tissue motion patterns, for example identifying normal or abnormal cerebral blood flow events, at multi-Hertz rates within a compact and static detection probe.
Dosing Transcranial Magnetic Stimulation of the Primary Motor and Dorsolateral Prefrontal Cortices With Multi-Scale Modeling
Authors: Turi Zsolt , Hananeia Nicholas , Shirinpour Sina , Opitz Alexander , Jedlicka Peter , Vlachos Andreas
Published: July 2022

Transcranial magnetic stimulation (TMS) can depolarize cortical neurons through the intact skin and skull. The characteristics of the induced electric field (E-field) have a major impact on specific outcomes of TMS. Using multi-scale computational modeling, we explored whether the stimulation parameters derived from the primary motor cortex (M1) induce comparable macroscopic E-field strengths and subcellular/cellular responses in the dorsolateral prefrontal cortex (DLPFC). To this aim, we calculated the TMS-induced E-field in 16 anatomically realistic head models and simulated the changes in membrane voltage and intracellular calcium levels of morphologically and biophysically realistic human pyramidal cells in the M1 and DLPFC. We found that the conventional intensity selection methods (i.e., motor threshold and fixed intensities) produce variable macroscopic E-fields. Consequently, it was challenging to produce comparable subcellular/cellular responses across cortical regions with distinct folding characteristics. Prospectively, personalized stimulation intensity selection could standardize the E-fields and the subcellular/cellular responses to repetitive TMS across cortical regions and individuals. The suggested computational approach points to the shortcomings of the conventional intensity selection methods used in clinical settings. We propose that multi-scale modeling has the potential to overcome some of these limitations and broaden our understanding of the neuronal mechanisms for TMS.
Predicting the Degree of Distracted Driving Based on fNIRS Functional Connectivity: A Pilot Study
Authors: Ogihara Takahiko , Tanioka Kensuke , Hiroyasu Tomoyuki , Hiwa Satoru
Published: July 2022

Distracted driving is one of the main causes of traffic accidents. By predicting the attentional state of drivers, it is possible to prevent distractions and promote safe driving. In this study, we developed a model that could predict the degree of distracted driving based on brain activity. Changes in oxyhemoglobin concentrations were measured in drivers while driving a real car using functional near-infrared spectroscopy (fNIRS). A regression model was constructed for each participant using functional connectivity as an explanatory variable and brake reaction time to random beeps while driving as an objective variable. As a result, we were able to construct a prediction model with the mean absolute error of 5.58 × 102 ms for the BRT of the 12 participants. Furthermore, the regression model with the highest prediction accuracy for each participant was analyzed to gain a better understanding of the neural basis of distracted driving. The 11 of 12 models that showed significant accuracy were classified into five clusters by hierarchical clustering based on their functional connectivity edges used in each cluster. The results showed that the combinations of the dorsal attention network (DAN)-sensory-motor network (SMN) and DAN-ventral attention network (VAN) connections were common in all clusters and that these networks were essential to predict the degree of distraction in complex multitask driving. They also confirmed the existence of multiple types of prediction models with different within- and between-network connectivity patterns. These results indicate that it is possible to predict the degree of distracted driving based on the driver's brain activity during actual driving. These results are expected to contribute to the development of safe driving systems and elucidate the neural basis of distracted driving.
Tuning Neural Synchronization: The Role of Variable Oscillation Frequencies in Neural Circuits
Authors: Lowet Eric , De Weerd Peter , Roberts Mark J. , Hadjipapas Avgis
Published: July 2022

Brain oscillations emerge during sensory and cognitive processes and have been classified into different frequency bands. Yet, even within the same frequency band and between nearby brain locations, the exact frequencies of brain oscillations can differ. These frequency differences (detuning) have been largely ignored and play little role in current functional theories of brain oscillations. This contrasts with the crucial role that detuning plays in synchronization theory, as originally derived in physical systems. Here, we propose that detuning is equally important to understand synchronization in biological systems. Detuning is a critical control parameter in synchronization, which is not only important in shaping phase-locking, but also in establishing preferred phase relations between oscillators. We review recent evidence that frequency differences between brain locations are ubiquitous and essential in shaping temporal neural coordination. With the rise of powerful experimental techniques to probe brain oscillations, the contributions of exact frequency and detuning across neural circuits will become increasingly clear and will play a key part in developing a new understanding of the role of oscillations in brain function.