bluuebunny/crossref_metadata_2025 huggingface dataset:
Pan-Cancer Integrated Analysis Identification of SASH3, a Potential Biomarker That Inhibits Lung Adenocarcinoma Progression
Authors: Chen Xi , Yuan Yixiao , Ren Wenjun , Zhou Fan , Huang Xiaobin , Pu Jun , Niu Xiaoqun , Jiang Xiulin
Published: June 2022

Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3) is an adaptor protein expressed mainly in lymphocytes, and plays significant roles in T-cell proliferation and cell survival. However, its expression level, clinical significance, and correlation with tumor-infiltrating immune cells across cancers remain unclear. In this study, we comprehensively examined the expression, dysregulation, and prognostic significance of SASH3, and the correlation with clinicopathological parameters and immune infiltration in pan-cancer. The mRNA and protein expression status of SASH3 were determined by TCGA, GTEx, and UALCAN. Kaplan–Meier analysis utilized the prognostic values of SASH3 in diverse cancers. The association between SASH3 expression and gene mutation, DNA methylation, immune cells infiltration, immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed using data from the TCGA database. High expression of SASH3 was not only linked to poor OS in ESCC, LAML, LGG, and UVM, but also associated with better OS in CESC, HNSC, LUAD, SARC, SKCM, THYM, and UCEC. As for DSS, a high level of SASH3 correlated with adverse DSS in ESCC, LGG, and UVM, and lowly expressed SASH3 was associated with shorter OS in CESC, HNSC, LUAD, SARC, SKCM, and UCEC. The results of Cox regression and nomogram analyses confirmed that SASH3 was an independent factor for LUAD prognosis. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) results showed that SASH3 was involved in natural killer cell-mediated cytotoxicity, Th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, NF-kappa B signaling pathway, B-cell receptor signaling pathway, and Toll-like receptor signaling pathway. SASH3 expression was correlated with TMB in 28 cancer types and associated with MSI in 22 cancer types, while there was a negative correlation between SASH3 expression and DNA methylation in diverse human cancer. The high DNA methylation level of SASH3 was correlated with better OS in KIRC and UVM, and associated with poor OS in SKCM. Moreover, we uncover that SASH3 expression was positively associated with the stroma score in 27 cancer types, the microenvironment score, and immune score in 32 cancer types, 38 types of immune cells in 32 cancer types, the 45 immune stimulators, 24 immune inhibitors, 41 chemokines, 18 receptors, and 21 major histocompatibility complex (MHC) molecules in 33 cancer types. Finally, forced SASH3 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and cell migration. Our findings confirmed that SASH3 may be a biomarker for the prognosis and diagnosis of human cancer.
Rapid-Onset Opioids for Management of Breakthrough Cancer Pain: Considerations for Daily Practice
Authors: Bossi Paolo , Escobar Yolanda , Pea Federico
Published: June 2022

Background and Objective

Rapid-onset opioids (ROOs) are effective treatments for breakthrough cancer pain (BTcP) given their rapid onset of action and relatively short duration of analgesia. The aim of this article is to describe specific considerations for the use of ROOs in daily practice, focusing on dose titration and treatment of specific populations.

Type of Review

We conducted a narrative review on the use of ROOs for BTcP. We selected papers according to the following search terms: “breakthrough cancer pain” and “rapid onset opioids”.

Results

ROOs may be considered as the most suitable drugs to treat BTcP and can be used “on-demand”. Several fentanyl formulations are available and have been associated with control of BTcP and with improvement in quality of life. Various titration schemes have been used to optimize ROO dosing; however, a dose-proportional scheme could be considered safe and effective in most patients. Specific formulations may be more suitable for specific patient subgroups; for example, patients with oral mucositis may prefer intranasal to oral formulations. Moreover, elderly patients or those without caregivers should be clearly educated on the use of these formulations. A key element in achieving successful treatment of BTcP is awareness of the barriers to pain management, including poor overall assessment, patient reluctance to take opioids or report pain, and physician reluctance to prescribe opioids.

Conclusion

A personalized approach is fundamental when prescribing a medication for BTcP, and careful attention should be given to drug choice and route of administration, and to the need for alternative therapeutic options.
Overweight/Obesity in Childhood and the Risk of Early Puberty: A Systematic Review and Meta-Analysis
Authors: Zhou Xuan , Hu Yang , Yang Ziqi , Gong Ziqiang , Zhang Senmao , Liu Xiaoling , Chen Yan , Ye Changxiang , Chen Lizhang , Wang Tingting
Published: June 2022

Purpose

To determine the relationship between childhood overweight/obesity and early puberty in both boys and girls. Specifically, this is the first time to conduct a meta-analysis of the relationship between childhood overweight/obesity and early puberty in boys.

Methods

Relevant studies were identified from PubMed, Web of Science, and EMBASE searches. The exposure of interest was overweight/obesity in childhood. Childhood was defined internationally as the age range of 0–18 years. The overall risk estimates were pooled using random effects models. Subgroup and sensitivity analyses were performed to explore possible sources of heterogeneity and to assess the robustness of the results.

