bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic features, antimicrobial susceptibility, and epidemiological insights into Burkholderia cenocepacia clonal complex 31 isolates from bloodstream infections in India
Authors: Saroha Tanu , Patil Prashant P. , Rana Rekha , Kumar Rajesh , Kumar Sanjeet , Singhal Lipika , Gautam Vikas , Patil Prabhu B.
Published: April 2023

Introduction

Burkholderia cepacia complex (Bcc) clonal complex (CC) 31, the predominant lineage causing devastating outbreaks globally, has been a growing concern of infections in non-cystic fibrosis (NCF) patients in India. B. cenocepacia is very challenging to treat owing to its virulence determinants and antibiotic resistance. Improving the management of these infections requires a better knowledge of their resistance patterns and mechanisms.

Methods

Whole-genome sequences of 35 CC31 isolates obtained from patient samples, were analyzed against available 210 CC31 genomes in the NCBI database to glean details of resistance, virulence, mobile elements, and phylogenetic markers to study genomic diversity and evolution of CC31 lineage in India.

Results

Genomic analysis revealed that 35 isolates belonging to CC31 were categorized into 11 sequence types (ST), of which five STs were reported exclusively from India. Phylogenetic analysis classified 245 CC31 isolates into eight distinct clades (I-VIII) and unveiled that NCF isolates are evolving independently from the global cystic fibrosis (CF) isolates forming a distinct clade. The detection rate of seven classes of antibiotic-related genes in 35 isolates was 35 (100%) for tetracyclines, aminoglycosides, and fluoroquinolones; 26 (74.2%) for sulphonamides and phenicols; 7 (20%) for beta-lactamases; and 1 (2.8%) for trimethoprim resistance genes. Additionally, 3 (8.5%) NCF isolates were resistant to disinfecting agents and antiseptics. Antimicrobial susceptibility testing revealed that majority of NCF isolates were resistant to chloramphenicol (77%) and levofloxacin (34%). NCF isolates have a comparable number of virulence genes to CF isolates. A well-studied pathogenicity island of B. cenocepacia, GI11 is present in ST628 and ST709 isolates from the Indian Bcc population. In contrast, genomic island GI15 (highly similar to the island found in B. pseudomallei strain EY1) is exclusively reported in ST839 and ST824 isolates from two different locations in India. Horizontal acquisition of lytic phage ST79 of pathogenic B. pseudomallei is demonstrated in ST628 isolates Bcc1463, Bcc29163, and BccR4654 amongst CC31 lineage.

Discussion

The study reveals a high diversity of CC31 lineages among B. cenocepacia isolates from India. The extensive information from this study will facilitate the development of rapid diagnostic and novel therapeutic approaches to manage B. cenocepacia infections.
Evaluating the effect of SARS-CoV-2 spike mutations with a linear doubly robust learner
Authors: Wang Xin , Hu Mingda , Liu Bo , Xu Huifang , Jin Yuan , Wang Boqian , Zhao Yunxiang , Wu Jun , Yue Junjie , Ren Hongguang
Published: April 2023

Driven by various mutations on the viral Spike protein, diverse variants of SARS-CoV-2 have emerged and prevailed repeatedly, significantly prolonging the pandemic. This phenomenon necessitates the identification of key Spike mutations for fitness enhancement. To address the need, this manuscript formulates a well-defined framework of causal inference methods for evaluating and identifying key Spike mutations to the viral fitness of SARS-CoV-2. In the context of large-scale genomes of SARS-CoV-2, it estimates the statistical contribution of mutations to viral fitness across lineages and therefore identifies important mutations. Further, identified key mutations are validated by computational methods to possess functional effects, including Spike stability, receptor-binding affinity, and potential for immune escape. Based on the effect score of each mutation, individual key fitness-enhancing mutations such as D614G and T478K are identified and studied. From individual mutations to protein domains, this paper recognizes key protein regions on the Spike protein, including the receptor-binding domain and the N-terminal domain. This research even makes further efforts to investigate viral fitness via mutational effect scores, allowing us to compute the fitness score of different SARS-CoV-2 strains and predict their transmission capacity based solely on their viral sequence. This prediction of viral fitness has been validated using BA.2.12.1, which is not used for regression training but well fits the prediction. To the best of our knowledge, this is the first research to apply causal inference models to mutational analysis on large-scale genomes of SARS-CoV-2. Our findings produce innovative and systematic insights into SARS-CoV-2 and promotes functional studies of its key mutations, serving as reliable guidance about mutations of interest.
Successful rescue of fulminant myocarditis with mechanical circulatory support and immunosuppression therapy: A case report
Authors: Zhou Chi
Published: April 2023

Myocarditis is challenging to diagnose because of its various clinical manifestations. Fulminant myocarditis (FM) is a severe type of myocarditis characterized by heart failure, malignant arrhythmia, cardiogenic shock, and cardiac arrest. Its early diagnosis and timely treatment are crucial for a positive long-term prognosis. Here we report a case of 42-year-old woman who presented with fever, chest pain, and cardiogenic shock. An initial examination showed increased myocardial enzyme levels and diffuse ST-segment elevation. Urgent coronary angiography excluded coronary artery stenosis. Echocardiography revealed decreased left ventricular systolic function. Cardiac magnetic resonance imaging revealed cardiomyocyte necrosis and interstitial inflammatory edema. The patient was diagnosed with FM and administered antiviral and anti-infective agents, glucocorticoid, immunoglobulin, and supported with temporary cardiac pacemaker and positive airway therapy, and treated with continuous renal replacement therapy. As her clinical condition deteriorated rapidly, we immediately started an intra-aortic balloon pump and veno-arterial extracorporeal membrane oxygenation. She was discharged on day 15 and recovered normally during follow-up. The early initiation of mechanical circulatory support and immunosuppression are life-saving tools for the treatment of FM.
Diazoxide is a powerful cardioprotectant but is not feasible in a realistic infarct scenario
Authors: Kleinbongard Petra , Lieder Helmut , Skyschally Andreas , Heusch Gerd
Published: April 2023

