Energy Landscapes for Proteins: From Single Funnels to Multifunctional Systems

This report advances the hypothesis that multifunctional systems may be associated with multifunnel potential and free energy landscapes, with particular focus on biomolecules. It compares systems that exhibit single, double, and multiple competing structures, and contrasts multifunnel landscapes associated with misfolded amyloidogenic oligomers, which presumably do not arise as an evolutionary target. In this context, intrinsically disordered proteins could be considered intrinsically multifunctional molecules, associated with multifunnel landscapes. Potential energy landscape theory enables biomolecules to be treated in a common framework together with self‐organizing and multifunctional systems based on inorganic materials, atomic and molecular clusters, crystal polymorphs, and soft matter.epsr

Acute severe non-traumatic muscle injury following reperfusion surgery for acute aortic occlusion: case report

Acute aortic occlusion is a rare but catastrophic disease with a high mortality rate. Severe perioperative complications could result from revascularization of infarcted muscles. Muscle cell ischaemia and massive volume cell death lead to the release of myoglobin, potassium, and lactic acid, which could be fatal if not recognised or treated early. We highlight the life-threatening adverse effects resulting from bulk tissue infarction from non-traumatic causes such as aortic occlusion followed by the metabolic sequelae of reperfusion. This is similar to the pathophysiology of traumatic crush injuries and rhabdomyolysis. The case highlights the vigorous pre-emptive treatment of acidosis and hyperkalaemia required during surgical revascularisation to potentially avert adverse surgical outcomes in acute aortic obstruction

Structure, Thermodynamics, and Folding Pathways for a Tryptophan Zipper as a Function of Local Rigidification

We investigate how the underlying potential energy landscape for a tryptophan zipper changes as indole rings, peptide bonds, termini, and trigonal planar centers are systematically grouped into local rigid bodies. The local rigid body framework results in a substantial computational speedup by effectively reducing the total number of degrees of freedom. Benchmarks are presented for the thermodynamics and folding mechanism. In general, the melting transition, as well as the precise sequence of folding events, is accurately reproduced with conservative local rigidification. However, aggressive rigidification leads to increased topological frustration and a concomitant slowing down of the global kinetics. Our results suggest that an optimal choice of local rigidification, and perhaps a hierarchical approach, could be very useful for investigating complex pathways in biomolecules.J.A.J. acknowledges financial support from the Gates Cambridge Trust

Cosmesis and breast-related quality of life outcomes following intra-operative radiotherapy for early breast cancer - a sub-study of the TARGIT - a trial

Purpose: The international randomized TARGIT-A trial compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to 3-7 weeks of daily conventional external beam radiotherapy (EBRT) in women with early breast cancer treatable with breast conserving surgery. TARGIT-A showed TARGIT-IORT to be non-inferior compared to EBRT in terms of reducing the risk of local cancer recurrence and found no difference in breast cancer survival however its effect on patient reported cosmesis and breast-related quality of life (QOL) have not yet been described. Methods and Materials: Longitudinal cosmesis and QOL data were collected from a sub-set of TARGIT-A participants who received TARGIT-IORT as a separate procedure (post-pathology). Patients completed a cosmetic assessment before radiotherapy and annually thereafter for at least five years. Patients also completed the combined EORTC core questionnaire (QLQ-C30) and Breast Specific Module (BR23) in addition to the Body Image after Breast Cancer Questionnaire (BIABC) at baseline and annually thereafter. The combined EORTC questionnaires were also collected 3, 6, and 9 months after wide local excision (WLE). Results: An Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points. TARGIT-IORT patients reported better breast-related QOL than EBRT patients. Statistically and clinically significant differences were seen at month-6 and Year-1, with EBRT patients having moderately worse breast symptoms (a statistically significant difference of more than 10 in a 100 point scale) than TARGIT-IORT patients at these time points. Conclusion: Patients treated with TARGIT-IORT on the TARGIT-A trial have similar self-reported cosmetic outcome but better breast-related QOL outcomes than patients treated with EBRT. This important evidence can facilitate the treatment decision making process for patients who have early breast cancer suitable for breast conserving surgery and inform their clinicians

Two real parton contributions to non-singlet kernels for exclusive QCD DGLAP evolution

Results for the two real parton differential distributions needed for implementing a next-to-leading order (NLO) parton shower Monte Carlo are presented. They are also integrated over the phase space in order to provide solid numerical control of the MC codes and for the discussion of the differences between the standard $\bar{MS}$ factorization and Monte Carlo implementation at the level of inclusive NLO evolution kernels. Presented results cover the class of non-singlet diagrams entering into NLO kernels. The classic work of Curci-Furmanski-Pertonzio was used as a guide in the calculations.Comment: 34 pages, 3 figure

The impact of an intervention to introduce malaria rapid diagnostic tests on fever case management in a high transmission setting in Uganda: A mixed-methods cluster-randomized trial (PRIME).

Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 95\% CI: 0.56, 1.17 p = 0.24). Most children (76.0\%) tested positive by reference mRDT, but many were not prescribed AL (22.5\% intervention versus 25.9\% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3\% invention vs 42.4\% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management

Wilson Loop Renormalization Group Flows

The locally BPS Wilson loop and the pure gauge Wilson loop map under AdS/CFT duality to string world-sheet boundaries with standard and alternate quantizations of the world-sheet fields. This implies an RG flow between the two operators, which we verify at weak coupling. Many additional loop operators exist at strong coupling, with a rich pattern of RG flows.Comment: 10 p, 2 figures. v3: Title change, expanded treatment of RG flow

Lymphatic Filariasis Control in Tanzania: Effect of Six Rounds of Mass Drug Administration with Ivermectin and Albendazole on Infection and Transmission.

Control of lymphatic filariasis (LF) in most countries of sub-Saharan Africa is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole, in order to interrupt transmission. We present findings from a detailed study on the effect of six rounds of MDA with this drug combination as implemented by the National Lymphatic Filariasis Elimination Programme (NLFEP) in a highly endemic rural area of north-eastern Tanzania.\ud The effect of treatment on transmission and human infection was monitored in a community- and a school-based study during an 8-year period (one pre-intervention and 7 post-intervention years) from 2003 to 2011. Before intervention, 24.5% of the community population had microfilariae (mf) in the blood, 53.3% had circulating filarial antigens (CFA) and 78.9% had specific antibodies to the recombinant filarial antigen Bm14. One year after the sixth MDA, these values had decreased considerably to 2.7%, 19.6% and 27.5%, respectively. During the same period, the CFA prevalence among new intakes of Standard 1 pupils in 10 primary schools decreased from 25.2% to 5.6%. In line with this, transmission by the three vectors (Anopheles gambiae, An. funestus and Culex quinquefasciatus) as determined by dissection declined sharply (overall vector infectivity rate by 99.3% and mean monthly transmission potential by 99.2% between pre-intervention and fifth post-intervention period). A major shift in vector species composition, from predominantly anopheline to almost exclusively culicine was observed over the years. This may be largely unrelated to the MDAs but may have important implications for the epidemiology of LF in the area. Six MDAs caused considerable decrease in all the measured indices for transmission and human infection. In spite of this, indices were still relatively high in the late period of the study, and it may take a long time to reach the recommended cut-off levels for interruption of transmission unless extra efforts are made. These should include increased engagement of the target population in the control activities, to ensure higher treatment coverage. It is expected that the recent initiative to distribute insecticide impregnated bed nets to every household in the area will also contribute towards reaching the goal of successful LF elimination