Ethyl 1-benzyl-4-hydr­oxy-2-methyl-5-oxopyrrolidine-3-carboxyl­ate

In the title oxopyrrolidine, C15H19NO4, the five-membered pyrrolidine ring is in a twist conformation and its mean plane makes an angle of 89.2 (3)° with the phenyl ring. In the crystal, mol­ecules pack as dimers via strong O—H⋯O [R 2 2(10)] inter­actions cross-linked by weaker C—H⋯O and C—H⋯π inter­actions. Full synthetic and spectroscopic details are given for the title compound and related dicarboxyl­ates

RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells.

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors

Pupil Dilation Is Sensitive to Semantic Ambiguity and Acoustic Degradation

© The Author(s) 2020. Speech comprehension is challenged by background noise, acoustic interference, and linguistic factors, such as the presence of words with more than one meaning (homonyms and homophones). Previous work suggests that homophony in spoken language increases cognitive demand. Here, we measured pupil dilation—a physiological index of cognitive demand—while listeners heard high-ambiguity sentences, containing words with more than one meaning, or well-matched low-ambiguity sentences without ambiguous words. This semantic-ambiguity manipulation was crossed with an acoustic manipulation in two experiments. In Experiment 1, sentences were masked with 30-talker babble at 0 and +6 dB signal-to-noise ratio (SNR), and in Experiment 2, sentences were heard with or without a pink noise masker at –2 dB SNR. Speech comprehension was measured by asking listeners to judge the semantic relatedness of a visual probe word to the previous sentence. In both experiments, comprehension was lower for high- than for low-ambiguity sentences when SNRs were low. Pupils dilated more when sentences included ambiguous words, even when no noise was added (Experiment 2). Pupil also dilated more when SNRs were low. The effect of masking was larger than the effect of ambiguity for performance and pupil responses. This work demonstrates that the presence of homophones, a condition that is ubiquitous in natural language, increases cognitive demand and reduces intelligibility of speech heard with a noisy background

Impact of Tobacco-Pack Pictorial Warnings on Youth and Young adults: A Systematic Review of Experimental Studies

Introduction:We conducted a systematic review of the experimental literature on the impact of tobacco-pack pictorial warning labels (PWLs) on youth and young adults. Methods:We systematically searched computerized databases and the reference list of relevant articles. We included studies that used an experimental protocol to assess PWLs. Studies had to report findings for youth or young adult samples (aged \u3c 30 years). Thirty-one studies met the inclusion criteria, with a total sample size of 27506. Two coders independently coded all study characteristics and outcomes. Results:Twenty-eight studies experimentally evaluated PWLs for cigarette packs while three studies evaluated PWLs for smokeless tobacco packs. Generally, PWLs led to higher attention, stronger cognitive and affective reactions, more negative pack attitudes and smoking attitudes, and increased intentions not to use tobacco products compared to text warnings. PWLs were perceived to be more effective than text warnings for both cigarette packs and smokeless tobacco packs. Conclusions:The systematic review showed that PWLs on tobacco products are effective across a wide range of tobacco-related outcomes among young people. Gaps in the literature include a lack of research on tobacco initiation and cessation and a dearth of literature on non-cigarette tobacco products

Non-enzymatic roles of human RAD51 at stalled replication forks

The central recombination enzyme RAD51 has been implicated in replication fork processing and restart in response to replication stress. Here, we use a separation-of-function allele of RAD51 that retains DNA binding, but not D-loop activity, to reveal mechanistic aspects of RAD51’s roles in the response to replication stress. Here, we find that cells lacking RAD51’s enzymatic activity protect replication forks from MRE11-dependent degradation, as expected from previous studies. Unexpectedly, we find that RAD51’s strand exchange activity is not required to convert stalled forks to a form that can be degraded by DNA2. Such conversion was shown previously to require replication fork regression, supporting a model in which fork regression depends on a non-enzymatic function of RAD51. We also show RAD51 promotes replication restart by both strand exchange-dependent and strand exchange-independent mechanisms

Child Acute Malnutrition and Mortality in Populations Affected by Displacement in the Horn of Africa, 1997–2009

Drought and conflict in the Horn of Africa are causing population displacement, increasing risks of child mortality and malnutrition. Humanitarian agencies are trying to mitigate the impact, with limited resources. Data from previous years may help guide decisions. Trends in different populations affected by displacement (1997–2009) were analyzed to investigate: (1) how elevated malnutrition and mortality were among displaced compared to host populations; (2) whether the mortality/malnutrition relation changed through time; and (3) how useful is malnutrition in identifying high mortality situations. Under-five mortality rates (usually from 90-day recall, as deaths/10,000/day: U5MR) and global acute malnutrition (wasting prevalences, < −2SDs of references plus edema: GAM) were extracted from reports of 1,175 surveys carried out between 1997–2009 in the Horn of Africa; these outcome indicators were analyzed by livelihood (pastoral, agricultural) and by displacement status (refugee/internally displaced, local resident/host population, mixed); associations between these indicators were examined, stratifying by status. Patterns of GAM and U5MR plotted over time by country and livelihood clarified trends and showed substantial correspondence. Over the period GAM was steady but U5MR generally fell by nearly half. Average U5MR was similar overall between displaced and local residents. GAM was double on average for pastoralists compared with agriculturalists (17% vs. 8%), but was not different between displaced and local populations. Agricultural populations showed increased U5MR when displaced, in contrast to pastoralist. U5MR rose sharply with increasing GAM, at different GAM thresholds depending on livelihood. Higher GAM cut-points for pastoralists than agriculturalists would better predict elevated U5MR (1/10,000/day) or emergency levels (2/10,000/day) in the Horn of Africa; cut-points of 20–25% GAM in pastoral populations and 10–15% GAM in agriculturalists are suggested. The GAM cut-points in current use do not vary by livelihood, and this needs to be changed, tailoring cut points to livelihood groups, to better identify priorities for intervention. This could help to prioritize limited resources in the current situation of food insecurity and save lives

Visuo-attentional correlates of Autism Spectrum Disorder (ASD) in children with Down syndrome: A comparative study with children with idiopathic ASD.

BACKGROUND: Children with Down syndrome (DS) are at increased likelihood of Autism Spectrum Disorder (ASD) relative to the general population. To better understand the nature of this comorbidity, we examined the visuo-attentional processes associated with autistic trait expression in children with DS, focusing specifically on attentional disengagement and visual search performance. METHOD: We collected eye-tracking data from children with DS (n = 15) and children with idiopathic ASD (iASD, n = 16) matched according to chronological age. Seven children with DS had a formal clinical diagnosis of ASD (DS+ASD). RESULTS: In children with iASD, but not DS, higher autistic trait levels were associated with decreased temporal facilitation on a gap-overlap task, implying increased visuospatial orienting efficiency. In all cases, higher autistic trait levels were associated with improved visual search performance according to decreased target detection latency. On a visual search task, children with DS+ASD outperformed their peers with DS-ASD, mirroring the phenotypic advantage associated with iASD. We found no evidence of a relationship between attentional disengagement and visual search performance, providing preliminary evidence of a differentiation in terms of underlying visuo-attentional mechanism. CONCLUSION: We illustrate the value of progressing beyond insensitive behavioural measures of phenotypic description to examine, in a more fine-grained way, the attentional features associated with ASD comorbidity in children with DS

B-Type Natriuretic Peptide in Pregnant Women With Heart Disease

ObjectivesThe objectives of this study were to examine: 1) B-type natriuretic peptide (BNP) response to pregnancy in women with heart disease; and 2) the relationship between BNP levels and adverse maternal cardiac events during pregnancy.BackgroundPregnancy imposes a hemodynamic stress on the heart. BNP might be a useful biomarker to assess the ability of the heart to adapt to the hemodynamic load of pregnancy.MethodsThis was a prospective study of women with structural heart disease seen at our center. Serial clinical data and plasma BNP measurements were obtained during the first trimester, third trimester, and after delivery (>6 weeks).ResultsSeventy-eight pregnant women were studied; 66 women with heart disease (age 31 ± 5 years), and 12 healthy women (age 33 ± 5 years). During pregnancy, the median peak BNP level was higher in women with heart disease compared with control subjects (median 79, interquartile range 51 to 152 pg/ml vs. median 35, interquartile range 21 to 43 pg/ml, p < 0.001). In women with heart disease, those with subaortic ventricular dysfunction had higher BNP levels (p = 0.03). A BNP >100 pg/ml was measured in all women with events during pregnancy (n = 8). Sixteen women had increased BNP levels during pregnancy but did not have clinical events. None of the women with BNP ≤100 pg/ml had events. BNP ≤100 pg/ml had a negative predictive value of 100% for identifying events during pregnancy.ConclusionsMany pregnant women with heart disease have increased BNP levels during pregnancy. Incorporating serial BNP levels in into clinical practice can be helpful, specifically in adjudicating suspected adverse cardiac events during pregnancy

Maternal cardiac output and fetal doppler predict adverse neonatal outcomes in pregnant women with heart disease

Background-The mechanistic basis of the proposed relationship between maternal cardiac output and neonatal complications in pregnant women with heart disease has not been well elucidated. Methods and Results-Pregnant women with cardiac disease and healthy pregnant women (controls) were prospectively followed with maternal echocardiography and obstetrical ultrasound scans at baseline, third trimester, and postpartum. Fetal/neonatal complications (death, small-for-gestational-age or low birthweight, prematurity, respiratory distress syndrome, or intraventricular hemorrhage) comprised the primary study outcome. One hundred and twenty-seven women with cardiac disease and 45 healthy controls were enrolled. Neonatal events occurred in 28 pregnancies and were more frequent in the heart disease group as compared with controls (n=26/127 or 21% versus n=2/45 or 4%; P=0.01). Multiple complications in an infant were counted as a single outcome event. Neonatal complications in the heart disease group were small-for-gestational-age/low birthweight (n=18), prematurity (n=14), and intraventricular hemorrhage/respiratory distress syndrome (n=5). Preexisting obstetric risk factors (P=0.003), maternal cardiac output decline from baseline to third trimester (P=0.017), and third trimester umbilical artery Doppler abnormalities (P \u3c 0.001) independently predicted neonatal complications and were incorporated into a novel risk index in which 0, 1, and \u3e 1 predictor corresponded to expected complication rates of 5%, 30%, and 76%, respectively. Conclusions-Decline in maternal cardiac output during pregnancy and abnormal umbilical artery Doppler flows independently predict neonatal complications. These findings will enhance the identification of higher risk pregnancies that would benefit from close antenatal surveillance