Claymcdonough5758

Many biological processes involve precise cellular state transitions controlled by complex gene regulation. Here, we use budding yeast cell cycle as a model system and explore how a gene regulatory circuit encodes essential information of state transitions. We present a generalized random circuit perturbation method for circuits containing heterogeneous regulation types and its usage to analyze both steady and oscillatory states from an ensemble of circuit models with random kinetic parameters. The stable steady states form robust clusters with a circular structure that are associated with cell cycle phases. This circular structure in the clusters is consistent with single-cell RNA sequencing data. The oscillatory states specify the irreversible state transitions along cell cycle progression. Furthermore, we identify possible mechanisms to understand the irreversible state transitions from the steady states. We expect this approach to be robust and generally applicable to unbiasedly predict dynamical transitions of a gene regulatory circuit.Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression but remains poorly understood. We found that the uncharacterized epigenetic factor chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a functional role for CDYL2 in malignancy, it positively regulated breast cancer cell migration, invasion, stem-like phenotypes, and epithelial-to-mesenchymal transition. CDYL2 regulation of these plasticity-associated processes depended on signaling via p65/NF-κB and STAT3. This, in turn, was downstream of CDYL2 regulation of MIR124 gene transcription. CDYL2 co-immunoprecipitated with G9a/EHMT2 and GLP/EHMT1 and regulated the chromatin enrichment of G9a and EZH2 at MIR124 genes. We propose that CDYL2 contributes to poor prognosis in breast cancer by recruiting G9a and EZH2 to epigenetically repress MIR124 genes, thereby promoting NF-κB and STAT3 signaling, as well as downstream cancer cell plasticity and malignant progression.Over the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.We demonstrate the nearly quantitative conversion of methanol to methyl formate (MF) with a reliable durability on the reduced-graphene-oxide-confined VTiOx nanoparticles (rGO@VTiO). The rGO@VTiO exhibits superior low-temperature reactivity than the rGO-free VTiO, and the MF yield of 98.8% is even comparable with the noble metal catalysts. Both experiments and simulations demonstrate that the ultrathin rGO shell significantly impacts the shell/core interfacial electronic structure and the surface chemistry of the resultant catalysts, leading to remarkable reactivity in methanol to MF. rGO enhances the dispersion and loading rates of active monomeric/oligomeric VOx. In particular, the electron migration between the rGO shell and oxides core reinforces the acidity of rGO@VTiO in the absence of sulfate acidic sites. Moreover, both in situ NAP-XPS and DRIFTS investigations suggest that the lattice oxygen was involved in the oxidation of methanol and the MF was formed via the hemiacetal mechanism.Background While gait assessments are recommended to evaluate fall risk in older adults, these often involve walking in a straight line, even though one-third of steps taken throughout the day involve turning. Falls that occur during a turn tend to be more serious than falls that occur during a straight walk, but little is known about how gait variables collected during a turn can predict falls. Research question How do gait characteristics collected from straight and turning walking phases predict falls in older adults? Methods We prospectively examined the association between six quantitative gait variables measured during normal walking turn and straight walking phases as predictors of incident falls in a community-based sample of older adults (N = 253; mean age 78.5; 51% women). Cox regressions adjusted for multiple potential confounders were used to examine the associations. Results Participants had significantly slower stride velocity (57.81 vs 83.26 cm/s), shorter stride length (74.76 vs 101.81 cm,), lower swing (30.1 vs 32.41%), higher double support (39.79 vs 35.19%), and more swing (30.09 vs 32.41%) and stride length variability (31.86 vs 6.35 %) during turns compared with straights. Higher swing percent in both turns (adjusted hazard ratio; HR 0.92, 95% CI 0.87, 0.97) and straights (HR 0.89, 95% CI 0.84, 0.96) was associated with reduced risk of falls. Higher double support percent during both turns (HR 1.04, 95% CI 1.01, 1.07) and straights (HR 1.06, 95% CI 1.02, 1.09) was associated with increased risk of falls. More swing variability during turns (HR 1.03, 95% CI 1.00, 1.06), but not straights, was associated with increased risk of falls. Significance Gait variables collected during turning and walking straight were similar in their predictions of future falls. In the future, clinical research that builds on these findings could improve identification and prevention of falls.Objectives Ocrelizumab (OCR) is a humanized monoclonal antibody targeting CD20 antigen exposed on B cells surface. Kinetic of B-cells repopulation after depletion therapy shows