Resistin and resistin-like molecules are pleiotropic cytokines that are involved in inflammatory diseases. Our previous work suggested that resistin has the potential to be used as a biomarker and ...therapeutic target for human pulmonary arterial hypertension. However, data are limited on the distribution of resistin in healthy human organs. In this study, we used our newly developed anti-human resistin (hResistin) antibody to immunohistochemically detect the expression, localization, and intracellular/extracellular compartmentalization of hResistin in a full human tissue panel from healthy individuals. The potential cross reactivity of this monoclonal anti-hResistin IgG1 with normal human tissues also was verified. Results showed that hResistin is broadly distributed and principally localized in the cytoplasmic granules of macrophages scattered in the interstitium of most human tissues. Bone marrow hematopoietic precursor cells also exhibited hResistin signals in their cytoplasmic granules. Additionally, hResistin labeling was observed in the cytoplasm of nervous system cells. Notably, the cytokine activity of hResistin was illustrated by positively stained extracellular material in most human tissues. These data indicate that our generated antibody binds to the secreted hResistin and support its potential use for immunotherapy to reduce circulating hResistin levels in human disease. Our findings comprehensively document the basal expression patterns of hResistin protein in normal human tissues, suggest a critical role of this cytokine in normal and pathophysiologic inflammatory processes, and offer key insights for using our antibody in future pharmacokinetic studies and immunotherapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (HDXMS) is a rapid and effective method for localizing and determining protein stability and dynamics. Localization is routinely ...limited to a peptide resolution of 5 to 20 amino acid residues. HDXMS data can contain information beyond that needed for defining protein stability at single amide resolution. Here we present a method for extracting this information from an HDX dataset to generate a HDXMS protein stability fingerprint. High resolution (HR)-HDXMS was applied to the analysis of a model protein of a spectrin tandem repeat that exemplified an intuitive stability profile based on the linkage of two triple helical repeats connected by a helical linker. The fingerprint recapitulated expected stability maximums and minimums with interesting structural features that corroborate proposed mechanisms of spectrin flexibility and elasticity. HR-HDXMS provides the unprecedented ability to accurately assess protein stability at the resolution of a single amino acid. The determination of HDX stability fingerprints may be broadly applicable in many applications for understanding protein structure and function as well as protein ligand interactions.
Background
Pseudotumors are sterile inflammatory lesions found in the soft tissues surrounding metal-on-metal (MOM) and metal-on-polyethylene hip arthroplasties. In patients with MOM hip ...arthroplasties, pseudotumors are thought to represent an adverse reaction to metal wear debris. However, the pathogenesis of these lesions remains unclear. Currently, there is inconsistent evidence regarding the influence of adverse cup position and increased wear in the formation of pseudotumors.
Questions/purposes
We therefore determined whether pseudotumor formation was associated with (1) adverse cup position, (2) raised metal ion levels, and (3) increased wear rates of the retrieved components.
Methods
We retrospectively reviewed all 352 patients for whom we had retrieved specimens from revisions of a current-generation MOM hip prosthesis between February 2008 and September 2010; of these, 105 met our inclusion criteria. We used multivariate logistic regression analysis to compare acetabular orientation, metal ion levels before revision, and component wear rates between patients with (n = 72) and without (n = 33) pseudotumors, according to findings on metal artifact reduction sequence MRI.
Results
The proportion of patients demonstrating evidence of a pseudotumor in well-positioned hips was similar to those with adverse cup positions (67% and 66%, respectively). Patients revised with pseudotumors had similar whole-blood metal ion levels and component wear rates to those who were not revised.
Conclusions
Pseudotumors were not associated with increased wear or metal ion levels, suggesting patient susceptibility is likely to be more important.
Abstract
In this single centre cohort study we assessed BNT162B2 vaccine uptake and effectiveness among UK healthcare workers (HCWs) during a time of high community COVID-19 prevalence. Early uptake ...among HCWs was 62.3% (1409/2260), however there were significant differences in uptake between age groups, ethnic origins, and job roles. Uptake increased to 72.9% after a vaccine hesitancy working group implemented specific measures. In the 42 days after vaccination, 49 new cases of COVID-19 were identified, of which 7 (14.3%) occurred in HCWs who were beyond 10 days of vaccination. Kaplan–Meier curves for partially vaccinated and unvaccinated groups were congruent until day 14 and continued to diverge up to 42 days. Cox regression analysis showed a 70.0% (95%CI 6.0–91.0;
p
=0.04) risk reduction for COVID-19 infection in partially vaccinated HCWs. Here we report early vaccination rates among HCWs are generally high although uptake is lower in certain groups. It is possible to improve vaccine uptake and efforts should focus on this, however, significant resource is required. The BNT162B2 vaccine is effective from 14 days post-vaccination in a frontline clinical setting and protection continues beyond 21 days post 1st dose without a 2nd dose, being given.
