bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Potential Novel Prognosis-Related Genes Through Transcriptome Sequencing, Bioinformatics Analysis, and Clinical Validation in Acute Myeloid Leukemia
Authors: Wang Jie , Uddin Md. Nazim , Hao Jian-ping , Chen Rong , Xiang Yun-xia , Xiong Dai-qin , Wu Yun
Published: October 2021

Background: Acute Myeloid Leukemia (AML) is a complex and heterogeneous hematologic malignancy. However, the function of prognosis-related signature genes in AML remains unclear.

Methods: In the current study, transcriptome sequencing was performed on 15 clinical samples, differentially expressed RNAs were identified using R software. The potential interactions network was constructed by using the common genes between target genes of differentially expressed miRNAs with transcriptome sequencing results. Functional and pathway enrichment analysis was performed to identify candidate gene-mediated aberrant signaling pathways. Hub genes were identified by the cytohubba plugin in Cytoscape software, which then expanded the potential interactions regulatory module for hub genes. TCGA-LAML clinical data were used for the prognostic analysis of the hub genes in the regulatory network, and GVSA analysis was used to identify the immune signature of prognosis-related hub genes. qRT-PCR was used to verify the expression of hub genes in independent clinical samples.

Results: We obtained 1,610 differentially expressed lncRNAs, 233 differentially expressed miRNAs, and 2,217 differentially expressed mRNAs from transcriptome sequencing. The potential interactions network is constructed by 12 lncRNAs, 25 miRNAs, and 692 mRNAs. Subsequently, a sub-network including 15 miRNAs as well as 12 lncRNAs was created based on the expanded regulatory modules of 25 key genes. The prognostic analysis results show that CCL5 and lncRNA UCA1 was a significant impact on the prognosis of AML. Besides, we found three potential interactions networks such as lncRNA UCA1/hsa-miR-16-5p/COL4A5, lncRNA UCA1/hsa-miR-16-5p/SPARC, and lncRNA SNORA27/hsa-miR-17-5p/CCL5 may play an important role in AML. Furthermore, the evaluation of the immune infiltration shows that CCL5 is positively correlated with various immune signatures, and lncRNA UCA1 is negatively correlated with the immune signatures. Finally, the result of qRT-PCR showed that CCL5 is down-regulated and lncRNA UCA1 is up-regulated in AML samples separately.

Conclusions: In conclusion, we propose that CCL5 and lncRNA UCA1 could be recognized biomarkers for predicting survival prognosis based on constructing competing endogenous RNAs in AML, which will provide us novel insight into developing novel prognostic, diagnostic, and therapeutic for AML.
Chromosome-Level Genome Assembly Reveals Significant Gene Expansion in the Toll and IMD Signaling Pathways of Dendrolimus kikuchii
Authors: Zhou Jielong , Wu Peifu , Xiong Zhongping , Liu Naiyong , Zhao Ning , Ji Mei , Qiu Yu , Yang Bin
Published: October 2021

A high-quality genome is of significant value when seeking to control forest pests such as Dendrolimus kikuchii, a destructive member of the order Lepidoptera that is widespread in China. Herein, a high quality, chromosome-level reference genome for D. kikuchii based on Nanopore, Pacbio HiFi sequencing and the Hi-C capture system is presented. Overall, a final genome assembly of 705.51 Mb with contig and scaffold N50 values of 20.89 and 24.73 Mb, respectively, was obtained. Of these contigs, 95.89% had unique locations on 29 chromosomes. In silico analysis revealed that the genome contained 15,323 protein-coding genes and 63.44% repetitive sequences. Phylogenetic analyses indicated that D. kikuchii may diverged from the common ancestor of Thaumetopoea. Pityocampa, Thaumetopoea ni, Heliothis virescens, Hyphantria armigera, Spodoptera frugiperda, and Spodoptera litura approximately 122.05 million years ago. Many gene families were expanded in the D. kikuchii genome, particularly those of the Toll and IMD signaling pathway, which included 10 genes in peptidoglycan recognition protein, 19 genes in MODSP, and 11 genes in Toll. The findings from this study will help to elucidate the mechanisms involved in protection of D. kikuchii against foreign substances and pathogens, and may highlight a potential channel to control this pest.
Evolutionary Tracks of Chromosomal Diversification in Surgeonfishes (Acanthuridae: Acanthurus) Along the World’s Biogeographic Domains
Authors: Fernandes Maria Aparecida , Cioffi Marcelo de Bello , Bertollo Luiz Antônio Carlos , Costa Gideão Wagner Werneck Félix da , Motta-Neto Clóvis Coutinho da , Borges Amanda Tôrres , Soares Rodrigo Xavier , Souza Allyson Santos de , Pinthong Krit , Supiwong Weerayuth , Tanomtong Alongklod , Molina Wagner Franco
Published: October 2021

