bluuebunny/crossref_metadata_2025 huggingface dataset:
How Toll-like receptors influence Parkinson’s disease in the microbiome–gut–brain axis
Authors: Zhang Ziyi , Liu Zhihui , Lv Ao , Fan Chenhui
Published: May 2023

Recently, a large number of experimenters have found that the pathogenesis of Parkinson’s disease may be related to the gut microbiome and proposed the microbiome–gut–brain axis. Studies have shown that Toll-like receptors, especially Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), are key mediators of gut homeostasis. In addition to their established role in innate immunity throughout the body, research is increasingly showing that the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways shape the development and function of the gut and enteric nervous system. Notably, Toll-like receptor 2 and Toll-like receptor 4 are dysregulated in Parkinson’s disease patients and may therefore be identified as the core of early gut dysfunction in Parkinson’s disease. To better understand the contribution of Toll-like receptor 2 and Toll-like receptor 4 dysfunction in the gut to early α-synuclein aggregation, we discussed the structural function of Toll-like receptor 2 and Toll-like receptor 4 and signal transduction of Toll-like receptor 2 and Toll-like receptor 4 in Parkinson’s disease by reviewing clinical, animal models, and in vitro studies. We also present a conceptual model of the pathogenesis of Parkinson’s disease, in which microbial dysbiosis alters the gut barrier as well as the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways, ultimately leading to a positive feedback loop for chronic gut dysfunction, promoting α-synuclein aggregation in the gut and vagus nerve.
Naproxen chemoprevention induces proliferation of cytotoxic lymphocytes in Lynch Syndrome colorectal mucosa
Authors: Bowen Charles M. , Deng Nan , Reyes-Uribe Laura , Parra Edwin Roger , Rocha Pedro , Solis Luisa M. , Wistuba Ignacio I. , Sepeda Valerie O. , Vornik Lana , Perloff Marjorie , Szabo Eva , Umar Asad , Sinha Krishna M. , Brown Powel H. , Vilar Eduardo
Published: May 2023

Background

Recent clinical trial data from Lynch Syndrome (LS) carriers demonstrated that naproxen administered for 6-months is a safe primary chemoprevention that promotes activation of different resident immune cell types without increasing lymphoid cellularity. While intriguing, the precise immune cell types enriched by naproxen remained unanswered. Here, we have utilized cutting-edge technology to elucidate the immune cell types activated by naproxen in mucosal tissue of LS patients.

Methods

Normal colorectal mucosa samples (pre- and post-treatment) from a subset of patients enrolled in the randomized and placebo-controlled ‘Naproxen Study’ were obtained and subjected to a tissue microarray for image mass cytometry (IMC) analysis. IMC data was processed using tissue segmentation and functional markers to ascertain cell type abundance. Computational outputs were then used to quantitatively compare immune cell abundance in pre- and post-naproxen specimens.

Results

Using data-driven exploration, unsupervised clustering identified four populations of immune cell types with statistically significant changes between treatment and control groups. These four populations collectively describe a unique cell population of proliferating lymphocytes within mucosal samples from LS patients exposed to naproxen.

Conclusions

Our findings show that daily exposure of naproxen promotes T-cell proliferation in the colonic mucosa, which paves way for developing combination of immunoprevention strategies including naproxen for LS patients.
Turicibacter and Acidaminococcus predict immune-related adverse events and efficacy of immune checkpoint inhibitor
Authors: Hamada Kazuyuki , Isobe Junya , Hattori Kouya , Hosonuma Masahiro , Baba Yuta , Murayama Masakazu , Narikawa Yoichiro , Toyoda Hitoshi , Funayama Eiji , Tajima Kohei , Shida Midori , Hirasawa Yuya , Tsurui Toshiaki , Ariizumi Hirotsugu , Ishiguro Tomoyuki , Suzuki Risako , Ohkuma Ryotaro , Kubota Yutaro , Sambe Takehiko , Tsuji Mayumi , Wada Satoshi , Kiuchi Yuji , Kobayashi Shinichi , Kuramasu Atsuo , Horiike Atsushi , Kim Yun-Gi , Tsunoda Takuya , Yoshimura Kiyoshi
Published: May 2023

Introduction

Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown.

Methods

We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).

Results

The genera Prevotella and Parabacteroides were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of Catenibacterium (P = 0.022) and Turicibacter (P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of Desulfovibrion (P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of Turicibacter (P = 0.001) and Acidaminococcus (P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of Blautia (P = 0.013) and the unclassified Clostridiales (P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group, Acidaminococcus and Turicibacter (both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast, Blautia (P = 0.021) and Bilophila (P= 0.033) were statistically significantly more common in those without irAEs.