Results

A total of 10 studies involving 13,338 girls and 12,796 boys were included. Results showed that childhood overweight/obesity were associated with a significantly higher risk of early puberty in girls [odds ratio (OR): 2.22, 95% CI: 1.65–2.99]. Although without statistical significance, a higher risk of early puberty was also found in boys who were overweight/obese in childhood (OR: 1.29, 95% CI: 0.98–1.70). Heterogeneity in the risk estimates of early puberty was partially explained by study design, sample size, follow-up duration, definitions of early puberty and confounders controlled. Sensitivity analyses validated the robustness of the findings.

Conclusions

Our findings showed that for girls the associate between overweight/obesity and early puberty is definite or strong whereas for males, such an association is possible, prompting that future studies need to further explore the possible relationship between overweight/obesity and early puberty in boys.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021264649, PROSPERO CRD42021264649.
Contemporary Trends in Global Mortality of Sepsis Among Young Infants Less Than 90 Days: A Systematic Review and Meta-Analysis
Authors: Gan Ming Ying , Lee Wen Li , Yap Bei Jun , Seethor Shu Ting Tammie , Greenberg Rachel G. , Pek Jen Heng , Tan Bobby , Hornik Christoph Paul Vincent , Lee Jan Hau , Chong Shu-Ling
Published: June 2022

Objective

Current knowledge on the global burden of infant sepsis is limited to population-level data. We aimed to summarize global case fatality rates (CFRs) of young infants with sepsis, stratified by gross national income (GNI) status and patient-level risk factors.

Methods

We performed a systematic review and meta-analysis on CFRs among young infants < 90 days with sepsis. We searched PubMed, Cochrane Central, Embase, and Web of Science for studies published between January 2010 and September 2019. We obtained pooled CFRs estimates using the random effects model. We performed a univariate analysis at patient-level and a meta-regression to study the associations of gestational age, birth weight, onset of sepsis, GNI, age group and culture-proven sepsis with CFRs.

Results

The search yielded 6314 publications, of which 240 studies (N= 437,796 patients) from 77 countries were included. Of 240 studies, 99 were conducted in high-income countries, 44 in upper-middle-income countries, 82 in lower-middle-income countries, 6 in low-income countries and 9 in multiple income-level countries. Overall pooled CFR was 18% (95% CI, 17–19%). The CFR was highest for low-income countries [25% (95% CI, 7–43%)], followed by lower-middle [25% (95% CI, 7–43%)], upper-middle [21% (95% CI, 18–24%)] and lowest for high-income countries [12% (95% CI, 11–13%)]. Factors associated with high CFRs included prematurity, low birth weight, age less than 28 days, early onset sepsis, hospital acquired infections and sepsis in middle- and low-income countries. Study setting in middle-income countries was an independent predictor of high CFRs. We found a widening disparity in CFRs between countries of different GNI over time.

Conclusion

Young infant sepsis remains a major global health challenge. The widening disparity in young infant sepsis CFRs between GNI groups underscore the need to channel greater resources especially to the lower income regions.

Systematic Review Registration

[www.crd.york.ac.uk/prospero], identifier [CRD42020164321].
Nomograms for Predicting the Incidence of Late-Onset Acute Cellular Rejection in Patients After Pediatric Liver Transplantation
Authors: Si Zhuyuan , Dong Chong , Sun Chao , Wang Kai , Zhang Wei , Zheng Weiping , Wei Xinzhe , Gao Wei , Shen Zhongyang
Published: June 2022

Background

Late-onset acute cellular rejection (LACR) is a special type of acute rejection (AR) only rarely studied after pediatric liver transplantation (pLT). Our study aimed to explore the influencing factors of LACR after pLT and establish a nomogram to provide an individualized prediction of LACR after pLT.

Materials and Methods

Data from 640 children who underwent pLT at Tianjin First Central Hospital from January 2016 to December 2019 were collected as part of this retrospective study. The nomogram was then established through the results of the multivariable analysis.

Results

Forty-one patients experienced LACR > 1 ≤ 2 years after pLT. Cold ischemia time, donor-specific antibodies (DSAs), and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.834 (95% confidence interval, 0.755–0.912). Ten-fold cross-validation showed that the accuracy of the nomogram was about 76%. Sixty-three patients experienced LACR > 2 years after pLT. Child–Pugh grade, cold ischemic time, DSAs, early acute cellular rejection, and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.827 (95% confidence interval, 0.774–0.881). Ten-fold cross-validation showed that the accuracy of the nomogram was about 80.9%.

