If a body in a stream is provided with small ridges aligned in the local flow direction, a remarkable drag reduction can be reached under turbulent flow conditions. This surprising phenomenon is ...called the 'shark skin effect'. We demonstrate, that a reduction of resistance can also be reached in creeping flows if the ridges are aligned perpendicular to the flow direction. We especially consider in gravity-driven film flows the effect of the bottom topography on the mean transport velocity.
We have constructed a phage-displayed library based on the human fibronectin tenth type III domain (FN3) scaffold by randomizing residues in its FG and BC loops. Screening against the SH3 domain of ...human c-Src yielded six different clones. Five of these contained proline-rich sequences in their FG loop that resembled class I (i.e., +xxPxxP) peptide ligands for the Src SH3 domain. The sixth clone lacked the proline-rich sequence and showed particularly high binding specificity to the Src SH3 domain among various SH3 domains tested. Competitive binding, loop replacement, and NMR perturbation experiments were conducted to analyze the recognition properties of selected binders. The strongest binder was able to pull down full-length c-Src from murine fibroblast cell extracts, further demonstrating the potential of this scaffold for use as an antibody mimetic.
The City of Fairbanks changed and evolved over the years. The fifty years of the core-area's roller coaster economy was a mirror reflection of the city, as a whole. The infamous Second Avenue, also ...known as "Two Street," held a key to social reform and economic growth. This thesis explored the issues surrounding the social infrastructure of the "core-area" and how that infrastructure affected the economy of downtown Fairbanks. In addition to the social and cultural phenomena, the political influences and their effect on the core-area's economic and social development was discussed. The government played a pivotal role in the economic direction of the downtown business district. The conclusion of this thesis showed that the core-area of Fairbanks no longer enjoyed the status of the economic mainstay of the Fairbanks economy. However, this area was held as a historical business district and social gathering place for many Fairbanks events.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that began in 2019. The coronavirus 3-chymotrypsin-like cysteine protease (3CLpro) controls ...replication and is therefore considered a major target for antiviral discovery. This study describes the evaluation of SARS-CoV-2 3CLpro inhibitors in a novel self-assembled monolayer desorption ionization mass spectrometry (SAMDI-MS) enzymatic assay. Compared with a traditional FRET readout, the label-free SAMDI-MS assay offers greater sensitivity and eliminates false positive inhibition from compound interference with the optical signal. The SAMDI-MS assay was optimized and validated with known inhibitors of coronavirus 3CLpro such as GC376 (IC50 = 0.060 μM), calpain inhibitors II and XII (IC50 ~20–25 μM). The FDA-approved drugs shikonin, disulfiram, and ebselen did not inhibit SARS-CoV-2 3CLpro activity in the SAMDI-MS assay under physiologically relevant reducing conditions. The three drugs did not directly inhibit human β-coronavirus OC-43 or SARS-CoV-2 in vitro, but instead induced cell death. In conclusion, the SAMDI-MS 3CLpro assay, combined with antiviral and cytotoxic assessment, provides a robust platform to evaluate antiviral agents directed against SARS-CoV-2.
•A novel label-free SARS-CoV-2 3CLpro enzymatic assay was developed using mass spectrometry (SAMDI-MS).•Protease inhibitors active in the SAMDI-MS assay under reducing conditions also have antiviral effects in cells.•Shikonin, disulfiram, and ebselen do not inhibit SARS-CoV-2 3CLpro in the SAMDI-MS assay.•Shikonin, disulfiram, and ebselen do not directly inhibit SARS-CoV-2 but instead are toxic to cells.
Initiatives that support and incentivize the integration of behavioral health and general medical care have become a focus of government strategies to achieve the triple aim of improved health, ...better patient experience, and reduced costs. The authors describe the components of four large-scale national initiatives aimed at integrating care for a wide range of behavioral health needs. Commonalities across these national initiatives highlight health care and social services needs that must be addressed to improve care for people with co-occurring behavioral health and general medical conditions. These findings can inform how to design, test, select, and align the most promising strategies for integrated care in a variety of settings.
Abstract Purpose We aimed to advance the internal and external validity of research by sharing our empirical experience and recommendations for systematically reporting contextual factors. Methods ...Fourteen teams conducting research on primary care practice transformation retrospectively considered contextual factors important to interpreting their findings (internal validity) and transporting or reinventing their findings in other settings/situations (external validity). Each team provided a table or list of important contextual factors and interpretive text included as appendices to the articles in this supplement. Team members identified the most important contextual factors for their studies. We grouped the findings thematically and developed recommendations for reporting context. Results The most important contextual factors sorted into 5 domains: (1) the practice setting, (2) the larger organization, (3) the external environment, (4) implementation pathway, and (5) the motivation for implementation. To understand context, investigators recommend (1) engaging diverse perspectives and data sources, (2) considering multiple levels, (3) evaluating history and evolution over time, (4) looking at formal and informal systems and culture, and (5) assessing the (often nonlinear) interactions between contextual factors and both the process and outcome of studies. We include a template with tabular and interpretive elements to help study teams engage research participants in reporting relevant context. Conclusions These findings demonstrate the feasibility and potential utility of identifying and reporting contextual factors. Involving diverse stakeholders in assessing context at multiple stages of the research process, examining their association with outcomes, and consistently reporting critical contextual factors are important challenges for a field interested in improving the internal and external validity and impact of health care research.
Background & Aims:The mechanisms of liver injury in chronic hepatitis C virus (HCV) infection are poorly understood. Indirect evidence suggests that oxidative stress and mitochondrial injury play a ...role. The aim of this study was to determine if the HCV core protein itself alters mitochondrial function and contributes to oxidative stress.
Methods:HCV core protein was expressed in 3 different cell lines, and reactive oxygen species (ROS) and lipid peroxidation products were measured.
Results:Core expression uniformly increased ROS. In 2 inducible expression systems, core protein also increased lipid peroxidation products and induced antioxidant gene expression as well. A mitochondrial electron transport inhibitor prevented the core-induced increase in ROS. A fraction of the expressed core protein localized to the mitochondria and was associated with redistribution of cytochrome c from mitochondrial to cytosolic fractions. Sensitivity to oxidative stress was also seen in HCV transgenic mice in which increased intrahepatic lipid peroxidation products occurred in response to carbon tetrachloride.
Conclusions:Oxidative injury occurs as a direct result of HCV core protein expression both in vitro and in vivo and may involve a direct effect of core protein on mitochondria. These results provide new in sight into the pathogenesis of hepatitis C and provide an experimental rationale for investigation of antioxidant therapy.
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