Introduction

Diazoxide is a powerful cardioprotective agent that activates mitochondrial ATP-dependent K-channels and stimulates mitochondrial respiration. Diazoxide reduced infarct size in isolated rodent heart preparations and upon pretreatment in juvenile pigs with coronary occlusion/reperfusion. We aimed to study the use of diazoxide in a more realistic adult pig model of reperfused acute myocardial infarction when diazoxide was administered just before reperfusion.

Methods and results

In a first approach, we pretreated anaesthetised adult Göttingen minipigs with 7 mg kg−1 diazoxide (n = 5) or placebo (n = 5) intravenously over 10 min and subjected them to 60 min coronary occlusion and 180 min reperfusion; blood pressure was maintained by use of an aortic snare. The primary endpoint was infarct size (triphenyl tetrazolium chloride staining) as a fraction of area at risk; no-reflow area (thioflavin-S staining) was the secondary endpoint. In a second approach, diazoxide (n = 5) was given from 50 to 60 min coronary occlusion, and blood pressure was not maintained. There was a significant reduction in infarct size (22% ± 11% of area at risk with diazoxide pretreatment vs. 47% ± 11% with placebo) and area of no-reflow (14% ± 14% of infarct size with diazoxide pretreatment vs. 46% ± 20% with placebo). With diazoxide from 50 to 60 min coronary occlusion, however, there was marked hypotension, and infarct size (44% ± 7%) and area of no-reflow were not reduced (35% ± 25%).

Conclusions

Cardioprotection by diazoxide pretreatment was confirmed in adult pigs with reperfused acute myocardial infarction but is not feasible when diazoxide is administered in a more realistic scenario before reperfusion and causes hypotension.
Study of deformation law and support design feasibility of right-angled trapezoidal roadways
Authors: Chen Feng , Wang Xuebin , Bai Xueyuan
Published: April 2023

Given the problems of serious asymmetric deformation and the difficulty in supporting right-angled trapezoidal roadways during the mining process, we established a mechanical model of surrounding rock for a right-angled trapezoidal roadway, determined the relationship between the deflection and tilt angle of the roadway roof, and determined that the typical failure mode of right-angled trapezoidal roadways is the upper slip of the high side. Two optimized support schemes are proposed, in which a constant resistance large deformation (CRLD) bolt + ordinary I-steel or a portal energy absorbing hydraulic (PEAH) support + ordinary bolt is used as the main support instead of an ordinary bolt + ordinary I-steel. Numerical simulation analysis shows that the aforementioned optimized support schemes can reduce the deformation, acoustic emission (AE) quantity, and AE energy of rock surrounding roadways and change how surrounding rock releases energy from main earthquake type to swarm earthquake type. The support scheme with CRLD bolt + ordinary I-steel or PEAH support + ordinary bolt as the main support can reduce the deformation of a roadway’s high side to 0.192 and 0.145 m, respectively. This shows that the two optimized schemes can effectively improve the overall bearing capacity and integrity of the rock surrounding roadways, which can be applied in the field.
Overexpression of IGF2 affects mouse weight and glycolipid metabolism and IGF2 is positively related to macrosomia
Authors: Zhang Qidi , Qin Shengtang , Huai Jing , Yang Huixia , Wei Yumei
Published: April 2023

Objective

To investigate the effects of insulin-like growth factor 2 (IGF2) on growth and glycolipid metabolism, as well as the underlying mechanism.

Methods

A mouse model of IGF2 overexpression was constructed to measure weight gain before adulthood, to obtain the values of adult glycolipid metabolism indicators in the peripheral blood and to detect the expression of genes in the IGF2 signaling pathway in different mouse tissues. The present study also explored the independent association between the IGF2 gene and macrosomia by detecting and comparing the expression levels of IGF2 mRNA/H19 RNA in maternal peripheral blood and fetal cord blood of 26 human pregnancies.

Results

In the mouse model, weights of the IGF2-overexpressing mice were significantly higher than those of the control mice at the age of 5-10 weeks. The glucose concentration, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels of IGF2-overexpressing mice were significantly lower than those of wild-type (WT) mice. Compared with the WT mice, the expression of H19 was significantly decreased in the pancreas and IGF1R was significantly decreased in the muscle of mice with IGF2 overexpression. The expression levels of STAT3 and AKT2 showed significant decrease in liver, muscle and increase in muscle of IGF2-overexpressing mice, respectively. GLUT2 expression showed significant increase in liver, kidney, muscle and decrease in pancreas of mice with IGF2 overexpression. This study also found that in normal mothers with the similar clinical characteristics, IGF2 expression in the maternal peripheral blood and fetal cord blood is an independent factor influencing macrosomia.

Conclusion

IGF2 expression was independently correlated with the occurrence of macrosomia, and overexpression of IGF2 significantly increased the weights of mice at the age of 5-10 weeks and significantly affected the values of adult glycolipid metabolism indicators, which might be the result of changes in the IGF2-IGF1R-STAT3/AKT2-GLUT2/GLUT4 pathway. These findings might suggest that IGF2 plays an important role in growth and glycolipid metabolism during both pregnancy and postnatal development.
Androgen receptor signaling regulates follicular growth and steroidogenesis in interaction with gonadotropins in the ovary during mini-puberty in mice
Authors: Devillers Marie M. , François Charlotte M. , Chester Mélanie , Corre Raphaël , Cluzet Victoria , Giton Frank , Cohen-Tannoudji Joëlle , Guigon Céline J.
Published: April 2023

In females, androgens contribute to ovarian diseases such as polycystic ovarian syndrome (PCOS), but their action is also crucial for ovarian physiology, i.e., follicular growth and estradiol (E2) synthesis during reproductive life, in interaction with the gonadotropins LH and FSH. However, it is unclear whether androgens already play a role in the ovary at mini-puberty, a phase of postnatal development with active follicular growth and high E2 levels. Therefore, we analyzed the potential actions of androgens on the ovary and their possible interaction with gonadotropins during this period in mice. We used molecular-based studies and pharmacological approaches in vivo and on cultured ovaries. We found that mini-pubertal ovaries produce significant amounts of testosterone and display androgen receptor (AR) expression in growing follicles, both under the control of LH. By blocking AR signaling either in vivo or in ovarian cultures, we found that this pathway may participate in the regulation of prepubertal E2 synthesis and follicular growth, possibly by regulating the expression of a number of key intra-ovarian regulators, including FSH receptor (Fshr), the aromatase enzyme converting androgens into estrogens (Cyp19a1) and the cell cycle inhibitor p27KIP1 (Cdkn1b). We further showed that AR may stimulate FSH-mediated regulation of Cyp19a1 through its action on Fshr mRNA abundance. Overall, this work supports the idea that AR signaling is already activated in mini-pubertal ovaries to regulate E2 synthesis and follicular growth, at the interplay with LH and FSH signaling. Its early action may, thus, contribute to the implementation of early ovarian function with possible impacts on reproductive function.
Influence of duration of preoperative treatment with phenoxybenzamine and secretory phenotypes on perioperative hemodynamics and postoperative outcomes in pheochromocytoma and paraganglioma
Authors: Yao Yao , Guo Ying , Fan Jing , Lin Tianxin , Wang Lin , Zhang Shaoling
Published: April 2023

Objectives

Resection of pheochromocytoma and paraganglioma (PPGL) carries risks with perioperative hemodynamic instability. Phenoxybenzamine (PXB) is a commonly used α-blockade to prevent it. It is unclear whether lengthening the preoperative duration of PXB is better for hemodynamic stability and postoperative outcomes. Furthermore, different types of catecholamines have varying effects on perioperative hemodynamics. Thus, our study aimed to investigate the impact of the duration of preoperative preparation with PXB and secretory phenotypes of the patients on intraoperative hemodynamic stability and postoperative complications in PPGL.

Methods

Between Dec 2014 and Jan 2022, 166 patients with PPGL were operated on by the same team at Sun Yat-sen Memorial Hospital. They were divided into group A(1-14d), Group B(15-21d), and Group C(>21d) based on the duration of management with PXB and into the adrenergic and the noradrenergic phenotype group based on secretory profiles. Data on intraoperative hemodynamics and postoperative outcomes were collected and compared among groups.

Results

A total of 96 patients occurred intraoperative hemodynamic instability, and 24 patients had 29 postoperative complications related to the surgery. Among the 145 patients treated with PXB, no significant differences were found in the cumulative time outside the target blood pressure(6.67%[0-17.16%] vs. 5.97%[0-23.08%] vs. 1.22%[0-17.27%], p=0.736) or in the median total HI-score(42.00[30.00-91.00] vs. 89.00[30.00-113.00] vs. 49.00[30.00-93.00], p=0.150) among group A(n=45), B(n=51) and C(n=49). Multivariate analysis demonstrated that the level of plasma-free metanephrine(MN) was an independent risk factor for intraoperative hemodynamic instability. And the median cumulative time outside of the target blood pressure in the adrenergic phenotype group was significantly greater than that in the noradrenergic phenotype group(8.17%[0-26.22%] vs. 1.86%[0-11.74%], p=0.029). However, the median total HI-score(99.50[85.00-113.25] vs. 90.00[78.00-105.00], p=0.570) and postoperative outcomes showed no differences between the two groups.

Conclusions

A preoperative duration of nearly 14 days with PXB is sufficient for ensuring intraoperative hemodynamic stability in PPGL. And lengthening the preparation duration may not provide additional benefits in the era of widespread application and advanced techniques of laparoscopic surgery. Additionally, patients with the adrenergic phenotype are more prone to intraoperative hemodynamic instability than the noradrenergic phenotype. Thus, more attention should be given to the adrenergic phenotype during surgery.
Effect of BMI on the value of serum progesterone to predict clinical pregnancy outcome in IVF/ICSI cycles: a retrospective cohort study
Authors: Shen Zhaoyang , Luo Xiaoyan , Xu Jianming , Jiang Yuqing , Chen Wenhui , Yang Qingling , Sun Yingpu
Published: April 2023

Background

Numerous research have investigated the predictor role of progesterone (P) level on the human Chorionic Gonadotropin (hCG) trigger day of assisted reproductive technology (ART) outcomes. However, the relationship of progesterone levels on hCG day to clinical pregnancy outcomes in IVF/ICSI cycles for patients with different BMI groups is still elusive. This study aimed to investigate the effects of progesterone elevation on triggering day on clinical pregnancy rate (CPR) of IVF/ICSI cycles in patients with different female BMI.

