RESUMEN

Background: Identification of the unknown pathogenic factor driving atherosclerosis not only enhances the development of disease biomarkers but also facilitates the discovery of new therapeutic targets, thus contributing to the improved management of coronary artery disease (CAD). We aimed to identify causative protein biomarkers in CAD etiology based on proteomics and 2-sample Mendelian randomization (MR) design. Methods: Serum samples from 33 first-onset CAD patients and 31 non-CAD controls were collected and detected using protein array. Differentially expressed analyses were used to identify candidate proteins for causal inference. We used 2-sample MR to detect the causal associations between the candidate proteins and CAD. Network MR was performed to explore whether metabolic risk factors for CAD mediated the risk of identified protein. Vascular expression of candidate protein in situ was also detected. Results: Among the differentially expressed proteins identified utilizing proteomics, we found that circulating Golgi protein 73 (GP73) was causally associated with incident CAD and other atherosclerotic events sharing similar etiology. Network MR approach showed low-density lipoprotein cholesterol and glycated hemoglobin serve as mediators in the causal pathway, transmitting 42.1% and 8.7% effects from GP73 to CAD, respectively. Apart from the circulating form of GP73, both mouse model and human specimens imply that vascular GP73 expression was also upregulated in atherosclerotic lesions and concomitant with markers of macrophage and phenotypic switching of vascular smooth muscle cells (VSMCs). Conclusions: Our study supported GP73 as a biomarker and causative for CAD. GP73 may involve in CAD pathogenesis mainly via dyslipidemia and hyperglycemia, which may enrich the etiological information and suggest future research direction on CAD.

Asunto(s)

Biomarcadores , Enfermedad de la Arteria Coronaria , Proteínas de la Membrana , Análisis de la Aleatorización Mendeliana , Proteómica , Humanos , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Ratones , Animales , Proteínas de la Membrana/genética , Proteínas de la Membrana/sangre , Masculino , Femenino , Biomarcadores/sangre , Persona de Mediana Edad , LDL-Colesterol/sangre , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Estudios de Casos y Controles , Aterosclerosis/sangre , Aterosclerosis/genética

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Anaerobic microbiologically influenced corrosion (MIC) of Fe (0) metals causes great harm to the environment and economy, which depends on the key electron transfer process between anaerobic microorganisms and Fe (0) metals. However, the key electron transfer process in microbiota dominating MIC remains unclear, especially for methanogenic microbiota wildly distributed in the environment. Herein, three different methanogenic microbiota (Methanothrix, Methanospirillum, and Methanobacterium) were acclimated to systematically investigate electron transfer pathways on corroding Q235A steel coupons. Results indicated that microbiota dominated by Methanothrix, Methanospirillum, or Methanobacterium accelerated the steel corrosion mainly through direct electron transfer (DET) pathway, H2 mediated electron transfer (HMET) pathway, and combined DET and HMET pathways, respectively. Compared with Methanospirillum dominant microbiota, Methanothrix or Methanobacterium dominant microbiota caused more methane production, higher weight loss, corrosion pits with larger areas, higher corrosion depth, and smaller corrosion pits density. Such results reflected that the DET process between microbiota and Fe (0) metals decided the biocorrosion degree and behavior of Fe (0) metals. This study insightfully elucidates the mechanisms of methanogenic microbiota on corroding steels, in turn providing new insights for anti-corrosion motives.

Asunto(s)

Hierro , Metano , Microbiota , Acero , Corrosión , Metano/metabolismo , Hierro/metabolismo , Transporte de Electrón

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Penile cancer is a rare malignant tumor of the male urinary system. The treatment benefit of standard first-line chemotherapy is not ideal for patients with locally advanced or metastatic lymph nodes. Immunotherapy has brought new treatment strategies and opportunities for patients with penile cancer. At present, clinical studies on immunotherapy for penile cancer have been reported, and the results show that it is effective but not conclusive. With the development of immunotherapy and the progress of molecular research technology, we can better screen the immunotherapy response population and explore new combination treatment regimens to evaluate the best combination regimen and obtain the optimal treatment options, which is also an important research direction for the immunotherapy of penile cancer in the future.

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A woman in her mid-20s presented with acute fever, chest pain, and exertional dyspnea. Electrocardiogram results showed sinus tachycardia, QRS widening, low-voltage complexes, and ST-segment elevation. What would you do next?

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BACKGROUND: Lymphatic metastasis is the major challenge in the treatment of penile cancer. The prognosis of individuals with lymphatic metastasis is extremely poor. Therefore, early identification of disease progression and lymphatic metastasis is an urgent task for researchers in penile cancer worldwide. METHODS: In this study, using single-cell RNA sequencing, an immune landscape was established for the cancer ecosystem based on 46,861 cells from six patients with penile cancer (four with lymphatic metastasis [stage IV] and two without lymphatic metastasis [stage I]). Using bulk RNA sequencing, the discrepancy between the cancers and their respective metastatic lymph nodes was depicted based on seven patients with penile cancer. RESULTS: The interaction between epithelial cells, fibroblasts, and endothelial cells, and the functional cooperation among invasion, epithelial-mesenchymal transition, and angiogenesis were found to be important landscapes in the penile cancer ecosystem, playing important roles in progression of cancer and lymph node metastasis. CONCLUSIONS: This study is the first to investigate the altered tumor microenvironment heterogeneity of penile cancer as it evolves from non-lymphatic to lymphatic metastasis and provides insights into the mechanisms underlying malignant progression, the premetastatic niche, and lymphatic metastasis in penile cancer.

Asunto(s)

Progresión de la Enfermedad , Metástasis Linfática , Neoplasias del Pene , Microambiente Tumoral , Humanos , Masculino , Neoplasias del Pene/patología , Transición Epitelial-Mesenquimal , Análisis de la Célula Individual , Persona de Mediana Edad , Pronóstico , Ganglios Linfáticos/patología

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The gut microbiota has been demonstrated to play a significant role in the pathogenesis of Parkinson's disease (PD). However, conflicting findings regarding specific microbial species have been reported, possibly due to confounding factors within human populations. Herein, our current study investigated the interaction between the gut microbiota and host in a non-human primate (NHP) PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a multi-omic approach and a self-controlled design. Our transcriptomic sequencing of peripheral blood leukocytes (PBL) identified key genes involved in pro-inflammatory cytokine dysregulation, mitochondrial function regulation, neuroprotection activation, and neurogenesis associated with PD, such as IL1B, ATP1A3, and SLC5A3. The metabolomic profiles in serum and feces consistently exhibited significant alterations, particularly those closely associated with inflammation, mitochondrial dysfunctions and neurodegeneration in PD, such as TUDCA, ethylmalonic acid, and L-homophenylalanine. Furthermore, fecal metagenome analysis revealed gut dysbiosis associated with PD, characterized by a significant decrease in alpha diversity and altered commensals, particularly species such as Streptococcus, Butyrivibrio, and Clostridium. Additionally, significant correlations were observed between PD-associated microbes and metabolites, such as sphingomyelin and phospholipids. Importantly, PDPC significantly reduced in both PD monkey feces and serum, exhibiting strong correlation with PD-associated genes and microbes, such as SLC5A3 and Butyrivibrio species. Moreover, such multi-omic differential biomarkers were linked to the clinical rating scales of PD monkeys. Our findings provided novel insights into understanding the potential role of key metabolites in the host-microbiota interaction involved in PD pathogenesis.

Asunto(s)

Heces , Microbioma Gastrointestinal , Macaca fascicularis , Animales , Heces/microbiología , Modelos Animales de Enfermedad , Disbiosis/microbiología , Masculino , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Trastornos Parkinsonianos/microbiología , Trastornos Parkinsonianos/metabolismo , Metabolómica/métodos , Metaboloma , Interacciones Microbiota-Huesped , Multiómica

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BACKGROUND: Cardiac aging represents an independent risk factor for aging-associated cardiovascular diseases. Although evidence suggests an association between NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome formation and numerous cardiovascular diseases, its role in cardiac aging remains largely unclear. METHODS AND RESULTS: The longevity of mice with wild-type and NLRP3 knockout (NLRP3-/-) genotypes was assessed, with or without d-galactose treatment. Cardiac function was evaluated using echocardiography, and cardiac histopathology was examined through hematoxylin and eosin and Masson's trichrome staining. Senescence-associated ß-galactosidase (SA-ß-gal) staining was employed to detect cardiac aging. Western blotting was used to assess aging-related proteins (p53, p21) and pyroptosis-related proteins. Additionally, dihydroethidium staining, lactate dehydrogenase release, and interleukin-1ß ELISA assays were performed, along with measurements of total superoxide dismutase and malondialdehyde levels. In vitro, H9c2 cells were exposed to d-galactose for 24 hours in the absence or presence of N-acetyl-l-cysteine (reactive oxygen species inhibitor), BAY-117082 (nuclear factor κ-light-chain enhancer of activated B cells inhibitor), MCC950 (NLRP3 inhibitor), and VX-765 (Caspase-1 inhibitor). Immunofluorescence staining was employed to detect p53, gasdermin D, and apoptosis-associated speck-like protein proteins. Intracellular reactive oxygen species levels were assessed using fluorescence microscopy and flow cytometry. Senescence-associated ß-galactosidase staining and Western blotting were also employed in vitro for the same purpose. The results showed that NLRP3 upregulation was implicated in aging and cardiovascular diseases. Inhibition of NLRP3 extended life span, mitigated the aging phenotype, improved cardiac function and blood pressure, ameliorated lipid metabolism abnormalities, inhibited pyroptosis in cardiomyocytes, and ultimately alleviated cardiac aging. In vitro, the inhibition of reactive oxygen species, nuclear factor κ-light-chain enhancer of activated B cells, NLRP3, or caspase-1 attenuated NLRP3 inflammasome-mediated pyroptosis. CONCLUSIONS: The reactive oxygen species/nuclear factor κ-light-chain enhancer of activated B cells/NLRP3 signaling pathway loop contributes to d-galactose-treated cardiomyocyte senescence and cardiac aging.

Asunto(s)

Galactosa , Inflamasomas , Ratones Noqueados , Miocitos Cardíacos , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Galactosa/toxicidad , Galactosa/metabolismo , Piroptosis/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Inflamasomas/metabolismo , Ratones , Envejecimiento/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Senescencia Celular/efectos de los fármacos , Masculino , Especies Reactivas de Oxígeno/metabolismo , FN-kappa B/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Ratas

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The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.

Asunto(s)

Proteínas Co-Represoras , Interleucina-10 , Ratones Noqueados , Microglía , Enfermedades Neuroinflamatorias , PPAR gamma , Transducción de Señal , Animales , Masculino , Ratones , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Depresión/metabolismo , Depresión/etiología , Interleucina-10/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/efectos de los fármacos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , PPAR gamma/metabolismo , PPAR gamma/genética , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos

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BACKGROUND: Magnetic resonance enteroclysis (MRE) has been widely applied to diagnose Crohn's disease (CD). Magnetic resonance (MR) at 3.0 T improves signal-to-noise ratio (SNR), shortens image acquisition time, and shows more advantages. OBJECTIVE: This study aimed to retrospectively analyze the diagnostic value of 3.0 T MR imaging for active CD. METHODS: 48 CD patients hospitalized in our hospital from January 2021 to December 2022 were selected as the study subjects. These 48 CD patients underwent both double-balloon enteroscopy and 3.0 T MRE. All patients' arterial phase signal, venous phase signal, bowel wall, and bowel lumen of MRE were observed to identify whether they suffered from active CD. Based on the results of enteroscopy, the number of true positives, true negatives, false negatives, and false positives diagnosed by MRE were screened; next, the diagnostic accuracy, sensitivity, and specificity of MRE in assessing active CD were calculated. RESULTS: Of the 48 patients, 39 were diagnosed with small bowel CD by MRE, which was not significantly different from the results of enteroscopy (P>0.05). According to MRE diagnostic results, the arterial phase predominantly presented high signal intensity, and the venous phase mainly presented low signal intensity or isointensity. Small bowel CD lesions were primarily characterized by bowel wall thickening, rare pneumatosis enhancement of the bowel wall, bowel lumen pneumatosis or dilatation, and rare strictures. Besides, MRE presented an accuracy of 93.75%, sensitivity of 97.37%, and specificity of 80.00% in diagnosing CD. CONCLUSION: 3.0 T MR imaging has diagnostic value for active CD and shows certain clinical application value.

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Asunto(s)

Enfermedad de Crohn , Imagen por Resonancia Magnética , Sensibilidad y Especificidad , Humanos , Enfermedad de Crohn/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Masculino , Femenino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Adulto Joven , Relación Señal-Ruido , Adolescente , Enteroscopía de Doble Balón/métodos , Intestino Delgado/diagnóstico por imagen

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BACKGROUND: It is unclear whether alternating placements during clinical clerkship, without an explicit emphasis on clinical competencies, would bring about optimal educational outcomes. METHODS: This is an explanatory sequential mixed-methods research. We enrolled a convenience sample of 41 eight-year programme medical students in Sun Yat-sen University who received alternating placements during clerkship. The effects of competence-based approach (n = 21) versus traditional approach (n = 20) to clerkship teaching were compared. In the quantitative phase, course satisfaction was measured via an online survey and academic performance was determined through final scores on summative assessment. Then, in the qualitative phase, students were invited for semi-structured interviews about their learning experiences, and the transcripts were used for thematic analysis. RESULTS: Quantitative findings showed that students in the study group rated high course satisfaction and performed significantly better in their final scores compared with those in the control group. Qualitative findings from thematic analysis showed that students were relatively neutral about their preference on placement models, but clearly perceived, capitalised, and appreciated that their competencies were being cultivated by an instructor who was regarded as a positive role model. CONCLUSION: A competence-based approach to clerkship teaching resulted in better course satisfaction and academic performance, and was perceived, capitalised, and appreciated by students.

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Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.

Asunto(s)

Progresión de la Enfermedad , Quinasas Janus , Metástasis Linfática , Neoplasias del Pene , Factor de Transcripción STAT4 , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Masculino , Neoplasias del Pene/patología , Neoplasias del Pene/genética , Neoplasias del Pene/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Metástasis Linfática/patología , Metástasis Linfática/genética , Quinasas Janus/metabolismo , Factor de Transcripción STAT4/metabolismo , Factor de Transcripción STAT4/genética , Regulación Neoplásica de la Expresión Génica , Carcinogénesis/genética , Carcinogénesis/patología , Transducción de Señal , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología

RESUMEN

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and ß-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

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E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPlus, Lancaster, CA, USA). Furthermore, tissue distribution and the human PK profiles of different administration dosages and forms were predicted. The 0.002 L/h of CL and 0.005 L of Vss in mice were calculated and optimized from observed PK data. The plasma exposure of E0703 was availably predicted by the CL using the simple allometry (SA) method. The plasma concentration-time profiles of other dosages (20 and 40 mg) and two oral administrations (30 mg) were well-fitted to the observed values. In addition, the PK profile of target organs for E0703 exhibited a higher peak concentration (Cmax) and AUC than plasma. The developed E0703-PBPK model, which is precisely applicable to multiple species, benefits from further clinical development to predict PK in humans.

Asunto(s)

Protectores contra Radiación , Ratones , Humanos , Animales , Perros , Modelos Biológicos , Administración Oral , Distribución Tisular , Farmacocinética

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Prunin of desirable bioactivity and bioavailability can be transformed from plant-derived naringin by the key enzyme α-L-rhamnosidase. However, the production was limited by unsatisfactory properties of α-L-rhamnosidase such as thermostability and organic solvent tolerance. In this study, biochemical characteristics, and hydrolysis capacity of a novel α-L-rhamnosidase from Spirochaeta thermophila (St-Rha) were investigated, which was the first characterized α-L-rhamnosidase for Spirochaeta genus. St-Rha showed a higher substrate specificity towards naringin and exhibited excellent thermostability and methanol tolerance. The Km of St-Rha in the methanol cosolvent system was decreased 7.2-fold comparing that in the aqueous phase system, while kcat/Km value of St-Rha was enhanced 9.3-fold. Meanwhile, a preliminary conformational study was implemented through comparative molecular dynamics simulation analysis to explore the mechanism underlying the methanol tolerance of St-Rha for the first time. Furthermore, the catalytic ability of St-Rha for prunin preparation in the 20% methanol cosolvent system was explored, and 200 g/L naringin was transformed into 125.5 g/L prunin for 24 h reaction with a corresponding space-time yield of 5.2 g/L/h. These results indicated that St-Rha was a novel α-L-rhamnosidase suitable for hydrolyzing naringin in the methanol cosolvent system and provided a better alternative for improving the efficient production yield of prunin.

Asunto(s)

Florizina/análogos & derivados , Spirochaeta , Metanol , Glicósido Hidrolasas/química , Solventes

RESUMEN

Background: The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. Methods: In this study, TCGA, Kaplan-Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co-expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Results: Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p < 0.0001) in the prognosis of KIRC. Immunotherapy (anti-PD-1 therapy, anti-PD-L1 therapy, and anti-CTLA4 therapy) and immunomodulator (immunoinhibitor, immunostimulator, and MHC molecule) in KIRC were significant associated with pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4), which were the important addition to clinical decision making for patients. Conclusions: Our study uncovered a mechanism for the effect of pain genes on KIRC outcome via the modulation of associated co-expression gene networks, gene variation, and tumor Immunotherapy.

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Although the primate brain contains numerous functionally distinct structures that have experienced diverse genetic changes during the course of evolution and development, these changes remain to be explored in detail. Here we utilize two classic metrics from evolutionary biology, the evolutionary rate index (ERI) and the transcriptome age index (TAI), to investigate the evolutionary alterations that have occurred in each area and developmental stage of the primate brain. We observed a higher evolutionary rate for those genes expressed in the non-cortical areas during primate evolution, particularly in human, with the highest rate of evolution being exhibited at brain developmental stages between late infancy and early childhood. Further, the transcriptome age of the non-cortical areas was lower than that of the cerebral cortex, with the youngest age apparent at brain developmental stages between late infancy and early childhood. Our exploration of the evolutionary patterns manifest in each brain area and developmental stage provides important reference points for further research into primate brain evolution.

Asunto(s)

Encéfalo , Primates , Animales , Humanos , Preescolar , Primates/genética , Perfilación de la Expresión Génica , Corteza Cerebral , Genómica

RESUMEN

AIMS: Red blood cell distribution width-to-albumin ratio (RAR), an innovate biomarker of inflammation, can independently predict adverse cardiovascular outcomes. However, the association between RAR and prognosis in patients with non-ischaemic heart failure (NIHF) remains unclear. METHODS AND RESULTS: A total of 2077 NIHF patients admitted to the Heart Failure Care Unit, Fuwai Hospital, were consecutively enrolled from December 2006 to October 2017 in this retrospective study. The primary endpoint was a composite outcome of all-cause mortality and heart transplantation. The correlation between RAR and the composite outcome was assessed by the Kaplan-Meier survival analysis and the Cox regression analysis. Incremental predictive values and the clinical performance of RAR for all-cause mortality or heart transplantation were also assessed based on a 12-variable traditional risk model. The median follow-up time in this study was 1433 (1341, 1525) days. As the gender no longer satisfied the Cox proportional risk assumption after 1150 days, we set 1095 days as the follow-up time for analysis. A total of 500 patients reached the composite outcome. Multivariable Cox regression showed that per log2 increase of RAR was significantly associated with a 132.9% [hazard ratio 2.329, 95% confidence interval (CI) 1.677-3.237, P < 0.001] increased risk of all-cause mortality or heart transplantation. Better model discrimination [concordance index: 0.766 (95% CI 0.754-0.778) vs. 0.758 (95% CI 0.746-0.770), P < 0.001], calibration (Akaike information criterion: 1487.3 vs. 1495.74; Bayesian information criterion: 1566.25 vs. 1569.43; Brier score: 1569.43 vs. 1569.43; likelihood ratio test P < 0.001), and reclassification (integrated discrimination improvement: 1.35%, 95% CI 0.63-2.07%, P < 0.001; net reclassification improvement: 13.73%, 95% CI 2.05-27.18%, P = 0.034) were improved after adding RAR to the traditional model (P < 0.001 for all). A higher overall net benefit was also obtained in the threshold risk probability of 20-55%. CONCLUSIONS: High level of RAR was an independent risk factor of poor outcome in NIHF.

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Insuficiencia Cardíaca , Humanos , Estudios Retrospectivos , Teorema de Bayes , Pronóstico , Eritrocitos

RESUMEN

Although previous studies have identified human-specific accelerated regions as playing a key role in the recent evolution of the human brain, the characteristics and cellular functions of rapidly evolving conserved elements (RECEs) in ancestral primate lineages remain largely unexplored. Here, based on large-scale primate genome assemblies, we identify 888 RECEs that have been highly conserved in primates that exhibit significantly accelerated substitution rates in the ancestor of the Simiiformes. This primate lineage exhibits remarkable morphological innovations, including an expanded brain mass. Integrative multiomic analyses reveal that RECEs harbor sequences with potential cis-regulatory functions that are activated in the adult human brain. Importantly, genes linked to RECEs exhibit pronounced expression trajectories in the adult brain relative to the fetal stage. Furthermore, we observed an increase in the chromatin accessibility of RECEs in oligodendrocytes from individuals with Alzheimer's disease (AD) compared to that of a control group, indicating that these RECEs may contribute to brain aging and AD. Our findings serve to expand our knowledge of the genetic underpinnings of brain function during primate evolution.

Asunto(s)

Enfermedad de Alzheimer , Animales , Humanos , Enfermedad de Alzheimer/genética , Evolución Molecular , Primates/genética , Encéfalo

RESUMEN

In order to achieve zero discharge and resource utilization of industrial high salt wastewater, a hybrid system of mechanical vapor recompression (MVR) and hollow fiber vacuum membrane distillation (HFVMD) was constructed, and several experiments of air tightness, single working condition and multiple working conditions were carried out with ammonium chloride solution as feed, then thermal economic performance were evaluated via a single factor analysis method. The obtained results showed that the system had excellent airtightness to ensure normal evaporation experiment, and high separation efficiency of 99.9% and lower evaporation energy consumption to achieve high efficient separation by combining the advantages of the hydrophobic membrane evaporation and latent heat recovery in view of MVR and HFVMD technologies. Furthermore, increasing feed temperature and feed flow rate increased evaporation rate and decreased evaporation energy consumption, while increasing feed concentration decreased evaporation rate and increased evaporation energy consumption. Finally, the single factor analysis indicated that total investment cost, annual operation cost and annual evaporation capacity were the main factors while environmental cost and equipment service life were the secondary factors which affected the specific evaporation cost. The above research provides theoretical and experimental bases for the development of the proposed system in the future.

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Destilación , Purificación del Agua , Vacio , Destilación/métodos , Temperatura , Calor , Purificación del Agua/métodos

RESUMEN

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Intrones