bluuebunny/crossref_metadata_2025 huggingface dataset:
The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation
Authors: Fernandez Garcia Emily , Paudel Usha , Noji Michael C. , Bowman Caitlyn E. , Rustgi Anil K. , Pitarresi Jason R. , Wellen Kathryn E. , Arany Zolt , Weissenrieder Jillian S. , Foskett J. Kevin
Published: June 2023

Introduction: The mitochondrial uniporter (MCU) Ca2+ ion channel represents the primary means for Ca2+ uptake by mitochondria. Mitochondrial matrix Ca2+ plays critical roles in mitochondrial bioenergetics by impinging upon respiration, energy production and flux of biochemical intermediates through the TCA cycle. Inhibition of MCU in oncogenic cell lines results in an energetic crisis and reduced cell proliferation unless media is supplemented with nucleosides, pyruvate or α-KG. Nevertheless, the roles of MCU-mediated Ca2+ influx in cancer cells remain unclear, in part because of a lack of genetic models.

Methods: MCU was genetically deleted in transformed murine fibroblasts for study in vitro and in vivo. Tumor formation and growth were studied in murine xenograft models. Proliferation, cell invasion, spheroid formation and cell cycle progression were measured in vitro. The effects of MCU deletion on survival and cell-death were determined by probing for live/death markers. Mitochondrial bioenergetics were studied by measuring mitochondrial matrix Ca2+ concentration, membrane potential, global dehydrogenase activity, respiration, ROS production and inactivating-phosphorylation of pyruvate dehydrogenase. The effects of MCU rescue on metabolism were examined by tracing of glucose and glutamine utilization for fueling of mitochondrial respiration.

Results: Transformation of primary fibroblasts in vitro was associated with increased MCU expression, enhanced MCU-mediated Ca2+ uptake, altered mitochondrial matrix Ca2+ concentration responses to agonist stimulation, suppression of inactivating-phosphorylation of pyruvate dehydrogenase and a modest increase of mitochondrial respiration. Genetic MCU deletion inhibited growth of HEK293T cells and transformed fibroblasts in mouse xenograft models, associated with reduced proliferation and delayed cell-cycle progression. MCU deletion inhibited cancer stem cell-like spheroid formation and cell invasion in vitro, both predictors of metastatic potential. Surprisingly, mitochondrial matrix [Ca2+], membrane potential, global dehydrogenase activity, respiration and ROS production were unaffected. In contrast, MCU deletion elevated glycolysis and glutaminolysis, strongly sensitized cell proliferation to glucose and glutamine limitation, and altered agonist-induced cytoplasmic Ca2+ signals.

Conclusion: Our results reveal a dependence of tumorigenesis on MCU, mediated by a reliance on MCU for cell metabolism and Ca2+ dynamics necessary for cell-cycle progression and cell proliferation.
Antibacterial and anti-inflammatory effects of PGLa-loaded TiO2 nanotube arrays
Authors: Xuan Bin , Li Lei , Zhang Hui , Liu Zhuojue , Luo Ruxi , Yang Wenpeng , Wang Weili
Published: June 2023

Objectives: This study investigated the antimicrobial effect and anti-inflammatory activities of PGLa-loaded TiO2 nanotube arrays (TiO2 NTs) in osteoblast-like MG-63 cells.

Methods: The surface morphology and roughness of three titanium (Ti) substrates (Ti, TiO2 NTs, PGLa-loaded TiO2 NTs) were evaluated by scanning electron microscopy (SEM) and atomic force microscope (AFM). The wettability of three titanium substrates was evaluated by contact angle. Biocompatibility of PGLa-loaded TiO2 NTs were evaluated in MG-63 cells (cell adhesion, proliferation, cytoskeletal evaluation and alkaline phosphatase activity). Spread plate counting method was used to evaluate antibacterial abilities of the titanium substrates. The calcein AM/PI staining evaluated cell viability of MG-63 cells on the substrates with or without proinflammatory factors (TNF-α).

Results: The average surface roughness of untreated Ti, TiO2 NTs, PGLa-loaded TiO2 NTs were found to be 135.8 ± 6.4 nm, 300.5 ± 10.5 nm, 348.9 ± 16.9 nm, respectively. The contact angle of the untreated Ti was 77.4° ± 6.6°. TiO2 NTs displayed excellent wettability which of contact angle was 12.1° ± 2.9°. The contact angle of the PGLa-loaded TiO2 NTs was 34.6° ± 4.9°. MG-63 cells on surface of PGLa-loaded TiO2 NTs showed better cell adhesion, proliferation and osteogenic activity. The antibacterial rate of PGLa-loaded TiO2 NTs group significantly increased (84.6% ± 5.5%, p < 0.05). The rate of dead cells on the surfaces of the PGLa-loaded TiO2 NTs with TNF-α decreased significantly (4.49% ± 0.02, p < 0.01).

Conclusion: PGLa-loaded TiO2 NTs have multi-biofunctions including biocompatibility, antibacterial and anti-inflammatory properties.
Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers
Authors: Mondin Alberto , Bertazza Loris , Barollo Susi , Pedron Maria Chiara , Manso Jacopo , Piva Ilaria , Basso Daniela , Merante Boschin Isabella , Iacobone Maurizio , Pezzani Raffaele , Mian Caterina , Censi Simona
Published: June 2023

Introduction

Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC.

