The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis

Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. Here, using follicular fluid from patients with the disease endometriosis, which affects 10% of women and is associated with reduced fertility, we find raised levels of Reactive Oxygen Species (ROS), which generate DNA damage and turn on the DDR-SAC pathway. Only follicular fluid from patients with endometriosis, and not controls, produced ROS and damaged DNA in the oocyte. This activated ATM kinase, leading to SAC mediated metaphase I arrest. Completion of meiosis I could be restored by ROS scavengers, showing this is the primary trigger for arrest and offering a novel clinical therapeutic treatment. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis

Regulation of lipid signaling at the Golgi by the lipid phosphatases hSAC1 and OCRL1

Phosphoinositides are key lipid signaling molecules present in membranes of all eukaryotes. Different species of phosphoinositides serve as membrane signposts at distinct cellular compartments. This assymetric distribution of phosphoinositides is achieved by the presence of an elaborate set of lipid kinases and phosphatases operating at specific organelle membranes. The lipid phosphatase SAC1 is found in both endoplasmic reticulum (ER) and Golgi. Similar to yeast Sac1p, human SAC1 (hSAC1) is the major phosphatidylinositol-4-phosphatase (PI(4)P-phosphatase). Distinct localization of hSAC1 in both ER and Golgi membranes suggests that this PI(4)P-phosphatase has compartment specific roles in regulating steady state distribution of PI(4)P in these organelles. OCRL1 is a Golgi and endosomal localized PI(4,5)P2 5-phosphatase that is implicated in a severe X-linked disease, Lowe syndrome, which is characterized by congenital cataracts, Fanconi syndrome and mental retardation. How mutations in OCRL1 cause Lowe syndrome is unknown. The functional analysis of hSAC1 and OCRL1 in regulating Golgi PI(4)P and PI(4,5)P2 is the main focus of this work. Confocal immunofluorescence and immuno-electron microscopy (immuno-EM) show that PI(4)P and hSAC1 form an opposing gradient in the Golgi. hSAC1 is highly enriched at Golgi cisternal membranes while PI(4)P is concentrated at the trans-Golgi network (TGN) where cargo proteins are packaged and exported. Golgi enzymes such as N-acetylglucosaminyltransferase I (NacT1) and mannosidase II (ManII) are preferentially found in these PI(4)P-depleted areas. siRNA-mediated knock-down of hSAC1 leads to accumulation of PI(4)P at Golgi, plasma membrane and endosomal like structures and causes mislocalization of ManII and NacT1. This data suggests that SAC1 establishes PI(4)P-depleted Golgi regions that are important for proper localization and recycling of Golgi resident enzymes. Conversely, depletion of OCRL1 does not disturb Golgi morphology or induce mislocalization of Golgi resident enzymes. However, bulk secretion is inhibited in OCRL1 depleted cells. The OCRL1-b splice variant populates TGN and early endosomal compartment whereas the OCRL1-a splice variant containing an extra 8 amino acid acidic cluster is found only in a subset of late endosomal/ lysosomal membranes. This distinct localization of OCRL1 splice variants indicates that each isoform might regulate different trafficking routes by regulating PI(4,5)P2 levels at these compartments. Together, the results show that hSAC1 and OCRL1 establish distinct phosphoinositide-specific domains within the Golgi that are instrumental for segregation of anterograde trafficking from the recycling of resident Golgi enzymes

Synthesis, Formation And Characterization Of Nanoscale Zeolite Type W Base Catalyst

Zeolite W (MER topology) is a very important zeolite in catalysis and separation industries but its synthesis requires the use of organic structure-directing agents (OSDAs) and long crystallization time. This project aims to synthesize and study the formation of nanosized zeolite W without organic structure-directing agent with shortened synthesis time while using it as heterogeneous catalyst for various base-catalyzed organic reactions. The first part focuses on studying the effect of the synthesis parameters such as heating temperature, reaction time and hydrogel chemical compositions on the crystallization behaviour of zeolite W. It is found that the synthesis parameters have significant impact on the crystallization rate, purity of the zeolite phase, particle size and morphology of the zeolite product. By tuning the synthesis parameters, zeolite W with four distinct morphologies (nanorods, wheatsheaf-like, bullet-like and prismatic) can be obtained. Further investigation into the relationship between different morphologies and their surface basicity found that the surface basicity is linearly proportional to the surface area of the zeolites. Next, the time-dependent study on the nucleation and crystal growth process of nanosized zeolite W synthesized with reactive bamboo leaves ash (BLA) was reported. Various spectroscopic, microscopic and analytical techniques are used to follow the whole crystallization process. The zeolite undergoes amorphous phase reorganization twice before the occurrence of nucleation, crystallization and crystal growth. The zeolite W obtained exhibit nanorods morphology and tend to assemble in parallel forming bulkier bundle-like secondary particles. Lastly, the synthesis of nanocrystalline zeolite W with hierarchical mesoporosity under microwave heating condition was discussed

Development, implementation and initial feasibility testing of the MediEmo mobile application to provide support during medically assisted reproduction.

STUDY QUESTION Is it possible to develop a patient smartphone application for medically assisted reproduction (MAR) that is acceptable to patients and fertility staff? SUMMARY ANSWER Staff and patients responded positively to the MediEmo smartphone application, perceiving it to be acceptable and feasible to implement in a busy clinic. WHAT IS KNOWN ALREADY Digital tools are increasingly popular to provide practical, administrative and psychological support alongside medical treatments. Apps and other digital tools have been developed for use alongside MAR but there is very limited research on the development or acceptability and feasibility of these tools. STUDY DESIGN, SIZE, DURATION Mixed methods research. This article outlines the development phase of the MediEmo smartphone app, which was guided by the Medical Research Council development framework for complex interventions. The resulting MediEmo app was then implemented into a single centre for MAR in the UK, acceptability evaluated and feasibility explored among 1106 potential participants undertaking IVF cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS Consultation and data collection took part at a single mid-sized urban fertility clinic. Development of the MediEmo smartphone application took place during 2013 to 2017. Implementation of the MediEmo took place from June 2017 to September 2020. The MediEmo app comprises three functions (six features) namely medication management (medication timeline, messaging), mood management (emotional tracking, coping support) and functional support (frequently asked questions, symptom checker). Data on age, fertility diagnosis, anti-Müllerian hormone level were collected about the users of the MediEmo in addition to MediEmo usage data and attitudes towards the MediEmo smartphone application. MAIN RESULTS AND THE ROLE OF CHANCE Informed by the developmental process described, MediEmo is an app combining patient medication diary management and ease of integration into clinic systems with emotional support, emotional tracking and data capture. This study demonstrates acceptability and feasibility of MediEmo, with good uptake (79.8%), mood data sensitivity and reliability and positive feedback. LIMITATIONS, REASONS FOR CAUTION Single centre, small number of users in questionnaire studies. WIDER IMPLICATIONS OF THE FINDINGS The findings suggest smartphone apps can contribute to fertility care and that patient engagement is high. Evaluation of any apps introduced into clinical pathways should be encouraged to promote development of the most useful digital tools for fertility patients. STUDY FUNDING/COMPETING INTEREST(S) This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. Outside of the submitted work, J.B. reports personal speaker fees from Merck KGaA, Darmstadt, Germany, Merck AB an affiliate of Merck KGaA, Darmstadt Germany, Theramex, MedThink China, Ferring Pharmaceuticals A/S, grant from Merck Serono Ltd, outside the submitted work and that she is co-developer of Fertility Quality of Life (FertiQoL) and MediEmo app; N.M and C.Y are minority shareholders and J.B.'s University (Cardiff University) owns one third of shares. None of the shareholders benefitted financially from MediEmo. I.R., C.H. and K.Y.B.N. declare no conflicts of interest

Surgical treatment of fibroids for subfertility

BACKGROUND: Fibroids are the most common benign tumours of the female genital tract and are associated with numerous clinical problems including a possible negative impact on fertility. In women requesting preservation of fertility, fibroids can be surgically removed (myomectomy) by laparotomy, laparoscopically or hysteroscopically depending on the size, site and type of fibroid. Myomectomy is however a procedure that is not without risk and can result in serious complications. It is therefore essential to determine whether such a procedure can result in an improvement in fertility and, if so, to then determine the ideal surgical approach.OBJECTIVES: To examine the effect of myomectomy on fertility outcomes and to compare different surgical approaches.SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Epistemonikos database, World Health Organization (WHO) International Clinical Trials Registry Platform search portal, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and reference list of relevant papers. The final search was in February 2019.SELECTION CRITERIA: Randomised controlled trials (RCTs) examining the effect of myomectomy compared to no intervention or where different surgical approaches are compared regarding the effect on fertility outcomes in a group of infertile women suffering from uterine fibroids.DATA COLLECTION AND ANALYSIS: Data collection and analysis were conducted in accordance with the procedure suggested in the Cochrane Handbook for Systematic Reviews of Interventions.MAIN RESULTS: This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I2 = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I2 = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I2 = 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I2 = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I2 = 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate. AUTHORS' CONCLUSIONS: There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.</p

Distinct Self-Renewal and Differentiation Phases in the Niche of Infrequently Dividing Hair Follicle Stem Cells

