bluuebunny/crossref_metadata_2025 huggingface dataset:
Insight into the degradation mechanism of fluorene by ferrous/humic acid activated persulfate: Free radical reactions, functional group verification and degradation pathway
Authors: Li Haonan , Liao Xiaoyong , Li You , Liu Qiongzhi , Luo Junpeng
Published: December 2022

This study evaluated the performance of humic acid (HA)/ferrous ion (Fe (II)) activating persulfate (PS) for fluorene (FLU) degradation. Results showed that HA/Fe(II)/PS system exhibited the best performance for PS activation to eliminate FLU. Compared to the non-activated case, the degradation efficiency of FLU had increased by 37%–43% in HA activated PS system. HA had significant synergistic effects on Fe (II) activated PS process, but ferric ion (Fe(III)) inhibited the degradation. We confirmed that semiquinone radical (SQ·-) acted as the dominant activating group by quenching and electron spin resonance (ESR) experiments, which promoted more radicals generated. The proportion of benzoquinone (BQ) and Fe(II) wielded a considerable influence on FLU degradation, and the optimal concentration ratio was 1:1. Four possible degradation pathways of FLU were deduced, involving ring-opening of the aromatic ring, decarboxylation, oxidative dehydrogenation and hydroxylation.
Case report: A heterozygous mutation in ZNF462 leads to growth hormone deficiency
Authors: Zhou Yikun , Liu Jianmei , Wu Shuai , Li Wanran , Zheng Yun
Published: December 2022

Weiss–Kruszka syndrome (WSKA) is a rare disease most often caused by mutations in the ZNF462 gene. To screen for hereditary diseases, exons from the patient’s genome were sequenced. Genomic PCR experiments followed by Sanger sequencing were used to confirm the mutated genomic regions in the patient and his parents. We report a new mutation site, a heterozygous mutation (NM_021224.6:c.6311dup) in ZNF462 in a male patient of 8 years old. The mutation in the ZNF462 gene caused WSKA. This patient is the first case with WSKA characterized by attention-deficit hyperactivity disorder and complete growth hormone deficiency without pituitary lesions. Our results suggest that the heterozygous mutation in ZNF462 is the direct cause of WSKA in this patient. Mutations in other genes interacting with ZNF462 result in similar symptoms of WSKA. Furthermore, ZNF462 and its interacting proteins ASXL2 and VPS13B may form a protein complex that is important for normal development but awaits more studies to reveal its detailed functions.
Increased diagnostic yield in a cohort of hearing loss families using a comprehensive stepwise strategy of molecular testing
Authors: Zeng Beiping , Xu Hongen , Yu Yanan , Li Siqi , Tian Yongan , Li Tiandong , Yang Zengguang , Wang Haili , Wang Guangke , Chang Mingxiu , Tang Wenxue
Published: December 2022

Hearing loss is one of the most common sensory disorders in humans. This study proposes a stepwise strategy of deafness gene detection using multiplex PCR combined with high-throughput sequencing, Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and whole-exome sequencing (WES) to explore its application in molecular diagnosis of hearing loss families. A total of 152 families with hearing loss were included in this study, the highest overall diagnosis rate was 73% (111/152). The diagnosis rate of multiplex PCR combined with high-throughput sequencing was 52.6% (80/152). One families was diagnosed by Sanger sequencing of GJB2 exon 1. Two families were diagnosed by MLPA analysis of the STRC gene. The diagnosis rate with additional contribution from WES was 18.4% (28/152). We identified 21 novel variants from 15 deafness genes by WES. Combining WES and deep clinical phenotyping, we diagnosed 11 patients with syndromic hearing loss (SHL). This study demonstrated improved diagnostic yield in a cohort of hearing loss families and confirmed the advantages of a stepwise strategy in the molecular diagnosis of hearing loss.
Differentially expressed gene profiles and associated ceRNA network in ATG7-Deficient lens epithelial cells under oxidative stress
Authors: Li Hongyu , Gao Lixiong , Du Jinlin , Ma Tianju , Ye Zi , Li Zhaohui
Published: December 2022

