bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcription start site signal profiling improves transposable element RNA expression analysis at locus-level
Authors: Savytska Natalia , Heutink Peter , Bansal Vikas
Published: October 2022

The transcriptional activity of Transposable Elements (TEs) has been involved in numerous pathological processes, including neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The TE expression analysis from short-read sequencing technologies is, however, challenging due to the multitude of similar sequences derived from singular TEs subfamilies and the exaptation of TEs within longer coding or non-coding RNAs. Specialised tools have been developed to quantify the expression of TEs that either relies on probabilistic re-distribution of multimapper count fractions or allow for discarding multimappers altogether. Until now, the benchmarking across those tools was largely limited to aggregated expression estimates over whole TEs subfamilies. Here, we compared the performance of recently published tools (SQuIRE, TElocal, SalmonTE) with simplistic quantification strategies (featureCounts in unique, fraction and random modes) at the individual loci level. Using simulated datasets, we examined the false discovery rate and the primary driver of those false positive hits in the optimal quantification strategy. Our findings suggest a high false discovery number that exceeds the total number of correctly recovered active loci for all the quantification strategies, including the best performing tool TElocal. As a remedy, filtering based on the minimum number of read counts or baseMean expression improves the F1 score and decreases the number of false positives. Finally, we demonstrate that additional profiling of Transcription Start Site mapping statistics (using a k-means clustering approach) significantly improves the performance of TElocal while reporting a reliable set of detected and differentially expressed TEs in human simulated RNA-seq data.
Donor-derived cell-free DNA as a diagnostic tool in transplantation
Authors: Oellerich Michael , Budde Klemens , Osmanodja Bilgin , Bornemann-Kolatzki Kirsten , Beck Julia , Schütz Ekkehard , Walson Philip D.
Published: October 2022

There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from a large number of published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. Dd-cfDNA indicates graft cell death without being rejection specific. It can be determined in plasma through droplet digital PCR using preselected SNPs or next generation sequencing. Changes in recipient cfDNA (e.g., by infection) can affect the results of dd-cfDNA fractional determination. This limitation can be overcome using absolute dd-cfDNA quantification. The combination of fractional and absolute determination including total cfDNA is recommended for meaningful interpretation of the results. The value proposition for the patient includes earlier transplant injury detection and intervention, less full blown rejection risk, an alternative to invasive biopsies, and personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would result from fewer biopsies as a result of the tests’ high negative predictive value, fewer re-transplantations, and less organ failure with return to dialysis. A pathway to implementation and metrics is suggested to measure the effectiveness of dd-cfDNA testing.
Unravelling the impact of aging on the human endothelial lncRNA transcriptome
Authors: Drekolia Maria-Kyriaki , Talyan Sweta , Cordellini Emídio Rebeca , Boon Reinier Abraham , Guenther Stefan , Looso Mario , Dumbović Gabrijela , Bibli Sofia-Iris
Published: October 2022

The incidence and prevalence of cardiovascular disease is highest among the elderly. There is a need to further understand the mechanisms behind endothelial cell aging in order to achieve vascular rejuvenation and minimize the onset of age-related vascular diseases. Long non-coding RNAs (lncRNAs) have been proposed to regulate numerous processes in the human genome, yet their function in vascular aging and their therapeutic potential remain largely unknown. This is primarily because the majority of studies investigating the impact of aging on lncRNA expression heavily rely on in vitro studies based on replicative senescence. Here, using a unique collection of young and aged endothelial cells isolated from native human arteries, we sought to characterize the age-related alterations in lncRNA expression profiles. We were able to detect a total of 4463 lncRNAs expressed in the human endothelium from which ∼17% (798) were altered in advanced age. One of the most affected lncRNAs in aging was the primate-specific, Prostate Cancer Associated Transcript (PCAT) 14. In our follow up analysis, using single molecule RNA FISH, we showed that PCAT14 is relatively abundant, localized almost exclusively in the nucleus of young endothelial cells, and silenced in the aged endothelium. Functionally, our studies proposed that downregulation of PCAT14 alters endothelial cell transcription profile and cell functions including endothelial cell migration, sprouting and inflammatory responses in vitro. Taken together, our data highlight that endothelial cell aging correlates with altered expression of lncRNAs, which could impair the endothelial regenerative capacity and enhance inflammatory phenotypes.
Effects of exogenous melatonin on expressional differences of immune-related genes in cashmere goats
Authors: Chai Yuan , Liu Zaixia , Fu Shaoyin , Liu Bin , Guo Lili , Dai Lingli , Sun Yanyong , Zhang Wenguang , Li Chun , Liu Taodi
Published: October 2022

The interplay between melatonin and immune system is well recognized in humans. The true integration of research on cashmere goat is still far from clear, especially for cashmere goat maintained in wool and cashmere growth. In this study, we applied various approaches to identify the complex regulated network between the immune-related genes and transcription factors (TFs) and to explore the relationship between melatonin and gene expression in cashmere goats. In total, 1,599 and 1756 immune-related genes were found in the blood and skin of cashmere goats, respectively, and 24 differentially expressed immune-related GO terms were highly expressed in blood after melatonin implantation. We studied the melatonin-dependent networks between the TFs and immune-related genes in cashmere goat. The 3 major regulatory networks were interconnected through TFs. The TFs, such asPHF5A, REXO4, STRAP, JUNB, GATAD2A, ZNF710,andVDR, were also expressed in the blood and skin tissue of cashmere goat. In addition, most genes in these networks, such asVDR, JUNB,andTrib3, were involved in WNT pathway, which is related to cashmere wool growth regulation.On the network basis, we developed a knockout mouse model to identify the network interaction. We observed that 8 high-sulfur protein genes, 12 keratin (KRT) genes, and 19 keratin associated protein (KRTAP) genes related to the growth of cashmere wool were almost not expressed inTrib3−/−rat skin. Our results suggested that the expression of genes related to wool and cashmere growth may be regulated by the interaction network between genes affected by melatonin and immune-related genes. In summary, we outlined some particularly promising ways for future research on immune-related genes of cashmere goats and the role of melatonin in wool and cashmere growth.
Molecular subtypes based on cuproptosis regulators and immune infiltration in kidney renal clear cell carcinoma
Authors: Liu Aibin , Li Yanyan , Shen Lin , Li Na , Zhao Yajie , Shen Liangfang , Li Zhanzhan
Published: October 2022

Copper toxicity involves the destruction of mitochondrial metabolic enzymes, triggering an unusual mechanism of cell death called cuproptosis, which proposes a novel approach using copper toxicity to treat cancer. However, the biological function of cuproptosis has not been fully elucidated in kidney renal clear cell carcinoma (KIRC). Using the expression profile of 13 cuproptosis regulators, we first identified two molecular subtypes related to cuproptosis defined as “hot tumor” and “cold tumor”, having different levels of biological function, clinical prognosis, and immune cell infiltration. We obtained three gene clusters using the differentially expressed genes between the two cuproptosis-related subtypes, which were associated with different molecular activities and clinical characteristics. Next, we developed and validated a cuproptosis prognostic model that included two genes (FDX1 and DBT). The calculated risk score could divide patients into high- and low-risk groups. The high-risk group had a poorer prognosis, lower level of immune infiltration, higher frequency of gene alterations, and greater levels of FDX1 methylation and limited DBT methylation. The risk score was also an independent predictive factor for overall survival in KIRC. The established nomogram calculating the risk score achieved a high predictive ability for the prognosis of individual patients (area under the curve: 0.860). We then identified small molecular inhibitors as potential treatments and analyzed the sensitivity to chemotherapy of the signature genes. Tumor immune dysfunction and exclusion (TIDE) showed that the high-risk group had a higher level of TIDE, exclusion and dysfunction that was lower than the low-risk group, while the microsatellite instability of the high-risk group was significantly lower. The results of two independent immunotherapy datasets indicated that cuproptosis regulators could influence the response and efficacy of immunotherapy in KIRC. Our study provides new insights for individualized and comprehensive therapy of KIRC.
Case report: Long response to PD-1 blockade after failure of trastuzumab plus chemotherapy in advanced Epstein-Barr virus-associated gastric cancer
Authors: Pan Yan , Lu Linbin , Liu Huan , Chen Di , Han Ning , Yao Ruirong , Wang Xinlin , Gao Xianchun , Yu Jun , Chen Ling , Zhou Fenli , Hao Guangjun , Lu Yuanyuan , Li Mengbin , He Guangbin , Kang Fei , Li Zengshan , Tang Yongqiang , Zhang Jinsong , Wei Lichun , Nie Yongzhan
Published: October 2022

Background

Trastuzumab-containing chemotherapy is the first-line treatment for advanced gastric cancer (GC) with HER2 positive. Although PD-1 inhibitors significantly improved the outcome of GC patient’s refractory to previous chemotherapy regimens, few studies explore the role of anti-PD-1 therapy overcomes resistance to trastuzumab plus chemotherapy in advanced Epstein-Barr Virus-associated gastric cancer (EBVaGC) with PD-L1 and HER2 positive.

Case Presentation

We report a case of advanced EBVaGC in a 45-year-old man presenting with fatigue, dysphagia, and weight loss for several months. Initial endoscopy revealed a large tumor at the gastroesophageal junction. Computed tomography revealed GC accompanied by multiple lymph nodes and hepatic and pulmonary metastases. The immunohistochemistry indicated that HER-2 and PD-L1 were overexpressed, and tumor cells were positive for EBV-encoded small RNA (EBER) by in situ hybridization. Trastuzumab plus DCS was started as first-line chemotherapy with a PFS of 4 months and shifted to trastuzumab plus FOLFIRI or gemcitabine as second-/third-line therapy. After five-cycle nivolumab monotherapy, the patient received partial response and was treated with total radical gastrectomy plus sequential radiotherapy. He continued the postoperative immunotherapy over 30 cycles with a PFS of 28 months. Due to a new abdominal lymph node metastasis confirmed by PET-CT, he received toripalimab as the next-line treatment and achieved complete remission as the best objective response.

