Changes in subcellular structures and states of pumilio 1 regulate the translation of target Mad2 and cyclin B1 mRNAs.

Temporal and spatial control of mRNA translation has emerged as a major mechanism for promoting diverse biological processes. However, the molecular nature of temporal and spatial control of translation remains unclear. In oocytes, many mRNAs are deposited as a translationally repressed form and are translated at appropriate times to promote the progression of meiosis and development. Here, we show that changes in subcellular structures and states of the RNA-binding protein pumilio 1 (Pum1) regulate the translation of target mRNAs and progression of oocyte maturation. Pum1 was shown to bind to Mad2 (also known as Mad2l1) and cyclin B1 mRNAs, assemble highly clustered aggregates, and surround Mad2 and cyclin B1 RNA granules in mouse oocytes. These Pum1 aggregates were dissolved prior to the translational activation of target mRNAs, possibly through phosphorylation. Stabilization of Pum1 aggregates prevented the translational activation of target mRNAs and progression of oocyte maturation. Together, our results provide an aggregation-dissolution model for the temporal and spatial control of translation.

Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility.

The development of oocytes and early embryos is dependent on mitochondrial ATP production. This reliance on mitochondrial activity, together with the exclusively maternal inheritance of mitochondria in development, places mitochondria as central regulators of both fertility and transgenerational inheritance mechanisms. Mitochondrial mass and mtDNA content massively increase during oocyte growth. They are highly dynamic organelles and oocyte maturation is accompanied by mitochondrial trafficking around subcellular compartments. Due to their key roles in generation of ATP and reactive oxygen species (ROS), oocyte mitochondrial defects have largely been linked with energy deficiency and oxidative stress. Pharmacological treatments and mitochondrial supplementation have been proposed to improve oocyte quality and fertility by enhancing ATP generation and reducing ROS levels. More recently, the role of mitochondria-derived metabolites in controlling epigenetic modifiers has provided a mechanistic basis for mitochondria-nuclear crosstalk, allowing adaptation of gene expression to specific metabolic states. Here, we discuss the multi-faceted mechanisms by which mitochondrial function influence oocyte quality, as well as longer-term developmental events within and across generations.

The use of digital technology to improve and monitor handwashing among children 12 years or younger in educational settings: a scoping review.

Our scoping review aimed to identify and describe the application of digital technology in hand hygiene research among children in educational settings. We searched for articles in PubMed, IEEE Xplore, and Web of Science. Original hand hygiene research with a form of digital technology used among children ≤12 years in educational settings was eligible for inclusion. Twelve studies met the eligibility criteria and the data were extracted by two teams of independent co-authors for narrative synthesis. Ten studies used digital technology as an intervention tool and two for monitoring purposes. Three main digital technologies were identified including computer games (n = 2), videos (n = 8), and video cameras (n = 2). Digital technologies found in our scoping review were reported to be effective in hand hygiene studies over short temporal periods especially when used in combination with other measures. Future research may demonstrate the effectiveness of digital technology in helping children develop sustainable handwashing behaviors.

Age-Varying Associations between Child Maltreatment, Depressive Symptoms, and Frequent Heavy Episodic Drinking.

Child maltreatment represents a prevalent public health issue that has been shown to predict both adolescent and young adult depressive symptoms and heavy episodic drinking; however, little is known regarding how associations between specific types of maltreatment (e.g., physical abuse, sexual abuse, care neglect, supervisory neglect) and depressive symptoms and heavy episodic drinking change across adolescence and into young adulthood. Similarly, there is lack of research that has examined how an accumulation of child maltreatment types relates to depressive symptoms and heavy episodic drinking across ages. Time-varying effect models-a statistical approach that allows researchers to pinpoint specific ages where the association between two variables is strongest-were used in the current study to address these gaps. Nationally representative data came from the first four waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 16,053; 49.4% female; 51.0% European American/White, 21.0% African American, 10.2% Biracial, 9.1% Hispanic; MAGE W1 = 17.00). Results suggested that certain types of maltreatment are more predictive of negative outcomes than others and that different types of maltreatment confer greater risk in different developmental periods. In addition, while victims of between one and three types of maltreatment had comparable prevalence of depressive symptoms and heavy episodic drinking across adolescence and young adulthood, victims of four types of maltreatment had a much higher prevalence of these outcomes indicating the extreme risk that accompanies an accumulation of maltreatment.

HENMT1 is involved in the maintenance of normal female fertility in the mouse.