Discussion

Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.
Revisiting Aire and tissue-restricted antigens at single-cell resolution
Authors: Matsumoto Minoru , Yoshida Hideyuki , Tsuneyama Koichi , Oya Takeshi , Matsumoto Mitsuru
Published: May 2023

The thymus is a highly specialized organ that plays an indispensable role in the establishment of self-tolerance, a process characterized by the “education” of developing T-cells. To provide competent T-cells tolerant to self-antigens, medullary thymic epithelial cells (mTECs) orchestrate negative selection by ectopically expressing a wide range of genes, including various tissue-restricted antigens (TRAs). Notably, recent advancements in the high-throughput single-cell analysis have revealed remarkable heterogeneity in mTECs, giving us important clues for dissecting the mechanisms underlying TRA expression. We overview how recent single-cell studies have furthered our understanding of mTECs, with a focus on the role of Aire in inducing mTEC heterogeneity to encompass TRAs.
Cell membrane-bound toll-like receptor-1/2/4/6 monomers and -2 heterodimer inhibit enterovirus 71 replication by activating the antiviral innate response
Authors: Sun Ping-Ping , Li Dan , Su Meng , Ren Qing , Guo Wen-Ping , Wang Jiang-Li , Du Luan-Ying , Xie Guang-Cheng
Published: May 2023

Host immune activation is critical for enterovirus 71 (EV71) clearance and immunopathogenesis. However, the mechanism of innate immune activation, especially of cell membrane-bound toll-like receptors (TLRs), against EV71 remains unknown. We previously demonstrated that TLR2 and its heterodimer inhibit EV71 replication. In this study, we systematically investigated the effects of TLR1/2/4/6 monomers and TLR2 heterodimer (TLR2/TLR1, TLR2/TLR6, and TLR2/TLR4) on EV71 replication and innate immune activation. We found that the overexpression of human- or mouse-derived TLR1/2/4/6 monomers and TLR2 heterodimer significantly inhibited EV71 replication and induced the production of interleukin (IL)-8 via activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways. Furthermore,human–mouse chimeric TLR2 heterodimer inhibited EV71 replication and activated innate immunity. Dominant-negative TIR-less (DN)-TLR1/2/4/6 did not exert any inhibitory effects, whereas DN-TLR2 heterodimer inhibited EV71 replication. Prokaryotic expression of purified recombinant EV71 capsid proteins (VP1, VP2, VP3, and VP4) or overexpression of EV71 capsid proteins induced the production of IL-6 and IL-8 via activation of the PI3K/AKT and MAPK pathways. Notably, two types of EV71 capsid proteins served as pathogen-associated molecular patterns for TLR monomers (TLR2 and TLR4) and TLR2 heterodimer (TLR2/TLR1, TLR2/TLR6, and TLR2/TLR4) and activated innate immunity. Collectively, our results revealed that membrane TLRs inhibited EV71 replication via activation of the antiviral innate response, providing insights into the EV71 innate immune activation mechanism.
Efficient ex vivo expansion of conserved element vaccine-specific CD8+ T-cells from SHIV-infected, ART-suppressed nonhuman primates
Authors: Dross Sandra , Venkataraman Rasika , Patel Shabnum , Huang Meei-Li , Bollard Catherine M. , Rosati Margherita , Pavlakis George N. , Felber Barbara K. , Bar Katharine J. , Shaw George M. , Jerome Keith R. , Mullins James I. , Kiem Hans-Peter , Fuller Deborah Heydenburg , Peterson Christopher W.
Published: May 2023

HIV-specific T cells are necessary for control of HIV-1 replication but are largely insufficient for viral clearance. This is due in part to these cells’ recognition of immunodominant but variable regions of the virus, which facilitates viral escape via mutations that do not incur viral fitness costs. HIV-specific T cells targeting conserved viral elements are associated with viral control but are relatively infrequent in people living with HIV (PLWH). The goal of this study was to increase the number of these cells via an ex vivo cell manufacturing approach derived from our clinically-validated HIV-specific expanded T-cell (HXTC) process. Using a nonhuman primate (NHP) model of HIV infection, we sought to determine i) the feasibility of manufacturing ex vivo-expanded virus-specific T cells targeting viral conserved elements (CE, CE-XTCs), ii) the in vivo safety of these products, and iii) the impact of simian/human immunodeficiency virus (SHIV) challenge on their expansion, activity, and function. NHP CE-XTCs expanded up to 10-fold following co-culture with the combination of primary dendritic cells (DCs), PHA blasts pulsed with CE peptides, irradiated GM-K562 feeder cells, and autologous T cells from CE-vaccinated NHP. The resulting CE-XTC products contained high frequencies of CE-specific, polyfunctional T cells. However, consistent with prior studies with human HXTC and these cells’ predominant CD8+ effector phenotype, we did not observe significant differences in CE-XTC persistence or SHIV acquisition in two CE-XTC-infused NHP compared to two control NHP. These data support the safety and feasibility of our approach and underscore the need for continued development of CE-XTC and similar cell-based strategies to redirect and increase the potency of cellular virus-specific adaptive immune responses.
Lipopolysaccharide-induced immune stress negatively regulates broiler chicken growth via the COX-2-PGE2-EP4 signaling pathway
Authors: Liu Kexin , Zhen Wenrui , Bai Dongying , Tan Haiqiu , He Xianglong , Li Yuqian , Liu Yanhao , Zhang Yi , Ito Koichi , Zhang Bingkun , Ma Yanbo
Published: May 2023

Aims

Immune stress in broiler chickens is characterized by the development of persistent pro-inflammatory responses that contribute to degradation of production performance. However, the underlying mechanisms that cause growth inhibition of broilers with immune stress are not well defined.