We presented an advanced HER2-positive EBVaGC patient with PD-L1 high expression, refractory to trastuzumab plus chemotherapy, and had a durable clinical benefit sequence with a single dose of the PD-1 inhibitor.
Tumor metabolic and secondary lymphoid organ metabolic markers on 18F-fludeoxyglucose positron emission tomography predict prognosis of immune checkpoint inhibitors in advanced lung cancer
Authors: Jin Peng , Bai Menglin , Liu Jie , Yu Jinming , Meng Xue
Published: October 2022

Background

The purpose of this study was to investigate the predictive value of tumor metabolic parameters in combination with secondary lymphoid metabolic parameters on positron emission tomography (PET)/computed tomography (CT) for immune checkpoint inhibitor (ICI) prognosis in advanced lung cancer.

Methods

This study retrospectively included 125 patients who underwent 18F-fludeoxyglucose (FDG) PET/CT before ICI therapy, including 41 patients who underwent a second PET/CT scan during ICI treatment. The measured PET/CT parameters included tumor metabolism parameters [maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV)] and secondary lymphoid organ metabolism parameters [spleen-to-liver SUVmax ratio (SLR) and bone marrow-to-liver SUVmax ratio (BLR)]. The correlation of PET/CT metabolic parameters with early ICI treatment response, progression-free survival (PFS), and overall survival (OS) was analyzed.

Results

Within a median follow-up of 28.7 months, there were 44 responders and 81 non-responders. The median PFS was 8.6 months (95% confidence interval (CI): 5.872–11.328), and the median OS was 20.4 months (95% CI: 15.526–25.274). Pretreatment tumor metabolic parameters were not associated with early treatment responses. The high bone marrow metabolism (BLR >1.03) was significantly associated with a shorter PFS (p = 0.008). Patients with a high TMTV (>168 mL) and high spleen metabolism (SLR >1.08) had poor OS (p = 0.019 and p = 0.018, respectively). Among the 41 patients who underwent a second PET/CT scan, the ΔSUVmax was significantly lower (p = 0.01) and the SLR was significantly higher (p = 0.0086) in the responders. Populations with low-risk characteristics (low TMTV, low SLR, and ΔSLR > 0) had the longest survival times.

Conclusion

High pretreatment TMTV and SLR are associated with poor OS, and increased spleen metabolism after ICI therapy predicts treatment benefit. This indicates that the combination of tumor and spleen metabolic parameters is a valuable prognostic strategy.
Keratinocyte-induced costimulation of human T cells through CD6 - but not CD2 - activates mTOR and prevents oxidative stress
Authors: Orlik Christian , Berschneider Karina M. , Jahraus Beate , Niesler Beate , Balta Emre , Schäkel Knut , Schröder-Braunstein Jutta , Souto-Carneiro Maria Margarida , Samstag Yvonne
Published: October 2022

In psoriasis and other inflammatory skin diseases, keratinocytes (KCs) secrete chemokines that attract T cells, which, in turn, cause epidermal hyperplasia by secreting proinflammatory cytokines. To date, it remains unclear whether skin-homing T cells, particularly memory T cells, can also be activated by direct cell contact with KCs. In this study, we demonstrated the ability of primary human KCs to activate human memory T cells directly by transmitting costimulatory signals through the CD6/CD166/CD318 axis. Interestingly, despite being negative for CD80/CD86, KCs initiate a metabolic shift within T cells. Blockade of the CD6/CD166/CD318 axis prevents mammalian target of rapamycin activation and T cell proliferation but promotes oxidative stress and aerobic glycolysis. In addition, it diminishes formation of central memory T cells. Importantly, although KC-mediated costimulation by CD2/CD58 also activates T cells, it cannot compensate for the lack of CD6 costimulation. Therefore, KCs likely differentially regulate T cell functions in the skin through two distinct costimulatory receptors: CD6 and CD2. This may at least in part explain the divergent effects observed when treating inflammatory skin diseases with antibodies to CD6 versus CD2. Moreover, our findings may provide a molecular basis for selective interference with either CD6/CD166/CD318, or CD2/CD58, or both to specifically treat different types of inflammatory skin diseases.
MicroRNAs in Kawasaki disease: An update on diagnosis, therapy and monitoring
Authors: Xiong Yiyi , Xu Jiawei , Zhang Deju , Wu Shuqin , Li Zhangwang , Zhang Jing , Xia Zhongbin , Xia Panpan , Xia Cai , Tang Xiaoyi , Liu Xiao , Liu Jianping , Yu Peng
Published: October 2022

