bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-Species and Human Inter-Tissue Network Analysis of Genes Implicated in Longevity and Aging Reveal Strong Support for Nutrient Sensing
Authors: Podder Avijit , Raju Anish , Schork Nicholas J.
Published: September 2021

Intensive research efforts have been undertaken to slow human aging and therefore potentially delay the onset of age-related diseases. These efforts have generated an enormous amount of high-throughput data covering different levels in the physiologic hierarchy, e.g., genetic, epigenetic, transcriptomic, proteomic, and metabolomic, etc. We gathered 15 independent sources of information about genes potentially involved in human longevity and lifespan (N = 5836) and subjected them to various integrated analyses. Many of these genes were initially identified in non-human species, and we investigated their orthologs in three non-human species [i.e., mice (N = 967), fruit fly (N = 449), and worm (N = 411)] for further analysis. We characterized experimentally determined protein-protein interaction networks (PPIN) involving each species’ genes from 9 known protein databases and studied the enriched biological pathways among the individually constructed PPINs. We observed three important signaling pathways: FoxO signaling, mTOR signaling, and autophagy to be common and highly enriched in all four species (p-value ≤ 0.001). Our study implies that the interaction of proteins involved in the mechanistic target of rapamycin (mTOR) signaling pathway is somewhat limited to each species or that a “rewiring” of specific networks has taken place over time. To corroborate our findings, we repeated our analysis in 43 different human tissues. We investigated conserved modules in various tissue-specific PPINs of the longevity-associated genes based upon their protein expression. This analysis also revealed mTOR signaling as shared biological processes across four different human tissue-specific PPINs for liver, heart, skeletal muscle, and adipose tissue. Further, we explored our results’ translational potential by assessing the protein interactions with all the reported drugs and compounds that have been experimentally verified to promote longevity in the three-comparator species. We observed that the target proteins of the FDA-approved drug rapamycin (a known inhibitor of mTOR) were conserved across all four species. Drugs like melatonin and metformin exhibited shared targets with rapamycin in the human PPIN. The detailed information about the curated gene list, cross-species orthologs, PPIN, and pathways was assembled in an interactive data visualization portal using RStudio’s Shiny framework (https://agingnetwork.shinyapps.io/frontiers/).
Landscape of Immune Microenvironment Under Immune Cell Infiltration Pattern in Breast Cancer
Authors: Xu Qianhui , Chen Shaohuai , Hu Yuanbo , Huang Wen
Published: September 2021

Background

Increasing evdence supports the suggestion that the immune cell infiltration (ICI) patterns play a pivotal role in tumor progression in breast cancer (BRCA). Nonetheless, there has been no comprehensive analysis of the ICI patterns effects on the clinical outcomes and immunotherapy.

Methods

Multiomic data for BRCA samples were downloaded from TCGA. ESTIMATE algorithm, ssGSEA method, and CIBERSORT analysis were used to uncover the landscape of the tumor immune microenvironment (TIME). BRCA subtypes based on the ICI pattern were identified by consensus clustering and principal-component analysis was performed to obtain the ICI scores to quantify the ICI patterns in individual tumors. Their prognostic value was validated by the Kaplan-Meier survival curves. Gene set enrichment analysis (GSEA) was applied for functional annotation. Immunophenoscore (IPS) was employed to explore the immunotherapeutic role of the ICI scores. Finally, the mutation data was analyzed by using the “maftools” R package.

Results

Three different immune infiltration patterns with a distinct prognosis and biological signature were recognized among 1,198 BRCA samples. The characteristics of TIME under these three patterns were highly consistent with three known immune profiles: immune- excluded, immune-desert, and immune-inflamed phenotypes, respectively. The identification of the ICI patterns within individual tumors based on the ICI score, developed under the ICI-related signature genes, contributed into dissecting biological processes, clinical outcome, immune cells infiltration, immunotherapeutic effect, and genetic variation. High ICI score subtype, characterized with a suppression of immunity, suggested an immune-exhausted phenotype. Abundant effective immune cells were discovered in the low ICI score patients, which corresponded to an immune-activated phenotype and might present an immunotherapeutic advantage. Immunophenoscore was implemented as a surrogate of immunotherapeutic outcome, low-ICI scores samples obtained a significantly higher immunophenoscore. Enrichment of the JAK/STAT and VEGF signal pathways were activated in the ICI low-score subgroup. Finally, the synergistic effect between the ICI score and the tumor mutation burden (TMB) was confirmed.

Conclusion

This work comprehensively elucidated that the ICI patterns served as an indispensable player in complexity and diversity of TIME. Quantitative identification of the ICI patterns in individual tumor will contribute into mapping the landscape of TIME further optimizing precision immunotherapy.
Structure of African Swine Fever Virus and Associated Molecular Mechanisms Underlying Infection and Immunosuppression: A Review
Authors: Wang Yue , Kang Weifang , Yang Wenping , Zhang Jing , Li Dan , Zheng Haixue
Published: September 2021