Oxidation is an essential factor during cataract development. Autophagy, usually a cytoprotective process, is always found elevated in lens epithelial cells under oxidation, yet its roles and associated molecular mechanisms under such circumstances are rarely elucidated. Herein, we extracted and re-analyzed the RNA sequencing data of the GSE161701 dataset from the Gene Expression Omnibus database to identify the differentially expressed mRNAs and lncRNAs by using the R package “DESeq2”. Further analyses of gene ontology and KEGG enrichment were implemented via the packages “clusterProfiler” and “enrichplot”. We found that after the knockout of ATG7, differentially expressed genes were more associated with hemopoiesis, vasculature development, axonogenesis, and hypoxia regulation. When stimulated with H2O2, LECs displayed a gene expression profile correlating with apoptotic and proliferative pathways, such as the MAPK signaling pathway and FoxO signaling pathway. The differentially expressed gene profiles of the two types of LECs (wild type and ATG7 deficient) under oxidation were distinct to a large extent. Furthermore, 1,341 up-regulated and 1912 down-regulated differential mRNAs and 263 up-regulated and 336 down-regulated differential lncRNAs between these two types of LECs subjected to H2O2 were detected, among which 292 mRNAs and 24 lncRNAs possibly interacted with ten cataract-related miRNAs. A competing endogenous lncRNA-miRNA-mRNA network based on such interactions was finally constructed.
Impact of oral administration of single strain Lactococcus lactis spp. cremoris on immune responses to keyhole limpet hemocyanin immunization and gut microbiota: A randomized placebo-controlled trial in healthy volunteers
Authors: Saghari Mahdi , Gal Pim , Grievink Hendrika W. , Klaassen Erica S. , Itano Andrea , McHale Duncan , Moerland Matthijs
Published: December 2022

Introduction

Lactococcus lactis spp. cremoris has been associated with promising immunomodulatory results in preclinical trials. The aim of this study was to investigate the pharmacodynamic (PD) effects of three monoclonal microbial formulations of L. lactis spp. cremoris (EDP1066) on the immune response to keyhole limpet hemocyanin (KLH). Potential effects on the gut microbiota were also investigated.

Methods

The trial was registered on Netherlands Trial Register (trial ID NL7519, https://trialsearch.who.int). Eighty-one healthy subjects (median 28, range 18–59 years) were randomized to 28 days of enteric-coated capsules at five doses (n = 13) (1.5 * 1012 total cells daily), freeze-dried powder at one dose (n = 12) (3.0 * 1011 total cells daily) or five doses (n = 12), minitablets at one dose (n = 12) or five doses (n = 12), or placebo (n = 20) prior to KLH immunization. Antibody responses and circulating regulatory T cells (Tregs) were measured after KLH immunization, and skin responses were evaluated after a KLH rechallenge by laser speckle contrast imaging and multispectral imaging. Ex vivo lymphocyte (phytohemagglutinin) and monocyte (lipopolysaccharide (LPS)) cytokine release assays were explored in the minitablet-treated groups only. The prevalence of L. lactis spp. cremoris in the gastrointestinal tract and the impact on the fecal microbiota were assessed by qPCR and 16S rRNA sequencing, respectively.

Results

Repeated-measures analysis of covariances revealed no significant treatment effects on the antibody responses to KLH, number of Tregs, or KLH skin rechallenge outcomes. Ex vivo LPS-driven cytokine responses in whole blood were lower in the low dose minitablet group compared to placebo: tumor necrosis factor (estimated difference (ED) from placebo: −44.2%, 95% confidence interval (CI) −65.3% to −10.3%), interleukin (IL)-1β (ED −41.4%, 95% CI −63.5% to −5.8%), and IL-6 (ED −39.2%, 95% CI −56.8% to −14.5%). The fecal presence of L. lactis spp. cremoris increased during treatment by all EDP1066 formulations and normalized 5 days after the last dose. Microbiome α-diversity did not change by the treatments compared to placebo.

Discussion

The EDP1066 formulations did not affect the immune response to KLH immunization in healthy individuals. However, exposure to L. lactis spp. cremoris in minitablet formulation impacted ex vivo whole blood LPS cytokine response. The clinical impact of these effects awaits further investigations.

Netherlands Trial Register

trialsearch.who.int, trial ID NL7519.
IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing differentiation and targeting of plasma cells
Authors: Alomari Nedaa , Totonchy Jennifer
Published: December 2022

Introduction

Factors influencing Kaposi’s sarcoma-associated herpesvirus (KSHV) transmission and the early stages of KSHV infection in the human immune system remain poorly characterized. KSHV is known to extensively manipulate the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHV-associated diseases. Our previous work identified the early targeting of plasma cells for KSHV infection. In this study, we examine whether IL-21, a cytokine known to profoundly influence plasma cell fate, influences the early stages of KSHV infection in B lymphocytes.

Methods

Using our unique model of ex vivo KSHV infection in tonsil lymphocytes, we investigate the influence of IL-21 supplementation, IL-21 neutralization, the distribution of IL-21 receptor on B cell subsets and IL-21 secreting T cell subsets on the establishment of KSHV infection in human B cells.

Results

We show that IL-21 signaling promotes KSHV infection by promoting both total plasma cell numbers and increasing KSHV infection in plasma cells as early as 3 days post-infection. We further demonstrate that the synergistic effect of KSHV infection and IL-21 treatment on plasma cell frequencies is due to differentiation of new plasma cells from naïve B cell precursors. We examine T cells secreting IL-21 in our tonsil specimens and determine that IL-21 producing CD8+ central memory T cells are correlated with plasma cell frequencies and KSHV targeting of plasma cells.

