PocketGraph : graph representation of binding site volumes

The representation of small molecules as molecular graphs is a common technique in various fields of cheminformatics. This approach employs abstract descriptions of topology and properties for rapid analyses and comparison. Receptor-based methods in contrast mostly depend on more complex representations impeding simplified analysis and limiting the possibilities of property assignment. In this study we demonstrate that ligand-based methods can be applied to receptor-derived binding site analysis. We introduce the new method PocketGraph that translates representations of binding site volumes into linear graphs and enables the application of graph-based methods to the world of protein pockets. The method uses the PocketPicker algorithm for characterization of binding site volumes and employs a Growing Neural Gas procedure to derive graph representations of pocket topologies. Self-organizing map (SOM) projections revealed a limited number of pocket topologies. We argue that there is only a small set of pocket shapes realized in the known ligand-receptor complexes

Mobilizing Communities to Sustainably Produce Face Masks: Public Health Practice in the Time of COVID-19

Background: Face mask shortages in health care and use recommendations and requirements in a variety of com-munity and professional contexts associated with the coronavirus disease 2019 (COVID-19) pandemic in the United States created initial and ongoing demand for face masks. In March 2020, the US Centers for Disease Control and Prevention (CDC) provided guidelines for use of cotton masks for individuals in health care settings and in public. Community volun-teers provide a potential workforce to rapidly and flexibly address critical needs in emergent circumstances. Methods: People Protecting Each-other Sustainably (PPEs) was developed to recruit and manage over 100 Northeast Ohio volunteers. People Protecting Each-other Sustainably used the social media platform Facebook to facilitate material donations, volunteer recruitment and training, and to function as an ongoing central communications hub. Leaders used an assembly line process with zero contact pick up and drop off at multiple stages of production to allow safe assembly and distribution of face masks. Results: A total of 7 695 handmade face masks were created to distribute to local frontline responders in 10 weeks. Use of upsourced and donated materials allowed this project to reduce potential landfill waste and made a zero cost project possible. Volunteers had positive responses to the project and reported benefits from their participation. Conclusion: This model has been successfully recreated by a smaller group in Geauga County, Ohio, with similarly successful results. Clearly this model of community mobilization has the potential to be replicated in other state of emer-gency crises and emergency response situations to produce lifesaving or necessary equipment when industry standard equipment is not readily available

Standalone smartphone apps for mental health—a systematic review and meta-analysis

While smartphone usage is ubiquitous, and the app market for smartphone apps targeted at mental health is growing rapidly, the evidence of standalone apps for treating mental health symptoms is still unclear. This meta-analysis investigated the efficacy of standalone smartphone apps for mental health. A comprehensive literature search was conducted in February 2018 on randomized controlled trials investigating the effects of standalone apps for mental health in adults with heightened symptom severity, compared to a control group. A random-effects model was employed. When insufficient comparisons were available, data was presented in a narrative synthesis. Outcomes included assessments of mental health disorder symptom severity specifically targeted at by the app. In total, 5945 records were identified and 165 full-text articles were screened for inclusion by two independent researchers. Nineteen trials with 3681 participants were included in the analysis: depression (k = 6), anxiety (k = 4), substance use (k = 5), self-injurious thoughts and behaviors (k = 4), PTSD (k = 2), and sleep problems (k = 2). Effects on depression (Hedges’ g = 0.33, 95%CI 0.10–0.57, P = 0.005, NNT = 5.43, I2 = 59%) and on smoking behavior (g = 0.39, 95%CI 0.21–0.57, NNT = 4.59, P ≤ 0.001, I2 = 0%) were significant. No significant pooled effects were found for anxiety, suicidal ideation, self-injury, or alcohol use (g = −0.14 to 0.18). Effect sizes for single trials ranged from g = −0.05 to 0.14 for PTSD and g = 0.72 to 0.84 for insomnia. Although some trials showed potential of apps targeting mental health symptoms, using smartphone apps as standalone psychological interventions cannot be recommended based on the current level of evidence

Compression-induced structural and mechanical changes of fibrin-collagen composites

Fibrin and collagen as well as their combinations play an important biological role in tissue regeneration and are widely employed in surgery as fleeces or sealants and in bioengineering as tissue scaffolds. Earlier studies demonstrated that fibrin-collagen composite networks displayed improved tensile mechanical properties compared to the isolated protein matrices. Unlike previous studies, here unconfined compression was applied to a fibrin-collagen filamentous polymer composite matrix to study its structural and mechanical responses to compressive deformation. Combining collagen with fibrin resulted in formation of a composite hydrogel exhibiting synergistic mechanical properties compared to the isolated fibrin and collagen matrices. Specifically, the composite matrix revealed a one order of magnitude increase in the shear storage modulus at compressive strains>0.8 in response to compression compared to the mechanical features of individual components. These material enhancements were attributed to the observed structural alterations, such as network density changes, an increase in connectivity along with criss-crossing, and bundling of fibers. In addition, the compressed composite collagen/fibrin networks revealed a non-linear transformation of their viscoelastic properties with softening and stiffening regimes. These transitions were shown to depend on protein concentrations. Namely, a decrease in protein content drastically affected the mechanical response of the networks to compression by shifting the onset of stiffening to higher degrees of compression. Since both natural and artificially composed extracellular matrices experience compression in various (patho)physiological conditions, our results provide new insights into the structural biomechanics of the polymeric composite matrix that can help to create fibrin-collagen sealants, sponges, and tissue scaffolds with tunable and predictable mechanical properties

Carfilzomib and dexamethasone versus eight cycles of bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma : an indirect comparison using data from the phase 3 ENDEAVOR and CASTOR trials

Altres ajuts: This analysis and the development of this manuscript were funded by Amgen (Europe) GmbH. Medical writing support, funded by Amgen (Europe) GmbH, was provided by Oxford PharmaGenesis, Oxford, UK. Editorial support was provided by Carine Thual of Amgen (Europe) GmbH.In ENDEAVOR, carfilzomib and dexamethasone (Kd56) demonstrated significant improvement in progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd). Both agents were administered until disease progression; the EU label for Vd, however, stipulates a maximum of eight treatment cycles. Here, matching-adjusted treatment comparison was used to compare efficacy of Kd56 with Vd, if Vd was administered for 8 cycles (Vd-8). Data from ENDEAVOR and CASTOR trials (which compared daratumumab, bortezomib, and dexamethasone with Vd-8) were used. Hazard ratios of PFS were estimated for Vd vs. Vd-8 and Kd vs. Vd-8. For cycles 1-8, risk reduction in PFS for Kd56 vs. Vd-8 was equal to that estimated in ENDEAVOR (HR: 0.53; 95% CI 0.44-0.65). Beyond eight cycles, risk reduction in PFS for Kd56 and Vd-8 was estimated to be 60% (HR: 0.40; 95% CI 0.26-0.63). The analysis suggested that PFS benefit of Kd56 over Vd increases when Vd is given for eight cycles only

Quantitative structural mechanobiology of platelet-driven blood clot contraction

© 2017 The Author(s). Blood clot contraction plays an important role in prevention of bleeding and in thrombotic disorders. Here, we unveil and quantify the structural mechanisms of clot contraction at the level of single platelets. A key elementary step of contraction is sequential extension-retraction of platelet filopodia attached to fibrin fibers. In contrast to other cell-matrix systems in wh ich cells migrate along fibers, the "hand-over-hand" longitudinal pulling causes shortening and bending of platelet-attached fibers, resulting in formation of fiber kinks. When attached to multiple fibers, platelets densify the fibrin network by pulling on fibers transversely to their longitudinal axes. Single platelets and aggregates use actomyosin contractile machinery and integrin-mediated adhesion to remodel the extracellular matrix, inducing compaction of fibrin into bundled agglomerates tightly associated with activated platelets. The revealed platelet-driven mechanisms of blood clot contraction demonstrate an important new biological application of cell motility principles

Vascular endothelial growth factor transgene expression in cell-transplanted hearts

AbstractObjectiveWe evaluated the effect of transplanted cell type, time, and region of the heart on transgene expression to determine the potential of combined gene and cell delivery for myocardial repair.MethodsLewis rats underwent myocardial cryoinjury 3 weeks before transplantation with heart cells (a mixed culture of cardiomyocytes, smooth muscle cells, endothelial cells and fibroblasts, n = 13), vascular endothelial growth factor–transfected heart cells (n = 13), skeletal myoblasts (n = 13), vascular endothelial growth factor–transfected skeletal myoblasts (n = 13), or medium (control, n = 12). Vascular endothelial growth factor expression in the scar, border zone, and normal myocardium was evaluated at 3 days and at 1, 2, and 4 weeks by means of quantitative polymerase chain reaction. Transplanted cells and vascular endothelial growth factor protein were identified immunohistologically on myocardial sections.ResultsVascular endothelial growth factor levels were very low in control scars but increased transiently after medium injection. Transplantation with heart cells and skeletal myoblasts significantly increased vascular endothelial growth factor expression in the scar and border zone. Transplantation of vascular endothelial growth factor–transfected heart cells and vascular endothelial growth factor–transfected skeletal myoblasts further augmented vascular endothelial growth factor expression, resulting in 4- to 5-fold greater expression of vascular endothelial growth factor in the scar at 1 week. Peak vascular endothelial growth factor expression was greater and earlier in vascular endothelial growth factor–transfected heart cells than in vascular endothelial growth factor–transfected skeletal myoblasts. Vascular endothelial growth factor was primarily expressed by the transplanted cells. Some of the transplanted heart cells and vascular endothelial growth factor–transfected heart cells were identified in the endothelial layer of blood vessels in the scar.ConclusionsTransplantation of heart cells and skeletal myoblasts induces vascular endothelial growth factor expression in myocardial scars and is greatly augmented by prior transfection with a vascular endothelial growth factor transgene. Vascular endothelial growth factor expression is limited to the scar and border zone for 4 weeks. Both heart cells and skeletal myoblasts may be excellent delivery vehicles for cell-based myocardial gene therapy

Abnormal clot microstructure formed in blood containing HIT-like antibodies

IntroductionThrombosis is a severe and frequent complication of heparin-induced thrombocytopenia (HIT). However, there is currently no knowledge of the effects of HIT-like antibodies on the resulting microstructure of the formed clot, despite such information being linked to thrombotic events. We evaluate the effect of the addition of pathogenic HIT-like antibodies to blood on the resulting microstructure of the formed clot.Materials and methodsPathogenic HIT-like antibodies (KKO) and control antibodies (RTO) were added to samples of whole blood containing Unfractionated Heparin and Platelet Factor 4. The formed clot microstructure was investigated by rheological measurements (fractal dimension; df) and scanning electron microscopy (SEM), and platelet activation was measured by flow cytometry.Results and conclusionsOur results revealed striking effects of KKO on clot microstructure. A significant difference in df was found between samples containing KKO (df = 1.80) versus RTO (df = 1.74; p < 0.0001). This increase in df was often associated with an increase in activated platelets. SEM images of the clots formed with KKO showed a network consisting of a highly branched and compact arrangement of thin fibrin fibres, typically found in thrombotic disease. This is the first study to identify significant changes in clot microstructure formed in blood containing HIT-like antibodies. These observed alterations in clot microstructure can be potentially exploited as a much-needed biomarker for the detection, management and monitoring of HIT-associated thrombosis