bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibodies against Spike protein correlate with broad autoantigen recognition 8 months post SARS-CoV-2 exposure, and anti-calprotectin autoantibodies associated with better clinical outcomes
Authors: Moody Rhiane , Sonda Sabrina , Johnston Fay H. , Smith Kylie J. , Stephens Nicola , McPherson Michelle , Flanagan Katie L. , Plebanski Magdalena
Published: August 2022

Autoantibodies to multiple targets are found during acute COVID-19. Whether all, or some, persist after 6 months, and their correlation with sustained anti-SARS-CoV-2 immunity, is still controversial. Herein, we measured antibodies to multiple SARS-CoV-2 antigens (Wuhan-Hu-1 nucleoprotein (NP), whole spike (S), spike subunits (S1, S2 and receptor binding domain (RBD)) and Omicron spike) and 102 human proteins with known autoimmune associations, in plasma from healthcare workers 8 months post-exposure to SARS-CoV-2 (n=31 with confirmed COVID-19 disease and n=21 uninfected controls (PCR and anti-SARS-CoV-2 negative) at baseline). IgG antibody responses to SARS-CoV-2 antigens were significantly higher in the convalescent cohort than the healthy cohort, highlighting lasting antibody responses up to 8 months post-infection. These were also shown to be cross-reactive to the Omicron variant spike protein at a similar level to lasting anti-RBD antibodies (correlation r=0.89). Individuals post COVID-19 infection recognised a common set of autoantigens, specific to this group in comparison to the healthy controls. Moreover, the long-term level of anti-Spike IgG was associated with the breadth of autoreactivity post-COVID-19. There were further moderate positive correlations between anti-SARS-CoV-2 responses and 11 specific autoantigens. The most commonly recognised autoantigens were found in the COVID-19 convalescent cohort. Although there was no overall correlation in self-reported symptom severity and anti-SARS-CoV-2 antibody levels, anti-calprotectin antibodies were associated with return to healthy normal life 8 months post infection. Calprotectin was also the most common target for autoantibodies, recognized by 22.6% of the overall convalescent cohort. Future studies may address whether, counter-intuitively, such autoantibodies may play a protective role in the pathology of long-COVID-19.
Secreted filarial nematode galectins modulate host immune cells
Authors: Loghry Hannah J. , Sondjaja Noelle A. , Minkler Sarah J. , Kimber Michael J.
Published: August 2022

Lymphatic filariasis (LF) is a mosquito-borne disease caused by filarial nematodes including Brugia malayi. Over 860 million people worldwide are infected or at risk of infection in 72 endemic countries. The absence of a protective vaccine means that current control strategies rely on mass drug administration programs that utilize inadequate drugs that cannot effectively kill adult parasites, thus established infections are incurable. Progress to address deficiencies in the approach to LF control is hindered by a poor mechanistic understanding of host-parasite interactions, including mechanisms of host immunomodulation by the parasite, a critical adaptation for establishing and maintaining infections. The canonical type 2 host response to helminth infection characterized by anti-inflammatory and regulatory immune phenotypes is modified by filarial nematodes during chronic LF. Current efforts at identifying parasite-derived factors driving this modification focus on parasite excretory-secretory products (ESP), including extracellular vesicles (EVs). We have previously profiled the cargo of B. malayi EVs and identified B. malayi galectin-1 and galectin-2 as among the most abundant EV proteins. In this study we further investigated the function of these proteins. Sequence analysis of the parasite galectins revealed highest homology to mammalian galectin-9 and functional characterization identified similar substrate affinities consistent with this designation. Immunological assays showed that Bma-LEC-2 is a bioactive protein that can polarize macrophages to an alternatively activated phenotype and selectively induce apoptosis in Th1 cells. Our data shows that an abundantly secreted parasite galectin is immunomodulatory and induces phenotypes consistent with the modified type 2 response characteristic of chronic LF infection.
The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases
Authors: He Yu-Yao , Zhou Hai-Feng , Chen Lu , Wang Yan-Ting , Xie Wan-Li , Xu Zhen-Zhen , Xiong Yue , Feng Yi-Qi , Liu Guo-Yang , Li Xia , Liu Jie , Wu Qing-Ping
Published: August 2022

Fra-1(Fos-related antigen1), a member of transcription factor activator protein (AP-1), plays an important role in cell proliferation, apoptosis, differentiation, inflammation, oncogenesis and tumor metastasis. Accumulating evidence suggest that the malignancy and invasive ability of tumors can be significantly changed by directly targeting Fra-1. Besides, the effects of Fra-1 are gradually revealed in immune and inflammatory settings, such as arthritis, pneumonia, psoriasis and cardiovascular disease. These regulatory mechanisms that orchestrate immune and non-immune cells underlie Fra-1 as a potential therapeutic target for a variety of human diseases. In this review, we focus on the current knowledge of Fra-1 in immune system, highlighting its unique importance in regulating tissue homeostasis. In addition, we also discuss the possible critical intervention strategy in diseases, which also outline future research and development avenues.
Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma
Authors: Liu Jichang , Shen Hongchang , Gu Wenchao , Zheng Haotian , Wang Yadong , Ma Guoyuan , Du Jiajun
Published: August 2022

Background

Glutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy.

Methods

We comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD.

Results

Patients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, “hot” immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells.

Conclusion

This study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.
Extracellular histones aggravate autoimmune arthritis by lytic cell death
Authors: Jung Jaeyong , Lee Lucy Eunju , Kim Hanna , Kim Ji Eun , Jang Sung Hoon , Roh Jong Seong , Lee Beomgu , Robinson William H. , Sohn Dong Hyun , Pyun Jae-Chul , Song Jason Jungsik
Published: August 2022

Although recent studies have demonstrated a proinflammatory effect of extracellular histones in sepsis via endothelial cytotoxicity, little is known about their contribution to autoimmune arthritis. Therefore, we investigated the role of extracellular histones in autoimmune arthritis and their cytotoxic effect on synoviocytes and macrophages. We measured histones in the synovial fluid of patients with rheumatoid arthritis (RA) and evaluated arthritis severity in a serum-transfer arthritis (STA) mouse model with intraperitoneal histone injection. Histone-induced cytotoxicity was measured using SYTOX green staining in the synoviocyte cell line MH7A and macrophages differentiated from the monocytic cell line THP-1, and the production of damage-associated molecular patterns (DAMPs) was measured by HMGB1 and ATP. Furthermore, we performed RNA-seq analysis of THP-1 cells stimulated with H2B-α1 peptide or with its citrullinated form. The levels of histones were elevated in RA synovial fluid, and histones aggravated arthritis in the STA model. Histones induced cytotoxicity and DAMP production in synoviocytes and macrophages. Chondroitin sulfate reduced histone-induced cytotoxicity, while lipopolysaccharides aggravated cytotoxicity. Moreover, the cytotoxicity decreased when the arginines in H2B-α1 were replaced with citrullines, which demonstrated its electrostatic nature. In transcriptome analysis, H2B-α1 changed the gene expression pattern of THP-1 cells involving chemokines, interleukin-1, -4, -10, -13, and toll-like receptor (TLR) signaling pathways. Extracellular histones were increased in RA synovial fluid and aggravated synovitis in STA. They induced lytic cell death through electrostatic interaction with synoviocytes and macrophages, leading to the secretion of DAMPs. These findings suggest that histones play a central role in autoimmune arthritis.
Antibiotic-induced alternations in gut microflora are associated with the suppression of immune-related pathways in grass carp (Ctenopharyngodon idellus)
Authors: Shi Fei , Huang Yao , Yang Mingxuan , Lu Zhijie , Li Yanan , Zhan Fanbin , Lin Li , Qin Zhendong
Published: August 2022

Gut microbiota play a vital role in fish health homeostasis. Antibiotics are known to alter microbial community composition and diversity; however, the substantial effects of antibiotics upon the gut microbiome with respect to immune-related pathways in healthy fish remain unclear. Accordingly, here we explored the impact of two antibiotics on the intestinal health, immune response, microbiome dynamics, and transcriptome profiles of grass carp. A two-week feeding trial was carried out in which the basal diet was complemented with enrofloxacin (10 mg/kg) or florfenicol (10 mg/kg). The results showed that: (1) Enrofloxacin and florfenicol both induced intestinal oxidative stress and reduced the digestive enzyme activity of grass carp. (2) High-throughput sequencing of 16S rDNA revealed that enrofloxacin but not the florfenicol treatment influenced gut microbiota diversity in grass carp by shifting α/β-diversity with more abundant pathogens detected. (3) Transcriptome profiling demonstrated that florfenicol down-regulated the immune-related pathways of grass carp, and the network analysis revealed that IgA was negatively correlated with certain pathogens, such as Shewanella and Aeromonas. (4) Antibiotic-induced alternations of gut core microbes were revealed via immune-related transcripts, as were lower mRNA expression levels of mucosal-related genes. (5) Apoptosis and histopathological changes were detected in the enrofloxacin- and florfenicol-treated groups compared with the control group. Overall, administering antibiotics will promote oxidative stress, cause intestinal flora dysbiosis, inhibit the mucosal immune system, and induce apoptosis in grass carp.
Identifying immune cells-related phenotype to predict immunotherapy and clinical outcome in gastric cancer
Authors: Jiang Sutian , Ding Xuzhong , Wu Qianqian , Cheng Tong , Xu Manyu , Huang Jianfei
Published: August 2022

Background

The tumor microenvironment is mainly composed of tumor-infiltrating immune cells (TIICs), fibroblast, extracellular matrix, and secreted factors. TIICs are often associated with sensitivity to immunotherapy and the prognosis of multiple cancers, yet the predictive role of individual cells on tumor prognosis is limited.

Methods

Based on single-sample gene set enrichment analysis, we combined three Gene Expression Omnibus (GEO) cohorts to build a TIIC model for risk stratification and prognosis prediction. The performance of the TIIC model was validated using our clinical cohort and the TCGA cohort. To assess the predictive power of the TIIC model for immunotherapy, we plotted the receiver operating characteristic curve with the IMvigor210 and GSE135222 cohorts.

Results

Chemokines, tumor-infiltrating immune cells, and immunomodulators differed between the two TIIC groups. The TIIC model was vital for predicting the outcome of immunotherapy. In our clinical samples, we verified that the expression levels of PD-1 and PD-L1 were higher in the low TIIC score group than in the high TIIC score group, both in the tumor and stroma.

Conclusions

Collectively, the TIIC model could provide a novel idea for immune cell targeting strategies in gastric cancer and predict the survival outcome of patients.
Environment variables affect CPUE and spatial distribution of fishing grounds on the light falling gear fishery in the northwest Indian Ocean at different time scales
Authors: Han Haibin , Yang Chao , Zhang Heng , Fang Zhou , Jiang Bohui , Su Bing , Sui Jianghua , Yan Yunzhi , Xiang Delong
Published: August 2022

To better develop and protect the pelagic fishery in the northwest Indian Ocean, China’s fishing enterprises have been producing pelagic fisheries in the said area for a long time. Based on the fishing log data of light falling gear in the northwest Indian Ocean from 2016 to 2020, this study analyzed the impact of different time scales on the catch rate and fishing ground center of gravity of light falling gear fishing grounds. We also explored the relationship between different time scales and catch per unit effort (CPUE) by using the fishing ground center of gravity, the Random Forest model (RF), and the generalized additive model (GAM). The results were shown as follows: (1) From 2016 to 2020, 76,576 t were captured, and 16,496 nets were operated; (2) The gravity center of fishing ground in the Northwest Indian Ocean moved to the northeast as a whole, and the monthly fishing ground gravity center changed first to the Southern and then to the northern; (3) RF model (R² = 0.709, RMSE = 0.2034, and prediction accuracy is 55.8%), which is better than the GAM model (R² = 0.632, RMSE = 0.2242, and prediction accuracy is 37.3%). In the RF model, the importance of time variables on CPUE was in the order of week, year, operation time, and lunar phase; in the GAM model, it was week, year, lunar phase, and operation time. On the whole, the importance of the long time scale (year, week) is greater than that of the short time scale (lunar phase and operation time). (4) The RF model and GAM model show that the most critical environmental variables were SST, DO, SSS, and Chla, and the least important were SSH, Δ50, and CV50. SST, Chla, and DO significantly impact pelagic fishing and CPUE and are critical reference indexes for predicting the Northwest Indian Ocean light falling gear fishing ground. (5) The 95% confidence interval showed that the suitable interval of time, space, and environmental variables in the RF model was much smaller than in the GAM model.
Changes in molecular characteristics and antimicrobial resistance of invasive Staphylococcus aureus infection strains isolated from children in Kunming, China during the COVID-19 epidemic
Authors: Ma Mingbiao , Tao Lvyan , Li Xinyue , Liang Yanqi , Li Jue , Wang Haiping , Jiang Hongchao , Dong Jing , Han Dingrui , Du Tingyi
Published: August 2022

Invasive Staphylococcus aureus (S. aureus) infection is associated with high rates of mortality in children. No studies have been reported on invasive S. aureus infection among children in Kunming, China, and it remains unknown whether the COVID-19 epidemic has affected S. aureus prevalence in this region. Thus, this study investigated the changes in molecular characteristics and antimicrobial resistance of invasive S. aureus strains isolated from children in Kunming during 2019–2021. In total, 66 invasive S. aureus strains isolated from children were typed by multilocus sequence typing (MLST), spa, and Staphylococcal cassette chromosome mec (SCCmec), and antimicrobial resistance and virulence genes were analyzed. A total of 19 ST types, 31 spa types and 3 SCCmec types were identified. Thirty nine (59.09%) strains were methicillin-sensitive S. aureus (MSSA) and 27 (40.91%) strains were methicillin-resistant S. aureus (MRSA). The most common molecular type was ST22-t309 (22.73%, 15/66), followed by ST59-t437 (13.64%, 9/66). In 2019 and 2021, the dominant molecular type was ST22-t309, while in 2020, it was ST59-t437. After 2019, the dominant molecular type of MRSA changed from ST338-t437 to ST59-t437. All strains were susceptible to tigecycline, ciprofloxacin, moxifloxacin, vancomycin, quinopudine-dafoputin, linezolid, levofloxacin, and rifampicin. From 2019 to 2021, the resistance to penicillin and sulfamethoxazole initially decreased and then increased, a trend that contrasted with the observed resistance to oxacillin, cefoxitin, erythromycin, clindamycin, and tetracycline. Sixteen antimicrobial resistance profiles were identified, with penicillin-tetracycline-erythromycin-clindamycin-oxacillin-cefoxitin being the most common, and the antimicrobial resistance profiles varied by year. The carrier rates of virulence genes, icaA, icaD, hla, fnbA, fnbB, clfA, clfB, and cna were 100.00%. Furthermore, sak, pvl, icaC, icaR, fib, lip, hlb, hysA, sea, seb, and tsst-1 had carrier rates of 96.97, 92.42, 87.88, 69.70, 84.85, 62.12, 56.06, 50, 37.87, 30.30, and 7.58%, respectively. Since COVID-19 epidemic, the annual number of invasive S. aureus strains isolated from children in Kunming remained stable, but the molecular characteristics and antimicrobial resistance profiles of prevalent S. aureus strains have changed significantly. Thus, COVID-19 prevention and control should be supplemented by surveillance of common clinical pathogens, particularly vigilance against the prevalence of multidrug-resistant and high-virulence strains.
Transcriptome analysis of heat resistance regulated by quorum sensing system in Glaesserella parasuis
Authors: Zhang Bingzhou , Jiang Changsheng , Cao Hua , Zeng Wei , Ren Jingping , Hu Yaofang , Li Wentao , He Qigai
Published: August 2022

The ability of bacteria to resist heat shock allows them to adapt to different environments. In addition, heat shock resistance is known for their virulence. Our previous study showed that the AI-2/luxS quorum sensing system affects the growth characteristics, biofilm formation, and virulence of Glaesserella parasuis. The resistance of quorum sensing system deficient G. parasuis to heat shock was obviously weaker than that of wild type strain. However, the regulatory mechanism of this phenotype remains unclear. To illustrate the regulatory mechanism by which the quorum sensing system provides resistance to heat shock, the transcriptomes of wild type (GPS2), ΔluxS, and luxS complemented (C-luxS) strains were analyzed. Four hundred forty-four differentially expressed genes were identified in quorum sensing system deficient G. parasuis, which participated in multiple regulatory pathways. Furthermore, we found that G. parasuis regulates the expression of rseA, rpoE, rseB, degS, clpP, and htrA genes to resist heat shock via the quorum sensing system. We further confirmed that rseA and rpoE genes exerted an opposite regulatory effect on heat shock resistance. In conclusion, the findings of this study provide a novel insight into how the quorum sensing system affects the transcriptome of G. parasuis and regulates its heat shock resistance property.
Prenatal valproic acid-induced autism marmoset model exhibits higher salivary cortisol levels
Authors: Nakamura Madoka , Nakagami Akiko , Nakagaki Keiko , Yasue Miyuki , Kawai Nobuyuki , Ichinohe Noritaka
Published: August 2022

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed throughout the day in VPA-exposed marmosets. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously, but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.
Comprehensive visual electrophysiological measurements discover crucial changes caused by alcohol addiction in humans: Clinical values in early prevention of alcoholic vision decline
Authors: Xie Xin , Feng Kang , Wang Juan , Zhang Min , Hong Jing , Zhang Haolin
Published: August 2022

Alcohol addiction often compromises vision by impairing the visual pathway, particularly the retina and optic nerve. Vision decline in alcoholics consists of a sequential transition from reversible functional deterioration of the visual pathway to irreversible clinical vision degeneration or vision loss. Thus, the control of alcoholic vision decline should focus on prevention before permanent damage occurs. Visual electrophysiology is a promising method for early detection of retinal dysfunction and optic neuropathy, including full-field electroretinography (ffERG) and pattern-reversal visual evoked potential (PR-VEP). So far, however, research studying the electrophysiological characteristics in the preclinical stage of vision decline caused by alcohol addiction is still lacking. Here we conducted a retrospective study with 11 alcoholics and 14 matched control individuals to address this need. We had performed comprehensive visual electrophysiological tests, including ffERG and PR-VEP. We next analyzed all electrophysiological parameters using multivariate statistical analyses and discovered some highly sensitive alterations to alcohol addiction. We found severely reduced amplitudes in scotopic ffERG oscillatory potentials (OPs) in alcohol addicts. These changes indicate the alcohol-induced disturbances of amacrine cells and retinal circulation. In subjects with alcohol addiction, the amplitudes of b-waves diminish significantly in scotopic but not photopic ffERG, implying the impaired function of the retinal rod system and the dysfunction of the inner retina. PR-VEPs elicited by checkerboard stimuli with large 1 degree (°) checks mainly reflect the state of the optic nerve and ganglion cells, and PR-VEPs provoked by small 0.25° checks mainly reflect the function of the macular. We performed both measurements and observed a robust amplitude reduction in all three peaks (N75–P100, P100–N135) and a significant peak time extension in P100. Our research provides an affordable and non-invasive tool to accurately evaluate visual pathway conditions in alcohol addicts and help clinicians take targeted treatment.
Case report: A double pathogenic mutation in a patient with late-onset MELAS/PEO overlap syndrome
Authors: Zhao Qiu Yan , Zhang Wen Zhao , Zhu Xue Lian , Qiao Fei , Jia Li Yuan , Li Bi , Xiao Yong , Chen Han , Zhang Yu , Chen Yun Guo , Wang Yong Liang
Published: August 2022

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and progressive external ophthalmoplegia (PEO) are established phenotypes of mitochondrial disorders. They are maternally-inherited, multisystem disorder that is characterized by variable clinical, biochemical, and imaging features. We described the clinical and genetic features of a Chinese patient with late-onset MELAS/PEO overlap syndrome, which has rarely been reported. The patient was a 48-year-old woman who presented with recurrent ischemic strokes associated with characteristic brain imaging and bilateral ptosis. We assessed her clinical characteristics and performed mutation analyses. The main manifestations of the patient were stroke-like episodes and seizures. A laboratory examination revealed an increased level of plasma lactic acid and a brain MRI showed multiple lesions in the cortex. A muscle biopsy demonstrated ragged red fibers. Genetic analysis from a muscle sample identified two mutations: TL1 m.3243A>G and POLG c.3560C>T, with mutation loads of 83 and 43%, respectively. This suggested that mitochondrial disorders are associated with various clinical presentations and an overlap between the syndromes and whole exome sequencing is important, as patients may carry multiple mutations.
Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan
Authors: Ando Masahiro , Higuchi Yujiro , Yuan Junhui H. , Yoshimura Akiko , Higashi Shuntaro , Takeuchi Mika , Hobara Takahiro , Kojima Fumikazu , Noguchi Yutaka , Takei Jun , Hiramatsu Yu , Nozuma Satoshi , Sakiyama Yusuke , Hashiguchi Akihiro , Matsuura Eiji , Okamoto Yuji , Nagai Masahiro , Takashima Hiroshi
Published: August 2022

The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.
Enhancement of lower limb motor imagery ability via dual-level multimodal stimulation and sparse spatial pattern decoding method
Authors: Hou Yao , Gu Zhenghui , Yu Zhu Liang , Xie Xiaofeng , Tang Rongnian , Xu Jinghan , Qi Feifei
Published: August 2022

Recently, motor imagery brain-computer interfaces (MI-BCIs) with stimulation systems have been developed in the field of motor function assistance and rehabilitation engineering. An efficient stimulation paradigm and Electroencephalogram (EEG) decoding method have been designed to enhance the performance of MI-BCI systems. Therefore, in this study, a multimodal dual-level stimulation paradigm is designed for lower-limb rehabilitation training, whereby visual and auditory stimulations act on the sensory organ while proprioceptive and functional electrical stimulations are provided to the lower limb. In addition, upper triangle filter bank sparse spatial pattern (UTFB-SSP) is proposed to automatically select the optimal frequency sub-bands related to desynchronization rhythm during enhanced imaginary movement to improve the decoding performance. The effectiveness of the proposed MI-BCI system is demonstrated on an the in-house experimental dataset and the BCI competition IV IIa dataset. The experimental results show that the proposed system can effectively enhance the MI performance by inducing the α, β and γ rhythms in lower-limb movement imagery tasks.
Transcutaneous auricular vagal nerve stimulation releases extrapineal melatonin and reduces thermal hypersensitivity in Zucker diabetic fatty rats
Authors: Wang Shuxing , Li Shaoyuan , Zhai Xu , Rong Peijing , He Jietao , Liu Lina , He Xinxin , Liu Wenguo
Published: August 2022

Type 2 diabetes (T2D) is the most common comorbidity of COVID-19, and both are related to the lack of circulating melatonin. In addition, chronic pain is a common sequela of both COVID-19 and T2D. Using a neuropathic pain model produced by sciatic nerve chronic constriction injury in Zucker diabetic fatty rats, a verified preclinical genetic T2D neuropathy animal model, this study aimed to show that transcutaneous auricular vagal nerve stimulation (taVNS) could elevate plasma melatonin concentration, upregulate the expression of melatonin receptors (MTRs) in the amygdala, and relieve peripheral neuropathic pain. Furthermore, taVNS would restore melatonin levels and relieve pain even in pinealectomized rats. On the contrary, intraperitoneally injected luzindole, a melatonin receptor antagonist, would attenuate the antinociceptive effects of taVNS. In conclusion, the mechanism of the therapeutic effect of taVNS on chronic pain involves the release of extrapineal melatonin and the positive regulation of the expression of central MTRs. This beneficial efficacy should be considered during COVID-19 rehabilitation in individuals with diabetes.
Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice
Authors: Samuel Itia , Ben-Haroush Schyr Rachel , Arad Yhara , Attali Tamar , Azulai Shira , Bergel Michael , Halfon Aviv , Hefetz Liron , Hirsch Tamir , Israeli Hadar , Lax Neta , Nitzan Keren , Sender Dana , Sweetat Sahar , Okun Eitan , Rosenmann Hanna , Ben-Zvi Danny
Published: August 2022

