To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis.
Three ...multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE.
A total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet's uveitis (ENDURE study) were enrolled.
After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study.
Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes.
After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies.
The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular ...cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.
There is a challenge for metalloenzymes to acquire their correct metals because some inorganic elements form more stable complexes with proteins than do others. These preferences can be overcome ...provided some metals are more available than others. However, while the total amount of cellular metal can be readily measured, the available levels of each metal have been more difficult to define. Metal-sensing transcriptional regulators are tuned to the intracellular availabilities of their cognate ions. Here we have determined the standard free energy for metal complex formation to which each sensor, in a set of bacterial metal sensors, is attuned: the less competitive the metal, the less favorable the free energy and hence the greater availability to which the cognate allosteric mechanism is tuned. Comparing these free energies with values derived from the metal affinities of a metalloprotein reveals the mechanism of correct metalation exemplified here by a cobalt chelatase for vitamin B
.
Microeconomics of Technology Adoption Foster, Andrew D; Rosenzweig, Mark R
Annual review of economics,
01/2010, Letnik:
2, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Differences in technology levels across countries account for a large component of the differences in wages and per-capita GDP across countries worldwide. This article reviews micro studies of the ...adoption of new technologies and the use of inputs complementary with new technologies to shed light on the barriers to technology diffusion in low-income countries. Among the factors examined affecting decisions pertaining to technology choice and input allocations are the financial and nonfinancial returns to adoption, one's own learning and social learning, technological externalities, scale economies, schooling, credit constraints, risk and incomplete insurance, and departures from behavioral rules implied by simple models of rationality.
•Patients prefer nursing homes with higher prevalence of residents of their own race.•Preference for distance and quality of care are same for patients of both the races.•Both distance and race ...preference contribute to racial disparity in quality of care.•Results are robust among subgroups based on Medicaid eligibility and clinical conditions.
In this paper, we examine the contributions of travel distance and preferences for racial homogeneity as sources of nursing home segregation and racial disparities in nursing home quality. We first theoretically characterize the distinctive implications of these mechanisms for nursing home racial segregation. We then use this model to structure an empirical analysis of nursing home sorting. We find little evidence of differential willingness to pay for quality by race among first-time nursing home entrants, but do find significant distance and race-based preference effects. Simulation exercises suggest that both effects contribute importantly to racial disparities in nursing home quality.
Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), ...and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
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•Invasive lobular carcinoma (ILC) is a clinically and molecularly distinct disease•ILCs show CDH1 and PTEN loss, AKT activation, and mutations in TBX3 and FOXA1•Proliferation and immune-related gene expression signatures define 3 ILC subtypes•Genetic features classify mixed tumors into lobular-like and ductal-like subgroups
A comprehensive analysis of 817 breast tumor samples determines invasive lobular carcinoma as a molecularly distinct disease with characteristic genetic features, providing key information for patient stratification that may allow a more informed clinical follow-up.
Computational fluid dynamics (CFD) analysis is widely used in chemical engineering. Although CFD calculations are accurate, the computational cost associated with complex systems makes it difficult ...to obtain empirical equations between system variables. Here, we combine active learning (AL) and symbolic regression (SR) to get a symbolic equation for system variables from CFD simulations. Gaussian process regression‐based AL allows for automated selection of variables by selecting the most instructive points from the available range of possible parameters. The results from these experiments are then passed to SR to find empirical symbolic equations for CFD models. This approach is scalable and applicable for any desired number of CFD design parameters. To demonstrate the effectiveness, we use this method with two model systems. We recover an empirical equation for the pressure drop in a bent pipe and a new equation for predicting backflow in a heart valve under aortic insufficiency.
Abstract
Subterranean habitats are generally very stable environments, and as such evolutionary transitions of organisms from surface to subterranean lifestyles may cause considerable shifts in ...physiology, particularly with respect to thermal tolerance. In this study we compared responses to heat shock at the molecular level in a geographically widespread, surface-dwelling water beetle to a congeneric subterranean species restricted to a single aquifer (Dytiscidae: Hydroporinae). The obligate subterranean beetle
Paroster macrosturtensis
is known to have a lower thermal tolerance compared to surface lineages (CT
max
38 °C cf. 42–46 °C), but the genetic basis of this physiological difference has not been characterized. We experimentally manipulated the thermal environment of 24 individuals to demonstrate that both species can mount a heat shock response at high temperatures (35 °C), as determined by comparative transcriptomics. However, genes involved in these responses differ between species and a far greater number were differentially expressed in the surface taxon, suggesting it can mount a more robust heat shock response; these data may underpin its higher thermal tolerance compared to subterranean relatives. In contrast, the subterranean species examined not only differentially expressed fewer genes in response to increasing temperatures, but also in the presence of the experimental setup employed here alone. Our results suggest
P. macrosturtensis
may be comparatively poorly equipped to respond to both thermally induced stress and environmental disturbances more broadly. The molecular findings presented here have conservation implications for
P. macrosturtensis
and contribute to a growing narrative concerning weakened thermal tolerances in obligate subterranean organisms at the molecular level.
5-Methylcytosine (5mC) is an epigenetic modification involved in regulation of gene activity during differentiation. Tet dioxygenases oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine ...(5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised from DNA by thymine-DNA glycosylase (TDG) followed by regeneration of unmodified cytosine via the base excision repair pathway. Despite evidence that this mechanism is operative in embryonic stem cells, the role of TDG-dependent demethylation in differentiation and development is currently unclear. Here, we demonstrate that widespread oxidation of 5hmC to 5caC occurs in postimplantation mouse embryos. We show that 5fC and 5caC are transiently accumulated during lineage specification of neural stem cells (NSCs) in culture and in vivo. Moreover, 5caC is enriched at the cell-type-specific promoters during differentiation of NSCs, and TDG knockdown leads to increased 5fC/5caC levels in differentiating NSCs. Our data suggest that active demethylation contributes to epigenetic reprogramming determining lineage specification in embryonic brain.
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•Widespread oxidation of 5hmC to 5caC occurs in ESCs and postimplantation embryos•5fC/5caC transiently accumulate during lineage specification of NSCs•5caC is enriched at promoters that are demethylated during NSC differentiation•TDG knockdown leads to an increase in 5fC/5caC in differentiating NSCs
DNA methylation (5mC) is involved in regulation of gene activity during differentiation. Tet dioxygenases oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Though both 5fC and 5caC can serve as intermediates of active demethylation, the role of this pathway in differentiation is unclear. Wheldon et al. now show that 5fC/5caC transiently accumulate during lineage specification of neural stem cells. Their data suggest that active demethylation contributes to epigenetic reprogramming during differentiation of postmitotic cell types.
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