Fishes of the genus Acanthurus (Acanthuridae) are strongly related to reef environments, in a broad biogeographic context worldwide. Although their biological aspects are well known, cytogenetic information related to this genus remains incipient. In this study, Acanthurus species from populations inhabiting coastal regions of the Southwest Atlantic (SWA), South Atlantic oceanic islands (Fernando de Noronha Archipelago and Trindade Island), Greater Caribbean (GC), and Indo-Pacific Ocean (the center of the origin of the group) were analyzed to investigate their evolutionary differentiation. For this purpose, we employed conventional cytogenetic procedures and fluorescence in situ hybridization of 18S rDNA, 5S rDNA, and H3 and H2B-H2A histone sequences. The Atlantic species (A. coeruleus, A. chirurgus, and A. bahianus) did not show variations among them, despite their vast continental and insular distribution. In contrast, A. coeruleus from SWA and GC diverged from each other in the number of 18S rDNA sites, a condition likely associated with the barrier created by the outflows of the Amazonas/Orinoco rivers. The geminate species A. tractus had a cytogenetic profile similar to that of A. bahianus. However, the chromosomal macrostructures and the distribution of rDNA and hisDNA sequences revealed moderate to higher rates of diversification when Acanthurus species from recently colonized areas (Atlantic Ocean) were compared to A. triostegus, a representative species from the Indian Ocean. Our cytogenetic data covered all Acanthurus species from the Western Atlantic, tracked phylogenetic diversification throughout the dispersive process of the genus, and highlighted the probable diversifying role of ocean barriers in this process.
PIV and PILE Score at Baseline Predict Clinical Outcome of Anti-PD-1/PD-L1 Inhibitor Combined With Chemotherapy in Extensive-Stage Small Cell Lung Cancer Patients
Authors: Zeng Ran , Liu Fang , Fang Chen , Yang Jin , Luo Lifeng , Yue Ping , Gao Beili , Dong Yuchao , Xiang Yi
Published: October 2021

Objectives

The objective of this study is to evaluate whether PIV (Pan-Immune-Inflammation Value) and PILE [a score derived from PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)] can predict clinical outcome of anti-PD-1/PD-L1 inhibitor combined with chemotherapy in patients with extensive-stage (ES) small cell lung cancer (SCLC).

Methods

A total of 53 patients with ES-SCLC in the control group of clinical trial (NCT03041311) were included in this study. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE scores were composited based on PIV, LDH levels, and ECOG PS. The Kaplan–Meier method and Cox hazards regression models were used for survival analyses. Moreover, the predictive ability of PIV and PILE was validated in an independent real-world group consisting of 84 patients.

Results

Patients in the low PIV group (PIV < median) had longer progression-free survival (PFS) and overall survival (OS) than those in the high PIV group (PIV ≥ median), along with the HR, which was 2.157 and 2.359, respectively (PFS HR 95% CI: 1.181–3.940, p = 0.012; OS HR 95% CI: 1.168–4.762, p = 0.020). High PILE score was observed relating to worse treatment efficacy (disease control rate (DCR): 84.21% vs. 100%, p = 0.047; durable clinical benefit (DCB) rate: 10% vs. 48.5%, p = 0.060) and poor clinical outcome (median PFS: 4.75 vs. 5.53 m, p = 0.043; median OS: 7.13 vs. 15.93 m, p = 0.002). Similar results were obtained about the predictive and prognostic abilities of PIV and PILE scores in the validation group.

Conclusions

High PIV and high PILE were correlated with worse clinical outcomes in ES-SCLC patients treated with anti-PD-1/PD-L1 inhibitor combined with chemotherapy, reflecting that PIV and PILE might be useful to identify patients unlikely to benefit from anti-PD-1/PD-L1 therapy.
Adeno-Associated Viruses (AAV) and Host Immunity – A Race Between the Hare and the Hedgehog
Authors: Rapti Kleopatra , Grimm Dirk
Published: October 2021

Adeno-associated viruses (AAV) have emerged as the lead vector in clinical trials and form the basis for several approved gene therapies for human diseases, mainly owing to their ability to sustain robust and long-term in vivo transgene expression, their amenability to genetic engineering of cargo and capsid, as well as their moderate toxicity and immunogenicity. Still, recent reports of fatalities in a clinical trial for a neuromuscular disease, although linked to an exceptionally high vector dose, have raised new caution about the safety of recombinant AAVs. Moreover, concerns linger about the presence of pre-existing anti-AAV antibodies in the human population, which precludes a significant percentage of patients from receiving, and benefitting from, AAV gene therapies. These concerns are exacerbated by observations of cellular immune responses and other adverse events, including detrimental off-target transgene expression in dorsal root ganglia. Here, we provide an update on our knowledge of the immunological and molecular race between AAV (the “hedgehog”) and its human host (the “hare”), together with a compendium of state-of-the-art technologies which provide an advantage to AAV and which, thus, promise safer and more broadly applicable AAV gene therapies in the future.
Sustained Post-Developmental T-Bet Expression Is Critical for the Maintenance of Type One Innate Lymphoid Cells In Vivo
Authors: Schroeder Jan-Hendrik , Roberts Luke B. , Meissl Katrin , Lo Jonathan W. , Hromadová Dominika , Hayes Kelly , Zabinski Tomasz , Read Emily , Moreira Heliodoro Catarina , Reis Rita , Howard Jane K. , Grencis Richard K. , Neves Joana F. , Strobl Birgit , Lord Graham M.
Published: October 2021

Innate lymphoid cells (ILC) play a significant role in the intestinal immune response and T-bet+ CD127+ group 1 cells (ILC1) have been linked to the pathogenesis of human inflammatory bowel disease (IBD). However, the functional importance of ILC1 in the context of an intact adaptive immune response has been controversial. In this report we demonstrate that induced depletion of T-bet using a Rosa26-Cre-ERT2 model resulted in the loss of intestinal ILC1, pointing to a post-developmental requirement of T-bet expression for these cells. In contrast, neither colonic lamina propria (cLP) ILC2 nor cLP ILC3 abundance were altered upon induced deletion of T-bet. Mechanistically, we report that STAT1 or STAT4 are not required for intestinal ILC1 development and maintenance. Mice with induced deletion of T-bet and subsequent loss of ILC1 were protected from the induction of severe colitis in vivo. Hence, this study provides support for the clinical development of an IBD treatment based on ILC1 depletion via targeting T-bet or its downstream transcriptional targets.
In Vivo Mouse Models for Hepatitis B Virus Infection and Their Application
Authors: Du Yanqin , Broering Ruth , Li Xiaoran , Zhang Xiaoyong , Liu Jia , Yang Dongliang , Lu Mengji
Published: October 2021

Despite the availability of effective vaccination, hepatitis B virus (HBV) infection continues to be a major challenge worldwide. Research efforts are ongoing to find an effective cure for the estimated 250 million people chronically infected by HBV in recent years. The exceptionally limited host spectrum of HBV has limited the research progress. Thus, different HBV mouse models have been developed and used for studies on infection, immune responses, pathogenesis, and antiviral therapies. However, these mouse models have great limitations as no spread of HBV infection occurs in the mouse liver and no or only very mild hepatitis is present. Thus, the suitability of these mouse models for a given issue and the interpretation of the results need to be critically assessed. This review summarizes the currently available mouse models for HBV research, including hydrodynamic injection, viral vector-mediated transfection, recombinant covalently closed circular DNA (rc-cccDNA), transgenic, and liver humanized mouse models. We systematically discuss the characteristics of each model, with the main focus on hydrodynamic injection mouse model. The usefulness and limitations of each mouse model are discussed based on the published studies. This review summarizes the facts for considerations of the use and suitability of mouse model in future HBV studies.
Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma
Authors: Subramanian Hariharan , Hashem Tanwir , Bahal Devika , Kammala Ananth K. , Thaxton Kanedra , Das Rupali
Published: October 2021

Asthma prevalence has increased considerably over the decades and it is now considered as one of the most common chronic disorders in the world. While the current anti-asthmatic therapies are effective for most asthma patients, there are 5-10% subjects whose disease is not controlled by such agents and they account for about 50% of the asthma-associated healthcare costs. Such patients develop severe asthma (SA), a condition characterized by a dominant Th1/Th17 cytokine response that is accompanied by Type 2 (T2)-low endotype. As JAK (Janus Kinase) signaling is very important for the activation of several cytokine pathways, we examined whether inhibition of JAKs might lessen the clinical and laboratory manifestations of SA. To that end, we employed a recently described murine model that recapitulates the complex immune response identified in the airways of human SA patients. To induce SA, mice were sensitized with house dust mite extract (HDME) and cyclic (c)-di-GMP and then subsequently challenged with HDME and a lower dose of c-di-GMP. In this model, treatment with the JAK inhibitor, Ruxolitinib, significantly ameliorated all the features of SA, including airway hyperresponsiveness and lung inflammation as well as total IgE antibody titers. Thus, these studies highlight JAKs as critical targets for mitigating the hyper-inflammation that occurs in SA and provide the framework for their incorporation into future clinical trials for patients that have severe or difficult-to manage asthma.
Cyanobacteria-Dominated Phytoplankton in the Oligotrophic South China Sea Maintain Photosynthetic Potential Despite Diurnal Photoinactivation of PSII
Authors: Yi Xiangqi , Zhang Di , Sun Jiazhen , Beardall John , Gao Kunshan
Published: October 2021

In the warm, oligotrophic oceans, phytoplankton frequently experience high light exposure and must compete for a potentially limited nutrient supply. Additionally, the light regimes are dynamic in view of the diel solar cycle, weather conditions, and depth. Dealing with these challenges is critical to their survival. Here, we explored, using active chlorophyll a fluorescence, the photophysiological responses of cyanobacteria-dominated phytoplankton assemblages to intra-day variations in the light regime in the oligotrophic South China Sea (SCS). Experiments were conducted at three stations (SEATS, DC2, and DC6) where phytoplankton communities were dominated by Prochlorococcus and Synechococcus, and environmental conditions were similar except for daytime light conditions. We found that, at each station, the maximum quantum yield of PSII (Fv/Fm) at dawn was as high as ∼0.5, although concentrations of both dissolved inorganic nitrogen and soluble reactive phosphate were below the detection limits. Subsequently, diurnal patterns of Fv/Fm diverged between stations. At stations DC2 and DC6, we observed significant drops (25–48%) of Fv/Fm around midday, coinciding with the incident solar photosynthetically active radiation (PAR) reaching over 2,000 μmol quanta m–2 s–1, but Fv/Fm was nearly stable at SEATS where the daily maximal PAR was less than 1,000 μmol quanta m–2 s–1. Further analysis suggests that the midday drops in Fv/Fm at DC2 and DC6 were a consequence of high light-induced PSII photoinactivation. On the other hand, we found that the patterns of diurnal variation in maximum relative electron transport rate (rETRmax) presented as being unimodal with a peak around midday at all three stations. Furthermore, we found that the diurnal pattern of rETRmax was mainly controlled by the extent of photochemical quenching (qP) which reflects the redox status of electron carriers downstream of PSII. In conclusion, our results indicate that, in the oligotrophic SCS, through increasing the activity of the electron-consuming mechanisms (high qP), the phytoplankton communities are able to maintain their midday photosynthetic potential (high rETRmax) even with a degree of PSII photoinactivation (low Fv/Fm).
Mutations in FIGLA Associated With Premature Ovarian Insufficiency in a Chinese Population
Authors: Mei Libin , Huang Yanru , Wu Xiaoling , He Huang , Ye Ronghui , Ma Jinxiu , He XueMei , Shi Yuhua , Li Ping
Published: October 2021

Objective: Premature ovarian insufficiency (POI) is one of the most common reproductive endocrinological causes of infertility in women of child-bearing age. The purpose of this study was to identify FIGLA gene mutations in Chinese patients with POI and to investigate the underlying mechanism.

Methods: A total of 113 patients with idiopathic POI and 100 healthy controls were recruited for the analysis of FIGLA variants. Based on the identification of common mutations in the FIGLA, wild-type and mutant plasmids were constructed and transfected into HEK293 cells. Luciferase reporter genes were used to determine the effect of wild-type and mutant FIGLA genotypes on the transcriptional activity of its downstream targets, the zona pellucida glycoprotein genes ZP1, ZP2, and ZP3. Chromatin immunoprecipitation was used to determine the level of binding between wild-type and mutant FIGLA with the ZP1, ZP2, and ZP3 promoters.

Results: Three different FIGLA mutations were identified in four patients with POI. Two patients carried the mutation c.11C>A (p.A4E), and the other two patients, respectively, carried the mutations c.625G>A (p.V209I) and c.84C>A (p.D28E). The luciferase reporter assay indicated that ZP1, ZP2, and ZP3 transcriptional activities were significantly reduced in individuals with FIGLA mutations. Chromatin immunoprecipitation indicated that the FIGLA mutation significantly decreased binding with the ZP1, ZP2, and ZP3 promoters.

Conclusion:FIGLA mutation affects gene transcriptional regulation of its downstream target genes ZP1, ZP2, and ZP3, highlighting a new candidate genetic factor that causes POI. Our study demonstrates that FIGLA has a regulatory effect on reproduction-specific genes, thereby providing a basis for elucidating the specific regulatory mechanism of FIGLA in germ cell growth and development.
Replication of Reduced Pattern Electroretinogram Amplitudes in Depression With Improved Recording Parameters
Authors: Friedel Evelyn B. N. , Tebartz van Elst Ludger , Schmelz Céline , Ebert Dieter , Maier Simon , Endres Dominique , Runge Kimon , Domschke Katharina , Bubl Emanuel , Kornmeier Jürgen , Bach Michael , Heinrich Sven P. , Nickel Kathrin
Published: October 2021

Background:The retina has gained increasing attention in non-ophthalmological research in recent years. The pattern electroretinogram (PERG), a method to evaluate retinal ganglion cell function, has been used to identify objective correlates of the essentially subjective state of depression. A reduction in the PERG contrast gain was demonstrated in patients with depression compared to healthy controls with normalization after remission. PERG responses are not only modulated by stimulus contrast, but also by check size and stimulation frequency. Therefore, the rationale was to evaluate potentially more feasible procedures for PERG recordings in daily diagnostics in psychiatry.

Methods:Twenty-four participants (12 patients with major depression (MDD) and 12 age- and sex-matched healthy controls) were examined in this pilot study. We investigated PERG amplitudes for two steady-state pattern reversal frequencies (12.5/18.75 rps) and four sizes of a checkerboard stimulus (0.8°, 1.6°, 3.2°, and 16°) to optimize the PERG recordings in MDD patients.

Results:Smaller PERG amplitudes in MDD patients were observed for all parameters, whereby the extent of the reduction appeared to be stimulus-specific. The most pronounced decline in the PERG of MDD patients was observed at the higher stimulation frequency and the finest pattern, whilst responses for the largest check size were less affected. Following the PERG ratio protocol for early glaucoma, where similar stimulus dependent modulations have been reported, we calculated PERG ratios (0.8°/16°) for all participants. At the higher frequency (18.75 rps), significantly reduced ratios were observed in MDD patients.