Conclusion

We established nomograms to predict the incidence of LACR > 1 ≤ 2 and > 2 years after pLT, respectively. The verification results showed that nomograms had good accuracy and clinical practicability.
Update on Treatment of Infantile Hemangiomas: What’s New in the Last Five Years?
Authors: Macca Laura , Altavilla Domenica , Di Bartolomeo Luca , Irrera Natasha , Borgia Francesco , Li Pomi Federica , Vaccaro Federico , Squadrito Violetta , Squadrito Francesco , Vaccaro Mario
Published: June 2022

Among benign vascular tumors of infancy, hemangiomas are the commonest, affecting approximately 5–10% of one-year-old children. They are derived from a benign proliferation of vascular endothelial cells (VECs) in the mesoderm and may arise anywhere on the body around 1–2 weeks after birth. Infantile hemangiomas (IHs) are characterized by an early proliferative phase in the first year followed by a spontaneous progressive regression within the following 5 years or longer. IH prevalence is estimated to be 5%–10% in one-year-old children and commonly affects female, Caucasian and low-birth weight infants. Although most of them spontaneously regress, approximately 10% requires treatment to prevent complications due to the site of occurrence such as bleeding, ulceration, cosmetically disfigurement, functional impairment, or life-threatening complications. For over 30 years, steroids have represented the first-line treatment for IHs, but recently topical or systemic β-blockers are increasingly being used and recognized as effective and safe. A search for “Cutaneous infantile hemangioma” [All Fields] AND “Treatment” [All Fields] was performed by using PubMed and EMBASE databases. Treatment of IHs with labeled drugs, such as oral propranolol, but also with off-label drugs, such as topical β-blockers, including topical timolol and carteolol, steroids, itraconazole or sirolimus, with a focus on formulations types and adverse events were described in our review. We also discussed the benefits of pulsed dye laser and the treatment of IHs with involvement of central nervous system, namely the PHACE and LUMBAR syndrome.
Full-Length Transcriptome Sequencing Analysis of Differentially Expressed Genes and Pathways After Treatment of Psoriasis With Oxymatrine
Authors: Xue Xiaoxiao , Yu Jiayu , Li Cheng , Wang Fang , Guo Yatao , Li Yongwen , Shi Huijuan
Published: June 2022

Psoriasis is a recurrent chronic inflammatory skin disease. Unlike many of the latest psoriasis treatments that only confer limited curative effects and have certain side effects, oxymatrine effectively improves severe plaque psoriasis with mild adverse reactions. Here, we explored the genes and pathways underlying the effects of oxymatrine on psoriasis. Briefly, patients with severe plaque psoriasis were treated with oxymatrine and their lesioned skin samples were sequenced by full-length transcriptomics. Next, the differentially expressed genes (DEGs) in psoriatic lesions were identified and compared in oxymatrine-treated patients and healthy controls, their genes were functionally annotated, and protein–protein interaction network analysis and immunohistochemistry were performed. Both Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA) scores were recovered significantly from all 16 patients (all p < 0.001). The number of DEGs in patients before and after oxymatrine treatment was 4232, and 4105 DEGs were found between the psoriasis group (before oxymatrine treatment) and the normal control group [p < 0.01, |log2 fold change, (FC)| >1.5]. While most of the DEGs recovered significantly after oxymatrine treatment, only 650 DEGs were observed between the psoriasis group (after oxymatrine treatment) and the normal control group (p < 0.01, |log2FC|> 1.5). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that 64 pathways were significantly activated after oxymatrine treatment (p < 0.05). Only 12 pathways were statistically significant between after oxymatrine treatment and the normal control group (p < 0 .05). Among all the restored pathways, the improvement of the IL-17 signaling pathway was the most significant (p = 1.18E-06). Gene loci of oxymatrine action was assessed by protein interaction analysis on 205 DEGs that were co-expressed in 5 patients before and after oxymatrine treatment (p < 0.05, FC > 1.5). After oxymatrine treatment, the expression of two mitosis-related genes namely, cyclin dependent kinase 1 (CDK1) and cyclin B1 (CCNB1), that affect cell proliferation recovered significantly. In light of these results, we conclude that oxymatrine likely alters the abnormal expression of some genes and pathways in psoriasis patients. Multipathway and multitarget therapy can greatly ameliorate abnormalities in genes and pathways and effectively treat psoriasis. Importantly, among the DEGs, the proliferation-related genes, such as CDK1 and CCNB1, are likely important targets for treating psoriasis by oxymatrine. We believe that these findings may lead to a new treatment strategy for psoriasis.
Identifying Candidate Flavonoids for Non-Alcoholic Fatty Liver Disease by Network-Based Strategy
Authors: Lee Won-Yung , Lee Choong-Yeol , Lee Jin-Seok , Kim Chang-Eop
Published: June 2022

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease and lacks guaranteed pharmacological therapeutic options. In this study, we applied a network-based framework for comprehensively identifying candidate flavonoids for the prevention and/or treatment of NAFLD. Flavonoid-target interaction information was obtained from combining experimentally validated data and results obtained using a recently developed machine-learning model, AI-DTI. Flavonoids were then prioritized by calculating the network proximity between flavonoid targets and NAFLD-associated proteins. The preventive effects of the candidate flavonoids were evaluated using FFA-induced hepatic steatosis in HepG2 and AML12 cells. We reconstructed the flavonoid-target network and found that the number of re-covered compound-target interactions was significantly higher than the chance level. Proximity scores have successfully rediscovered flavonoids and their potential mechanisms that are reported to have therapeutic effects on NAFLD. Finally, we revealed that discovered candidates, particularly glycitin, significantly attenuated lipid accumulation and moderately inhibited intracellular reactive oxygen species production. We further confirmed the affinity of glycitin with the predicted target using molecular docking and found that glycitin targets are closely related to several proteins involved in lipid metabolism, inflammatory responses, and oxidative stress. The predicted network-level effects were validated at the levels of mRNA. In summary, our study offers and validates network-based methods for the identification of candidate flavonoids for NAFLD.
Cytoplasmic Beta and Gamma Actin Isoforms Reorganization and Regulation in Tumor Cells in Culture and Tissue
Authors: Dugina V. B. , Shagieva G. S. , Kopnin P. B.
Published: June 2022