Discussion

These results demonstrate the novel finding that differentiation of new plasma cells is involved in the early stages of KSHV infection in B cells, and that IL-21 signaling can potentiate this effect thereby increasing the overall magnitude of KSHV infection at early timepoints. These results suggest that IL-21 signaling represents a host-level susceptibility factor for the establishment of KSHV infection.
An immune risk score predicts progression-free survival of melanoma patients in South China receiving anti-PD-1 inhibitor therapy—a retrospective cohort study examining 66 circulating immune cell subsets
Authors: Chi Peidong , Jiang Hang , Li Dandan , Li Jingjing , Wen Xizhi , Ding Qiyue , Chen Linbin , Zhang Xiaoshi , Huang Junqi , Ding Ya
Published: December 2022

Introduction

Immune checkpoint blockade inhibitor (ICI) therapy offers significant survival benefits for malignant melanoma. However, some patients were observed to be in disease progression after the first few treatment cycles. As such, it is urgent to find convenient and accessible indicators that assess whether patients can benefit from ICI therapy.

Methods

In the training cohort, flow cytometry was used to determine the absolute values of 66 immune cell subsets in the peripheral blood of melanoma patients (n=29) before treatment with anti-PD-1 inhibitors. The least absolute shrinkage and selection operator (LASSO) Cox regression model was followed for the efficacy of each subset in predicting progression-free survival. Then we validated the performance of the selected model in validation cohorts (n=20), and developed a nomogram for clinical use.

Results

A prognostic immune risk score composed of CD1c+ dendritic cells and three subsets of T cells (CD8+CD28+, CD3+TCRab+HLA-DR+, CD3+TCRgd+HLA-DR+) with a higher prognostic power than individual features (AUC = 0.825). Using this model, patients in the training cohort were divided into high- and low-risk groups with significant differences in mean progression-free survival (3.6 vs. 12.3 months), including disease control rate (41.2% vs. 91.7%), and objective response rate (17.6% vs. 41.6%). Integrating four-immune cell-subset based classifiers and three clinicopathologic risk factors can help to predict which patients might benefit from anti-PD-1 antibody inhibitors and remind potential non-responders to pursue effective treatment options in a timely way.

Conclusions

The prognostic immune risk score including the innate immune and adaptive immune cell populations could provide an accurate prediction efficacy in malignant melanoma patients with ICI therapy.
The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity
Authors: Bulygin Aleksey S. , Khantakova Julia N. , Shkaruba Nadezhda S. , Shiku Hiroshi , Sennikov Sergey S.
Published: December 2022

Regulatory CD4+ T (Treg) cells play a key role in the induction of immune tolerance and in the prevention of autoimmune diseases. Treg cells are defined by the expression of transcription factor FOXP3, which ensures proliferation and induction of the suppressor activity of this cell population. In a tumor microenvironment, after transplantation or during autoimmune diseases, Treg cells can respond to various signals from their environment and this property ensures their suppressor function. Recent studies showed that a metabolic signaling pathway of Treg cells are essential in the control of Treg cell proliferation processes. This review presents the latest research highlights on how the influence of extracellular factors (e.g. nutrients, vitamins and metabolites) as well as intracellular metabolic signaling pathways regulate tissue specificity of Treg cells and heterogeneity of this cell population. Understanding the metabolic regulation of Treg cells should provide new insights into immune homeostasis and disorders along with important therapeutic implications for autoimmune diseases, cancer and other immune-system–mediated disorders.
Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy
Authors: Dubuisson Nicolas , Davis-López de Carrizosa María A. , Versele Romain , Selvais Camille M. , Noel Laurence , Van den Bergh P. Y. D. , Brichard Sonia M. , Abou-Samra Michel
Published: December 2022

Background

Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3.

Methods

Four‐week‐old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx‐T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes.

Results

After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx‐T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes.

Conclusion

Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.
Interaction between glycolysis‒cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer
Authors: Chen Yan-Jie , Guo Xi , Liu Meng-Ling , Yu Yi-Yi , Cui Yue-Hong , Shen Xi-Zhong , Liu Tian-Shu , Liang Li
Published: December 2022

Background

Metabolic reprogramming is a feature of cancer. However, colon cancer subtypes based on the glycolysis‒cholesterol synthesis axis have not been identified, and little is known about connections between metabolic features and the tumor microenvironment.

Methods

Data for 430 colon cancer cases were extracted from The Cancer Genome Atlas, including transcriptome data, clinical information, and survival outcomes. Glycolysis and cholesterol synthesis-related gene sets were obtained from the Molecular Signatures Database for a gene set variation analysis. The relationship between the genomic landscape and immune landscape were investigated among four metabolic subtypes. Hub genes were determined. The clinical significance of candidate hub gene was evaluated in 264 clinical samples and potential functions were validated in vitro and in vivo.

