Association between life's essential 8 and male biochemical androgen deficiency: evidence from NHANES 2013-2016.

Purpose: To evaluate the association of Life's Essential 8 (LE8) and its subscales with male biochemical androgen deficiency (MBAD) and total testosterone based on the data from the national health and nutrition examination survey (NHANES) database. Methods: Data of males aged 20 years or older from NHANES of 2013-2016 were extracted. LE8 score was calculated based on American Heart Association definitions. Total testosterone (TT) values were measured in NHANES using precise isotope dilution liquid chromatography. MBAD was defined as serum TT of <300 ng/dL. Univariate and multivariable analyses were conducted. Propensity score matching (PSM) and weighted regression after matching were added as sensitivity analyses. The generalized additive model, smooth curve fitting, and the recursive algorithm were used to determine the potential inflection points. Piecewise regression models with log-likelihood ratio test were used to quantify nonlinear effects. Results: A total of 3094 participants who were males and aged 20 years or above were included. Out of them, 805 males were diagnosed with MBAD. After adjusting the confounders in the multivariable model, LE8 was independently associated with MBAD (OR 0.96, P < 0.001) and TT (ß 2.7, P < 0.001). The association remained robust even after PSM. The non-linear relationship of LE8 behaviors score with MBAD and TT was revealed. Conclusion: LE8 was an independent protective factor of MBAD and a feasible approach to promote male endocrine sexual function.

Research on molecular characteristics of ADME-related genes in kidney renal clear cell carcinoma.

Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are named ADME genes. However, the comprehensive role of ADME genes in kidney renal clear cell carcinoma (KIRC) remains unclear. Using the clinical and gene expression data of KIRC patients downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and the Gene Expression Omnibus (GEO) databases, we cluster patients into two patterns, and the population with a relatively poor prognosis demonstrated higher level of immunosuppressive cell infiltration and higher proportion of glycolytic subtypes. Then, 17 ADME genes combination identified through the least absolute shrinkage and selection operator algorithm (LASSO, 1000 times) was utilized to calculate the ADME score. The ADME score was found to be an independent predictor of prognosis in KIRC and to be tightly associated with the infiltration level of immune cells, metabolic properties, tumor-related signaling pathways, genetic variation, and responses to chemotherapeutics. Our work revealed the characteristics of ADME in KIRC. Assessing the ADME profiles of individual patients can deepen our comprehension of tumor microenvironment (TME) features in KIRC and can aid in developing more personalized and effective therapeutic strategies.

Intracardiac and Cerebral Thrombosis Complicated With Mycoplasma Pneumonia.

A seven-year-old girl developed multiposition thrombosis after fever and respiratory symptoms. Chest computed tomography (CT) scan demonstrated bilateral infiltrates, consolidation of the right lower lobe, and pleural effusion in the right lung field. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals in the brain with limited diffusion, and cerebral infarction could not be excluded. Echocardiography revealed hypoechoic mitral valve tips, which are likely to be suspected as vegetation. Mycoplasma pneumoniae infection was clarified by a four-fold increase in IgG antibodies to M. pneumoniae sera. D-dimer levels were elevated increasingly. We found and reported this rare pediatric case of an M. pneumoniae-induced severe pneumonia complicated with intracardiac and cerebral thrombosis. We investigate the clinical characteristics, diagnosis, and treatment of refractory mycoplasma pneumonia complicated with intracardiac and cerebral thrombosis in children.

CXCL10 could be a prognostic and immunological biomarker in bladder cancer.

INTRODUCTION: As proteins that promote immune cell differentiation, chemokines have attracted great interest regarding their role in anti-tumor immune responses within the cancer environment. However, the exact role of CXCL10, a chemokine, in bladder cancer (BLCA) is still not fully elucidated. METHOD: In the present study, we employed bioinformatics approaches to examine the expression pattern, prognostic value, and immune infiltration of CXCL10 in BLCA. Furthermore, we focused on examining the impact of CXCL10 on immune therapy in BLCA. Additionally, we validated the expression of CXCL10 in various BLCA cell lines using PCR techniques. RESULTS: We observed an upregulation of CXCL10 in BLCA tissues as well as in different cell lines. Additionally, upregulation of CXCL10 indicates a better prognosis for BLCA patients. ESTIMATE and CIBERSORT algorithms suggest that CXCL10 is closely associated with the immune microenvironment of BLCA. Through multiple immune therapy cohorts, we also identified that CXCL10 has shown promising predictive value for assessing the efficacy of immune therapy in in BLCA. CONCLUSION: Our study indicates that CXCL10 has the potential to serve as a favorable prognostic factor and is strongly associated with immune infiltration in BLCA.

A primary study of ethanol production in postmortem liver and muscle tissue of rats.

OBJECTIVE: To study the characteristics of postmortem ethanol production and its relation with alcohol congeners in postmortem rat liver and muscle tissues. METHOD: Postmortem liver and muscle tissues in Sprague-Dawley rats, from postmortem time interval (PMI) day 0-20, were analyzed via headspace gas chromatograph flame ionization detection to observe production of postmortem ethanol and 5 selected alcohol congeners. RESULT: 1. Putrid ethanol production increased gradually to a peak and then decreased with the prolongation of PMI; 2. Acetaldehyde, 1-propanol, and 3-methyl-butyraldehyde were produced along with postmortem ethanol; 1-butanol was only detected from day 11-20; 3. The concentrations of acetaldehyde, 1-propanol and 3-methyl-butyraldehyde was related with ethanol production. Fifteen mathematical models were constructed for putrid ethanol production based on acetaldehyde, 1-propanol, and 3-methyl-butyraldehyde. CONCLUSION: A peak in postmortem ethanol production was identified. The production trends of acetaldehyde, 1-propanol, and 3-methyl-butyraldehyde in the liver, and of 1-propanol in muscle, were consistent with those of ethanol, and could potentially to be used as biomarkers of postmortem ethanol production. Further human samples and data analysis are needed to verify this.

The Role of Protein Degradation in Estimation Postmortem Interval and Confirmation of Cause of Death in Forensic Pathology: A Literature Review.

It is well known that proteins are important bio-macromolecules in human organisms, and numerous proteins are widely used in the clinical practice, whereas their application in forensic science is currently limited. This limitation is mainly attributed to the postmortem degradation of targeted proteins, which can significantly impact final conclusions. In the last decade, numerous methods have been established to detect the protein from a forensic perspective, and some of the postmortem proteins have been applied in forensic practice. To better understand the emerging issues and challenges in postmortem proteins, we have reviewed the current application of protein technologies at postmortem in forensic practice. Meanwhile, we discuss the application of proteins in identifying the cause of death, and postmortem interval (PMI). Finally, we highlight the interpretability and limitations of postmortem protein challenges. We believe that utilizing the multi-omics method can enhance the comprehensiveness of applying proteins in forensic practice.

Neural Correlates of Early-Life Urbanization and Their Spatial Relationships with Gene Expression, Neurotransmitter, and Behavioral Domain Atlases.

Previous neuroimaging research has established associations between urban exposure during early life and alterations in brain function and structure. However, the molecular mechanisms and behavioral relevance of these associations remain largely unknown. Here, we aimed to address this question using a combined analysis of multimodal data. Initially, we calculated amplitude of low-frequency fluctuations (ALFF) and gray matter volume (GMV) using resting-state functional and structural MRI to investigate their associations with early-life urbanization in a large sample of 511 healthy young adults. Then, we examined the spatial relationships of the identified neural correlates of early-life urbanization with gene expression, neurotransmitter, and behavioral domain atlases. Results showed that higher early-life urbanization scores were correlated with increased ALFF of the right fusiform gyrus and decreased GMV of the left dorsal medial prefrontal cortex and left precuneus. Remarkably, the identified neural correlates of early-life urbanization were spatially correlated with expression of gene categories primarily involving immune system process, signal transduction, and cellular metabolic process. Concurrently, there were significant associations between the neural correlates and specific neurotransmitter systems including dopamine, acetylcholine, and serotonin. Finally, we found that the ALFF correlates were associated with behavioral terms including "perception," "sensory," "cognitive control," and "reasoning." Apart from expanding existing knowledge of early-life urban environmental risk for mental disorders and health in general, our findings may contribute to an emerging framework for integrating social science, neuroscience, genetics, and public policy to respond to the major health challenge of world urbanization.

Catalytic Synthesis of Silanols by Hydroxylation of Hydrosilanes: From Chemoselectivity to Enantioselectivity.

As a crucial class of functional molecules in organosilicon chemistry, silanols are found valuable applications in the fields of modern science and will be a potentially powerful framework for biologically active compounds or functional materials. It has witnessed an increasing demand for non-natural organosilanols, as well as the progress in the synthesis of these structural features. From the classic preparative methods to the catalytic selective oxidation of hydrosilanes, electrochemical hydrolysis of hydrosilanes, and then the construction of the most challenging silicon-stereogenic silanols. This review summarized the progress in the catalyzed synthesis of silanols via hydroxylation of hydrosilanes in the last decade, with a particular emphasis on the latest elegant developments in the desymmetrization strategy for the enantioselective synthesis of silicon-stereogenic silanols from dihydrosilanes.

An unusual autocatalysis with an air-stable Pd complex to promote enantioselective synthesis of Si-stereogenic enynes.

Given the powerful potential of chiral-at-silicon chemistry, enantioselective synthesis of Si-stereogenic centers has attracted substantial research interest in recent years. However, the catalytic asymmetric synthesis of Si-stereogenic organosilicon compounds remains an appealing venture and is a challenging subject because of the difficulty in achieving high reactivity and stereoselectivity for "silicon-center" transformations. Herein, we disclose a highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes, which enables the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields and excellent ees (up to >99%) by desymmetrization. The unusual stereoselectivity in this reaction is achieved by precisely controlling the steric hindrance and electronic effect of the newly developed chiral ligands, resulting in a wide range of chiral silanes and a Si-containing polymer bearing a Si-stereogenic center which is otherwise difficult to access. The key to the high enantioselectivity relies on catalyst aggregation-induced non-covalent interaction, which exerts a remarkably positive influence on the Si-H bond activation and enhancement of enantioselectivity, in which the palladium/P-ligand complex was proved to be air-stable and moisture-insensitive in this reaction.

Cerebral blood flow changes and their genetic mechanisms in major depressive disorder: a combined neuroimaging and transcriptome study.

BACKGROUND: Extensive research has shown abnormal cerebral blood flow (CBF) in patients with major depressive disorder (MDD) that is a heritable disease. The objective of this study was to investigate the genetic mechanisms of CBF abnormalities in MDD. METHODS: To achieve a more thorough characterization of CBF changes in MDD, we performed a comprehensive neuroimaging meta-analysis of previous literature as well as examined group CBF differences in an independent sample of 133 MDD patients and 133 controls. In combination with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial association analyses were conducted to identify genes whose expression correlated with CBF changes in MDD, followed by a set of gene functional feature analyses. RESULTS: We found increased CBF in the reward circuitry and default-mode network and decreased CBF in the visual system in MDD patients. Moreover, these CBF changes were spatially associated with expression of 1532 genes, which were enriched for important molecular functions, biological processes, and cellular components of the cerebral cortex as well as several common mental disorders. Concurrently, these genes were specifically expressed in the brain tissue, in immune cells and neurons, and during nearly all developmental stages. Regarding behavioral relevance, these genes were associated with domains involving emotion and sensation. In addition, these genes could construct a protein-protein interaction network supported by 60 putative hub genes with functional significance. CONCLUSIONS: Our findings suggest a cerebral perfusion redistribution in MDD, which may be a consequence of complex interactions of a wide range of genes with diverse functional features.

Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.

In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy.

Vibrio salinus sp. nov., a marine nitrogen-fixing bacterium isolated from the lagoon sediment of an islet inside an atoll in the western Pacific Ocean.

A marine, facultatively anaerobic, nitrogen-fixing bacterium, designated strain DNF-1T, was isolated from the lagoon sediment of Dongsha Island, Taiwan. Cells grown in broth cultures were Gram-negative rods that were motile by means of monotrichous flagella. Cells grown on plate medium produced prosthecae and vesicle-like structures. NaCl was required and optimal growth occurred at about 2-3% NaCl, 25-30 °C and pH 7-8. The strain grew aerobically and was capable of anaerobic growth by fermenting D-glucose or other carbohydrates as substrate. Both the aerobic and anaerobic growth could be achieved with NH4Cl as a sole nitrogen source. When N2 served as the sole nitrogen source only anaerobic growth was observed. Major cellular fatty acids were C14:0, C16:0 and C16:1 ω7c, while major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content was 42.2 mol% based on the genomic DNA data. Phylogenetic analyses based on 16S rRNA genes and the housekeeping genes, gapA, pyrH, recA and gyrB, revealed that the strain formed a distinct lineage at species level in the genus Vibrio of the family Vibrionaceae. These results and those from genomic, chemotaxonomic and physiological studies strongly support the assignment of a novel Vibrio species. The name Vibrio salinus sp. nov. is proposed for the novel species, with DNF-1T (= BCRC 81209T = JCM 33626T) as the type strain. This newly proposed species represents the second example of the genus Vibrio that has been demonstrated to be capable of anaerobic growth by fixing N2 as the sole nitrogen source.

The potential prolonged effect at one-year follow-up after 18-month randomized controlled trial of a 90 g/day low-carbohydrate diet in patients with type 2 diabetes.

OBJECTIVES: To evaluate the effect at a one-year follow-up after an 18-month randomized controlled trial (RCT) of 90 gm/day low-carbohydrate diet (LCD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Eighty-five poorly controlled type 2 diabetic patients with an initial HbA1c ≥ 7.5% who have completed an 18-month randomized controlled trial (RCT) on 90 g/day low-carbohydrate diet (LCD) were recruited and followed for one year. A three-day weighted food record, relevant laboratory tests, and medication effect score (MES) were obtained at the end of the previous trial and one year after for a total of 30 months period on specific diet. RESULTS: 71 (83.5%) patients completed the study, 35 were in TDD group and 36 were in LCD group. Although the mean of percentage changes in daily carbohydrate intake was significantly lower for those in TDD group than those in LCD group (30.51 ± 11.06% vs. 55.16 ± 21.79%, p = 0.0455) in the period between 18 months and 30 months, patients in LCD group consumed significantly less amount of daily carbohydrate than patients in TDD group (131.8 ± 53.9 g vs. 195.1 ± 50.2 g, p < 0.001). The serum HbA1C, two-hour serum glucose, serum alanine aminotransferase (ALT), and MES were also significantly lower for the LCD group patients than those in the TDD group (p = 0.017, p < 0.001, p = 0.017, and p = 0.008 respectively). The mean of percentage changes of HbA1C, fasting serum glucose, 2 h serum glucose, as well as serum cholesterol, triglyceride, low-density lipoprotein, ALT, creatinine, and urine microalbumin, however, were not significantly different between the two groups (p > 0.05). CONCLUSIONS: The one-year follow-up for patients on 90 g/d LCD showed potential prolonged and better outcome on glycaemic control, liver function and MES than those on TDD for poorly controlled diabetic patients.

Highly Diastereoselective Hydrosilane-Assisted Rhodium-Catalyzed Spiro-Type Cycloisomerization of Succinimide and Pyrazolone-Based Functional 1,6-Dienes.

Organosilicon compounds are important reagents and synthetic intermediates that play a key role in the construction of new materials and complex products. Here we show a highly diastereoselective rhodium-catalyzed cycloisomerization of 1,6-dienes, in which the use of (EtO)3 SiH accelerates the intramolecular cyclization reaction to afford a novel spiro-fused succinimide and pyrazolone derivatives in moderate to excellent yields as a single diastereoisomer. The proposed mechanism involves an active Rh-H species from the hydrosilane that is the H-donor in this spiro-type cycloisomerization reaction.

Vibrio nitrifigilis sp. nov., a marine nitrogen-fixing bacterium isolated from the lagoon sediment of an islet inside an atoll.

A nitrogen-fixing isolate of facultatively anaerobic, marine bacterium, designated strain NFV-1T, was recovered from the lagoon sediment of Dongsha Island, Taiwan. It was a Gram-negative rod which exhibited motility with monotrichous flagellation in broth cultures. The strain required NaCl for growth and grew optimally at about 25-35 °C, 3% NaCl and pH 7-8. It grew aerobically and could achieve anaerobic growth by fermenting D-glucose or other carbohydrates as substrates. NH4Cl could serve as a sole nitrogen source for growth aerobically and anaerobically, whereas growth with N2 as the sole nitrogen source was observed only under anaerobic conditions. Cellular fatty acids were predominated by C16:1 ω7c, C16:0, and C18:1 ω7c. The major polar lipids consisted of phosphatidylethanolamine and phosphatidylserine. Strain NFV-1T had a DNA G + C content of 42.5 mol%, as evaluated according to the chromosomal DNA sequencing data. Analyses of sequence similarities and phylogeny based on the 16S rRNA genes, together with the housekeeping genes, gyrB, ftsZ, mreB, topA and gapA, indicated that the strain formed a distinct species-level lineage in the genus Vibrio of the family Vibrionaceae. These phylogenetic data and those from genomic and phenotypic characterisations support the establishment of a novel Vibrio species, for which the name Vibrio nitrifigilis sp. nov. (type strain NFV-1T = BCRC 81211T = JCM 33628T) is proposed.

Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer.

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.

Adjacent segment disease following Dynesys stabilization for lumbar disorders: A case series of mid- and long-term follow-ups.

BACKGROUND: Radiologic adjacent segment degeneration (ASDeg) can occur after spinal surgery. Adjacent segment disease (ASDis) is defined as the development of new clinical symptoms corresponding to radiographic changes adjacent to the level of previous spinal surgery. Greater pre-existing ASDeg is generally considered to result in more severe ASDis; nonetheless, whether the ASDeg status before index surgery influences the postoperative risk of revision surgery due to ASDis warrants investigation. AIM: To identify possible risk factors for ASDis and verify the concept that greater preexisting ASDeg leads to more severe ASDis. METHODS: Data from 212 patients who underwent posterior decompression with Dynesys stabilization from January 2006 to June 2016 were retrospectively analyzed. Patients who underwent surgery for ASDis were categorized as group A (n = 13), whereas those who did not were classified as group B (n = 199). Survival analysis and Cox proportional hazards models were used to compare the modified Pfirrmann grade, University of California-Los Angeles grade, body mass index, number of Dynesys-instrumented levels, and age. RESULTS: The mean time of reoperation was 7.22 (1.65-11.84) years in group A, and the mean follow-up period was 6.09 (0.10-12.76) years in group B. No significant difference in reoperation risk was observed: Modified Pfirrmann grade 3 vs 4 (P = 0.53) or 4 vs 5 (P = 0.46) for the upper adjacent disc, University of California-Los Angeles grade 2 vs 3 for the upper adjacent segment (P = 0.66), age of < 60 vs > 60 years (P = 0.9), body mass index < 25 vs > 25 kg/m2 (P = 0.3), and sex (P = 0.8). CONCLUSION: Greater preexisting upper ASDeg was not associated with a higher rate of reoperation for ASDis after Dynesys surgery. Being overweight tended to increase reoperation risk after Dynesys surgery for ASDis.

Effect of a 90 g/day low-carbohydrate diet on glycaemic control, small, dense low-density lipoprotein and carotid intima-media thickness in type 2 diabetic patients: An 18-month randomised controlled trial.

AIM: This study explored the effect of a moderate (90 g/d) low-carbohydrate diet (LCD) in type 2 diabetes patients over 18 months. METHODS: Ninety-two poorly controlled type 2 diabetes patients aged 20-80 years with HbA1c ≥7.5% (58 mmol/mol) in the previous three months were randomly assigned to a 90 g/d LCD r traditional diabetic diet (TDD). The primary outcomes were glycaemic control status and change in medication effect score (MES). The secondary outcomes were lipid profiles, small, dense low-density lipoprotein (sdLDL), serum creatinine, microalbuminuria and carotid intima-media thickness (IMT). RESULTS: A total of 85 (92.4%) patients completed 18 months of the trial. At the end of the study, the LCD and TDD group consumed 88.0±29.9 g and 151.1±29.8 g of carbohydrates, respectively (p < 0.05). The 18-month mean change from baseline was statistically significant for the HbA1c (-1.6±0.3 vs. -1.0±0.3%), 2-h glucose (-94.4±20.8 vs. -18.7±25.7 mg/dl), MES (-0.42±0.32 vs. -0.05±0.24), weight (-2.8±1.8 vs. -0.7±0.7 kg), waist circumference (-5.7±2.7 vs. -1.9±1.4 cm), hip circumference (-6.1±1.8 vs. -2.9±1.7 cm) and blood pressure (-8.3±4.6/-5.0±3 vs. 1.6±0.5/2.5±1.6 mmHg) between the LCD and TDD groups (p<0.05). The 18-month mean change from baseline was not significantly different in lipid profiles, sdLDL, serum creatinine, microalbuminuria, alanine aminotransferase (ALT) and carotid IMT between the groups. CONCLUSIONS: A moderate (90 g/d) LCD showed better glycaemic control with decreasing MES, lowering blood pressure, decreasing weight, waist and hip circumference without adverse effects on lipid profiles, sdLDL, serum creatinine, microalbuminuria, ALT and carotid IMT than TDD for type 2 diabetic patients.