African swine fever (ASF) is an acute, highly contagious, and deadly infectious disease. The mortality rate of the most acute and acute ASF infection is almost 100%. The World Organization for Animal Health [Office International des épizooties (OIE)] lists it as a legally reported animal disease and China lists it as class I animal epidemic. Since the first diagnosed ASF case in China on August 3, 2018, it has caused huge economic losses to animal husbandry. ASF is caused by the African swine fever virus (ASFV), which is the only member of Asfarviridae family. ASFV is and the only insect-borne DNA virus belonging to the Nucleocytoplasmic Large DNA Viruses (NCLDV) family with an icosahedral structure and an envelope. Till date, there are still no effective vaccines or antiviral drugs for the prevention or treatment of ASF. The complex viral genome and its sophisticated ability to regulate the host immune response may be the reason for the difficulty in developing an effective vaccine. This review summarizes the recent findings on ASFV structure, the molecular mechanism of ASFV infection and immunosuppression, and ASFV-encoded proteins to provide comprehensive proteomic information for basic research on ASFV. In addition, it also analyzes the results of previous studies and speculations on the molecular mechanism of ASFV infection, which aids the study of the mechanism of clinical pathological phenomena, and provides a possible direction for an intensive study of ASFV infection mechanism. By summarizing the findings on molecular mechanism of ASFV- regulated host cell immune response, this review provides orientations and ideas for fundamental research on ASFV and provides a theoretical basis for the development of protective vaccines against ASFV.
Type 2 Diabetes Mellitus and Latent Tuberculosis Infection Moderately Influence Innate Lymphoid Cell Immune Responses in Uganda
Authors: Ssekamatte Phillip , Nakibuule Marjorie , Nabatanzi Rose , Egesa Moses , Musubika Carol , Bbuye Mudarshiru , Hepworth Matthew R. , Doherty Derek G. , Cose Stephen , Biraro Irene Andia
Published: September 2021

Background

Type 2 diabetes mellitus (T2DM) is a major risk factor for the acquisition of latent tuberculosis (TB) infection (LTBI) and development of active tuberculosis (ATB), although the immunological basis for this susceptibility remains poorly characterised. Innate lymphoid cells (ILCs) immune responses to TB infection in T2DM comorbidity is anticipated to be reduced. We compared ILC responses (frequency and cytokine production) among adult patients with LTBI and T2DM to patients (13) with LTBI only (14), T2DM only (10) and healthy controls (11).

Methods

Using flow cytometry, ILC phenotypes were categorised based on (Lin−CD127+CD161+) markers into three types: ILC1 (Lin−CD127+CD161+CRTH2-CD117−); ILC2 (Lin−CD127+CD161+CRTH2+) and ILC3 (Lin−CD127+CD161+CRTH2−NKp44+/−CD117+). ILC responses were determined using cytokine production by measuring percentage expression of interferon-gamma (IFN-γ) for ILC1, interleukin (IL)-13 for ILC2, and IL-22 for ILC3. Glycaemic control among T2DM patients was measured using glycated haemoglobin (HbA1c) levels. Data were analysed using FlowJo version 10.7.1, and GraphPad Prism version 8.3.

Results

Compared to healthy controls, patients with LTBI and T2DM had reduced frequencies of ILC2 and ILC3 respectively (median (IQR): 0.01 (0.005-0.04) and 0.002 (IQR; 0.002-0.007) and not ILC1 (0.04 (0.02-0.09) as expected. They also had increased production of IFN-γ [median (IQR): 17.1 (5.6-24.9)], but decreased production of IL-13 [19.6 (12.3-35.1)]. We however found that patients with T2DM had lower ILC cytokine responses in general but more marked for IL-22 production (median (IQR): IFN-γ 9.3 (4.8-22.6); IL-13 22.2 (14.7-39.7); IL-22 0.7 (IQR; 0.1-2.1) p-value 0.02), which highlights the immune suppression status of T2DM. We also found that poor glycaemic control altered ILC immune responses.

Conclusion

This study demonstrates that LTBI and T2DM, and T2DM were associated with slight alterations of ILC immune responses. Poor T2DM control also slightly altered these ILC immune responses. Further studies are required to assess if these responses recover after treatment of either TB or T2DM.
Periostin in Allergy and Inflammation
Authors: Sonnenberg-Riethmacher Eva , Miehe Michaela , Riethmacher Dieter
Published: September 2021

Matricellular proteins are involved in the crosstalk between cells and their environment and thus play an important role in allergic and inflammatory reactions. Periostin, a matricellular protein, has several documented and multi-faceted roles in health and disease. It is differentially expressed, usually upregulated, in allergic conditions, a variety of inflammatory diseases as well as in cancer and contributes to the development and progression of these diseases. Periostin has also been shown to influence tissue remodelling, fibrosis, regeneration and repair. In allergic reactions periostin is involved in type 2 immunity and can be induced by IL-4 and IL-13 in bronchial cells. A variety of different allergic diseases, among them bronchial asthma and atopic dermatitis (AD), have been shown to be connected to periostin expression. Periostin is commonly expressed in fibroblasts and acts on epithelial cells as well as fibroblasts involving integrin and NF-κB signalling. Also direct signalling between periostin and immune cells has been reported. The deposition of periostin in inflamed, often fibrotic, tissues is further fuelling the inflammatory process. There is increasing evidence that periostin is also expressed by epithelial cells in several of the above-mentioned conditions as well as in cancer. Augmented periostin expression has also been associated with chronic inflammation such as in inflammatory bowel disease (IBD). Periostin can be expressed in a variety of different isoforms, whose functions have not been elucidated yet. This review will discuss potential functions of periostin and its different isoforms in allergy and inflammation.
Sex Differences in Primary HIV Infection: Revisiting the Role of TLR7-Driven Type 1 IFN Production by Plasmacytoid Dendritic Cells in Women
Authors: Guéry Jean-Charles
Published: September 2021

Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) during HIV-1 infection in response to TLR7 stimulation. However, IFN-I-signaling has been shown to play opposite effects in HIV-1 and SIV infection. TLR7-driven type I interferon production in pDCs is higher in women than in men due to the cell-intrinsic actions of estrogen and X-chromosome complement. Indeed, TLR7 is encoded on the X-chromosome, and the TLR7 gene escapes the X-chromosome inactivation in immune cells of women which express significantly higher levels of TLR7 protein than male cells. Following HIV infection, women have a lower viremia during acute infection and exhibit stronger antiviral responses than men, which has been attributed to the increased capacity of female pDCs to produce IFN-α upon TLR7-stimulation. However, a deleterious functional impact of an excessive TLR7 response on acute viremia in women has been recently revealed by the analysis of the frequent rs179008 c.32A>T SNP of TLR7. This SNP was identified as a sex-specific protein abundance quantitative trait locus (pQTL) causing a difference in the TLR7 protein dosage and effector function in females only. T allele expression was associated with a lower TLR7 protein synthesis, blunted production of IFN-α by pDCs upon TLR7 stimulation, and an unexpectedly lower viral load during primary HIV-1 infection in women. In the present review, the author will revisit the role of TLR7-driven pDC innate function in the context of HIV-1 infection to discuss at what stage of primary HIV-1 infection the TLR7 rs179008 T allele is likely to be protective in women.
Enriched Environment Cues Suggest a New Strategy to Counteract Glioma: Engineered rAAV2-IL-15 Microglia Modulate the Tumor Microenvironment
Authors: Mormino Alessandro , Bernardini Giovanni , Cocozza Germana , Corbi Nicoletta , Passananti Claudio , Santoni Angela , Limatola Cristina , Garofalo Stefano
Published: September 2021

Several types of cancer grow differently depending on the environmental stimuli they receive. In glioma, exposure to an enriched environment (EE) increases the overall survival rate of tumor-bearing mice, acting on the cells that participate to define the tumor microenvironment. In particular, environmental cues increase the microglial production of interleukin (IL)-15 which promotes a pro-inflammatory (antitumor) phenotype of microglia and the cytotoxic activity of natural killer (NK) cells, counteracting glioma growth, thus representing a virtuous mechanism of interaction between NK cells and microglia. To mimic the effect of EE on glioma, we investigated the potential of creating engineered microglia as the source of IL-15 in glioma. We demonstrated that microglia modified with recombinant adeno-associated virus serotype 2 (rAAV2) carrying IL-15 (rAAV2-IL-15), to force the production of IL-15, are able to increase the NK cells viability in coculture. Furthermore, the intranasal delivery of rAAV2-IL-15 microglia triggered the interplay with NK cells in vivo, enhancing NK cell recruitment and pro-inflammatory microglial phenotype in tumor mass of glioma-bearing mice, and ultimately counteracted tumor growth. This approach has a high potential for clinical translatability, highlighting the therapeutic efficacy of forced IL-15 production in microglia: the delivery of engineered rAAV2-IL-15 microglia to boost the immune response paves the way to design a new perspective therapy for glioma patients.
RETRACTED: Mesenchymal Stem/Stromal Cells as a Vehicle for Cytokine Delivery: An Emerging Approach for Tumor Immunotherapy
Authors: Razeghian Ehsan , Margiana Ria , Chupradit Supat , Bokov Dmitry O. , Abdelbasset Walid Kamal , Marofi Faroogh , Shariatzadeh Siavash , Tosan Foad , Jarahian Mostafa
Published: September 2021

Pro-inflammatory cytokines can effectively be used for tumor immunotherapy, affecting every step of the tumor immunity cycle. Thereby, they can restore antigen priming, improve the effector immune cell frequencies in the tumor microenvironment (TME), and eventually strengthen their cytolytic function. A renewed interest in the anticancer competencies of cytokines has resulted in a substantial promotion in the number of trials to address the safety and efficacy of cytokine-based therapeutic options. However, low response rate along with the high toxicity associated with high-dose cytokine for reaching desired therapeutic outcomes negatively affect their clinical utility. Recently, mesenchymal stem/stromal cells (MSCs) due to their pronounced tropism to tumors and also lower immunogenicity have become a promising vehicle for cytokine delivery for human malignancies. MSC-based delivery of the cytokine can lead to the more effective immune cell-induced antitumor response and provide sustained release of target cytokines, as widely evidenced in a myriad of xenograft models. In the current review, we offer a summary of the novel trends in cytokine immunotherapy using MSCs as a potent and encouraging carrier for antitumor cytokines, focusing on the last two decades' animal reports.
Enhanced Recovery of Microbial Genes and Genomes From a Marine Water Column Using Long-Read Metagenomics
Authors: Haro-Moreno Jose M. , López-Pérez Mario , Rodriguez-Valera Francisco
Published: September 2021

Third-generation sequencing has penetrated little in metagenomics due to the high error rate and dependence for assembly on short-read designed bioinformatics. However, second-generation sequencing metagenomics (mostly Illumina) suffers from limitations, particularly in the assembly of microbes with high microdiversity and retrieval of the flexible (adaptive) fraction of prokaryotic genomes. Here, we have used a third-generation technique to study the metagenome of a well-known marine sample from the mixed epipelagic water column of the winter Mediterranean. We have compared PacBio Sequel II with the classical approach using Illumina Nextseq short reads followed by assembly to study the metagenome. Long reads allow for efficient direct retrieval of complete genes avoiding the bias of the assembly step. Besides, the application of long reads on metagenomic assembly allows for the reconstruction of much more complete metagenome-assembled genomes (MAGs), particularly from microbes with high microdiversity such as Pelagibacterales. The flexible genome of reconstructed MAGs was much more complete containing many adaptive genes (some with biotechnological potential). PacBio Sequel II CCS appears particularly suitable for cellular metagenomics due to its low error rate. For most applications of metagenomics, from community structure analysis to ecosystem functioning, long reads should be applied whenever possible. Specifically, for in silico screening of biotechnologically useful genes, or population genomics, long-read metagenomics appears presently as a very fruitful approach and can be analyzed from raw reads before a computationally demanding (and potentially artifactual) assembly step.
Dietary Supplementation With Creatine Pyruvate Alters Rumen Microbiota Protein Function in Heat-Stressed Beef Cattle
Authors: Li Yanjiao , Zang Yitian , Zhao Xianghui , Liu Lin , Qiu Qinghua , Ouyang Kehui , Qu Mingren
Published: September 2021

Creatine pyruvate (CrPyr) is a new multifunctional nutrient that can provide both pyruvate and creatine. It has been shown to relieve the heat stress of beef cattle by improving antioxidant activity and rumen microbial protein synthesis, but the mechanism of CrPyr influencing rumen fermentation remains unclear. This study aimed to combine 16S rDNA sequencing and metaproteomics technologies to investigate the microbial composition and function in rumen fluid samples taken from heat-stressed beef cattle treated with or without 60 g/day CrPyr. 16S rDNA sequencing revealed that there were no significant differences in the α-diversity indices between the two groups. By analyzing the level profiles of 700 distinct proteins, we found that the CrPyr administration increased the expression of enzymes involved in specific metabolic pathways including (i) fatty acid β-oxidation; (ii) interconversion from pyruvate to phosphoenolpyruvate, oxaloacetate, acetyl-CoA, and malate; (iii) glycolysis/gluconeogenesis and citrate cycle metabolism; and (iv) biosynthesis of amino acids. These results indicated that the increased generation of adenosine triphosphate during fatty acid β-oxidation or citrate cycle and the up-regulation synthesis of microbial protein in rumen of beef cattle treated with CrPyr may help decrease oxidative stress, regulate energy metabolism, and further improve the rumen fermentation characteristic under heat stress.
Ecology and Evolution of Marine Fungi With Their Adaptation to Climate Change
Authors: Kumar Vinit , Sarma V. Venkateswara , Thambugala Kasun M. , Huang Jun-Jie , Li Xiang-Yang , Hao Ge-Fei
Published: September 2021

Climate change agitates interactions between organisms and the environment and forces them to adapt, migrate, get replaced by others, or extinct. Marine environments are extremely sensitive to climate change that influences their ecological functions and microbial community including fungi. Fungi from marine habitats are engaged and adapted to perform diverse ecological functions in marine environments. Several studies focus on how complex interactions with the surrounding environment affect fungal evolution and their adaptation. However, a review addressing the adaptation of marine fungi to climate change is still lacking. Here we have discussed the adaptations of fungi in the marine environment with an example of Hortaea werneckii and Aspergillus terreus which may help to reduce the risk of climate change impacts on marine environments and organisms. We address the ecology and evolution of marine fungi and the effects of climate change on them to explain the adaptation mechanism. A review of marine fungal adaptations will show widespread effects on evolutionary biology and the mechanism responsible for it.
Circadian Rhythm Modulation of Microbes During Health and Infection
Authors: Pearson James Alexander , Voisey Alexander Christopher , Boest-Bjerg Kathrine , Wong F. Susan , Wen Li
Published: September 2021

Circadian rhythms, referring to 24-h daily oscillations in biological and physiological processes, can significantly regulate host immunity to pathogens, as well as commensals, resulting in altered susceptibility to disease development. Furthermore, vaccination responses to microbes have also shown time-of-day-dependent changes in the magnitude of protective immune responses elicited in the host. Thus, understanding host circadian rhythm effects on both gut bacteria and viruses during infection is important to minimize adverse effects on health and identify optimal times for therapeutic administration to maximize therapeutic success. In this review, we summarize the circadian modulations of gut bacteria, viruses and their interactions, both in health and during infection. We also discuss the importance of chronotherapy (i.e., time-specific therapy) as a plausible therapeutic administration strategy to enhance beneficial therapeutic responses.
Screening of Fungi for Antimycobacterial Activity Using a Medium-Throughput Bioluminescence-Based Assay
Authors: Grey Alexander B. J. , Cadelis Melissa M. , Diao Yiwei , Park Duckchul , Lumley Thomas , Weir Bevan S. , Copp Brent R. , Wiles Siouxsie
Published: September 2021

There is a real and urgent need for new antibiotics able to kill Mycobacteria, acid-fast bacilli capable of causing multiple deadly diseases. These include members of the Mycobacterium tuberculosis complex, which causes the lung disease tuberculosis (TB) as well as non-tuberculous Mycobacteria (NTM) a growing cause of lung, skin, soft tissue, and other infections. Here we describe a medium-throughput bioluminescence-based pipeline to screen fungi for activity against Mycobacteria using the NTM species Mycobacterium abscessus and Mycobacterium marinum. We used this pipeline to screen 36 diverse fungal isolates from the International Collection of Microorganisms from Plants (ICMP) grown on a wide variety of nutrient-rich and nutrient-poor media and discovered that almost all the tested isolates produced considerable anti-mycobacterial activity. Our data also provides strong statistical evidence for the impact of growth media on antibacterial activity. Chemical extraction and fractionation of a subset of the ICMP isolates revealed that much of the activity we observed may be due to the production of the known anti-mycobacterial compound linoleic acid. However, we have identified several ICMP isolates that retained their anti-mycobacterial activity in non-linoleic acid containing fractions. These include isolates of Lophodermium culmigenum, Pseudaegerita viridis, and Trametes coccinea, as well as an unknown species of Boeremia and an isolate of an unknown genus and species in the family Phanerochaetaceae. Investigations are ongoing to identify the sources of their anti-mycobacterial activity and to determine whether any may be due to the production of novel bioactive compounds.
Codon Optimization of Insect Odorant Receptor Genes May Increase Their Stable Expression for Functional Characterization in HEK293 Cells
Authors: Roberts Rebecca E. , Yuvaraj Jothi Kumar , Andersson Martin N.
Published: September 2021

Insect odorant receptor (OR) genes are routinely expressed in Human Embryonic Kidney (HEK) 293 cells for functional characterization (“de-orphanization”) using transient or stable expression. However, progress in this research field has been hampered because some insect ORs are not functional in this system, which may be due to insufficient protein levels. We investigated whether codon optimization of insect OR sequences for expression in human cells could facilitate their functional characterization in HEK293 cells with stable and inducible expression. We tested the olfactory receptor co-receptor (Orco) proteins from the bark beetles Ips typographus (“Ityp”) and Dendroctonus ponderosae (“Dpon”), and six ItypORs previously characterized in Xenopus laevis oocytes and/or HEK cells. Western blot analysis indicated that codon optimization yielded increased cellular protein levels for seven of the eight receptors. Our experimental assays demonstrated that codon optimization enabled functional characterization of two ORs (ItypOR25 and ItypOR29) which are unresponsive when expressed from wildtype (non-codon optimized) genes. Similar to previous Xenopus oocyte recordings, ItypOR25 responded primarily to the host/conifer monoterpene (+)-3-carene. ItypOR29 responded primarily to (+)-isopinochamphone and similar ketones produced by fungal symbionts and trees. Codon optimization also resulted in significantly increased responses in ItypOR49 to its pheromone ligand (R)-(−)-ipsdienol, and improved responses to the Orco agonist VUAA1 in ItypOrco. However, codon optimization did not result in functional expression of DponOrco, ItypOR23, ItypOR27, and ItypOR28 despite higher protein levels as indicated by Western blots. We conclude that codon optimization may enable or improve the functional characterization of insect ORs in HEK cells, although this method is not sufficient for all ORs that are not functionally expressed from wildtype genes.
Statin Treatment in the Acute Phase and the Risk of Post-stroke Pneumonia: A Retrospective Cohort Study
Authors: Li Changling , Ma Mengmeng , Dong Shuju , Hong Ye , Bao Jiajia , Zhang Yang , Gao Lijie , Cui Chaohua , Guo Jian , He Li
Published: September 2021

Background: We aimed to investigate the impact of statin treatment in the acute phase on the risk and severity of post-stroke pneumonia because of the uncertain effects of statins on post-stroke pneumonia.

Methods: Consecutive cases of acute ischemic stroke (AIS) between January 2014 and February 2019 were retrospectively analyzed. Additionally, the association of statin treatment in the acute phase with the risk and severity of post-stroke pneumonia was estimated with logistic regression. We registered the present study in the Chinese Clinical Trial Registry (ChiCTR 2000032838).

Results: Of the 1,258 enrolled patients, no significant difference was observed in post-stroke pneumonia risk between the two groups (with/without statin treatment in the acute phase) after propensity score matching (35.1 vs. 27.9%, p = 0.155). We did not find statin treatment in the acute phase to significantly increase the risk of post-stroke pneumonia both before and after matched analysis [odds ratio (OR) = 1.51, 95% confidence interval (CI) = 0.85–2.67, p = 0.157; OR = 1.57, 95% CI = 0.77–3.18, p = 0.213, respectively]. In the 271 patients with post-stroke pneumonia, no significant difference was found in its severity between two groups (19.6 vs. 19.4%, p = 0.964). No significant association was found between statin treatment and post-stroke pneumonia severity (OR = 0.95, 95% CI = 0.39–2.31, p = 0.918).

Conclusions: There appeared to be no additional benefits of statin treatment in the acute phase for post-stroke pneumonia reduction among AIS patients.

Clinical Trial Registration:http://www.chictr.org.cn, identifier: ChiCTR2000032838.
Effects of Transcutaneous Spinal Direct Current Stimulation (tsDCS) in Patients With Chronic Pain: A Clinical and Neurophysiological Study
Authors: Guidetti Matteo , Ferrucci Roberta , Vergari Maurizio , Aglieco Giada , Naci Anisa , Versace Sara , Pacheco-Barrios Kevin , Giannoni-Luza Stefano , Barbieri Sergio , Priori Alberto , Bocci Tommaso
Published: September 2021

Background and Aims: Chronic pain is a complex clinical condition, often devastating for patients and unmanageable with pharmacological treatments. Converging evidence suggests that transcutaneous spinal Direct Current Stimulation (tsDCS) might represent a complementary therapy in managing chronic pain. In this randomized, double-blind and sham-controlled crossover study, we assessed tsDCS effects in chronic pain patients.

Methods: Sixteen patients (aged 65.06 ± 16.16 years, eight women) with chronic pain of different etiology underwent sham and anodal tsDCS (anode over the tenth thoracic vertebra, cathode over the somatosensory cortical area: 2.5 mA, 20 min, 5 days for 1 week). As outcomes, we considered the Visual Analog Scale (VAS), the Neuropathic Pain Symptom Inventory (NPSI), and the components of the lower limb flexion reflex (LLFR), i.e., RIII threshold, RII latency and area, RIII latency and area, and flexion reflex (FR) total area. Assessments were conducted before (T0), immediately at the end of the treatment (T1), after 1 week (T2) and 1 month (T3).

Results: Compared to sham, anodal tsDCS reduced RIII area at T2 (p = 0.0043) and T3 (p = 0.0012); similarly, FR total area was reduced at T3 (p = 0.03). Clinically, anodal tsDCS dampened VAS at T3 (p = 0.015), and NPSI scores at T1 (p = 0.0012), and T3 (p = 0.0015), whereas sham condition left them unchanged. Changes in VAS and NPSI scores linearly correlated with the reduction in LLFR areas (p = 0.0004).

Conclusions: Our findings suggest that tsDCS could modulate nociceptive processing and pain perception in chronic pain syndromes.
Factors That Influence Compliance to Long-Term Remote Ischemic Conditioning Treatment in Patients With Ischemic Stroke
Authors: Zhao Jie , Fan Kaiting , Zhao Wenbo , Yao Hui , Ma Jiayue , Chang Hong
Published: September 2021

Objectives: To investigate the treatment compliance of patients with ischemic stroke to remote ischemic conditioning (RIC) and to determine the factors that influence compliance.

Methods: We conducted a retrospective study of patients with ischemic stroke who were treated with RIC. Treatment compliance was determined and analyzed in patients who had received 1 year of RIC training. Factors that influenced patient compliance were also determined using univariate and multivariate regression analyses.

Results: Between March 2017 and February 2018, 91 patients were recruited into this study. The mean (±SD) age was 57.98 ± 10.76 years, and 78 (85.7%) patients were male. The baseline Kolcaba comfort scale of patients with good compliance scores were higher than those with poor compliance. The scores of the four dimensions in the scale and the total score are as follows: physiological dimensions, 15.0 (12.0,17.0) vs 17.0 (13.0,19.0); psychological dimensions, 30.0 (25.0,34.0) vs 31.0 (27.0,35.0); sociological dimensions, 20.0 (18.0,24.0) vs 21.0 (18.0,23.0); environmental dimensions, 19.0 (12.0,24.0) vs 20.0 (17.0,22.0); and total points, 82.0 (69.0,94.0) vs 91.0 (78.0,98.0). the differences between the groups were significant (p < 0.05), except for the sociological dimensions. A history of hypertension, number of follow-ups, and the physiological, psychological, and environmental dimensions of the comfort scale were related to patient compliance, out of which the number of follow-ups (Adjusted OR = 2.498, 95% confidence interval (CI) 1.257–4.964) and the physiological discomfort (Adjusted OR = 1.128, 95% CI 1.029–1.236) independently influenced compliance (p < 0.05).

Conclusion: In patients with ischemic cerebrovascular disease who were treated with RIC, the number of follow-up visits and physiological discomfort associated with RIC treatment independently influenced patient compliance. Further studies are needed to investigate the RIC protocols and their corresponding nursing models.
Changes in Mortality Related to Traumatic Brain Injuries in the Seychelles from 1989 to 2018
Authors: Abio Anne , Bovet Pascal , Valentin Bernard , Bärnighausen Till , Shaikh Masood Ali , Posti Jussi P. , Lowery Wilson Michael
Published: September 2021

Introduction: Traumatic Brain Injuries (TBIs) are a significant source of disability and mortality, which disproportionately affect low- and middle-income countries. The Republic of Seychelles is a country in the African region that has experienced rapid socio-economic development and one in which all deaths and the age distribution of the population have been enumerated for the past few decades. The aim of this study was to investigate TBI-related mortality changes in the Republic of Seychelles during 1989–2018.

Methods: All TBI-related deaths were ascertained using the national Civil Registration and Vital Statistics System. Age- and sex-standardised mortality rates (per 100,000 person-years) were standardised to the age distribution of the World Health Organisation standard population.

Results: The 30-year age-standardised TBI-related mortality rates were 22.6 (95% CI 19.9, 25.2) in males and 4.0 (95% CI 2.9, 5.1) in females. Road traffic collisions were the leading contributor to TBI-related mortality [10.0 (95% CI 8.2, 11.8) in males and 2.7 (95% CI 1.8, 3.6) in females, P > 0.05]. TBI-related mortality was most frequent at age 20–39 years in males (8.0) and at age 0–19 in females (1.4). Comparing 2004–2018 vs. 1989–2003, the age-standardised mortality rates changed in males/females by −20%/−11% (all cause mortality), −24%/+39.4% (TBIs) and +1%/+34.8% (road traffic injury-related TBI).

Conclusion: TBI-related mortality rates were much higher in males but decreased over time. Road traffic collisions were the single greatest contributor to TBI mortality, emphasising the importance of road safety measures.
Elevated Expression and Activity of Sodium Leak Channel Contributes to Neuronal Sensitization of Inflammatory Pain in Rats
Authors: Li Jia , Chen Yali , Liu Jin , Zhang Donghang , Liang Peng , Lu Peilin , Shen Jiefei , Miao Changhong , Zuo Yunxia , Zhou Cheng
Published: September 2021

Inflammatory pain encompasses many clinical symptoms, and there is no satisfactory therapeutic target. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn are critical to the development and maintenance of inflammatory pain. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability. It is unknown whether abnormal activity of NALCN mediates the pathological process of inflammatory pain. Complete Freund’s adjuvant (CFA) was injected into the left footpad of rats to induce inflammatory pain. The thresholds of mechanical and thermal sensation and spontaneous pain behaviors were assessed. The expression of NALCN in DRG and spinal dorsal cord was measured. NALCN currents and the contribution of NALCN to neuronal excitability in the DRG and spinal dorsal cord were recorded using whole-cell patch-clamping recording. NALCN was abundantly expressed in neurons of the DRG and spinal dorsal cord. In acutely isolated DRG neurons and spinal cord slices from rats with CFA-induced inflammatory pain, NALCN currents and neuronal excitability were increased. Subsequently, intrathecal and sciatic nerve injection of NALCN-small interfering RNA (siRNA) decreased NALCN mRNA and reverted NALCN currents to normal levels, and then reduced CFA-induced neuronal excitability and alleviated pain symptoms. Furthermore, pain-related symptoms were significantly prevented by the NALCN-shRNA-mediated NALCN knockdown in DRG and spinal cord. Therefore, increased expression and activity of NALCN contributed to neuronal sensitization in CFA-induced inflammatory pain. NALCN may be a novel molecular target for the control of inflammatory pain.
Linking Dietary Patterns to Environmental Degradation: The Spatiotemporal Analysis of Rural Food Nitrogen Footprints in China
Authors: Xian Chao-Fan , Gong Cheng , Lu Fei , Zhang Lu , Ouyang Zhi-Yun
Published: September 2021

Background: China has a large emerging economy that illustrates how dietary patterns can affect food-source nitrogen (N) cycling. The indicator of food nitrogen footprint (NF) reflects the amount of reactive nitrogen (Nr) emissions and impacts of these emissions on the environment. It is a result of food production and consumption to satisfy basic dietary demands of a given population. Different from urban food consumption with improved waste treatment, rural food consumption significantly affects the environment from food production to waste disposal. We therefore, performed a nationwide case study to link dietary patterns to environmental degradation based on rural food NF accounting.

Methods: The N-Calculator model was adopted to reveal the spatiotemporal characteristics of food NFs per capita, and regional food NFs related to rural diets in China from 2000 to 2019. Then, food-source Nr emissions to regional environment were quantified based on food NF accounting and relevant inventory of regional Nr emissions.

Results: (i) The average annual food NF per-capita in rural regions was lower than that of its national counterpart, but exhibited regional differences, mainly attributed to the dietary role of cereals. (ii) There existed significant spatiotemporal characteristics among regional food NFs that were mainly contributed by plant-derived food consumptions (73%). Sichuan, Henan, Shandong, and Hunan exhibited larger regional food NFs, and Beijing, Shanghai, and Tibet showed a growth in NFs, wherein rural diets were dominated by animal-derived food. (iii) Rural diets affected the environment by the pathways of ammonia and nitrous oxide volatilization processes, as well as Nr loss to water, accounting for a 33, 5, and 62% average of food NFs across regions. (iv) Although current rural dietary patterns suggest reliance on cereal and vegetable consumptions, more animal-derived types of food would be consumed as urbanization continues, especially in developed regions, creating a barrier for further reduction in national food NF.

Conclusion: The findings of this study highlight the importance of changing dietary patterns to the human health-environment dilemma. Strategies that include improvements in N recycling rates, adjustments in dietary patterns, and reductions in food wastes could mitigate regional N pollution with rural dietary shifts.
ATF2-Induced Overexpression of lncRNA LINC00882, as a Novel Therapeutic Target, Accelerates Hepatocellular Carcinoma Progression via Sponging miR-214-3p to Upregulate CENPM
Authors: Ren Hua , Wei Zhi-cheng , Sun Yan-xia , Qiu Chun-yan , Zhang Wen-jue , Zhang Wei , Liu Tao , Che Xu
Published: September 2021

Background

Long intergenic non-protein coding RNA 882 (LINC00882) are abnormally expressed in several tumors. Our research aimed to uncover the functions and the potential mechanisms of LINC00882 in hepatocellular carcinoma (HCC) progression.

Methods

RT-qPCR was applied to identify LINC00882 and miR-214-3p levels in HCC specimens and cells. Luciferase reporter was applied for the exploration of whether activating transcription factor 2 (ATF2) could bind to the promoter region of LINC00882. Cell proliferation, invasion, and migration were evaluated. In vivo tumor xenograft models were constructed to assess tumorigenicity. RT-PCR, Western blot and Luciferase reporter assays were conducted to examine the regulatory relationships among LINC00882, miR-214-3p and ATF2.

Results

LINC00882 was markedly upregulated in HCC cells and clinical specimens. Additionally, ATF2 could bind directly to the LINC00882 promoter region and activate its transcription. Loss-of-function studies further demonstrated that LINC00882 knockdown inhibited proliferation, invasion, and migration of HCC cells. Mechanistically, LINC00882 adsorbed miR-214-3p, thus promoting the expressions of CENPM. Rescue assays demonstrated that functions of LINC00882 deficiency in HCC cells were reversed through suppressing miR-214-3p.

Conclusion

Our group identified a novel regulatory axis of ATF2/LINC00882/miR-214-3p/CENPM, which may provide potential therapeutic targets for HCC.
Role of Extracellular Vesicles on Cancer Lymphangiogenesis and Lymph Node Metastasis
Authors: Wang Linlin , Li Ling , Zhu Guiquan
Published: September 2021

Lymph node metastasis (LNM) of tumors is an established indicator of poor prognosis in patients. Tumor-associated lymphangiogenesis is a key step in LNM and has gained much attention. However, currently, there is no anti-tumor lymphangiogenesis drug used in clinical practice. Recently, studies on extracellular vesicles (EVs) have shown that different types of cells in the tumor microenvironment can release EVs that encapsulate a variety of molecules, including proteins, nucleic acids, and metabolites. Lymph endothelial cells (LECs) regulate tumor lymphangiogenesis through the uptake of EVs packed with different biologically active contents. In this review, we will discuss the possible mechanisms by which EVs participate in the regulation of tumor-associated lymphangiogenesis and LNM, summarize the potential value of EVs that can be used as biomarkers for the determination of tumor LNM, and indicate the potential anti-tumor lymphangiogenesis therapy.
Ruxolitinib in Patients With Chronic Active Epstein-Barr Virus Infection: A Retrospective, Single-Center Study
Authors: Song Yue , Wang Jingshi , Wang Yini , Wang Zhao
Published: September 2021

Background: Chronic active Epstein-Barr virus (CAEBV) infection is one of the EBV-positive T- or NK-cell lymphoproliferative diseases. There is no safe and effective treatment currently and the only proven curable therapy is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The JAK1/2 inhibitor, ruxolitinib, is now considered a novel therapy in inflammatory disease, and hypercytokinemia is an important feature of CAEBV.

Method: All patients who suffered active CAEBV and were treated with ruxolitinib as compassionate use in our center from Sep 1, 2017, and Apr 30, 2019, were retrospectively analyzed.

Results: In general, seven out of nine patients responded to ruxolitinib. Six out of seven patients became afebrile within 48 h. The AST/ALT level of three out of four patients decreased after ruxolitinib treatment. Two patients with cytopenia recovered. No significant decrease in the EBV-DNA copy number was observed (p = 0.161). For those seven patients who responded to ruxolitinib, the median continuing period in remission was 7.1 weeks (range, 3.4–101.0 weeks). Two patients achieved long-term stable remission with ruxolitinib monotherapy. None of these patients discontinued ruxolitinib due to the possible toxicity.

Conclusion: Ruxolitinib is an effective and rather safe option for controlling the inflammatory symptoms of active CAEBV, especially in patients with CAEBV who have failed previous treatments or have relapsed. It can also play a promising role in improving the quality of daily life of patients and successfully bridging to allo-HSCT.
Erythropoietin and Non-Erythropoietic Derivatives in Cognition
Authors: Newton Samuel S. , Sathyanesan Monica
Published: September 2021

Cognitive deficits are widespread in psychiatric disorders, including major depression and schizophrenia. These deficits are known to contribute significantly to the accompanying functional impairment. Progress in the development of targeted treatments of cognitive deficits has been limited and there exists a major unmet need to develop more efficacious treatments. Erythropoietin (Epo) has shown promising procognitive effects in psychiatric disorders, providing support for a neurotrophic drug development approach. Several preclinical studies with non-erythropoietic derivatives have demonstrated that the modulation of behavior is independent of erythropoiesis. In this review, we examine the molecular, cellular and cognitive actions of Epo and non-erythropoietic molecular derivatives by focusing on their neurotrophic, synaptic, myelin plasticity, anti-inflammatory and neurogenic mechanisms in the brain. We also discuss the role of receptor signaling in Epo and non-erythropoietic EPO-mimetic molecules in their procognitive effects.
Designing Short Peptides to Block the Interaction of SARS-CoV-2 and Human ACE2 for COVID-19 Therapeutics
Authors: Basit Abdul , Karim Asad Mustafa , Asif Muhammad , Ali Tanveer , Lee Jung Hun , Jeon Jeong Ho , Rehman Shafiq ur , Lee Sang Hee
Published: September 2021

To date, the current COVID-19 pandemic caused by SARS-CoV-2 has infected 99.2 million while killed 2.2 million people throughout the world and is still spreading widely. The unavailability of potential therapeutics against this virus urges to search and develop new drugs. SARS-CoV-2 enters human cells by interacting with human angiotensin-converting enzyme 2 (ACE2) receptor expressed on human cell surface through utilizing receptor-binding domain (RBD) of its spike glycoprotein. The RBD is highly conserved and is also a potential target for blocking its interaction with human cell surface receptor. We designed short peptides on the basis of our previously reported truncated ACE2 (tACE2) for increasing the binding affinity as well as the binding interaction network with RBD. These peptides can selectively bind to RBD with much higher affinities than the cell surface receptor. Thus, these can block all the binding residues required for binding to cell surface receptor. We used selected amino acid regions (21–40 and 65–75) of ACE2 as scaffold for the de novo peptide design. Our designed peptide Pep1 showed interactions with RBD covering almost all of its binding residues with significantly higher binding affinity (−13.2 kcal mol−1) than the cell surface receptor. The molecular dynamics (MD) simulation results showed that designed peptides form a stabilized complex with RBD. We suggest that blocking the RBD through de novo designed peptides can serve as a potential candidate for COVID-19 treatment after further clinical investigations.