Results

Colon cancer cases were clustered into four metabolic subtypes: quiescent, glycolytic, cholesterogenic, and mixed. The metabolic subtypes differed with respect to the immune score, stromal score, and estimate score using the ESTIMATE algorithm, cancer-immunity cycle, immunomodulator signatures, and signatures of immunotherapy responses. Patients in the cholesterogenic group had better survival outcomes than those for other subtypes, especially glycolytic. The glycolytic subtype was related to unfavorable clinical characteristics, including high mutation rates in TTN, APC, and TP53, high mutation burden, vascular invasion, right colon cancer, and low-frequency microsatellite instability. GGH, CACNG4, MME, SLC30A2, CKMT2, SYN3, and SLC22A31 were identified as differentially expressed both in glycolytic-cholesterogenic subgroups as well as between colon cancers and healthy samples, and were involved in glycolysis‒cholesterol synthesis. GGH was upregulated in colon cancer; its high expression was correlated with CD4+ T cell infiltration and longer overall survival and it was identified as a favorable independent prognostic factor. The overexpression of GGH in colon cancer-derived cell lines (SW48 and SW480) inhibited PKM, GLUT1, and LDHA expression and decreased the extracellular lactate content and intracellular ATP level. The opposite effects were obtained by GGH silencing. The phenotype associated with GGH was also validated in a xenograft nude mouse model.

Conclusions

Our results provide insight into the connection between metabolism and the tumor microenvironment in colon cancer and provides preliminary evidence for the role of GGH, providing a basis for subsequent studies.
Micro-Fourier transform infrared spectroscopy of degradation-resistant organic microfossils; Influence of preservation environment and phylogeny
Authors: Versteegh Gerard J. M. , Zonneveld Karin A. F.
Published: December 2022

To gain more insight into the effect of early diagenetic processes in different redox environments on the molecular characteristics of degradation resistant particulate organic matter, the molecular cyst wall characteristics of the closely related dinoflagellates Impagidinium aculeatum and I. patulum from oxic and anoxic sedimentary environments in the Madeira Abyssal Plain F-turbidite and in the surface sediments of the eastern Mediterranean Sea have been analysed with micro-FTIR spectroscopy. Both species have cysts that are representatives of particulate organic matter being extremely resistant against degradation in natural environments. Their walls primarily consist of a carbohydrate-based polymer. Spectral differences could not be observed between cysts from oxic and anoxic environments, neither from different areas nor from different geological times. However, we identify consistent compositional differences between both species. Compared to I. patulum, cyst walls of I. aculeatum contain more C-O probably of secondary alcohols that might imply a slightly higher resistance to decay of I. patulum. Comparison with cyst species that represent particular organic matter being extremely sensitive and slightly resistant against aerobic degradation in natural settings reveals that cysts walls of the most vulnerable species show C=N, N-H, N-O, C-N bending/stretching, as well as the presence of C=O and C-O bounds. Cyst species that are somewhat less sensitive have a strong indication of the presence of nitrogen in their macromolecules. More resistant species lack nitrogen whereas the most resistant cyst species I. aculeatum and I. patulum show low amounts of C=O.
Effect of dietary cholesterol on ovarian development of Chinese mitten crabs (Eriocheir sinensis)
Authors: Guo Huixing , Wang Mangmang , Wang Xi , Xiao Kang , Huang Yangyang , Hua Haokun , Xiong Wei , Liu Wenbin , Abasubong Kenneth Prudence , Qiang Wei , Chi Cheng , Jiang Guangzhen
Published: December 2022

This study was conducted to evaluate the effect of cholesterol (CHO) on ovarian development of Eriocheir sinensis through a feeding trial. Crabs (average weight 43.35 ± 0.05 g) were randomly fed with one of three diets: 0% CHO, 0.4% CHO and 1.6% CHO for 16 weeks. Results indicated that the hepatosomatic index (HSI) and gonad index (GSI) of crabs fed with 0.4% CHO diet were significantly higher than those in the control group. (P < 0.05). Meanwhile, 0.4% CHO can significantly increase the gene expression of vtg and vgr in ovary (P < 0.05), thus promoting the accumulation of Vtg. The protein expression of MEK1/2, ERK, p-ERK1/2, Cyclin B and CDC2 were significantly increased in the 0.4% CHO group, therefore dietary CHO might promote oocyte maturation by activating MAPK signal pathway and cooperating with maturation promoting factor (MPF). Further exploration results showed that 0.4% CHO was able to significantly up-regulate the protein expression of STAR and SR-B1 to promote the transport of CHO to ovary, thereby providing sufficient substrates for estradiol (E2) synthesis. In addition, the results in vivo and in vitro shown that CHO could regulate the activities of enzymes such as CYP11A1 and CYP19A1 through the cAMP-PKA-CREB/SF-1 signal pathway and then affects the level of E2 in the organism. In summary, supplementing the appropriate amount of CHO in the diet can improve the E2 level of the organism, thus increasing the accumulation of nutrients in the ovary, promoting the completion of meiosis, and finally achieving the purpose of promoting ovarian maturation.
Finite element and analytical modelling of PVC-confined concrete columns under axial compression
Authors: Isleem Haytham F. , P Jagadesh , Ahmad Jawad , Qaidi Shaker , Althoey Fadi , Najm Hadee Mohammed , Sabri Mohanad Muayad Sabri
Published: December 2022

