AMMOS: A Software Platform to Assist in silico Screening

Three software packages based on the common platform of AMMOS (Automated Molecular Mechanics Optimization tool for in silico Screening) for assisting virtual ligand screening purposes have been recently developed. DG-AMMOS allows generation of 3D conformations of small molecules using distance geometry and molecular mechanics optimization. AMMOS_SmallMol is a package for structural refinement of compound collections that can be used prior to docking experiments. AMMOS_ProtLig is a package for energy minimization of protein-ligand complexes. It performs an automatic procedure for molecular mechanics minimization at different levels of flexibility - from rigid to fully flexible structures of both the ligand and the receptor. The packages have been tested on small molecules with a high structural diversity and proteins binding sites of completely different geometries and physicochemical properties. The platform is developed as an open source software and can be used in a broad range of in silico drug design studies

Comparison of 30 THz impulsive burst time development to microwaves, H-alpha, EUV, and GOES soft X-rays

The recent discovery of impulsive solar burst emission in the 30 THz band is raising new interpretation challenges. One event associated with a GOES M2 class flare has been observed simultaneously in microwaves, H-alpha, EUV, and soft X-ray bands. Although these new observations confirm some features found in the two prior known events, they exhibit time profile structure discrepancies between 30 THz, microwaves, and hard X-rays (as inferred from the Neupert effect). These results suggest a more complex relationship between 30 THz emission and radiation produced at other wavelength ranges. The multiple frequency emissions in the impulsive phase are likely to be produced at a common flaring site lower in the chromosphere. The 30 THz burst emission may be either part of a nonthermal radiation mechanism or due to the rapid thermal response to a beam of high-energy particles bombarding the dense solar atmosphere.Comment: accepted to Astronomy and Astrophysic

Single-Cell Analysis Uncovers Osteoblast Factor Growth Differentiation Factor 10 as Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation Associated with Plaque Rupture in Human Carotid Artery Disease

(1) Background: Vascular smooth muscle cells (VSMCs) undergo a complex phenotypic switch in response to atherosclerosis environmental triggers, contributing to atherosclerosis disease progression. However, the complex heterogeneity of VSMCs and how VSMC dediffer-entiation affects human carotid artery disease (CAD) risk has not been clearly established. (2) Method: A single-cell RNA sequencing analysis of CD45 12 cells derived from the atherosclerotic aorta of Apolipoprotein E-deficient (Apoe 12/ 12) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the site-specific predisposition to atherosclerosis was performed. Growth Differentiation Factor 10 (GDF10) role in VSMCs phenotypic switch was investigated via flow cytometry, immunofluorescence in human atherosclerotic plaques. (3) Results: scRNAseq analysis revealed the transcriptomic profile of seven clusters, five of which showed disease-relevant gene signature of VSMC macrophagic calcific phenotype, VSMC mesenchymal chondrogenic phenotype, VSMC inflammatory and fibro-phenotype and VSMC inflammatory phenotype. Osteoblast factor GDF10 involved in ossification and osteoblast differentiation emerged as a hallmark of VSMCs undergoing phenotypic switch. Under hypercholesteremia, GDF10 triggered VSMC osteogenic switch in vitro. The abundance of GDF10 expressing osteogenic-like VSMCs cells was linked to the occurrence of carotid artery disease (CAD) events. (4) Conclusions: Taken together, these results provide evidence about GDF10-mediated VSMC osteogenic switch, with a likely detrimental role in atherosclerotic plaque stability

NLRP3 inflammasome activation controls vascular smooth muscle cells phenotypic switch in atherosclerosis

Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced \u3b1-SMA, SM22\u3b1, Oct-4, and upregulation of KLF-4 and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1\u3b2 secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1\u3b2 in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis

Health-related quality of life in patients with β-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept

BACKGROUND: Patients with transfusion-dependent (TD) β-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). METHODS: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD β-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. RESULTS: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). CONCLUSIONS: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders

Tyrosine Kinase Syk Non-Enzymatic Inhibitors and Potential Anti-Allergic Drug-Like Compounds Discovered by Virtual and In Vitro Screening

In the past decade, the spleen tyrosine kinase (Syk) has shown a high potential for the discovery of new treatments for inflammatory and autoimmune disorders. Pharmacological inhibitors of Syk catalytic site bearing therapeutic potential have been developed, with however limited specificity towards Syk. To address this topic, we opted for the design of drug-like compounds that could impede the interaction of Syk with its cellular partners while maintaining an active kinase protein. To achieve this challenging task, we used the powerful potential of intracellular antibodies for the modulation of cellular functions in vivo, combined to structure-based in silico screening. In our previous studies, we reported the anti-allergic properties of the intracellular antibody G4G11. With the aim of finding functional mimics of G4G11, we developed an Antibody Displacement Assay and we isolated the drug-like compound C-13, with promising in vivo anti-allergic activity. The likely binding cavity of this compound is located at the close vicinity of G4G11 epitope, far away from the catalytic site of Syk. Here we report the virtual screen of a collection of 500,000 molecules against this new cavity, which led to the isolation of 1000 compounds subsequently evaluated for their in vitro inhibitory effects using the Antibody Displacement Assay. Eighty five compounds were selected and evaluated for their ability to inhibit the liberation of allergic mediators from mast cells. Among them, 10 compounds inhibited degranulation with IC50 values ≤10 µM. The most bioactive compounds combine biological activity, significant inhibition of antibody binding and strong affinity for Syk. Moreover, these molecules show a good potential for oral bioavailability and are not kinase catalytic site inhibitors. These bioactive compounds could be used as starting points for the development of new classes of non-enzymatic inhibitors of Syk and for drug discovery endeavour in the field of inflammation related disorders

Role of HSV-1 in Alzheimer's disease pathogenesis: A challenge for novel preventive/therapeutic strategies

Herpes simplex virus-1 (HSV-1) is a ubiquitous DNA virus able to establish a life-long latent infection in host sensory ganglia. Following periodic reactivations, the neovirions usually target the site of primary infection causing recurrent diseases in susceptible individuals. However, reactivated HSV-1 may also reach the brain resulting in severe herpetic encephalitis or in asymptomatic infections. These have been reportedly linked to neurodegenerative disorders, such as Alzheimer's disease (AD), suggesting antiviral preventive or/therapeutic treatments as possible strategies to counteract AD onset and progression. Here, we provide an overview of the AD-like mechanisms driven by HSV-1-infection in neurons and discuss the ongoing trials repurposing anti-herpetic drugs to treat AD as well as preventive strategies aimed at blocking virus infection

Optimizing land use decision-making to sustain Brazilian agricultural profits, biodiversity and ecosystem services

AbstractDesigning landscapes that can meet human needs, while maintaining functioning ecosystems, is essential for long-term sustainability. To achieve this goal, we must better understand the trade-offs and thresholds in the provision of ecosystem services and economic returns. To this end, we integrate spatially explicit economic and biophysical models to jointly optimize agricultural profit (sugarcane production and cattle ranching), biodiversity (bird and mammal species), and freshwater quality (nitrogen, phosphorus, and sediment retention) in the Brazilian Cerrado. We generate efficiency frontiers to evaluate the economic and environmental trade-offs and map efficient combinations of agricultural land and natural habitat under varying service importance. To assess the potential impact of the Brazilian Forest Code (FC), a federal policy that aims to promote biodiversity and ecosystem services on private lands, we compare the frontiers with optimizations that mimic the habitat requirements in the region. We find significant opportunities to improve both economic and environmental outcomes relative to the current landscape. Substantial trade-offs between biodiversity and water quality exist when land use planning targets a single service, but these trade-offs can be minimized through multi-objective planning. We also detect non-linear profit-ecosystem services relationships that result in land use thresholds that coincide with the FC requirements. Further, we demonstrate that landscape-level planning can greatly improve the performance of the FC relative to traditional farm-level planning. These findings suggest that through joint planning for economic and environmental goals at a landscape-scale, Brazil's agricultural sector can expand production and meet regulatory requirements, while maintaining biodiversity and ecosystem service provision

How do practitioners characterize land tenure security?

Improving land tenure security (LTS) is a significant challenge for sustainable development. The Sustainable Development Goals and other recent global initiatives have renewed and increased the need to improve LTS to address climate change, biodiversity loss, food security, poverty reduction, and other challenges. At the same time, policymakers are increasingly interested in evidence- based policies and decisions, creating urgency for practitioners and researchers to work together. Yet, incongruent characterizations of LTS (identifying the key components of LTS) by practitioners and researchers can limit collaboration and information flows necessary for research and effective policymaking. While there are systematic reviews of how LTS is characterized in the academic literature, no prior study has assessed how practitioners characterize LTS. We address this gap using data from 54 interviews of land tenure practitioners working in 10 countries of global importance for biodiversity and climate change mitigation. Practitioners characterize LTS as complex and multifaceted, and a majority of practitioners refer to de jure terms (e.g., titling) when characterizing it. Notably, in our data just one practitioner characterized LTS in terms of perceptions of the landholder, contrasting the recent emphasis in the academic literature on landholder perceptions in LTS characterizations. Researchers should be aware of incongruence in how LTS is characterized in the academic literature when engaging practitioners.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155485/1/csp2186.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155485/2/csp2186_am.pd