Anticytomegalovirus Peptides Point to New Insights for CMV Entry Mechanisms and the Limitations of In Vitro Screenings

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease following in utero exposure, during primary infection, or la- tent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation. These treatments have unwanted side effects, and HCMV is be- coming resistant to them. Therefore, we sought to develop an alternative treatment that targets a different stage in viral infection. Currently, small antiviral peptides are being investigated as anti-influenza and anti-HIV treatments. We have developed heparan sulfate-binding peptides as tools for preventing CMV infections. These pep- tides are highly effective at stopping infection of fibroblasts with in vitro-derived HCMV and murine cytomegalovirus (MCMV). However, they do not prevent MCMV infection in vivo. Interestingly, these peptides inhibit infectivity of in vivo-derived CMVs, albeit not as well as tissue culture-grown CMVs. We further demonstrate that this class of heparan sulfate-binding peptides is incapable of inhibiting MCMV cell- to-cell spread, which is independent of heparan sulfate usage. These data indicate that inhibition of CMV infection can be achieved using synthetic polybasic peptides, but cell-to-cell spread and in vivo-grown CMVs require further investigation to de- sign appropriate anti-CMV peptides

The Human Cytomegalovirus Chemokine vCXCL-1 Modulates Normal Dissemination Kinetics of Murine Cytomegalovirus In Vivo

Human cytomegalovirus (HCMV) is a betaherpesvirus that is a significant pathogen within newborn and immunocompromised populations. Morbidity associated with HCMV infection is the consequence of viral dissemination. HCMV has evolved to manipulate the host immune system to enhance viral dissemination and ensure long-term survival within the host. The immunomodulatory protein vCXCL-1, a viral chemokine functioning primarily through the CXCR2 chemokine receptor, is hypothesized to attract CXCR2+ neutrophils to infection sites, aiding viral dissemination. Neutrophils harbor HCMV in vivo; however, the interaction between vCXCL-1 and the neutrophil has not been evaluated in vivo. Using the mouse model and mouse cytomegalovirus (MCMV) infection, we show that murine neutrophils harbor and transfer infectious MCMV and that virus replication initiates within this cell type. Utilizing recombinant MCMVs expressing vCXCL-1 from the HCMV strain (Toledo), we demonstrated that vCXCL-1 significantly enhances MCMV dissemination kinetics. Through cellular depletion experiments, we observe that neutrophils impact dissemination but that overall dissemination is largely neutrophil independent. This work adds neutrophils to the list of innate cells (i.e., dendritic and macrophages/monocytes) that contribute to MCMV dissemination but refutes the hypothesis that neutrophils are the primary cell responding to vCXCL-1

Alternatives to antibiotics-a pipeline portfolio review

Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.</p

Rights, Knowledge, and Governance for Improved Health Equity in Urban Settings

All three of the interacting aspects of daily urban life (physical environment, social conditions, and the added pressure of climate change) that affect health inequities are nested within the concept of urban governance, which has the task of understanding and managing the interactions among these different factors so that all three can be improved together and coherently. Governance is defined as: “the process of collective decision making and processes by which decisions are implemented or not implemented”: it is concerned with the distribution, exercise, and consequences of power. Although there appears to be general agreement that the quality of governance is important for development, much less agreement appears to exist on what the concept really implies and how it should be used. Our review of the literature confirmed significant variation in meaning as well as in the practice of urban governance arrangements. The review found that the linkage between governance practices and health equity is under-researched and/or has been neglected. Reconnecting the fields of urban planning, social sciences, and public health are essential “not only for improving local governance, but also for understanding and addressing global political change” for enhanced urban health equity. Social mobilization, empowering governance, and improved knowledge for sustainable and equitable development in urban settings is urgently needed. A set of strategic research questions are suggested

Overfeeding Reduces Insulin Sensitivity and Increases Oxidative Stress, without Altering Markers of Mitochondrial Content and Function in Humans

BACKGROUND: Mitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered. METHODOLOGY AND PRINCIPAL FINDINGS: Forty (37±2 y) non-obese (25.6±0.6 kg/m2) sedentary men (n = 20) and women (n = 20) were overfed (+1040±100 kcal/day, 46±1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6±0.1 and 2.7±0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5 mmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P,<.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1a) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO2 production at either time point. CONCLUSIONS: Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.Dorit Samocha-Bonet, Lesley V. Campbell, Trevor A. Mori, Kevin D. Croft, Jerry R. Greenfield, Nigel Turner and Leonie K. Heilbron

Emerging Strategies for Healthy Urban Governance

Urban health promotion is not simply a matter of the right interventions, or even the necessary resources. Urban (and indeed global) health depends to an important extent on governance, the institutions and processes through which societies manage the course of events. This paper describes the concept of governance, distinguishing between reforms aimed at improving how government works and innovations that more fundamentally reinvent governance by developing new institutions and processes of local stakeholder control. The paper highlights strategies urban governors can use to maximize their influence on the national and international decisions that structure urban life. It concludes with some observations on the limitations of local governance strategies and the importance of establishing a “virtuous circuit” of governance through which urban dwellers play a greater role in the formation and implementation of policy at the national and global levels

Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment

A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is to measure the $\mathcal{O}(10)$ MeV neutrinos produced by a Galactic core-collapse supernova if one should occur during the lifetime of the experiment. The liquid-argon-based detectors planned for DUNE are expected to be uniquely sensitive to the $\nu_e$ component of the supernova flux, enabling a wide variety of physics and astrophysics measurements. A key requirement for a correct interpretation of these measurements is a good understanding of the energy-dependent total cross section $\sigma(E_\nu)$ for charged-current $\nu_e$ absorption on argon. In the context of a simulated extraction of supernova $\nu_e$ spectral parameters from a toy analysis, we investigate the impact of $\sigma(E_\nu)$ modeling uncertainties on DUNE's supernova neutrino physics sensitivity for the first time. We find that the currently large theoretical uncertainties on $\sigma(E_\nu)$ must be substantially reduced before the $\nu_e$ flux parameters can be extracted reliably: in the absence of external constraints, a measurement of the integrated neutrino luminosity with less than 10\% bias with DUNE requires $\sigma(E_\nu)$ to be known to about 5%. The neutrino spectral shape parameters can be known to better than 10% for a 20% uncertainty on the cross-section scale, although they will be sensitive to uncertainties on the shape of $\sigma(E_\nu)$. A direct measurement of low-energy $\nu_e$-argon scattering would be invaluable for improving the theoretical precision to the needed level.Comment: 25 pages, 21 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead