Ultrastructural and functional fate of recycled vesicles in hippocampal synapses

Efficient recycling of synaptic vesicles is thought to be critical for sustained information transfer at central terminals. However, the specific contribution that retrieved vesicles make to future transmission events remains unclear. Here we exploit fluorescence and time-stamped electron microscopy to track the functional and positional fate of vesicles endocytosed after readily releasable pool (RRP) stimulation in rat hippocampal synapses. We show that most vesicles are recovered near the active zone but subsequently take up random positions in the cluster, without preferential bias for future use. These vesicles non-selectively queue, advancing towards the release site with further stimulation in an actin-dependent manner. Nonetheless, the small subset of vesicles retrieved recently in the stimulus train persist nearer the active zone and exhibit more privileged use in the next RRP. Our findings reveal heterogeneity in vesicle fate based on nanoscale position and timing rules, providing new insights into the origins of future pool constitution

From L-Dopa to Dihydroxyphenylacetaldehyde: A Toxic Biochemical Pathway Plays a Vital Physiological Function in Insects

One protein in Aedes aegypti, classified into the aromatic amino acid decarboxylase (AAAD) family based on extremely high sequence homology (∼70%) with dopa decarboxylase (Ddc), was biochemically investigated. Our data revealed that this predicted AAAD protein use L-dopa as a substrate, as does Ddc, but it catalyzes the production of 3,4-dihydroxylphenylacetaldehyde (DHPAA) directly from L-dopa and apparently has nothing to do with the production of any aromatic amine. The protein is therefore named DHPAA synthase. This subsequently led to the identification of the same enzyme in Drosophila melanogaster, Anopheles gambiae and Culex quinquefasciatus by an initial prediction of putative DHPAA synthase based on sequence homology and subsequent verification of DHPAA synthase identity through protein expression and activity assays. DHPAA is highly toxic because its aldehyde group readily reacts with the primary amino groups of proteins, leading to protein crosslinking and inactivation. It has previously been demonstrated by several research groups that Drosophila DHPAA synthase was expressed in tissues that produce cuticle materials and apparent defects in regions of colorless, flexible cuticular structures have been observed in its gene mutants. The presence of free amino groups in proteins, the high reactivity of DHPAA with the free amino groups, and the genetically ascertained function of the Drosophila DHPAA synthase in the formation of colorless, flexible cuticle, when taken together, suggest that mosquito and Drosophila DHPAA synthases are involved in the formation of flexible cuticle through their reactive DHPAA-mediated protein crosslinking reactions. Our data illustrate how a seemingly highly toxic pathway can serve for an important physiological function in insects

The Social Production of Altruism: Motivations for Caring Action in a Low-Income Urban Community

Contemporary social science paints a bleak picture of inner-city relational life. Indeed, the relationships of low-income, urban-residing Americans are represented as rife with distress, violence and family disruption. At present, no body of social scientific work systematically examines the factors that promote loving or selfless interactions among low-income, inner-city American individuals, families and communities. In an effort to fill that gap, this ethnographic study examined the motivations for altruism among a sample of adults (n = 40) who reside in an economically distressed housing community (i.e., housing project) in New York City. Content analyses of interviews indicated that participants attributed altruism to an interplay between 14 motives that were then ordered into four overarching categories of motives: (1) needs-centered motives, (2) norm-based motives deriving from religious/spiritual ideology, relationships and personal factors, (3) abstract motives (e.g., humanism), and (4) sociopolitical factors. The implications of these findings are discussed

Return to work, work productivity loss and activity impairment in Chinese breast cancer survivors 12-month post-surgery: a longitudinal study

IntroductionExisting evidence of returning-to-work (RTW) after cancer comes predominately from Western settings, with none prospectively examined since the initial diagnostic phase. This study prospectively documents RTW-rate, time-to-RTW, work productivity loss, and activity impairment, within the first-year post-surgery among Chinese women with breast cancer (BCW) and identify potential causal co-variants.MethodsThis observational longitudinal study followed 371 Chinese BCW who were employed/self-employed at the time of diagnosis at 4-week post-surgery (baseline). RTW-status and time-to-RTW were assessed at baseline (T1), 4-month (T2), 6-month (T3), and 12-month (T4) post-baseline. WPAI work productivity loss and activity impairment were assessed at T4. Baseline covariates included demographics, medical-related factors, work satisfaction, perceived work demand, work condition, RTW self-efficacy, B-IPQ illness perception, COST financial well-being, EORTC QLQ-C30 and QLQ-BR23 physical and psychosocial functioning, and HADS psychological distress.ResultsA 68.2% RTW-rate (at 12-month post-surgery), prolonged delay in RTW (median = 183 days), and significant proportions of T4 work productivity loss (20%), and activity impairment (26%), were seen. BCW who were blue-collar workers with lower household income, poorer financial well-being, lower RTW self-efficacy, poorer job satisfaction, poorer illness perception, greater physical symptom distress, impaired physical functioning, and unfavorable work conditions were more likely to experience undesired work-related outcomes.DiscussionUsing a multifactorial approach, effective RTW interventions should focus on not only symptom management, but also to address psychosocial and work-environmental concerns. An organizational or policy level intervention involving a multidisciplinary team comprising nurses, psychologists, occupational health professionals, and relevant stakeholders in the workplace might be helpful in developing a tailored organizational policy promoting work-related outcomes in BCW

Estratégia Teórico-Prática no Ensino de Enfermagem em Doenças Transmissíveis com o Foco na Vigilância em Saúde

