bluuebunny/crossref_metadata_2025 huggingface dataset:
Matrix Remodeling-Associated Protein 8 as a Novel Indicator Contributing to Glioma Immune Response by Regulating Ferroptosis
Authors: Xu Zhijie , Chen Xi , Song Liying , Yuan Fang , Yan Yuanliang
Published: February 2022

Glioma is a highly malignant brain tumor with a poor survival rate. Novel biomarkers that act as prompt indicators of glioma are urgently needed. In this study, we identified and validated prognosis-related differentially expressed genes by datasets of glioma in the GEO and TCGA databases. Ferroptosis is a newly recognized process of cell death playing a vital role in cancer biology. Pearson correlation coefficient were used to discovery the prognosis-related genes which have the highest correlation with ferroptosis. Matrix remodeling-associated protein 8 (MXRA8) was identified as a novel prognosis indicator which may be involved in ferroptosis. The expression of MXRA8 was significantly higher in glioma compared with normal brain tissue, and increased expression of MXRA8 was associated with unfavorable survivals. Furthermore, in vitro analysis showed that knockdown of MXRA8 inhibited the cell viability in T98G and U251 cells and increased the sensitivity of glioma cells to temozolomide. We further observed that downregulation of MXRA8 elevated the levels of intracellular ferrous iron and lipid peroxidation, accompanied by upregulation of NCOA4 and suppression of FTH1. Moreover, co-expression analyses showed that GO term and KEGG pathways were mainly enriched in immunity-related pathways, such as neutrophil-related immunity, adaptive immune response, and cytokine binding. Through ssGSEA algorithm and TISIDB database, immunological analyses showed that MXRA8 was significantly correlated with various immune infiltration cells including NK cells, macrophages, and neutrophils. Meanwhile, MXRA8 was also associated with chemokines and multiple immunoinhibitory molecules, such as TGF-β1, IL-10, PD-L1, and CTLA4. We also found that MXRA8 was positively associated with immune infiltration score, and patients with higher immune score underwent worse overall survivals. Moreover, IHC staining indicated a highly positive correlation of MXRA8 with a macrophage marker CSF1R. The co-cultured models of glioma cells and M2 macrophages showed MXRA8 knockdown glioma cells alleviated the infiltration of M2 macrophage, while the reduced M2 macrophage infiltration generated by MXRA8 could be rescued by Fer-1 treatment. These results suggest that MXRA8 promotes glioma progression and highlight the pivotal role of MXRA8 in ferroptosis and immune microenvironment of glioma. Therefore, MXRA8 may serve as a novel prognostic marker and therapeutic target for glioma.
CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma
Authors: Gambella Massimiliano , Carlomagno Simona , Raiola Anna Maria , Giannoni Livia , Ghiggi Chiara , Setti Chiara , Giordano Chiara , Luchetti Silvia , Serio Alberto , Bo Alessandra , Falco Michela , Della Chiesa Mariella , Angelucci Emanuele , Sivori Simona
Published: February 2022

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient’s immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients.
Comparison of the Seven Interleukin-32 Isoforms’ Biological Activities: IL-32θ Possesses the Most Dominant Biological Activity
Authors: Shim Saerok , Lee Siyoung , Hisham Yasmin , Kim Sinae , Nguyen Tam T. , Taitt Afeisha S. , Hwang Jihyeong , Jhun Hyunjhung , Park Ho-Young , Lee Youngmin , Yeom Su Cheong , Kim Sang-Yeob , Kim Yong-Gil , Kim Soohyun
Published: February 2022

Cytokines are significantly associated with the homeostasis of immune responses in health and disease. Interleukin-32 (IL-32) is a cytokine originally discovered in natural killer cell transcript 4. IL-32 with different disorders has been described in terms of pathogenesis and the progression of diseases. Clinical studies have investigated IL-32 under various conditions, such as viral infection, autoimmune diseases, inflammatory diseases, certain types of cancer, vascular disease, and pulmonary diseases. The high expression of IL-32 was identified in different tissues with various diseases and found to have multiple transcripts of up to seven isoforms. However, the purification and biological activities of these isoforms have not been investigated yet. Therefore, in this study, we purified and compared the biological activity of recombinant IL-32 (rIL-32) isoforms. This is the first time for seven rIL-32 isoforms (α, β, δ, γ, ϵ, ζ, and θ) to be cloned and purified using an Escherichia coli expression system. Next, we evaluate the biological activities of these seven rIL-32 isoforms, which were used to treat different types of cells by assessing the levels of inflammatory cytokine production. The results revealed that rIL-32θ possessed the most dominant biological activity in both immune and non-immune cells.
An Immune-Related Gene Pair Index Predicts Clinical Response and Survival Outcome of Immune Checkpoint Inhibitors in Melanoma
Authors: Yan Junya , Wu Xiaowen , Yu Jiayi , Kong Yan , Cang Shundong
Published: February 2022

The durable responses and favorable long-term outcomes are limited to a proportion of advanced melanoma patients treated with immune checkpoint inhibitors (ICI). Considering the critical role of antitumor immunity status in the regulation of ICI therapy responsiveness, we focused on the immune-related gene profiles and aimed to develop an individualized immune signature for predicting the benefit of ICI therapy. During the discovery phase, we integrated three published datasets of metastatic melanoma treated with anti-PD-1 (n = 120) and established an immune-related gene pair index (IRGPI) for patient classification. The IRGPI was constructed based on 31 immune-related gene pairs (IRGPs) consisting of 51 immune-related genes (IRGs). The ROC curve analysis was performed to evaluate the predictive accuracy of IRGPI with AUC = 0.854. Then, we retrospectively collected one anti-PD-1 therapy dataset of metastatic melanoma (n = 55) from Peking University Cancer Hospital (PUCH) and performed the whole-transcriptome RNA sequencing. Combined with another published dataset of metastatic melanoma received anti-CTLA-4 (VanAllen15; n = 42), we further validated the prediction accuracy of IRGPI for ICI therapy in two datasets (PUCH and VanAllen15) with AUCs of 0.737 and 0.767, respectively. Notably, the survival analyses revealed that higher IRGPI conferred poor survival outcomes in both the discovery and validation datasets. Moreover, correlation analyses of IRGPI with the immune cell infiltration and biological functions indicated that IRGPI may be an indicator of the immune status of the tumor microenvironment (TME). These findings demonstrated that IRGPI might serve as a novel marker for treating of melanoma with ICI, which needs to be validated in prospective clinical trials.
Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients
Authors: Aschauer Constantin , Jelencsics Kira , Hu Karin , Gregorich Mariella , Reindl-Schwaighofer Roman , Wenda Sabine , Wekerle Thomas , Heinzel Andreas , Oberbauer Rainer
Published: February 2022

Background

Pre-sensitized kidney transplant recipients have a higher risk for rejection following kidney transplantation and therefore receive lymphodepletional induction therapy with anti-human T-lymphocyte globulin (ATLG) whereas non-sensitized patients are induced in many centers with basiliximab. The time course of lymphocyte reconstitution with regard to the overall and donor-reactive T-cell receptor (TCR) specificity remains elusive.

Methods/Design

Five kidney transplant recipients receiving a 1.5-mg/kg ATLG induction therapy over 7 days and five patients with 2 × 20 mg basiliximab induction therapy were longitudinally monitored. Peripheral mononuclear cells were sampled pre-transplant and within 1, 3, and 12 months after transplantation, and their overall and donor-reactive TCRs were determined by next-generation sequencing of the TCR beta CDR3 region. Overall TCR repertoire diversity, turnover, and donor specificity were assessed at all timepoints.

Results

We observed an increase in the donor-reactive TCR repertoire after transplantation in patients, independent of lymphocyte counts or induction therapy. Donor-reactive CD4 T-cell frequency in the ATLG group increased from 1.14% + -0.63 to 2.03% + -1.09 and from 0.93% + -0.63 to 1.82% + -1.17 in the basiliximab group in the first month. Diversity measurements of the entire T-cell repertoire and repertoire turnover showed no statistical difference between the two induction therapies. The difference in mean clonality between groups was 0.03 and 0.07 pre-transplant in the CD4 and CD8 fractions, respectively, and was not different over time (CD4: F(1.45, 11.6) = 0.64 p = 0.496; CD8: F(3, 24) = 0.60 p = 0.620). The mean difference in R20, a metric for immune dominance, between groups was -0.006 in CD4 and 0.001 in CD8 T-cells and not statistically different between the groups and subsequent timepoints (CD4: F(3, 24) = 0.85 p = 0.479; CD8: F(1.19, 9.52) = 0.79 p = 0.418).

Conclusion

Reduced-dose ATLG induction therapy led to an initial lymphodepletion followed by an increase in the percentage of donor-reactive T-cells after transplantation similar to basiliximab induction therapy. Furthermore, reduced-dose ATLG did not change the overall TCR repertoire in terms of a narrowed or skewed TCR repertoire after immune reconstitution, comparable to non-depletional induction therapy.
Alteration of Endocrine Hormones and Antibody Responses in Different Spectrum of Tuberculosis Disease
Authors: Tsegaye Yosef , Admassu Wasihun , Edao Abebe , Kinde Samuel , Gentu Meaza , Negash Markos , Wondmagegn Tadelo , Gize Addisu , Zewdie Martha , Bobosha Kidist , Wassie Liya
Published: February 2022

Effective control of Mycobacterium tuberculosis (Mtb) infection is mediated by multifaceted factors that involve both the endocrine and immune system. Profiling hormones and antibodies in different stages of TB provides insight in the pathogenesis of the disease. In this study, we profiled endocrine hormones (dehydroepiandrosterone (DHEA), cortisol, testosterone, estradiol, growth hormone and leptins) and Mtb strain H37RV lipoarabinomannan (LAM)-specific antibody levels in plasma samples, collected from pulmonary TB (PTB) patients, TB lymphadenitis (TBLN) patients and latently infected (QFT-positive) or uninfected (QFT-negative) apparently healthy individuals using ELISA. Plasma levels of leptin and DHEA were significantly low in PTB and TBLN patients compared to healthy controls (P<0.0001 and P=0.02, respectively), whereas these levels significantly increased following anti-TB treatment (P=0.002 and P=0.0001, respectively) among TB patients. The levels of estradiol and testosterone significantly improved following anti-TB treatment (P=0.03 and P=0.0003, respectively), whereas cortisol and growth hormones declined significantly (P <0.05). Similarly, LAM-specific IgG, IgM and IgA were significantly higher in PTB patients compared to other groups, whereas levels of IgG1 subtype were significantly higher among LTBI groups compared to both TB patients and QFT-negative individuals (P<0.0001). Overall, we observed significantly variable levels of endocrine hormones as well as immunoglobulins across the spectrum of TB illness and such profiling has a significant contribution in selection of effective biomarkers that have roles in TB treatment monitoring or diagnostics. Although this study did not show a functional association between hormones and antibodies, alterations in the levels of these biomarkers suggest the key roles these markers play in TB pathogenesis.
Immune-Related Genes for Predicting Future Kidney Graft Loss: A Study Based on GEO Database
Authors: Dou Meng , Ding Chenguang , Zheng Bingxuan , Deng Ge , Zhu Kun , Xu Cuixiang , Xue Wujun , Ding Xiaoming , Zheng Jin , Tian Puxun
Published: February 2022

Objective

We aimed to identify feature immune-related genes that correlated with graft rejection and to develop a prognostic model based on immune-related genes in kidney transplantation.

Methods

Gene expression profiles were obtained from the GEO database. The GSE36059 dataset was used as a discovery cohort. Then, differential expression analysis and a machine learning method were performed to select feature immune-related genes. After that, univariate and multivariate Cox regression analyses were used to identify prognosis-related genes. A novel Riskscore model was built based on the results of multivariate regression. The levels of these feature genes were also confirmed in an independent single-cell dataset and other GEO datasets.

Results

15 immune-related genes were expressed differently between non-rejection and rejection kidney allografts. Those differentially expressed immune-related genes (DE-IRGs) were mainly associated with immune-related biological processes and pathways. Subsequently, a 5-immune-gene signature was constructed and showed favorable predictive results in the GSE21374 dataset. Recipients were divided into the high-risk and low-risk groups according to the median value of RiskScore. The GO and KEGG analysis indicated that the differentially expressed genes (DEGs) between high-risk and low-risk groups were mainly involved in inflammatory pathways, chemokine-related pathways, and rejection-related pathways. Immune infiltration analysis demonstrated that RiskScore was potentially related to immune infiltration. Kaplan-Meier survival analysis suggested that recipients in the high-risk group had poor graft survival. AUC values of 1- and 3-year graft survival were 0.804 and 0.793, respectively.

Conclusion

Our data suggest that this immune-related prognostic model had good sensitivity and specificity in predicting the 1- and 3-year kidney graft survival and might act as a useful tool for predicting kidney graft loss.
Evaluation of Gonad Reproductive Condition Using Non-invasive Ultrasonography in Red Abalone (Haliotis rufescens)
Authors: Boles Sara E. , Neylan Isabelle P. , Rogers-Bennett Laura , Gross Jackson A.
Published: February 2022

The reproductive status in abalone (Haliotis spp.) can be difficult to discern using traditional visual inspection methods and may therefore rely on lethal histological analyses for a definitive determination. With endangered species of abalone, lethal histological examinations are strictly prohibited due to their imperiled status. This research investigated the effectiveness of using non-invasive ultrasound technology as an alternate means of identifying the reproductive status of abalone rather than through invasive biopsies or lethal histological methods. Twelve abalone were randomly selected from cultured red abalone broodstock cohort (n = 200) produced at The Cultured Abalone Farm (Goleta, CA) to initially test these methods. Following initial gonad ultrasound determination, a subset of another cohort of 5 year-old (n = 62) red abalone produced at the UC Davis Bodega Marine Laboratory were monitored using ultrasonography to detect seasonal changes in gonad size for 7 weeks. Following the 7-week assessment period, the full cohort of 5-year old abalone (n = 122) were then spawned and gonads were also evaluated using ultrasound technology before and immediately after spawning. Ultrasound imaging technology accurately differentiated between digestive and reproductive tissues, allowing for the characterization of an ultrasound gonad index score for rapid assessment. Mean gonad thickness determined via ultrasound imaging was categorized on a scale of 1–5, with an index of 1 being the lowest (gonad tissue thin or absent) and an index of 5 being the highest (gonad margin has increased and is compressing the digestive gland) for red abalone. Ultrasound imaging technology was successful in rendering a gonad index score that can be used to track gonad maturation over time in cultured or captive species. Tracking ultrasound gonad scores over time is a useful tool for improving abalone culture production, and increasing animal welfare by reducing handling stress associated with gonad assessments. Individual abalone that are empirically determined ready to be spawned can then be selected for broodstock. Non-invasive ultrasound technology has the potential for broad applications within abalone aquaculture to enhance both food and conservation aquaculture breeding programs.
Determination of Long-Term (1993–2019) Sea Level Rise Trends Around the Korean Peninsula Using Ocean Tide-Corrected, Multi-Mission Satellite Altimetry Data
Authors: Lee KyungJae , Nam SungHyun , Cho Yang-Ki , Jeong Kwang-Young , Byun Do-Seong
Published: February 2022