Methods

We conducted a retrospective cohort study included 6982 normal-weight parents (18.5Kg/m2≤BMI<25Kg/m2) and 2628 overweight/obese patients (BMI≥25Kg/m2) who underwent fresh day 3 cleavage embryo transfer (ET) in IVF/ICSI cycles utilizing GnRH agonist to control ovarian stimulation.

Results

The interaction between BMI and P level on triggering day on CPRs was significant (p<0.001). The average level of serum P was reduced with the increase in maternal BMI. Serum P adversely affected CPR in distinct BMI groups. In the normal weight group, CPRs were decreasedas serum P concentrations gradually increased (p<0.001 for overall trend). The CPRs (lower than 65.8%) of progesterone level > 1.00 ng/ml on triggering day were significantly lower than that (72.4%) of progesterone level <0.5 ng/ml. In the overweight/obese group, CPRs showed a decrease statistically with progesterone levels of ≥2.00 ng/ml compared to progesterone levels of <0.5 ng/ml (51.0% VS. 64.9%, p=0.016). After adjusting for confounders, progesterone elevation (PE) negatively correlated with CPRs only in the normal weight group (OR: 0.755 [0.677–0.841], p<0.001), not in the overweight/obese group (p=0.063).

Conclusion

Women with higher BMI exhibited a lower progesterone level on triggering day. Additionally, PE on hCG day is related to decreased CPRs in GnRH agonist IVF/ICSI cycles with cleavage embryo transfers regardless of women’s BMI level (normal weight VS. overweight/obesity).
Influence of fiber hollowness on the local thermo-electro-elastic field in a thermoelectric composite
Authors: Yu Chuanbin , Liu Haoxin , Du Chaofan , Xing Shichao
Published: April 2023

The fiber geometry is one of the important parameters in the effective conversion performance and local strength of thermoelectric composites. In this study, the plane problem of a hollow fiber embedded within a non-linear thermoelectric medium in the presence of a uniform remote in-plane electric current and a uniform remote energy flux is investigated based on the complex variable method. Closed-form expressions for all the potential functions characterizing the thermoelectric field and the associated thermal stress field in both the matrix and fiber are obtained by solving the corresponding boundary value problem. Numerical examples are presented to illustrate the effect of hollowness ratio of the fiber on the local energy conversion efficiency and interfacial thermal stress concentration. It is found that a higher conversion efficiency and a lower amount of thermal stress concentration around a hollow fiber than that around a solid fiber could be achieved simultaneously by appropriate selection of the hollowness ratio of the fiber. The results can be directly used for performance optimization and reliability evaluation in design of thermoelectric composites in engineering.
Examining the immunoepigenetic-gut microbiome axis in the context of self-esteem among Native Hawaiians and other Pacific Islanders
Authors: Becerra Celyna Y. , Wells Riley K. , Kunihiro Braden P. , Lee Rosa H. , Umeda Lesley , Allan Nina P. , Rubas Noelle C. , McCracken Trevor A. , Nunokawa Chandler K. L. , Lee Ming-Hao , Pidlaoan Felix Gerard S. , Phankitnirondorn Krit , Dye Christian K. , Yamamoto Brennan Y , Peres Rafael , Juarez Ruben , Maunakea Alika K.
Published: April 2023

Introduction: Native Hawaiian and other Pacific Islander (NHPI) populations experience higher rates of immunometabolic diseases compared to other racial-ethnic groups in Hawaii. As annual NHPI mortality rates for suicide and type 2 diabetes mellitus (T2DM) exceed those of the state as a whole, understanding the social and biological mechanisms underlying these disparities are urgently needed to enable preventive strategies.

Methods: A community-based approach was used to investigate the immunoepigenetic-gut microbiome axis in an NHPI-enriched cohort of Oahu residents (N = 68). Self-esteem (SE) data was collected using a modified Rosenberg self-esteem (SE) assessment as a proxy measure for mental wellbeing in consideration for cultural competency. T2DM status was evaluated using point-of-care A1c (%) tests. Stool samples were collected for 16s-based metagenomic sequencing analyses. Plasma from blood samples were isolated by density-gradient centrifugation. Peripheral blood mononuclear cells (PBMCs) were collected from the same samples and enriched for monocytes using negative selection techniques. Flow-cytometry was used for immunoprofiling assays. Monocyte DNA was extracted for Illumina EPIC array-based methylation analysis.

Results: Compared to individuals with normal SE (NSE), those with low SE (LSE) exhibited significantly higher plasma concentrations (pg/ml) of proinflammatory cytokines IL-8 (p = 0.051) and TNF-α (p = 0.011). Metagenomic analysis revealed that the relative abundance (%) of specific gut bacteria significantly differed between SE groups - some of which directly correlated with SE scores. Gene ontology analysis revealed that 104 significantly differentially methylated loci (DML) between SE groups were preferentially located at genes involved in immunometabolic processes. Horvath clock analyses indicated epigenetic age (Epi-Age) deceleration in individuals with LSE and acceleration in individuals with NSE (p = 0.042), yet was not reproduced by other clocks.

Discussion: These data reveal novel differences in the immunoepigenetic-gut microbiome axis with respect to SE, warranting further investigation into its relationship to brain activity and mental health in NHPI. Unexpected results from Epi-Age analyses warrant further investigation into the relationship between biological age and disparate health outcomes among the NHPI population. The modifiable component of epigenetic processes and the gut microbiome makes this axis an attractive target for potential therapeutics, biomarker discovery, and novel prevention strategies.
Case report: A novel FARS2 deletion and a missense variant in a child with complicated, rapidly progressive spastic paraplegia
Authors: Panzeri Elena , Citterio Andrea , Martinuzzi Andrea , Ancona Vera , Martini Eleonora , Bassi Maria Teresa
Published: April 2023

Defects in FARS2 are associated with either epileptic phenotypes or a spastic paraplegia subtype known as SPG77. Here, we describe an 8-year-old patient with severe and complicated spastic paraplegia, carrying a missense variant (p.Pro361Leu) and a novel intragenic deletion in FARS2. Of note, the disease is unexpectedly progressing rapidly and in a biphasic way differently from the previously reported cases. Our study provides the first detailed molecular characterization of a FARS2 deletion and its underlying molecular mechanism, and demonstrates the need for combining different tools to improve the diagnostic rate.
NALCN is a potential biomarker and therapeutic target in human cancers
Authors: He Jian , Xu Jie , Chang Zhiwei , Yan Jiaqin , Zhang Limin , Qin Yanru
Published: April 2023

Background: Sodium leak channel non-selective (NALCN), known as a voltage-independent Na+ channel, is increasingly considered to play vital roles in tumorigenesis and metastasis of human cancers. However, no comprehensive pan-cancer analysis of NALCN has been conducted. Our study aims to explore the potential diagnostic, prognostic and therapeutic value of NALCN in human cancers.

Methods: Through comprehensive application of datasets from Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Enhanced Version of Tumor Immune Estimation Resource (TIMER2.0), Tumor and Immune System Interaction Database (TISIDB), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cBioPortal, GeneMANIA and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) databases, we explored the potential roles of NALCN in different cancers. The differential expression, prognostic implications, pathological stages and grades, molecular and immune subtypes, diagnostic accuracy, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, immune checkpoint genes, chemokine genes, major histocompatibility complex (MHC)-related genes, tumor-infiltrating immune cells (TIICs), promoter methylation, mutations, copy number alteration (CNA), and functional enrichment related to NALCN were analyzed.

Results: Most cancers lowly expressed NALCN. Upregulated NALCN expression was associated with poor or better prognosis in different cancers. Moreover, NALCN was correlated with clinicopathological features in multiple cancers. NALCN showed high diagnostic accuracy in 5 caner types. NALCN is highly linked with immune-related biomarkers, immune-related genes and TIICs. Significant methylation changes and genetic alteration of NALCN can be observed in many cancers. Enrichment analysis showed that NALCN is closely related to multiple tumor-related signaling pathways.

Conclusion: Our study revealed the vital involvement of NALCN in cancer. NALCN can be used as a prognostic biomarker for immune infiltration and clinical outcomes, and has potential diagnostic and therapeutic implications.
Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment
Authors: Zhao Peiwei , Hu Yanqiu , Hu Juan , Li Cheng , Huang Yufeng , Zhang Lei , Luo Sukun , Zhu Hongmin , Jiang Jun , He Xuelian
Published: April 2023

Introduction: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycosylation. DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose synthase (DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported.

Methods: Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase. Sanger sequencing was used to validate the variants identified in the siblings and their parents. In vitro functional study was performed.

Results: A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES). In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also reviewed the 4 previously reported patients carrying homozygous or compound heterozygous variants of DMP2 gene, and found that patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain. However, the actual genotype-phenotype relationship needs more study.

Discussion: Overall, our study broadens the variant spectrum of DPM2 gene, attempts to explain the different phenotypes in patients with different DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotypic heterogeneity.
Classification related to immunogenic cell death predicts prognosis, immune microenvironment characteristics, and response to immunotherapy in lower-grade gliomas
Authors: Kuang Yirui , Jiang Bincan , Zhu Hecheng , Zhou Yi , Huang Haoxuan , Li Can , Zhang Wenlong , Li Xuewen , Cao Yudong
Published: April 2023

Background

Immunogenic cell death (ICD) is a form of cell death that elicits immune responses against the antigens found in dead or dying tumor cells. Growing evidence implies that ICD plays a significant role in triggering antitumor immunity. The prognosis for glioma remains poor despite many biomarkers being reported, and identifying ICD-related biomarkers is imminent for better-personalized management in patients with lower-grade glioma (LGG).

Materials and methods

We identified ICD-related differentially expressed genes (DEGs) by comparing gene expression profiles obtained across Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) cohorts. On the foundation of ICD-related DEGs, two ICD-related clusters were identified through consensus clustering. Then, survival analysis, functional enrichment analysis, somatic mutation analysis, and immune characteristics analysis were performed in the two ICD-related subtypes. Additionally, we developed and validated a risk assessment signature for LGG patients. Finally, we selected one gene (EIF2AK3) from the above risk model for experimental validation.

Results

32 ICD-related DEGs were screened, dividing the LGG samples from the TCGA database into two distinct subtypes. The ICD-high subgroup showed worse overall survival (OS), greater immune infiltration, more active immune response process, and higher expression levels of HLA genes than the ICD-low subgroup. Additionally, nine ICD-related DEGs were identified to build the prognostic signature, which was highly correlated with the tumor-immune microenvironment and could unambiguously be taken as an independent prognostic factor and further verified in an external dataset. The experimental results indicated that EIF2AK3 expression was higher in tumors than paracancerous tissues, and high-expression EIF2AK3 was enriched in WHO III and IV gliomas by qPCR and IHC, and Knockdown of EIF2AK3 suppressed cell viability and mobility in glioma cells.

Conclusion

We established novel ICD-related subtypes and risk signature for LGG, which may be beneficial to improving clinical outcome prediction and guiding individualized immunotherapy.
Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment
Authors: Duncan R. Scott , Keightley Andrew , Lopez Adam A. , Hall Conner W. , Koulen Peter
Published: April 2023

Age related macular degeneration (AMD) is the most common cause of blindness in the elderly. Oxidative stress contributes to retinal pigment epithelium (RPE) dysfunction and cell death thereby leading to AMD. Using improved RPE cell model systems, such as human telomerase transcriptase-overexpressing (hTERT) RPE cells (hTERT-RPE), pathophysiological changes in RPE during oxidative stress can be better understood. Using this model system, we identified changes in the expression of proteins involved in the cellular antioxidant responses after induction of oxidative stress. Some antioxidants such as vitamin E (tocopherols and tocotrienols) are powerful antioxidants that can reduce oxidative damage in cells. Alpha-tocopherol (α-Toc or αT) and gamma-tocopherol (γ-Toc or γT) are well-studied tocopherols, but signaling mechanisms underlying their respective cytoprotective properties may be distinct. Here, we determined what effect oxidative stress, induced by extracellularly applied tBHP in the presence and absence of αT and/or γT, has on the expression of antioxidant proteins and related signaling networks. Using proteomics approaches, we identified differential protein expression in cellular antioxidant response pathways during oxidative stress and after tocopherol treatment. We identified three groups of proteins based on biochemical function: glutathione metabolism/transfer, peroxidases and redox-sensitive proteins involved in cytoprotective signaling. We found that oxidative stress and tocopherol treatment resulted in unique changes in these three groups of antioxidant proteins indicate that αT and γT independently and by themselves can induce the expression of antioxidant proteins in RPE cells. These results provide novel rationales for potential therapeutic strategies to protect RPE cells from oxidative stress.
A combination of pre-infusion serum ferritin, CRP and IL-6 predicts outcome in relapsed/refractory multiple myeloma patients treated with CAR-T cells
Authors: Liu Yang , Jie Xingxing , Nian Li , Wang Ying , Wang Congyue , Ma Jin , Jiang Jingjing , Wu Qingyun , Qiao Jianlin , Chen Wei , Cao Jiang , Yan Zhiling , Shi Ming , Cheng Hai , Zhu Feng , Sang Wei , Li Depeng , Chen Chong , Xu Kailin , Li Zhenyu
Published: April 2023

Background

Chimeric antigen receptor - T (CAR-T) cell therapy has shown remarkable efficacy in patients with relapsed/refractory multiple myeloma (R/R MM). However, a subset of patients still experienced progression or relapse, and the predictors of prognosis are little known. We analyzed the inflammatory markers before CAR-T cell infusion, to clarify their correlation with survival and toxicity.

Methods

This study involved 109 R/R MM patients who received CAR-T therapy between June 2017 and July 2021. Inflammatory markers, including ferritin, c-reactive protein (CRP), and interleukin-6 (IL-6) before CAR-T cell infusion were detected and then categorized by quartiles. Adverse events and clinical outcomes were compared between patients with upper quartile of inflammatory markers and patients with lower three quartiles of inflammatory markers. An inflammatory prognostic index (InPI) based on these three inflammatory markers was developed in this study. Patients were divided into 3 groups according to the InPI score, progression-free survival (PFS) and overall survival (OS) were compared among the groups. In addition, we explored the correlation between cytokine release syndrome (CRS) and pre-infusion inflammatory markers.

Results

We found that the pre-infusion high ferritin (hazard ratio [HR], 3.382; 95% confidence interval [CI], 1.667 to 6.863; P = .0007), high CRP (HR, 2.043; 95% CI, 1.019 to 4.097; P = .044), and high IL-6 (HR, 3.298; 95% CI, 1.598 to 6.808; P = .0013) were significantly associated with inferior OS. The formula of the InPI score was based on the HR value of these 3 variables. Three risk groups were formed: (good, 0 to 0.5 point; intermediate, 1 to 1.5 points; poor, 2 to 2.5 points). Median OS for patients with good, intermediate, and poor InPI was not reached, 24 months, and 4 months, respectively, and median PFS was 19.1 months, 12.3 months, and 2.9 months, respectively. In the cox proportional hazards model, poor InPI remained an independent prognostic factor for PFS and OS. Pre-infusion ferritin was negatively associated with CAR T-cell expansion normalized to baseline tumor burden. Spearman correlation analysis showed that pre-infusion ferritin and IL-6 levels positively correlated with the grade of CRS (P = .0369 and P = .0117, respectively). The incidence of severe CRS was higher in patients with high IL-6 compared with patients with low IL-6 (26% vs. 9%, P = .0405). Pre-infusion ferritin, CRP and IL-6 were positively correlated with each peak values within the first month after infusion.

Conclusions

Our results suggest that patients with elevated inflammation markers before CAR-T cell infusion are more likely to have poor prognosis.
Towards a better understanding of human iNKT cell subpopulations for improved clinical outcomes
Authors: Look Alex , Burns Daniel , Tews Ivo , Roghanian Ali , Mansour Salah
Published: April 2023

Invariant natural killer T (iNKT) cells are a unique T lymphocyte population expressing semi-invariant T cell receptors (TCRs) that recognise lipid antigens presented by CD1d. iNKT cells exhibit potent anti-tumour activity through direct killing mechanisms and indirectly through triggering the activation of other anti-tumour immune cells. Because of their ability to induce potent anti-tumour responses, particularly when activated by the strong iNKT agonist αGalCer, they have been the subject of intense research to harness iNKT cell-targeted immunotherapies for cancer treatment. However, despite potent anti-tumour efficacy in pre-clinical models, the translation of iNKT cell immunotherapy into human cancer patients has been less successful. This review provides an overview of iNKT cell biology and why they are of interest within the context of cancer immunology. We focus on the iNKT anti-tumour response, the seminal studies that first reported iNKT cytotoxicity, their anti-tumour mechanisms, and the various described subsets within the iNKT cell repertoire. Finally, we discuss several barriers to the successful utilisation of iNKT cells in human cancer immunotherapy, what is required for a better understanding of human iNKT cells, and the future perspectives facilitating their exploitation for improved clinical outcomes.
A relay of anticyclonic eddies transferring North Pacific subtropical mode water into the South China Sea
Authors: Wang Ran , Ren Qiang , Nan Feng , Yu Fei
Published: April 2023

North Pacific subtropical mode waters (STMWs), which are subducted with air-sea interaction signals and characterized by low potential vorticity (PV), play an important role in climate change issues. STMW (PV<2×10−10 m−1· s−1) can be advected westward by large-scale ocean circulation and mesoscale eddies. However, whether and how the STMW intrudes into the South China Sea (SCS) remains unclear. Low PV signals that originate from the STMW and intruding into the SCS are investigated by comparing observations and ocean general circulation models during 2003-2017. These signals mostly move across the Luzon Strait (LS) into the SCS during the 2008-2009 and 2014-2016 periods. The results of case studies selected from these two periods indicate that the low PV signals can move to the LS and are trapped by anticyclonic eddies (AEs). When the velocity vorticity is negative southwest of Taiwan Island, vertical stratification becomes weaker west of the coming AE (AE1), and low PV signals can consequently be transported along the STMW layer (25.0 σθ- 25.5 σθ isopycnal layer). Thus, an AE (AE2) forms east of AE1 and isolates the low PV signal from AE1, and then AE2 transports the low PV water southwestward in the SCS. In contrast, the low PV signal has difficulty migrating eastward when the velocity vorticity is positive west of AE1, as vertical stratification strengthens and then weakens that signal. The results suggest that only AEs can relay low PV signals from east of the LS and carry them over long distances in the SCS.
Bearing capacities of single piles under combined HM loading near slopes
Authors: Bian Meihua , Peng Jianing , Zhang Xingsen , Li Junhua , Qin Songlin
Published: April 2023

Piles are widely used to transfer the horizontal load of high-rise buildings, transmission towers, and bridges, especially for superstructures constructed near slopes. This study investigated bearing capacities of single piles under the combined horizontal force (H) and bending moment (M) for the pile in sloping ground. A 3D finite element model was proposed to simulate the non-linear pile–soil interaction and was verified by a model test. A series of numerical tests were conducted to obtain the failure envelope of bearing capacities of single piles under various combinations of H and M. The existence of slopes significantly reduced the bearing capacity of piles, especially when the horizontal and rotational displacements moved to the dip direction of the slope. An oblique ellipse was able to describe the failure envelope of bearing capacities of single piles near slopes in the HM plane. As the pile was installed away from the crest of the slope, both the width and height of the ellipse increased and the center of the ellipse was approaching the origin. The results of this article can provide useful references for designing horizontally loaded piles near slopes.
Untargeted metabolomics of the cochleae from two laryngeally echolocating bats
Authors: Wang Hui , Sun Ruyi , Xu Ningning , Wang Xue , Bao Mingyue , Li Xin , Li Jiqian , Lin Aiqing , Feng Jiang
Published: April 2023

High-frequency hearing is regarded as one of the most functionally important traits in laryngeally echolocating bats. Abundant candidate hearing-related genes have been identified to be the important genetic bases underlying high-frequency hearing for laryngeally echolocating bats, however, extensive metabolites presented in the cochleae have not been studied. In this study, we identified 4,717 annotated metabolites in the cochleae of two typical laryngeally echolocating bats using the liquid chromatography–mass spectroscopy technology, metabolites classified as amino acids, peptides, and fatty acid esters were identified as the most abundant in the cochleae of these two echolocating bat species, Rhinolophus sinicus and Vespertilio sinensis. Furthermore, 357 metabolites were identified as significant differentially accumulated (adjusted p-value <0.05) in the cochleae of these two bat species with distinct echolocating dominant frequencies. Downstream KEGG enrichment analyses indicated that multiple biological processes, including signaling pathways, nervous system, and metabolic process, were putatively different in the cochleae of R. sinicus and V. sinensis. For the first time, this study investigated the extensive metabolites and associated biological pathways in the cochleae of two laryngeal echolocating bats and expanded our knowledge of the metabolic molecular bases underlying high-frequency hearing in the cochleae of echolocating bats.
The efficacy and safety of asleep and awake subthalamic deep brain stimulation for Parkinson’s disease patients: A 1-year follow-up
Authors: Chen Wanru , Zhang Changming , Jiang Nan , Jiang Lulu , Guo Qiyu , Gu Jing , Xian Wenbiao , Ling Yuting , Liu Yanmei , Zheng Yifan , Wu Lei , Yang Chao , Xu Shaohua , Hu Yu , Yang Yang , Chen Jinhua , Xuan Ruoheng , Liu Yi , Liu Jinlong , Chen Ling
Published: April 2023

Introduction

Traditional DBS is usually conducted under local anesthesia (LA) which is intolerable to some patients, DBS under general anesthesia (GA) was opted to extended surgical indication. This study aimed to compare the efficacy and safety of bilateral subthalamic deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) under asleep and awake anesthesia state in 1-year postoperative follow-up.

Methods

Twenty-one PD patients were assigned to asleep group and 25 patients to awake group. Patients received bilateral STN-DBS under different anesthesia state. The PD participants were interviewed and assessed preoperatively and at 1-year postoperative follow-up.

Results

At 1-year follow-up, compared surgical coordinate in two groups, the left-side Y of asleep group showed more posterior than awake group (Y was-2.39 ± 0.23 in asleep group, −1.46 ± 0.22 in awake group, p = 0.007). Compared with preoperative OFF MED state, MDS-UPDRS III scores in OFF MED/OFF STIM state remained unchanged, while in OFF MED/ON STIM state were significantly improved in awake and asleep groups, yet without significant difference. Compared with preoperative ON MED state, MDS-UPDRS III scores in ON MED/OFF STIM, and ON MED/ON STIM state remained unchanged in both groups. In non-motor outcomes, PSQI, HAMD, and HAMA score significantly improved in asleep group compared to awake group at 1-year follow-up (PSQI, HAMD, and HAMA score in 1-year follow-up were 9.81 ± 4.43; 10.00 ± 5.80; 5.71 ± 4.75 in awake group, 6.64 ± 4.14; 5.32 ± 3.78; 3.76 ± 3.87 in asleep group, p = 0.009; 0.008; 0.015, respectively), while there was no significant difference in PDQ-39, NMSS, ESS, PDSS score, and cognitive function. Anesthesia methods was significantly associated with improvement of HAMA and HAMD score (p = 0.029; 0.002, respectively). No difference in LEDD, stimulation parameters and adverse events was observed between two groups.

Discussion

Asleep STN-DBS may be considered a good alternative method for PD patients. It is largely consistent with awake STN-DBS in motor symptoms and safety. Yet, it showed higher improvement in terms of mood and sleep compared to awake group at 1-year follow-up.
Brain Functional Alteration at Different Stages of Neuropathic Pain With Allodynia and Emotional Disorders
Authors: Zhang Ya-Nan , Xing Xiang-Xin , Chen Liu , Dong Xin , Pan Hao-Tian , Hua Xu-Yun , Wang Ke
Published: April 2023

Graphical Abstract

Brain functional alteration at different stages of neuropathic pain.
Optimizing Processing Technology of Cornus officinalis: Based on Anti-Fibrotic Activity
Authors: Han Xin , Ding Chuan , Ning Yan , Shan QiYuan , Niu Minjie , Cai Hao , Xu Peng , Cao Gang
Published: April 2023

Graphical Abstract

The processing technology of C. officinalis was optimized in terms of its anti-fibrotic activity. Differences in its chemical composition after the preparation were detected by UHPLC-Q-TOF-MS/MS. These results provide material basis for further exploring the role of C. officinalis in liver and kidney protection.
Dendrobium Nobile Lindl. Alkaloid Suppresses NLRP3-Mediated Pyroptosis to Alleviate LPS-Induced Neurotoxicity
Authors: Li Dai-Di , Fan Hong-Xia , Yang Rong , Li Ying-Ying , Zhang Feng , Shi Jing-Shan
Published: April 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder recognized as a global public health priority. Although available treatments temporarily relieve the symptoms, they could not prevent the progression of cognitive decline. Natural compounds have been rich sources for drug discovery. Dendrobium nobile Lindl. alkaloid (DNLA) is the main active compound in Dendrobium nobile Lindl, a traditional Chinese herbal medicine. Recent studies indicated that DNLA produced neuroprotection. However, the mechanisms underlying DNLA-generated neuroprotection remain unknown. To investigate neuroprotection and the underlying mechanisms of DNLA, mouse hippocampus injection of lipopolysaccharide (LPS)-induced neuronal damage was performed. DNLA protected hippocampus neurons and working memory disorder against LPS-induced neurotoxicity. In addition, DNLA suppressed cell undergoing membrane lysis and cell swelling and inhibited the essential mediator of pyroptosis GSDMD-N expressions. Furthermore, DNLA-mediated neuroprotection was dependent on the inhibition of NLRP3 inflammasome activation, as evidenced by the fact that DNLA reduced pro-inflammatory factor (IL-18 and IL-1β) production and inhibited the expression of related proteins. DNLA-exerted neuroprotection against LPS-induced neuronal damage, and cognitive impairment was not observed in NLRP3 knockout mice. Together, this study suggested that DNLA attenuated NLRP3-mediated pyroptosis to generate neuroprotection against LPS-induced neuronal damage and cognitive impairment.