Binding of Ru(terpyridine)(pyridine)dipyridophenazine to DNA studied with polarized spectroscopy and calorimetry

Linear and circular dichroism (LD and CD) spectroscopy as well as isothermal titration calorimetry (ITC) have been used to investigate the interaction of Ru(tpy)(py)dppz(2+) (tpy = 2,2': 6',2 ''-terpyridyl; py = pyridine; dppz = dipyrido[3,2-a: 2' 3'-c]phenazine) with DNA, providing detailed information about the DNA binding thermodynamics and binding geometry of the metal complex. Flow LD, CD and isotropic absorption indicate that Ru(tpy)(py)dppz(2+) bind to DNA from the minor groove with the dppz ligand intercalated between base pairs, very similar to its chiral structural isomers Delta- and Delta-Ru(bpy)(2)dppz(2+) (bpy = 2,2'-bipyridine). A simple cooperative binding model with one binding geometry provide an excellent fit for calorimetric and absorption titration data. The values of the neighbor interaction thermodynamic parameters for Ru(tpy)(py)dppz(2+) suggest that complexes bound contiguously prefer to have their tpy ligands oriented towards the same strand

Localization and extinction of bacterial populations under inhomogeneous growth conditions

The transition from localized to systemic spreading of bacteria, viruses and other agents is a fundamental problem that spans medicine, ecology, biology and agriculture science. We have conducted experiments and simulations in a simple one-dimensional system to determine the spreading of bacterial populations that occurs for an inhomogeneous environment under the influence of external convection. Our system consists of a long channel with growth inhibited by uniform UV illumination except in a small ``oasis'', which is shielded from the UV light. To mimic blood flow or other flow past a localized infection, the oasis is moved with a constant velocity through the UV-illuminated ``desert''. The experiments are modeled with a convective reaction-diffusion equation. In both the experiment and model, localized or extinct populations are found to develop, depending on conditions, from an initially localized population. The model also yields states where the population grows everywhere. Further, the model reveals that the transitions between localized, extended, and extinct states are continuous and non-hysteretic. However, it does not capture the oscillations of the localized population that are observed in the experiment.Comment: 11 pages, 7 figure

The Phase Diagram of the Quantum Curie-Weiss Model

This paper studies a generalization of the Curie-Weiss model (the Ising model on a complete graph) to quantum mechanics. Using a natural probabilistic representation of this model, we give a complete picture of the phase diagram of the model in the parameters of inverse temperature and transverse field strength. Further analysis computes the critical exponent for the decay of the order parameter in the approach to the critical curve and gives useful stability properties of a variational problem associated with the representation.Comment: 20 pages/Removed Bracket from titl

High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of \u3ci\u3ePlasmodium falciparum\u3c/i\u3e

In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-D-xylulose-5- phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure−activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Mass drug administration of ivermectin, diethylcarbamazine, plus albendazole compared with diethylcarbamazine plus albendazole for reduction of lymphatic filariasis endemicity in Papua New Guinea: a cluster-randomised trial

Background: A single co-administered dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to be safe and more efficacious for clearing Wuchereria bancrofti microfilariae than the standard two-drug regimen of diethylcarbamazine plus albendazole in clinical trials. However, the effectiveness of mass drug administration with the triple-drug regimen compared with the two-drug regimen is unknown. We compared the effectiveness of mass drug administration with the triple-drug and two-drug regimens for reducing microfilariae prevalence to less than 1% and circulating filarial antigen prevalence to less than 2%, levels that are unlikely to sustain transmission of lymphatic filariasis, in Papua New Guinea. Methods: This open-label, cluster-randomised study was done in 24 villages in a district endemic for lymphatic filariasis in Papua New Guinea. Villages paired by population size were randomly assigned to receive mass drug administration with a single dose of the triple-drug oral regimen of ivermectin (200 μg per kg of bodyweight) plus diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg) or a single dose of the two-drug oral regimen of diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg). This is a follow-on study of a previously reported safety study (ClinicalTrials.gov NCT02899936). All residents aged 5 years or older and non-pregnant women were asked to participate. After cross-sectional night blood microfilariae and circulating filarial antigen surveys, mass drug administration was provided at baseline and repeated 12 months later. The primary outcomes were mean prevalence of microfilariae and circulating filarial antigen at 12 months and 24 months, assessed in all residents willing to participate at each timepoint. This study is registered with ClinicalTrials.gov, NCT03352206. Findings: Between Nov 18, 2016, and May 26, 2017, 4563 individuals were enrolled in 24 clusters; 12 clusters (2382 participants) were assigned to the triple-drug regimen and 12 clusters (2181 participants) to the two-drug regimen. Mean drug ingestion rates (of residents aged ≥5 years) were 66·1% at baseline and 63·2% at 12 months in communities assigned to the triple-drug regimen and 65·9% at baseline and 54·9% at 12 months in communities assigned to the two-drug regimen. Microfilariae prevalence in the triple-drug regimen group decreased from 105 (4·4%) of 2382 participants (95% CI 3·6–5·3) at baseline to nine (0·4%) of 2319 (0·1–0·7) at 12 months and four (0·2%) of 2086 (0·1–0·5) at 24 months. In the two-drug regimen group, microfilariae prevalence decreased from 93 (4·3%) of 2181 participants (95% CI 3·5–5·2) at baseline to 29 (1·5%) of 1963 (1·0–2·1) at 12 months and eight (0·4%) of 1844 (0·2–0·9) at 24 months (adjusted estimated risk ratio 4·5, 95% CI 1·4–13·8, p=0·0087, at 12 months; 2·9, 95% CI 1·0–8·8, p=0·058, at 24 months). The prevalence of circulating filarial antigen decreased from 523 (22·0%) of 2382 participants (95% CI 20·3–23·6) at baseline to 378 (16·3%) of 2319 (14·9–17·9) at 12 months and 156 (7·5%) of 2086 (6·4–8·7) at 24 months in the triple-drug regimen group and from 489 (22·6%) of 2168 participants (20·7–24·2) at baseline to 358 (18·2%) of 1963 (16·7–20·1) at 12 months and 184 (10·0%) of 1840 (8·7–11·5) at 24 months in the two-drug regimen group; after adjustment, differences between groups were not significant. Interpretation: Mass administration of the triple-drug regimen was more effective than the two-drug regimen in reducing microfilariae prevalence in communities to less than the target level of 1%, but did not reduce circulating filarial antigen prevalence to less than 2%. These results support the use of mass drug administration with the triple-drug regimen to accelerate elimination of lymphatic filariasis