Kawasaki disease (KD) is an acute autoimmune vascular disease featured with a long stage of febrile. It predominantly afflicts children under 5 years old and causes an increased risk of cardiovascular combinations. The onset and progression of KD are impacted by many aspects, including genetic susceptibility, infection, and immunity. In recent years, many studies revealed that miRNAs, a novel class of small non-coding RNAs, may play an indispensable role in the development of KD via differential expression and participation in the central pathogenesis of KD comprise of the modulation of immunity, inflammatory response and vascular dysregulation. Although specific diagnose criteria remains unclear up to date, accumulating clinical evidence indicated that miRNAs, as small molecules, could serve as potential diagnostic biomarkers and exhibit extraordinary specificity and sensitivity. Besides, miRNAs have gained attention in affecting therapies for Kawasaki disease and providing new insights into personalized treatment. Through consanguineous coordination with classical therapies, miRNAs could overcome the inevitable drug-resistance and poor prognosis problem in a novel point of view. In this review, we systematically reviewed the existing literature and summarized those findings to analyze the latest mechanism to explore the role of miRNAs in the treatment of KD from basic and clinical aspects retrospectively. Our discussion helps to better understand the pathogenesis of KD and may offer profound inspiration on KD diagnosis, treatment, and prognosis.
Establishment and validation of a novel prognostic model for lower-grade glioma based on senescence-related genes
Authors: Li Junsheng , Wang Jia , Liu Dongjing , Tao Chuming , Zhao Jizong , Wang Wen
Published: October 2022

Objective

Increasing studies have indicated that senescence was associated with tumorigenesis and progression. Lower-grade glioma (LGG) presented a less invasive nature, however, its treatment efficacy and prognosis prediction remained challenging due to the intrinsic heterogeneity. Therefore, we established a senescence-related signature and investigated its prognostic role in LGGs.

Methods

The gene expression data and clinicopathologic features were from The Cancer Genome Atlas (TCGA) database. The experimentally validated senescence genes (SnGs) from the CellAge database were obtained. Then LASSO regression has been performed to build a prognostic model. Cox regression and Kaplan-Meier survival curves were performed to investigate the prognostic value of the SnG-risk score. A nomogram model has been constructed for outcome prediction. Immunological analyses were further performed. Data from the Chinese Glioma Genome Atlas (CGGA), Repository of Molecular Brain Neoplasia Data (REMBRANDT), and GSE16011 were used for validation.

Results

The 6-SnG signature has been established. The results showed SnG-risk score could be considered as an independent predictor for LGG patients (HR=2.763, 95%CI=1.660-4.599, P<0.001). The high SnG-risk score indicated a worse outcome in LGG (P<0.001). Immune analysis showed a positive correlation between the SnG-risk score and immune infiltration level, and the expression of immune checkpoints. The CGGA datasets confirmed the prognostic role of the SnG-risk score. And Kaplan-Meier analyses in the additional datasets (CGGA, REMBRANDT, and GSE16011) validated the prognostic role of the SnG-signature (P<0.001 for all).

Conclusion

The SnG-related prognostic model could predict the survival of LGG accurately. This study proposed a novel indicator for predicting the prognosis of LGG and provided potential therapeutic targets.
A positive feedback loop between two C-type lectins originated from gene duplication and relish promotes the expression of antimicrobial peptides in Procambarus clarkii
Authors: Dai Xiaoling , Sun Mengling , Nie Ximei , Zhao Yuqi , Xu Hao , Han Zhengxiao , Gao Tianheng , Huang Xin , Ren Qian
Published: October 2022

Gene duplication (GD) leads to the expansion of gene families that contributes organisms adapting to stress or environment and dealing with the infection of various pathogens. C-type lectins (CTLs) in crustaceans undergo gene expansion and participate in various immune responses. However, the functions of different CTL produced by GD are not fully characterized. In the present study, two CTL genes (designated as PcLec-EPS and PcLec-QPS, respectively) were identified from Procambarus clarkii. PcLec-EPS and PcLec-QPS originate from GD and the main difference between them is exon 3. PcLec-EPS and PcLec-QPS respectively contains EPS and QPS motif in their carbohydrate recognition domain. The mRNA levels of PcLec-EPS and PcLec-QPS in hemocytes, gills, intestine and lymph underwent time-dependent enhancement after D-Mannose and D-Galactose challenge. Recombinant PcLec-EPS and PcLec-QPS could bind to carbohydrates and microbes, and agglutinate bacteria. The results of experiments on recombinant protein injection and RNA interference indicate that PcLec-EPS and PcLec-QPS can respectively strong recognize and bind D-Mannose and D-Galactose, activate the Relish transcriptional factor, and further upregulate the expression of different antimicrobial peptides (AMPs). In addition, these two CTLs and Relish could positively regulate the expression of each other, suggesting that there is a positive feedback loop between two CTLs and Relish that regulates the expression of AMPs. It may contribute to the expansion of the immune response for host quickly and efficiently eliminating pathogenic microorganisms. This study provides new knowledge for clear understanding the significance and function of different CTL generated by GD in immune defenses in crustacean.
Tumor infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival
Authors: Vlaming Martijn , Bilemjian Vrouyr , Freile Jimena Álvarez , Melo Vinicio , Plat Annechien , Huls Gerwin , Nijman Hans W. , de Bruyn Marco , Bremer Edwin
Published: October 2022

Reactivation of tumor infiltrating T lymphocytes (TILs) with immune checkpoint inhibitors or co-stimulators has proven to be an effective anti-cancer strategy for a broad range of malignancies. However, epithelial ovarian cancer (EOC) remains largely refractory to current T cell-targeting immunotherapeutics. Therefore, identification of novel immune checkpoint targets and biomarkers with prognostic value for EOC is warranted. Combining multicolor immunofluorescent staining’s with single cell RNA-sequencing analysis, we here identified a TIM-3/CXCL13-positive tissue-resident memory (CD8/CD103-positive) T cell (Trm) population in EOC. Analysis of a cohort of ~175 patients with high-grade serous EOC revealed TIM-3-positive Trm were significantly associated with improved patient survival. As CXCL13-positive CD8-positive T cells have been strongly linked to patient response to anti-PD1 immune checkpoint blockade, combinatorial TIM-3 and PD-1 blockade therapy may be of interest for the (re)activation of anti-cancer immunity in EOC.
Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B
Authors: Xie Si , Yang Liu , Bi Xiaoyue , Deng Wen , Jiang Tingting , Lin Yanjie , Wang Shiyu , Zhang Lu , Liu Ruyu , Chang Min , Wu Shuling , Gao Yuanjiao , Hao Hongxiao , Shen Ge , Xu Mengjiao , Chen Xiaoxue , Hu Leiping , Lu Yao , Song Rui , Xie Yao , Li Minghui
Published: October 2022

Objective

We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV.

Methods

This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg.

Results

The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (β=-0.025, t=-2.613, P=0.014; β=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (β=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (β=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (β=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (β=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (β=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (β=-0.137, t=-3.273, P=0.003).

Conclusions

The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.
Metabolic Reprogramming in SARS-CoV-2 Infection Impacts the Outcome of COVID-19 Patients
Authors: Martínez-Gómez Laura E. , Ibarra-González Isabel , Fernández-Lainez Cynthia , Tusie Teresa , Moreno-Macías Hortensia , Martinez-Armenta Carlos , Jimenez-Gutierrez Guadalupe Elizabeth , Vázquez-Cárdenas Paola , Vidal-Vázquez Patricia , Ramírez-Hinojosa Juan P. , Rodríguez-Zulueta Ana P. , Vargas-Alarcón Gilberto , Rojas-Velasco Gustavo , Sánchez-Muñoz Fausto , Posadas-Sanchez Rosalinda , Martínez-Ruiz Felipe de J. , Zayago-Angeles Dulce M. , Moreno Mariana L. , Barajas-Galicia Edith , Lopez-Cisneros Gerardo , Gonzalez-Fernández Nadia C. , Ortega-Peña Silvestre , Herrera-López Brígida , Olea-Torres Jessel , Juárez-Arias Manuel , Rosas-Vásquez Maritza , Cabrera-Nieto Sara Aileen , Magaña Jonathan J. , Camacho-Rea María del Carmen , Suarez-Ahedo Carlos , Coronado-Zarco Irma , Valdespino-Vázquez M. Y. , Martínez-Nava Gabriela Angélica , Pineda Carlos , Vela-Amieva Marcela , López-Reyes Alberto ,   Mex-Gen-COVID Initiative Group
Published: October 2022

Introduction

Severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) infection triggers inflammatory clinical stages that affect the outcome of patients with coronavirus disease 2019 (COVID-19). Disease severity may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. The aim of this study was to characterize the profile of amino acids and acylcarnitines in COVID-19 patients. A multicenter, cross-sectional study was carried out. A total of 453 individuals were classified by disease severity. Levels of 11 amino acids, 31 acylcarnitines, and succinylacetone in serum samples were analyzed by electrospray ionization–triple quadrupole tandem mass spectrometry. Different clusters were observed in partial least squares discriminant analysis, with phenylalanine, alanine, citrulline, proline, and succinylacetone providing the major contribution to the variability in each cluster (variable importance in the projection >1.5). In logistic models adjusted by age, sex, type 2 diabetes mellitus, hypertension, and nutritional status, phenylalanine was associated with critical outcomes (odds ratio=5.3 (95% CI 3.16-9.2) in the severe vs. critical model, with an area under the curve of 0.84 (95% CI 0.77-0.90). In conclusion the metabolic imbalance in COVID-19 patients might affect disease progression. This work shows an association of phenylalanine with critical outcomes in COVID-19 patients, highlighting phenylalanine as a potential metabolic biomarker of disease severity.
Why do tumor-infiltrating lymphocytes have variable efficacy in the treatment of solid tumors?
Authors: Li Biaoru
Published: October 2022

Lymphocytes in tumor tissue are called tumor-infiltrating lymphocytes (TILs), and they play a key role in the control and treatment of tumor diseases. Since the discovery in 1987 that cultured TILs can kill tumor cells more than 100 times more effectively than T-cells cultured from peripheral blood in melanoma, it has been confirmed that cultured TILs can successfully cure clinical patients with melanoma. Since 1989, after we investigated TIL isolation performance from solid tumors, we modified some procedures to increase efficacy, and thus successfully established new TIL isolation and culture methods in 1994. Moreover, our laboratory and clinicians using our cultured TILs have published more than 30 papers. To improve the efficacy of TILs, we have been carrying out studies of TIL efficacy to treat solid tumor diseases for approximately 30 years. The three main questions of TIL study have been “How do TILs remain silent in solid tumor tissue?”, “How do TILs attack homologous and heterologous antigens from tumor cells of solid tumors?”, and “How do TILs infiltrate solid tumor tissue from a distance into tumor sites to kill tumor cells?”. Research on these three issues has increasingly answered these questions. In this review I summarize the main issues surrounding TILs in treating solid tumors. This review aims to study the killing function of TILs from solid tumor tissues, thereby ultimately introducing the optimal strategy for patients suffering from solid tumors through personalized immunotherapy in the near future.
Hematological changes in human lymphotropic-T virus type 1 carriers
Authors: Ribeiro Jairo Falcão , Nobre Akim Felipe Santos , Covre Louise Canto Ferreira , de Almeida Viana Maria de Nazaré do Socorro , Silva Ingrid Christiane , dos Santos Leonardo Miranda , Ishikawa Edna Aoba , da Costa Carlos Araújo , de Sousa Maísa Silva
Published: October 2022