The cytoplasmic actin isoforms (β- and γ-actins) contribute greatly to cellular processes such as cel-cell and cell-matrix interactions, as well as cell polarization, motility and division. Distinct isoforms modulations are linked to serious pathologies, so investigations of underlying mechanisms would be of major relevance not only for fundamental research but also for clinical applications. Therefore, the study of the relevant mechanisms of change in the isoform’s balance is important for basic research and for clinical studies. The disruption of actin cytoskeleton and intercellular adhesions contribute to the neoplastic transformation, as it is important for the tumor growth, invasiveness and metastasis. Cytoplasmic actins display the functional diversity: β-actin is responsible for contractility, whereas γ-actin participates in the submembrane flexible cortex organization and direction cell motility. The involvement of β- and γ-actin in cell architecture, motility, division, and adhesion junctions in normal cells is not equivalent, and the major question was following: whether isoform ratio and the distribution in the cell corresponds to pathological function. Significant data were obtained in the study of tumor and normal cells in culture, as well as on clinical material of human tissues, and via selective regulation of β- and γ-actin’s expression. Investigation of the actins’ diversity and function in cancers may help to choose the benefit treatment strategies, and to design new therapies.
A Scoping Review on the Therapeutic Potential of Resin From the Species Larix decidua Mill. [Pinaceae] to Treat Ulcerating Wounds
Authors: Batista João V. C. , Uecker Annekathrin , Holandino Carla , Boylan Fabio , Maier Jakob , Huwyler Jörg , Baumgartner Stephan
Published: June 2022

Malignant ulcerating wounds or neoplastic lesions are a considerable burden for patients suffering from advanced cancer. These wounds have no effective treatment and are very difficult to manage. The present review summarizes evidence in support of a hypothesis put forward in anthroposophic medicine, which suggests a beneficial role of resin from the species Larix decidua Mill. [Pinaceae] for treating such wounds. A systematic search strategy was performed using the databases PubMed, EMBASE and SciFinder. The included publications described the chemical composition of this species, as well as in vitro, in vivo, and ex vivo experiments using plant extracts and isolated compounds. The results show that among the phytochemical classes, terpenoids were the major components of this species, especially in the resin. The summarized biological experiments revealed antimicrobial, antioxidant and anti-inflammatory effects, with promising potential for the extracts and isolated compounds. However, the molecular mechanisms and toxicological effects are as of yet not conclusively evaluated. From the data of our study, we can conclude that L. decidua might indeed have a promising potential for the treatment of malignant wounds, but definitive information that can prove its effectiveness is still lacking. We therefore suggest that future efforts should be dedicated to the evaluation of L. decidua resin's therapeutic use considering its antiseptic action and proposed wound healing properties.
Benefits and Risks of Rapid Initiation of Antiretroviral Therapy: A Systematic Review and Meta-Analysis
Authors: Bai Ruojing , Du Juan , Lv Shiyun , Hua Wei , Dai Lili , Wu Hao
Published: June 2022

Objectives: To compare the benefits and risks between Rapid ART and standard/delayed treatment for HIV.

Methods: Databases of PubMed, Cochrane Library, Embase and Web of science were searched from the inception to 28 October 2021. Two investigators independently screened studies related to Rapid ART, extracted data, and evaluated the literature quality. The risk of bias was assessed by Cochrane Collaboration Risk of Bias Tool and the statistical software Stata15.0 was used for meta-analysis.

Results: Ten eligible studies were included in this meta-analysis, the results showed Rapid ART was superior to standard/delayed treatment in continuing care for at least 8 months (RR = 1.13, 95%CI: 1.03∼1.25, Z = 2.44, p = 0.015), and severe bacterial infection (RR = 0.42, 95%CI: 0.25∼0.70, Z = 3.33, p = 0.001). At 12 months following treatment, there was no statistically significant difference in viral load <100 copies/mL (RR = 1.05, 95%CI: 0.80∼1.39, Z = 0.35, p = 0.726), mortality (RR = 0.77, 95%CI: 0.47∼1.24, Z = 1.09, p = 0.277), or the incidence of adverse events (RR = 0.52, 95%CI: 0.16∼1.76, Z = 1.05, p = 0.294) compared with standard/delayed treatment.

Conclusion: In comparison to standard/delayed treatment, rapid ART can reduce the incidence of TB and severe bacterial infections in HIV patients. Our findings suggest that rapid ART should be utilized when clinical conditions and the patient’s physical state allow.

