bluuebunny/crossref_metadata_2025 huggingface dataset:
N-acetyl-L-cysteine alleviated the oxidative stress-induced inflammation and necroptosis caused by excessive NiCl2 in primary spleen lymphocytes
Authors: Zhang Xintong , Xu Lihua , Ma Wenxue , Shi Bendong , Liu Qiaohan , Song Yinghao , Fang Cheng , Liu Pinnan , Qiao Senqiu , Cai Jingzeng , Zhang Ziwei
Published: April 2023

Introduction

Nickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes.

Methods

In this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments.

Results

Our findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-α) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-α could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure.

Discussion

Our findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.
Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors
Authors: Inaba Hidefumi , Morita Shuhei , Kosugi Daisuke , Asai Yuki , Kaido Yosuke , Ito Saya , Hirobata Tomonao , Inoue Gen , Yamamoto Yuki , Jinnin Masatoshi , Kimura Hiroaki , Ota Masao , Okudaira Yuko , Nakatani Hiroyasu , Kobayashi Tomoko , Iwama Shintaro , Arima Hiroshi , Matsuoka Takaaki
Published: April 2023

Introduction

Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear.

Methods

We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules.

Results and Discussion

Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.
Rehabilitation treatment of multiple sclerosis
Authors: Duan Haoyang , Jing Yuling , Li Yinghua , Lian Yawen , Li Jianfang , Li Zhenlan
Published: April 2023

Multiple sclerosis is a slowly progressive disease, immunosuppressants and other drugs can delay the progression and progression of the disease, but the most patients will be left with varying degrees of neurological deficit symptoms, such as muscle weakness, muscle spasm, ataxia, sensory impairment, dysphagia, cognitive dysfunction, psychological disorders, etc. From the early stage of the disease to the stage of disease progression, professional rehabilitation treatment can reduce the functional dysfunction of multiple sclerosis patients, improve neurological function, and reduce family and social burdens. With the development of various new rehabilitation technologies such as transcranial magnetic stimulation, virtual reality technology, robot-assisted gait, telerehabilitation and transcranial direct current stimulation, the advantages of rehabilitation therapy in multiple sclerosis treatment have been further established, and more treatment means have also been provided for patients.
A senescence-based prognostic gene signature for colorectal cancer and identification of the role of SPP1-positive macrophages in tumor senescence
Authors: Yu Sifei , Chen Mengdi , Xu Lili , Mao Enqiang , Sun Silei
Published: April 2023

Background

Senescence is significantly associated with cancer prognosis. This study aimed to construct a senescence-related prognostic model for colorectal cancer (CRC) and to investigate the influence of senescence on the tumor microenvironment.

Methods

Transcriptome and clinical data of CRC cases were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Senescence-related prognostic genes detected by univariate Cox regression were included in Least Absolute Shrinkage and Selection Operator (LASSO) analysis to construct a model. The efficacy of the model was validated using the receiver operating characteristic (ROC) curve and survival analysis. Differentially expressed genes (DEGs) were identified and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed. CIBERSORT and Immuno-Oncology Biological Research (IOBR) were used to investigate the features of the tumor microenvironment. Single-cell RNA-seq data were used to investigate the expression levels of model genes in various cell types. Immunofluorescence staining for p21, SPP1, and CD68 was performed with human colon tissues.

Results

A seven-gene (PTGER2, FGF2, IGFBP3, ANGPTL4, DKK1, WNT16 and SPP1) model was finally constructed. Patients were classified as high- or low-risk using the median score as the threshold. The area under the ROC curve (AUC) for the 1-, 2-, and 3-year disease-specific survival (DSS) were 0.731, 0.651, and 0.643, respectively. Survival analysis showed a better 5-year DSS in low-risk patients in the construction and validation cohorts. GO and KEGG analyses revealed that DEGs were enriched in extracellular matrix (ECM)-receptor interactions, focal adhesion, and protein digestion and absorption. CIBERSORT and IOBR analyses revealed an abundance of macrophages and an immunosuppressive environment in the high-risk subgroup. Low-risk patients had higher response rates to immunotherapy than high-risk patients. ScRNA-seq data revealed high expression of SPP1 in a subset of macrophages with strong senescence-associated secretory phenotype (SASP) features. Using CRC tumor tissues, we discovered that SPP1+ macrophages were surrounded by a large number of senescent tumor cells in high-grade tumors.

Conclusion

Our study presents a novel model based on senescence-related genes that can identify CRC patients with a poor prognosis and an immunosuppressive tumor microenvironment. SPP1+ macrophages may correlate with cell senescence leading to poor prognosis.
Diving deeper: Mesopelagic fish biomass estimates comparison using two different models
Authors: Hill Cruz Mariana , Kriest Iris , Getzlaff Julia
Published: April 2023

A growing population on a planet with limited resources demands finding new sources of protein. Hence, fisheries are turning their perspectives towards mesopelagic fish, which have, so far, remained relatively unexploited and poorly studied. Large uncertainties are associated with regards to their biomass, turn-over rates, susceptibility to environmental forcing and ecological and biogeochemical role. Models are useful to disentangle sources of uncertainties and to understand the impact of different processes on the biomass. In this study, we employed two food-web models – OSMOSE and the model by Anderson et al. (2019, or A2019) – coupled to a regional physical–biogeochemical model to simulate mesopelagic fish in the Eastern Tropical South Pacific ocean. The model by A2019 produced the largest biomass estimate, 26 to 130% higher than OSMOSE depending on the mortality parameters used. However, OSMOSE was calibrated to match observations in the coastal region off Peru and its temporal variability is affected by an explicit life cycle and food web. In contrast, the model by A2019 is more convenient to perform uncertainty analysis and it can be easily coupled to a biogeochemical model to estimate mesopelagic fish biomass. However, it is based on a flow analysis that had been previously applied to estimate global biomass of mesopelagic fish but has never been calibrated for the Eastern Tropical South Pacific. Furthermore, it assumes a steady-state in the energy transfer between primary production and mesopelagic fish, which may be an oversimplification for this highly dynamic system. OSMOSE is convenient to understand the interactions of the ecosystem and how including different life stages affects the model response. The combined strengths of both models allow us to study mesopelagic fish from a holistic perspective, taking into account energy fluxes and biomass uncertainties based on primary production, as well as complex ecological interactions.
Distinct histological patterns in chronic hepatitis D with nucleos(t)ide analogue therapy
Authors: Hercun Julian , Heller Theo , Glenn Jeffrey S. , Kleiner David E. , Koh Christopher
Published: April 2023

Background

Chronic hepatitis delta virus (HDV) infection leads to a more severe hepatitis than hepatitis B virus (HBV) infection alone. Specific histological staining patterns have been described in HBV mono-infection, however this has not been extensively investigated in HDV co-infection. This study evaluated whether the use of nucleos(t)ide analogs (NAs) for concurrent HBV infection has an impact on the histological appearance of chronic HDV.

Methods

Liver biopsies of all patients referred for management of HDV infection were reviewed and hepatitis-specific stains for HBV antigens were evaluated. Clinical and histological characteristics were compared between patients on and off-NA therapy.

Results

50 patients were included in our analysis, of which 26 (52%) were on NA therapy at the time of the biopsy. Overall, 8% stained for HBV core antigen and 86% stained for HBV surface antigen. On and off-NA groups had similar degrees of fibrosis and inflammation, however NA patients had an odds ratio of 7.15 for membranous staining and 0.13 for scattered granular staining (p = 0.001). No association was found with markers of disease severity or viral activity, with nonetheless a lower score of total inflammation noted in biopsies with a positive membranous stain (8.5 vs. 10.3 p = 0.04).

Conclusion

In chronic HDV infection, patients treated with nucleos(t)ide analogs demonstrate a unique membranous staining pattern for hepatitis B surface antigen, which is not associated with HBV or HDV replicative activity. These findings may help improve the understanding of the role of HBV directed therapy in HDV pathophysiology.

Highlights

Histological staining is associated with viral activity in chronic HBV, however this has been infrequently explored in HDV. In HDV, staining patterns differ based on HBV treatment status and do not appear to be associated with markers of viral activity.
Diversity, morphology, and molecular phylogeny of Diatrypaceae from southern China
Authors: Li Qi-Rui , Long Si-Han , Lin Yan , Wu You-Peng , Wu Qian-Zhen , Hu Hong-Min , Shen Xiang-Chun , Zhang Xu , Wijayawardene Nalin Nilusha , Kang Ji-Chuan , Kumla Jaturong , Kang Ying-Qian
Published: April 2023

During an investigation of Diatrypaceae from southern China, 10 xylariales-like taxa have been collected. Morphological and multi-gene analyses confirmed that these taxa reside in Diatrypaceae and represent eight novel taxa and two new records belonging to six genera (viz., Allocryptovalsa, Diatrype, Diatrypella, Paraeutypella, Peroneutypa, and Vasilyeva gen. nov.). Vasilyeva gen. nov. was proposed to accommodate Vasilyeva cinnamomi sp. nov. Among the other collections, seven new species were introduced (viz., Diatrype camelliae-japonicae sp. nov., Diatrype rubi sp. nov., Diatrypella guiyangensis sp. nov., Diatrypella fatsiae-japonicae sp. nov., Paraeutypella subguizhouensis sp. nov., Peroneutypa hainanensis sp. nov., and Peroneutypa qianensis sp. nov.), while two were reported as new records from China (Allocryptovalsa rabenhorstii and Diatrype enteroxantha). For Diatrypaceae, the traditional taxonomic approach based on morphology may not be applicable.
Biogenic silver nanoparticles eradicate of Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA) isolated from the sputum of COVID-19 patients
Authors: Hawsawi Nahed M. , Hamad Arshad M. , Rashid Sahar N. , Alshehri Fatma , Sharaf Mohamed , Zakai Shadi A. , Al Yousef Sulaiman A. , Ali Ahmed Mohamed , Abou-Elnour Amira , Alkhudhayri Abdulsalam , Elrefaei Nadia Gouda , Elkelish Amr
Published: April 2023

In recent investigations, secondary bacterial infections were found to be strongly related to mortality in COVID-19 patients. In addition, Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA) bacteria played an important role in the series of bacterial infections that accompany infection in COVID-19. The objective of the present study was to investigate the ability of biosynthesized silver nanoparticles from strawberries (Fragaria ananassa L.) leaf extract without a chemical catalyst to inhibit Gram-negative P. aeruginosa and Gram-positive Staph aureus isolated from COVID-19 patient’s sputum. A wide range of measurements was performed on the synthesized AgNPs, including UV–vis, SEM, TEM, EDX, DLS, ζ -potential, XRD, and FTIR. UV-Visible spectral showed the absorbance at the wavelength 398 nm with an increase in the color intensity of the mixture after 8 h passed at the time of preparation confirming the high stability of the FA-AgNPs in the dark at room temperature. SEM and TEM measurements confirmed AgNPs with size ranges of ∼40-∼50 nm, whereas the DLS study confirmed their average hydrodynamic size as ∼53 nm. Furthermore, Ag NPs. EDX analysis showed the presence of the following elements: oxygen (40.46%), and silver (59.54%). Biosynthesized FA-AgNPs (ζ = −17.5 ± 3.1 mV) showed concentration-dependent antimicrobial activity for 48 h in both pathogenic strains. MTT tests showed concentration-dependent and line-specific effects of FA-AgNPs on cancer MCF-7 and normal liver WRL-68 cell cultures. According to the results, synthetic FA-AgNPs obtained through an environmentally friendly biological process are inexpensive and may inhibit the growth of bacteria isolated from COVID-19 patients.
Antimicrobial susceptibility surveillance and antimicrobial resistance in Neisseria gonorrhoeae in Africa from 2001 to 2020: A mini-review
Authors: Kakooza Francis , Kiggundu Reuben , Mboowa Gerald , Kateete Patrick David , Nsangi Olga Tendo , Kabahita Jupiter Marina , Ssentalo Bagaya Bernard , Golparian Daniel , Unemo Magnus
Published: April 2023

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae (NG), compromising gonorrhea treatment, is a global public health concern. Improved, quality-assured NG AMR monitoring at the global level is essential. This mini-review examined NG AMR susceptibility surveillance and AMR data from the African continent from 2001 to 2020. Eligible peer-reviewed publications (n = 30) containing NG AMR data for antimicrobials currently recommended for gonorrhea treatment were included. Overall, very limited NG surveillance and AMR data was available. Furthermore, the NG AMR surveillance studies varied greatly regarding surveillance protocols (e.g., populations and samples tested, sample size, antimicrobials examined), methodologies (e.g., antimicrobial susceptibility testing method [agar dilution, minimum inhibitory concentration (MIC) gradient strip test, disc diffusion test] and interpretative criteria), and quality assurance (internal quality controls, external quality assessments [EQA], and verification of AMR detected). Moreover, most studies examined a suboptimal number of NG isolates, i.e., less than the WHO Global Gonococcal Antimicrobial Surveillance Program (GASP) and WHO Enhanced GASP (EGASP) recommendations of ≥100 isolates per setting and year. The notable inter-study variability and frequently small sample sizes make appropriate inter-study and inter-country comparisons of AMR data difficult. In conclusion, it is imperative to establish an enhanced, standardized and quality-assured NG AMR surveillance, ideally including patient metadata and genome sequencing as in WHO EGASP, in Africa, the region with the highest gonorrhea incidence globally. This will enable the monitoring of AMR trends, detection of emerging AMR, and timely refinements of national and international gonorrhea treatment guidelines. To achieve this aim, national and international leadership, political and financial commitments are imperative.
Genetic characterization of ESBL-producing and ciprofloxacin-resistant Escherichia coli from Belgian broilers and pigs
Authors: De Koster Sien , Ringenier Moniek , Xavier Basil Britto , Lammens Christine , De Coninck Dieter , De Bruyne Katrien , Mensaert Klaas , Kluytmans-van den Bergh Marjolein , Kluytmans Jan , Dewulf Jeroen , Goossens Herman ,   on behalf of the i-4-1-Health Study Group
Published: April 2023

Background

The increasing number of infections caused by Escherichia coli resistant to clinically important antibiotics is a global concern for human and animal health. High overall levels of extended-spectrum beta-lactamase (ESBL)-producing and ciprofloxacin-resistant (ciproR) Escherichia coli in livestock are reported in Belgium. This cross-sectional study aimed to genotypically characterize and trace ESBL-and ciproR-E. coli of Belgian food-producing animals.

Methods

A total of 798 fecal samples were collected in a stratified-random sampling design from Belgian broilers and sows. Consequently, 77 ESBL-E. coli and 84 ciproR-E. coli were sequenced using Illumina MiSeq. Minimum inhibitory concentration (MIC) for fluoroquinolones and cephalosporins were determined. Molecular in silico typing, resistance and virulence gene determination, and plasmid identification was performed. Scaffolds harboring ESBL or plasmid-mediated quinolone resistance (PMQR) genes were analyzed to detect mobile genetic elements (MGEs) and plasmid origins. Core genome allelic distances were used to determine genetic relationships among isolates.

Results

A variety of E. coli sequence types (ST) (n = 63), resistance genes and virulence profiles was detected. ST10 was the most frequently encountered ST (8.1%, n = 13). The pandemic multidrug-resistant clone ST131 was not detected. Most farms harbored more than one ESBL type, with blaCTX-M-1 (41.6% of ESBL-E. coli) being the most prevalent and blaCTX M-15 (n = 3) being the least prevalent. PMQR genes (15.5%, n = 13) played a limited role in the occurrence of ciproR-E. coli. More importantly, sequential acquisition of mutations in quinolone resistance-determining regions (QRDR) of gyrA and parC led to increasing MICs for fluoroquinolones. GyrA S83L, D87N and ParC S80I mutations were strongly associated with high-level fluoroquinolone resistance. Genetically related isolates identified within the farms or among different farms highlight transmission of resistant E. coli or the presence of a common reservoir. IncI1-I(alpha) replicon type plasmids carried different ESBL genes (blaCTX-M-1, blaCTX-M-32 and blaTEM-52C). In addition, the detection of plasmid replicons with associated insertion sequence (IS) elements and ESBL/PMQR genes in different farms and among several STs (e.g., IncI1-I(alpha)/IncX3) underline that plasmid transmission could be another important contributor to transmission of resistance in these farms.

Conclusion

Our findings reveal a multifaceted narrative of transmission pathways. These findings could be relevant in understanding and battling the problem of antibiotic resistance in farms.
Single-nucleotide resolution detection of Topo IV cleavage activity in the Escherichia coli genome with Topo-Seq
Authors: Sutormin Dmitry , Galivondzhyan Alina , Gafurov Azamat , Severinov Konstantin
Published: April 2023

Topoisomerase IV (Topo IV) is the main decatenation enzyme in Escherichia coli; it removes catenation links that are formed during DNA replication. Topo IV binding and cleavage sites were previously identified in the E. coli genome with ChIP-Seq and NorfIP. Here, we used a more sensitive, single-nucleotide resolution Topo-Seq procedure to identify Topo IV cleavage sites (TCSs) genome-wide. We detected thousands of TCSs scattered in the bacterial genome. The determined cleavage motif of Topo IV contained previously known cleavage determinants (−4G/+8C, −2A/+6 T, −1 T/+5A) and additional, not observed previously, positions −7C/+11G and −6C/+10G. TCSs were depleted in the Ter macrodomain except for two exceptionally strong non-canonical cleavage sites located in 33 and 38 bp from the XerC-box of the dif-site. Topo IV cleavage activity was increased in Left and Right macrodomains flanking the Ter macrodomain and was especially high in the 50–60 kb region containing the oriC origin of replication. Topo IV enrichment was also increased downstream of highly active transcription units, indicating that the enzyme is involved in relaxation of transcription-induced positive supercoiling.
MAPKAP Kinase-2 phosphorylation of PABPC1 controls its interaction with 14-3-3 proteins after DNA damage: A combined kinase and protein array approach
Authors: Stehn Justine R. , Floyd Scott R. , Wilker Erik W. , Reinhardt H. Christian , Clarke Scott M. , Huang Qiuying , Polakiewicz Roberto D. , Sonenberg Nahum , Kong Yi Wen , Yaffe Michael B.
Published: April 2023

