Clarkbentsen5497

Caspase-2 was discovered almost three decades ago. GW788388 It was one of the first two mammalian homologs of CED-3, the other being interleukin 1β-converting enzyme (ICE/caspase-1). Despite high similarity with CED-3 and its fly and mammalian counterparts (DRONC and caspase-9, respectively), the function of caspase-2 in apoptosis has remained enigmatic. A number of recent studies suggest that caspase-2 plays an important role in the regulation of p53 in response to cellular stress and DNA damage to prevent the proliferation and accumulation of damaged or aberrant cells. Here, we review these recent observations and their implications in caspase-2-mediated cellular death, senescence, and tumor suppression.Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.The functional properties of cuprates are strongly determined by the doping state and carrier density. We present an oxygen doping study of YBa2Cu3O7-δ (YBCO) thin films from underdoped to overdoped state, correlating the measured charge carrier density, [Formula see text], the hole doping, p, and the critical current density, [Formula see text]. Our results show experimental demonstration of strong increase of [Formula see text] with [Formula see text], up to Quantum Critical Point (QCP), due to an increase of the superconducting condensation energy. The ultra-high [Formula see text] achieved, 90 MA cm-2 at 5 K corresponds to about a fifth of the depairing current, i.e. a value among the highest ever reported in YBCO films. The overdoped regime is confirmed by a sudden increase of [Formula see text], associated to the reconstruction of the Fermi-surface at the QCP. Overdoping YBCO opens a promising route to extend the current carrying capabilities of rare-earth barium copper oxide (REBCO) coated conductors for applications.Hydrocarbon chemistry in the C-O-H system at high pressure and high temperature is important for modelling the internal structure and evolution of giant icy planets, such as Uranus and Neptune, as their interiors are thought to be mainly composed of water and methane. In particular, the formation of diamond from the simplest hydrocarbon, i.e., methane, under the internal conditions of these planets has been discussed for nearly 40 years. Here, we demonstrate the formation of diamond from methane hydrate up to 3800 K and 45 GPa using a CO2 laser-heated diamond anvil cell combined with synchrotron X-ray diffraction, Raman spectroscopy, and scanning electron microscopy observations. The results show that the process of dissociation and polymerisation of methane molecules to produce heavier hydrocarbons while releasing hydrogen to ultimately form diamond proceeds at milder temperatures (~ 1600 K) and pressures (13-45 GPa) in the C-O-H system than in the C-H system due to the influence of water. Our findings suggest that diamond formation can also occur in the upper parts of the icy mantles of giant icy planets.Hydrogen sulfide (H2S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which H2S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions. Voltage-gated K+ channels, including Kv2.1, are fundamental components of neuronal excitability. Here, we show that both recombinant and native rat Kv2.1 channels are inhibited by the H2S donors, NaHS and GYY4137. Biochemical investigations revealed that NaHS treatment leads to S-sulfhydration of the full length wild type Kv2.1 protein which was absent (as was functional regulation by H2S) in the C73A mutant form of the channel. Functional experiments utilising primary rat hippocampal neurons indicated that NaHS augments action potential firing and thereby increases neuronal excitability. These studies highlight an important role for H2S in shaping cellular excitability through S-sulfhydration of Kv2.1 at C73 within the central nervous system.Rifted margins are the result of the successful process of thinning and breakup of the continental lithosphere leading to the formation of new oceanic lithosphere. Observations on rifted margins are now integrating an increasing amount of multi-channel seismic data and drilling of several Continent-Ocean Transitions. Based on large scale geometries and domains observed on high-quality multi-channel seismic data, this article proposes a classification reflecting the mechanical behavior of the crust from localized to diffuse deformation (strong/coupled to weak/decoupled mechanical behaviors) and magmatic intensity leading to breakup from magma-rich to magma-poor margins. We illustrate a simple classification based on mechanical behavior and magmatic production with examples of rifted margins. We propose a non-exhaustive list of forcing parameters that can control the initial rifting conditions but also their evolution through time. Therefore, rifted margins are not divided into opposing types, but described as a combination and continuum that can evolve through time and space.The NAD+-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD+ boosters alleviate metabolic complications. We previously reported that SIRT1-depletion in 3T3-L1 preadipocytes led to C-Myc activation, adipocyte hyperplasia, and dysregulated adipocyte metabolism. Here, we characterized SIRT1-depleted adipocytes by quantitative mass spectrometry-based proteomics, gene-expression and biochemical analyses, and mitochondrial studies. We found that SIRT1 promoted mitochondrial biogenesis and respiration in adipocytes and expression of molecules like leptin, adiponectin, matrix metalloproteinases, lipocalin 2, and thyroid responsive protein was SIRT1-dependent. Independent validation of the proteomics dataset uncovered SIRT1-dependence of SREBF1c and PPARα signaling in adipocytes. SIRT1 promoted nicotinamide mononucleotide acetyltransferase 2 (NMNAT2) expression during 3T3-L1 differentiation and constitutively repressed NMNAT1 and 3 levels. Supplementing preadipocytes with the NAD+ booster nicotinamide mononucleotide (NMN) during differentiation increased expression levels of leptin, SIRT1, and PGC-1α and its transcriptional targets, and reduced levels of pro-fibrotic collagens (Col6A1 and Col6A3) in a SIRT1-dependent manner. Investigating the metabolic impact of the functional interaction of SIRT1 with SREBF1c and PPARα and insights into how NAD+ metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications.Based on data from national surveys, the prevalence of hypertension rests at 40-60% in Japan, the USA, and in European countries. This suggests there has been little progress in the prevention of hypertension in even high-income countries despite their well-functioning health systems. In particular, compared with the USA and European countries, the improvement in awareness, treatment, and control of hypertension has been relatively low in Japan. For example, the rates of hypertension awareness, treatment, and control were observed, respectively, in 60-70%, 50-60%, and 20-30% of Japanese compared with 80-90%, 70-80%, and 50-60% of US citizens in the years around 2015. The lower proportions in Japan might be explained by the slower progress in lowering the accepted thresholds for diagnosis of hypertension and initiation of treatment compared with Western countries; however, the underlying reasons for the differences warrant further study. The high prevalence (>40%) of uncontrolled hypertension in even high-income countries has major implications for the prevention of cardiovascular disease. Health policy and research on early control of high blood pressure at the individual and public health levels will contribute to decreases in the prevalence of hypertension. Furthermore, proactive treatment and strict adherence to intensified antihypertensive treatment guidelines will more effectively achieve targeted blood pressure levels. In this context, it is important to continue to carefully monitor and compare trends in hypertension across countries.To track blood pressure (BP) and resting heart rate (RHR) in children and adolescents is important due to its associations with cardiovascular outcomes in the adulthood. Therefore, the aim of this study was to examine BP and RHR over a decade among children and adolescents living in Germany using national examination data. Cross-sectional data from 3- to 17-year-old national survey participants (KiGGS 2003-06, n = 14,701; KiGGS 2014-17, n = 3509) including standardized oscillometric BP and RHR were used for age- and sex-standardized analysis. Measurement protocols were identical with the exception of the cuff selection rule, which was accounted for in the analyses. Different BP and RHR trends were observed according to age-groups. In 3- to 6-year-olds adjusted mean SBP and DBP were significantly higher in 2014-2017 compared to 2003-2006 (+2.4 and +1.9 mm Hg, respectively), while RHR was statistically significantly lower by -3.8 bpm. No significant changes in BP or in RHR were observed in 7- to 10-year-olds over time. In 11- to 13-year-olds as well as in 14- to 17-year-olds lower BP has been observed (SBP -2.4 and -3.2 mm Hg, respectively, and DBP -1.8 and -1.7 mm Hg), while RHR was significantly higher (+2.7 and +3.7 bpm). BP trends did not parallel RHR trends. The downward BP trend in adolescents seemed to follow decreasing adult BP trends in middle and high-income countries. The increase in BP in younger children needs confirmation from other studies as well as further investigation. In school-aged children and adolescents, the increased RHR trend may indicate decreased physical fitness.