Methods

A total of 252 1-day-old Arbor Acres(AA) broilers were randomly allocated to three groups with six replicates per group and 14 broilers per replicate. The three groups comprised a saline control group, an Lipopolysaccharide (LPS) (immune stress) group, and an LPS and celecoxib group corresponding to an immune stress group treated with a selective COX-2 inhibitor. Birds in LPS group and saline group were intraperitoneally injected with the same amount of LPS or saline from 14d of age for 3 consecutive days. And birds in the LPS and celecoxib group were given a single intraperitoneal injection of celecoxib 15 min prior to LPS injection at 14 d of age.

Results

The feed intake and body weight gain of broilers were suppressed in response to immune stress induced by LPS which is an intrinsic component of the outer membrane of Gram-negative bacteria. Cyclooxygenase-2 (COX-2), a key enzyme that mediates prostaglandin synthesis, was up-regulated through MAPK-NF-κB pathways in activated microglia cells in broilers exposed to LPS. Subsequently, the binding of prostaglandin E2 (PGE2) to the EP4 receptor maintained the activation of microglia and promoted the secretion of cytokines interleukin-1β and interleukin-8, and chemokines CX3CL1 and CCL4. In addition, the expression of appetite suppressor proopiomelanocortin protein was increased and the levels of growth hormone-releasing hormone were reduced in the hypothalamus. These effects resulted in decreased expression of insulin-like growth factor in the serum of stressed broilers. In contrast, inhibition of COX-2 normalized pro-inflammatory cytokine levels and promoted the expression of Neuropeptide Y and growth hormone-releasing hormone in the hypothalamus which improved the growth performance of stressed broilers. Transcriptomic analysis of the hypothalamus of stressed broilers showed that inhibition of COX-2 activity significantly down-regulated the expression of the TLR1B, IRF7, LY96, MAP3K8, CX3CL1, and CCL4 genes in the MAPK-NF-κB signaling pathway.

Conclusion

This study provides new evidence that immune stress mediates growth suppression in broilers by activating the COX-2-PGE2-EP4 signaling axis. Moreover, growth inhibition is reversed by inhibiting the activity of COX-2 under stressed conditions. These observations suggest new approaches for promoting the health of broiler chickens reared in intensive conditions.
Different behaviors of organic matter under physical-biological controls in the eastern Indian Ocean
Authors: Zhang Yixue , Wu Ying , Zhang Jing , Xu Yi , Huang Ke , Jin Jie , Dai Jinlong , Ye Qi , Li Jian , Zhang Zhenqiu
Published: May 2023

Marine organic matter (OM) pools are the key to understanding biogeochemical cycles and carbon storage, especially under ongoing ocean warming. The tropical eastern Indian Ocean (IO) is ideal for unraveling marine OM pools for being one of the least understood ocean basins in terms of its complex physical and biogeochemical dynamics. So far, OM transformation and export remain underexplored and enigmatic in the IO. Here, we integrated in situ observations and incubation experiments in the Central IO (CIO) and Bay of Bengal (BoB). A large OM pool was found in the CIO, where we emphasized the prominent contribution of production in the deep euphotic layer, with physical forcing seasonally playing a supporting role. The dissolved organic matter (DOM)-degradation experiment results revealed high efficiency of in situ DOM consumption in the BoB, whereas dark carbon fixation by ammonia-oxidizing microorganisms was considered an alternative strategy in the euphotic CIO. Water mixing was found to highly influence the OM pools in the mesopelagic waters in the tropical eastern IO, but active microbial respiration could also regulate the OM degradation in the CIO. Our results emphasized the heterogeneity of OM pools between the BoB and CIO, and stated their different regulators of carbon reservoir considering an ocean warming scenario.
Transcriptome analysis of germ cell changes in male Chinese mitten crabs (Eriocheir sinensis) induced by rhizocephalan parasite, Polyascus gregaria
Authors: Feng Chengcheng , Zhang Jinbing , Bao Jie , Luan Daiwei , Jiang Ning , Chen Qijun
Published: May 2023

