Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

On the Origin of the Outgoing Black Hole Modes

The question of how to account for the outgoing black hole modes without drawing upon a transplanckian reservoir at the horizon is addressed. It is argued that the outgoing modes must arise via conversion from ingoing modes. It is further argued that the back-reaction must be included to avoid the conclusion that particle creation cannot occur in a strictly stationary background. The process of ``mode conversion" is known in plasma physics by this name and in condensed matter physics as ``Andreev reflection" or ``branch conversion". It is illustrated here in a linear Lorentz non-invariant model introduced by Unruh. The role of interactions and a physical short distance cutoff is then examined in the sonic black hole formed with Helium-II.Comment: 12 pages, plain latex, 2 figures included using psfig; Analogy to ``Andreev reflection" in superfluid systems noted, references and acknowledgment added, format changed to shorten tex

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma

Evaluation of the Collaborative Use of an Evidence-Based Care Bundle in Emergency Laparotomy

YesIMPORTANCE Patients undergoing emergency laparotomy have high mortality, but few studies exist to improve outcomes for these patients. OBJECTIVE To assess whether a collaborative approach to implement a 6-point care bundle is associated with reduction in mortality and length of stay and improvement in the delivery of standards of care across a group of hospitals. DESIGN, SETTING, AND PARTICIPANTS The Emergency Laparotomy Collaborative (ELC) was a UK-based prospective quality improvement study of the implementation of a care bundle provided to patients requiring emergency laparotomy between October 1, 2015, and September 30, 2017. Participants were 28 National Health Service hospitals and emergency surgical patients who were treated at these hospitals and whose data were entered into the National Emergency Laparotomy Audit (NELA) database. Post-ELC implementation outcomes were compared with baseline data from July 1, 2014, to September 30, 2015. Data entry and collection were performed through the NELA. INTERVENTIONS A 6-point, evidence-based care bundle was used. The bundle included prompt measurement of blood lactate levels, early review and treatment for sepsis, transfer to the operating room within defined time goals after the decision to operate, use of goal-directed fluid therapy, postoperative admission to an intensive care unit, and multidisciplinary involvement of senior clinicians in the decision and delivery of perioperative care. Change management and leadership coaching were provided to ELC leadership teams. MAIN OUTCOME AND MEASURES Primary outcomes were in-hospital mortality, both crude and Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (P-POSSUM) risk-adjusted, and length of stay. Secondary outcomes were the changes after implementation of the separate metrics in the care bundle. RESULTS A total of 28 hospitals participated in the ELC and completed the project. The baseline group included 5562 patients (2937 female [52.8%] and a mean [range] age of 65.3 [18.0-114.0] years), whereas the post-ELC group had 9247 patients (4911 female [53.1%] and a mean [range] age of 65.0 [18.0-99.0] years). Unadjusted mortality rate decreased from 9.8% at baseline to 8.3% in year 2 of the project, and so did risk-adjusted mortality from a baseline of 5.3% to 4.5% post-ELC. Mean length of stay decreased from 20.1 days during year 1 to 18.9 days during year 2. Significant changes in 5 of the 6 metrics in the care bundle were achieved. CONCLUSIONS AND RELEVANCE A collaborative approach using a quality improvement methodology and a care bundle appeared to be effective in reducing mortality and length of stay in emergency laparotomy, suggesting that hospitals should adopt such an approach to see better patient outcomes and care delivery performance.This study was funded by The Health Foundation, United Kingdom, as part of a Scaling Up Award

Theoretical description of deformed proton emitters: nonadiabatic coupled-channel method

The newly developed nonadiabatic method based on the coupled-channel Schroedinger equation with Gamow states is used to study the phenomenon of proton radioactivity. The new method, adopting the weak coupling regime of the particle-plus-rotor model, allows for the inclusion of excitations in the daughter nucleus. This can lead to rather different predictions for lifetimes and branching ratios as compared to the standard adiabatic approximation corresponding to the strong coupling scheme. Calculations are performed for several experimentally seen, non-spherical nuclei beyond the proton dripline. By comparing theory and experiment, we are able to characterize the angular momentum content of the observed narrow resonance.Comment: 12 pages including 10 figure

Tectonic controls on post-subduction granite genesis and emplacement : the late Caledonian suite of Britain and Ireland

Rates of magma emplacement commonly vary as a function of tectonic setting. The late Caledonian granites of Britain and Ireland are associated with closure of the Iapetus Ocean and were emplaced into a varying regime of transpression and transtension throughout the Silurian and into the early Devonian. Here we evaluate a new approach for examining how magma volumes vary as a function of tectonic setting. Available radiometric ages from the late Caledonian granites are used to calculate probability density functions (age spectra), with each pluton weighted by outcrop area as a proxy for its volume. These spectra confirm an absence of magmatic activity during Iapetus subduction between c. 455 Ma and 425 Ma and a dominance of post-subduction magmas between c. 425 Ma and 380 Ma. We review possible reasons why, despite the widespread outcrop of the late Caledonian granites, magmatism appears absent during Iapetus subduction. These include shallow angle subduction or extensive erosion and tectonic removal of the arc. In contrast to previous work we find no strong difference in the age or major element chemistry of post-subduction granites across all terranes. We propose a common causal mechanism in which the down-going Iapetus oceanic slab peeled back and detached beneath the suture following final Iapetus closure. The lithospheric mantle was delaminated beneath the suture and for about 100 km back beneath the Avalonian margin. While magma generation is largely a function of gravitationally driven lithosphere delamination, strike-slip dominated kinematics in the overlying continental crust is what modulated granitic magma emplacement. Early Devonian (419–404 Ma) transtension permitted large volumes of granite emplacement, whereas the subsequent Acadian (late Early Devonian, 404–394 Ma) transpression reduced and eventually suppressed magma emplacement

Pharyngeal carriage of Neisseria species in the African meningitis belt.

OBJECTIVES: Neisseria meningitidis, together with the non-pathogenic Neisseria species (NPNs), are members of the complex microbiota of the human pharynx. This paper investigates the influence of NPNs on the epidemiology of meningococcal infection. METHODS: Neisseria isolates were collected during 18 surveys conducted in six countries in the African meningitis belt between 2010 and 2012 and characterized at the rplF locus to determine species and at the variable region of the fetA antigen gene. Prevalence and risk factors for carriage were analyzed. RESULTS: A total of 4694 isolates of Neisseria were obtained from 46,034 pharyngeal swabs, a carriage prevalence of 10.2% (95% CI, 9.8-10.5). Five Neisseria species were identified, the most prevalent NPN being Neisseria lactamica. Six hundred and thirty-six combinations of rplF/fetA_VR alleles were identified, each defined as a Neisseria strain type. There was an inverse relationship between carriage of N. meningitidis and of NPNs by age group, gender and season, whereas carriage of both N. meningitidis and NPNs was negatively associated with a recent history of meningococcal vaccination. CONCLUSION: Variations in the prevalence of NPNs by time, place and genetic type may contribute to the particular epidemiology of meningococcal disease in the African meningitis belt.MenAfriCar was funded by the Wellcome Trust (086546/Z/08/Z) and the Bill and Melinda Gates Foundation (51251). Kanny Diallo holds a Wellcome Trust Training Fellowship in Public Health and Tropical Medicine.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.jinf.2016.03.01

High-spin study of rotational structures in 72Br

High-spin states in 3572Br37 were studied using the 40Ca(36Ar, 3pn) reaction. The existing level scheme has been significantly modified and extended. Evidence has been found for a spin reassignment of -1ℏh to the previously observed negative-parity band, which carries implications for the interpretation of a signature inversion in this structure. One signature of the previously assigned positive-parity band is interpreted as negative parity and has been extended to I π=(22-) and its signature partner has been observed up to Iπ = (19-) for the first time. The remaining positive-parity band has been extended to Iπ=(29+). A sequence of states observed to Iπ=(22+) may be the signature partner of this structure. Configurations have been assigned to each of these three structures through comparisons to cranked Nilsson-Strutinsky calculations

On the Holographic RG-flow and the Low-energy, Strong Coupling, Large N Limit

From the AdS/CFT correspondence, we learn that the classical evolution of supergravity in the bulk can be reduced to a RG-flow equation for the dual low-energy, strongly coupled and large N gauge theory on the boundary. This result has been used to obtain interesting relations between the various terms in the gravitational part of the boundary effective action, in particular the term that affect the cosmological constant. It is found that once the cosmological constant is cancelled in the UV theory, the RG-flow symmetry of the boundary effective action automatically implies the existence of zero cosmological constant solutions that extend all the way into the IR. Given the standard (and well founded) contradiction between the RG-flow idea and the observational evidence of a small cosmological constant, this is considered to be an important progress, albeit incomplete, towards the final solution. Motivated by this success, it would be interesting to see whether this RG-stability extends outside the scope of strong 't Hooft coupling and large N regime that are implicitly assumed in the de Boer-Verlinde-Verlinde Hamilton-Jacobi formulation of the holographic RG-flow equations of the boundary theory. In this paper, we address this question. Taking into account the leading order corrections in the 1/N and $\alpha'/{R^2}$ parameters, we derive new bulk/boundary relations, from which one can read all the local terms in the boundary effective action. Next, we use the resulting constraints, to examine whether the RG-stability of the cosmological constant extends to the new coupling regime. It would be also interesting to use these constraints to study the Randall-Sundrum scenario in this case.Comment: 27 pages, LateX, no figures, minor changes, typos corrected and added more reference