Conclusion:The “normalization” of the PERG responses—via building a ratio—appears to be a very promising approach with regard to the development of an objective biomarker of the depressive state, facilitating inter-individual assessments of PERG recordings in patients with psychiatric disorders.
Astrocytes Downregulate Inflammation in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: Applicability to COVID-19
Authors: Izrael Michal , Molakandov Kfir , Revel Ariel , Slutsky Shalom Guy , Sonnenfeld Tehila , Weiss Julia Miriam , Revel Michel
Published: October 2021

Background: An acute respiratory distress syndrome (ARDS) is caused by the increased amounts of pro-inflammatory cytokines and neutrophil-mediated tissue injury. To date, there is no effective treatment for the ARDS available, while the need for one is growing due to the most severe complications of the current coronavirus disease-2019 (COVID-19) pandemic. The human astrocytes (AstroRx) have shown immunomodulatory properties in the central nervous system (CNS). This study aimed to evaluate the capacity of astrocytes to decrease lung inflammation and to be applied as a treatment therapy in ARDS.

Methods: First, we assessed the ability of clinical-grade AstroRx to suppress T-cell proliferation in a mixed lymphocyte reaction test. Next, we tested the therapeutical potential of AstroRx cells in a lipopolysaccharide (LPS)-based ARDS mouse model by injecting AstroRx intravenously (i.v). We determined the degree of lung injury by using a severity scoring scale of 0–2, based on the American Thoracic Society. The scoring measured the presence of neutrophils, fibrin deposits, and the thickening of alveolar walls. The state of inflammation was further assessed by quantifying the immune-cell infiltration to the bronchoalveolar lavage fluid (BALF) and by the presence of proinflammatory cytokines and chemokines in the BALF and serum.

Results: We detected that AstroRx cells were capable to suppress T-cell proliferation in vitro after exposure to the mitogen concanavalin A (ConA). In vivo, AstroRx cells were able to lower the degree of lung injury in LPS-treated animals compared with the sham injected animals (P = 0.039). In this study, 30% of AstroRx treated mice showed no lung lesions (responder mice), these mice presented a steady number of eosinophils, T cells, and neutrophils comparable with the level of naïve control mice. The inflammatory cytokines and chemokines, such as TNFα, IL1b, IL-6, and CXCL1, were also kept in check in responder AstroRx-treated mice and were not upregulated as in the sham-injected mice (P < 0.05). As a result, the LPS-treated ARDS mice had a higher survival rate when they were treated with AstroRx.

Conclusions: Our results demonstrate that the immunosuppressive activity of AstroRx cells support the application of AstroRx cells as a cell therapy treatment for ARDS. The immunoregulatory activity may also be a part of the mechanism of action of AstroRx reported in the amyotrophic lateral sclerosis (ALS) neurodegenerative disease.
Tubular Cell Glucose Metabolism Shift During Acute and Chronic Injuries
Authors: Faivre Anna , Verissimo Thomas , Auwerx Hannah , Legouis David , de Seigneux Sophie
Published: October 2021

Acute and chronic kidney disease are responsible for large healthcare costs worldwide. During injury, kidney metabolism undergoes profound modifications in order to adapt to oxygen and nutrient shortage. Several studies highlighted recently the importance of these metabolic adaptations in acute as well as in chronic phases of renal disease, with a potential deleterious effect on fibrosis progression. Until recently, glucose metabolism in the kidney has been poorly studied, even though the kidney has the capacity to use and produce glucose, depending on the segment of the nephron. During physiology, renal proximal tubular cells use the beta-oxidation of fatty acid to generate large amounts of energy, and can also produce glucose through gluconeogenesis. In acute kidney injury, proximal tubular cells metabolism undergo a metabolic shift, shifting away from beta-oxidation of fatty acids and gluconeogenesis toward glycolysis. In chronic kidney disease, the loss of fatty acid oxidation is also well-described, and data about glucose metabolism are emerging. We here review the modifications of proximal tubular cells glucose metabolism during acute and chronic kidney disease and their potential consequences, as well as the potential therapeutic implications.
Longitudinal Associations Between Hand Grip Strength and Non-Alcoholic Fatty Liver Disease in Adults: A Prospective Cohort Study
Authors: Xia Yang , Cao Limin , Liu Yashu , Wang Xuena , Zhang Shunming , Meng Ge , Zhang Qing , Liu Li , Wu Hongmei , Gu Yeqing , Wang Yawen , Zhang Tingjing , Wang Xing , Sun Shaomei , Zhou Ming , Jia Qiyu , Song Kun , Niu Kaijun , Zhao Yuhong
Published: October 2021

Purpose: This study aimed to determine the longitudinal association between hand grip strength (HGS) and the development of non-alcoholic fatty liver disease (NAFLD) in adults.

Design: A cohort study.

Methods: This study was conducted in a general Chinese population (n = 14,154) from 2013–2018. NAFLD was diagnosed by liver ultrasonography during evaluating alcohol consumption. The associations between the HGS and NAFLD were assessed using a multivariable Cox proportional hazards regression model.