14-3-3 proteins play critical roles in controlling multiple aspects of the cellular response to stress and DNA damage including regulation of metabolism, cell cycle progression, cell migration, and apoptotic cell death by binding to protein substrates of basophilic protein kinases following their phosphorylation on specific serine/threonine residues. Although over 200 mammalian proteins that bind to 14-3-3 have been identified, largely through proteomic studies, in many cases the relevant protein kinase responsible for conferring 14-3-3-binding to these proteins is not known. To facilitate the identification of kinase-specific 14-3-3 clients, we developed a biochemical approach using high-density protein filter arrays and identified the translational regulatory molecule PABPC1 as a substrate for Chk1 and MAPKAP Kinase-2 (MK2) in vitro, and for MK2 in vivo, whose phosphorylation results in 14-3-3-binding. We identify Ser-470 on PABPC1 within the linker region connecting the RRM domains to the PABC domain as the critical 14-3-3-binding site, and demonstrate that loss of PABPC1 binding to 14-3-3 results in increased cell proliferation and decreased cell death in response to UV-induced DNA damage.
Hybrid FES-exoskeleton control: Using MPC to distribute actuation for elbow and wrist movements
Authors: Dunkelberger Nathan , Berning Jeffrey , Schearer Eric M. , O'Malley Marcia K.
Published: April 2023

Introduction

Individuals who have suffered a cervical spinal cord injury prioritize the recovery of upper limb function for completing activities of daily living. Hybrid FES-exoskeleton systems have the potential to assist this population by providing a portable, powered, and wearable device; however, realization of this combination of technologies has been challenging. In particular, it has been difficult to show generalizability across motions, and to define optimal distribution of actuation, given the complex nature of the combined dynamic system.

Methods

In this paper, we present a hybrid controller using a model predictive control (MPC) formulation that combines the actuation of both an exoskeleton and an FES system. The MPC cost function is designed to distribute actuation on a single degree of freedom to favor FES control effort, reducing exoskeleton power consumption, while ensuring smooth movements along different trajectories. Our controller was tested with nine able-bodied participants using FES surface stimulation paired with an upper limb powered exoskeleton. The hybrid controller was compared to an exoskeleton alone controller, and we measured trajectory error and torque while moving the participant through two elbow flexion/extension trajectories, and separately through two wrist flexion/extension trajectories.

Results

The MPC-based hybrid controller showed a reduction in sum of squared torques by an average of 48.7 and 57.9% on the elbow flexion/extension and wrist flexion/extension joints respectively, with only small differences in tracking accuracy compared to the exoskeleton alone.

Discussion

To realize practical implementation of hybrid FES-exoskeleton systems, the control strategy requires translation to multi-DOF movements, achieving more consistent improvement across participants, and balancing control to more fully leverage the muscles' capabilities.
2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine
Authors: Qiu Tao , Zhou Yanjie , Hu Luyu , Shan Zhengming , Zhang Yu , Fang Yuting , Huang Wanbin , Zhang Lily , Fan Shanghua , Xiao Zheman
Published: April 2023

Background

Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine.

Methods

We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation.

Results

In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia.

Conclusion

The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.
Beneficial effects and safety of traditional Chinese medicine for chronic inflammatory demyelinating polyradiculoneuropathy: A case report and literature review
Authors: Xie Yao , Li Lesang , Xie Le , Jiang Junlin , Yao Ting , Mao Guo , Wang Shiliang , Lin Anchao , Ge Jinwen , Wu Dahua
Published: April 2023

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy. First-line treatments for CIDP include corticosteroids, intravenous immunoglobulin, and plasma exchange. However, the application is always limited by high costs, effectiveness, and adverse events. This study investigated a new potentially effective and safe therapeutic treatment to alleviate CIDP symptoms and improve the quality of life. In the present case, a 47-year-old rural woman presented with weakness and numbness of progressive extremities. She was diagnosed with CIDP based on abnormal cerebrospinal fluid and electromyography. The patient was treated with intravenous dexamethasone for 1 week and with Huangqi-Guizhi-Wuwu and Bu-Yang-Huan-Wu decoctions for 90 days. Surprisingly, after the treatment, the weakness and numbness were eliminated, and the quality of life improved. The varying INCAT, MRC, and BI scores also reflected the treatment effects. After 8 months of discharge, the symptoms did not relapse during the follow-up. We also searched “traditional Chinese medicine (TCM)” and “CIDP” in PubMed, EMBASE, the Web of Science, the Cochrane Library, the Chinese National Knowledge Infrastructure Databases, Wanfang Data, and the Chongqing Chinese Science and Technology Periodical Database. Finally, only ten studies were included in the literature review. Three studies were randomized controlled trials, and seven were case reports or case series. There were 419 CIDP patients, but all study sites were in China. Nine TCM formulas involving 44 herbs were reported, with Huang Qi (Astragalus membranaceus) being the most important herb. In conclusion, the case and literature demonstrated that TCM treatment might be a more effective, low-cost, and safe option for treating CIDP. Although these preliminary findings are promising, a larger sample size and higher-quality randomized clinical trials are urgently required to confirm our findings.
Specialized intensive inpatient rehabilitation is crucial and time-sensitive for functional recovery from disorders of consciousness
Authors: Zhang Bei , O'Brien Katherine , Woo Jean , Chi Bradley , Reeh Colton , Li Sheng , Kothari Sunil
Published: April 2023