Confined concrete in pipes provides a solution for the structures to resist lateral forces and avoids the problems associated with production of confined concrete and lateral reinforcement. To evaluate the influence of PVC pipe on the compressive behavior of concrete filled composite tubes, ABAQUS software was used to simulate 44 concrete filled PVC pipes (CFPT). The influence of internal steel reinforcement, unconfined concrete strength, slenderness ratio, specimen’s size and thickness of PVC tube on failure mode load carrying capacity, and strain of PVC confined reinforced concrete column was studied. The present discussion show that the existing analytical models failed to capture the effect of these parameters. On the other hand, the proposed finite element (FE) models achieve a very good agreement between the experimental and analytical values. The proposed FE model can provide an acceptable portrayal of the CFPT’s response. The response of confined concrete was estimated using trial and error approach and as a result a model for the strain of confined concrete was proposed. The effect of these parameters on the CFPT leads to development of analytical models.
Succinyl-CoA:acetate CoA-transferase functioning in the oxidative tricarboxylic acid cycle in Desulfurella acetivorans
Authors: Pettinato Eugenio , Böhnert Pauline , Berg Ivan A.
Published: December 2022

Desulfurella acetivorans is a strictly anaerobic sulfur-reducing deltaproteobacterium that possesses a very dynamic metabolism with the ability to revert the citrate synthase version of the tricarboxylic acid (TCA) cycle for autotrophic growth (reversed oxidative TCA cycle) or to use it for acetate oxidation (oxidative TCA cycle). Here we show that for heterotrophic growth on acetate D. acetivorans uses a modified oxidative TCA cycle that was first discovered in acetate-oxidizing sulfate reducers in which a succinyl-CoA:acetate CoA-transferase catalyzes the conversion of succinyl-CoA to succinate, coupled with the activation of acetate to acetyl-CoA. We identified the corresponding enzyme in this bacterium as the AHF96498 gene product and characterized it biochemically. Our phylogenetic analysis of CoA-transferases revealed that the CoA-transferase variant of the oxidative TCA cycle has convergently evolved several times in different bacteria. Its functioning is especially important for anaerobes, as it helps to increase the energetic efficiency of the pathway by using one enzyme for two enzymatic reactions and by allowing to spend just one ATP equivalent for acetate activation.
Metabolic changes of the acetogen Clostridium sp. AWRP through adaptation to acetate challenge
Authors: Kwon Soo Jae , Lee Joungmin , Lee Hyun Sook
Published: December 2022

In this study, we report the phenotypic changes that occurred in the acetogenic bacterium Clostridium sp. AWRP as a result of an adaptive laboratory evolution (ALE) under the acetate challenge. Acetate-adapted strain 46 T-a displayed acetate tolerance to acetate up to 10 g L−1 and increased ethanol production in small-scale cultures. The adapted strain showed a higher cell density than AWRP even without exogenous acetate supplementation. 46 T-a was shown to have reduced gas consumption rate and metabolite production. It was intriguing to note that 46 T-a, unlike AWRP, continued to consume H2 at low CO2 levels. Genome sequencing revealed that the adapted strain harbored three point mutations in the genes encoding an electron-bifurcating hydrogenase (Hyt) crucial for autotrophic growth in CO2 + H2, in addition to one in the dnaK gene. Transcriptome analysis revealed that most genes involved in the CO2-fixation Wood-Ljungdahl pathway and auxiliary pathways for energy conservation (e.g., Rnf complex, Nfn, etc.) were significantly down-regulated in 46 T-a. Several metabolic pathways involved in dissimilation of nucleosides and carbohydrates were significantly up-regulated in 46 T-a, indicating that 46 T-a evolved to utilize organic substrates rather than CO2 + H2. Further investigation into degeneration in carbon fixation of the acetate-adapted strain will provide practical implications for CO2 + H2 fermentation using acetogenic bacteria for long-term continuous fermentation.
A comprehensive analysis focusing on cuproptosis to investigate its clinical and biological relevance in uterine corpus endometrial carcinoma and its potential in indicating prognosis
Authors: Wu Qihui , Tian Ruotong , Tan Hong , Liu Jiaxin , Ou Chunlin , Li Yimin , Fu Xiaodan
Published: December 2022