Systematic Review Registration: [https://inplasy.com/?s=202210004], identifier [INPLASY202210004].
Research Progress in Pharmacological Activities and Applications of Cardiotonic Steroids
Authors: Ren Junwei , Gao Xinyuan , Guo Xi , Wang Ning , Wang Xin
Published: June 2022

Cardiotonic steroids (CTS) are a group of compounds existing in animals and plants. CTS are commonly referred to cardiac glycosides (CGs) which are composed of sugar residues, unsaturated lactone rings and steroid cores. Their traditional mechanism of action is to inhibit sodium-potassium ATPase to strengthen the heart and regulate heart rate, so it is currently widely used in the treatment of cardiovascular diseases such as heart failure and tachyarrhythmia. It is worth noticing that recent studies have found an avalanche of inestimable values of CTS applications in many fields such as anti-tumor, anti-virus, neuroprotection, and immune regulation through multi-molecular mechanisms. Thus, the pharmacological activities and applications of CTS have extensive prospects, which would provide a direction for new drug research and development. Here, we review the potential applications of CTS in cardiovascular system and other systems. We also provide suggestions for new clinical practical strategies of CTS, for many diseases. Four main themes will be discussed, in relation to the impact of CTS, on 1) tumors, 2) viral infections, 3) nervous system diseases and 4) immune-inflammation-related diseases.
Structural Advances in Voltage-Gated Sodium Channels
Authors: Jiang Daohua , Zhang Jiangtao , Xia Zhanyi
Published: June 2022

Voltage-gated sodium (NaV) channels are responsible for the rapid rising-phase of action potentials in excitable cells. Over 1,000 mutations in NaV channels are associated with human diseases including epilepsy, periodic paralysis, arrhythmias and pain disorders. Natural toxins and clinically-used small-molecule drugs bind to NaV channels and modulate their functions. Recent advances from cryo-electron microscopy (cryo-EM) structures of NaV channels reveal invaluable insights into the architecture, activation, fast inactivation, electromechanical coupling, ligand modulation and pharmacology of eukaryotic NaV channels. These structural analyses not only demonstrate molecular mechanisms for NaV channel structure and function, but also provide atomic level templates for rational development of potential subtype-selective therapeutics. In this review, we summarize recent structural advances of eukaryotic NaV channels, highlighting the structural features of eukaryotic NaV channels as well as distinct modulation mechanisms by a wide range of modulators from natural toxins to synthetic small-molecules.
Pyridoxamine and Aminoguanidine Attenuate the Abnormal Aggregation of β-Tubulin and Suppression of Neurite Outgrowth by Glyceraldehyde-Derived Toxic Advanced Glycation End-Products
Authors: Ooi Hayahide , Nasu Ryuto , Furukawa Ayako , Takeuchi Masayoshi , Koriyama Yoshiki
Published: June 2022

Diabetes mellitus (DM) has been identified as a risk factor for the onset and progression of Alzheimer’s disease (AD). In our previous study, we demonstrated that glyceraldehyde (GA)-derived toxic advanced glycation end-products (toxic AGEs, TAGE) induced similar alterations to those observed in AD. GA induced dysfunctional neurite outgrowth via TAGE-β-tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation in human neuroblastoma SH-SY5Y cells. However, the effects of inhibitors of AGE formation on dysfunctional neurite outgrowth caused by GA-induced abnormalities in the aggregation of β-tubulin and tau phosphorylation remain unknown. Aminoguanidine (AG), an AGE inhibitor, and pyridoxamine (PM), a natural form of vitamin B6 (VB6), are effective AGE inhibitors. Therefore, the present study investigated whether AG or PM ameliorate TAGE-β-tubulin aggregation and the suppression of neurite outgrowth by GA. The results obtained showed that AG and PM inhibited the formation of TAGE-β-tubulin, mitigated the GA-induced suppression of neurite outgrowth, and reduced GA-mediated increases in tau phosphorylation levels. Collectively, these results suggest the potential of AG and PM to prevent the DM-associated onset and progression of AD.
Stimulatory G-Protein α Subunit Modulates Endothelial Cell Permeability Through Regulation of Plasmalemma Vesicle-Associated Protein
Authors: He Lifan , Lu Hanlin , Ji Xuyang , Chu Jianying , Qin Xiaoteng , Chen Min , Weinstein Lee S. , Gao Jiangang , Yang Jianmin , Zhang Qunye , Zhang Cheng , Zhang Wencheng
Published: June 2022

Endothelial cell leakage occurs in several diseases. Intracellular junctions and transcellular fashion are involved. The definite regulatory mechanism is complicated and not fully elucidated. The alpha subunit of the heterotrimeric G-stimulatory protein (Gsα) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of Gsα in the endothelial barrier remains unclear. In this study, mice with knockout of endothelial-specific Gsα (GsαECKO) were generated by crossbreeding Gsαflox/flox mice with Cdh5-CreERT2 transgenic mice, induced in adult mice by tamoxifen treatment. GsαECKO mice displayed phenotypes of edema, anemia, hypoproteinemia and hyperlipoproteinemia, which indicates impaired microvascular permeability. Mechanistically, Gsα deficiency reduces the level of endothelial plasmalemma vesicle-associated protein (PLVAP). In addition, overexpression of Gsα increased phosphorylation of cAMP response element-binding protein (CREB) as well as the mRNA and protein levels of PLVAP. CREB could bind to the CRE site of PLVAP promoter and regulate its expression. Thus, Gsα might regulate endothelial permeability via cAMP/CREB-mediated PLVAP expression.
Time and Quantum Clocks: A Review of Recent Developments
Authors: Altaie M. Basil , Hodgson Daniel , Beige Almut
Published: June 2022