The parasitism by Polyascus gregaria on Eriocheir sinensis induces feminization of the appearance of male crabs, misleading fishermen to bring them to the breeding ponds as female crabs to cultivate broodstock selection. However, there are few studies on whether P. gregaria feminizes the male germ cells, resulting in a decline in the fecundity of male crabs. Therefore, this study aims to clarify the changes in gene expression levels of male crab testes after being parasitized by P. gregaria through transcriptome sequencing to evaluate the change in fecundity. We selected parasitized and healthy male crabs from a pond culture for comparison of gene expression in germ cells. The results showed that, compared with healthy male crabs, there were 104 genes with significantly different expressions, of which 79 were up-regulated and 25 were down-regulated. These genes are mainly focused on the cytoskeleton pathway in cell components and cellular protein complex assembly in biological processes. Several spermatogenesis-related genes, such as Kazal-type protease inhibitor, which inhibits gelatinolytic activities of sperm proteases, and juvenile hormone esterase 6, which degrades methyl farnesoate, were up-regulated; while the down-regulated expression of certain heat shock proteins may lead to spermatogenic dysfunction. In addition, some immune-related genes, such as double whey acidic protein domain-containing protein and serine proteinase inhibitor 3, were significantly up-regulated. These results indicated that P. gregaria changed the development process and cell structure of male host germ cells to inhibit sperm proliferation and maturation, while multiple immune pathways in the hosts were activated to resist P. gregaria invasion.
Dietary hydrolyzable tannins reduce growth performance and induce histological damage of Chinese seabass (Lateolabrax maculatus)
Authors: Qiu Jianqiang , Huang Wen , Cao Junming , Zhao Hongxia , Chen Bing , Jiun-Yan Loh , Peng Kai
Published: May 2023

Chinese seabass (Lateolabrax maculatus) is a popular carnivorous fish with delicious taste. Although the feed value of condensed tannins has been well documented for L. maculatus, information about the effects of hydrolyzable tannins (HTs) on the growth and health of L. maculatus is limited. This study was conducted to assess the effects of dietary HTs on growth performance, body composition, intestinal digestive enzyme activities, serum metabolites, antioxidant and immune response, and intestine and liver morphology of L. maculatus. A total of 640 fish were randomly divided into four groups with four replicates per group and 40 fish per replicate. Four diets were prepared to contain 0 (G0), 1 (G1), 2 (G2), and 4 (G4) g/kg of HTs. Fish were fed to apparent satiation twice a day during the 56-day feeding trial. Results showed that the final body weight, weight gain rate, specific growth rate, and feed intake were linearly decreased (p< 0.001) as dietary HTs increased. All fish had similar (p > 0.05) whole body compositions. Fish fed G2 and G4 had lower (p< 0.05) intestinal trypsin and lipase activities than those fed G0 and G1, whereas G4 had higher (p< 0.05) aspartate aminotransferase and alanine aminotransferase activities than G0. Serum total antioxidant capacity and lysozyme were linearly decreased (p< 0.01), but the malondialdehyde concentration was linearly increased (p< 0.01) as dietary HTs increased. Intestinal villi in G2 and G4 showed increased deformation, and the vacuolation of liver cells began to appear in G1 and was aggravated as dietary HTs increased. This study showed that HTs should be used with caution due to their growth-inhibiting effect, and the dietary HT level for L. maculatus is recommended to be less than 1 g/kg.
Investigating volatile compounds in the Bacteroides secretome
Authors: Shagaleeva Olga Yu , Kashatnikova Daria A. , Kardonsky Dmitry A. , Konanov Dmitry N. , Efimov Boris A. , Bagrov Dmitry V. , Evtushenko Evgeniy G. , Chaplin Andrei V. , Silantiev Artemiy S. , Filatova Julia V. , Kolesnikova Irina V. , Vanyushkina Anna A. , Stimpson Joanna , Zakharzhevskaya Natalya B.
Published: May 2023

Microorganisms and their hosts communicate with each other by secreting numerous components. This cross-kingdom cell-to-cell signaling involves proteins and small molecules, such as metabolites. These compounds can be secreted across the membrane via numerous transporters and may also be packaged in outer membrane vesicles (OMVs). Among the secreted components, volatile compounds (VOCs) are of particular interest, including butyrate and propionate, which have proven effects on intestinal, immune, and stem cells. Besides short fatty acids, other groups of volatile compounds can be either freely secreted or contained in OMVs. As vesicles might extend their activity far beyond the gastrointestinal tract, study of their cargo, including VOCs, is even more pertinent. This paper is devoted to the VOCs secretome of the Bacteroides genus. Although these bacteria are highly presented in the intestinal microbiota and are known to influence human physiology, their volatile secretome has been studied relatively poorly. The 16 most well-represented Bacteroides species were cultivated; their OMVs were isolated and characterized by NTA and TEM to determine particle morphology and their concentration. In order to analyze the VOCs secretome, we propose a headspace extraction with GC–MS analysis as a new tool for sample preparation and analysis of volatile compounds in culture media and isolated bacterial OMVs. A wide range of released VOCs, both previously characterized and newly described, have been revealed in media after cultivation. We identified more than 60 components of the volatile metabolome in bacterial media, including fatty acids, amino acids, and phenol derivatives, aldehydes and other components. We found active butyrate and indol producers among the analyzed Bacteroides species. For a number of Bacteroides species, OMVs have been isolated and characterized here for the first time as well as volatile compounds analysis in OMVs. We observed a completely different distribution of VOC in vesicles compared to the bacterial media for all analyzed Bacteroides species, including almost complete absence of fatty acids in vesicles. This article provides a comprehensive analysis of the VOCs secreted by Bacteroides species and explores new perspectives in the study of bacterial secretomes in relation the intercellular communication.
Catechol siderophores framed on 2,3-dihydroxybenzoyl-L-serine from Streptomyces varsoviensis
Authors: Liu Zhixiang , Huang Tingting , Shi Qing , Deng Zixin , Lin Shuangjun
Published: May 2023

Enterobactin is an archetypical catecholate siderophore that plays a key role in the acquisition of ferric iron by microorganisms. Catechol moieties have been shown to be promising siderophore cores. Variants of the conserved 2,3-dihydroxybenzoate (DHB) moiety with structural modifications expand the bioactivity. Streptomyces are characterized by metabolites with diverse structures. The genomic sequence of Streptomyces varsoviensis indicated that it possessed a biosynthetic gene cluster for DHB containing siderophores and metabolic profiling revealed metabolites correlated with catechol-type natural products. Here, we report the discovery of a series of catecholate siderophores produced by S. varsoviensis and a scale-up fermentation was performed to purify these compounds for structural elucidation. A biosynthetic route for the catecholate siderophores is also proposed. These new structural features enrich the structural diversity of the enterobactin family compounds. One of the new linear enterobactin congeners shows moderate activity against a food-borne pathogen Listeria monocytogenes. This work demonstrated that changing culture conditions is still a promising approach to explore unexplored chemical diversity. The availability of the biosynthetic machinery will enrich the genetic toolbox of catechol siderophores and facilitate such engineering efforts.
Choose your tools carefully: a comparative evaluation of deterministic vs. stochastic and binary vs. analog neuron models for implementing emerging computing paradigms
Authors: Morshed Md Golam , Ganguly Samiran , Ghosh Avik W.
Published: May 2023

Neuromorphic computing, commonly understood as a computing approach built upon neurons, synapses, and their dynamics, as opposed to Boolean gates, is gaining large mindshare due to its direct application in solving current and future computing technological problems, such as smart sensing, smart devices, self-hosted and self-contained devices, artificial intelligence (AI) applications, etc. In a largely software-defined implementation of neuromorphic computing, it is possible to throw enormous computational power or optimize models and networks depending on the specific nature of the computational tasks. However, a hardware-based approach needs the identification of well-suited neuronal and synaptic models to obtain high functional and energy efficiency, which is a prime concern in size, weight, and power (SWaP) constrained environments. In this work, we perform a study on the characteristics of hardware neuron models (namely, inference errors, generalizability and robustness, practical implementability, and memory capacity) that have been proposed and demonstrated using a plethora of emerging nano-materials technology-based physical devices, to quantify the performance of such neurons on certain classes of problems that are of great importance in real-time signal processing like tasks in the context of reservoir computing. We find that the answer on which neuron to use for what applications depends on the particulars of the application requirements and constraints themselves, i.e., we need not only a hammer but all sorts of tools in our tool chest for high efficiency and quality neuromorphic computing.
Does the functional polymorphism-1562C/T of MMP-9 gene influence brain disorders?
Authors: Pabian-Jewuła Sylwia , Rylski Marcin
Published: May 2023

Metalloproteinase-9 (MMP-9) is one of the most strongly expressed matrix metalloproteinases (MMPs) in the brain. The MMP-9 activity in the brain is strictly regulated, and any disruptions in this regulation contribute to a development of many disorders of the nervous system including multiple sclerosis, brain strokes, neurodegenerative disorders, brain tumors, schizophrenia, or Guillain-Barré syndrome. This article discusses a relationship between development of the nervous system diseases and the functional single nucleotide polymorphism (SNP) at position -1562C/T within the MMP-9 gene. A pathogenic influence of MMP-9-1562C/T SNP was observed both in neurological and psychiatric disorders. The presence of the allele T often increases the activity of the MMP-9 gene promoter and consequently the expression of MMP-9 when compared to the allele C. This leads to a change in the likelihood of an occurrence of diseases and modifies the course of certain brain diseases in humans, as discussed below. The presented data indicates that the MMP-9-1562C/T functional polymorphism influences the course of many neuropsychiatric disorders in humans suggesting a significant pathological role of the MMP-9 metalloproteinase in pathologies of the human central nervous system.
Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome
Authors: Mavashov Anat , Brusel Marina , Liu Jiaxing , Woytowicz Victoria , Bae Haneui , Chen Ying-Hsin , Dani Vardhan S. , Cardenal-Muñoz Elena , Spinosa Vittoria , Aibar José Ángel , Rubinstein Moran
Published: May 2023

Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ∼20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic phenotypes of a novel preclinical Dravet mouse model harboring the R613X nonsense Scn1a mutation. Scn1aWT/R613X mice, on a mixed C57BL/6J:129S1/SvImJ background, exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, modeling some non-epileptic Dravet-associated phenotypes. Conversely, Scn1aWT/R613X mice, on the pure 129S1/SvImJ background, had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice (pure 129S1/SvImJ background) died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and NaV1.1 protein levels to ∼50% in heterozygous Scn1aWT/R613X mice (on either genetic background), with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet.
Examining the neural mechanisms of rTMS: a naturalistic pilot study of acute and serial effects in pharmacoresistant depression
Authors: Cosmo Camila , Zandvakili Amin , Petrosino Nicholas J. , Toutain Thaise Graziele L. de O. , Miranda José Garcia Vivas , Philip Noah S.
Published: May 2023

Introduction

Previous studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course.