The human T-lymphotropic virus type 1 (HTLV-1), isolated in 1980, causes T-cell leukemia/lymphoma in adulthood, a type of lymphoproliferative disease, and chronic HTLV-1-associated myelopathy, a disease that causes paralysis of the lower limbs, which occur in about 5% of cases in this viral infection. This study aimed to establish the hematological profile of patients with HTLV-1 infection in Belém do Pará, describing the hematological parameters under study, estimating the frequency of lymphocytic atypical, and associating the hematological profile with diseases and symptoms. Hematologic data from 202 individuals were analyzed, including 87 HTLV-1 infected individuals and 115 non-HTLV-1 infected individuals as a control group, composed, at a great part, of relatives of the infected. The seroprevalence of HTLV-1 infection was observed in 71.3% of female individuals, with predominance in the group older than 50 years (44.8%). The analysis of hematological parameters showed a significant difference in the counts of the segmented cells (p = 0.0303) and eosinophils (p = 0.0092) in HTLV-1 carriers. Lymphocytic atypical was a finding present only in HTLV-1 carriers (p = 0.0001). There was no high frequency in the leukocyte counts of those infected by HTLV-1 not among them concerning a significant increase or decrease. It is concluded that HTLV-1 infection is prominent in women over 50 years old. The hematological profile of those infected shows a reduction of segmented cells, an increase of eosinophils, and the presence of atypical lymphocytes. The hematological profile of the HTLV-1 carrier should always be evaluated to identify early some diseases associated with the infection.
Characterization and genomic analysis of a bensulfuron methyl-degrading endophytic bacterium Proteus sp. CD3 isolated from barnyard grass (Echinochloa crus-galli)
Authors: Wang Yanhui , Chen Xianyan , Li Honghong , Ma Yonglin , Zeng Dongqiang , Du Liangwei , Jin Decai
Published: October 2022

Bensulfuron methyl (BSM) is a widely used sulfonylurea herbicide in agriculture. However, the large-scale BSM application causes severe environmental problems. Biodegradation is an important way to remove BSM residue. In this study, an endophytic bacterium strain CD3, newly isolated from barnyard grass (Echinochloa crus-galli), could effectively degrade BSM in mineral salt medium. The strain CD3 was identified as Proteus sp. based on the phenotypic features, physiological biochemical characteristics, and 16S rRNA gene sequence. The suitable conditions for BSM degradation by this strain were 20–40°C, pH 6–8, the initial concertation of 12.5–200 mg L−1 with 10 g L−1 glucose as additional carbon source. The endophyte was capable of degrading above 98% BSM within 7 d under the optimal degrading conditions. Furthermore, strain CD3 could also effectively degrade other sulfonylurea herbicides including nicosulfuron, halosulfuron methyl, pyrazosulfuron, and ethoxysulfuron. Extracellular enzyme played a critical role on the BSM degradation by strain CD3. Two degrading metabolites were detected and identified by using liquid chromatography–mass spectrometry (LC–MS). The biochemical degradation pathways of BSM by this endophyte were proposed. The genomic analysis of strain CD3 revealed the presence of putative hydrolase or esterase genes involved in BSM degradation, suggesting that a novel degradation enzyme for BSM was present in this BSM-degrading Proteus sp. CD3. The results of this research suggested that strain CD3 may have potential for using in the bioremediation of BSM-contaminated environment.
Serum investigation of antibodies against porcine circovirus 4 Rep and Cap protein in Jiangxi Province, China
Authors: Hu Xifeng , Ding Zhen , Li Yu , Chen Zheng , Wu Huansheng
Published: October 2022