Obesity and hyperglycemia are risk factors for cognitive decline and for the development of Alzheimer’s Disease (AD). Bariatric surgery is an effective treatment for obesity that was shown to improve cognitive decline in obese patients. Bariatric surgery was shown to exert weight loss independent effects on metabolic diseases such as type 2 diabetes. We tested whether sleeve gastrectomy (SG), a common bariatric surgery, can affect the cognitive impairment in lean, normoglycemic female 5xFAD mice, a genetic model for AD. 5xFAD mice and wild-type (WT) littermates underwent SG or sham surgery at the age of 5 months and were tested for metabolic, behavioral, and molecular phenotypes 90 days later. SG led to a reduction in blood glucose levels and total plasma cholesterol levels in 5xFAD mice without inducing weight loss. However, the surgery did not affect the outcomes of long-term spatial memory tests in these mice. Analysis of β-Amyloid plaques corroborated the behavioral studies in showing no effect of surgery on the molecular phenotype of 5xFAD mice. In conclusion, SG leads to an improved metabolic profile in lean female 5xFAD mice without inducing weight loss but does not affect the brain pathology or behavioral phenotype. Our results suggest that the positive effects of bariatric surgery on cognitive decline in obese patients are likely attributed to weight loss and improvement in obesity sequelae, and not to weight loss independent effects of surgery.
Opioidergic pathways and kisspeptin in the regulation of female reproduction in mammals
Authors: Uenoyama Yoshihisa , Tsuchida Hitomi , Nagae Mayuko , Inoue Naoko , Tsukamura Hiroko
Published: August 2022

Endogenous opioid peptides have attracted attention as critical neuropeptides in the central mechanism regulating female reproduction ever since the discovery that arcuate dynorphin neurons that coexpress kisspeptin and neurokinin B (NKB), which are also known as kisspeptin/neurokinin B/dynorphin (KNDy) neurons, play a role as a master regulator of pulsatile gonadotropin-releasing hormone (GnRH) release in mammals. In this study, we first focus on the role of dynorphin released by KNDy neurons in the GnRH pulse generation. Second, we provide a historical overview of studies on endogenous opioid peptides. Third, we discuss how endogenous opioid peptides modulate tonic GnRH/gonadotropin release in female mammals as a mediator of inhibitory internal and external cues, such as ovarian steroids, nutritional status, or stress, on reproduction. Then, we discuss the role of endogenous opioid peptides in GnRH surge generation in female mammals.
On the accuracy of cell-attached current-clamp recordings from cortical neurons
Authors: Vazetdinova Alina , Valiullina-Rakhmatullina Fliza , Rozov Andrei , Evstifeev Alexander , Khazipov Roustem , Nasretdinov Azat
Published: August 2022

Cell-attached current-clamp (CA/CC) recordings have been proposed to measure resting membrane potential and synaptic/agonist responses in neurons without disrupting the cell membrane, thus avoiding the intracellular dialysis that occurs in conventional whole-cell recordings (WC). However, the accuracy of CA/CC recordings in neurons has not been directly assessed. Here, we used concomitant CA and WC current clamp recordings from cortical neurons in brain slices. Resting membrane potential values and slow voltage shifts showed variability and were typically attenuated during CA/CC recordings by ~10–20% relative to WC values. Fast signals were slowed down and their amplitude was greatly reduced: synaptic potentials by nearly 2-fold, and action potentials by nearly 10-fold in CA/CC mode compared to WC. The polarity of GABAergic postsynaptic responses in CA/CC mode matched the responses in WC, and depolarising GABAergic potentials were predominantly observed during CA/CC recordings of intact neonatal CA3 hippocampal pyramidal neurons. Similarly, CA/CC recordings reliably detected neuronal depolarization and excitation during network-induced giant depolarizing potentials in the neonatal CA3 hippocampus, and revealed variable changes, from depolarization to hyperpolarization, in CA1 pyramidal cells during sharp wave ripples in the adult hippocampus. Thus, CA/CC recordings are suitable for assessing membrane potential but signal distortion, probably caused by leakage via the seal contact and RC filtering should be considered.
Metabolomics approach reveals high energy diet improves the quality and enhances the flavor of black Tibetan sheep meat by altering the composition of rumen microbiota
Authors: Zhang Xue , Han Lijuan , Hou Shengzhen , Raza Sayed Haidar Abbas , Gui Linsheng , Sun Shengnan , Wang Zhiyou , Yang Baochun , Yuan Zhenzhen , Simal-Gandara Jesus , El-Shehawi Ahmed M. , Alswat Amal , Alenezi Muneefah A. , Shukry Mustafa , Sayed Samy M. , Aloufi Bandar Hamad
Published: August 2022