high intra and inter-individual variability. The aim of this study was to explore the influence of Body Mass Index (BMI) on kinetic of B-cell repopulation after treatment with OCR and on treatment response. see more Methods 108 Multiple Sclerosis (MS) patients were enrolled at the time of the first dose of OCR administration and prospectively evaluated. Clinical, instrumental activity and disability progression were analyzed. According to B cells count, patients were divided into two groups with fast (FR) and with slow (SR) repopulation rate, respectively. Results Significant reduction of disease activity was observed in all patients and a stabilization of disease was obtained in progressive patients. Patients with FR had higher BMI compared to patients with a SR (p less then 0.001). Contrariwise no correlation between repopulation rate and treatment effectiveness was disclosed. Conclusions In a real world setting we confirmed the effectiveness of OCR in relapsing remitting and progressive patients; patients with higher BMI had a FR. This suggests considering BMI for administration schedule although further investigations with longer follow up could improve treatment protocol and patient selection.Background The Symbol Digit Modalities Tests (SDMT) is the most sensitive measure to multiple sclerosis (MS)-related cognitive dysfunction. However, existing normative data has been under scrutiny. Specifically, they are outdated, do not take into account gender, and are poorly stratified by education. More importantly, there exists no oral only version norms, which is typical administration among individuals with MS. Objective The present investigation aimed to develop updated normative data of the oral version SDMT in which age, gender, and education were taken into consideration. Methods A total of 675 healthy individuals, stratified by age, gender, and education completed the oral version SDMT. Results Significant effects were found for age, gender, and education, consistent with previous contentions. Specifically, performance on the SDMT tends to decline with age, with the most noticeable decline beginning in the third decade of life and continuing into the sixth decade. Women, in general perform better than men, with an average of 5.1 more points. Finally, education effects were apparent among those aged 25-54. Conclusion Based on these findings, updated normative data are provided. Utilization of these updated norms will result in a much needed and more accurate assessment of processing speed for individuals with MS.Trans-Resveratrol (3, 5, 4'-trihydroxystilbene) is a naturally occurring polyphenol easily oxidizable and extremely photosensitive with a short biological half-life that must be encapsulated to maintain its beneficial properties on the human body. The aim of this work is to increase the amount of resveratrol encapsulated using concentrated double water-in-oil-in-water (W1/O/W2) emulsions, making these systems more interesting as ingredient for functional food products and/or pharmaceutical formulations. The concentration of the inner emulsion (W1/O) for several external (W1O/W2) ratios was optimized in terms of encapsulation efficiency (EE), colloidal stability and rheological behaviour. W1/O emulsions formulated with ratios of 30/70 and 40/60 were used to obtain double emulsions (with ratios of 20/80 up to 80/20 of W1O/W2). Trans-Resveratrol EE increased up to 90 % when the most concentrated double emulsions were prepared for both W1/O ratios tested. The maximum resveratrol concentrations on double emulsions were 10.8 mg/L and 14.4 mg/L when 30/70 and 40/60 of W1/O ratios were used, respectively. However, longer time stability was found for double high internal phase emulsions (W1O/W2) with a ratio of 30/70 of W1/O. The double emulsion formulated with a 80/20 W1O/W2 volumetric ratio together with 30/70 of W1/O seems suitable to be used as ingredient for pharmaceutical and food devices/products due to its high colloidal stability, clearly pseudoplastic and elastic behaviour, high EE and large trans-Resveratrol carrier capacity.Nanoparticles (NPs) are being studied due to their potential use as therapeutic and immunomodulatory tools, including their ability to transport antigens with the aim to induce a specific immune response. The production of snake antivenoms (AV) involves several inoculations of venom (V) in the presence of adjuvants (ADJ) to improve the immune response of inoculated animals, causing a decrease in its quality and shelf life. Therefore, it is interesting to develop new strategies for reduce these side effects. For that reason, associating V to NPs to replace conventional ADJ could be a useful tool for future AV production. In this work, nanovenoms (NVs) were generated by the adsorption of Crotalus durissus terrificus (Cdt) V proteins over silica NPs (SiNPs) synthesized according to the Stöber method. Microphotographies obtained under Transmission Electron Microscopy (TEM) displayed a protein crown over NPs and Fourier Transform Infrared (FT-IR) presented the expected spectra for NVs resulting from the sum of those exhibited by Cdt V and SiNPs separately.