Methods

A total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR).

Results

We found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820,p= 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37,p= 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093,p= 0.017) and IDS-SR (t (14) = 2.5278,p= 0.024) and progressed along the treatment course.

Discussion

Our findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response.
Changes in self-other boundaries modulate children’s body image attitudes
Authors: Cook Caryn , Crucianelli Laura , Filippetti Maria Laura
Published: May 2023

One’s own face is a key distinctive feature of our physical appearance, yet multisensory visuo-tactile stimulation can alter self-other boundaries, eliciting changes in adult’s self-face representation and social cognition processes. This study tested whether changing self-face representation by altering self-other boundaries with the enfacement illusion modulates body image attitudes toward others in 6−11-year-old children (N = 51; 31 girls; predominantly White). Across all ages, congruent multisensory information led to stronger enfacement (η2p = 0.06). Participants who experienced a stronger enfacement illusion showed preference for larger body size, suggesting increased positive body size attitudes. This effect was stronger in 6–7-year-olds compared to 8–9-year-olds. Thus, blurring self-other boundaries successfully modulates self-face representation and body image attitudes toward others in children. Our results suggest that increased self-resemblance through self-other blurring resulting from the enfacement illusion may reduce social comparisons between self and other and result in positive body size attitudes.
Multiple sclerosis and breast cancer risk: a meta-analysis of observational and Mendelian randomization studies
Authors: Fang Tian , Zhang Zhihao , Zhou Huijie , Wu Wanchun , Zou Liqun
Published: May 2023

Background

Several observational studies have explored the relationships between multiple sclerosis (MS) and breast cancer; however, whether an association exists remains unknown.

Methods

We conducted a meta-analysis of observational studies and Mendelian randomization (MR) based on genetic variants to identify the relationship between MS and breast cancer. The observational studies were searched from PubMed, Embase, Web of Science, and Scopus to assess the relationship between MS and breast cancer from inception to 07 Nov 2022. Moreover, we explored the association between genetically pre-disposed MS and breast cancer risk based on an MR study. The summary analysis for MS from two separate databases [International Multiple Sclerosis Genetics Consortium (IMSGC), FinnGen] and the summary analysis for breast cancer from Breast Cancer Association Consortium.

Results

Fifteen cohort studies involving 173,565 female MS patients were included in this meta-analysis. The correlation between MS and breast cancer was not statistically significant [relative ratio (RR) = 1.08, 95% confidence interval (CI) = 0.99–1.17]. In the MR analysis, we did not observe causal associations of genetically determined MS with breast cancer and its subtypes from both the IMSGC and FinnGen datasets.

Conclusion

The meta-analysis of observational and MR based on genetic variants does not support the correlation between MS and breast cancer.
Effect and mechanisms of exercise for complex regional pain syndrome
Authors: Li Tian-Shu , Wang Rui , Su Xuan , Wang Xue-Qiang
Published: May 2023

Complex regional pain syndrome characterized by severe pain and dysfunction seriously affects patients’ quality of life. Exercise therapy is gaining attention because it can effectively relieve pain and improve physical function. Based on the previous studies, this article summarized the effectiveness and underlying mechanisms of exercise interventions for complex regional pain syndrome, and described the gradual multistage exercise program. Exercises suitable for patients with complex regional pain syndrome mainly include graded motor imagery, mirror therapy, progressive stress loading training, and progressive aerobic training. In general, exercise training for patients with complex regional pain syndrome not only alleviates pain but also improves physical function and positive mental status. The underlying mechanisms of exercise interventions for complex regional pain syndrome include the remodeling of abnormal central and peripheral nervous system, the regulation of vasodilation and adrenaline levels, the release of endogenous opioids, and the increased anti-inflammatory cytokines. This article provided a clear explanation and summary of the research on exercise for complex regional pain syndrome. In the future, more high-quality studies with sufficient sample sizes may provide more exercise regimens and better evidence of efficacy.
Clinical validation of the novel CLIA-CA-62 assay efficacy for early-stage breast cancer detection
Authors: Sekacheva Marina , Boroda Alexander , Fatyanova Anastasia , Rozhkov Alexander , Bagmet Nikolai
Published: May 2023

Background

Without organized screening programs up to 60-70% of breast cancers are diagnosed at advanced stages that have significantly lower five-year survival rate and poorer outcomes, which is a serious global public health problem. The purpose of the blind clinical study was the assessment of the novel in-vitro diagnostic chemiluminescent CLIA-CA-62 assay for early-stage breast cancer detection.

Methods

Blind serum samples of 196 BC patients with known TNM staging, 85% with DCIS, Stage I & IIA, and 73 healthy control subjects were analyzed with the CLIA-CA-62 and CA 15-3 ELISA assays. Results were also compared to the pathology findings and to published data from mammography, MRI, ultrasound, and multi-cancer early detection test (MCED).

Results

The CLIA-CA-62 overall sensitivity for BC was 92% (100% for DCIS) at 93% specificity and it decreased in invasive stages (Stage I=97%, Stage II=85% and Stage III=83%). For the CA 15-3 assay sensitivity was 27-46% at 80% specificity. Sensitivity for mammography was 63-80% at 60% specificity, depending on the stage and the parenchymal density.

Conclusion

These results demonstrate that CLIA-CA-62 immunoassay could prove useful as a supplement to current mammography screening and other imaging methods, thus increasing the diagnostic sensitivity in DCIS and Stage I breast cancer detection.
WIPI2 enhances the vulnerability of colorectal cancer cells to erastin via bioinformatics analysis and experimental verification
Authors: Yu Liying , Luo Yan , Ding Xile , Tang Miaomiao , Gao Huan , Zhang Renfang , Chen Mingfu , Liu Yuchen , Chen Qiongxia , Ouyang Yanli , Wang Xiang , Zhen Hongyan
Published: May 2023

Introduction

WD Repeat Domain Phosphoinositide Interacting 2 (WIPI2) is a WD repeat protein that interacts with phosphatidylinositol and regulates multiprotein complexes by providing a b-propeller platform for synchronous and reversible protein-protein interactions assembled proteins. Ferroptosis is a novel iron-dependent form of cell death. It is usually accompanied with the accumulation of membrane lipid peroxides. Our study is to focus on investigating the effect of WIPI2 on the growth and ferroptosis of colorectal cancer (CRC) cells and its potential mechanism.

Methods

We analyzed the expression of WIPI2 in colorectal cancer versus normal tissues through The Cancer Genome Atlas (TCGA), and the relationship between clinical traits and WIPI2 expression and prognosis was assessed by univariate and multifactorial cox analysis. Next, we constructed the siRNAs targeting the WIPI2 sequence si-WIPI2 to further investigate the mechanism of WIPI2 in CRC cells through vitro experiments.

Results

Public data from the TCGA platform showed that WIPI2 expression was significantly elevated in colorectal cancer tissues compared to paracancerous tissues, and high WIPI2 expressionpredicted poor prognosis for CRC patients. Moreover, we found that the knockdown of WIPI2 expression could inhibit the growth and proliferation of HCT116 and HT29 cells. Furthermore, we found that the expression level of ACSL4 decreased and that of GPX4 increased when WIPI2 was knocked down, suggesting that WIPI2 can potentially positively regulate CRC ferroptosis. Meanwhile, both NC and si groups were able to further inhibit cell growth activity, as well as increase WIPI2 and decrease GPX4 expression when treated with Erastin, but the rate of cell viability inhibition and the trend of protein changes were more significantly in the NC group than si groups, which indicated that Erastin induced CRC ferroptosis through the WIPI2/GPX4 pathway thereby enhancing the sensitivity of colorectal cancer cells to Erastin.

Conclusions

Our study suggested that WIPI2 had a promotional effect on the growth of colorectal cancer cells, and it also played an important role in the ferroptosis pathway.
Nonbacterial and bacterial osteomyelitis in children: a case–control retrospective study
Authors: Kostik Mikhail M. , Maletin Alexey S. , Petukhova Veronika V. , Mushkin Alexander Yu.
Published: May 2023

Purpose

Osteomyelitis is a group of bone infectious (bacterial osteomyeilitis—BO) and noninfectious inflammatory diseases (nonbacterial osteomyelitis—NBO) with similar clinical, radiology, and laboratory features. Many patients with NBO are misdiagnosed as BO and receive unnecessary antibiotics and surgery. Our study aimed to compare clinical and laboratory features of NBO and BO in children, to define key discriminative criteria, and to create an NBO diagnostic score (NBODS).

Methods

The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about histologically confirmed NBO (n = 91) and BO (n = 31). The variables allowed us to differentiate both conditions used to construct and validate the NBO DS.

Results

The main differences between NBO and BO are as follows: onset age—7.3 (2.5; 10.6) vs. 10.5 (6.5; 12.7) years (p = 0.03), frequency of fever (34.1% vs. 90.6%, p = 0.0000001), symptomatic arthritis (67% vs. 28.1%, p = 0.0001), monofocal involvement (28.6% vs. 100%, p = 0.0000001), spine (32% vs. 6%, p = 0.004), femur (41% vs. 13%, p = 0.004), foot bones (40% vs. 13%, p = 0.005), clavicula (11% vs. 0%, p = 0.05), and sternum (11% vs. 0%, p = 0.039) involvement. The following four criteria are included in the NBO DS: CRP ≤ 55 mg/l (56 points), multifocal involvement (27 points), femur involvement (17 points), and neutrophil bands ≤ 220 cell/μl (15 points). The sum > 17 points allowed to differentiate NBO from BO with a sensitivity of 89.0% and a specificity of 96.9%.