Cuproptosis, a novel copper-dependent cell death involving mitochondrial respiration, is distinct from other known death mechanisms, which inspires us to study further in uterine corpus endometrial carcinoma (UCEC). Herein, leveraging comprehensive data from TCGA-UCEC, we conducted transcriptional and genetic analyses of 13 recently identified cuproptosis genes. We discovered severe genetic instability of cuproptosis genes, extensive positive correlations among those genes with each other at the mRNA level, and their involvement in oncogenic pathways in UCEC samples. Next, WGCNA was performed to identify a potential module regulating cuproptosis, in which the hub genes, in addition to 13 cuproptosis genes, were drawn to construct a scoring system termed Cu. Score. Furthermore, its clinical and biological relevance and tumor immune landscape, genetic alterations, as well as predicted sensitivity of chemotherapy drugs in different Cu. Score subgroups had been discussed extensively and in detail. Additionally, univariate Cox and LASSO regression were performed to identify 13 cuproptosis-related prognostic genes to establish a prognostic signature, the Risk. Score. Integrating the Risk. Score and clinical parameters, we established a nomogram with excellent performance to predict the 1-/3-/5-year survival probabilities of UCEC patients. To conclude, we conducted a comprehensive analysis encompassing cuproptosis and developed a cuproptosis scoring system and a prognostic prediction model for UCEC, which may offer help with individualized assessment and treatment for UCEC patients from the perspective of a novel death mechanism.
Gene expression profile analysis to discover molecular signatures for early diagnosis and therapies of triple-negative breast cancer
Authors: Alam Md Shahin , Sultana Adiba , Wang Guanghui , Haque Mollah Md Nurul
Published: December 2022

Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer (BC), and it accounts for approximately 10%–20% of all invasive BCs diagnosed worldwide. The survival rate of TNBC in stages III and IV is very low, and a large number of patients are diagnosed in these stages. Therefore, the purpose of this study was to identify TNBC-causing molecular signatures and anti-TNBC drug agents for early diagnosis and therapies. Five microarray datasets that contained 304 TNBC and 109 control samples were collected from the Gene Expression Omnibus (GEO) database, and RNA-Seq data with 116 tumor and 124 normal samples were collected from TCGA database to identify differentially expressed genes (DEGs) between TNBC and control samples. A total of 64 DEGs were identified, of which 29 were upregulated and 35 were downregulated, by using the statistical limma R-package. Among them, seven key genes (KGs) were commonly selected from microarray and RNA-Seq data based on the high degree of connectivity through PPI (protein–protein interaction) and module analysis. Out of these seven KGs, six KGs (TOP2A, BIRC5, AURKB, ACTB, ASPM, and BUB1B) were upregulated and one (EGFR) was downregulated. We also investigated their differential expression patterns with different subtypes and progression stages of BC by the independent datasets of RNA-seq profiles from UALCAN database, which indicated that they may be potential biomarkers for early diagnosis. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses with the proposed DEGs were performed using the online Enrichr database to investigate the pathogenetic processes of TNBC highlighting KGs. Then, we performed gene regulatory network analysis and identified three transcriptional (SOX2, E2F4, and KDM5B) and three post-transcriptional (hsa-mir-1-3p, hsa-mir-124-3p, and hsa-mir-34a-5p) regulators of KGs. Finally, we proposed five KG-guided repurposable drug molecules (imatinib, regorafenib, pazopanib, teniposide, and dexrazoxane) for TNBC through network pharmacology and molecular docking analyses. These drug molecules also showed significant binding performance with some cancer-related PTM-sites (phosphorylation, succinylation, and ubiquitination) of top-ranked four key proteins (EGFR, AURKB, BIRC5, and TOP2A). Therefore, the findings of this computational study may play a vital role in early diagnosis and therapies against TNBC by wet-lab validation.
Ab-initio evaluation of acid influence on chemical stability of hydrophilic diglycolamides
Authors: Luštinec Jakub , Koubský Tomáš , Kalvoda Ladislav
Published: December 2022

Diglycolamides (DGA) form one of the most promising groups of organic ligands used in bio-inspired solvent extraction processes of lanthanide and actinide ions. Continuous experimental and theoretical research is still performed in order to further improve their application properties including their chemical stability in the real extraction environment. This work provides results of our theoretical approach focused on inclusion of an acid influence on the DGAs chemical structure, treated in frame of the density functional theory. Three different models describing the acid action are proposed and investigated in attempt to increase the resulting accuracy of the chemical stability predictions based on verified theoretical descriptors. The procedure is applied and tested on the set of selected hydrophilic DGA representatives. Comparison of the model results obtained with and without acid action shows that two types of protection effects may occur: a ‘direct’ protection, accompanied by an explicit change of the ligand stability indicators, and an ‘indirect’ one consisting in reaction of acid molecules with radicals preceding the contact of latter with the extracting ligands. The possibility of the direct acid protection route is supported by the significant decrease of the Fukui charges found with the acid models included. On the other hand, there is in general no significant difference of trends in the calculated chemical stability descriptors suggesting that an indirect mechanism must be also considered in order to explain the experimentally observed protective role of acids on the chemical stability of investigated DGA derivatives.
The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease
Authors: Clark Christopher , Rabl Miriam , Dayon Loïc , Popp Julius
Published: December 2022

