Building the centriole: Plk4 phosphorylates STIL to direct procentriole assembly

Centrioles are small microtubule-based cellular structures that form the centrosome, the cell’s major microtubule-organizing center responsible for forming the bipolar spindle in mitosis. Each centriole duplicates exactly once per cell cycle at the onset of S phase by forming one new centriole on the wall of each of the two pre-existing parental centrioles. Polo-like kinase 4 (PLK4) has emerged as an upstream master regulator of centriole biogenesis, but how PLK4’s activity is regulated to control centriole duplication specifically at the G1/S phase transition remains unclear. Here, we used CRISPR genome engineering to create a chemical genetic system in which endogenous PLK4 can be specifically inhibited using a cell-permeable ATP analog. Using this system, we demonstrate that the centriolar localization of the core centriole component STIL requires continued PLK4 activity. Most importantly, we show that direct binding of STIL to PLK4 activates PLK4 by promoting self-phosphorylation of the kinase’s activation loop. PLK4 subsequently phosphorylates STIL at two distant sites to promote centriole assembly. One site allows STIL to bind to and recruit SAS6, the major component of the centriolar cartwheel, the inner framework of the centriole governing its architecture. The other site allows STIL to increase its binding to and promote the stable integration of CPAP, the centriole protein that links the cartwheel to the centriole’s outer microtubule walls. Thus, our findings describe the first key steps in the initiation of centriole assembly through activation of PLK4 and identify STIL as the first in vivo substrate of PLK4

NeuroGraph: Benchmarks for Graph Machine Learning in Brain Connectomics

Machine learning provides a valuable tool for analyzing high-dimensional functional neuroimaging data, and is proving effective in predicting various neurological conditions, psychiatric disorders, and cognitive patterns. In functional magnetic resonance imaging (MRI) research, interactions between brain regions are commonly modeled using graph-based representations. The potency of graph machine learning methods has been established across myriad domains, marking a transformative step in data interpretation and predictive modeling. Yet, despite their promise, the transposition of these techniques to the neuroimaging domain has been challenging due to the expansive number of potential preprocessing pipelines and the large parameter search space for graph-based dataset construction. In this paper, we introduce NeuroGraph, a collection of graph-based neuroimaging datasets, and demonstrated its utility for predicting multiple categories of behavioral and cognitive traits. We delve deeply into the dataset generation search space by crafting 35 datasets that encompass static and dynamic brain connectivity, running in excess of 15 baseline methods for benchmarking. Additionally, we provide generic frameworks for learning on both static and dynamic graphs. Our extensive experiments lead to several key observations. Notably, using correlation vectors as node features, incorporating larger number of regions of interest, and employing sparser graphs lead to improved performance. To foster further advancements in graph-based data driven neuroimaging analysis, we offer a comprehensive open-source Python package that includes the benchmark datasets, baseline implementations, model training, and standard evaluation.Comment: NeurIPS2

Nurses\u27 Alumnae Association Bulletin, April 1959

Alumnae News Anniversary Class of /34 Article from Pennsylvania Nurse Committee Reports Current Events at Jefferson Greetings from the President Jefferson Story Lost Members Letter - Past President Marriages Necrology New Arrivals Notices Pictured - Student Nurses\u27 Residence Report of the School of Nursing and Nursing Services Staff Nurses Social Functions Student Activities Voluntary Service Year of Great Activity and Expansio

Maternity care provider knowledge, attitudes, and practices regarding provision of postpartum intrauterine contraceptive devices at a tertiary center in Ghana

ObjectiveTo assess knowledge, attitudes, and practices of maternity care providers regarding the provision of postpartum intrauterine contraceptive devices (IUDs) in Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana.MethodsA descriptive, cross‐sectional study was conducted between June 28 and July 15, 2011. Specialists, residents, house officers, and nurse midwives who had been working in the Department of Obstetrics and Gynecology for at least 3 months were included. Self‐administered questionnaires assessed formal training, current proficiency in IUD insertion, and attitudes toward postpartum IUD provision.ResultsOf 91 providers surveyed, 70 (77%) reported previous training in contraceptive counseling. Fewer than one in three respondents had ever inserted an IUD: 17 (44%) of 39 physicians and 9 (17%) of 52 midwives reported ever having inserted an IUD. A total of 33 (36%) respondents reported that they would recommend an IUD in the immediate postpartum period.ConclusionAlthough most maternity care providers at KATH had received training in contraceptive counseling, few felt confident in their ability to insert an IUD. Further training in postpartum contraceptive management is needed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135552/1/ijgo137.pd

CDK1 Prevents Unscheduled PLK4-STIL Complex Assembly in Centriole Biogenesis

The deposited article is a post-print version (author's manuscript from PMC and available in PMC 2017 May 9).This publication hasn't any creative commons license associated.This deposit is composed by the main article and the supplementary materials are present in the publisher's page in the following link: https://www.sciencedirect.com/science/article/pii/S0960982216303001?via%3Dihub#sec4Centrioles are essential for the assembly of both centrosomes and cilia. Centriole biogenesis occurs once and only once per cell cycle and is temporally coordinated with cell-cycle progression, ensuring the formation of the right number of centrioles at the right time. The formation of new daughter centrioles is guided by a pre-existing, mother centriole. The proximity between mother and daughter centrioles was proposed to restrict new centriole formation until they separate beyond a critical distance. Paradoxically, mother and daughter centrioles overcome this distance in early mitosis, at a time when triggers for centriole biogenesis Polo-like kinase 4 (PLK4) and its substrate STIL are abundant. Here we show that in mitosis, the mitotic kinase CDK1-CyclinB binds STIL and prevents formation of the PLK4-STIL complex and STIL phosphorylation by PLK4, thus inhibiting untimely onset of centriole biogenesis. After CDK1-CyclinB inactivation upon mitotic exit, PLK4 can bind and phosphorylate STIL in G1, allowing pro-centriole assembly in the subsequent S phase. Our work shows that complementary mechanisms, such as mother-daughter centriole proximity and CDK1-CyclinB interaction with centriolar components, ensure that centriole biogenesis occurs once and only once per cell cycle, raising parallels to the cell-cycle regulation of DNA replication and centromere formation.ERC grant: (ERC-2010-StG-261344); FCT grants: (FCT Investigator, EXPL/BIM-ONC/0830/2013, PTDC/SAU-BD/105616/2008); EMBO installation grant.info:eu-repo/semantics/publishedVersio

The impact of first and second language exposure on learning second language constructions

We study how the learning of argument structure constructions in a second language (L2) is affected by two basic input properties often discussed in literature – the amount of input and the time of L2 onset. To isolate the impact of the two factors on learning, we use a computational model that simulates bilingual construction learning. In the first two experiments we manipulate the sheer amount of L2 exposure, both in absolute and in relative terms (that is, in relation to the amount of L1 exposure). The results show that higher cumulative amount of L2 exposure leads to higher performance. In the third experiment we manipulate the prior amount of L1 input before the L2 onset (that is, the time of L2 onset). Given equal exposure, we find no negative effect of the later onset on learners’ performance. This has implications for theories of order of acquisition and bilingual construction learning

A structured telephone-delivered intervention to reduce problem alcohol use (Ready2Change): study protocol for a parallel group randomised controlled trial

Background: Current population surveys suggest around 20% of Australians meet diagnostic criteria for an alcohol use disorder. However, only a minority seek professional help due to individual and structural barriers, such as low health literacy, stigma, geography, service operating hours and wait lists. Telephone-delivered interventions are readily accessible and ideally placed to overcome these barriers. We will conduct a randomised controlled trial (RCT) to examine the efficacy of a standalone, structured telephone-delivered intervention to reduce alcohol consumption, problem severity and related psychological distress among individuals with problem alcohol use. Methods/design: This is a single site, parallel group, two-arm superiority RCT. We will recruit 344 participants from across Australia with problem alcohol use. After completing a baseline assessment, participants will be randomly allocated to receive either the Ready2Change (R2C) intervention (n = 172, four to six sessions of structured telephone-delivered intervention, R2C self-help resource, guidelines for alcohol consumption and stress management pamphlets) or the control condition (n = 172, four phone check-ins < 5 min, guidelines for alcohol consumption and stress management pamphlets). Telephone follow-up assessments will occur at 4-6 weeks, 3 months, 6 months and 12 months post-baseline. The primary outcome is the Alcohol Use Disorders Identification Test (AUDIT) score administered at 3 months post-baseline. Secondary outcomes include change in AUDIT score (6 and 12 months post-baseline), change in number of past-month heavy drinking days, psychological distress, health and wellbeing, quality of life, client treatment evaluation and cost effectiveness. Discussion: This study will be one of the first RCTs conducted internationally to examine the impact of a standalone, structured telephone-delivered intervention to address problem alcohol use and associated psychological morbidity. The proposed intervention is expected to contribute to the health and wellbeing of individuals who are otherwise unlikely to seek treatment through mainstream service models, to reduce the burden on specialist services and primary care providers and to provide an accessible and proportionate response, with resulting cost savings for the health system and broader community. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000828224. Pre-registered on 16 May 2018