The meniscus is crucial in maintaining knee function and protecting the joint from secondary pathologies, including osteoarthritis. The meniscus has been shown to absorb up to 75% of the total load ...on the knee joint. Mechanical behavior of meniscal tissue in compression can be predicted by quantifying the mechanical parameters including; aggregate modulus (
) and Poisson modulus (ν), and the fluid transport parameter: hydraulic permeability (
). These parameters are crucial to develop a computational model of the tissue and for the design and development of tissue engineered scaffolds mimicking the native tissue. Hence, the objective of this study was to characterize the mechanical and fluid transport properties of human meniscus and relate them to the tissue composition. Specimens were prepared from the axial and the circumferential anatomical planes of the tissue. Stress relaxation tests yielded the
, while finite element modeling was used to curve fit for ν and
. Correlations of moduli with water and glycosaminoglycans (GAGs) content were investigated. On average
was found to be 0.11 ± 0.078 MPa, ν was 0.32 ± 0.057, and
was 2.9 ± 2.27 × 10
m
N
s
. The parameters
, ν, and
were not found to be statistically different across compression orientation or compression level. Water content of the tissue was 77 ± 3.3% while GAG content was 8.79 ± 1.1%. Interestingly, a weak negative correlation was found between
and water content (R
~ 34%) and a positive correlation between
and GAG content (R
~ 53%). In conclusion, while no significant differences in transport and compressive properties can be found across sample orientation and compression levels, data trends suggest potential relationships between magnitudes of H and K, and GAG content.
Pan-Africa convection-permitting regional climate model simulations have been performed to study the impact of high resolution and the explicit representation of atmospheric moist convection on the ...present and future climate of Africa. These unique simulations have allowed European and African climate scientists to understand the critical role that the representation of convection plays in the ability of a contemporary climate model to capture climate and climate change, including many impact-relevant aspects such as rainfall variability and extremes. There are significant improvements in not only the small-scale characteristics of rainfall such as its intensity and diurnal cycle, but also in the large-scale circulation. Similarly, effects of explicit convection affect not only projected changes in rainfall extremes, dry spells, and high winds, but also continental-scale circulation and regional rainfall accumulations. The physics underlying such differences are in many cases expected to be relevant to all models that use parameterized convection. In some cases physical understanding of small-scale change means that we can provide regional decision-makers with new scales of information across a range of sectors. We demonstrate the potential value of these simulations both as scientific tools to increase climate process understanding and, when used with other models, for direct user applications. We describe how these ground-breaking simulations have been achieved under the U.K. Government’s Future Climate for Africa Programme. We anticipate a growing number of such simulations, which we advocate should become a routine component of climate projection, and encourage international coordination of such computationally and human- resource expensive simulations as effectively as possible.
Bladder hyperreflexia is a common non-motor feature of Parkinson's disease. We now report on the contractility of the isolated primate detrusor strips devoid of nerve input and show that following ...MPTP, the amplitude and frequency of spontaneous contraction was increased. These responses were unaffected by dopamine D1 and D2 receptor agonists A77636 and ropinirole respectively. Contractions by exogenous carbachol, histamine or ATP were similar and no differences in the magnitude of noradrenaline-induced relaxation were seen in detrusor strip obtained from normal and MPTP-treated common marmosets (Callithrix jacchus). However, the neurogenic contractions following electrical field stimulation of the intrinsic nerves (EFS) were markedly greater in strips obtained from MPTP treated animals. EFS evoked non-cholinergic contractions following atropine were also greater but the contribution of the cholinergic innervation as a proportion of the overall contraction was smaller in the detrusor strips of MPTP treated animals, suggesting a preferential enhancement of the non-cholinergic transmission. Although dopaminergic mechanism has been proposed to underlie bladder hyperreflexia in MPTP-treated animals with intact bladder, the present data indicates that the increased neurogenically mediated contractions where no extrinsic innervation exists might be due to long-term adaptive changes locally as a result of the loss of the nigrostriatal output.
Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of ...advanced age, during humoral autoimmunity and following viral infection, the functional properties of this cellular subset remain incompletely defined. In the current study, we demonstrate that ABCs fulfill the criteria for memory B cells (MBCs), based on evidence of Ag-dependent expansion and persistence in a state poised for rapid differentiation into Ab-secreting plasma cells during secondary responses. First, we show that a majority of ABCs are not actively cycling but exhibit an extensive replication history consistent with prior Ag engagement. Second, despite unswitched surface IgM expression, ABCs show evidence of activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Third, BCRs cloned from sorted ABCs exhibit broad autoreactivity and polyreactivity. Although the overall level of ABC self-reactivity was not increased relative to naive B cells, ABCs lacked features of functional anergy characteristic of autoreactive B cells. Fourth, ABCs express MBC surface markers consistent with being poised for rapid plasma cell differentiation during recall responses. Finally, in a murine model of viral infection, adoptively transferred CD11c
B cells rapidly differentiated into class-switched Ab-secreting cells upon Ag rechallenge. In summary, we phenotypically and functionally characterize ABCs as IgM-expressing MBCs, findings that together implicate ABCs in the pathogenesis of systemic autoimmunity.
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection ...disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
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•scATAC-seq and scRNA-seq reveal expansion of an MBC subset in chronic LCMV infection•A distinct chronic MBC subset is associated with increased IFN-I-associated ISG signature•The chromatin landscape of MBCs is established during a critical window early in infection•IFN-I dynamics govern memory B cell epigenome and phenotype in chronic viral infection
Chronic viral infection disrupts the ability to form long-lived B cell-mediated protective immunity, but the mechanisms are unclear. Cooper et al. demonstrate a key role of type I interferon (IFN-I) in governing memory B cell identity and show that the chromatin landscape and phenotype of memory B cells are set during a critical early window of IFN-I exposure.
Semaglutide and Cardiovascular Outcomes Taqueti, Viviany R; Shaw, Leslee J
The New England journal of medicine,
2024-Feb-22, Letnik:
390, Številka:
8
Journal Article
Translocation to the nucleus of diacylglycerol kinase (DGK)- ζ is dependent on a sequence homologous to the effector domain of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS). These data would ...suggest that MARCKS could also localize to the nucleus. A single report demonstrated immunofluorescence staining of MARCKS in the nucleus; however, further experimental evidence confirming the specific domain responsible for this localization has not been reported. Here, we report that MARCKS is present in the nucleus in GBM cell lines. We then over-expressed wild-type MARCKS (WT) and MARCKS with the effector domain deleted (ΔED), both tagged with V5-epitope in a GBM cell line with low endogenous MARCKS expression (U87). We found that MARCKS-WT localized to the nucleus, while the MARCKS construct without the effector domain remained in the cytoplasm. We also found that over-expression of MARCKS-WT resulted in a significant increase in total cellular phosphatidyl-inositol (4,5) bisphosphate (PIP2) levels, consistent with prior evidence that MARCKS can regulate PIP2 levels. We also found increased staining for PIP2 in the nucleus with MARCKS-WT over-expression compared to MARCKS ΔED by immunofluorescence. Interestingly, we observed MARCKS and PIP2 co-localization in the nucleus. Lastly, we found changes in gene expression when MARCKS was not present in the nucleus (MARCKS ΔED). These data indicate that the MARCKS effector domain can function as a nuclear localization signal and that this sequence is critical for the ability of MARCKS to regulate PIP2 levels, nuclear localization, and gene expression. These data suggests a novel role for MARCKS in regulating nuclear functions such as gene expression.
The American Indian (AI) population in North Carolina has limited access to the Indian Health Service. Consequently, cancer burden and disparities may differ from national estimates. We describe the ...AI cancer population and examine AI-White disparities in cancer incidence and mortality.
We identified cancer cases diagnosed among adult AI and White populations between 2014 and 2018 from the North Carolina Central Cancer Registry. We estimated incidence and mortality rate ratios (IRR and MRR) by race. In addition, between the AI and White populations, we estimated the ratio of relative frequency differences RRF, with 95% confidence limits (CL) of clinical and sociodemographic characteristics. Finally, we evaluated the geographic distribution of incident diagnoses among AI populations.
Our analytic sample included 2,161 AI and 204,613 White individuals with cancer. Compared with the White population, the AI population was more likely to live in rural areas (48% vs. 25%; RRF, 1.89; 95% CL, 1.81-1.97) and to have Medicaid (18% vs. 7%; RRF, 2.49; 95% CL, 2.27-2.71). Among the AI population, the highest age-standardized incidence rates were female breast, followed by prostate and lung and bronchus. Liver cancer incidence was significantly higher among the AI population than White population (IRR, 1.27; 95% CL, 1.01-1.59). AI patients had higher mortality rates for prostate (MRR, 1.72; CL, 1.09-2.70), stomach (MRR, 1.82; 95% CL, 1.15-2.86), and liver (MRR, 1.70; 95% CL, 1.25-2.33) cancers compared with White patients.
To reduce prostate, stomach, and liver cancer disparities among AI populations in North Carolina, multi-modal interventions targeting risk factors and increasing screening and treatment are needed.
This study identifies cancer disparities that can inform targeted interventions to improve outcomes among AI populations in North Carolina.
Supplemental long-chain omega-3 (n–3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA omega-3 index (O3I) concentrations, but the magnitude or variability of this effect is unclear.
The purpose ...of this study was to model the effects of supplemental EPA + DHA on the O3I.
Deidentified data from 1422 individuals from 14 published n–3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form ethyl ester (EE) compared with triglyceride (TG), and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion.
Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products.
Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.
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