Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment

Little is known about the biochemical environment in phagosomes harboring an infectious agent. To assess the state of this organelle we captured the transcriptional responses of Mycobacterium tuberculosis (MTB) in macrophages from wild-type and nitric oxide (NO) synthase 2–deficient mice before and after immunologic activation. The intraphagosomal transcriptome was compared with the transcriptome of MTB in standard broth culture and during growth in diverse conditions designed to simulate features of the phagosomal environment. Genes expressed differentially as a consequence of intraphagosomal residence included an interferon � – and NO-induced response that intensifies an iron-scavenging program, converts the microbe from aerobic to anaerobic respiration, and induces a dormancy regulon. Induction of genes involved in the activation and �-oxidation of fatty acids indicated that fatty acids furnish carbon and energy. Induction of �E-dependent, sodium dodecyl sulfate–regulated genes and genes involved in mycolic acid modification pointed to damage and repair of the cell envelope. Sentinel genes within the intraphagosomal transcriptome were induced similarly by MTB in the lungs of mice. The microbial transcriptome thus served as a bioprobe of the MTB phagosomal environment

Community intervention for cardiovascular disease risk factors in Kalutara, Sri Lanka.

BACKGROUND:The effectiveness of a 2015-17 community intervention to reduce cardiovascular disease (CVD) and type 2 diabetes (T2DM) risk factors is assessed in a Sri Lanka adult population, using a before-and-after study design. METHODS:Four contiguous Public Health Midwife (PHM) areas in Kalutara district (Western Province) were exposed to a Sri Lankan designed community health promotion initiatives (without screening) to lower CVD and T2DM risk factors. Pre- and post-intervention surveys (2014, n=1,019; 2017, n=908) were of 25-64 year males (M) and females (F) from dissimilar randomly selected clusters (villages or settlements) from PHMs, with probability of selection proportional to population size, followed by household sampling, then individual selection to yield equal-probability samples. Differences in resting blood pressure (BP), fasting plasma glucose (FPG), total cholesterol, body mass index and tobacco smoking, adjusting for cluster sampling, age and socio-economic differences, were examined. RESULTS:Hypertension prevalence declined from 25% to 16% (F) (p<.0001), and 21% to 17% (M). Both mean systolic and diastolic BP declined. T2DM declined from 18% to 13% (F), and 18% to 15% (M), as did mean fasting plasma glucose. Elevated total cholesterol declined from 21% to 15% in women (p=0.003) and mean cholesterol declined. Frequency distributions, medians and means of these continuous CVD risk factors shifted to lower levels, and were mostly statistically significant (p< 0.05). CONCLUSIONS:Community health promotion can lower key CVD and T2DM risk factors. Lowering tobacco consumption in males and obesity remain challenges in Sri Lanka

Paediatric radiology seen from Africa. Part I: providing diagnostic imaging to a young population

Article approval pendingPaediatric radiology requires dedicated equipment, specific precautions related to ionising radiation, and specialist knowledge. Developing countries face difficulties in providing adequate imaging services for children. In many African countries, children represent an increasing proportion of the population, and additional challenges follow from extreme living conditions, poverty, lack of parental care, and exposure to tuberculosis, HIV, pneumonia, diarrhoea and violent trauma. Imaging plays a critical role in the treatment of these children, but is expensive and difficult to provide. The World Health Organisation initiatives, of which the World Health Imaging System for Radiography (WHIS-RAD) unit is one result, needs to expand into other areas such as the provision of maintenance servicing. New initiatives by groups such as Rotary and the World Health Imaging Alliance to install WHIS-RAD units in developing countries and provide digital solutions, need support. Paediatric radiologists are needed to offer their services for reporting, consultation and quality assurance for free by way of teleradiology. Societies for paediatric radiology are needed to focus on providing a volunteer teleradiology reporting group, information on child safety for basic imaging, guidelines for investigations specific to the disease spectrum, and solutions for optimising imaging in children

PRISM protocol: A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established

Cellulose acetate phthalate, a common pharmaceutical excipient, inactivates HIV-1 and blocks the coreceptor binding site on the virus envelope glycoprotein gp120

BACKGROUND: Cellulose acetate phthalate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was shown to inhibit infection by the human immunodeficiency virus type 1 (HIV-1) and several herpesviruses. CAP formulations inactivated HIV-1, herpesvirus types 1 (HSV-1) and 2 (HSV-2) and the major nonviral sexually transmitted disease (STD) pathogens and were effective in animal models for vaginal infection by HSV-2 and simian immunodeficiency virus. METHODS: Enzyme-linked immunoassays and flow cytometry were used to demonstrate CAP binding to HIV-1 and to define the binding site on the virus envelope. RESULTS: 1) CAP binds to HIV-1 virus particles and to the envelope glycoprotein gp120; 2) this leads to blockade of the gp120 V3 loop and other gp120 sites resulting in diminished reactivity with HIV-1 coreceptors CXCR4 and CCR5; 3) CAP binding to HIV-1 virions impairs their infectivity; 4) these findings apply to both HIV-1 IIIB, an X4 virus, and HIV-1 BaL, an R5 virus. CONCLUSIONS: These results provide support for consideration of CAP as a topical microbicide of choice for prevention of STDs, including HIV-1 infection

HamLib: A library of Hamiltonians for benchmarking quantum algorithms and hardware