Hydrogen–deuterium exchange mass spectrometry (HDX MS) has become an important technique for the analysis of protein structure and dynamics. Data analysis remains a bottleneck in the workflow. ...Sophisticated computer analysis is required to scan through the voluminous MS output in order to find, identify, and validate many partially deuterated peptides, elicit the HDX information, and extend the results to higher structural resolution. We previously made available two software suites, ExMS for identification and analysis of peptide isotopic envelopes in the HDX MS raw data and HDsite for residue-level resolution. Further experience has led to advances in the usability and performance of both programs. Also, newly added modules deal with ETD/ECD analysis, multimodal mass spectra analysis, and presentation options. These advances have been integrated into a stand-alone software solution named ExMS2. The package has been successfully tested by many workers in fine scale epitope mapping, in protein folding studies, and in dissecting structure and structure change of large protein complexes. A description and tutorial for this major upgrade are given here.
The inclusion of Indigenous cultures, known as the cultural determinants of health, in healthcare policy and health professional education accreditation and registration requirements, is increasingly ...being recognised as imperative for improving the appalling health and well-being of Indigenous Australians. These inclusions are a strengths-based response to tackling the inequities in Indigenous Australians' health relative to the general population. However, conceptualising the cultural determinants of health in healthcare practice has its contextual challenges, and gaps in implementation evidence are apparent. In this paper, we provide a case example, namely the Katherine Hospital, of how healthcare services can implement the cultural determinants of health into clinical practice. However, to be effective, health professionals must concede that Australia's Indigenous peoples' knowledges involving cultural ways of being, knowing and doing must co-exist with western and biomedical knowledges of health practice. We use the Katherine Hospital ABC Radio National Background Briefing interview, which was mentioned by two research participants in a 2020 study, as an example of good practice that we can learn from. Additionally, the six Aboriginal and Torres Strait Islander Health actions contained in the 2nd Edition of the Australian National Safety and Quality Health Service Standards provide governance and accountability examples of how to enable Indigenous people's cultures and their knowledges in the provision of services. The role of non-Indigenous clinical allies and accomplices is imperative when embedding and enacting Indigenous Australians' cultures in service systems of health. When Indigenous Peoples access mainstream hospitals, deep self-reflection by allies and accomplices is necessary to enable safe, quality care, and treatment that is culturally safe and free from racism. Doing so can increase cultural responsiveness free of racism, thereby reducing the inherent power imbalances embedded within mainstream health services.
To examine the relationship between protein structural dynamics and measurable hydrogen exchange (HX) data, the detailed exchange behavior of most of the backbone amide hydrogens of Staphylococcal ...nuclease was compared with that of their neighbors, with their structural environment, and with other information. Results show that H‐bonded hydrogens are protected from exchange, with HX rate effectively zero, even when they are directly adjacent to solvent. The transition to exchange competence requires a dynamic structural excursion that removes H‐bond protection and allows exposure to solvent HX catalyst. The detailed data often make clear the nature of the dynamic excursion required. These range from whole molecule unfolding, through smaller cooperative unfolding reactions of secondary structural elements, and down to local fluctuations that involve as little as a single peptide group or side chain or water molecule. The particular motion that dominates the exchange of any hydrogen is the one that allows the fastest HX rate. The motion and the rate it produces are determined by surrounding structure and not by nearness to solvent or the strength of the protecting H‐bond itself or its acceptor type (main chain, side chain, structurally bound water). Many of these motions occur over time scales that are appropriate for biochemical function.
Recent publications have drawn attention to the fact that some brands of joint replacement may contain variants which perform significantly worse (or better) than their 'siblings'. As a result, the ...National Joint Registry has performed much more detailed analysis on the larger families of knee arthroplasties in order to identify exactly where these differences may be present and may hitherto have remained hidden. The analysis of the Nexgen knee arthroplasty brand identified that some posterior-stabilized combinations have particularly high revision rates for aseptic loosening of the tibia, and consequently a medical device recall has been issued for the Nexgen 'option' tibial component which was implicated. More elaborate signal detection is required in order to identify such variation in results in a routine fashion if patients are to be protected from such variation in outcomes between closely related implant types.
American marten (Martes americana) in Interior Alaska are at the northwestern limit of their North American range. To investigate factors that may be associated with reproduction we determined the ...cementum age and the presence or absence of blastocysts in 118 female martens for 3 years (2012, 2014, and 2016) in two regions. For each marten we collected fur samples and measured steroid hormone concentrations (cortisol, testosterone, and progesterone) and stable isotopes (δ15N and δ13C values, a proxy for diet). These parameters reflect the diet and endocrine activity between June and October when fur is grown. We also collected two claws from a subset of 39 female marten from one region in 2012 and 2014. Progesterone concentrations were measured in one whole claw and from a second claw divided into proximal (recent growth) and distal sections. Differences in the probability of blastocysts being present were associated with geographic region and sample year suggesting that reproduction in female marten varies on a fine scale. We found the that presence of blastocysts was positively associated with marten age and δ15N values in fur but negatively associated with fur cortisol concentrations. These findings suggest that the likelihood a female marten will reproduce in a given year is influenced, in part, by the proportion of protein in their diet and stressors encountered during late summer and fall, months before active gestation begins.
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