Results: During the study period with a mean follow-up duration of 3.20 years, 2,452 participants developed NAFLD. The risk of NAFLD decreased progressively with increasing HGS in both men and women (P for trend <0.0001). The multivariate-adjusted hazard ratios (95% CI) for NAFLD incidence across the quartiles of HGS were 1 (reference), 0.90 (0.79, 1.02), 0.69 (0.60, 0.79), and 0.44 (0.37, 0.52) for men and 1 (reference), 0.82 (0.69, 0.96), 0.54 (0.45, 0.66), and 0.41 (0.33, 0.52) for women, respectively. The interaction terms for body mass index (BMI)-HGS and waist-HGS were significant in men and women (all P < 0.0001). The participants with normal BMIs and waist circumferences had the lowest hazard ratios on the subgroup analyses. The sensitivity analysis that defined NAFLD using the hepatic steatosis and fatty liver indices revealed results that were similar to the main analyses.

Conclusion: The present study indicates that the HGS is inversely associated with the incidence of NAFLD.
Challenges in the Microbiological Diagnosis of Implant-Associated Infections: A Summary of the Current Knowledge
Authors: Oliva Alessandra , Miele Maria Claudia , Al Ismail Dania , Di Timoteo Federica , De Angelis Massimiliano , Rosa Luigi , Cutone Antimo , Venditti Mario , Mascellino Maria Teresa , Valenti Piera , Mastroianni Claudio Maria
Published: October 2021

Implant-associated infections are characterized by microbial biofilm formation on implant surface, which renders the microbiological diagnosis challenging and requires, in the majority of cases, a complete device removal along with a prolonged antimicrobial therapy. Traditional cultures have shown unsatisfactory sensitivity and a significant advance in the field has been represented by both the application of the sonication technique for the detachment of live bacteria from biofilm and the implementation of metabolic and molecular assays. However, despite the recent progresses in the microbiological diagnosis have considerably reduced the rate of culture-negative infections, still their reported incidence is not negligible. Overall, several culture- and non-culture based methods have been developed for diagnosis optimization, which mostly relies on pre-operative and intra-operative (i.e., removed implants and surrounding tissues) samples. This review outlines the principal culture- and non-culture based methods for the diagnosis of the causative agents of implant-associated infections and gives an overview on their application in the clinical practice. Furthermore, advantages and disadvantages of each method are described.
Arginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing
Authors: Szondi Denis C. , Wong Jason K. , Vardy Leah A. , Cruickshank Sheena M.
Published: October 2021

Arginase (ARG) represents an important evolutionarily conserved enzyme that is expressed by multiple cell types in the skin. Arg acts as the mediator of the last step of the urea cycle, thus providing protection against excessive ammonia under homeostatic conditions through the production of L-ornithine and urea. L-ornithine represents the intersection point between the ARG-dependent pathways and the urea cycle, therefore contributing to cell detoxification, proliferation and collagen production. The ARG pathways help balance pro- and anti-inflammatory responses in the context of wound healing. However, local and systemic dysfunctionalities of the ARG pathways have been shown to contribute to the hindrance of the healing process and the occurrence of chronic wounds. This review discusses the functions of ARG in macrophages and fibroblasts while detailing the deleterious implications of a malfunctioning ARG enzyme in chronic skin conditions such as leg ulcers. The review also highlights how ARG links with the microbiota and how this impacts on infected chronic wounds. Lastly, the review depicts chronic wound treatments targeting the ARG pathway, alongside future diagnosis and treatment perspectives.
Characterizing Sex Differences in Depressive-Like Behavior and Glial Brain Cell Changes Following Peripheral Nerve Injury in Mice
Authors: Michailidis Vassilia , Lidhar Navdeep K. , Cho Chulmin , Martin Loren J.
Published: October 2021

Chronic pain and depression are intimately linked; the combination of the two leads to higher health care costs, lower quality of life, and worse treatment outcomes with both conditions exhibiting higher prevalence among women. In the current study, we examined the development of depressive-like behavior in male and female mice using the spared nerve injury (SNI) model of neuropathic pain. Males displayed increased immobility on the forced-swim test – a measure of depressive-like behavior – 2 weeks following injury, while females developed depressive-like behavior at 3-week. Since the pathogenesis of chronic pain and depression may involve overlapping mechanisms including the activation of microglial cells, we explored glial cell changes in brain regions associated with pain processing and affect. Immunohistochemical analyses revealed that microglial cells were more numerous in female SNI mice in the contralateral ventral anterior cingulate cortex (ACC), a brain region important for pain processing and affect behavior, 2-week following surgery. Microglial cell activation was not different between any of the groups for the dorsal ACC or nucleus accumbens. Analysis of astrocyte density did not reveal any significant changes in glial fibrillary acidic protein (GFAP) staining in the ACC or nucleus accumbens. Overall, the current study characterized peripheral nerve injury induced depression-like behavior in male and female mice, which may be associated with different patterns of glial cell activation in regions important for pain processing and affect.
Post-acquisition CO2 Inhalation Enhances Fear Memory and Depends on ASIC1A
Authors: Taugher Rebecca J. , Wunsch Amanda M. , Wang Grace Z. , Chan Aubrey C. , Dlouhy Brian J. , Wemmie John A.
Published: October 2021