This study aims to determine the impact of dietary energy levels on rumen microbial composition and its relationship to the quality of Black Tibetan sheep meat by applying metabolomics and Pearson's correlation analyses. For this purpose, UHPLC-QTOF-MS was used to identify the metabolome, whereas 16S rDNA sequencing was used to detect the rumen microbiota. Eventually, we observed that the high energy diet group (HS) improved the carcass quality of Black Tibetan sheep and fat deposition in the longissimus lumborum (LL) compared to the medium energy diet group (MS). However, HS considerably increased the texture, water holding capacity (WHC), and volatile flavor of the LL when compared to that of MS and the low energy diet group (LS). Metabolomics and correlation analyses revealed that dietary energy levels mainly affected the metabolism of carbohydrates and lipids of the LL, which consequently influenced the content of volatile flavor compounds (VOCs) and fats. Furthermore, HS increased the abundance of Quinella, Ruminococcus 2, (Eubacterium) coprostanoligenes, and Succinivibrionaceae UCG-001, all of which participate in the carbohydrate metabolism in rumen and thus influence the metabolite levels (stachyose, isomaltose, etc.) in the LL. Overall, a high-energy diet is desirable for the production of Black Tibetan sheep mutton because it improves the mouthfeel and flavor of meat by altering the composition of rumen microbiota, which influences the metabolism in the LL.
Nigella sativa supplementation improves cardiometabolic indicators in population with prediabetes and type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials
Authors: Saadati Saeede , Naseri Kaveh , Asbaghi Omid , Abhari Khadijeh , Zhang Pangzhen , Li Hua-Bin , Gan Ren-You
Published: August 2022

Objective

Nigella sativa (N. sativa) from the family Ranunculaceae has medicinal properties. Previous studies have reported promising findings showing that N. sativa may benefit cardiometabolic health; however, current evidence on its cardiometabolic effects on those with prediabetes and type 2 diabetes mellitus (T2DM) is still unclear. Hence, we conducted a systematic review and meta-analysis to assess the efficacy of N. sativa on cardiometabolic parameters in population with prediabetes and T2DM.

Methods

PubMed/Medline, ISI Web of Science, Scopus, and Cochrane library were systematically searched up to June 20, 2022. Meta-analyses using random-effects models were used.

Results

Eleven randomized controlled trials (RCTs) were included in the meta-analysis. N. sativa intervention resulted in significant changes in fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), c-reactive protein (CRP), and malondialdehyde (MDA), without overall changes in glucose levels after oral glucose tolerance test (OGTT), fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride, high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI) when compared with the control group. In subgroup analyses, N. sativa supplementation enhanced serum levels of HDL-C in subjects with baseline HDL-C lower than 40 mg/dL. Furthermore, HOMA-IR and BMI values decreased in the N. sativa-supplemented group compared with the control group, when the length of follow-up was more than 8 weeks and the dose was more than 1 g/day for N. sativa supplementation, respectively.

Conclusion

Our findings indicate that N. sativa supplementation may effectively improve cardiometabolic profiles in individuals with prediabetes and T2DM.
A new technique for performing interstitial implants for gynecologic malignancies using transvaginal ultrasound guidance
Authors: Yan Xiao-Jing , Yang Yi , Chen Xi , Wang Shi-Guang , Niu Shu-Huai , Niu Hui-Xian , Liu Hong
Published: August 2022

Objectives

This study concerns a new technique that aims to achieve precise interstitial brachytherapy of pelvic recurrent tumors under transvaginal ultrasound (US) guidance, enhance the conformity index of the brachytherapy (BT), and improve the curative effect of radiotherapy for gynecological oncology patients with pelvic relapse.

Methods

A real-time transvaginal US-guided interstitial implant device was developed to assist in implant BT. Prior to implant brachytherapy, the size and location of the tumor in the pelvis and the interrelationship with adjacent organs were first assessed with intracavitary ultrasound. The transvaginal US-guided interstitial implant device was then placed on the endoluminal ultrasound probe, the probe was oriented intravaginally to determine a safe needle path, the implant needle was placed into the needle passage of the device, and the implant needle was inserted into the tumor tissue in the direction guided by the ultrasound puncture guide line. After the implant needle was placed in place, the cover of the transvaginal US-guided interstitial implant device was opened perpendicular to the ultrasound probe, and the needle was separated from the ultrasound probe smoothly, and then the cover was re-covered for subsequent implantation.

Results

In this study, 56 patients who underwent real-time transvaginal ultrasound-guided implantation for gynecologic oncology were enrolled, and insertion of 736 implant needles was completed. Among them, 13 patients had recurrent pelvic tumors after cervical cancer surgery and 6 patients had recurrent pelvic tumors after endometrial cancer surgery. Thirty-two patients who underwent radical radiation therapy for cervical cancer did not have adequate regression of parametrial invaded tissue after completion of standard EBRT treatment; and 5 patients had recurrent tumors in the radiation field after previous standard course of pelvic radiotherapy. The accuracy of the implant therapy was improved. The radiotherapy dose for recurrent pelvic masses was successfully increased, and the cumulative dose of external irradiation combined with BT was augmented to 80–100 Gy. The use of a new device for transvaginal implant for recurrent masses located in the lateral wall of the pelvic cavity was successful.

Conclusion

This intravascular US-guided interstitial implant device can realize interstitial implant with the shortest path under transvaginal US guidance. With convenient operation, high precision, and good security, the device not only improves the accuracy of implant therapy, but it also reduces the risks of anesthesia and organ injury, so it is suitable for widespread promotion and use.
Compound Kushen injection reduces severity of radiation-induced gastrointestinal mucositis in rats
Authors: Harata-Lee Yuka , Qu Zhipeng , Bateman Emma , Xiao Xi , Keller Marianne D. , Bowen Joanne , Wang Wei , Adelson David L.
Published: August 2022

Mucositis, or damage/injury to mucous membranes of the alimentary, respiratory, or genitourinary tract, is the major side effect associated with anticancer radiotherapies. Because there is no effective treatment for mucositis at present, this is a particular issue as it limits the dose of therapy in cancer patients and significantly affects their quality of life. Gastrointestinal mucositis (GIM) occurs in patients receiving radiotherapies to treat cancers of the stomach, abdomen, and pelvis. It involves inflammation and ulceration of the gastrointestinal (GI) tract causing diarrhea, nausea and vomiting, abdominal pain, and bloating. However, there is currently no effective treatment for this debilitating condition. In this study, we investigated the potential of a type of traditional Chinese medicine (TCM), compound Kushen injection (CKI), as a treatment for GIM. It has previously been shown that major groups of chemical compounds found in CKI have anti-inflammatory effects and are capable of inhibiting the expression of pro-inflammatory cytokines. Intraperitoneal administration of CKI to Sprague Dawley (SD) rats that concurrently received abdominal irradiation over five fractions resulted in reduced severity of GIM symptoms compared to rats administered a vehicle control. Histological examination of the intestinal tissues revealed significantly less damaged villus epithelium in CKI-administered rats that had reduced numbers of apoptotic cells in the crypts. Furthermore, it was also found that CKI treatment led to decreased levels of inflammatory factors including lower levels of interleukin (IL)-1β and IL-6 as well as myeloperoxidase (MPO)-producing cells in the intestinal mucosa. Together, our data indicate a novel effect of CKI to reduce the symptoms of radiation-induced GIM by inhibiting inflammation in the mucosa and apoptosis of epithelial cells.
Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma?
Authors: Gonvers Stéphanie , Tabrizian Parissa , Melloul Emmanuel , Dormond Olivier , Schwartz Myron , Demartines Nicolas , Labgaa Ismail
Published: August 2022

Liver transplant (LT) is the most favorable treatment option for patients with early stage hepatocellular carcinoma (HCC). Numerous attempts have been pursued to establish eligibility criteria and select HCC patients for LT, leading to various systems that essentially integrate clinico-morphological variables. Lacking of sufficient granularity to recapitulate the biological complexity of the disease, all these alternatives display substantial limitations and are thus undeniably imperfect. Liquid biopsy, defined as the molecular analysis of circulating analytes released by a cancer into the bloodstream, was revealed as an incomparable tool in the management of cancers, including HCC. It appears as an ideal candidate to refine selection criteria of LT in HCC. The present comprehensive review analyzed the available literature on this topic. Data in the field, however, remain scarce with only 17 studies. Although rare, these studies provided important and encouraging findings highlighting notable prognostic values and supporting the contribution of liquid biopsy in this specific clinical scenario. These results underpinned the critical and urgent need to intensify and accelerate research on liquid biopsy, in order to determine whether and how liquid biopsy may be integrated in the decision-making of LT in HCC.
Current treatments for non-small cell lung cancer
Authors: Guo Qianqian , Liu Liwei , Chen Zelong , Fan Yannan , Zhou Yang , Yuan Ziqiao , Zhang Wenzhou
Published: August 2022

Despite improved methods of diagnosis and the development of different treatments, mortality from lung cancer remains surprisingly high. Non-small cell lung cancer (NSCLC) accounts for the large majority of lung cancer cases. Therefore, it is important to review current methods of diagnosis and treatments of NSCLC in the clinic and preclinic. In this review, we describe, as a guide for clinicians, current diagnostic methods and therapies (such as chemotherapy, chemoradiotherapy, targeted therapy, antiangiogenic therapy, immunotherapy, and combination therapy) for NSCLC.