SummaryIn homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here, we examine the dynamic behavior of adult hair follicle stem cells in their normal setting by employing mice with repressible H2B-GFP expression to track cell divisions and Cre-inducible mice to perform long-term single-cell lineage tracing. We provide direct evidence for the infrequent stem cell division model in intact tissue. Moreover, we find that differentiation of progenitor cells occurs at different times and tissue locations than self-renewal of stem cells. Distinct fates of differentiation or self-renewal are assigned to individual cells in a temporal-spatial manner. We propose that large clusters of tissue stem cells behave as populations whose maintenance involves unidirectional daughter-cell-fate decisions

Compatibility of the Omnican (R) Pen Needles with Insulin Pens, Humapen (R) and Novopen (R)

This study was carried out to assess accuracy of Omnican (R) insulin pen needles (29G and 30G) by measuring the weight of insulin delivered in each of 10 depressions of the plunger comparing these using other pen-injectors (Humapen (R) and Novopen (R) for each gauge. We found that the needle-to-needle variation was not statistically significant when the needles were used to dispense insulin using either of the insulin pens (Humapen (R) and Novopen (R). HumaPen (R) insulin pen was found to deliver the insulin closer to set target volume using either gauge (29G and 30G) of the Omnican (R) needles in some of the insulin ranges used in this study

Iodine Deficiency Disorder and Goitre among School Children in Sarawak -A Nationwide Study.

Iodine deficiency disorders (IDD), is one of the most important micronutrient deficiencies which has multiple adverse effects on growth and development. The aim of this study was to determine the prevalence of IDD among school children and to elucidate the distribution of iodized salt at household level in Sarawak, East Malaysia. This cross-sectional study was conducted among school children aged 8 to 10 years in 2008. A multi-stage probability proportionate to population size(PPS) cluster sampling method was used to obtain a representative state sample of 1200 school children. Spot urine samples were collected for the determination of urinary iodine concentration while the iodine content in salt was determined using field rapid test kits. The thyroid status was determined by palpation. Response rate was 92.0% (n=1104/1200). The prevalence of goitre among school children in Sarawak was 2.9% (5.2% in urban, 0.7% in rural). The median urinary iodine concentration (UIC) among the school children was 102.1 μg/L (IQR, 62.3-146.5 μg/L). Urban children had significantly higher median UIC of 109.3 μg/L (IQR, 72.4-159.0 μg/L) than their rural counterparts [91.9 μg/L (IQR, 55.7-140.2 μg/L)]. The salt samples tested by rapid test kit (RTK) showed only 46.0% of household salt contained iodine. The present study revealed that the population in Sarawak were of borderline iodine sufficient with mild IDD seen in rural areas. Hence, the state IDD control programmes need to encourage and advocate the consumption of iodized salt in order to eliminate IDD-related health problems in Sarawak

Academic visual identity of higher education institutions : a multimodal communication through pictorial representations

Empirical studies on branding of higher education institutions have increasingly explored the notion of identity in the modern university context. The positive effects of brand communication, especially offline communication, may be well investigated, whereas few studies have analyzed how online brand communication can be realized. This study examines an under-discovered visual source, namely pictures, that performs a pivotal function to display the visual identity of Chinese universities. This study investigates the multimodal discourse of the ‘About Us’ web genre which employs pictures to portray the universities’ brand identity, and examines their meaning potentials. Drawing upon the visual grammar framework of Kress and van Leeuwen (2006), the sample for visual analysis in this study was collected from the ‘About Us’ webpages of nine elite Chinese universities (C9 League). Findings of the qualitative analysis indicate that pictures are ingeniously employed to display the virtual identity of the Chinese universities. The multifaceted brand identity of the universities may be projected through a heavy use of symbolic representations, along with a diversity of communication strategies to portray their representational meanings. The study provides information for universities to effectively use visual resources in constructing their brand identities and offering information to their target audience via the web-mediated multimodal discourses

Production, safety, health effects and applications of diacylglycerol functional oil in food systems: a review

Diacylglycerol (DAG) is a world leading anti-obesity functional cooking oil synthesized via structural modification of conventional fats and oils. DAG exits in three stereoisomers namely sn-1,2-DAG, sn-1,3-DAG, and sn-2,3-DAG. DAG particularly sn-1,3-DAG demonstrated to have the potential in suppressing body fat accumulation and lowering postprandial serum triacylglycerol, cholesterol and glucose level. DAG also showed to improve bone health. This is attributed to DAG structure itself that caused it to absorb and digest via different metabolic pathway than conventional fats and oils. With its purported health benefits, many studies attempt to enzymatically or chemically synthesis DAG through various routes. DAG has also received wide attention as low calorie fat substitute and has been incorporated into various food matrixes. Despite being claimed as healthy cooking oil the safety of DAG still remained uncertain. DAG was banned from sale as it was found to contain probable carcinogen glycidol fatty acid esters. The article aims to provide a comprehensive and latest review of DAG emphasizing on its structure and properties, safety and regulation, process developments, metabolism and beneficial health attributes as well as its applications in the food industry