Este relato apresenta a estratégia de ensino teórico-prática para o conteúdo de vigilância em saúde na Disciplina ENS 0425 – Enfermagem em Doenças Transmissíveis com Enfoque em Saúde Coletiva, do curso de bacharelado em Enfermagem, por meio do estágio em unidades de vigilância em saúde localizadas na cidade de São Paulo no ano de 2016. As atividades em campo de estágio tiveram como resultado a produção de relatórios em formato de estudo de caso, tanto no âmbito individual quanto no âmbito populacional de enfrentamento das doenças transmissíveis. A estratégia de ensino pode ser considerada inovadora, porque estimulou o estudante ao desenvolvimento do trabalho articulado com diversos atores envolvidos na vigilância em saúde e ao debate sobre os conceitos de morbidade, letalidade, prevalência e incidência, tendo como ponto de partida a desigualdade territorial das necessidades em saúde com vistas à atuação individual e populacional.This report presents the strategy of theoretical and practical teaching for the content of health surveillance in elective course ENS 0425 – Nursing in Communicable Diseases with a Focus on Collective Health, of the baccalaureate course in Nursing, by means of the internship in localized health surveillance units in the city of São Paulo in 2016. The activities in the field of internships have resulted in the production of reports in a case study format both in the individual and in the population context of coping with communicable diseases. The teaching strategy can be considered innovative because it has stimulated the student to develop the work articulated with several actors involved in health surveillance and the debate on the concepts of morbidity, lethality, prevalence and incidence, starting from the territorial inequality of the needs in health for individual and population performance

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

CT/MRI and CEUS LI-RADS Major Features Association with Hepatocellular Carcinoma: Individual Patient Data Meta-Analysis

Background The Liver Imaging Reporting and Data System (LI-RADS) assigns a risk category for hepatocellular carcinoma (HCC) to imaging observations. Establishing the contributions of major features can inform the diagnostic algorithm. Purpose To perform a systematic review and individual patient data meta-analysis to establish the probability of HCC for each LI-RADS major feature using CT/MRI and contrast-enhanced US (CEUS) LI-RADS in patients at high risk for HCC. Materials and Methods Multiple databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus) were searched for studies from January 2014 to September 2019 that evaluated the accuracy of CT, MRI, and CEUS for HCC detection using LI-RADS (CT/MRI LI-RADS, versions 2014, 2017, and 2018; CEUS LI-RADS, versions 2016 and 2017). Data were centralized. Clustering was addressed at the study and patient levels using mixed models. Adjusted odds ratios (ORs) with 95% CIs were determined for each major feature using multivariable stepwise logistic regression. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) (PROSPERO protocol: CRD42020164486). Results A total of 32 studies were included, with 1170 CT observations, 3341 MRI observations, and 853 CEUS observations. At multivariable analysis of CT/MRI LI-RADS, all major features were associated with HCC, except threshold growth (OR, 1.6; 95% CI: 0.7, 3.6; P = .07). Nonperipheral washout (OR, 13.2; 95% CI: 9.0, 19.2; P = .01) and nonrim arterial phase hyperenhancement (APHE) (OR, 10.3; 95% CI: 6.7, 15.6; P = .01) had stronger associations with HCC than enhancing capsule (OR, 2.4; 95% CI: 1.7, 3.5; P = .03). On CEUS images, APHE (OR, 7.3; 95% CI: 4.6, 11.5; P = .01), late and mild washout (OR, 4.1; 95% CI: 2.6, 6.6; P = .01), and size of at least 20 mm (OR, 1.6; 95% CI: 1.04, 2.5; P = .04) were associated with HCC. Twenty-five studies (78%) had high risk of bias due to reporting ambiguity or study design flaws. Conclusion Most Liver Imaging Reporting and Data System major features had different independent associations with hepatocellular carcinoma; for CT/MRI, arterial phase hyperenhancement and washout had the strongest associations, whereas threshold growth had no association. © RSNA, 2021 Online supplemental material is available for this article

The Prostate Specific Membrane Antigen Regulates the Expression of IL-6 and CCL5 in Prostate Tumour Cells by Activating the MAPK Pathways1

The interleukin-6 (IL-6) and the chemokine CCL5 are implicated in the development and progression of several forms of tumours including that of the prostate. The expression of the prostate specific membrane antigen (PSMA) is augmented in high-grade and metastatic tumors. Observations of the clinical behaviour of prostate tumors suggest that the increased secretion of IL-6 and CCL5 and the higher expression of PSMA may be correlated. We hypothesized that PSMA could be endowed with signalling properties and that its stimulation might impact on the regulation of the gene expression of IL-6 and CCL5. We herein demonstrate that the cross-linking of cell surface PSMA with specific antibodies activates the small GTPases RAS and RAC1 and the MAPKs p38 and ERK1/2 in prostate carcinoma LNCaP cells. As downstream effects of the PSMA-fostered RAS-RAC1-MAPK pathway activation we observed a strong induction of NF-κB activation associated with an increased expression of IL-6 and CCL5 genes. Pharmacological blockade with specific inhibitors revealed that both p38 and ERK1/2 participate in the phenomenon, although a major role exerted by p38 was evident. Finally we demonstrate that IL-6 and CCL5 enhanced the proliferative potential of LNCaP cells synergistically and in a dose-dependent manner and that CCL5 functioned by receptor-mediated activation of the STAT5-Cyclin D1 pro-proliferative pathway. The novel functions attributable to PSMA which are described in the present report may have profound influence on the survival and proliferation of prostate tumor cells, accounting for the observation that PSMA overexpression in prostate cancer patients is related to a worse prognosis