PIWI-interacting small RNAs (piRNAs) maintain genome stability in animal germ cells, with a predominant role in silencing transposable elements. Mutations in the piRNA pathway in the mouse uniformly lead to failed spermatogenesis and male sterility. By contrast, mutant females are fertile. In keeping with this paradigm, we previously reported male sterility and female fertility associated with loss of the enzyme HENMT1, which is responsible for stabilising piRNAs through the catalysation of 3'-terminal 2'-O-methylation. However, the Henmt1 mutant females were poor breeders, suggesting they could be subfertile. Therefore, we investigated oogenesis and female fertility in these mice in greater detail. Here, we show that mutant females indeed have a 3- to 4-fold reduction in follicle number and reduced litter sizes. In addition, meiosis-II mutant oocytes display various spindle abnormalities and have a dramatically altered transcriptome which includes a down-regulation of transcripts required for microtubule function. This down-regulation could explain the spindle defects observed with consequent reductions in litter size. We suggest these various effects on oogenesis could be exacerbated by asynapsis, an apparently universal feature of piRNA mutants of both sexes. Our findings reveal that loss of the piRNA pathway in females has significant functional consequences.

Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes.

STUDY QUESTION: Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans? SUMMARY ANSWER: Exposure to MitoQ or BGP-15 during IVM protected against spindle and chromosomal defects in mouse oocytes exposed to oxidative stress or derived from reproductively aged mice whilst MitoQ promoted nuclear maturation and protected against chromosomal misalignments in human oocytes. WHAT IS KNOWN ALREADY: Spindle and chromosomal abnormalities in oocytes are more prevalent with maternal aging, increasing the risk of aneuploidy, miscarriage and genetic disorders such as Down's syndrome. The origin of compromised oocyte function may be founded in mitochondrial dysfunction and increased reactive oxygen species (ROS). STUDY DESIGN, SIZE, DURATION: Oocytes from young and old mice were treated with MitoQ and/or BGP-15 during IVM. To directly induce mitochondrial dysfunction, oocytes were treated with H2O2, and then treated the MitoQ and/or BGP-15. Immature human oocytes were cultured with or without MitoQ. Each experiment was repeated at least three times, and data were analyzed by unpaired-sample t-test or chi-square test. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immature germinal vesicle (GV) stage oocytes from 1-, 12- and 18-month-old mice were obtained from preovulatory ovarian follicles. Oocytes were treated with MitoQ and/or BGP-15 during IVM. GV-stage human oocytes were cultured with or without MitoQ. Mitochondrial membrane potential and mitochondrial ROS were measured by live-cell imaging. Meiotic spindle and chromosome alignments were visualized by immunofluorescent labeling of fixed oocytes and the 3-dimensional images were analyzed by Imaris. MAIN RESULTS AND THE ROLE OF CHANCE: MitoQ or BGP-15 during IVM protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and in oocytes from aged mice (P < 0.001). In human oocytes, the presence of MitoQ during IVM promoted nuclear maturation and had a similar positive effect in protecting against chromosomal misalignments (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Our study identifies two excellent candidates that may help to improve fertility in older women. However, these potential therapies must be tested for efficacy in clinical IVM systems, and undergo thorough examination of resultant offspring in preclinical models before utilization. WIDER IMPLICATIONS OF THE FINDINGS: Our results using in-vitro systems for oocyte maturation in both mouse and human provide proof of principle that mitochondrially targeted molecules such as MitoQ and BGP-15 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities. STUDY FUNDING/COMPETING INTEREST(S): The project was financially supported by the National Health and Medical Research Council and Australian Research Council, Australia. U.A.-Z. was supported by the Iraqi Higher Education and Scientific Research Ministry PhD scholarship and O.C. was supported by TUBITAK-1059B191601275. M.P.M. consults for MitoQ Inc. and holds patents in mitochondria-targeted therapies. R.L.R. is an inventor on patents relating to the use of BGP-15 to improve gamete quality. TRIAL REGISTRATION NUMBER: N/A.

Parameter estimation for a point-source diffusion-decay morphogen model.