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

FORUM:Remote testing for psychological and physiological acoustics

Acoustics research involving human participants typically takes place in specialized laboratory settings. Listening studies, for example, may present controlled sounds using calibrated transducers in sound-attenuating or anechoic chambers. In contrast, remote testing takes place outside of the laboratory in everyday settings (e.g., participants' homes). Remote testing could provide greater access to participants, larger sample sizes, and opportunities to characterize performance in typical listening environments at the cost of reduced control of environmental conditions, less precise calibration, and inconsistency in attentional state and/or response behaviors from relatively smaller sample sizes and unintuitive experimental tasks. The Acoustical Society of America Technical Committee on Psychological and Physiological Acoustics launched the Task Force on Remote Testing (https://tcppasa.org/remotetesting/) in May 2020 with goals of surveying approaches and platforms available to support remote testing and identifying challenges and considerations for prospective investigators. The results of this task force survey were made available online in the form of a set of Wiki pages and summarized in this report. This report outlines the state-of-the-art of remote testing in auditory-related research as of August 2021, which is based on the Wiki and a literature search of papers published in this area since 2020, and provides three case studies to demonstrate feasibility during practice

A PLENA-like gene of peach is involved in carpel formation and subsequent transformation into a fleshy fruit

MADS-box genes have been shown to play a role in the formation of fruits, both in Arabidopsis and in tomato. In peach, two C-class MADS-box genes have been isolated. Both of them are expressed during flower and mesocarp development. Here a detailed analysis of a gene that belongs to the PLENA subfamily of MADS-box genes is shown. The expression of this PLENA-like gene (PpPLENA) increases during fruit ripening, and its ectopic expression in tomato plants causes the transformation of sepals into carpel-like structures that become fleshy and ripen like real fruits. Interestingly, the transgenic berries constitutively expressing the PpPLENA gene show an accelerated ripening, as judged by the expression of genes that are important for tomato fruit ripening. It is suggested that PpPLENA might interfere with the endogenous activity of TAGL1, thereby activating the fruit ripening pathway earlier compared with wild-type tomato plants

Barriers to Treatment for Female Problem Gamblers: A UK Perspective

There is a paucity of research in the UK which examines problem gambling and that which does exist is mainly quantitative, focuses on male samples and fails to look at treatment seeking populations or obstacles preventing problem gamblers from seeking treatment. This paper presents findings from part of a larger qualitative study that explored the experience of treatment for female problem gamblers. Data were collected using semi-structured interviews with eight women who had received individual cognitive-behavioural therapy in the National Health Service for their gambling problem. An interpretative phenomenological analysis approach was applied in the research process, identifying three main themes, of which the subtheme ‘Barriers to Treatment’ is examined here. Internal and external barriers to treatment organically emerged in all female participants’ accounts and appear to have an impact on service utilisation. Input directly from gamblers can be combined with findings from other studies to devise better ways of reaching female problem gamblers. A better understanding of barriers to treatment can also provide valuable direction for future research and suggest applications in clinical service provision and treatment planning