Methods

We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis.

Results

Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis.

Conclusion

Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
Case Report - Multinodular goiter in a patient with Congenital Hypothyroidism and Bannayan-Riley-Ruvalcaba syndrome: the possible synergic role of TPO and PTEN mutation
Authors: Vincenzi Gaia , Petralia Ilenia Teresa , Abbate Marco , Tarantola Giulia , Meroni Silvia Laura Carla , Maggiore Riccardo , Mari Gilberto , Patricelli Maria Grazia , Schiavo Lena Marco , Barera Graziano , Vigone Maria Cristina
Published: June 2023

We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.
Harnessing solar and wind for sustainable cross-border electricity trade in the Greater Mekong Subregion
Authors: Do Thang Nam , Burke Paul J. , Lu Bin
Published: June 2023

Sustainable, low-emission electricity generation options are needed in the Greater Mekong Subregion, including for cross-border electricity trade. Large-scale investment in solar and wind power, together with off-river pumped hydro energy storage, is identified as a promising way forward. The GMS has many potential off-river pumped hydro sites. Actionable recommendations include greater use of bilateral power purchase agreements for cross-border solar and wind power supply, and potential development of a high-voltage direct current grid. Institutional prioritization and ongoing evaluation are required to ensure desired social, environmental, and economic outcomes from the transition.
A rapid approach for ecological assessments in Carolina Bay wetlands that were previously converted to agriculture
Authors: Moritz Christopher M. , Vepraskas Michael J. , Ricker Matthew C.
Published: June 2023

Restoring wetlands is expensive, and methods for evaluating restoration condition are needed. This study developed chronosequences for use in ecological assessments (EAs) of restoration projects for Carolina Bay wetlands (CBWs) in the Southeastern US that were previously used for agriculture. An empirical method was also developed to estimate saturation levels to be used with the chronosequences. Data were collected from nine restored CBWs whose restoration ages ranged from 0 to 23 years. Plots were sorted into four Hydrologic Groups: 0–13 (Group 1), 14–50 (Group 2), 51–100 (Group 3), and 101+ (Group 4) consecutive days of saturation within 30 cm of the soil surface during the growing season. Litter thickness, tree basal area, and potential tree height were measured within a variable radius plot using a 10-factor prism across all Hydrologic Groups. Litter thickness and tree height reached an equilibrium at 15 years since restoration once crown closure occurred at the sites. In Groups 1 and 2, tree basal area reached an equilibrium at 15 years, and in Groups 3 and 4 it increased linearly to 23 and 21 years. Regression equations were developed (R2 = 0.57–0.73) to estimate saturation duration based on hydrology indicators, litter thickness, potential tree height, and soil type. These results showed that chronosequences and saturation duration would be useful for proposing performance standards in restored CBWs at time periods ranging from 5 to 23 years.
Identification of differentially expressed genes and SNPs linked to harvest body weight of genetically improved rohu carp, Labeo rohita
Authors: Nandanpawar P. , Sahoo L. , Sahoo B. , Murmu K. , Chaudhari A. , Pavan kumar A. , Das P.
Published: June 2023

In most of the aquaculture selection programs, harvest body weight has been a preferred performance trait for improvement. Molecular interplay of genes linked to higher body weight is not elucidated in major carp species. The genetically improved rohu carp with 18% average genetic gain per generation with respect to harvest body weight is a promising candidate for studying genes’ underlying performance traits. In the present study, muscle transcriptome sequencing of two groups of individuals, with significant difference in breeding value, belonging to the tenth generation of rohu carp was performed using the Illumina HiSeq 2000 platform. A total of 178 million paired-end raw reads were generated to give rise to 173 million reads after quality control and trimming. The genome-guided transcriptome assembly and differential gene expression produced 11,86,119 transcripts and 451 upregulated and 181 downregulated differentially expressed genes (DEGs) between high-breeding value and low-breeding value (HB & LB) groups, respectively. Similarly, 39,158 high-quality coding SNPs were identified with the Ts/Tv ratio of 1.23. Out of a total of 17 qPCR-validated transcripts, eight were associated with cellular growth and proliferation and harbored 13 SNPs. The gene expression pattern was observed to be positively correlated with RNA-seq data for genes such as myogenic factor 6, titin isoform X11, IGF-1 like, acetyl-CoA, and thyroid receptor hormone beta. A total of 26 miRNA target interactions were also identified to be associated with significant DETs (p-value < 0.05). Genes such as Myo6, IGF-1-like, and acetyl-CoA linked to higher harvest body weight may serve as candidate genes in marker-assisted breeding and SNP array construction for genome-wide association studies and genomic selection.
Trapalyzer: a computer program for quantitative analyses in fluorescent live-imaging studies of neutrophil extracellular trap formation
Authors: Ciach Michał Aleksander , Bokota Grzegorz , Manda-Handzlik Aneta , Kuźmicka Weronika , Demkow Urszula , Gambin Anna
Published: June 2023