In 2019, a novel porcine circovirus 4 (PCV4) was first identified in Hunan Province, China. The circular PCV4 DNA was detected in both diseased and healthy pigs. Recently, PCV4 prevalence surveys have been analyzed in many provinces in both China and South Korea with low positive rates. However, no serological data has been conducted to investigate the prevalence of PCV4 in pigs from Jiangxi Province. To address this issue, an indirect anti-PCV4 antibody enzyme-linked immunosorbent assay (ELISA) based on Cap and Rep protein as a coating antigen was established and applied to study the serum epidemiology of PCV4 in Jiangxi Province. Purified PCV4-His-tagged Cap and Rep were used as the coating antigen to develop an ELISA detection kit. There was no cross-reaction of the Cap/Rep-based ELISA with antisera against PCV2, TGEV and PRRSV, indicating a high specificity of this ELISA assay. The intra-assay coefficient variations (CVs) of Cap-based were 1.239%−9.796%, Rep-based 1.288%−5.011%, and inter-assay CVs of 1.167%−4.694% and 1.621%−8.979%, respectively, indicating a good repeatability. Finally, a total number of 507 serum samples were collected from Jiangxi Province to test for antibody prevalence of PCV4, and 17 (3.35%) and 36 (7.10%) of the samples were Cap and Rep antibody positive, respectively. In summary, our established ELISA kit could be used to detect PCV4 antibodies in serum with good repeatability and high specificity. In addition, field samples detection results showed that the antibody of PCV4 was poorly distributed in intensive pig farms in Jiangxi Province, China.
In vitro activities of licochalcone A against planktonic cells and biofilm of Enterococcus faecalis
Authors: Liu Xiaoju , Xiong Yanpeng , Shi Yiyi , Deng Xiangbin , Deng Qiwen , Liu Yansong , Yu Zhijian , Li Duoyun , Zheng Jinxin , Li Peiyu
Published: October 2022

This study aims to evaluate the in vitro antibacterial and anti-biofilm activities of licochalcone A on Enterococcus faecalis and to investigate the possible target genes of licochalcone A in E. faecalis. This study found that licochalcone A had antibacterial activities against E. faecalis, with the MIC50 and MIC90 were 25 μM. Licochalcone A (at 4 × MIC) indicated a rapid bactericidal effect on E. faecalis planktonic cells, and killed more E. faecalis planktonic cells (at least 3-log10 cfu/ml) than vancomycin, linezolid, or ampicillin at the 2, 4, and 6 h of the time-killing test. Licochalcone A (at 10 × MIC) significantly reduced the production of E. faecalis persister cells (at least 2-log10 cfu/ml) than vancomycin, linezolid, or ampicillin at the 24, 48, 72, and 96 h of the time-killing test. Licochalcone A (at 1/4 × MIC) significantly inhibited the biofilm formation of E. faecalis. The RNA levels of biofilm formation-related genes, agg, esp, and srtA, markedly decreased when the E. faecalis isolates were treated with licochalcone A at 1/4 × MIC for 6 h. To explore the possible target genes of licochalcone A in E. faecalis, the licochalcone A non-sensitive E. faecalis clones were selected in vitro by induction of wildtype strains for about 140 days under the pressure of licochalcone A, and mutations in the possible target genes were detected by whole-genome sequencing. This study found that there were 11 nucleotide mutations leading to nonsynonymous mutations of 8 amino acids, and among these amino acid mutations, there were 3 mutations located in transcriptional regulator genes (MarR family transcriptional regulator, TetR family transcriptional regulator, and MerR family transcriptional regulator). In conclusion, this study found that licochalcone A had an antibacterial effect on E. faecalis, and significantly inhibited the biofilm formation of E. faecalis at subinhibitory concentrations.
Roles of peripheral immune cells in the recovery of neurological function after ischemic stroke
Authors: Zhang Zhaolong , Lv Mengfei , Zhou Xin , Cui Yu
Published: October 2022

Stroke is a leading cause of mortality and long-term disability worldwide, with limited spontaneous repair processes occurring after injury. Immune cells are involved in multiple aspects of ischemic stroke, from early damage processes to late recovery-related events. Compared with the substantial advances that have been made in elucidating how immune cells modulate acute ischemic injury, the understanding of the impact of the immune system on functional recovery is limited. In this review, we summarized the mechanisms of brain repair after ischemic stroke from both the neuronal and non-neuronal perspectives, and we review advances in understanding of the effects on functional recovery after ischemic stroke mediated by infiltrated peripheral innate and adaptive immune cells, immune cell-released cytokines and cell-cell interactions. We also highlight studies that advance our understanding of the mechanisms underlying functional recovery mediated by peripheral immune cells after ischemia. Insights into these processes will shed light on the double-edged role of infiltrated peripheral immune cells in functional recovery after ischemic stroke and provide clues for new therapies for improving neurological function.
The effects of painless nerve growth factor on human microglia polarization
Authors: Lisi Lucia , Marinelli Silvia , Ciotti Gabriella Maria Pia , Pizzoferrato Michela , Palmerio Federica , Chiavari Marta , Cattaneo Antonino , Navarra Pierluigi
Published: October 2022

Previous studies in the rat suggest that microglial cells represent a potential druggable target for nerve growth factor (NGF) in the brain. The painless human Nerve Growth Factor (hNGFp) is a recombinant mutated form of human nerve growth factor (hNGF) that shows identical neurotrophic and neuroprotective properties of wild-type NGF but displays at least 10-fold lower algogenic activity. From the pharmacological point of view, hNGFp is a biased tropomyosin receptor kinase A (TrkA) agonist and displays a significantly lower affinity for the p75 neurotrophin receptor (p75NTR). This study aimed to evaluate the expression of TrkA and p75NTR NGF receptors in two different human microglia cell lines, and to investigate the effects of hNGFp and wild-type NGF (NGF) on L-arginine metabolism, taken as a marker of microglia polarization. Both NGF receptors are expressed in human microglia cell lines and are effective in transducing signals triggered by NGF and hNGFp. The latter and, to a lesser extent, NGF inhibit cytokine-stimulated inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in these cells. Conversely NGF but not hNGFp stimulates arginase-mediated urea production.
Global and non-Global slow oscillations differentiate in their depth profiles
Authors: Seok Sang-Cheol , McDevitt Elizabeth , Mednick Sara C. , Malerba Paola
Published: October 2022

Sleep slow oscillations (SOs, 0.5–1.5 Hz) are thought to organize activity across cortical and subcortical structures, leading to selective synaptic changes that mediate consolidation of recent memories. Currently, the specific mechanism that allows for this selectively coherent activation across brain regions is not understood. Our previous research has shown that SOs can be classified on the scalp as Global, Local or Frontal, where Global SOs are found in most electrodes within a short time delay and gate long-range information flow during NREM sleep. The functional significance of space-time profiles of SOs hinges on testing if these differential SOs scalp profiles are mirrored by differential depth structure of SOs in the brain. In this study, we built an analytical framework to allow for the characterization of SO depth profiles in space-time across cortical and sub-cortical regions. To test if the two SO types could be differentiated in their cortical-subcortical activity, we trained 30 machine learning classification algorithms to distinguish Global and non-Global SOs within each individual, and repeated this analysis for light (Stage 2, S2) and deep (slow wave sleep, SWS) NREM stages separately. Multiple algorithms reached high performance across all participants, in particular algorithms based on k-nearest neighbors classification principles. Univariate feature ranking and selection showed that the most differentiating features for Global vs. non-Global SOs appeared around the trough of the SO, and in regions including cortex, thalamus, caudate nucleus, and brainstem. Results also indicated that differentiation during S2 required an extended network of current from cortical-subcortical regions, including all regions found in SWS and other basal ganglia regions, and amygdala and hippocampus, suggesting a potential functional differentiation in the role of Global SOs in S2 vs. SWS. We interpret our results as supporting the potential functional difference of Global and non-Global SOs in sleep dynamics.
Brain connectivity markers in degenerative cervical myelopathy patients with depression for predicting the prognosis following decompression surgery
Authors: Zhao Rui , Chu Xu , Ge Yuqi , Guo Xing , Xue Yuan
Published: October 2022

Objective

To determine if brain functional connectivity (FC) is associated with the prognosis in depressed degenerative cervical myelopathy patients (DCM) and to investigate the possible brain functional mechanism.

Methods

Resting-state fMRI scans and peripheral blood cell counts from 33 depressed DCM patients, 33 age and gender-matched DCM patients without depression were analyzed. All patients were evaluated using Japanese Orthopedic Association score before and 6 weeks after decompression surgery. JOA recovery rate was calculated to assess the functional recovery for DCM patients. For each participant, seed-based functional connectivity maps based on sub-regions centered on the striatum were computed and compared between groups. Pearson correlations were performed to explore the relationships between clinical measures and brain alterations in depressed DCM patients. To further investigate the relationships between brain alterations and clinical measures in depressed DCM patients, mediation analyses were performed. Flow cytometry was also performed on the three of the 33 depressed DCM patients, and the results were analyzed.

Results

In comparison to patients without depression, DCM patients exhibited lower FC between the dorsal caudate (dC) and the inferior frontal operculum, which is located in the dorsal lateral prefrontal cortex (dlPFC). In depressed DCM patients, the altered dC-dlPFC FC was associated with inflammation as determined by the neutrophils/lymphocyte's ratio and prognosis. Furthermore, the mediation analysis demonstrated that the dC-dlPFC FC mediated the effect of inflammation on prognosis. The outcomes of our three cases followed a similar pattern to these findings.

Conclusion

In conclusion, our findings imply that inflammation slowed the functional recovery in depressed DCM patients through the striatal-frontal FC pathway.
Adult-onset Krabbe disease presenting with progressive myoclonic epilepsy and asymmetric occipital lesions: A case report
Authors: Wang Yu , Wang Su-yue , Li Kai , Zhu Yu-long , Xia Kun , Sun Dan-dan , Ai Wen-long , Fu Xiao-ming , Ye Qun-rong , Li Jun , Chen Huai-zhen
Published: October 2022

Krabbe disease (KD), also known as globoid cell leukodystrophy, is a rare autosomal recessive condition caused by mutations in the galactocerebrosidase (GALC) gene. KD is more common in infants and young children than in adults. We reported the case of an adult-onset KD presenting with progressive myoclonic epilepsy (PME) and cortical lesions mimicking mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. The whole-exome sequencing (WES) identified a pathogenic homozygous missense mutation of the GALC gene. Parents of the patient were heterozygous for the mutation. The clinical, electrophysiological, and radiological data of the patient were retrospectively analyzed. The patient was a 24-year-old woman presenting with generalized seizures, progressive cognitive decline, psychiatric symptoms, gait ataxia, and action-induced myoclonus. The brain magnetic resonance imaging (MRI) revealed a right occipital cortical ribbon sign without any other damage. This single case expands the clinical phenotypes of adult-onset KD.