It is vital to improve estimations of long-term trends in global and regional sea level rise to help mitigate and adapt to climate change. Satellite altimetry data have been widely used for this purpose; however, data collected in regions with strong tidalmotions often suffer from significant aliasing effects unless they are sufficiently corrected using accurate ocean tide models.Long-term trends estimated from altimetry data are often also considerably affected by regional circulation changes, and by artificial effects arising from inconsistencies between different satellite missions. Here, we focused on two regions with high (>5 mm⋅yr–1) rates of long-term linear trend in sea level rise (LTSLR) around the Korean Peninsula (KP). We addressed the impacts of tidal correction and mission inconsistency in satellite altimetry data, and discussed the potential impacts of circulation changes on LTSLR. Because the LTSLR estimation is affected by the aliasing effects of altimetry data when the tidal motions are not corrected sufficiently, yet the correction depends on the performance of ocean tide models, we employed eight ocean tide models to correct altimetry data for comparison and validated the results against observations from 13 tide gauge (TG) stations around the KP. We also estimated LTSLR from 1993 to 2019 using annual mean sea level anomalies (SLAs) from two satellite (two-sat) and all 21 satellite (all-sat) missions, with corrections for ocean tides. The TPXO9 model showed the most reasonable spatial LTSLR rate pattern (∼3 mm⋅yr–1), with the smallest difference from TG observations. It performed best near the west coast where the tidal range was the largest and when using two-sat data, because of inconsistencies in all-sat altimetry data. In contrast, off the east coast, where the impact of tidal correction is negligible, the high (∼7 mm⋅yr–1) LTSLR rates were robust regardless of ocean tide models and altimetry missions, potentially driven by long-term changes in regional circulation. Our results highlight the importance of tidal correction and mission inconsistency for improving LTSLR estimations around the KP. They also have significant implications for determining regional sea level rise under changing circulation patterns, within and beyond the region.
Marine Natural Products: A Promising Source of Environmentally Friendly Antifouling Agents for the Maritime Industries
Authors: Gomez-Banderas Jessica
Published: February 2022

Biofouling in the marine environment refers to an unwanted build-up of marine organisms on subsea surfaces including harbor docks, hulls of ships and offshore installations. The first stage of marine fouling occurs as a microbial biofilm which forms via the aggregation of bacterial, algal, and fungal cells. This biofilm provides a favorable substrate for the larval settlement of larger organisms such as mussels, barnacles and hard corals which accumulate to uncontrollable extents, causing issues for the maritime industries. Since the ban of tributyltin (TBT) in 2008 by the International Maritime Organisation, alternative antifouling agents have been used such as algaecides and copper-based coatings. Recent studies are showing that these can accumulate in the marine environment and have toxic effects against non-target species. Marine microbes and invertebrates are known to be prolific producers of bioactive molecules, including antifouling active compounds. These compounds are often produced by marine organisms as a means of chemical defense to deter predators and prevent fouling of their own surfaces, making them a promising source of new antifouling agents. This article discusses the effects of biofouling on the maritime industries, the environmental dangers of currently used antifouling compounds and why natural products from marine organisms could be a source of environmentally friendly antifouling agents.
Progress on Rapidly and Self-Assembly Magnetically Responsive Photonic Crystals With High Tunability and Stability
Authors: Liu Nan , Deng Lugang , Wang Peixi , Tang Shuge , Li Pinle , Wang Caiqin , Li Ya , Ayyanu Ravikumar , Zheng Fengjiao
Published: February 2022

Magnetically induced self-assembling is considered a novel method to form photonic crystals (PCs) by the directive arrangement of nanoparticles (NPs) under a magnetic field. Magnetically responsive PCs (MRPCs) have become one of the most promising materials due to their adjustable bandgap along with the field intensity and direction, and rapid and reversible response. In this paper, we review the basic principles of MRPCs, the research progress of magnetically induced self-assembling PCs including synthesis and modification of magnetically induced NPs, the formation of an ordered structure of MRPCs, the non-spherical materials self-assemble into PC structure, and the non-magnetic materials self-assembling into PC structure. And then we also summarize the regulatory factors of the physical and chemical responses under magnetic field, and give an outlook as to the applications of MRPCs.
Sepsis and the Risks of Long-Term Renal Adverse Outcomes in Patients With Chronic Kidney Disease
Authors: Ou Shuo-Ming , Lee Kuo-Hua , Tsai Ming-Tsun , Tseng Wei-Cheng , Chu Yuan-Chia , Tarng Der-Cherng
Published: February 2022

Background

Sepsis is known to cause renal function fluctuations during hospitalization, but whether these patients discharged from sepsis were still at greater risks of long-term renal adverse outcomes remains unknown.

Methods

From 2011 to 2018, we included 1,12,628 patients with chronic kidney disease (CKD) aged ≥ 20 years. The patients with CKD were further divided into 11,661 sepsis group and 1,00,967 non-sepsis group. The following outcome of interest was included: all-cause mortality, readmission for acute kidney injury, estimated glomerular filtration rate decline ≥50% or doubling of serum creatinine, and end-stage renal disease.

Results

After propensity score matching, the sepsis group was at higher risks of all-cause mortality [hazard ratio (HR) 1.39, 95% CI, 1.31–1.47], readmission for acute kidney injury (HR 1.67, 95% CI 1.58–1.76), eGFR decline ≥ 50% or doubling of serum creatinine (HR 3.34, 95% CI 2.78–4.01), and end-stage renal disease (HR 1.43, 95% CI 1.34–1.53) than non-sepsis group.

Conclusions

Our study found that patients with CKD discharged from hospitalization for sepsis have higher risks of subsequent renal adverse events.
Intensified Antituberculosis Therapy Regimen Containing Higher Dose Rifampin for Tuberculous Meningitis: A Systematic Review and Meta-Analysis
Authors: Zhang Mengmeng , Wang Minggui , He Jian-Qing
Published: February 2022

Background

Tuberculous meningitis is difficult to diagnose and is associated with high mortality. Recently, several studies evaluated the intensified regimen containing higher dose rifampin to treat tuberculous meningitis. However, this topic remains to be concluded. Therefore, this systematic review and meta-analysis was conducted to evaluate pharmacokinetics parameters, safety, and survival benefits of high-dose rifampin for tuberculous meningitis.

Method

Data were searched from PubMed, EMBASE, The Cochrane Library, and Web of Science for studies describing an antituberculosis regimen including a higher dose of rifampin for patients with tuberculous meningitis. The quality of eligible studies was evaluated via The Cochrane Risk of Bias Tool. The meta-analysis was performed by Review Manager 5.3 software, the synthesis of the data was shown in mean difference (MD) or relative risk (RR), and 95% confidence intervals (CIs).

Results

There were six randomized control trails included in this meta-analysis. The results showed that the concentration in plasma and cerebrospinal fluid (CSF) were significantly higher in the intervention group than the standard group [MD = 22.08, 95%CI (16.24, 27.92), p < 0.00001; MD = 0.74, 95%CI (0.42, 1.05), p < 0.00001], as well as the area under the time concentration curve between 0 and 24 h (AUC0−24) of rifampin [MD 203.56, 95%CI (153.07, 254.05), p < 0.00001] in plasma, but the overall survival did not improve [RR = 0.92, 95%CI (0.67, 1.26), p = 0.61]. For adverse events, the results showed a statistically significant lower incidence of hypersensitivity compared with the intervention group [RR = 1.72, 95%CI (1.13, 2.62), p = 0.01]. Fortunately, other common adverse drug reactions such as liver injury, neurological events, myelosuppression, and cardiotoxicity had no significant increase [RR = 0.98, 95%CI (0.77, 1.26), p = 0.90; RR = 1.10, 95%CI (0.94, 1.30), p = 0.23; RR = 0.82, 95%CI (0.59, 1.13), p = 0.22; RR = 1.11, 95%CI (0.66, 1.86), p = 0.70].

Conclusion

This meta-analysis suggested that the intensified treatment regimen including a higher dose of rifampin significantly increased the rifampin concentration both in the plasma and CSF, and it was safe in patients with tuberculous meningitis, but resulted in no improvement in survival rates.
Case Report: Pemphigus in Young Patients With Thymic Anomalies
Authors: Lin Naiyu , Li Xiaoli , Lang Yuejiao , Han Jiande
Published: February 2022

Pemphigus is an autoimmune disease that occurs mainly in elderly individuals. Young patients with pemphigus are rare, and the risk factors are unclear. The thymus is associated with a variety of autoimmune diseases, and there have been reports of pemphigus complicated with thymic diseases. Here, we report three cases of young patients with pemphigus that were associated with thymic anomalies. We suggest that thymic anomalies may be a risk factor for the early onset of pemphigus and may be associated with increased severity of the disease. Interventions for thymic diseases have certain benefits for improving the effect of treatments and prognosis of these patients.
Case Report: Chemotherapy-Associated Systemic Sclerosis: Is DNA Damage to Blame?
Authors: Du Amy X. , Gniadecki Robert , Storek Jan , Osman Mohamed
Published: February 2022

Systemic sclerosis, also known as scleroderma, is an autoimmune disease characterized by cutaneous and visceral fibrosis, immune dysregulation, and vasculopathy. Generally, the degree of skin fibrosis is associated with an increased likelihood of visceral organ involvement. Its pathogenesis is poorly understood; however, it is clear that changes in both the innate and adaptive immune responses are associated with fibroblast dysfunction and vascular damage. Further, DNA damage has been postulated as one of the triggering factors in systemic sclerosis, although the association of DNA damage with the progression of this disease is more poorly established. Recently, abnormal DNA damage response repair pathways have also been identified in patients with systemic sclerosis, suggesting that cells from patients with this disease may be more susceptible to DNA damaging agents. Chemotherapeutic drugs and other DNA damaging agents have been associated with the development of systemic sclerosis, as these agents may provide additional “hits” that promote abnormal DNA damage responses and subsequent inflammatory changes. Herein, we present the case of a 39-year-old female who developed scleroderma after the treatment of her breast cancer with chemotherapeutic agents. Her scleroderma was subsequently successfully treated with autologous hematopoietic stem cell transplantation. We also completed a literature review for previously published cases of chemotherapy associated with systemic sclerosis and highlighted a role of DNA damage in promoting the disease. Our case is the first case of chemotherapy associated with systemic sclerosis treated with hematopoietic stem cell transplantation.
In-depth Analysis of IS6110 Genomic Variability in the Mycobacterium tuberculosis Complex
Authors: Comín Jessica , Otal Isabel , Samper Sofía
Published: February 2022

