Human Vault Nanoparticle Targeted Delivery of Antiretroviral Drugs to Inhibit Human Immunodeficiency Virus Type 1 Infection.

"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1

Efficacy and microbiota modulation induced by limpial 2.5%, a new medical device for the inverse psoriasis treatment

(1) Inverse psoriasis (IP), also known as intertriginous, typically affects the groin, armpits, navel, intergluteal fissure, and external genitalia. Skin lesions are erythematous plaques of inflammatory nature, smooth, well-delimited, non-scaly, and non-infiltrated. Lesions may be accompanied by itching, pain, or burning sensation. The aim of this study is both to investigate the modulation of the skin microbiota induced by IP and, on the other hand, to test the effectiveness of the new biotechnological product LimpiAL 2.5%. (2) Patients affected by IP were recruited in a private practice and treated for 4 weeks with LimpiAL 2.5% exclusively. The clinical effects on the lesion skin were evaluated, and the skin microbiotas before and after treatment were compared. (3) The clinical outcomes reveled a significant beneficial effect of the tested product. At the same time, LimpiAL increased the biological diversity of the skin microbiota and exerted a significant decrease of some Corynebacterium species, and the increase of some Staphylococcus species. (4) Together, the clinical outcomes and the microbiota analysis suggest that LimpiAL treatment improves the skin condition of affected patients, basically restoring the eubiosis conditions of the affected sites and modulating the bacterial composition of the resident microbiota

Scaling up sustainability in commodity agriculture: Transferability of governance mechanisms across the coffee and cattle sectors in Brazil

A number of governance mechanisms address socio-environmental challenges associated with commodity agriculture in tropical forested countries. Governance mechanisms that prove effective in one agricultural sector are often applied to other sectors as well. For example, voluntary certification programs have been adopted by producers of commodities as diverse as beef, coffee, palm oil, and soy. However, there are substantial differences in the extent to which governance mechanisms scale up and achieve impact in different sectors. This paper analyzes how the potential for scaling up a particular governance mechanism is influenced by environmental, market, and social geographies that differ between sectors. Through stakeholder interviews, farm-level surveys, and a literature review, we examine two types of voluntary governance mechanisms (third-party certification, and sustainable intensification programs) in the coffee and cattle sectors in Brazil, to understand why the two governance mechanisms have scaled differently between these two sectors. We find that third-party certification programs have scaled up relatively well in Brazil\u27s coffee sector, more so than its cattle sector, in part owing to differences in sustainability priorities, market orientations, supply chain traceability, and social networks between the two sectors. We also find that pilot sustainable intensification programs in the cattle sector have had more success than certification in engaging farmers, in part because they involve less investment from participating farmers. We conclude that the distribution and quality of environmental resources, markets, knowledge, actors, and networks can play an important role in the ability of a governance mechanism to effectively take root

Immundefekte bei chronischer Rhinosinusitis : eine bedeutende und oft unterschätzte Ursache

Background Chronic rhinosinusitis (CRS) is one of the most frequent chronic diseases. Among these patients the prevalence of immune defects is higher than in the healthy general population. Methods A selective review of the literature was carried out in PubMed and Medline covering the period between 2008 and 2019. Additionally, recent German publications in journals not listed in the abovementioned databases were analyzed. Results The diagnostic workflow with respect to the immunodeficiency consists of a detailed anamnesis and physical examination, laboratory tests and the antibody reaction to polysaccharide vaccines and antigens. Beside antibiotic treatment, vaccinations and immunoglobulin replacement are available. Notwithstanding the above, functional endoscopic surgery of the paranasal sinuses should be performed according to guideline recommendations. Conclusion Patients with CRS who do not sufficiently respond to conservative and surgical treatment should be checked for underlying immunodeficiencies

Psoriasis bei Dupilumab-behandeltem atopischem Ekzem

Dupilumab ist ein monoklonaler Antikörper, der an die gemeinsame α‑Kette des IL(Interleukin)-4- und IL-13-Rezeptors bindet und den Th(T-Helferzelle)2-Signalweg blockiert, der bei der Entstehung des atopischen Ekzems eine Schlüsselrolle spielt. Wir berichten über den Fall eines 40-jährigen Patienten, der nach 6 Wochen Dupilumab-Therapie eine histologisch gesicherte Psoriasis entwickelte. Das eigenmächtige, abrupte Absetzen der ungewöhnlichen, nicht leitliniengerechten oralen Steroidtherapie und die Blockade des Th2-Signalwegs durch Dupilumab dürften die entscheidenden Auslösefaktoren für die erstmalige Ausbildung der Psoriasis bei unserem Patienten gewesen sein

The microlocal spectrum condition and Wick polynomials of free fields on curved spacetimes

Quantum fields propagating on a curved spacetime are investigated in terms of microlocal analysis. We discuss a condition on the wave front set for the corresponding n-point distributions, called ``microlocal spectrum condition'' ($\mu$SC). On Minkowski space, this condition is satisfied as a consequence of the usual spectrum condition. Based on Radzikowski's determination of the wave front set of the two-point function of a free scalar field, satisfying the Hadamard condition in the Kay and Wald sense, we construct in the second part of this paper all Wick polynomials including the energy-momentum tensor for this field as operator valued distributions on the manifold and prove that they satisfy our microlocal spectrum condition.Comment: 21 pages, AMS-LaTeX, 2 figures appended as Postscript file

Dupilumab provides rapid and sustained improvement in SCORAD outcomes in adults with moderate-to-severe atopic dermatitis: combined results of four randomized phase 3 trials

Background:Dupilumab, a first-in-class therapy targeting the two key cytokines involved in the persistent underlying inflammatory pathway in atopic dermatitis (AD), is approved for treatment of moderate-to-severe AD in Europe, USA, Japan and several other countries. Objective:To assess dupilumab effects on SCORing Atopic Dermatitis (SCORAD) and component scores (objective and subjective SCORAD) over time in adults with moderate-to-severe AD. Methods:Thispost hocanalysis included 2,444 patients in four placebo-controlled, double-blind, randomized, phase 3 trials. SOLO 1 and 2 (NCT02277743; NCT02277769) evaluated 16 weeks of dupilumab monotherapy against placebo. CAFe (NCT02755649) and CHRONOS (NCT02260986) evaluated dupilumab with concomitant topical corticosteroids (TCS) against TCS alone for 16 and 52 weeks, respectively. Results:2,444 patients randomized to treatment in SOLO 1 and 2 (N = 1,379), CAFe (N = 325) and CHRONOS (N = 740) were analyzed. Dupilumab treatment significantly improved overall SCORAD and individual components as early as Week 1 or 2, with significant and clinically meaningful differences vs. control through end of treatment (p < .0001). These results occurred irrespective of dupilumab regimen, 300 mg subcutaneously weekly or every 2 weeks. Conclusions:In four large phase 3 trials in adults with moderate-to-severe AD, dupilumab treatment with or without concomitant TCS resulted in rapid and sustained improvements in all SCORAD outcomes vs. placebo or TCS alone

Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice.

Neural progenitor cells (NPC) represent potential cell transplantation therapies for CNS injuries. To understand how lesion environments influence transplanted NPC fate in vivo, we derived NPC expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling of transplanted NPC. Here, we show that NPC grafted into uninjured mouse CNS generate cells that are transcriptionally similar to healthy astrocytes and oligodendrocyte lineages. In striking contrast, NPC transplanted into subacute CNS lesions after stroke or spinal cord injury in mice generate cells that share transcriptional, morphological and functional features with newly proliferated host astroglia that restrict inflammation and fibrosis and isolate lesions from adjacent viable neural tissue. Our findings reveal overlapping differentiation potentials of grafted NPC and proliferating host astrocytes; and show that in the absence of other interventions, non-cell autonomous cues in subacute CNS lesions direct the differentiation of grafted NPC towards a naturally occurring wound repair astroglial phenotype