Neutrophil extracellular traps (NETs), pathogen-ensnaring structures formed by neutrophils by expelling their DNA into the environment, are believed to play an important role in immunity and autoimmune diseases. In recent years, a growing attention has been put into developing software tools to quantify NETs in fluorescent microscopy images. However, current solutions require large, manually-prepared training data sets, are difficult to use for users without background in computer science, or have limited capabilities. To overcome these problems, we developed Trapalyzer, a computer program for automatic quantification of NETs. Trapalyzer analyzes fluorescent microscopy images of samples double-stained with a cell-permeable and a cell-impermeable dye, such as the popular combination of Hoechst 33342 and SYTOX™ Green. The program is designed with emphasis on software ergonomy and accompanied with step-by-step tutorials to make its use easy and intuitive. The installation and configuration of the software takes less than half an hour for an untrained user. In addition to NETs, Trapalyzer detects, classifies and counts neutrophils at different stages of NET formation, allowing for gaining a greater insight into this process. It is the first tool that makes this possible without large training data sets. At the same time, it attains a precision of classification on par with state-of-the-art machine learning algorithms. As an example application, we show how to use Trapalyzer to study NET release in a neutrophil-bacteria co-culture. Here, after configuration, Trapalyzer processed 121 images and detected and classified 16 000 ROIs in approximately three minutes on a personal computer. The software and usage tutorials are available at https://github.com/Czaki/Trapalyzer.
Intestinal fungi and antifungal secretory immunoglobulin A in Crohn’s disease
Authors: Sun Meng , Ju Jingyi , Xu Hongzhen , Wang Yufang
Published: June 2023

The human gastrointestinal tract harbors trillions of commensal microorganisms. Emerging evidence points to a possible link between intestinal fungal dysbiosis and antifungal mucosal immunity in inflammatory bowel disease, especially in Crohn’s disease (CD). As a protective factor for the gut mucosa, secretory immunoglobulin A (SIgA) prevents bacteria from invading the intestinal epithelium and maintains a healthy microbiota community. In recent years, the roles of antifungal SIgA antibodies in mucosal immunity, including the regulation of intestinal immunity binding to hyphae-associated virulence factors, are becoming increasingly recognized. Here we review the current knowledge on intestinal fungal dysbiosis and antifungal mucosal immunity in healthy individuals and in patients with CD, discuss the factors governing antifungal SIgA responses in the intestinal mucosa in the latter group, and highlight potential antifungal vaccines targeting SIgA to prevent CD.
The landscape of mitophagy in sepsis reveals PHB1 as an NLRP3 inflammasome inhibitor
Authors: Chen Shipeng , Ma Jinqi , Yin Ping , Liang Fang
Published: June 2023

Mitophagy is a selective autophagy targeting damaged and potential cytotoxic mitochondria, which can effectively prevent excessive cytotoxic production from damaged mitochondria and alleviate the inflammatory response. However, the potential role of mitophagy in sepsis remains poorly explored. Here, we studied the role of mitophagy in sepsis and its immune heterogeneity. By performing mitophagy-related typing on 348 sepsis samples, three clusters (A, B, and C) were obtained. Cluster A had the highest degree of mitophagy accompanied by lowest disease severity, while cluster C had the lowest degree of mitophagy with the highest disease severity. The three clusters had unique immune characteristics. We further revealed that the expression of PHB1 in these three clusters was significantly different and negatively correlated with the severity of sepsis, suggesting that PHB1 was involved in the development of sepsis. It has been reported that impaired mitophagy leads to the over-activation of inflammasomes, which promotes sepsis development. Further analysis showed that the expressions of NLRP3 inflammasomes core genes in cluster C were significantly up-regulated and negatively correlated with PHB1. Next, we verified whether PHB1 downregulation caused the activation of inflammasomes and found that the PHB1 knockdown increased the levels of mtDNA in the cytoplasm and enhanced the activation of NLRP3 inflammasomes. In addition, mitophagy inhibitor treatment abolished PHB1 knockdown-mediated activation of NLRP3 inflammasomes, suggesting that PHB1 inhibited the activation of inflammasomes through mitophagy. In conclusion, this study reveals that a high degree of mitophagy may predict a good outcome of sepsis, and PHB1 is a key NLRP3 inflammasome regulator via mitophagy in inflammatory diseases such as sepsis.
Postoperative adjuvant tyrosine kinase inhibitors combined with anti-PD-1 antibodies improves surgical outcomes for hepatocellular carcinoma with high-risk recurrent factors
Authors: Li Jian , Wang Wen-qiang , Zhu Rong-hua , Lv Xing , Wang Jin-lin , Liang Bin-yong , Zhang Er-lei , Huang Zhi-yong
Published: June 2023

Background

The clinical value of postoperative adjuvant therapy (PAT) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore the effect of PAT with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies on the surgical outcomes of HCC patients with high-risk recurrent factors (HRRFs).