In this review we present the problem of time in quantum physics, including a short history of the problem and the known objections about considering time as a quantum observable. The need to deal with time as an observable is elaborated through some unresolved problems. The lack of a consistent theory of time is currently hindering the formulation of a full-fledged theory of quantum gravity. It is argued that the proposal set forth by several authors of considering an intrinsic measurement of quantum time, besides having the conventional external time, is compelling. Recently several suggestions have been put forward to revive the proposal of Page and Wootters (1983), elaborating and resolving some of the main ambiguities of the original proposal and opening new scope for understanding its content. The approach followed in these new contributions exposes the need to go beyond the limitations enforced by the conventional approach of quantum physics. The attitude of covariant loop quantum gravity, in which it is called to completely ignore time, is also discussed. This review could be a step forward in an endeavour to reform our outlook of the unification of the theory of relativity and quantum physics by furnishing the conceptual ground needed for this goal. Intentionally, some technical details are avoided since we aim to present the approaches to resolve the problem in a simple way with the clearest possible outlook. These can be looked up in the original references provided.
CT Attenuation and Cross-Sectional Area of the Pectoralis Are Associated With Clinical Characteristics in Chronic Obstructive Pulmonary Disease Patients
Authors: Qiao Xin , Hou Gang , Kang Jian , Wang Qiu-Yue , Yin Yan
Published: June 2022

Purpose:Muscle wasting is associated with prognosis in patients with chronic obstructive pulmonary disease (COPD). Computed tomography (CT) could serve as a method for muscle assessment due to its ability to measure both muscle quantity (e.g., cross-sectional muscle area) and muscle quality (e.g., muscle attenuation). Our study aimed to compare the differences in CT-derived pectoralis muscle cross-sectional area (PMA) and pectoralis muscle attenuation (PMT) between COPD patients and healthy controls and explore the association between PMA and PMT measurements and clinical characteristics in patients with COPD.

Methods:A total of 252 participants included in our analysis consisted of 80 healthy controls and 172 patients with COPD. PMA and PMT were measured from a single axial slice of the CT scan above the aortic arch. Linear regression analysis was used to determine the correlation between PMA and PMT measurements and clinical characteristics in patients with COPD. Associations were adjusted for age, sex, BMI, FEV1%pred, smoking pack-years, current smoking status, emphysema percentage, and total airway count (TAC) of the right upper lobe apical bronchus (RB1).

Results:PMA and PMT were lower in COPD patients, especially those with acute exacerbation, than in healthy controls. PMA and PMT were significantly associated with the severity of emphysema and the TAC of RB1 (p< 0.05). Patients with stable COPD, who had lower PMA and lower PMT, had significantly worse pulmonary function, poorer exercise tolerance, decreased quality of life, and worse dyspnea scores. In addition, patients with acute COPD exacerbation, who had lower PMA and lower PMT, had a higher risk of respiratory failure on admission.

Conclusion:CT-derived measurements of the pectoralis muscle may be helpful in detecting declines in muscle quantity and quality and predicting disease severity in patients with COPD.
Expression Regulation of Water Reabsorption Genes and Transcription Factors in the Kidneys of Lepus yarkandensis
Authors: Luo Shengjie , Li Yongle , Li Shuwei , Jiang Renjun , Deng Fang , Liu Guoquan , Zhang Jianping
Published: June 2022

Lepus yarkandensis is a desert-dwelling animal that has various adaptations to cope with drought. The kidney maintains water and acid-base balance mainly through the vasopressin-regulated water reabsorption pathway and proximal tubular bicarbonate reabsorption pathway. In this study, we compared the differentially expressed genes (DEGs) and transcription factors in the kidneys of L. yarkandensis and Oryctolagus cuniculus to explore the relationship between the DEGs in kidneys and the animals’ adaptations. Transcriptome sequencing data were used to predict the differentially-expressed water reabsorption genes and their transcription factors. Quantitative real-time PCR, immunohistochemistry, and western blotting were used to detect and verify the expression of DEGs in the kidney at mRNA and protein levels. Transcriptome analysis of the kidney of L. yarkandensis and O. cuniculus showed that 6,610 genes were up-regulated and 5,727 genes down-regulated in data shared by both species. According to the data, 232 transcription factors and their corresponding target genes were predicted, from which genes and transcription factors related to renal water reabsorption were screened. Quantitative RT-PCR results showed AQP1, AQP2, ADCY3, HIF1A, CREB3, and NFATc1 had higher expression in the L. yarkandensis kidney; in comparison, FXYD2 mRNA expression levels were lower. In western blotting, transcription factors HIF1A, NFATc1, NF-κB1, and critical genes ADCY3, ATPA1, and SLC4A4, were highly expressed in the kidneys of L. yarkandensis. Immunohistochemical results showed that the ADCY3 protein was in the basolateral membrane of the collecting duct, the ATP1A1 protein was in the basolateral membrane and medulla of proximal tubules, and the SLC4A4 protein was in the basolateral membrane of proximal tubules. According to these results can be inferred that HIF1A, NFATc1, and NF-κB1 play a certain role in regulating the expression of genes related to water reabsorption in the kidney of L. yarkandensis, thus improving the water reclamation efficiency of L. yarkandensis, so as to adapt to the arid desert environment.
Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD
Authors: Taivassalo Tanja , Hepple Russell T.
Published: June 2022

The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology.
Dynamics of the Zebrafish Skeleton in Three Dimensions During Juvenile and Adult Development
Authors: Nguyen Stacy V. , Lanni Dominic , Xu Yongqi , Michaelson James S. , McMenamin Sarah K.
Published: June 2022

Zebrafish are a valuable model for normal vertebrate skeletogenesis and the study of myriad bone disorders. Bones grow, ossify and change shape throughout the zebrafish lifetime, and 3D technologies allow us to examine skeletogenic processes in detail through late developmental stages. To facilitate analysis of shape, orientation and tissue density of skeletal elements throughout ontogeny and adulthood, we generated a high-resolution skeletal reference dataset of wild-type zebrafish development. Using microCT technology, we produced 3D models of the skeletons of individuals ranging from 12 to 25 mm standard length (SL). We analyzed the dynamics of skeletal density and volume as they increase during juvenile and adult growth. Our resource allows anatomical comparisons between meristic units within an individual—e.g., we show that the vertebral canal width increases posteriorly along the spine. Further, structures may be compared between individuals at different body sizes: we highlight the shape changes that the lower jaw undergoes as fish mature from juvenile to adult. We show that even reproductively mature adult zebrafish (17–25 mm SL) continue to undergo substantial changes in skeletal morphology and composition with continued adult growth. We provide a segmented model of the adult skull and a series of interactive 3D PDFs at a range of key stages. These resources allow changes in the skeleton to be assessed quantitatively and qualitatively through late stages of development, and can serve as anatomical references for both research and education.
Effects of Forearm Compression Sleeves on Muscle Hemodynamics and Muscular Strength and Endurance Parameters in Sports Climbing: A Randomized, Controlled Crossover Trial
Authors: Limmer Mirjam , de Marées Markus , Roth Ralf
Published: June 2022

Purpose: Wearing compression garments is a commonly used intervention in sports to improve performance and facilitate recovery. Some evidence supports the use of forearm compression to improve muscle tissue oxygenation and enhance sports climbing performance. However, evidence is lacking for an effect of compression garments on hand grip strength and specific sports climbing performance. The purpose of this study was to evaluate the immediate effects of forearm compression sleeves on muscular strength and endurance of finger flexor muscles in sports climbers.

Materials and Methods: This randomized crossover study included 24 sports climbers who performed one familiarization trial and three subsequent test trials while wearing compression forearm sleeves (COMP), non-compressive placebo forearm sleeves (PLAC), or no forearm sleeves (CON). Test trials consisted of three performance measurements (intermittent hand grip strength and endurance measurements, finger hang, and lap climbing) at intervals of at least 48 h in a randomized order. Muscle oxygenation during hand grip and finger hang measurements was assessed by near-infrared spectroscopy. The maximum blood lactate level, rate of perceived exertion, and forearm muscle pain were also determined directly after the lap climbing trials.

Results: COMP resulted in higher changes in oxy[heme] and tissue oxygen saturation (StO2) during the deoxygenation (oxy[heme]: COMP –10.7 ± 5.4, PLAC –6.7 ± 4.3, CON –6.9 ± 5.0 [μmol]; p = 0.014, ηp2 = 0.263; StO2: COMP –4.0 ± 2.2, PLAC –3.0 ± 1.4, CON –2.8 ± 1.8 [%]; p = 0.049, ηp2 = 0.194) and reoxygenation (oxy [heme]: COMP 10.2 ± 5.3, PLAC 6.0 ± 4.1, CON 6.3 ± 4.9 [μmol]; p = 0.011, ηp2 = 0.274; StO2: COMP 3.5 ± 1.9, PLAC 2.4 ± 1.2, CON 2.3 ± 1.9 [%]; p = 0.028, ηp2 = 0.225) phases of hand grip measurements, whereas total [heme] concentrations were not affected. No differences were detected between the conditions for the parameters of peak force and fatigue index in the hand grip, time to failure and hemodynamics in the finger hang, or performance-related parameters in the lap climbing measurements (p ≤ 0.05).

Conclusions: Forearm compression sleeves did not enhance hand grip strength and endurance, sports climbing performance parameters, physiological responses, or perceptual measures. However, they did result in slightly more pronounced changes of oxy [heme] and StO2 in the deoxygenation and reoxygenation phases during the hand grip strength and endurance measurements.
Roles of NRF2 in Fibrotic Diseases: From Mechanisms to Therapeutic Approaches
Authors: Hao Wenlong , Li Minghao , Cai Qingmin , Wu Shiying , Li Xiangyao , He Quanyu , Hu Yongbin
Published: June 2022

Fibrosis is a persistent inflammatory response that causes scarring and tissue sclerosis by stimulating myofibroblasts to create significant quantities of extracellular matrix protein deposits in the tissue. Oxidative stress has also been linked to the development of fibrosis in several studies. The nuclear erythroid 2-related factor 2 (NRF2) transcription factor controls the expression of several detoxification and antioxidant genes. By binding to antioxidant response elements, NRF2 is activated by oxidative or electrophilic stress and promotes its target genes, resulting in a protective effect on cells. NRF2 is essential for cell survival under oxidative stress conditions. This review describes Kelch-like epichlorohydrin-associated protein 1 (KEAP1)/NRF2 signaling mechanisms and presents recent research advances regarding NRF2 and its involvement in primary fibrotic lesions such as pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, and renal fibrosis. The related antioxidant substances and drugs are described, along with the mechanisms by which KEAP1/NRF2 regulation positively affects the therapeutic response. Finally, the therapeutic prospects and potential value of NRF2 in fibrosis are summarized. Further studies on NRF2 may provide novel therapeutic approaches for fibrosis.
Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy
Authors: Wang Xian , Jiang Ling , Liu Xue-Qi , Huang Yue-Bo , Zhu Wei , Zeng Han-Xu , Gao Li , Ma Li-Juan , Zhang Meng-Ya , Zhu Qi-Jin , Wu Yong-Gui
Published: June 2022

Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN.

Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset.

Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group.

Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11).
Isolated Soy Protein Supplementation Combined With Resistance Training Improves Muscle Strength, Mass, and Physical Performance of Aging Female Mice
Authors: Lee Mon-Chien , Hsu Yi-Ju , Wu Fang-Yu , Huang Chi-Chang , Li Hsueh-Yu , Chen Wen-Chyuan
Published: June 2022

Background/Purpose: In recent years, the aging population has gradually increased, and the aging process is accompanied by health-associated problems, such as loss of muscle mass and weakness. Therefore, it is important to explore alternative strategies for improving the health status and physical fitness of the aged population. In this study, we investigated the effect of soy protein supplementation combined with resistance training on changes in the muscle mass, muscle strength, and functional activity performance of aging mice.

Methods: Female Institute of Cancer Research (ICR) mice were divided into four groups (n = 8 per group): sedentary control (SC), isolated soy protein (ISP) supplementation, resistance training (RT), and a combination of ISP and RT (ISP + RT). The mice in designated groups received oral ISP supplementation (0.123 g/kg/day), RT (5 days/week for a period of 4 weeks), or a combination of both ISP plus RT for 4 weeks. Afterward, we assessed muscle strength, endurance, and anaerobic endurance performance and analyzed blood biochemical and pathological tissue sections to investigate whether there were adverse effects or not in mice.

Results: ISP supplementation effectively improved the muscle mass, muscle endurance, and endurance performance of aging female mice. The RT group not only showed similar results with ISP but also increased muscle strength and glycogen content. Nevertheless, the combination of ISP supplementation and RT had greater beneficial effects on muscle strength, physical performance, and glycogen levels (p < 0.05). In addition, the combination of ISP supplementation and RT had significantly increased type II muscle percentage and cross-sectional area (p < 0.05).

Conclusion: Although ISP or RT alone improved muscle mass and performance, the combination of ISP with RT showed greater beneficial effects in aging mice. Our findings suggest that regular exercise along with protein supplementation could be an effective strategy to improve overall health and physical fitness among the elderly.
Optical Identification of Fruitfly Species Based on Their Wingbeats Using Convolutional Neural Networks
Authors: Kalfas Ioannis , De Ketelaere Bart , Beliën Tim , Saeys Wouter
Published: June 2022

The spotted wing Drosophila (SWD),Drosophila suzukii, is a significant invasive pest of berries and soft-skinned fruits that causes major economic losses in fruit production worldwide. Automatic identification and monitoring strategies would allow to detect the emergence of this pest in an early stage and minimize its impact. The small size ofDrosophila suzukiiand similar flying insects makes it difficult to identify them using camera systems. Therefore, an optical sensor recording wingbeats was investigated in this study. We trained convolutional neural network (CNN) classifiers to distinguishD. suzukiiinsects from one of their closest relatives,Drosophila Melanogaster, based on their wingbeat patterns recorded by the optical sensor. Apart from the original wingbeat time signals, we modeled their frequency (power spectral density) and time-frequency (spectrogram) representations. A strict validation procedure was followed to estimate the models’ performance in field-conditions. First, we validated each model on wingbeat data that was collected under the same conditions using different insect populations to train and test them. Next, we evaluated their robustness on a second independent dataset which was acquired under more variable environmental conditions. The best performing model, named “InceptionFly,” was trained on wingbeat time signals. It was able to discriminate between our two target insects with a balanced accuracy of 92.1% on the test set and 91.7% on the second independent dataset. This paves the way towards early, automated detection ofD. suzukiiinfestation in fruit orchards.