Background

Disorders of consciousness (DoCs) after severe brain injury are considered to be conditions with dire prognosis. Despite the accumulating evidence, inpatient rehabilitation is often denied by payers referring to the Medicare/Medicaid criteria, under the assumption that such patients will not “actively” participate in therapy or make “measurable improvements.”

Objective

This study aimed to report on the effectiveness and efficiency of a specialized inpatient DoC rehabilitation program based on measurable clinical parameters.

Methods

A retrospective cohort study was conducted. The cohort comprised 137 patients with DoC admitted to a specialized acute inpatient rehabilitation program between January 2014 and October 2018. Patients were categorized as having been admitted at the acute stage (<=28 days post-injury), subacute stage (29–365 days following a traumatic brain injury (TBI) or 29–90 days following a non-TBI), or chronic stage (>365 days following a TBI or >90 days following a non-TBI). Outcomes included changes in level of consciousness (based on the Coma Recovery Scale–Revised (CRS-R), while also acknowledging scenarios beyond those captured by the CRS-R via Individualized Qualitative Behavioral Assessment and team consensus); Functional Independence Measure (FIM) levels; achievements in decannulation and initiation of oral diet; and time to those achievements.

Results

The rates of emergence from a minimally conscious state were 90, 62, and 18% among patients admitted at the acute, subacute, and chronic stages, respectively. Among patients who emerged, 100, 85, and 67%, respectively, had measurable FIM scores. Approximately 60 and 20% of patients at the acute and subacute stages, respectively, required moderate assistance or less in transfer/communication/eating/grooming/upper body dressing by the time of discharge from Phase I admission. The decannulation rates were 94, 67, and 17%. The oral diet initiation rates were 70, 23, and 6%. The time to reach these achievements lengthened as chronicity increased. There was a weak positive correlation (rs = 0.308) in the case of decannulation and a strong positive correlation (rs = 0.606, both p < 0.01) in the case of oral diet between days since injury on admission and days to the achievement after admission. Patients with TBI and hypoxic brain injury had comparable recovery rates when admitted at the acute and subacute stages.

Conclusion

Specialized intensive inpatient rehabilitation is crucial and time-sensitive for functional recovery from DoC caused by TBI and hypoxic–ischemic brain injury. Specific goals and different outcome measures need to be developed to appraise the benefits of acute inpatient rehabilitation for DoC.
The art and science of using quality control to understand and improve fMRI data
Authors: Teves Joshua B. , Gonzalez-Castillo Javier , Holness Micah , Spurney Megan , Bandettini Peter A. , Handwerker Daniel A.
Published: April 2023

Designing and executing a good quality control (QC) process is vital to robust and reproducible science and is often taught through hands on training. As FMRI research trends toward studies with larger sample sizes and highly automated processing pipelines, the people who analyze data are often distinct from those who collect and preprocess the data. While there are good reasons for this trend, it also means that important information about how data were acquired, and their quality, may be missed by those working at later stages of these workflows. Similarly, an abundance of publicly available datasets, where people (not always correctly) assume others already validated data quality, makes it easier for trainees to advance in the field without learning how to identify problematic data. This manuscript is designed as an introduction for researchers who are already familiar with fMRI, but who did not get hands on QC training or who want to think more deeply about QC. This could be someone who has analyzed fMRI data but is planning to personally acquire data for the first time, or someone who regularly uses openly shared data and wants to learn how to better assess data quality. We describe why good QC processes are important, explain key priorities and steps for fMRI QC, and as part of the FMRI Open QC Project, we demonstrate some of these steps by using AFNI software and AFNI’s QC reports on an openly shared dataset. A good QC process is context dependent and should address whether data have the potential to answer a scientific question, whether any variation in the data has the potential to skew or hide key results, and whether any problems can potentially be addressed through changes in acquisition or data processing. Automated metrics are essential and can often highlight a possible problem, but human interpretation at every stage of a study is vital for understanding causes and potential solutions.
Analysis of independent risk factors for progression of different degrees of diabetic retinopathy as well as non-diabetic retinopathy among type 2 diabetic patients
Authors: Li Zheng , Tong Jie , Liu Chang , Zhu Mingqiong , Tan Jia , Kuang Guoping
Published: April 2023

Purpose

To study the independent risk factors for development of different degrees of diabetic retinopathy (DR) as well as non-DR (NDR) among type 2 diabetic patients.