Methods

HCC patients who underwent radical hepatectomy at Tongji Hospital between January 2019 and December 2021 were retrospectively enrolled, and those with HRRFs were divided into PAT group and non-PAT group. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups after propensity score matching (PSM). Prognostic factors associated with RFS and OS were determined by Cox regression analysis, and subgroup analysis was also conducted.

Results

A total of 250 HCC patients were enrolled, and 47 pairs of patients with HRRFs in the PAT and non-PAT groups were matched through PSM. After PSM, the 1- and 2-year RFS rates in the two groups were 82.1% vs. 40.0% (P < 0.001) and 54.2% vs. 25.1% (P = 0.012), respectively. The corresponding 1- and 2-year OS rates were 95.4% vs. 69.8% (P = 0.001) and 84.3% vs. 55.5% (P = 0.014), respectively. Multivariable analyses indicated that PAT was an independent factor related to improving RFS and OS. Subgroup analysis demonstrated that HCC patients with tumor diameter > 5 cm, satellite nodules, or vascular invasion could significantly benefit from PAT in RFS and OS. Common grade 1-3 toxicities, such as pruritus (44.7%), hypertension (42.6%), dermatitis (34.0%), and proteinuria (31.9%) were observed, and no grade 4/5 toxicities or serious adverse events occurred in patients receiving PAT.

Conclusions

PAT with TKIs and anti-PD-1 antibodies could improve surgical outcomes for HCC patients with HRRFs.
Biotransformation of gallate esters by a pH-stable tannase of mangrove-derived yeast Debaryomyces hansenii
Authors: Song Lei , Wang Xiao-Chen , Feng Zhen-Quan , Guo Yan-Feng , Meng Guo-Qing , Wang Hai-Ying
Published: June 2023

Introduction: Tannase is a crucial enzyme that finds wide applications in the pharmaceutical industry, feed processing, and beverage manufacturing. Although extensive studies have been conducted on tannases from fungi and bacteria, reports on tannases exhibiting favorable pH stability are relatively limited.

Methods: In this study, a tannin-degrading strain Debaryomyces hansenii was screened to induce tannase production, and the corresponding tannase coding gene TANF was successfully cloned and expressed in Yarrowia lipolytica. SDS-PAGE analysis revealed that the purified TanF tannase had a molecular weight of approximately 70 kDa.

Results and Discussion: The enzyme demonstrated optimal activity at 40°C and retained over 80% of its activity in the range of 35°C–60°C. Of particular interest, TanF exhibited remarkable enzyme activity at pH 5.0 and retained more than 70% of its relative activity across a wide pH range of 3.0–8.0. Furthermore, TanF exhibited broad substrate specificity for gallate esters. The final gallic acid production by TanF from tannic acid achieved 18.32 g/L. Therefore, the excellent properties TanF has been demonstrated to be an efficient tool for the preparation of gallic acid.
Relationship between insulin-like growth factor-1 and cerebral small vessel disease and its mechanisms: advances in the field
Authors: Du Hao , Xia Jian , Huang Lei , Zheng Lan , Gu Wenping , Yi Fang
Published: June 2023

Insulin-like growth factor-1 (IGF-1) is an active polypeptide protein that closely resembles the structural sequence of insulin and is involved in a variety of metabolic processes in the body. Decreased IGF-1 circulation levels are associated with an increased risk of stroke and a poorer prognosis, but the relationship with cerebral small vessel disease (cSVD) is unclear. Some studies found that the level of IGF-1 in patients with cSVD was significantly reduced, but the clinical significance and underlying mechanisms are unknown. This article reviews the correlation between IGF-1 and cerebrovascular disease and explores the potential relationship and mechanism between IGF-1 and cSVD.
Regulation of microglia polarization after cerebral ischemia
Authors: Wang Hao , Li Jingjing , Zhang Han , Wang Mengyao , Xiao Lifang , Wang Yitong , Cheng Qiong
Published: June 2023

Stroke ranks second as a leading cause of death and permanent disability globally. Microglia, innate immune cells in the brain, respond rapidly to ischemic injury, triggering a robust and persistent neuroinflammatory reaction throughout the disease’s progression. Neuroinflammation plays a critical role in the mechanism of secondary injury in ischemic stroke and is a significant controllable factor. Microglia activation takes on two general phenotypes: the pro-inflammatory M1 type and the anti-inflammatory M2 type, although the reality is more complex. The regulation of microglia phenotype is crucial to controlling the neuroinflammatory response. This review summarized the key molecules and mechanisms of microglia polarization, function, and phenotypic transformation following cerebral ischemia, with a focus on the influence of autophagy on microglia polarization. The goal is to provide a reference for the development of new targets for the treatment for ischemic stroke treatment based on the regulation of microglia polarization.
Long-term effects of the gait treatment using a wearable cyborg hybrid assistive limb in a patient with spinal and bulbar muscular atrophy: a case report with 5 years of follow-up
Authors: Iijima Kensuke , Watanabe Hiroki , Nakashiro Yuichi , Iida Yuki , Nonaka Michio , Moriwaka Fumio , Hamada Shinsuke
Published: June 2023

Background

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular degenerative disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem and neurogenic atrophy of the skeletal muscle. Although the short-term effectiveness of gait treatment using a wearable cyborg hybrid assistive limb (HAL) has been demonstrated for the rehabilitation of patients with SBMA, the long-term effects of this treatment are unclear. Thus, this study aimed to investigate the long-term effects of the continued gait treatment with HAL in a patient with SBMA.