The insertion sequence (IS) 6110 is a repetitive mobile element specific for the Mycobacterium tuberculosis complex (MTBC) used for years to diagnose and genotype this pathogen. It contains the overlapping reading frames orfA and orfB that encode a transposase. Its genetic variability is difficult to study because multiple copies are present in the genome. IS6110 is randomly located, nevertheless some preferential locations have been reported, which could be related to the behaviour of the strains. The aim of this work was to determine the intra- and inter-strain genetic conservation of this element in the MTBC. For this purpose, we analysed 158 sequences of IS6110 copies from 55 strains. Eighty-four copies were from 17 strains for which we knew all the locations in their genome. In addition, we studied 74 IS6110 copies in 38 different MTBC strains in which the location was characteristic of different families including Haarlem, LAM, S, and L6 strains. We observed mutation in 13.3% of the copies studied and we found 10 IS6110 variants in 21 copies belonging to 16 strains. The high copy number strains showed 6.2% of their IS6110 copies mutated, in contrast with the 31.1% in the low-copy-number strains. The apparently more ancient copy localised in the DR region was that with more variant copies, probably because this was the most studied location. Notably, all Haarlem and X family strains studied have an IS6110 in Rv0403c, suggesting a common origin for both families. Nevertheless, we detected a variant specific for the X family that would have occurred in this location after the phylogenetic separation. This variant does not prevent transposition although it may occur at a lower frequency, as X strains remain with low copy number (LCN) of IS6110.
Oxidative Stress and Autophagy Are Important Processes in Post Ripeness and Brown Film Formation in Mycelium of Lentinula edodes
Authors: Tang Lihua , Chu Ting , Shang Junjun , Yang Ruiheng , Song Chunyan , Bao Dapeng , Tan Qi , Jian Huahua
Published: February 2022

Lentinula edodes (Berk.) Pegler, the shiitake mushroom, is one of the most important mushrooms in the global mushroom industry. Although mycelium post ripeness and brown film (BF) formation are crucial for fruiting body initiation, the underlying molecular mechanisms of BF formation are largely unknown. In this study, proteomic quantification (relative and absolute) and metabolomic profiling of L. edodes were performed using isobaric tags and gas chromatography-mass spectroscopy, respectively. A total of 2,474 proteins were identified, which included 239 differentially expressed proteins. Notably, several proteins associated with autophagy were upregulated, including RPD3, TOR1, VAC8, VPS1, and VPS27. Transmission electron microscopy also indicated that autophagy occurred in post ripeness and BF formation. In time-dependent analysis of the metabolome, metabolites associated with oxidative stress and autophagy changed significantly, including mannitol, trehalose, myo-inositol, glucose, leucine, valine, glutamine, and 4-aminobutyric acid. Thus, oxidative stress and autophagy were important processes in post ripeness and BF formation in L. edodes, and new insights were gained into molecular mechanisms at proteome and metabolome levels.
Alleviation of Hepatic Steatosis: Dithizone-Related Gut Microbiome Restoration During Paneth Cell Dysfunction
Authors: Zhang Saisai , Tun Hein M. , Zhang Dengwei , Chau Hau-Tak , Huang Fung-Yu , Kwok Hin , Wong Danny Ka-Ho , Mak Lung-Yi , Yuen Man-Fung , Seto Wai-Kay
Published: February 2022

Non-alcoholic fatty liver disease (NAFLD), the world’s most common chronic liver disease, is increasingly linked to gut dysbiosis. Paneth cells secrete antimicrobial peptides that regulate the gut microbiome, but their role in the pathogenesis of NAFLD remains unclear. Here, we determine the changes in NAFLD development and gut microbial composition and function via the injection of dithizone that can pharmacologically deplete the granules of Paneth cells. Eight-week-old C57BL/6J male mice (n = 31) were given a high-fat diet (HFD) or standard control diet for 12 weeks. Dithizone (10 mg/kg) was intravenously injected every 3 weeks during the period of diet feeding. Metagenomic DNA was extracted from fecal samples for PacBio Single-Molecule Real-Time sequencing to identify changes in microbial composition and predicted function. We observed dithizone-treated HFD mice, when compared to non-treated HFD mice, to have significant reductions in hepatic triglyceride content (28.98 vs. 53.52 mg/g, p = 0.0419); plasma insulin level (2.18 vs. 6.63 ng/ml, p = 0.0079); and relative mRNA levels of fatty acid synthase (0.52 vs. 1.57, p = 0.0428) and stearoyl-CoA desaturase-1 (0.43 vs. 1.20, p = 0.0121). Bacterial taxonomic profiling found dithizone-treated HFD mice, when compared to non-treated HFD mice, had a lower Firmicutes/Bacteroidetes ratio (2.53 vs. 5.26, p = 0.0541); a higher relative abundance of Bacteroides ASV21 and ASV42 (1.04 vs. 0.22%, p = 0.0277 and 0.96 vs. 0.09%, p = 0.0213); and a reduction in microbes belonging to Firmicutes (all p < 0.05). Bacteroides species correlated positively with predicted microbial functions such as L-methionine (r = 0.54, p = 0.0019) and tetrahydrofolate (r = 0.52, p = 0.0029) biosynthesis. Collectively, dithizone treatment was associated with alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in Bacteroides, suggesting microbiome-targeted therapies may have a role in the treatment of NAFLD.
Molecular Epidemiology and Transmission Dynamics of the HIV-1 Epidemic in Ethiopia: Epidemic Decline Coincided With Behavioral Interventions Before ART Scale-Up
Authors: Arimide Dawit Assefa , Esquivel-Gómez Luis Roger , Kebede Yenew , Sasinovich Sviataslau , Balcha Taye , Björkman Per , Kühnert Denise , Medstrand Patrik
Published: February 2022

