Multiple ATR-Chk1 Pathway Proteins Preferentially Associate with Checkpoint-Inducing DNA Substrates

The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

6. sınıf zekâ oyunları dersi öğrencilerinin problem çözme stratejilerinin ve akıl yürütme becerilerinin incelenmesi.

The aim of the present study was to investigate the effects of Puzzles and Games course on the 6th grade students’ problem solving and reasoning skills. For this purpose, this study sought for the students’ problem solving strategies and underlying reasoning skills in the beginning and at the end of the course. Another specific interest of the study was to determine the students’ views about the effectiveness of Puzzles and Games course. The study was conducted during the Fall semester of 2014-2015 academic year. The participants were 40 6th grade students who took Puzzles and Games course in a private middle school in Ankara. Data were collected through the Mathematical Problem Solving Test (MPT), Puzzles and Games course evaluation forms and semi-structured interviews. MPT was constructed by the researcher depending on the literature, had eight open-ended, non-routine and real life problems, and was implemented as pretest and posttest. Paired samples t-test was run to compare the result of the pre and posttests. Semi-structured interviews were conducted with seven students to understand their solutions to the problems better. Additionally, the evaluation forms were filled by all the participants to get information about the effectiveness of Puzzles and Games course. Findings indicated that there was a statistically significant increase in the scores from pretest to posttest. It showed that students who experienced Puzzles and Games course developed their problem solving strategies and underlying reasoning skills. The main reason of this improvement was that reasoning and operation puzzles strategy games and problems, which students engaged in Puzzles and Games course. Finally, it was revealed that students had positive views about Puzzles and Games course and addressed course activities enjoyable and beneficial.M.S. - Master of Scienc

Dynamic Lead-Time Quotation for an M/M/1 Base-Stock Inventory Queue

We study a dynamic lead-time quotation problem in a base-stock inventory system characterized by lead-time sensitive Poisson demand and exponentially distributed service times. We show that the optimal profit is unimodal in the base-stock level. We compare the base-stock system with a make-to-order (MTO) system and show that the lead-time quotes are lower in an MTO system and that increasing the base-stock level does not necessarily decrease the expected number of customers waiting. Numerical results show that when customers are less sensitive to lead-time quotes, the benefit of quoting lead times with a higher precision is significant, whereas when customers are more sensitive to lead-time quotes, the benefit of holding inventory is significant

Percutaneous treatment of congenital splenic cysts: Drainage and sclerotherapy with polidocanol

Congenital "true" splenic cysts are rare lesions. Therapeutic methods for the management of these lesions have been based on preserving splenic function due to the immunologic role of spleen. We report three different cases of congenital splenic cysts treated by percutaneous drainage and polidocanol sclerotherapy. This less invasive treatment appears to be safe and effective after 6 to 36 months of follow-up

Orbital varices: imaging findings and the role of color Doppler sonography in the diagnosis

The orbital varices are infrequent intraorbital masses, which cause intermittent. positional exophthalmos. They have low venous pressure inside which causes difficulties in detection by routine protocols of nearly all imaging modalities. Color Doppler sonography is a simple procedure that can easily detect orbital varices which avoids further evaluation in non-complicated patients. We report the imaging findings of a case of orbital varix and discuss the role of color Doppler sonography in the diagnosis and follow-up. (C) 2001 Elsevier Science Ltd. All rights reserved