In order to characterize and benchmark computational hardware, software, and algorithms, it is essential to have many problem instances on-hand. This is no less true for quantum computation, where a large collection of real-world problem instances would allow for benchmarking studies that in turn help to improve both algorithms and hardware designs. To this end, here we present a large dataset of qubit-based quantum Hamiltonians. The dataset, called HamLib (for Hamiltonian Library), is freely available online and contains problem sizes ranging from 2 to 1000 qubits. HamLib includes problem instances of the Heisenberg model, Fermi-Hubbard model, Bose-Hubbard model, molecular electronic structure, molecular vibrational structure, MaxCut, Max-k-SAT, Max-k-Cut, QMaxCut, and the traveling salesperson problem. The goals of this effort are (a) to save researchers time by eliminating the need to prepare problem instances and map them to qubit representations, (b) to allow for more thorough tests of new algorithms and hardware, and (c) to allow for reproducibility and standardization across research studies

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of "dead-end" gp41 six-helix bundles

BACKGROUND: Cellulose acetate phthalate (CAP), a promising candidate microbicide for prevention of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted disease (STD) pathogens, was shown to inactivate HIV-1 and to block the coreceptor binding site on the virus envelope glycoprotein gp120. It did not interfere with virus binding to CD4. Since CD4 is the primary cellular receptor for HIV-1, it was of interest to study CAP binding to HIV-1 complexes with soluble CD4 (sCD4) and its consequences, including changes in the conformation of the envelope glycoprotein gp41 within virus particles. METHODS: Enzyme-linked immunosorbent assays (ELISA) were used to study CAP binding to HIV-1-sCD4 complexes and to detect gp41 six-helix bundles accessible on virus particles using antibodies specific for the α-helical core domain of gp41. RESULTS: 1) Pretreatment of HIV-1 with sCD4 augments subsequent binding of CAP; 2) there is synergism between CAP and sCD4 for inhibition of HIV-1 infection; 3) treatment of HIV-1 with CAP induced the formation of gp41 six-helix bundles. CONCLUSIONS: CAP and sCD4 bind to distinct sites on HIV-1 IIIB and BaL virions and their simultaneous binding has profound effects on virus structure and infectivity. The formation of gp41 six-helical bundles, induced by CAP, is known to render the virus incompetent for fusion with target cells thus preventing infection

Design and baseline characteristics of a prospective cohort study for determinants of osteoporotic fracture in community-dwelling elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and osteoporotic fracture in men are significant public health problems in an aging society. However, information on male osteoporosis remains impressively lacking, especially for Asians. We designed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study as an ancillary study of a cohort study, the Fujiwara-kyo study, to determine risk factors for osteoporotic fractures in Japanese men.</p> <p>Methods/Design</p> <p><it><b>Design</b></it>: A community-based single-centre prospective cohort study with at least a 5-year follow-up</p> <p><it><b>Subjects</b></it>: All the male participants of the Fujiwara-kyo study who were living in the four cities studied, aged 65 years and older, and able to walk without aid from others.</p> <p><it><b>Primary outcome</b></it>: Incidence of osteoporotic fractures including vertebral and clinical non-vertebral fractures.</p> <p><it><b>Additional outcomes</b></it>: Change in bone mineral density (BMD), change in hip geometry, onset of receiving benefits from Long-term Care Insurance (LCI), health-related quality of life, and mortality.</p> <p><it><b>Baseline measurements</b></it>: BMD at the lumbar spine (LS) and hip (TH), hip geometry, vertebral deformity assessment, bone turnover markers, physical and cognitive performance, various medical and lifestyle factors, and geriatric psychosocial measures confirmed by interviews based on self-administrated questionnaires.</p> <p><it><b>Outcome surveillance</b></it>: Annual mail surveys and a follow-up survey at the fifth year comprising similar items to the baseline study will be used to determine the outcomes. Receipt of benefits from LCI and mortality will be obtained from the city governments.</p> <p><it><b>Current status</b></it>: The baseline study was conducted for 2174 eligible men, and 2012 completed the study and were eligible for follow-up. Prevalence rates of osteoporosis (BMD 2.5 SD or more below the young adult mean (YAM)) and low BMD (BMD 1 SD or more below YAM) in at least one of LS and TH were calculated to be 4.4% and 41.8%, respectively. The proportion of men with low BMD only at TH showed a significant increasing trend with aging (p < 0.0001) while that only at LS showed a decreasing trend (p = 0.0386). The prevalence rate of osteoporosis was underestimated when diagnosed using only BMD at LS. Other baseline measurements were successfully obtained.</p> <p>Discussion</p> <p>FORMEN baseline study was performed as designed and the FORMEN cohort study was successfully launched.</p

Mutation Size Optimizes Speciation in an Evolutionary Model

The role of mutation rate in optimizing key features of evolutionary dynamics has recently been investigated in various computational models. Here, we address the related question of how maximum mutation size affects the formation of species in a simple computational evolutionary model. We find that the number of species is maximized for intermediate values of a mutation size parameter μ; the result is observed for evolving organisms on a randomly changing landscape as well as in a version of the model where negative feedback exists between the local population size and the fitness provided by the landscape. The same result is observed for various distributions of mutation values within the limits set by μ. When organisms with various values of μ compete against each other, those with intermediate μ values are found to survive. The surviving values of μ from these competition simulations, however, do not necessarily coincide with the values that maximize the number of species. These results suggest that various complex factors are involved in determining optimal mutation parameters for any population, and may also suggest approaches for building a computational bridge between the (micro) dynamics of mutations at the level of individual organisms and (macro) evolutionary dynamics at the species level