Background

Ethiopia is one of the sub-Saharan countries hit hard by the HIV epidemic. Previous studies have shown that subtype C dominates the Ethiopian HIV-1 epidemic, but the evolutionary and temporal dynamics of HIV-1 in Ethiopia have not been closely scrutinized. Understanding the evolutionary and epidemiological pattern of HIV is vital to monitor the spread, evaluate and implement HIV prevention strategies.

Methods

We analyzed 1,276 Ethiopian HIV-1 subtype C polymerase (pol sequences), including 144 newly generated sequences, collected from different parts of the country from 1986 to 2017. We employed state-of-art maximum likelihood and Bayesian phylodynamic analyses to comprehensively describe the evolutionary dynamics of the HIV-1 epidemic in Ethiopia. We used Bayesian phylodynamic models to estimate the dynamics of the effective population size (Ne) and reproductive numbers (Re) through time for the HIV epidemic in Ethiopia.

Results

Our analysis revealed that the Ethiopian HIV-1 epidemic originated from two independent introductions at the beginning of the 1970s and 1980s from eastern and southern African countries, respectively, followed by epidemic growth reaching its maximum in the early 1990s. We identified three large clusters with a majority of Ethiopian sequences. Phylodynamic analyses revealed that all three clusters were characterized by high transmission rates during the early epidemic, followed by a decline in HIV-1 transmissions after 1990. Re was high (4–6) during the earlier time of the epidemic but dropped significantly and remained low (Re < 1) after the mid-1990. Similarly, with an expected shift in time, the effective population size (Ne) steadily increased until the beginning of 2000, followed by a decline and stabilization until recent years. The phylodynamic analyses corroborated the modeled UNAIDS incidence and prevalence estimates.

Conclusion

The rapid decline in the HIV epidemic took place a decade before introducing antiretroviral therapy in Ethiopia and coincided with early behavioral, preventive, and awareness interventions implemented in the country. Our findings highlight the importance of behavioral interventions and antiretroviral therapy scale-up to halt and maintain HIV transmissions at low levels (Re < 1). The phylodynamic analyses provide epidemiological insights not directly available using standard surveillance and may inform the adjustment of public health strategies in HIV prevention in Ethiopia.
Transformations of Diatom-Derived Dissolved Organic Matter by Bacillus pumilus Under Warming and Acidification Conditions
Authors: Liu Yang , Wang Xueru , Sun Jun
Published: February 2022

Heterotrophic bacteria are assumed to play an important role in processing of phytoplankton-derived dissolved organic matter (DOM). Although the algae-derived organic matter is commonly studied, the transformation and processing of DOM by epiphytic bacteria for phytoplankton have rarely been investigated, especially under warming and acidification. In this study, Bacillus pumilus is used to explore the ecologically important marine diatom Skeletonema dohrnii-derived DOM under different conditions (temperature, 27°C and 31°C; pCO2, 400 and 1,000 ppm), utilizing fluorescence excitation-emission matrix (EEM) combined with parallel factor analysis (EEM-PARAFAC). Fluorescence regional integration and the peak selecting method are used to generate B, T, N, A, M, and C peaks in the EEM fluorescence spectroscopy. The main known fluorophores including that protein-like components (peaks B and T), unknown components (peak N), and humic-like component (peaks A, M, and C). Our experimental results showed that under higher temperature and pressure of CO2 (pCO2) conditions, S. dohrnii-derived DOM fluorescence was dominated by a protein-like signal that slower waning throughout the experiment, becoming an increasingly humic-like substance, implying that processing by the epiphytic bacteria (B. pumilus) produced more complex molecules. In addition, spectroscopic indices (e.g., fluorescence index, biological index, freshness index β/α, and humification index) were changed in varying degrees. This study reveals and confirms the direct participation of heterotrophic bacteria in the transformation and generation of algae-derived DOM in the laboratory, underlining the influence of global warming and ocean acidification on this process.
Microbial Community and Metabolite Dynamics During Soy Sauce Koji Making
Authors: Tan Guiliang , Hu Min , Li Xiangli , Li Xueyan , Pan Ziqiang , Li Mei , Li Lin , Wang Yi , Zheng Ziyi
Published: February 2022

