Synthetically tuneable biomimetic artificial photosynthetic reaction centres that closely resemble the natural system in purple bacteria

© 2016 The Royal Society of Chemistry. Porphyrin-based photosynthetic reaction centre (PRC) mimics, ZnPQ-Q2HP-C60 and MP2Q-Q2HP-C60 (M = Zn or 2H), designed to have a similar special-pair electron donor and similar charge-separation distances, redox processes and photochemical reaction rates to those in the natural PRC from purple bacteria, have been synthesised and extensive photochemical studies performed. Mechanisms of electron-transfer reactions are fully investigated using femtosecond and nanosecond transient absorption spectroscopy. In benzonitrile, all models show picosecond-timescale charge-separations and the final singlet charge-separations with the microsecond-timescale. The established lifetimes are long compared to other processes in organic solar cells or other organic light harvesting systems. These rigid, synthetically flexible molecules provide the closest mimics to the natural PRC so far synthesised and present a future direction for the design of light harvesters with controllable absorption, redox, and kinetics properties

The phenotype of type 1 diabetes in sub-Saharan Africa

This is the final version. Available from Frontiers Media via the DOI in this record. The phenotype of type 1 diabetes in Africa, especially sub-Saharan Africa, is poorly understood. Most previously conducted studies have suggested that type 1 diabetes may have a different phenotype from the classical form of the disease described in western literature. Making an accurate diagnosis of type 1 diabetes in Africa is challenging, given the predominance of atypical diabetes forms and limited resources. The peak age of onset of type 1 diabetes in sub-Saharan Africa seems to occur after 18-20 years. Multiple studies have reported lower rates of islet autoantibodies ranging from 20 to 60% amongst people with type 1 diabetes in African populations, lower than that reported in other populations. Some studies have reported much higher levels of retained endogenous insulin secretion than in type 1 diabetes elsewhere, with lower rates of type 1 diabetes genetic susceptibility and HLA haplotypes. The HLA DR3 appears to be the most predominant HLA haplotype amongst people with type 1 diabetes in sub-Saharan Africa than the HLA DR4 haplotype. Some type 1 diabetes studies in sub-Saharan Africa have been limited by small sample sizes and diverse methods employed. Robust studies close to diabetes onset are sparse. Large prospective studies with well-standardized methodologies in people at or close to diabetes diagnosis in different population groups will be paramount to provide further insight into the phenotype of type 1 diabetes in sub-Saharan Africa.National Institute for Health Research (NIHR

Latent Autoimmune Diabetes of Adults (LADA) is likely to represent a mixed population of autoimmune (Type 1) and nonautoimmune (Type 2) diabetes

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordLatent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes–associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to 1) true autoimmune diabetes with a milder phenotype at older onset ages that initially appears similar to type 2 diabetes but later requires insulin, 2) a disease syndrome where the pathophysiologies of type 1 and type 2 diabetes are both present in each patient, or 3) a heterogeneous group resulting from difficulties in classification. Herein, we suggest that difficulties in classification are a major component resulting from defining LADA using a diagnostic test—islet autoantibody measurement—with imperfect specificity applied in low-prevalence populations. This yields a heterogeneous group of true positives (autoimmune type 1 diabetes) and false positives (nonautoimmune type 2 diabetes). For clinicians, this means that islet autoantibody testing should not be undertaken in patients who do not have clinical features suggestive of autoimmune diabetes: in an adult without clinical features of type 1 diabetes, it is likely that a single positive antibody will represent a false-positive result. This is in contrast to patients with features suggestive of type 1 diabetes, where false-positive results will be rare. For researchers, this means that current definitions of LADA are not appropriate for the study of autoimmune diabetes in later life. Approaches that increase test specificity, or prior likelihood of autoimmune diabetes, are needed to avoid inclusion of participants who have nonautoimmune (type 2) diabetes. Improved classification will allow improved assignment of prognosis and therapy as well as an improved cohort in which to analyze and better understand the detailed pathophysiological components acting at onset and during disease progression in late-onset autoimmune diabetes.National Institute for Health Research (NIHR)Wellcome TrustNIH NIDDKJDR

Real-world outcomes in thoracic cancer patients with severe Acute respiratory syndrome Coronavirus 2 (COVID-19): Single UK institution experience.