Beyond the core features of Alzheimer’s disease (AD) pathology, i.e. amyloid pathology, tau-related neurodegeneration and microglia response, multiple other molecular alterations and pathway dysregulations have been observed in AD. Their inter-individual variations, complex interactions and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical levels complicates diagnosis, prognosis, treatment and drug design and testing. High-throughput “omics” comprise unbiased and untargeted data-driven methods which allow the exploration of a wide spectrum of disease-related changes at different endophenotype levels without focussing a priori on specific molecular pathways or molecules. Crucially, new methodological and statistical advances now allow for the integrative analysis of data resulting from multiple and different omics methods. These multi-omics approaches offer the unique advantage of providing a more comprehensive characterisation of the AD endophenotype and to capture molecular signatures and interactions spanning various biological levels. These new insights can then help decipher disease mechanisms more deeply. In this review, we describe the different multi-omics tools and approaches currently available and how they have been applied in AD research so far. We discuss how multi-omics can be used to explore molecular alterations related to core features of the AD pathologies and how they interact with comorbid pathological alterations. We further discuss whether the identified pathophysiological changes are relevant for the clinical manifestation of AD, in terms of both cognitive impairment and neuropsychiatric symptoms, and for clinical disease progression over time. Finally, we address the opportunities for multi-omics approaches to help discover novel biomarkers for diagnosis and monitoring of relevant pathophysiological processes, along with personalised intervention strategies in AD.
Risk for intracranial hemorrhage in individuals after mild traumatic brain injury who are taking serotonergic antidepressants
Authors: Isokuortti Harri , Iverson Grant L. , Posti Jussi P. , Berghem Ksenia , Kotilainen Anna-Kerttu , Luoto Teemu M.
Published: December 2022

Background

Serotonergic antidepressants may predispose to bleeding, but little is known of the risk for traumatic intracranial bleeding.

Methods

This was a prospective case-control study of 218 patients with mild traumatic brain injuries (TBI) who were treated at a Finnish tertiary trauma hospital. Injury-related information and clinical findings were prospectively collected in the emergency department. Detailed pre-injury health history was collected from electronic medical records. Information on the use of serotonergic antidepressants was attained from the Finnish national prescription registry. All head CT scans were reviewed by a neuroradiologist based on the Common Data Elements. Cases were patients with traumatic intracranial hemorrhage on head CT. Controls were patients from the same cohort, but without traumatic intracranial lesions on CT. The proportion with traumatic intracranial bleeding for patients on serotonergic antidepressant medication was compared to the proportion for patients not on serotonergic medication.

Results

The study cohort consisted of 24 cases with traumatic intracranial bleeding and 194 injured controls. The median age of the sample was 70 years (interquartile range = 50–83). One fifth (21.6%) of all the patients were taking a serotonergic antidepressant. Of the patients on an antidepressant, 10.6% (5/47) had an acute hemorrhagic lesion compared to 11.1% (19/171) of those who were not on an antidepressant (p = 0.927). In the regression analysis, traumatic intracranial hemorrhage was not associated with antidepressant use.

Conclusion

Serotonergic antidepressant use was not associated with an increased risk of traumatic intracranial hemorrhage after a mild TBI. The patients in this relatively small cohort were mostly middle-aged and older adults. These factors limit the generalizability of the results in younger patients with mild TBI.
Adhesion molecules and cerebral microvascular hemodynamic abnormalities in sickle cell disease
Authors: Abi Rached Noor Mary , Gbotosho Oluwabukola T. , Archer David R. , Jones Jayre A. , Sterling Morgan S. , Hyacinth Hyacinth I.
Published: December 2022

Cerebrovascular abnormalities are a common feature of sickle cell disease that may be associated with risk of vaso-occlusive pain crises, microinfarcts, and cognitive impairment. An activated endothelium and adhesion factors, VCAM-1 and P-selectin, are implicated in sickle cell vasculopathy, including abnormal hemodynamics and leukocyte adherence. This study examined the association between cerebral expression of these adhesion factors and cortical microvascular blood flow dynamics by usingin-vivotwo-photon microscopy. We also examined the impact of blood transfusion treatment on these markers of vasculopathy. Results showed that sickle cell mice had significantly higher maximum red blood cell (RBC) velocity (6.80 ± 0.25 mm/sec,p≤ 0.01 vs. 5.35 ± 0.35 mm/sec) and more frequent blood flow reversals (18.04 ± 0.95 /min,p≤ 0.01 vs. 13.59 ± 1.40 /min) in the cortical microvasculature compared to controls. In addition, sickle cell mice had a 2.6-fold (RFU/mm2) increase in expression of VCAM-1 and 17-fold (RFU/mm2) increase in expression of P-selectin compared to controls. This was accompanied by an increased frequency in leukocyte adherence (4.83 ± 0.57 /100 μm/min vs. 2.26 ± 0.37 /100 μm/min,p≤ 0.001). We also found that microinfarcts identified in sickle cell mice were 50% larger than in controls. After blood transfusion, many of these parameters improved, as results demonstrated that sickle cell mice had a lower post-transfusion maximum RBC velocity (8.30 ± 0.98 mm/sec vs. 11.29 ± 0.95 mm/sec), lower frequency of blood flow reversals (12.80 ± 2.76 /min vs. 27.75 ± 2.09 /min), and fewer instances of leukocyte adherence compared to their pre-transfusion imaging time point (1.35 ± 0.32 /100 μm/min vs. 3.46 ± 0.58 /100 μm/min). Additionally, we found that blood transfusion was associated with lower expression of adhesion factors. Our results suggest that blood transfusion and adhesion factors, VCAM-1 and P-selectin, are potential therapeutic targets for addressing cerebrovascular pathology, such as vaso-occlusion, in sickle cell disease.
Effect of prebiotics, probiotics, and synbiotics on gastrointestinal outcomes in healthy adults and active adults at rest and in response to exercise—A systematic literature review
Authors: Rauch Christopher E. , Mika Alice S. , McCubbin Alan J. , Huschtscha Zoya , Costa Ricardo J. S.
Published: December 2022

Introduction

A systematic literature search was undertaken to assess the impact of pre-, pro-, and syn-biotic supplementation on measures of gastrointestinal status at rest and in response to acute exercise.

Methods

Six databases (Ovid MEDLINE, EMBASE, Cinahl, SportsDISCUS, Web of Science, and Scopus) were used. Included were human research studies in healthy sedentary adults, and healthy active adults, involving supplementation and control or placebo groups. Sedentary individuals with non-communicable disease risk or established gastrointestinal inflammatory or functional diseases/disorders were excluded.

Results

A total of n = 1,204 participants were included from n = 37 papers reported resting outcomes, and n = 13 reported exercise-induced gastrointestinal syndrome (EIGS) outcomes. No supplement improved gastrointestinal permeability or gastrointestinal symptoms (GIS), and systemic endotoxemia at rest. Only modest positive changes in inflammatory cytokine profiles were observed in n = 3/15 studies at rest. Prebiotic studies (n = 4/5) reported significantly increased resting fecal Bifidobacteria, but no consistent differences in other microbes. Probiotic studies (n = 4/9) increased the supplemented bacterial species-strain. Only arabinoxylan oligosaccharide supplementation increased total fecal short chain fatty acid (SCFA) and butyrate concentrations. In response to exercise, probiotics did not substantially influence epithelial injury and permeability, systemic endotoxin profile, or GIS. Two studies reported reduced systemic inflammatory cytokine responses to exercise. Probiotic supplementation did not substantially influence GIS during exercise.

Discussion

Synbiotic outcomes resembled probiotics, likely due to the minimal dose of prebiotic included. Methodological issues and high risk of bias were identified in several studies, using the Cochrane Risk of Bias Assessment Tool. A major limitation in the majority of included studies was the lack of a comprehensive approach of well-validated biomarkers specific to gastrointestinal outcomes and many included studies featured small sample sizes. Prebiotic supplementation can influence gut microbial composition and SCFA concentration; whereas probiotics increase the supplemented species-strain, with minimal effect on SCFA, and no effect on any other gastrointestinal status marker at rest. Probiotic and synbiotic supplementation does not substantially reduce epithelial injury and permeability, systemic endotoxin and inflammatory cytokine profiles, or GIS in response to acute exercise.
Serum vitamin D status and circulating irisin levels in older adults with sarcopenia
Authors: Wang Yawen , Gu Yeqing , Huang Jian , Wu Hongmei , Meng Ge , Zhang Qing , Liu Li , Zhang Shunming , Wang Xuena , Zhang Juanjuan , Sun Shaomei , Wang Xing , Zhou Ming , Jia Qiyu , Song Kun , Huo Junsheng , Zhang Bing , Ding Gangqiang , Du Peng , Niu Kaijun
Published: December 2022

Background

Emerging evidence suggests sarcopenia, which is involved in the serum vitamin D deficiency and development of abnormal muscle metabolism, is predominately centered in the general older population. In the present study, we aimed to explore the relationship between the level of serum vitamin D and irisin concentrations in the older adults with sarcopenia.

Methods

A cross-sectional study was conducted which included 422 sarcopenia participants (146 males and 276 females). Sarcopenia was assessed according to the recommended diagnostic criteria of the Asia Working Group for Sarcopenia (AWGS). The levels of serum 25-hydroxyvitamin D (25(OH)D), 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) were determined by LC-MS/MS. Irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). The relationship between serum concentration of vitamin D and irisin were determined using multiple linear regression analysis.

Results

After adjustment for potential confounding factors, a significant and positive relationship between changes in irisin across 25(OH)D, and 25(OH)D3 was observed (standard regression coefficients of 0.150 and 0.151, respectively, P < 0.05). However, no significant relationship was observed between serum vitamin D concentrations and irisin levels in males.

Conclusions

This study demonstrated that a higher level of serum vitamin D is independently related to the increment of irisin in sarcopenia females, not in males. These investigations need to be verified in other large-scale prospective studies.