5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action

In the effort to identify and develop new HIV-1 inhibitors endowed with innovative mechanisms, we focused our attention on the possibility to target more than one viral encoded enzymatic function with a single molecule. In this respect, we have previously identified by virtual screening a new indolinone-based scaffold for dual allosteric inhibitors targeting both reverse transcriptase-associated functions: polymerase and RNase H. Pursuing with the structural optimization of these dual inhibitors, we synthesized a series of 35 new 3-[2-(4-aryl-1,3-thiazol-2-ylidene)hydrazin-1-ylidene]1-indol-2-one and 3-[3-methyl-4-arylthiazol-2-ylidene)hydrazine-1-ylidene)indolin-2-one derivatives, which maintain their dual inhibitory activity in the low micromolar range. Interestingly, compounds 1a, 3a, 10a, and 9b are able to block HIV-1 replication with EC50 < 20 µM. Mechanism of action studies showed that such compounds could block HIV-1 integrase. In particular, compound 10a is the most promising for further multitarget compound development

Localism: a planning panacea?

© 2019 Liverpool University Press. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.3828/tpr.2019.31It has been observed that there is a 'global trend' towards devolution of power from national governments to regional and local authorities, and planning is one of the activities often devolved. In England, the UK government has since 2011 gone further and, it claims, devolved planning powers to the community level. The introduction of a new form of statutory planning - neighbourhood planning - was heralded by the UK government as an embodiment of their commitment to 'localism', representing a shift from top-down to bottom-up control in the English planning system. This Policy and Practice explores some of the tensions inherent in localism as exemplified through the practical implementation of neighbourhood planning.Peer reviewedFinal Accepted Versio

Behaviour and passage of European silver eels (Anguilla anguilla) at a small hydropower plant during their downstream migration

Between 2004 and 2007, 116 downstream migrant silver eels (Anguilla anguilla) were monitored at a hydropower plant on the Gave de Pau river in South-West France using radio and PIT telemetry. The objectives of the study were: (i) to determine the environmental conditions when eels arrived and passed the facility; (ii) to determine the rate of eel escapement (passage other than via the turbines); (iii) to describe the behaviour of eels faced with the intake structure and the permeability of the intake trashracks for the different sizes of eel; and (iv) to determine whether surface bypasses originally designed for salmon could be effective for eels. Five types of behaviour of silver eels in the forebay and at the plant intakes were identified. The study showed the key factor influencing both eel behaviour and the route taken through the plant was variation in river discharge. Escapement rate was related to eel length and the spill flow to river flow ratio, which could be described by a logistic regression model. The surface bypasses originally designed for salmon were found to aid downstream eel migration significantly. At velocities < 0.40 m·s−1, no eels, even the largest, for which the racks are a physical barrier, were found impinged on the trashracks

Public Talks and Science Listens: A Community-Based Participatory Approach to Characterizing Environmental Health Risk Perceptions and Assessing Recovery Needs in the Wake of Hurricanes Katrina and Rita

In response to the human health threats stemming from Hurricanes Katrina and Rita, inter-disciplinary working groups representing P30-funded Centers of the National Institute Environmental Health Sciences were created to assess threats posed by mold, harmful alga blooms, chemical toxicants, and various infectious agents at selected sites throughout the hurricane impact zone. Because of proximity to impacted areas, UTMB NIEHS Center in Environmental Toxicology was charged with coordinating direct community outreach efforts, primarily in south Louisiana. In early October 2005, UTMB/NIEHS Center Community Outreach and Education Core, in collaboration with outreach counterparts at The University of Texas MD Anderson Cancer Center @ Smithville TX/Center for Research in Environmental Disease sent two groups into southern Louisiana. One group used Lafourche Parish as a base to deliver humanitarian aid and assess local needs for additional supplies during local recovery/reclamation. A second group, ranging through New Iberia, New Orleans, Chalmette, rural Terrebonne, Lafourche and Jefferson Parishes and Baton Rouge met with community environmental leaders, emergency personnel and local citizens to 1) sample public risk perceptions, 2) evaluate the scope and reach of ongoing risk communication efforts, and 3) determine how the NIEHS could best collaborate with local groups in environmental health research and local capacity building efforts. This scoping survey identified specific information gaps limiting efficacy of risk communication, produced a community “wish list” of potential collaborative research projects. The project provided useful heuristics for disaster response and management planning and a platform for future collaborative efforts in environmental health assessment and risk communication with local advocacy groups in south Terrebonne-Lafourche parishes

Acoustic separation of circulating tumor cells

Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (~100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.National Institutes of Health (U.S.) (Grant 1 R01 GM112048-01A1)National Institutes of Health (U.S.) (Grant 1R33EB019785-01)National Science Foundation (U.S.)Penn State Center for Nanoscale Science (Materials Research Science and Engineering Center Grant DMR-0820404)National Institutes of Health (U.S.) (Grant U01HL114476

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases

Pre-transplant CD45RC expression on blood T cells differentiates patients with cancer and rejection after kidney transplantation

Background Biological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence. Methods We performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively. Results After a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24–11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh&lt;51.9% were 84.0, 54.7, 89.8 and 42.0% respectively. Confirming our previous results, frequency of CD8+CD45RChigh T cells above 52.1% was associated with AR, conferring a 20-fold increased risk (HR 21.7 [2.67–176.2], p = 0.0004). The sensibility, specificity, negative predictive and positive predictive values of CD8+CD45RChigh&gt;52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (p&lt;0.0001), suggesting that recipients with high AR risk display a low cancer risk. Conclusion High frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation