Paxillin facilitates timely neurite initiation on soft-substrate environments by interacting with the endocytic machinery.

Neurite initiation is the first step in neuronal development and occurs spontaneously in soft tissue environments. Although the mechanisms regulating the morphology of migratory cells on rigid substrates in cell culture are widely known, how soft environments modulate neurite initiation remains elusive. Using hydrogel cultures, pharmacologic inhibition, and genetic approaches, we reveal that paxillin-linked endocytosis and adhesion are components of a bistable switch controlling neurite initiation in a substrate modulus-dependent manner. On soft substrates, most paxillin binds to endocytic factors and facilitates vesicle invagination, elevating neuritogenic Rac1 activity and expression of genes encoding the endocytic machinery. By contrast, on rigid substrates, cells develop extensive adhesions, increase RhoA activity and sequester paxillin from the endocytic machinery, thereby delaying neurite initiation. Our results highlight paxillin as a core molecule in substrate modulus-controlled morphogenesis and define a mechanism whereby neuronal cells respond to environments exhibiting varying mechanical properties

Predicting one-year mortality among elderly survivors of hospitalization for an acute myocardial infarction: results from the Cooperative Cardiovascular Project

AbstractOBJECTIVESWe sought to develop a model based on information available from the medical record that would accurately stratify elderly patients who survive hospitalization with an acute myocardial infarction (AMI) according to their risk of one-year mortality.BACKGROUNDPrediction of the risk of mortality among older survivors of an AMI has many uses, yet few studies have determined the prognostic importance of demographic, clinical and functional data that are available on discharge in a population-based sample.METHODSIn a cohort of patients aged ≥65 years who survived hospitalization for a confirmed AMI from 1994 to 1995 at acute care, nongovernmental hospitals in the U.S., we developed a parsimonious model to stratify patients by their risk of one-year mortality.RESULTSThe study sample of 103,164 patients, with a mean age of 76.8 years, had a one-year mortality of 22%. The factors with the strongest association with mortality were older age, urinary incontinence, assisted mobility, presence of heart failure or cardiomegaly any time before discharge, presence of peripheral vascular disease, body mass index <20 kg/m2, renal dysfunction (defined as creatinine >2.5 mg/dl or blood urea nitrogen >40 mg/dl) and left ventricular dysfunction (left ventricular ejection fraction <40%). On the basis of the coefficients in the model, patients were stratified into risk groups ranging from 7% to 49%.CONCLUSIONSWe demonstrate that a simple risk model can stratify older patients well by their risk of death one year after discharge for AMI

Optimal extraction parameters of Theabrownin from Sichuan Dark Tea

Background: Sichuan Dark Tea is a popular beverage with hypolipidemic and lifting greasy properties in the minority neighborhoods of Sichuan and Tibet regions. The theabrownin, an important pigment of dark tea, has been proven for the role of the hypolipidemic property in Sichuan Dark Tea. The objective of the study investigated the extraction process of theabrownin.Materials and Methods: Theabrownin was extracted from Sichuan Dark Tea with water and organic solvents. The quadratic regression orthogonally rotational combinational design experiment was performed to obtain the optimal extraction parameters.Results: The extraction yield of theabrownin was significantly influenced by both water extraction temperature and solid-liquid ratio, and the contribution of these factors on theabrownin yield was as follows: water temperature﹥solid-liquid ratio﹥organic solvent temperature. Moreover, the polynomial regression model established could predict the experimental value accurately.Conclusion: The optimum extraction process of theabrownin from Sichuan Dark Tea was established, which water temperature at 65.69-77.88℃, organic solvent temperature at 13.65-17.48℃ and a solid liquid ratio of 1:43.58-1:50.75(g/mL).Keywords: theabrownin; extraction; optimization; Sichuan Dark TeaAbbreviations list: SDT: Sichuan Dark Tea; TB: Theabrowni

Political and social determinants of life expectancy in less developed countries: A longitudinal study

EstE livro corrEspondE à primeira experiência didática do Grupo de trabalho desenvolvimento Urbano do conselho latinoamericano de ciências sociais (clAcso), que reúne cerca de quarenta pesquisadores de diferentes instituições da região. Esta experiência tornou-se possível, graças ao fato da proposta deste curso ter sido aprovada no âmbito da cátedra Florestan Fernandes do conselho. completamente desenvolvida através do campus virtual do clAcso, teve, por principal objetivo, estimular a reflexão sobre alguns dos principais eixos teórico-conceituais e empíricos orientadores da análise da urbanização latino-americana

Modulation of nucleosome-binding activity of FACT by poly(ADP-ribosyl)ation

Chromatin-modifying factors play key roles in transcription, DNA replication and DNA repair. Post-translational modification of these proteins is largely responsible for regulating their activity. The FACT (facilitates chromatin transcription) complex, a heterodimer of hSpt16 and SSRP1, is a chromatin structure modulator whose involvement in transcription and DNA replication has been reported. Here we show that nucleosome binding activity of FACT complex is regulated by poly(ADP-ribosyl)ation. hSpt16, the large subunit of FACT, is poly(ADP-ribosyl)ated by poly(ADP-ribose) polymerase-1 (PARP-1) resulting from physical interaction between these two proteins. The level of hSpt16 poly(ADP-ribosyl)ation is elevated after genotoxic treatment and coincides with the activation of PARP-1. The enhanced hSpt16 poly(ADP-ribosyl)ation level correlates with the dissociation of FACT from chromatin in response to DNA damage. Our findings suggest that poly(ADP-ribosyl)ation of hSpt16 by PARP-1 play regulatory roles for FACT-mediated chromatin remodeling

Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin–PKA–Ena/VASP pathway

Syndecan-2 induced filopodia before spinogenesis; therefore, filopodia formation was used here as a model to study the early downstream signaling of syndecan-2 that leads to spinogenesis. Screening using kinase inhibitors indicated that protein kinase A (PKA) is required for syndecan-2–induced filopodia formation in both human embryonic kidney cells and hippocampal neurons. Because neurofibromin, a syndecan-2–binding partner, activates the cyclic adenosine monophosphate pathway, the role of neurofibromin in syndecan-2–induced filopodia formation was investigated by deletion mutant analysis, RNA interference, and dominant-negative mutant. The results showed that neurofibromin mediates the syndecan-2 signal to PKA. Among actin-associated proteins, Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) were predicted as PKA effectors downstream of syndecan-2, as Ena/VASP, which is activated by PKA, induces actin polymerization. Indeed, when the activities of Ena/VASP were blocked, syndecan-2 no longer induced filopodia formation. Finally, in addition to filopodia formation, neurofibromin and Ena/VASP contributed to spinogenesis. This study reveals a novel signaling pathway in which syndecan-2 activates PKA via neurofibromin and PKA consequently phosphorylates Ena/VASP, promoting filopodia and spine formation

Apoptosis Induction in Primary Human Colorectal Cancer Cell Lines and Retarded Tumor Growth in SCID Mice by Sulforaphane

We have investigated the anticancer effects of the dietary isothiocyanate sulforaphane (SFN) on colorectal cancer (CRC), using primary cancer cells lines isolated from five Taiwanese colorectal cancer patients as the model for colorectal cancer. SFN-treated cells accumulated in metaphase (SFN 6.25 μM) and subG1 (SFN 12.5 and 25 μM) as determined by flow cytometry. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-3, and loss of mitochondrial membrane potential (ΔΨm). Incubations at higher SFN doses (12.5 and 25 μM) resulted in cleavage of procaspase-3 and elevated caspase-2, -3, -8, and -9 activity, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Daily SFN s.c. injections (400 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with primary human CRC (CP1 to CP5) s.c. tumors resulted in a decrease of mean tumor weight by 70% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have antitumor activity in established colorectal cancer

Epidemiological characteristics and behaviors of online broadcast suicidality in China: implications for targeted prevention strategies

ObjectivesSuicide is a global health concern, exacerbated by stigma around mental illnesses. Online platforms like Twitter and Sina Weibo have seen a rise in “online broadcast suicide,” where individuals share suicidal thoughts and actions. However, there is limited understanding of the epidemiological characteristics, particularly in China. This study aims to analyze the demographics and behaviors of individuals engaging in online broadcast suicide in China to inform targeted prevention strategies.MethodsA total of 525 incidents were identified through systematic retrieval of relevant news reports from online sources. Subsequently, a content analysis was performed on these reports to extract detailed information on the characteristics of each individual incident.ResultsAmong the incidents analyzed, the male-to-female ratio was 1:1.6, with an average age of 23.1 ± 5.9 years. Approximately 71.9% took place in Southern China. Unemployment was reported in 15.0% of incidents. Relationship breakup (62.3%) was cited as the leading cause of suicide. Wrist cutting (58.2%) emerged as the predominant suicide method, and home (36.2%) was the most common location for these tragic events. Instant messaging apps were the primary platforms (54.7%) for conveying suicidal thoughts and actions. Additionally, among the 525 incidents examined, 12.0% disclosed having a mental disorder, and 7.6% had a history of prior suicide attempts. Significant variations were observed across age, gender, region, and occupation categories.ConclusionThis study emphasizes the importance of developing suicide prevention programs for internet users. Besides, interventions should be customized to meet the specific needs of various populations