Results

A 68-year-old man with SBMA had lower limb muscle weakness and atrophy, gait asymmetry, and decreased walking endurance. The patient performed nine courses of HAL gait treatment (as one course three times per week for 3 weeks, totaling nine times) for ~5 years. The patient performed HAL gait treatment to improve gait symmetry and endurance. A physical therapist adjusted HAL based on the gait analysis and physical function of the patient. Outcome measurements, such as 2-min walking distance (2MWD), 10-meter walking test (maximal walking speed, step length, cadence, and gait symmetry), muscle strength, Revised Amyotrophic Lateral Sclerosis Functional Assessment Scale (ALSFRS-R), and patient-reported outcomes, were evaluated immediately before and after gait treatment with HAL for each course. 2MWD improved from 94 m to 101.8 m, and the ALSFRS-R gait items remained unchanged (score 3) for approximately 5 years. The patient could maintain walking ability in terms of gait symmetry, walking endurance, and independence walking despite disease progression during HAL treatment.

Conclusion

The long-term gait treatment with HAL in a patient with SBMA may contribute to the maintenance and improvement of the gait endurance and ability to perform activities of daily living. The cybernics treatment using HAL may enable patients to relearn correct gait movements. The gait analysis and physical function assessment by a physical therapist might be important to maximize the benefits of HAL treatment.
Prognostic value of inflammatory markers for in-hospital mortality in intensive care patients with acute ischemic stroke: a retrospective observational study based on MIMIC-IV
Authors: Hu Xuyang , Liang Jiaru , Hao Wenjian , Zhou Jiaqi , Gao Yuling , Gong Xiaoyang , Liu Yong
Published: June 2023

Background

Acute ischemic stroke (AIS) is a primary cause of death and disability worldwide. Four markers that can be readily determined from peripheral blood, namely, the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and total bilirubin, were measured in this study. We examined the relationship between the SII and in-hospital mortality after AIS and evaluated which of the above four indicators was most accurate for predicting in-hospital mortality after AIS.

Methods

We selected patients from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database who were aged >18 years and who were diagnosed with AIS on admission. We collected the patients’ baseline characteristics, including various clinical and laboratory data. To investigate the relationship between the SII and in-hospital mortality in patients with AIS, we employed the generalized additive model (GAM). Differences in in-hospital mortality between the groups were summarized by the Kaplan–Meier survival analysis and the log-rank test. The receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of the four indicators (SII, NLR, PLR, and total bilirubin) for predicting in-hospital mortality in patients with AIS.

Results

The study included 463 patients, and the in-hospital mortality rate was 12.31%. The GAM analysis showed a positive correlation between the SII and in-hospital mortality in patients with AIS, but the correlation was not linear. Unadjusted Cox regression identified a link between a high SII and an increased probability of in-hospital mortality. We also found that patients with an SII of >1,232 (Q2 group) had a considerably higher chance of in-hospital mortality than those with a low SII (Q1 group). The Kaplan–Meier analysis demonstrated that patients with an elevated SII had a significantly lower chance of surviving their hospital stay than those with a low SII. According to the results of the ROC curve analysis, the in-hospital mortality of patients with AIS predicted by the SII had an area under the ROC curve of 0.65, which revealed that the SII had a better discriminative ability than the NLR, PLR, and total bilirubin.

Conclusion

The in-hospital mortality of patients with AIS and the SII were positively correlated, but not linearly. A high SII was associated with a worse prognosis in patients with AIS. The SII had a modest level of discrimination for forecasting in-hospital mortality. The SII was slightly better than the NLR and significantly better than the PLR and total bilirubin for predicting in-hospital mortality in patients with AIS.
Cerebrolysin and repetitive transcranial magnetic stimulation (rTMS) in patients with traumatic brain injury: a three-arm randomized trial
Authors: Verisezan Rosu Olivia , Jemna Nicoleta , Hapca Elian , Benedek Irina , Vadan Iulia , Muresanu Ioana , Chira Diana , Radu Constantin , Cherecheş Răzvan , Strilciuc Stefan , Muresanu Dafin
Published: June 2023

Introduction

Traumatic brain injury (TBI) is a major public health problem affecting millions worldwide. Despite significant advances in medical care, there are limited effective interventions for improving cognitive and functional outcomes in TBI patients.

Methods

This randomized controlled trial investigated the safety and efficacy of combining repetitive transcranial magnetic stimulation (rTMS) and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. Ninety-three patients with TBI were randomized to receive either Cerebrolysin and rTMS (CRB + rTMS), Cerebrolysin and sham stimulation (CRB + SHM), or placebo and sham stimulation (PLC + SHM). The primary outcome measures were the composite cognitive outcome scores at 3 and 6 months after TBI. Safety and tolerability were also assessed.