Koji making is a pre-fermentation stage in soy sauce manufacturing that impacts final product quality. Previous studies have provided valuable insights into the microbial species present in koji. However, changes in microbial community functional potential during koji-making are not well-known, nor are the associations among microbial populations and flavoring characteristics. In the present study, we investigated the succession of microbial communities, microbial community functional potential, metabolite profiles, and associations among microbial community members/functions with metabolites during koji making using shotgun metagenomic and metabolomic analyses. Firmicutes, Proteobacteria, and Ascomycota were identified as the most abundant microbial phyla in early koji making (0–12 h). Aspergillus (fungi) and Weissella (bacteria) exhibited marked abundance increases (0.98–38.45% and 0.31–30.41%, respectively) after 48 h of fermentation. Metabolite analysis revealed that aspartic acid, lysine, methyl acetate, isovaleraldehyde, and isoamyl alcohol concentrations increased ∼7-, 9-, 5-, 49-, and 10-fold after 48 h of fermentation. Metagenomic profiling demonstrated that koji communities were dominated by genes related to carbohydrate metabolism and amino acid metabolism, but functional profiles exhibited marked shifts after 24 h of fermentation. The abundances of genes within the categories of carbohydrate and amino acid metabolism all increased during koji making, except for pyruvate metabolism, glycolysis/gluconeogenesis, and the citrate cycle. Correlational analyses indicated that Aspergillus, Lactococcus, Enterococcus, Corynebacterium, and Kocuria abundances were positively correlated with 15 amino acid concentrations (all p < 0.05), while Weissella abundances were positively correlated with concentrations of volatile flavor compounds, including eight amino acids, phenylacetaldehyde, acetic acid, 2,3-butanediol, ethyl acetate, and ethanol (p < 0.05). These results provide valuable information for understanding the microbial-associated mechanisms of flavor formation during koji making.
Dishevelled-Associated Activator of Morphogenesis 2 (DAAM2) Predicts the Immuno-Hot Phenotype in Pancreatic Adenocarcinoma
Authors: Zhang Qinglin , Pan Jiadong , Nie He , Wang Hui , An Fangmei , Zhan Qiang
Published: February 2022

Background: DAAM2 participates in the oncogenesis and progression of human cancers. Although the role of DAAM2 in cancers has been preliminarily investigated, its correlations with antitumor immunity are unclear.

Methods: A pancancer analysis was conducted to explore the immunological role of DAAM2 based on RNA sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between DAAM2 and immunological characteristics in the tumor microenvironment (TME) of pancreatic adenocarcinoma (PAAD) were evaluated. In addition, the role of DAAM2 in predicting the clinical characteristics and the response to various therapies in PAAD were also assessed. In addition, the correlations between DAAM2 and the emerging immunobiomarker N6-methyladenosine (m6A) genes were also evaluated.

Results: Pancancer analysis revealed that DAAM2 exhibited positive correlations with a majority of immunomodulators, tumor-infiltrating immune cells (TIICs) and inhibitory immune checkpoints in several cancer types, including PAAD. In addition, DAAM2 was associated with an inflamed phenotype in the tumor microenvironment (TME). DAAM2 also predicted significantly higher responses to chemotherapy, anti-EGFR therapy and immunotherapy but lower responses to anti-ERBB2 and antiangiogenic therapy. In addition, DAAM2 was correlated with immune-related microbiota.

Conclusion: In PAAD, DAAM2 is associated with an immuno-hot phenotype and can help predict the outcome of various therapeutic options. Overall, DAAM2 is a promising indicator for assessing high immunogenicity in PAAD.
The Photoreaction of the Proton-Pumping Rhodopsin 1 From the Maize Pathogenic Basidiomycete Ustilago maydis
Authors: La Greca Mariafrancesca , Chen Jheng-Liang , Schubert Luiz , Kozuch Jacek , Berneiser Tim , Terpitz Ulrich , Heberle Joachim , Schlesinger Ramona
Published: February 2022

Microbial rhodopsins have recently been discovered in pathogenic fungi and have been postulated to be involved in signaling during the course of an infection. Here, we report on the spectroscopic characterization of a light-driven proton pump rhodopsin (UmRh1) from the smut pathogen Ustilago maydis, the causative agent of tumors in maize plants. Electrophysiology, time-resolved UV/Vis and vibrational spectroscopy indicate a pH-dependent photocycle. We also characterized the impact of the auxin hormone indole-3-acetic acid that was shown to influence the pump activity of UmRh1 on individual photocycle intermediates. A facile pumping activity test was established of UmRh1 expressed in Pichia pastoris cells, for probing proton pumping out of the living yeast cells during illumination. We show similarities and distinct differences to the well-known bacteriorhodopsin from archaea and discuss the putative role of UmRh1 in pathogenesis.
Identification of Group II Intron RmInt1 Binding Sites in a Bacterial Genome
Authors: Molina-Sánchez María Dolores , García-Rodríguez Fernando Manuel , Andrés-León Eduardo , Toro Nicolás
Published: February 2022

RmInt1 is a group II intron encoding a reverse transcriptase protein (IEP) lacking the C-terminal endonuclease domain. RmInt1 is an efficient mobile retroelement that predominantly reverse splices into the transient single-stranded DNA at the template for lagging strand DNA synthesis during host replication, a process facilitated by the interaction of the RmInt1 IEP with DnaN at the replication fork. It has been suggested that group II intron ribonucleoprotein particles bind DNA nonspecifically, and then scan for their correct target site. In this study, we investigated RmInt1 binding sites throughout the Sinorhizobium meliloti genome, by chromatin-immunoprecipitation coupled with next-generation sequencing. We found that RmInt1 binding sites cluster around the bidirectional replication origin of each of the three replicons comprising the S. meliloti genome. Our results provide new evidence linking group II intron mobility to host DNA replication.
Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators
Authors: Morales Paula , Muller Chanté , Jagerovic Nadine , Reggio Patricia H.
Published: February 2022

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.