A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO2) during retrieval. In light of this finding, we hypothesized that 10% CO2 inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO2 exposure after fear acquisition. The effect of CO2 was time-dependent, as CO2 inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO2 inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO2 exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO2 may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO2 inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO2, likely via its ability to sense acidosis induced during CO2 inhalation. We found that CO2 inhalation did not alter cued or context fear memory in Asic1a–/– mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.
Cross-Sectional Characterization of Local Brain Network Connectivity Pre and Post Breast Cancer Treatment and Distinct Association With Subjective Cognitive and Psychological Function
Authors: Kesler Shelli R. , Tang Tien , Henneghan Ashley M. , Wright Michelle , Gaber M. Waleed , Palesh Oxana
Published: October 2021

Objective: We aimed to characterize local brain network connectivity in long-term breast cancer survivors compared to newly diagnosed patients.

Methods: Functional magnetic resonance imaging (fMRI) and subjective cognitive and psychological function data were obtained from a group of 76 newly diagnosed, pre-treatment female patients with breast cancer (mean age 57 ± 7 years) and a separate group of 80, post-treatment, female breast cancer survivors (mean age 58 ± 8; mean time since treatment 44 ± 43 months). The network-based statistic (NBS) was used to compare connectivity of local brain edges between groups. Hubs were defined as nodes with connectivity indices one standard deviation or more above network mean and were further classified as provincial (higher intra-subnetwork connectivity) or connector (higher inter-subnetwork connectivity) using the participation coefficient. We determined the hub status of nodes encompassing significantly different edges and correlated the centralities of edges with behavioral measures.

Results: The post-treatment group demonstrated significantly lower subjective cognitive function (W = 3,856, p = 0.004) but there were no group differences in psychological distress (W = 2,866, p = 0.627). NBS indicated significantly altered connectivity (p < 0.042, corrected) in the post-treatment group compared to the pre-treatment group largely in temporal, frontal-temporal and temporal-parietal areas. The majority of the regions projecting these connections (78%) met criteria for hub status and significantly less of these hubs were connectors in the post-treatment group (z = 1.85, p = 0.031). Subjective cognitive function and psychological distress were correlated with largely non-overlapping edges in the post-treatment group (p < 0.05).

Conclusion: Widespread functional network alterations are evident in long-term survivors of breast cancer compared to newly diagnosed patients. We also demonstrated that there are both overlapping and unique brain network signatures for subjective cognitive function vs. psychological distress.
Adapting the UK Biobank Brain Imaging Protocol and Analysis Pipeline for the C-MORE Multi-Organ Study of COVID-19 Survivors
Authors: Griffanti Ludovica , Raman Betty , Alfaro-Almagro Fidel , Filippini Nicola , Cassar Mark Philip , Sheerin Fintan , Okell Thomas W. , Kennedy McConnell Flora A. , Chappell Michael A. , Wang Chaoyue , Arthofer Christoph , Lange Frederik J. , Andersson Jesper , Mackay Clare E. , Tunnicliffe Elizabeth M. , Rowland Matthew , Neubauer Stefan , Miller Karla L. , Jezzard Peter , Smith Stephen M.
Published: October 2021

SARS-CoV-2 infection has been shown to damage multiple organs, including the brain. Multiorgan MRI can provide further insight on the repercussions of COVID-19 on organ health but requires a balance between richness and quality of data acquisition and total scan duration. We adapted the UK Biobank brain MRI protocol to produce high-quality images while being suitable as part of a post-COVID-19 multiorgan MRI exam. The analysis pipeline, also adapted from UK Biobank, includes new imaging-derived phenotypes (IDPs) designed to assess the possible effects of COVID-19. A first application of the protocol and pipeline was performed in 51 COVID-19 patients post-hospital discharge and 25 controls participating in the Oxford C-MORE study. The protocol acquires high resolution T1, T2-FLAIR, diffusion weighted images, susceptibility weighted images, and arterial spin labelling data in 17 min. The automated imaging pipeline derives 1,575 IDPs, assessing brain anatomy (including olfactory bulb volume and intensity) and tissue perfusion, hyperintensities, diffusivity, and susceptibility. In the C-MORE data, IDPs related to atrophy, small vessel disease and olfactory bulbs were consistent with clinical radiology reports. Our exploratory analysis tentatively revealed some group differences between recovered COVID-19 patients and controls, across severity groups, but not across anosmia groups. Follow-up imaging in the C-MORE study is currently ongoing, and this protocol is now being used in other large-scale studies. The protocol, pipeline code and data are openly available and will further contribute to the understanding of the medium to long-term effects of COVID-19.
BlocTrain: Block-Wise Conditional Training and Inference for Efficient Spike-Based Deep Learning
Authors: Srinivasan Gopalakrishnan , Roy Kaushik
Published: October 2021

Spiking neural networks (SNNs), with their inherent capability to learn sparse spike-based input representations over time, offer a promising solution for enabling the next generation of intelligent autonomous systems. Nevertheless, end-to-end training of deep SNNs is both compute- and memory-intensive because of the need to backpropagate error gradients through time. We propose BlocTrain, which is a scalable and complexity-aware incremental algorithm for memory-efficient training of deep SNNs. We divide a deep SNN into blocks, where each block consists of few convolutional layers followed by a classifier. We train the blocks sequentially using local errors from the classifier. Once a given block is trained, our algorithm dynamically figures out easy vs. hard classes using the class-wise accuracy, and trains the deeper block only on the hard class inputs. In addition, we also incorporate a hard class detector (HCD) per block that is used during inference to exit early for the easy class inputs and activate the deeper blocks only for the hard class inputs. We trained ResNet-9 SNN divided into three blocks, using BlocTrain, on CIFAR-10 and obtained 86.4% accuracy, which is achieved with up to 2.95× lower memory requirement during the course of training, and 1.89× compute efficiency per inference (due to early exit strategy) with 1.45× memory overhead (primarily due to classifier weights) compared to end-to-end network. We also trained ResNet-11, divided into four blocks, on CIFAR-100 and obtained 58.21% accuracy, which is one of the first reported accuracy for SNN trained entirely with spike-based backpropagation on CIFAR-100.
Blood–Brain Barrier Disruption Is Not Associated With Disease Aggressiveness in Amyotrophic Lateral Sclerosis
Authors: Prell Tino , Vlad Benjamin , Gaur Nayana , Stubendorff Beatrice , Grosskreutz Julian
Published: October 2021

The pathogenesis of the fatal neurodegenerative condition amyotrophic lateral sclerosis (ALS) remains to be fully understood. Blood–brain barrier damage (BBBD) has been implicated as an exacerbating factor in several neurodegenerative conditions, including ALS. Therefore, this cross-sectional study used the novel D50 progression model to assess the clinical relevance of BBBD within a cohort of individuals with either ALS (n = 160) or ALS mimicking conditions (n = 31). Routine laboratory parameters in cerebrospinal fluid (CSF) and blood were measured, and the ratio of CSF to serum albumin levels (Qalb) was used as a proxy measure of BBBD. In the univariate analyses, Qalb levels correlated weakly with disease aggressiveness (as indicated by individual D50 values) and physical function (as measured by ALS Functional Rating Scale). However, after adjustment for cofactors in the elastic net regularization, only having limb-onset disease was associated with BBBD. The results reported here emphasize the clinical heterogeneity of ALS and the need for additional longitudinal and multi-modal studies to fully clarify the extent and effect of BBBD in ALS.
Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain
Authors: Go Eun Jin , Ji Jeongkyu , Kim Yong Ho , Berta Temugin , Park Chul-Kyu
Published: October 2021

Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.
Feeding Frequency Modulates the Intestinal Transcriptome Without Affecting the Gut Microbiota in Pigs With the Same Daily Feed Intake
Authors: Zhang He , Xia Pengke , Feng Lufen , Jia Menglan , Su Yong
Published: October 2021

The objective of this study was to elucidate the impacts of irregular eating patterns on gut microbiota and transcriptomic responses in a pig model with different feeding regimens. The experiment involved 24 growing pigs (Duroc × Landrace × Large White, 48 days of age) which were randomly allocated to one of three feeding patterns: one-meal (M1), three-meals (M3), or five-meals (M5) per day with the same daily feed intake. The results showed that different feeding frequencies had no significant effects on the microbial composition of ileal digesta, colonic digesta, colon mucosa, as well as the concentration of SCFAs in colonic digesta. Mucosa transcriptomic profiling data showed the pathways related to vitamin metabolism were enriched in the ileum and colon of pigs in the pairwise comparison between M3 and M1 groups. On the other hand, the pathways related to lipid metabolism were enriched in the ileum and colon of pigs in the pairwise comparison between M5 and M1 groups. Lastly, the pathways related to protein metabolism were enriched in the colon in the pairwise comparison between M3 and M1 groups, M5 and M1 groups, M5 and M3 groups, while the ileum was not enriched. Differentially expressed genes (DEG) related to metabolism showed that carbohydrate transport was suppressed in the ileum and enhanced in the colon in M5 and M3 groups compared with the M1 group. Compared with the M3 group, carbohydrate transport in the ileum was enhanced in the M5 group, while in the colon was inhibited. With the increase of feeding frequency, the catabolism, biosynthesis, and transport of lipid in the ileum were suppressed, while those in the colon were enhanced. Compared with the M1 group, amino acid transport in the ileum and colon in the M3 group was enhanced. Amino acid catabolism in the ileum in the M5 group was enhanced compared with M1 and M3 groups. In summary, different feeding frequencies affected the transport of carbohydrate, lipid, and amino acid in the ileum and colon, and affected the catabolism and biosynthesis of lipid in the ileum and colon with a low impact on intestinal microbiota.
Toxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma
Authors: Yang Yonghao , Li Jun , Till Brian G. , Wang Jun , Zhang Bicheng , Wang Hanping , Huang Hao , Li Tiepeng , Gao Quanli , Li Hongle , Wang Zibing
Published: October 2021

Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.