Results

The study results demonstrated that the combined intervention of rTMS and Cerebrolysin was safe and well-tolerated by patients with TBI. Although no statistically significant differences were observed in the primary outcome measures, the descriptive trends in the study support existing literature on the efficacy and safety of rTMS and Cerebrolysin.

Discussion

The findings of this study suggest that rTMS and Cerebrolysin may be effective interventions for improving cognitive and functional outcomes in TBI patients. However, limitations of the study, such as the small sample size and exclusion of specific patient populations, should be considered when interpreting the results. This study provides preliminary evidence for the safety and potential efficacy of combining rTMS and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. The study highlights the importance of multidisciplinary approaches in TBI rehabilitation and the potential for combining neuropsychological measurements and interventions to optimize patient outcomes.

Conclusion

Further research is needed to establish these findings’ generalizability and identify the optimal dosages and treatment protocols for rTMS and Cerebrolysin.
Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers
Authors: Matarazzo Jerico V. , Ajay Elise A. , Payne Sophie C. , Trang Ella P. , Thompson Alex C. , Marroquin Jason B. , Wise Andrew K. , Fallon James B. , Richardson Rachael T.
Published: June 2023

Introduction

Electrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges. In this study we employed a combined protocol of optical and electrical stimulation to the sciatic nerve in an optogenetic mouse model to allow for better selectivity, efficiency, and safety to overcome fundamental limitations of electrical-only and optical-only stimulation.

Methods

The sciatic nerve was surgically exposed in anesthetized mice (n = 12) expressing the ChR2-H134R opsin via the parvalbumin promoter. A custom-made peripheral nerve cuff electrode and a 452 nm laser-coupled optical fiber were used to elicit neural activity utilizing optical-only, electrical-only, or combined stimulation. Activation thresholds for the individual and combined responses were measured.

Results

Optically evoked responses had a conduction velocity of 34.3 m/s, consistent with ChR2-H134R expression in proprioceptive and low-threshold mechanoreceptor (Aα/Aβ) fibers which was also confirmed via immunohistochemical methods. Combined stimulation, utilizing a 1 ms near-threshold light pulse followed by an electrical pulse 0.5 ms later, approximately halved the electrical threshold for activation (p = 0.006, n = 5) and resulted in a 5.5 dB increase in the Aα/Aβ hybrid response amplitude compared to the electrical-only response at equivalent electrical levels (p = 0.003, n = 6). As a result, there was a 3.25 dB increase in the therapeutic stimulation window between the Aα/Aβ fiber and myogenic thresholds (p = 0.008, n = 4).

Discussion

The results demonstrate that light can be used to prime the optogenetically modified neural population to reside near threshold, thereby selectively reducing the electrical threshold for neural activation in these fibers. This reduces the amount of light needed for activation for increased safety and reduces potential off-target effects by only stimulating the fibers of interest. Since Aα/Aβ fibers are potential targets for neuromodulation in chronic pain conditions, these findings could be used to develop effective strategies to selectively manipulate pain transmission pathways in the periphery.
Outcomes in children with rheumatic diseases following COVID-19 vaccination and infection: data from a large two-center cohort study in Thailand
Authors: Lerkvaleekul Butsabong , Charuvanij Sirirat , Sukharomana Maynart , Pirojsakul Kwanchai , Kamolwatwong Malisa , Vilaiyuk Soamarat
Published: June 2023

Introduction

Vaccination against coronavirus disease 2019 (COVID-19) is effective in protecting patients from severe COVID-19 infection. Disease flare-up following immunization in children with rheumatic disorders may result in patient reluctance to receive the vaccine. Underlying rheumatic diseases or the use of immunosuppressive drugs may influence the outcomes of COVID-19 vaccination and infection. We aimed to describe outcomes in children with rheumatic diseases following COVID-19 immunization and infection.

Methods

This retrospective study was performed at two large academic centers in Thailand. During the COVID-19 pandemic, all patients were routinely queried about COVID-19-related conditions. We included patients with rheumatic diseases aged <18 years who received at least one dose of a COVID-19 vaccine or had a history of COVID-19 infection with more than 6 months of recorded follow-up after the last vaccine dose or COVID-19 illness. Demographic information and data on clinical symptoms, disease activity, treatment, outcomes, and COVID-19 vaccination and infection were collected.

Results

A total of 479 patients were included. Most (229; 47.81%) patients had juvenile idiopathic arthritis, followed by connective tissue diseases (189; 39.46%), vasculitis syndromes (42; 8.76%), and other rheumatic diseases (19; 3.97%). Approximately 90% of patients received at least one dose of COVID-19 vaccination, and half of the patients had COVID-19 infection. Among patients, 10.72% and 3.27% developed a flare after COVID-19 vaccination and COVID-19 illness, respectively. Flare severity after COVID immunization and infection was mainly mild to moderate. The predictor of flare after COVID-19 vaccination was the use of prednisolone ≥10 mg/day before vaccination (hazard ratio: 2.04, 95% confidence interval: 1.05–3.97, p = 0.037). Inactive disease before receiving the COVID-19 vaccination was a predictor of inactive status after a flare (hazard ratio: 2.95, 95% confidence interval: 1.04–8.40; p = 0.043). Overall, 3.36% and 1.61% of patients experienced a new onset of rheumatic disease after receiving the COVID-19 vaccine and after COVID-19 infection, respectively.

Conclusion

The COVID-19 vaccine is recommended for children with rheumatic disease, particularly those who are in stable condition. After COVID-19 vaccination, patients—especially those with active disease before vaccination or those receiving concurrent prednisolone doses of ≥10 mg/day—should be closely monitored.
Exploring the mechanism of JiGuCao capsule formula on treating hepatitis B virus infection via network pharmacology analysis and in vivo/vitro experiment verification
Authors: Cao Xu , Zhang Ningyi , Chen Hening , Wang Wei , Liang Yijun , Zhang Jiaxin , Liu Ruijia , Li Shuo , Yao Yuhao , Jin Qian , Guo Ziwei , Chen Yue , Gong Yuanyuan , Li Xiaoke , Zao Xiaobin , Ye Yong’an
Published: June 2023

The JiGuCao capsule formula (JCF) has demonstrated promising curative effects in treating chronic hepatitis B (CHB) in clinical trials. Here, we aimed to investigate JCF’s function and mechanism in diseases related to the hepatitis B virus (HBV). We used mass spectrometry (MS) to identify the active metabolites of JCF and established the HBV replication mouse model by hydrodynamically injecting HBV replication plasmids into the mice’s tail vein. Liposomes were used to transfect the plasmids into the cells. The CCK-8 kit identified cell viability. We detected the levels of HBV s antigen (HBsAg) and HBV e antigen (HBeAg) by the quantitative determination kits. qRT-PCR and Western blot were used to detect the genes’ expression. The key pathways and key genes related to JCF on CHB treatment were obtained by network pharmacological analysis. Our results showed that JCF accelerated the elimination of HBsAg in mice. JCF and its medicated serum inhibited HBV replication and proliferation of HBV-replicating hepatoma cells in vitro. And the key targets of JCF in treating CHB were CASP3, CXCL8, EGFR, HSPA8, IL6, MDM2, MMP9, NR3C1, PTGS2, and VEGFA. Furthermore, these key targets were related to pathways in cancer, hepatitis B, microRNAs in cancer, PI3K-Akt signaling, and proteoglycans in cancer pathways. Finally, Cholic Acid, Deoxycholic Acid, and 3′, 4′, 7-Trihydroxyflavone were the main active metabolites of JCF that we obtained. JCF employed its active metabolites to perform an anti-HBV effect and prevent the development of HBV-related diseases.
Role of heparanase in ARDS through autophagy and exosome pathway (review)
Authors: Feng Fei , Wang Lin-Jun , Li Jian-Chun , Chen Ting-Ting , Liu Liping
Published: June 2023

Acute respiratory distress syndrome (ARDS) is the most common respiratory disease in ICU. Although there are many treatment and support methods, the mortality rate is still high. The main pathological feature of ARDS is the damage of pulmonary microvascular endothelium and alveolar epithelium caused by inflammatory reaction, which may lead to coagulation system disorder and pulmonary fibrosis. Heparanase (HPA) plays an significant role in inflammation, coagulation, fibrosis. It is reported that HPA degrades a large amount of HS in ARDS, leading to the damage of endothelial glycocalyx and inflammatory factors are released in large quantities. HPA can aggrandize the release of exosomes through syndecan-syntenin-Alix pathway, leading to a series of pathological reactions; at the same time, HPA can cause abnormal expression of autophagy. Therefore, we speculate that HPA promotes the occurrence and development of ARDS through exosomes and autophagy, which leads to a large amount of release of inflammatory factors, coagulation disorder and pulmonary fibrosis. This article mainly describes the mechanism of HPA on ARDS.
Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway
Authors: Siddiqui M. Rizwan , Reddy Narsa M. , Faridi Hafeez M. , Shahid Mohd , Shanley Thomas P.
Published: June 2023

Background: Microvascular endothelial hyperpermeability is an earliest pathological hallmark in Acute Lung Injury (ALI), which progressively leads to Acute Respiratory Distress Syndrome (ARDS). Recently, vascular protective and anti-inflammatory effect of metformin, irrespective of glycemic control, has garnered significant interest. However, the underlying molecular mechanism(s) of metformin’s barrier protective benefits in lung-endothelial cells (ECs) has not been clearly elucidated. Many vascular permeability-increasing agents weakened adherens junctions (AJ) integrity by inducing the reorganization of the actin cytoskeleton and stress fibers formation. Here, we hypothesized that metformin abrogated endothelial hyperpermeability and strengthen AJ integrity via inhibiting stress fibers formation through cofilin-1-PP2AC pathway.

Methods: We pretreated human lung microvascular ECs (human-lung-ECs) with metformin and then challenged with thrombin. To investigate the vascular protective effects of metformin, we studied changes in ECs barrier function using electric cell-substrate impedance sensing, levels of actin stress fibers formation and inflammatory cytokines IL-1β and IL-6 expression. To explore the downstream mechanism, we studied the Ser3-phosphorylation-cofilin-1 levels in scramble and PP2AC-siRNA depleted ECs in response to thrombin with and without metformin pretreatment.

Results: In-vitro analyses showed that metformin pretreatment attenuated thrombin-induced hyperpermeability, stress fibers formation, and the levels of inflammatory cytokines IL-6 and IL-β in human-lung-ECs. We found that metformin mitigated Ser3-phosphorylation mediated inhibition of cofilin-1 in response to thrombin. Furthermore, genetic deletion of PP2AC subunit significantly inhibited metformin efficacy to mitigate thrombin-induced Ser3-phosphorylation cofilin-1, AJ disruption and stress fibers formation. We further demonstrated that metformin increases PP2AC activity by upregulating PP2AC-Leu309 methylation in human-lung-ECs. We also found that the ectopic expression of PP2AC dampened thrombin-induced Ser3-phosphorylation-mediated inhibition of cofilin-1, stress fibers formation and endothelial hyperpermeability.

Conclusion: Together, these data reveal the unprecedented endothelial cofilin-1/PP2AC signaling axis downstream of metformin in protecting against lung vascular endothelial injury and inflammation. Therefore, pharmacologically enhancing endothelial PP2AC activity may lead to the development of novel therapeutic approaches for prevention of deleterious effects of ALI on vascular ECs.
Structural analysis of mitochondrial rRNA gene variants identified in patients with deafness
Authors: Vila-Sanjurjo Antón , Mallo Natalia , Elson Joanna L. , Smith Paul M. , Blakely Emma L. , Taylor Robert W.
Published: June 2023

The last few years have witnessed dramatic advances in our understanding of the structure and function of the mammalian mito-ribosome. At the same time, the first attempts to elucidate the effects of mito-ribosomal fidelity (decoding accuracy) in disease have been made. Hence, the time is right to push an important frontier in our understanding of mitochondrial genetics, that is, the elucidation of the phenotypic effects of mtDNA variants affecting the functioning of the mito-ribosome. Here, we have assessed the structural and functional role of 93 mitochondrial (mt-) rRNA variants thought to be associated with deafness, including those located at non-conserved positions. Our analysis has used the structural description of the human mito-ribosome of the highest quality currently available, together with a new understanding of the phenotypic manifestation of mito-ribosomal-associated variants. Basically, any base change capable of inducing a fidelity phenotype may be considered non-silent. Under this light, out of 92 previously reported mt-rRNA variants thought to be associated with deafness, we found that 49 were potentially non-silent. We also dismissed a large number of reportedly pathogenic mtDNA variants, 41, as polymorphisms. These results drastically update our view on the implication of the primary sequence of mt-rRNA in the etiology of deafness and mitochondrial disease in general. Our data sheds much-needed light on the question of how mt-rRNA variants located at non-conserved positions may lead to mitochondrial disease and, most notably, provide evidence of the effect of haplotype context in the manifestation of some mt-rRNA variants.
Effect of nitrogen application on enhancing high-temperature stress tolerance of tomato plants during the flowering and fruiting stage
Authors: Luo Jing , Yang Zaiqiang , Zhang Fengyin , Li Chunying
Published: June 2023

This study was conducted to investigate the effects of nitrogen application on growth, photosynthetic performance, nitrogen metabolism activities, and fruit quality of tomato plants under high-temperature (HT) stress. Three levels of daily minimum/daily maximum temperature were adopted during the flowering and fruiting stage, namely control (CK; 18°C/28°C), sub-high temperature (SHT; 25°C/35°C), and high-temperature (HT; 30°C/40°C) stress. The levels of nitrogen (urea, 46% N) were set as 0 (N1), 125 (N2), 187.5 (N3), 250 (N4), and 312.5 (N5) kg hm2, respectively, and the duration lasted for 5 days (short-term). HT stress inhibited the growth, yield, and fruit quality of tomato plants. Interestingly, short-term SHT stress improved growth and yield via higher photosynthetic efficiency and nitrogen metabolism whereas fruit quality was reduced. Appropriate nitrogen application can enhance the high-temperature stress tolerance of tomato plants. The maximum net photosynthetic rate (PNmax), stomatal conductance (gs), stomatal limit value (LS), water-use efficiency (WUE), nitrate reductase (NR), glutamine synthetase (GS), soluble protein, and free amino acids were the highest in N3, N3, and N2, respectively, for CK, SHT, and HT stress, whereas carbon dioxide concentration (Ci), was the lowest. In addition, maximum SPAD value, plant morphology, yield, Vitamin C, soluble sugar, lycopene, and soluble solids occurred at N3-N4, N3-N4, and N2-N3, respectively, for CK, SHT, and HT stress. Based on the principal component analysis and comprehensive evaluation, we found that the optimum nitrogen application for tomato growth, yield, and fruit quality was 230.23 kg hm2 (N3-N4), 230.02 kg hm2 (N3-N4), and 115.32 kg hm2 (N2), respectively, at CK, SHT, and HT stress. Results revealed that the high yield and good fruit quality of tomato plants at high temperatures can be maintained by higher photosynthesis, nitrogen efficiency, and nutrients with moderate nitrogen.