Abstract X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate ...for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h-deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors.
In this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as second-line therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before ...autologous stem-cell transplantation (ASCT).
This was a multicenter, open-label, phase I–II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day ‒1 to 3 + 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT.
A total of 66 patients were recruited (median age 36 years; range 18–66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n = 25, 35% neutropenic), including 3 deaths. Grade 3–4 hematological toxicity presented in 28 cases: neutropenia (n = 21), thrombocytopenia (n = 14), and anemia (n = 7). Grade ≥3–4 extrahematological adverse events (≥5%) were non-neutropenic fever (n = 13) and hypomagnesaemia (n = 3). Sixty-four patients underwent stem-cell mobilization; all collected >2×10e6/kg CD34+ cells (median 5.75; range 2.12–33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%).
BRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.
Rationale
Whether asthma constitutes a risk factor for coronavirus disease‐2019 (COVID‐19) is unclear. Here, we aimed to assess whether asthma, the most common chronic disease in children, is ...associated with higher COVID‐19 risk or severity in pediatric populations.
Methods
We performed a systematic literature search in three stages: first, we reviewed PubMed, EMBASE, and CINAHL for systematic reviews of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and COVID‐19 in pediatric populations, and reviewed their primary articles; second, we searched PubMed for studies on COVID‐19 or SARS‐CoV‐2 and asthma/wheeze, and evaluated whether the resulting studies included pediatric populations; third, we repeated the second search in BioRxiv.org and MedRxiv.org to find pre‐prints that may have information on pediatric asthma.
Results
In the first search, eight systematic reviews were found, of which five were done in pediatric populations; none of the 67 primary studies included data on pediatric asthma as a comorbidity for COVID‐19. In the second search, we found 34 results in PubMed, of which five reported asthma in adults, but none included data on children. In the third search, 25 pre‐prints in MedRxiv included data on asthma, but none on children. We found one report by the US Centers for Disease Control and Prevention stating that 40/345 (~11.5%) children with data on chronic conditions had “chronic lung diseases including asthma,” and one from a tertiary hospital in New York that reported asthma in 11/46 (~23.9%) children hospitalized for COVID‐19.
Conclusion
There is scarcely any data on whether childhood asthma (or other pediatric respiratory diseases) constitute risk factors for SARS‐CoV‐2 infection or COVID‐19 severity. Studies are needed that go beyond counting the number of cases in the pediatric age range.
The active sites over commercial copper/zinc oxide/aluminum oxide (Cu/ZnO/Al₂O₃) catalysts for carbon dioxide (CO₂) hydrogenation to methanol, the Zn-Cu bimetallic sites or ZnO-Cu interfacial sites, ...have recently been the subject of intense debate. We report a direct comparison between the activity of ZnCu and ZnO/Cu model catalysts for methanol synthesis. By combining x-ray photoemission spectroscopy, density functional theory, and kinetic Monte Carlo simulations, we can identify and characterize the reactivity of each catalyst. Both experimental and theoretical results agree that ZnCu undergoes surface oxidation under the reaction conditions so that surface Zn transforms into ZnO and allows ZnCu to reach the activity of ZnO/Cu with the same Zn coverage. Our results highlight a synergy of Cu and ZnO at the interface that facilitates methanol synthesis via formate intermediates.
Conspectus The abundance of cheap, natural gas has transformed the energy landscape, whereby revealing new possibilities for sustainable chemical technologies or impacting those that have relied on ...traditional fossil fuels. The primary component, methane, is underutilized and wastefully exhausted, leading to anthropogenic global warming. Historically, the manipulation of methane remained “clavis aurea,” an insurmountable yet rewarding challenge and thus the focus of intense research. This is primarily due to an inability to dissociate C–H bonds in methane selectively, which requires a high energy penalty and is an essential prerequisite for the direct conversion of methane into a large set of value-added products. The discovery of such processes would promise an energy gainful use of natural gas benefiting several essential chemical processes associated with C1 chemistry. This first C–H bond dissociation step of the methane molecule appears in numerous catalytic mechanisms as the rate-determining step or most essential barrier sequence for all subsequent steps that follow in the production of C–C, C–O, or C x –H y –O z bonds found in value added products. A main goal is to catalytically reduce the energy barrier for the first C–H bond dissociation to be able to achieve the activation of methane at low or moderate temperatures. As such there is great value in understanding the fundamental nature of the active sites responsible for bond breaking or formation and thus be able to facilitate better control of this chemistry, leading to the development of new technologies for fuel production and chemical conversion. Surface science studies offer enhanced perspectives for a careful manipulation of bonds over the last layer atoms of catalyst surfaces, an essential factor for the design of atomically precise catalysts and unravelling of the reaction mechanism. With the advent of new surface imaging, spectroscopy, and in situ tools, it has been possible to decipher the surface chemistry of complex materials systems and further our understanding of atomic active sites on the surfaces of metals, oxides, and carbides or metal–oxide and metal–carbide interfaces. The once considered near impossible step of C–H bond activation is now observed at low temperatures with high propensity over a collection of oxide, metal–oxide, and metal–carbide systems in a conventional or inverse configuration (oxide or carbide on metal). The enabling of C–H activation at low temperature has opened interesting possibilities for the specific production of chemicals such as methanol directly from methane, a step toward facile synthesis of liquid fuels. We highlight the most recent of these results and present the key aspects of active site configurations engineered from surface science studies which enable such a simple reactive event through careful manipulation of the last surface layer of atoms found in the catalyst structure. New concepts which help in the activation and conversion of methane are discussed.
Interactions induced by electromagnetic fluctuations, such as van der Waals and Casimir forces, are of universal nature present at any length scale between any types of systems. Such interactions are ...important not only for the fundamental science of materials behavior, but also for the design and improvement of micro- and nanostructured devices. In the past decade, many new materials have become available, which has stimulated the need for understanding their dispersive interactions. The field of van der Waals and Casimir forces has experienced an impetus in terms of developing novel theoretical and computational methods to provide new insights into related phenomena. The understanding of such forces has far reaching consequences as it bridges concepts in materials, atomic and molecular physics, condensed-matter physics, high-energy physics, chemistry, and biology. This review summarizes major breakthroughs and emphasizes the common origin of van der Waals and Casimir interactions. Progress related to novel ab initio modeling approaches and their application in various systems, interactions in materials with Dirac-like spectra, force manipulations through nontrivial boundary conditions, and applications of van der Waals forces in organic and biological matter are examined. The outlook of the review is to give the scientific community a materials perspective of van der Waals and Casimir phenomena and stimulate the development of experimental techniques and applications.
The transformation of methane into methanol or higher alcohols at moderate temperature and pressure conditions is of great environmental interest and remains a challenge despite many efforts. ...Extended surfaces of metallic nickel are inactive for a direct CH4 → CH3OH conversion. This experimental and computational study provides clear evidence that low Ni loadings on a CeO2(111) support can perform a direct catalytic cycle for the generation of methanol at low temperature using oxygen and water as reactants, with a higher selectivity than ever reported for ceria-based catalysts. On the basis of ambient pressure X-ray photoemission spectroscopy and density functional theory calculations, we demonstrate that water plays a crucial role in blocking catalyst sites where methyl species could fully decompose, an essential factor for diminishing the production of CO and CO2, and in generating sites on which methoxy species and ultimately methanol can form. In addition to water-site blocking, one needs the effects of metal–support interactions to bind and activate methane and water. These findings should be considered when designing metal/oxide catalysts for converting methane to value-added chemicals and fuels.
Deciphering Tacrolimus‐Induced Toxicity in Pancreatic β Cells Triñanes, J.; Rodriguez‐Rodriguez, A. E.; Brito‐Casillas, Y. ...
American journal of transplantation,
November 2017, 2017-Nov, 2017-11-00, 20171101, Volume:
17, Issue:
11
Journal Article
Peer reviewed
Open access
β Cell transcription factors such as forkhead box protein O1 (FoxO1), v‐maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation ...1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma β cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 μM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in β cells, possibly by sharing common pathways of β cell dysfunction. TAC‐induced β cell dysfunction is potentially reversible. Inhibition of the calcineurin–NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.
Tacrolimus, but not cyclosporine, potentiates glucolipotoxicity in β cells by sharing common pathways of β cell dysfunction, while the inhibition of the calcineurin–NFAT pathway does not explain the greater diabetogenic effect of tacrolimus compared to cyclosporine.
The transformation of CO2 into alcohols or other hydrocarbon compounds is challenging because of the difficulties associated with the chemical activation of CO2 by heterogeneous catalysts. Pure ...metals and bimetallic systems used for this task usually have low catalytic activity. Here we present experimental and theoretical evidence for a completely different type of site for CO2 activation: a copper-ceria interface that is highly efficient for the synthesis of methanol. The combination of metal and oxide sites in the copper-ceria interface affords complementary chemical properties that lead to special reaction pathways for the CO2→CH3OH conversion.
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