Activity- and reactivity-based proteomics: Recent technological advances and applications in drug discovery.

Activity-based protein profiling (ABPP) is recognized as a powerful and versatile chemoproteomic technology in drug discovery. Central to ABPP is the use of activity-based probes to report the activity of specific enzymes or reactivity of amino acid types in complex biological systems. Over the last two decades, ABPP has facilitated the identification of new drug targets and discovery of lead compounds in human and infectious disease. Furthermore, as part of a sustained global effort to illuminate the druggable proteome, the repertoire of target classes addressable with activity-based probes has vastly expanded in recent years. Here, we provide an overview of ABPP and summarise the major technological advances with an emphasis on probe development

Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype.

Background: Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Methods: Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results: Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. Conclusion: This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema

Algebraic description of anharmonic stretching vibrations

A U(2) algebraic model is presented to describe stretching vibrations of XY$_n$ (n=2, 3, and 4) systems, where anharmonic interactions between the bond modes are considered. This model in a limit corresponds to an anharmonically coupled local mode model. As an example, the model for a molecule XY$_4$ is applied to recently observed spectra of methane in both gas and liquid phases, and the results obtained are in good agreement with the experiments

Resonances in rotationally inelastic scattering of OH(X2ΠX^2\Pi) with helium and neon

We present detailed calculations on resonances in rotationally and spin-orbit inelastic scattering of OH (X\,^2\Pi, j=3/2, F_1, f) radicals with He and Ne atoms. We calculate new \emph{ab initio} potential energy surfaces for OH-He, and the cross sections derived from these surfaces compare favorably with the recent crossed beam scattering experiment of Kirste \emph{et al.} [Phys. Rev. A \textbf{82}, 042717 (2010)]. We identify both shape and Feshbach resonances in the integral and differential state-to-state scattering cross sections, and we discuss the prospects for experimentally observing scattering resonances using Stark decelerated beams of OH radicals.Comment: 14 pages, 15 Figure

Algebraic approach to vibrational spectra of tetrahedral molecules: a case study of silicon tetrafluoride

Both the stretch and bend vibrational spectrum and the intensity of infrared transitions in a tetrahedral molecule are studied in a U(2) algebraic model, where the spurious states in the model Hamiltonian and the wavefunctions are exactly removed. As an example, we apply the model to silicon tetrafluoride SiF$_4$.Comment: Revtex, 7 pages, no figure, to appear in Chem. Phys. Let

How colonization bottlenecks, tissue niches, and transmission strategies shape protozoan infections

Protozoan pathogens such as Plasmodium spp., Leishmania spp., Toxoplasma gondii, and Trypanosoma spp. are often associated with high-mortality, acute and chronic diseases of global health concern. For transmission and immune evasion, protozoans have evolved diverse strategies to interact with a range of host tissue environments. These interactions are linked to disease pathology, yet our understanding of the association between parasite colonization and host homeostatic disruption is limited. Recently developed techniques for cellular barcoding have the potential to uncover the biology regulating parasite transmission, dissemination, and the stability of infection. Understanding bottlenecks to infection and the in vivo tissue niches that facilitate chronic infection and spread has the potential to reveal new aspects of parasite biology

Prevention and management of excessive gestational weight gain: a survey of overweight and obese pregnant women

Background - Excessive gestational weight gain is associated with adverse infant, childhood and maternal outcomes and research to develop interventions to address this issue is ongoing. The views of women on gestational weight gain and the resources they would consider helpful in addressing this are however largely unknown. This survey aimed to determine the views of newly pregnant women, living in areas of social disadvantage, on 1) their current body weight and potential gestational weight gain and 2) the resources or interventions they would consider helpful in preventing excessive gestational weight gain. Methods - A convenience sample of overweight and obese pregnant women living in Fife, UK, were invited to complete a short anonymised questionnaire at their 12 week booking visit. Results - 428 women, BMI>25 kg/m2, completed the questionnaire. Fifty-four per cent of respondents were obese (231) and 62% were living in areas of mild to moderate deprivation. Over three-quarters of participants felt dissatisfied with their current weight (81%). The majority of women (60%) expressed some concern about potential weight gain. Thirty-nine percent were unconcerned about weight gain during their pregnancy, including 34 women (19%) who reported having retained weight gained in earlier pregnancies. Amongst those concerned about weight gain advice on physical activity (41%) and access to sports/leisure facilities were favoured resources (36%). Fewer women (12%) felt that group sessions on healthy eating or attending a clinic for individualised advice (14%) would be helpful. "Getting time off work" was the most frequently cited barrier (48%) to uptake of resources other than leaflets. Conclusions- These data suggest a lack of awareness amongst overweight and obese women regarding excessive gestational weight gain. Monitoring of gestational weight gain, and approaches for its management, should be formally integrated into routine antenatal care. Barriers to the uptake of resources to address weight gain are numerous and must be considered in the design of future interventions and services

Utilisation of Postnatal Care among Rural Women in Nepal

Background: Postnatal care is uncommon in Nepal, and where it is available the quality is often poor. Adequate utilisation of postnatal care can help reduce mortality and morbidity among mothers and their babies. Therefore, our study assessed the utilisation of postnatal care at a rural community level. Methods: A descriptive, cross-sectional study was carried out in two neighbouring villages in early 2006. A total of 150 women who had delivered in the previous 24 months were asked to participate in the study using a semi-structured questionnaire. Results: The proportion of women who had received postnatal care after delivery was low (34%). Less than one in five women (19%) received care within 48 hours of giving birth. Women in one village had less access to postnatal care than women in the neighbouring one. Lack of awareness was the main barrier to the utilisation of postnatal care. The woman's own occupation and ethnicity, the number of pregnancies and children and the husband's socio-economic status, occupation and education were significantly associated with the utilisation of postnatal care. Multivariate analysis showed that wealth as reflected in occupation and having attended antenatal are important factors associated with the uptake of postnatal care. In addition, women experiencing health problems appear strongly motivated to seek postnatal care. Conclusion: The postnatal care has a low uptake and is often regarded as inadequate in Nepal. This is an important message to both service providers and health-policy makers. Therefore, there is an urgent need to assess the actual quality of postnatal care provided. Also there appears to be a need for awareness-raising programmes highlighting the availability of current postnatal care where this is of sufficient quality

Access and utilisation of maternity care for disabled women who experience domestic abuse:a systematic review

BACKGROUND: Although disabled women are significantly more likely to experience domestic abuse during pregnancy than non-disabled women, very little is known about how maternity care access and utilisation is affected by the co-existence of disability and domestic abuse. This systematic review of the literature explored how domestic abuse impacts upon disabled women’s access to maternity services. METHODS: Eleven articles were identified through a search of six electronic databases and data were analysed to identify: the factors that facilitate or compromise access to care; the consequences of inadequate care for pregnant women’s health and wellbeing; and the effectiveness of existing strategies for improvement. RESULTS: Findings indicate that a mental health diagnosis, poor relationships with health professionals and environmental barriers can compromise women’s utilisation of maternity services. Domestic abuse can both compromise, and catalyse, access to services and social support is a positive factor when accessing care. Delayed and inadequate care has adverse effects on women’s physical and psychological health, however further research is required to fully explore the nature and extent of these consequences. Only one study identified strategies currently being used to improve access to services for disabled women experiencing abuse. CONCLUSIONS: Based upon the barriers and facilitators identified within the review, we suggest that future strategies for improvement should focus on: understanding women’s reasons for accessing care; fostering positive relationships; being women-centred; promoting environmental accessibility; and improving the strength of the evidence base