BACKGROUND: UK COVID-19 mortality rates are amongst the highest globally. Controversy exists on the vulnerability of thoracic cancer patients. We describe the characteristics and sequelae of patients with thoracic cancer treated at a UK cancer centre infected with COVID-19. METHODS: Patients undergoing care for thoracic cancer diagnosed with COVID-19 (RT-PCR/radiology/clinically) between March-June 2020 were included. Data were extracted from patient records. RESULTS: Thirty-two patients were included: 14 (43%) diagnosed by RT-PCR, 18 (57%) by radiology and/or convincing symptoms. 88% had advanced thoracic malignancies. Eleven of 14 (79%) patients diagnosed by RT-PCR and 12 of 18 (56%) patients diagnosed by radiology/clinically were hospitalised, of which four (29%) and 2 (11%) patients required high-dependency/intensive care respectively. Three (21%) patients diagnosed by RT-PCR and 2 (11%) patients diagnosed by radiology/clinically required non-invasive ventilation; none were intubated. Complications included pneumonia and sepsis (43% and 14% respectively in patients diagnosed by RT-PCR; 17% and 11% respectively in patients diagnosed by radiology/clinically). In patients receiving active cancer treatment, therapy was delayed/ceased in 10/12 (83%) and 7/11 (64%) patients diagnosed by RT-PCR and radiology/clinically respectively. Nine (28%) patients died; all were smokers. Median time from symptom onset to death was 7 days (range 3-37). CONCLUSIONS: The immediate morbidity from COVID-19 is high in thoracic cancer patients. Hospitalisation and treatment interruption rates were high. Improved risk-stratification models for UK cancer patients are urgently needed to guide safe cancer-care delivery without compromising efficacy

Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.

Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.This study was supported by Cancer Research UK (to A.-M.B. and N.A.W.), the Medical Research Council (to B.C. and S.A.C.M.), the Engineering and Physical Sciences Research Council (to A.G.F.), Microsoft Research (to A.G.F.), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.R.J.), the Dutch Cancer Research Foundation (to M.J.), the Wellcome Trust (to B.D.S.), and Higher Education Funding Council for England (to T.A.G.)

Leptogenesis from loop effects in curved spacetime

We describe a new mechanism -- radiatively-induced gravitational leptogenesis -- for generating the matter-antimatter asymmetry of the Universe. We show how quantum loop effects in C and CP violating theories cause matter and antimatter to propagate differently in the presence of gravity, and prove this is forbidden in flat space by CPT and translation symmetry. This generates a curvature-dependent chemical potential for leptons, allowing a matter-antimatter asymmetry to be generated in thermal equilibrium in the early Universe. The time-dependent dynamics necessary for leptogenesis is provided by the interaction of the virtual self-energy cloud of the leptons with the expanding curved spacetime background, which violates the strong equivalence principle and allows a distinction between matter and antimatter. We show here how this mechanism is realised in a particular BSM theory, the see-saw model, where the quantum loops involve the heavy sterile neutrinos responsible for light neutrino masses. We demonstrate by explicit computation of the relevant two-loop Feynman diagrams how the size of the radiative corrections relevant for leptogenesis becomes enhanced by increasing the mass hierarchy of the sterile neutrinos, and show that for realistic phenomenological parameters this mechanism can generate the observed baryon-to-photon ratio of the Universe

Age of diagnosis does not alter the presentation or progression of robustly defined adult onset type 1 diabetes