Methods

This cross-sectional study included 218 patients with type 2 diabetes between January 2022 and June 2022. All the patients were divided into two groups: the DR group and the NDR group. The DR group was subdivided into the mild, moderate and severe non-proliferative DR (NPDR) group and the proliferative DR (PDR) group. Data recorded for all patients included age, gender, duration of diabetes, blood pressure, glycated hemoglobin (HbA1c), fasting blood glucose (FBG), blood lipids, best corrected visual acuity (BCVA), intraocular pressure (IOP), axial length (AL), anterior chamber depth (ACD), and renal function. Logistic regression methods were used to analyze the risk factors for DR.

Results

The prevalence of DR in type 2 diabetes was 28.44%. The duration of diabetes, age, mean arterial pressure (MAP), HbA1c, FBG, urinary albumin/creatinine ratio (UACR), BCVA, AL, and ACD were significantly different between the DR and the NDR groups (p < 0.05). Multivariate logistic regression analysis identified age, FBG, UACR, and AL as the independent risk factors for DR (OR = 0.843, 2.376, 1.049, 0.005; p = 0.034, 0.014, 0.016, p < 0.001).

Conclusion

Young age, short AL, higher levels of FBG and UACR were the independent risk factors for the progression of DR in type 2 diabetes.
Glycolysis mediates neuron specific histone acetylation in valproic acid-induced human excitatory neuron differentiation
Authors: Chen Andi , Wang Mengmeng , Xu Chao , Zhao Youyi , Xian Panpan , Li Yuqian , Zheng Weian , Yi Xuyang , Wu Shengxi , Wang Yazhou
Published: April 2023

Pregnancy exposure of valproic acid (VPA) is widely adopted as a model of environmental factor induced autism spectrum disorder (ASD). Increase of excitatory/inhibitory synaptic transmission ratio has been proposed as the mechanism of VPA induced ASD. How this happened, particularly at the level of excitatory neuron differentiation in human neural progenitor cells (NPCs) remains largely unclear. Here, we report that VPA exposure remarkably inhibited human NPC proliferation and induced excitatory neuronal differentiation without affecting inhibitory neurons. Following VPA treatment, mitochondrial dysfunction was observed before neuronal differentiation, as showed by ultrastructural changes, respiratory complex activity, mitochondrial membrane potential and oxidation levels. Meanwhile, extracellular acidification assay revealed an elevation of glycolysis by VPA stimulation. Interestingly, inhibiting glycolysis by 2-deoxy-d-glucose-6-phosphate (2-DG) efficiently blocked the excitatory neuronal differentiation of human NPCs induced by VPA. Furthermore, 2-DG treatment significantly compromised the VPA-induced expression of H3ac and H3K9ac, and the VPA-induced binding of H3K9ac on the promoter of Ngn2 and Mash1, two key transcription factors of excitatory neuron fate determination. These data, for the first time, demonstrated that VPA biased excitatory neuron differentiation by glycolysis-mediated histone acetylation of neuron specific transcription factors.
Enhancing motor imagery detection efficacy using multisensory virtual reality priming
Authors: Amini Gougeh Reza , Falk Tiago H.
Published: April 2023

Brain-computer interfaces (BCI) have been developed to allow users to communicate with the external world by translating brain activity into control signals. Motor imagery (MI) has been a popular paradigm in BCI control where the user imagines movements of e.g., their left and right limbs and classifiers are then trained to detect such intent directly from electroencephalography (EEG) signals. For some users, however, it is difficult to elicit patterns in the EEG signal that can be detected with existing features and classifiers. As such, new user control strategies and training paradigms have been highly sought-after to help improve motor imagery performance. Virtual reality (VR) has emerged as one potential tool where improvements in user engagement and level of immersion have shown to improve BCI accuracy. Motor priming in VR, in turn, has shown to further enhance BCI accuracy. In this pilot study, we take the first steps to explore if multisensory VR motor priming, where haptic and olfactory stimuli are present, can improve motor imagery detection efficacy in terms of both improved accuracy and faster detection. Experiments with 10 participants equipped with a biosensor-embedded VR headset, an off-the-shelf scent diffusion device, and a haptic glove with force feedback showed that significant improvements in motor imagery detection could be achieved. Increased activity in the six common spatial pattern filters used were also observed and peak accuracy could be achieved with analysis windows that were 2 s shorter. Combined, the results suggest that multisensory motor priming prior to motor imagery could improve detection efficacy.
Effect of radiotherapy interruption on nasopharyngeal cancer
Authors: Zhao Fangrui , Yang Dashuai , Li Xiangpan
Published: April 2023

