Nickel-Catalyzed Asymmetric Reductive Cross-Coupling of a-Chloroesters with (Hetero)Aryl Iodides

An asymmetric reductive cross-coupling of alpha-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording alpha-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the alpha-chloroester substrate and ligand on enantioselectivity

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases

Cross-correlating Carbon Monoxide Line-intensity Maps with Spectroscopic and Photometric Galaxy Surveys

Line-intensity mapping (LIM or IM) is an emerging field of observational work, with strong potential to fit into a larger effort to probe large-scale structure and small-scale astrophysical phenomena using multiple complementary tracers. Taking full advantage of such complementarity means, in part, undertaking line-intensity surveys with galaxy surveys in mind. We consider the potential for detection of a cross-correlation signal between COMAP and blind surveys based on photometric redshifts (as in COSMOS) or based on spectroscopic data (as with the HETDEX survey of Lyman-$\alpha$ emitters). We find that obtaining $\sigma_z/(1+z)\lesssim0.003$ accuracy in redshifts and $\gtrsim10^{-4}$ sources per Mpc$^3$ with spectroscopic redshift determination should enable a CO-galaxy cross spectrum detection significance at least twice that of the CO auto spectrum. Either a future targeted spectroscopic survey or a blind survey like HETDEX may be able to meet both of these requirements.Comment: 19 pages + appendix (31 pages total), 16 figures, 6 tables; accepted for publication in Ap

Associations of Mail Survey Length and Layout With Response Rates.

We assess the association between survey layout and response rates (RRs) in the 2017 Medicare Advantage Consumer Assessment of Healthcare Providers and Systems mail survey. Among 438 Medicare Advantage plans surveyed by six vendors, there was latitude in survey layout, and plans could add up to 12 supplemental items. Regression models predicted survey response from survey characteristics (page count, number of supplemental items, and survey attractiveness), and beneficiary sociodemographics. Beneficiary-age-by-survey-characteristic interactions assessed whether survey characteristics were more strongly related to RRs among older beneficiaries. We found that surveys with more supplemental items and less attractive layouts had lower adjusted odds of response. RRs were more sensitive to format among older beneficiaries. The difference in adjusted RRs for the most favorable versus the least favorable survey design was 14.5%. For a 65-year-old, this difference was 13.6%; for an 80-year-old, it was 21.0%. These findings suggest that even within a relatively standardized survey, formatting can substantially influence RRs

Evaluation of Food Insecurity in Adults and Children With Cystic Fibrosis: Community Case Study

Advances in the care and treatment of cystic fibrosis (CF) have led to improved mortality rates; therefore, considerably more individuals with CF are living into adulthood. With an increased number of CF patients advancing into adulthood, there is the need for more research that surrounds the aging adult CF patient. It is important to conduct research and collect results on the aging CF population to help better prepare the CF patient, who is dealing with the heavy treatment and financial burden of their disease, build autonomy and increase their quality of life. Of note, research has found that social, behavioral, and physical factors influence the ability of those with CF to follow dietary recommendations. A primary treatment goal in CF is a high calorie, high protein, and high fat diet. A socio-economic factor that has not been adequately investigated with regards to dietary compliance of individuals with CF is food insecurity. The aim of this community case study was to document the experiences and estimate the prevalence of food insecurity among CF patients residing in Idaho. The correlation between food insecurity and health outcomes (lung function and body mass index) was also examined. Participants included adult patients and parents of pediatric patients with CF. Food insecurity rates among CF patients of all ages were found to be significantly higher than that seen in the overall community; however, no specific correlation between food insecurity and body mass index (BMI) or lung function emerged. This case study highlights the need for continued research around food access issues in this patient population. The data resulting from this study shows the value of CF advocacy organizations promoting efforts to build resources and provide education around food insecurity issues

Neighborhoods of trees in circular orderings

In phylogenetics, a common strategy used to construct an evolutionary tree for a set of species X is to search in the space of all such trees for one that optimizes some given score function (such as the minimum evolution, parsimony or likelihood score). As this can be computationally intensive, it was recently proposed to restrict such searches to the set of all those trees that are compatible with some circular ordering of the set X. To inform the design of efficient algorithms to perform such searches, it is therefore of interest to find bounds for the number of trees compatible with a fixed ordering in the neighborhood of a tree that is determined by certain tree operations commonly used to search for trees: the nearest neighbor interchange (nni), the subtree prune and regraft (spr) and the tree bisection and reconnection (tbr) operations. We show that the size of such a neighborhood of a binary tree associated with the nni operation is independent of the tree’s topology, but that this is not the case for the spr and tbr operations. We also give tight upper and lower bounds for the size of the neighborhood of a binary tree for the spr and tbr operations and characterize those trees for which these bounds are attained

A Fully Integrated Real-Time Detection, Diagnosis, and Control of Community Diarrheal Disease Clusters and Outbreaks (the INTEGRATE Project):Protocol for an Enhanced Surveillance System

BACKGROUND:Diarrheal disease, which affects 1 in 4 people in the United Kingdom annually, is the most common cause of outbreaks in community and health care settings. Traditional surveillance methods tend to detect point-source outbreaks of diarrhea and vomiting; they are less effective at identifying low-level and intermittent food supply contamination. Furthermore, it can take up to 9 weeks for infections to be confirmed, reducing slow-burn outbreak recognition, potentially impacting hundreds or thousands of people over wide geographical areas. There is a need to address fundamental problems in traditional diarrheal disease surveillance because of underreporting and subsequent unconfirmed infection by patients and general practitioners (GPs); varying submission practices and selective testing of samples in laboratories; limitations in traditional microbiological diagnostics, meaning that the timeliness of sample testing and etiology of most cases remains unknown; and poorly integrated human and animal surveillance systems, meaning that identification of zoonoses is delayed or missed. OBJECTIVE:This study aims to detect anomalous patterns in the incidence of gastrointestinal disease in the (human) community; to target sampling; to test traditional diagnostic methods against rapid, modern, and sensitive molecular and genomic microbiology methods that identify and characterize responsible pathogens rapidly and more completely; and to determine the cost-effectiveness of rapid, modern, sensitive molecular and genomic microbiology methods. METHODS:Syndromic surveillance will be used to aid identification of anomalous patterns in microbiological events based on temporal associations, demographic similarities among patients and animals, and changes in trends in acute gastroenteritis cases using a point process statistical model. Stool samples will be obtained from patients' consulting GPs, to improve the timeliness of cluster detection and characterize the pathogens responsible, allowing health protection professionals to investigate and control outbreaks quickly, limiting their size and impact. The cost-effectiveness of the proposed system will be examined using formal cost-utility analysis to inform decisions on national implementation. RESULTS:The project commenced on April 1, 2013. Favorable approval was obtained from the Research Ethics Committee on June 15, 2015, and the first patient was recruited on October 13, 2015, with 1407 patients recruited and samples processed using traditional laboratory techniques as of March 2017. CONCLUSIONS:The overall aim of this study is to create a new One Health paradigm for detecting and investigating diarrhea and vomiting in the community in near-real time, shifting from passive human surveillance and management of laboratory-confirmed infection toward an integrated, interdisciplinary enhanced surveillance system including management of people with symptoms. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13941

Attenuated Auditory Event-Related Potentials and Associations with Atypical Sensory Response Patterns in Children with Autism

Neurobiological underpinnings of unusual sensory features in individuals with autism are unknown. Event-related potentials (ERPs) elicited by task-irrelevant sounds were used to elucidate neural correlates of auditory processing and associations with three common sensory response patterns (hyperresponsiveness; hyporesponsiveness; sensory seeking). Twenty-eight children with autism and 39 typically developing children (4–12 year-olds) completed an auditory oddball paradigm. Results revealed marginally attenuated P1 and N2 to standard tones and attenuated P3a to novel sounds in autism versus controls. Exploratory analyses suggested that within the autism group, attenuated N2 and P3a amplitudes were associated with greater sensory seeking behaviors for specific ranges of P1 responses. Findings suggest that attenuated early sensory as well as later attention-orienting neural responses to stimuli may underlie selective sensory features via complex mechanisms