In this paper we present a novel method for finding unknown parameters for an unknown morphogen. We postulate the existence of an unknown morphogen in a given three-dimensional domain due to the spontaneous arrangement of a downstream species on the domain boundary for which data is known. Assuming a modified Helmholtz model for the morphogen and that it is produced from a single source in the domain, our method accurately estimates the source location and other model parameters. Notably, our method does not require the forward solution of the model to be computed which can often be a challenge for three-dimensional PDE model parameter fitting. Instead, an extension is made from the problem domain to an infinite domain and the analytic nature of the fundamental solution is exploited. We explore in this manuscript strategies for best conditioning the problem and rigorously explore the accuracy of the method on two test problems. Our tests focus on the effect of source location on accuracy but also the robustness of the algorithm to experimental noise.

Does social support modify the relationship between food insecurity and poor mental health? Evidence from thirty-nine sub-Saharan African countries.

OBJECTIVE: The present study aimed to determine the relationship among food insecurity, social support and mental well-being in sub-Saharan Africa, a region presenting the highest prevalence of severe food insecurity and a critical scarcity of mental health care. DESIGN: Food insecurity was measured using the Food Insecurity Experience Scale (FIES). Social support was assessed using dichotomous indicators of perceived, foreign perceived, received, given, integrative and emotional support. The Negative and Positive Experience Indices (NEI and PEI) were used as indicators of mental well-being. Multilevel mixed-effect linear models were applied to examine the associations between mental well-being and food security status, social support and their interaction, respectively, accounting for random effects at country level and covariates.ParticipantsNationally representative adults surveyed through Gallup World Poll between 2014 and 2016 in thirty-nine sub-Saharan African countries (n 102 235). RESULTS: The prevalence of severe food insecurity was 39 %. The prevalence of social support ranged from 30 to 72 % by type. In the pooled analysis using the adjusted model, food insecurity was dose-responsively associated with increased NEI and decreased PEI. Perceived, integrative and emotional support were associated with lower NEI and higher PEI. The differences in NEI and PEI between people with and without social support were the greatest among the most severely food insecure. CONCLUSIONS: Both food insecurity and lack of social support constitute sources of vulnerability to poor mental well-being. Social support appears to modify the relationship between food security and mental well-being among those most affected by food insecurity in sub-Saharan Africa.

Do demographic factors and a health-promoting lifestyle influence the self-rated health of college nursing students?

BACKGROUND: To adopt a healthy lifestyle is considered an essential component of nursing education. Self-rated health is a subjective assessment of health status and is consistent with objective health status. Previous studies have shown an association between self-rated health and engagement in a healthy lifestyle. Nursing students need to feel good about their subjective health status and to be able to adopt health improvements in their lifestyle before attempting to disseminate health messages to clients. The aims of this study were to compare the difference in self-rated health and health promotion lifestyle profile between senior and junior nursing students, describe correlations between self-rated health and health promotion lifestyle profile, and identify the predictors of self-rated health. METHODS: A cross-sectional descriptive survey was adopted. The study sample consisted of 314 junior and senior year nursing students from a tertiary institution. The self-reported questionnaire consisted of a single-item question to examine their self-rated health. The Health Promoting Lifestyle Profile-II: Chinese version short form (HPLP-IICR) was used to investigate the health-promoting lifestyles of the students. Descriptive statistics, Mann-Whitney U test, Chi-square test, Fisher's exact test, Spearman's correlation, and ordinal logistic regression were used to analyze the data. RESULTS: The median scores for self-rated health were 3 (Mean 3.26, IQR 3-4) and 3 (Mean 3.19, IQR 3-4) out of 5 for Year 2 and Year 5 students, respectively, with no significant difference between the two groups. The two groups of students showed no significant differences in overall score and in most subscales of the HPLP-IICR. An ordinal logistic regression showed that those students with higher health management score (OR: 1.12, 95% CI: 1.04-1.21) and who had experienced no family conflicts in the recent month than having family conflict (OR: 1.64, 95% CI: 1.01-2.66) were more likely to have higher self-rated health. CONCLUSION: Nursing education and clinical practice can undoubtedly increase the health knowledge of students, but may not lead to changes in actual health-promoting behaviours. Students with a higher health management score and no family conflicts are more likely to give a positive appraisal of their health status.

Radiofrequency ablation versus transarterial chemoembolization for unresectable solitary hepatocellular carcinomas sized 5-8 cm.

OBJECTIVES: This retrospective review was conducted to compare the efficacy of radiofrequency ablation (RFA) with that of transarterial chemoembolization (TACE) in treating large (5-8 cm) unresectable solitary hepatocellular carcinomas (HCCs). METHODS: Patients with large unresectable solitary HCCs primarily treated by RFA or TACE were reviewed. The primary endpoint was overall survival. Secondary endpoints were tumour response, time to disease progression, and treatment-related morbidity and mortality. RESULTS: There were 15 patients in the RFA group. Of these, 12 achieved complete ablation, one had ablation site recurrence, and five developed complications. Median disease-free survival in this group was 13.0 months (range: 2.8-38.0 months). The TACE group included 26 patients, of whom four obtained a partial response, none achieved a complete response, and five developed complications. The median time to disease progression in this group was 8.0 months (range: 1.0-68.0 months). There were no hospital deaths in this series. Median survival was 39.8 months in the RFA group and 19.8 months in the TACE group (P = 0.257). Rates of 1-, 2- and 5-year survival were 93.3%, 86.2% and 20.9%, respectively, in the RFA group and 73.1%, 40.6% and 18.3%, respectively, in the TACE group. CONCLUSIONS: Both RFA and TACE are feasible treatments for large unresectable solitary HCCs. Both modes show comparable rates of complications and longterm survival, but RFA achieves better initial tumour control and results in better short-term survival.

Group I and II mammalian PAKs have different modes of activation by Cdc42.

p21-activated kinases (PAKs) are Cdc42 effectors found in metazoans, fungi and protozoa. They are subdivided into PAK1-like (group I) or PAK4-like (group II) kinases. Human PAK4 is widely expressed and its regulatory mechanism is unknown. We show that PAK4 is strongly inhibited by a newly identified auto-inhibitory domain (AID) formed by amino acids 20 to 68, which is evolutionarily related to that of other PAKs. In contrast to group I kinases, PAK4 is constitutively phosphorylated on Ser 474 in the activation loop, but held in an inactive state until Cdc42 binding. Thus, group II PAKs are regulated through conformational changes in the AID rather than A-loop phosphorylation.

Improved anterior hepatic transection for isolated hepatocellular carcinoma in the caudate.

BACKGROUND: One of the best treatments for isolated hepatocellular carcinoma in the caudate lobe is major hepatectomy with caudate lobectomy, but it is not suitable for patients with poor liver function reserve. Isolated caudate lobectomy, which is a very difficult operation, is thus an alternative option. METHODS: Here we report an isolated caudate lobectomy with an anterior approach in the treatment of a large hepatocellular carcinoma with underlying cirrhosis, with focus on the technical aspects. RESULTS: In the operation, both the left and right lobes of the liver were mobilized. Hepatotomy was done along the round ligament where parenchymal transection was minimal. After exposure of the left and middle hepatic veins and the hilar plate, the caudate lobe and the tumor were resected en bloc with a 5-mm margin. CONCLUSION: Isolated caudate lobectomy can be performed safely with this anterior approach on patients with poor liver function reserve.

Surgical management of recurrent pyogenic cholangitis: 10 years of experience in a tertiary referral centre in Hong Kong.

BACKGROUND: Recurrent pyogenic cholangitis (RPC) is common in Asia. Its management differs from centre to centre. METHODS: A retrospective review of 80 patients undergoing surgery for RPC was performed. Immediate and longterm outcomes were analysed. RESULTS: All patients underwent hepaticocutaneousjejunostomy (HCJ) for biliary drainage and stone removal. Additional hepatectomy was performed in 38 patients with intrahepatic ductal stricture or liver segmental atrophy. Twenty-three patients had residual stones and 25 had recurrent stones. All patients with residual stones underwent repeated choledochoscopy (median: four sessions) for stone removal and obtained confirmation of ductal clearance. Four patients developed cholangiocarcinoma, of which two died. The complication rate was 17.5%. Most of the complications were wound infections. No mortality related to surgery occurred. Multivariate analysis found that gender, disease extent (unilobar versus bilobar) and surgery type (HCJ alone versus HCJ with hepatectomy) were not associated with increased risk for residual or recurrent stones. A raised preoperative bilirubin level was the only risk factor identified as associated with an increased risk for recurrent stones (P < 0.001); it was not associated with an increased risk for residual stones. CONCLUSIONS: Recurrent pyogenic cholangitis is a distinct disease, the management of which requires a high level of surgical expertise. Hepaticojejunostomy is recommended as the primary drainage procedure, but hepatectomy should be reserved for complicated RPC.

Flavonoids and post haemorrhoidectomy recovery: a systematic review and meta-analysis.

