Function of the SNARE Ykt6 on autophagosomes requires the Dsl1 complex and the Atg1 kinase complex

The mechanism and regulation of fusion between autophagosomes and lysosomes/vacuoles are still only partially understood in both yeast and mammals. In yeast, this fusion step requiresSNAREproteins, the homotypic vacuole fusion and protein sorting (HOPS) tethering complex, theRAB7GTPase Ypt7, and its guanine nucleotide exchange factor (GEF) Mon1-Ccz1. We and others recently identified Ykt6 as the autophagosomalSNAREprotein. However, it has not been resolved when and how lipid-anchored Ykt6 is recruited onto autophagosomes. Here, we show that Ykt6 is recruited at an early stage of the formation of these carriers through a mechanism that depends on endoplasmic reticulum (ER)-resident Dsl1 complex andCOPII-coated vesicles. Importantly, Ykt6 activity on autophagosomes is regulated by the Atg1 kinase complex, which inhibits Ykt6 through direct phosphorylation. Thus, our findings indicate that the Ykt6 pool on autophagosomal membranes is kept inactive by Atg1 phosphorylation, and once an autophagosome is ready to fuse with vacuole, Ykt6 dephosphorylation allows its engagement in the fusion event

Atg9 establishes Atg2-dependent contact sites between the endoplasmic reticulum and phagophores

The autophagy-related (Atg) proteins play a key role in the formation of autophagosomes, the hallmark of autophagy. The function of the cluster composed by Atg2, Atg18, and transmembrane Atg9 is completely unknown despite their importance in autophagy. In this study, we provide insights into the molecular role of these proteins by identifying and characterizing Atg2 point mutants impaired in Atg9 binding. We show that Atg2 associates to autophagosomal membranes through lipid binding and independently from Atg9. Its interaction with Atg9, however, is key for Atg2 confinement to the growing phagophore extremities and subsequent association of Atg18. Assembly of the Atg9-Atg2-Atg18 complex is important to establish phagophore-endoplasmic reticulum (ER) contact sites. In turn, disruption of the Atg2-Atg9 interaction leads to an aberrant topological distribution of both Atg2 and ER contact sites on forming phagophores, which severely impairs autophagy. Altogether, our data shed light in the interrelationship between Atg9, Atg2, and Atg18 and highlight the possible functional relevance of the phagophore-ER contact sites in phagophore expansion

Anderson's ethical vulnerability: animating feminist responses to sexual violence

Pamela Sue Anderson argues for an ethical vulnerability which “activates an openness to becoming changed” that “can make possible a relational accountability to one another on ethical matters”. In this essay I pursue Anderson’s solicitation that there is a positive politics to be developed from acknowledging and affirming vulnerability. I propose that this politics is one which has a specific relevance for animating the terms of feminist responses to sexual violence, something which has proved difficult for feminist theorists and activists alike. I will demonstrate the contribution of Anderson’s work to such questions by examining the way in which “ethical vulnerability” as a framework can illuminate the intersectional feminist character of Tarana Burke’s grassroots Me Too movement when compared with the mainstream, viral version of the movement. I conclude by arguing that Anderson’s “ethical vulnerability” contains ontological insights which can allay both activist and academic concerns regarding how to respond to sexual violence

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

JolliBIDA Ka Sa Pasko

Christmas is given much important in Philippines due to the fact that is a predominantly Christian country. Christmas has come to be known as a time for the family, most especially children, and also as a time of giving, a season of giving, spreading Christ-like acts especially to the less fortunate as a way of venerating Christ in his time of the year. It is through this season of giving that Jollibee has come up with a way to celebrate Christmas, to celebrate Christ, by means of a toy and book donation drive, JolliBIDA Ka Sa Pasko. The campaign aims to collect books and toys from key cities all over the country. Based on surveys conducted, the campaign will have a primary target market that consists of mothers aged 29-39 and a secondary target market that consists of children aged 5-12 years old. JoliBIDA Ka Sa Pasko contains 2 parts, an in store tree decorating event and the JolliBEE-BEEP-BEEP. The first part of the campaign will happen in all Jollibee outlets nationwide. Each outlet will contain a Jolli-tree which will be decorated by anyone who wishes to participate in the event

Informant Discrepancy in Trauma Reporting among Juvenile Offenders and their Parents

Extant literature indicates that mental health professionals receive a substantial amount of discrepant information from youth and their caregivers regarding the youth’s history of traumatic exposure and related symptoms. However, no studies to date have focused on discrepancy in reports of traumatic exposure between youths in the juvenile justice system and their caregivers. The aim of this study was to examine differences between reports of trauma exposure and current symptomology between juvenile justice-involved youth and their parents/caregivers. Based on the existing literature, it was hypothesized that parents would underreport trauma exposures experienced by their children as well as their child’s mental health symptoms when directly compared with their child’s reports. This study is part of a larger feasibility pilot study nearing completion. Recently arrested youth (N=27) and their parents or legal guardians were recruited for this feasibility pilot study from a Midwestern juvenile detention facility. Eligible participants included youth ages 18 or younger, who have pending and/or recently adjudicated criminal charges (i.e., within 30 days), and who were either residing in the detention center or at home under house arrest or probation status. Legal guardians completed the UCLA PTSD Reaction Index-Parent Version (PTSD-RI-P) and the Child Behavior Checklist (CBCL). After obtaining parental consent, youth who assented to participate completed the PTSD-RI and the Youth Self-Report (YSR). Participant recruitment for the feasibility pilot study phase of this longitudinal project is nearly complete, with a total of 27 youth enrolled to date. The sample is predominately male (77.8%, n=21) and Caucasian (70.4%, n=19), with an average age of 16 (M=16.48, SD=1.67). To test whether caregivers would underreport their child’s exposure to traumatic events and trauma-related symptoms, a paired samples t-test was used to compare parents’ scores on the PTSD-RI-P to youths’ corresponding scores on the PTSD-RI. Results indicated that, on average, youth reported experiencing a slightly higher number of traumatic events (DSM-IV criterion A; M=2.18, SD=1.63) when compared to their exposure to such events as reported by their parent/caregivers (M=1.65, SD=1.73); however, the reported differences did not reach statistical significance. Moreover, no statistical differences were reported between youth and parent/caregiver’s reports regarding any other DSM-IV PTSD criteria. Although mean differences were not as large as anticipated, low inter-rater agreement, as reflected in intraclass correlation coefficient (ICC) analyses, was observed as expected. Specifically, youth vs. parent agreement on youth’s trauma exposure and symptoms was observed as follows: Criterion A (trauma exposure): ICC=.287, p=.122; Criterion B (re-experiencing symptoms): ICC=.453, p=.053; Criterion C (avoidance): ICC=.157, p=.299; Criterion D (arousal): ICC=.558, p=.019; and Total PTSD symptom severity score: ICC = .395, p=.082. With respect to related psychological symptoms, significant differences emerged between parents’ and youths’ reports on the CBCL and YSR, respectively on the following subscales: rule-breaking [t(15)=-4.62, p\u3c.001], aggression [t(15)=-3.35, p=.004], internalizing symptoms [t(15)=-3.65, p=.002], and externalizing symptoms [t(15)=-4.48, p\u3c.001], and overall symptoms scores [t(15)=-4.24, p=.001], with similarly low ICC inter-rater agreement scores. This study is one of the first to begin to examine the informant discrepancy phenomenon among juvenile justice-involved youth and their parents/caregivers

Alterações agudas induzidas por competição de ciclismo em biomarcadores enzimáticos e imunológicos

O ciclismo é uma modalidade esportiva aeróbia de longa duração com momentos de alta intensidade e tempo considerável na faixa do limiar anaeróbio. É instituído que esforços intensos e/ou longos provocam alterações em biomarcadores enzimáticos e imunológicos, dessa forma foi investigado se uma competição de ciclismo de nível nacional (integrante do calendário da Confederação Brasileira de Ciclismo) provoca alteração significativa nas enzimas creatina-quinase (CK), aspartato-aminotransferase (AST) e alanina-aminotransferase (ALT), e no comportamento imunológico. Participaram 20 ciclistas treinados e habituados a competições (35 ± 7,9 anos de idade, 25,4 ± 2,59 kg/m2 de índice de massa corporal , 18,7 ± 4,12% de gordura corporal). Foram realizadas duas coletas de sangue venoso (pré e pós-competição). Os atletas tiveram concentração média de lactato após a competição de 5,2 ± 2,4 mMol. As enzimas tiveram aumento significativo (p < 0,05) após a competição (CK 176 ± 57,4 U/L : 216 ± 59,8 U/L, p = 0,0001; AST 21 ± 7,7 U/L : 26 ± 7,7 U/L, p = 0,0001; ALT 17,7 ± 6,7 U/L : 22 ± 7,4 U/L, p = 0,0001), assim como as seguintes populações imunológicas: leucócitos (4950 ± 1302,1 : 5900 ± 2395 mm3, p = 0,0001), neutrófilos (2928 ± 108,3 : 5104 ± 270,5 mm3, p = 0,03) e linfócitos (1763 ± 409,3 : 2832 ± 725,5 mm3, p = 0,0001). Os resultados indicam que a competição de nível nacional provoca significativa alteração na concentração plasmática de enzimas musculares e no comportamento imunológico. Acute changes induced by cycling competition in enzymatic and immunological biomarkersCycling is an aerobic long term sport with moments of high intensity and considerable time at the anaerobic threshold. It is established that intensive and/or long term efforts cause changes in enzymatic and immunological biomarkers, thus was investigated whether a cycling competition at the national level (schedule at Brazilian Cycling Federation calendar) causes significant changes in the enzymes creatine-kinase (CK) aspartate-aminotransferase (AST) and alanine-aminotransferase (ALT), and immunological behavior. Participated 20 trained cyclists and accustomed to competitions (35 ± 7.9 years, 25.4 ± 2.59 kg/m2 body mass index, 18.7 ± 4.12% of body fat). Two venous blood (pre-and post-competition) were performed. The athletes had a mean lactate concentration after the competition of 5.2 ± 2.4 mMol. Enzymes were significant (p < 0.05) after competition (CK 176 ± 57.4 : 216 ± 59.8 U/L, p = 0,0001; AST 21 ± 7.7 : 26 ± 7.7 U/L, p = 0,0001; ALT 17.7 ± 6.7 22 ± 7.4 U/L, p = 0,0001) and the following immunological populations: leukocytes (1302.1 ± 4950 : 5900 ± 2395 mm3, p = 0,0001; ), neutrophils (2928 ± 108,3 : 5104 ± 270.5 mm3, p = 0,03) and lymphocytes (1763 ± 409.3 : 2832 ± 725.5 mm3, p = 0,0001). The results indicate that competition from national level causes significant changes in plasma muscle enzymes and immunological behavior.