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelial cells of the nasopharynx with a unique geographic distribution, and is particularly prevalent in East and Southeast Asia. Due to its anatomical location, the surgery is difficult to access and the high sensitivity of nasopharyngeal cancer to radiotherapy (RT) makes it the main treatment modality. Radical radiotherapy is the first-line treatment for early-stage nasopharyngeal carcinoma and the cornerstone of multidisciplinary treatment for patients with locally advanced nasopharyngeal carcinoma. Nevertheless, radiotherapy interruption is inevitable as a consequence of unavoidable factors such as public holidays, machine malfunction, patient compliance, and adverse response to treatment, which in turn leads to a reduction in bioactivity and causes sublethal loss of tumor cells to repair. Unirradiated tumor cells are more likely to repopulate at or near their original fastest growth rate during this interval. If no measures are taken after the radiotherapy interruption, such as increasing the dose of radiotherapy and systemic therapy, the tumor is most likely to go uncontrolled and then progress. This review describes the effects of radiotherapy interruption on nasopharyngeal carcinoma, the mechanism of the effect, and explores the measures that can be taken in response to such interruption.
Emerging bone marrow failure syndromes- new pieces to an unsolved puzzle
Authors: Feurstein Simone
Published: April 2023

Inherited bone marrow failure (BMF) syndromes are genetically diverse — more than 100 genes have been associated with those syndromes and the list is rapidly expanding. Risk assessment and genetic counseling of patients with recently discovered BMF syndromes is inherently difficult as disease mechanisms, penetrance, genotype-phenotype associations, phenotypic heterogeneity, risk of hematologic malignancies and clonal markers of disease progression are unknown or unclear. This review aims to shed light on recently described BMF syndromes with sparse concise data and with an emphasis on those associated with germline variants in ADH5/ALDH2, DNAJC21, ERCC6L2 and MECOM. This will provide important data that may help to individualize and improve care for these patients.
Transmembrane protein 88 suppresses hepatocellular carcinoma progression and serves as a novel prognostic factor
Authors: Cai Lin , Du Yu , Song Kai , Peng Peng , Han Fei
Published: April 2023

Background

Transmembrane protein 88 (TMEM88) is known to be involved in the canonical Wnt signaling pathway and is implicated in several malignancies. However, the expression, function, and prognostic significance of TMEM88 in hepatocellular carcinoma (HCC) remain unclear.

Methods

In this study, we analyzed mRNA levels of TMEM88 in HCC specimens from the TCGA dataset (n=374) to explore the correlation between TMEM88 and HCC. We also overexpressed TMEM88 in the Huh7 human HCC cell line to investigate its tumor-related role in HCC. Additionally, we conducted in vivo experiments using a mouse model to further validate the critical function of TMEM88 in modulating HCC growth.

Results

Our results showed that TMEM88 is negatively correlated with the T stage, TNM stage, and pathological grade of HCC. Higher levels of TMEM88 can help predict better overall survival of HCC in both univariate and multivariate analyses. Similarly, higher TMEM88 is a novel prognostic factor for better disease-specific survival of HCC. Overexpression of TMEM88 in Huh7 cells led to a decreased cell proliferation capacity. Xenograft experiments in a mouse model showed that TMEM88 overexpression can remarkably suppress HCC progression.

Conclusions

Transmembrane protein 88 suppresses HCC growth both in vitro and in vivo, which can act as a potential prognostic factor with clinical application potential.
Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment
Authors: Matamala Montoya María , van Slobbe Gijs J. J. , Chang Jung-Chin , Zaal Esther A. , Berkers Celia R.
Published: April 2023

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance. Metabolic reprogramming is emerging as a hallmark of cancer that can potentially be exploited for cancer treatment. Recent studies show that metabolism is further adjusted in MM cells during the development of drug resistance. However, little is known about the role of BMSCs in inducing metabolic changes that are associated with drug resistance. In this Perspective, we summarize current knowledge concerning the metabolic reprogramming of MM, with a focus on those changes associated with drug resistance to the proteasome inhibitor Bortezomib (BTZ). In addition, we present proof-of-concept fluxomics (glucose isotope-tracing) and Seahorse data to show that co-culture of MM cells with BMSCs skews the metabolic phenotype of MM cells towards a drug-resistant phenotype, with increased oxidative phosphorylation (OXPHOS), serine synthesis pathway (SSP), TCA cycle and glutathione (GSH) synthesis. Given the crucial role of BMSCs in conveying drug resistance, insights into the metabolic interaction between MM and BMSCs may ultimately aid in the identification of novel metabolic targets that can be exploited for therapy.