BACKGROUND: Haemorrhoidectomy is the gold standard for definitive treatment of high-grade symptomatic haemorrhoids but is often associated with substantial pain. This systematic review aims to explore the potential of flavonoids in alleviating the postoperative symptom burden following excisional haemorrhoidectomy. METHODS: A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD42023472711). Randomized controlled trials (RCTs) published PubMed, MEDLINE, Embase, and Scopus from inception to 1st December 2023 were retrieved. The primary outcome investigated was post-operative pain. Meta-analysis was performed using Review Manager version 5.4.1. RESULTS: Ten articles with 775 patients were included. The meta-analysis identified statistically significant decreases in post-operative pain in favour of the flavonoid groups (Standardized Mean Difference -0.66 [95% confidence intervals (CI) -0.82, -0.52]; P < 0.00001), and bleeding (Odds Ratio 0.13 [95% CI 0.09, 0.19]; P < 0.00001). CONCLUSION: Flavonoids show promise as a means of reducing pain associated with excisional haemorrhoidectomy. Further research is required to investigate topical routes of administration and standardize regimes.

Effectiveness of Computerized Cognitive Training on Working Memory in Pediatric Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: Interactive features of computerized cognitive training (CCT) may enhance adherence to training, providing a relatively low-cost intervention. A robust systematic review on the effectiveness of CCT for improving working memory (WM) among pediatric survivors with cancer is lacking. OBJECTIVE: To summarize the available evidence and determine the effectiveness of CCT for WM among pediatric survivors with cancer. INTERVENTIONS/METHODS: Five databases were searched. The Effective Public Health Practice Project was used to assess the study quality. ReviewerManager was used. The primary outcome was WM performance. Secondary outcomes included processing speed, attention, intervention adherence, and number of adverse events. RESULTS: Six studies were included. Regarding overall quality, 1 study was weak, and 5 studies were moderate. Five studies reported a significant improvement of WM postintervention (P < .05). The meta-analysis of Cogmed interventions on symbolic WM revealed a significant difference between groups (vs placebo), with an overall pooled effect size of 0.71 (95% confidence interval, 0.02-1.41; P = .04). Two and 4 studies investigated the effects of CCT on processing speed and attention, respectively, with conflicting results. Four studies reported adherence of 80% or greater. Two studies reported no adverse events. CONCLUSIONS: Computerized cognitive training using Cogmed has a significant positive effect on WM. The effects of CCT on processing speed and attention remain inconclusive. IMPLICATIONS FOR PRACTICE: More rigorous trials should be conducted to elucidate the cognitive effects of CCT, particularly processing speed and attention, in the pediatric population with cancer. Further studies should consider combining CCT with other existing interventions to strengthen their effectiveness.

Long-term survival analysis of pure laparoscopic versus open hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a single-center experience.

INTRODUCTION: Laparoscopic liver resection has been reported as a safe and effective approach to the management of liver cancer. However, studies of long-term outcomes regarding tumor recurrence and patient survival in comparison with the conventional open approach are limited. The aim of this study was to analyze the survival outcome of laparoscopic liver resection versus open liver resection. PATIENTS AND METHODS: Between October 2002 and September 2009, 32 patients underwent pure laparoscopic liver resection for hepatocellular carcinoma (HCC). Case-matched control patients (n = 64) who received open liver resection for HCC were included for comparison. Patients were matched in terms of cancer stage, tumor size, location of tumor, and magnitude of resection. Immediate operation outcomes, operation morbidity, disease-free survival, and overall survival were compared between groups. RESULTS: With the laparoscopic group compared with the open resection group, operation time was 232.5 minutes versus 204.5 minutes (P = 0.938), blood loss was 150 mL versus 300 mL (P = 0.001), hospital stay was 4 days versus 7 days (P < 0.0001), postoperative complication was 2 (6.3%) versus 12 (18.8%) (P = 0.184), disease-free survival was 78.5 months versus 29 months (P = 0.086), and overall survival was 92 months versus 71 months (P = 0.142). The disease-free survival for stage II HCC was 22.1 months versus 12.4 months (P = 0.075). CONCLUSIONS: Laparoscopic liver resection for HCC is associated with less blood loss, shorter hospital stay, and fewer postoperative complications in selected patients with no compromise in survival.

A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells.

KLF1 regulates a diverse suite of genes to direct erythroid cell differentiation from bipotent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as Hbb-b1, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of alpha- and beta-globin protein chains, heme biosynthesis, coordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 cooperation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment.

A robust protocol to map binding sites of the 14-3-3 interactome: Cdc25C requires phosphorylation of both S216 and S263 to bind 14-3-3.

Modern proteomic techniques have identified hundreds of proteins that bind 14-3-3s, the most widespread eukaryotic phosphoserine/threonine sensors, but accurate prediction of the target phospho-sites is difficult. Here we describe a systematic approach using synthetic peptides that tests large numbers of potential binding sites in parallel for human 14-3-3. By profiling the sequence requirements for three diverse 14-3-3 binding sites (from IRS-1, IRSp53 and GIT2), we have generated enhanced bioinformatics tools to score sites and allow more tractable testing by co-immunoprecipitation. This approach has allowed us to identify two additional sites other than Ser216 in the widely studied cell division cycle (Cdc) protein 25C, whose function depends on 14-3-3 binding. These Ser247 and Ser263 sites in human Cdc25C, which were not predicted by the existing Scansite search, are conserved across species and flank the nuclear localization region. Furthermore, we found strong interactions between 14-3-3 and peptides with the sequence Rxx[S/T]xR typical for PKC sites, and which is as abundant as the canonical Rxx[S/T]xP motif in the proteome. Two such sites are required for 14-3-3 binding in the polarity protein Numb. A recent survey of >200 reported sites identified only a handful containing this motif, suggesting that it is currently under-appreciated as a candidate binding site. This approach allows one to rapidly map 14-3-3 binding sites and has revealed alternate motifs.

Polo-like kinase 1 promotes Cdc42-induced actin polymerization for asymmetric division in oocytes.

Polo-like kinase I (Plk1) is a highly conserved seronine/threonine kinase essential in meiosis and mitosis for spindle formation and cytokinesis. Here, through temporal application of Plk1 inhibitors, we identify a new role for Plk1 in the establishment of cortical polarity essential for highly asymmetric cell divisions of oocyte meiosis. Application of Plk1 inhibitors in late metaphase I abolishes pPlk1 from spindle poles and prevents the induction of actin polymerization at the cortex through inhibition of local recruitment of Cdc42 and Neuronal Wiskott-Aldrich Syndrome protein (N-WASP). By contrast, an already established polar actin cortex is insensitive to Plk1 inhibitors, but if the polar cortex is first depolymerized, Plk1 inhibitors completely prevent its restoration. Thus, Plk1 is essential for establishment but not maintenance of cortical actin polarity. These findings indicate that Plk1 regulates recruitment of Cdc42 and N-Wasp to coordinate cortical polarity and asymmetric cell division.

Developing International Classification of Disease code definitions for the study of enteric infection sequelae in Canada.

Background: Enteric infections and their chronic sequelae are a major cause of disability and death. Despite the increasing use of administrative health data in measuring the burden of chronic diseases in the population, there is a lack of validated International Classification of Disease (ICD) code-based case definitions, particularly in the Canadian context. Our objective was to validate ICD code definitions for sequelae of enteric infections in Canada: acute kidney injury (AKI); hemolytic uremic syndrome (HUS); thrombotic thrombocytopenic purpura (TTP); Guillain-Barré syndrome/Miller-Fisher syndrome (GBS/MFS); chronic inflammatory demyelinating polyneuropathy (CIDP); ankylosing spondylitis (AS); reactive arthritis; anterior uveitis; Crohn's disease, ulcerative colitis, celiac disease, erythema nodosum (EN); neonatal listeriosis (NL); and Graves' disease (GD). Methods: We used a multi-step approach by conducting a literature review to identify existing validated definitions, a clinician assessment of the validated definitions, a chart review to verify proposed definitions and a final clinician review. We measured the sensitivity and positive predictive value (PPV) of proposed definitions. Results: Forty studies met inclusion criteria. We identified validated definitions for 12 sequelae; clinicians developed three (EN, NL, GD). We reviewed 181 charts for 6 sequelae (AKI, HUS, TTP, GBS/MFS, CIDP, AS). Sensitivity (42.8%-100%) and PPV (63.6%-100%) of ICD code definitions varied. Six definitions were modified by clinicians following the chart review (AKI, TTP, GBS/MFS, CIDP, AS, reactive arthritis) to reflect coding practices, increase specificity or sensitivity, and address logistical constraints. Conclusion: The multi-step design to derive ICD code definitions provided flexibility to identify existing definitions, to improve their sensitivity and PPV and adapt them to the Canadian context.