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record OBJECTIVE: To determine whether presentation, progression, and genetic susceptibility of robustly defined adult-onset type 1 diabetes (T1D) are altered by diagnosis age. RESEARCH DESIGN AND METHODS: We compared the relationship between diagnosis age and presentation, C-peptide loss (annual change in urine C-peptide-creatinine ratio [UCPCR]), and genetic susceptibility (T1D genetic risk score [GRS]) in adults with confirmed T1D in the prospective StartRight study, 1,798 adults with new-onset diabetes. T1D was defined in two ways: two or more positive islet autoantibodies (of GAD antibody, IA-2 antigen, and ZnT8 autoantibody) irrespective of clinical diagnosis (n = 385) or one positive islet autoantibody and a clinical diagnosis of T1D (n = 180). RESULTS: In continuous analysis, age of diagnosis was not associated with C-peptide loss for either definition of T1D (P > 0.1), with mean (95% CI) annual C-peptide loss in those diagnosed before and after 35 years of age (median age of T1D defined by two or more positive autoantibodies): 39 (31-46) vs. 44% (38-50) with two or more positive islet autoantibodies and 43 (33-51) vs. 39% (31-46) with clinician diagnosis confirmed by one positive islet autoantibody (P > 0.1). Baseline C-peptide and T1D GRS were unaffected by age of diagnosis or T1D definition (P > 0.1). In T1D defined by two or more autoantibodies, presentation severity was similar in those diagnosed before and after 35 years of age: unintentional weight loss, 80 (95% CI 74-85) vs. 82% (76-87); ketoacidosis, 24 (18-30) vs. 19% (14-25); and presentation glucose, 21 (19-22) vs. 21 mmol/L (20-22) (all P ≥ 0.1). Despite similar presentation, older adults were less likely to be diagnosed with T1D, insulin-treated, or admitted to hospital. CONCLUSIONS: When adult-onset T1D is robustly defined, the presentation characteristics, progression, and T1D genetic susceptibility are not altered by age of diagnosis.Diabetes UKNational Institute for Health Research (NIHR)European Foundation for the Study of Diabete

Four small puzzles that Rosetta doesn't solve

A complete macromolecule modeling package must be able to solve the simplest structure prediction problems. Despite recent successes in high resolution structure modeling and design, the Rosetta software suite fares poorly on deceptively small protein and RNA puzzles, some as small as four residues. To illustrate these problems, this manuscript presents extensive Rosetta results for four well-defined test cases: the 20-residue mini-protein Trp cage, an even smaller disulfide-stabilized conotoxin, the reactive loop of a serine protease inhibitor, and a UUCG RNA tetraloop. In contrast to previous Rosetta studies, several lines of evidence indicate that conformational sampling is not the major bottleneck in modeling these small systems. Instead, approximations and omissions in the Rosetta all-atom energy function currently preclude discriminating experimentally observed conformations from de novo models at atomic resolution. These molecular "puzzles" should serve as useful model systems for developers wishing to make foundational improvements to this powerful modeling suite.Comment: Published in PLoS One as a manuscript for the RosettaCon 2010 Special Collectio

Routine Islet Autoantibody Testing in Clinically Diagnosed Adult-Onset Type 1 Diabetes Can Help Identify Misclassification and the Possibility of Successful Insulin Cessation

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordOBJECTIVE Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population. RESEARCH DESIGN AND METHODS We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide–to–creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months. We also evaluated changes in treatment and glycemia over 2 years after informing participants and their clinicians of autoantibody results. RESULTS Of 722 participants diagnosed with type 1 diabetes, 24.8% (179) were autoantibody negative. This group had genetic and C-peptide characteristics suggestive of a high prevalence of nonautoimmune diabetes: lower mean type 1 diabetes genetic risk score (islet autoantibody negative vs. positive: 10.85 vs. 13.09 [P < 0.001] [type 2 diabetes 10.12]) and lower annual change in C-peptide (UCPCR), −24% vs. −43% (P < 0.001). After median 24 months of follow-up, treatment change occurred in 36.6% (60 of 164) of autoantibody-negative participants: 22.6% (37 of 164) discontinued insulin, with HbA1c similar to that of participants continuing insulin (57.5 vs. 60.8 mmol/mol [7.4 vs. 7.7%], P = 0.4), and 14.0% (23 of 164) added adjuvant agents to insulin. CONCLUSIONS In adult-onset clinically diagnosed type 1 diabetes, negative islet autoantibodies should prompt careful consideration of other diabetes subtypes. When routinely measured, negative antibodies are associated with successful insulin cessation. These findings support recent recommendations for routine islet autoantibody assessment in adult-onset type 1 diabetes.National Institute for Health Research (NIHR)Diabetes UKWellcome Trus