Conclusion

The diagnostic criteria may help discriminate NBO and BO and avoid excessive antibacterial treatment and surgery.
Resting-state heart rate variability, level of stress and resilience in internet gaming disorder and alcohol use disorder
Authors: Park Jong Hu , Yoo So Young , Park Hye Yoon , Choi Jung-Seok
Published: May 2023

Stress and resilience are involved in the pathophysiology of addictive disorders, and heart rate variability (HRV) is an index of an individual’s global capability to regulate psychological responses. In this study, we aimed to identify transdiagnostic and disorder-specific markers in people with addictive disorders by analyzing resting-state HRV and associations with the levels of stress and resilience. We compared relevant data between patients with internet gaming disorder (IGD) and/or alcohol use disorder (AUD) and healthy controls (HCs). In all, 163 adults aged 18–35 years (53 with IGD, 49 with AUD, 61 HCs) participated. The levels of stress and resilience were measured using the Psychosocial Wellbeing Index and the Connor-Davidson Resilience Scale, respectively. The HRV was obtained from each participant during a 5 min resting-state. The IGD and AUD patients exhibited increased levels of stress and decreased resilience compared to the HCs. Patients with either addictive disorder exhibited a lower standard deviation of the normal-to-normal beat interval (SDNN) index [SDNNi] compared to HCs even after adjusting for clinical variables such as depression, anxiety, and impulsivity. In multiple comparison tests among the three groups, the AUD group had lower HRV than HCs, but no differences were observed among the groups after adjusting for the clinical variables. The HRV indices were correlated with the levels of stress, resilience, and disease severity. In conclusion, IGD and AUD patients exhibit lower HRV as indicated by the SDNNi compared to HCs, revealing their vulnerability to stress as well as a common transdiagnostic marker of addiction.
Fresh Gastrodia elata Blume alleviates simulated weightlessness-induced cognitive impairment by regulating inflammatory and apoptosis-related pathways
Authors: Zhang Yiwen , Huang Hong , Yao Caihong , Sun Xinran , He Qinghu , Choudharyc Muhammad Iqbal , Chen Shanguang , Liu Xinmin , Jiang Ning
Published: May 2023

In aerospace medicine, the influence of microgravity on cognition has always been a risk factor threatening astronauts’ health. The traditional medicinal plant and food material Gastrodia elata Blume has been used as a therapeutic drug for neurological diseases for a long time due to its unique neuroprotective effect. To study the effect of fresh Gastrodia elata Blume (FG) on cognitive impairment caused by microgravity, hindlimb unloading (HU) was used to stimulate weightlessness in mice. The fresh Gastrodia elata Blume (0.5 g/kg or 1.0 g/kg) was intragastrically administered daily to mice exposed to HU and behavioral tests were conducted after four weeks to detect the cognitive status of animals. The behavioral tests results showed that fresh Gastrodia elata Blume therapy significantly improved the performance of mice in the object location recognition test, Step-Down test, and Morris Water Maze test, including short-term and long-term spatial memory. According to the biochemical test results, fresh Gastrodia elata Blume administration not only reduced serum factor levels of oxidative stress but also maintained the balance of pro-inflammatory and anti-inflammatory factors in the hippocampus, reversing the abnormal increase of NLRP3 and NF-κB. The apoptosis-related proteins were downregulated which may be related to the activation of the PI3K/AKT/mTOR pathway by fresh Gastrodia elata Blume therapy, and the abnormal changes of synapse-related protein and glutamate neurotransmitter were corrected. These results identify the improvement effect of fresh Gastrodia elata Blume as a new application form of Gastrodia elata Blume on cognitive impairment caused by simulated weightlessness and advance our understanding of the mechanism of fresh Gastrodia elata Blume on the neuroprotective effect.
Relationships between task awareness, comprehension strategies, and literacy outcomes
Authors: Higgs Karyn P. , Santuzzi Alecia M. , Gibson Cody , Kopatich Ryan D. , Feller Daniel P. , Magliano Joseph P.
Published: May 2023

Reading is typically guided by a task or goal (e.g., studying for a test, writing a paper). A reader’s task awareness arises from their mental representation of the task and plays an important role in guiding reading processes, ultimately influencing comprehension outcomes and task success. As such, a better understanding of how task awareness arises and how it affects comprehension is needed. The present study tested the Task Awareness Mediation Hypothesis. This hypothesis assumes that the strategies that support reading comprehension (e.g., paraphrasing, bridging, and elaborative strategies) also support a reader’s task awareness while engaged in a literacy task. Further, it assumes that the reader’s level of task awareness partially mediates the relationship between these comprehension strategies and a comprehension outcome. At two different time points in a semester, college students completed an assessment of their propensity to engage in comprehension strategies and a complex academic literacy task that provided a measure of comprehension outcomes and an assessment of task awareness. Indirect effects analyses provided evidence for the Task Awareness Mediation Hypothesis showing that the propensity to engage in paraphrasing and elaboration was positively predictive of task awareness, and that task awareness mediated the relationships between these comprehension strategies and performance on the complex academic literacy task. These results indicate that task awareness has complex relationships with comprehension strategies and performance on academic literacy tasks and warrants further consideration as a possible malleable factor to improve student success.