Alginate Microsponges as a Scaffold for Delivery of a Therapeutic Peptide against Rheumatoid Arthritis

The quest for biocompatible drug-delivery devices that could be able to open new administration routes is at the frontier of biomedical research. In this contribution, porous polysaccharide-based microsponges based on crosslinked alginate polymers were developed and characterized by optical spectroscopy and nanoscopic microscopy techniques. We show that macropores with a size distribution ranging from 50 to 120 nm enabled efficient loading and delivery of a therapeutic peptide (CIGB814), presently under a phase 3 clinical trial for the treatment of rheumatoid arthritis. Alginate microsponges showed 80% loading capacity and sustained peptide release over a few hours through a diffusional mechanism favored by partial erosion of the polymer scaffold. The edible and biocompatible nature of alginate polymers open promising perspectives for developing a new generation of polysaccharide-based carriers for the controlled delivery of peptide drugs, exploiting alternative routes with respect to intravenous administration

Comparative isotopic natural history of two native passerines (Troglodytes cobbi and Cinclodes antarcticus) and the invasive rats (Rattus norvegicus) that extirpate them

While several studies have shown that invasive rats can have negative effects on island birds through predation (both direct predation and nest predation), other mechanisms for the effects of invasives on island biota have been given less attention. Here we explore another potential mechanism by which invasive rats can affect native island birds: the competitive use of common resources. We used stable isotope analyses to estimate the fraction of marine and terrestrial sources incorporated into the tissues of two species of passerines (Troglodytes cobbi, Troglodytidae; and Cinclodes antarcticus, Furnariidae) and Norway rats (Rattus norvegicus, Muridae) in the Falkland Islands. These two passerines are absent on islands where rats are present. We found significant incorporation of marine resources in the three species, with the highest incorporation in tissues of T. cobbi. This species appears to be one of the passerines most reliant on marine sources and the most marine member of the family Troglodytidae. We also used the results of these isotopic analyses to estimate the isotopic niche breadth of each of these species and the isotopic niche overlap among them. Rattus norvegicus had a large isotopic niche that overlapped broadly with those of the two passerine species. We propose that different ways of both depicting and estimating isotopic niche widths are complementary rather than alternative. Our results are consistent with the notion that invasive rats might have an impact on these two species of Falkland Island passerines by using common resources, but do not rule out the possibility that part of their effect is through direct predation.MT and CMR were partially funded by National Science Foundation Grants # 0841298 and DIOS-0848028, respectively. SP and KP were funded by Antarctic Research Trust, UK Overseas Territories Environment Programme, Royal Society for Protection of Birds, Joint Nature Conservation Committee, and the Falkland Islands Government.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1442-99932017-10-31hb2017Zoology and Entomolog

Ancient Mitogenomes Shed Light on the Evolutionary History and Biogeography of Sloths

International audienc

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the "Collaborative Cross" project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines. IMPORTANCE Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.This work, including the efforts of Hardy Kornfeld, was funded by HHS | National Institutes of Health (NIH) (HL081149). This work, including the efforts of Sam Behar, was funded by HHS | National Institutes of Health (NIH) (AI123286-01). This work, including the efforts of Clare Margaret Smith and Christopher Sassetti, was funded by Howard Hughes Medical Institute (HHMI)

Structural determination of the Si(111) √3×√3-Bi surface by x-ray standing waves and scanning tunneling microscopy

X-ray standing-wave measurements and tunneling microscopy have been combined to solve the atomic geometry of the √3×√3R30° honeycomb phase of Bi on Si(111). The standing-wave measurements utilize three different diffracting planes to triangulate the surface position of Bi atoms. The unoccupied surface sites required to completely determine the structure can be deduced from Rutherford-backscattering coverage and low-energy electron-diffraction symmetry arguments. These arguments are completely confirmed by a tunneling-microscope study, which is free of the ambiguities of previous studies. The final result is a 2/3-ML √3×√3R30° structure with Bi atoms in the T1 sites directly above first-layer Si atoms.Physic

Recommendations for defining preventable HIV-related mortality for public health monitoring in the era of Getting to Zero: an expert consensus

Getting to Zero is a commonly cited strategic aim to reduce mortality due to both HIV and avoidable deaths among people with HIV. However, no clear definitions are attached to these aims with regard to what constitutes HIV-related or preventable mortality, and their ambition is limited. This Position Paper presents consensus recommendations to define preventable HIV-related mortality for a pragmatic approach to public health monitoring by use of national HIV surveillance data. These recommendations were informed by a comprehensive literature review and agreed by 42 international experts, including clinicians, public health professionals, researchers, commissioners, and community representatives. By applying the recommendations to 2019 national HIV surveillance data from the UK, we show that 30% of deaths among people with HIV were HIV-related or possibly HIV-related, and at least 63% of these deaths were preventable or potentially preventable. The application of these recommendations by health authorities will ensure consistent monitoring of HIV elimination targets and allow for the identification of inequalities and areas for intervention

Investigation into the Presence of and Serological Response to XMRV in CFS Patients

The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS. In addition, sera from our CFS patients were assayed for the presence of xenotropic virus envelope protein, as well as a serological response to it. The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK

Bacterial Causes of Empyema in Children, Australia, 2007–2009

Most infections were caused by non–7-valent pneumococcal conjugate vaccine serotypes