Brixwatts5625

Acetyl-CoA carboxylase (ACCase) catalyzes the first committed step in de novo synthesis of fatty acids. The multisubunit ACCase in the chloroplast is activated by a shift to pH 8 upon light adaptation and is inhibited by a shift to pH 7 upon dark adaptation. Here, titrations with the purified ACCase BADC and BCCP subunits from Arabidopsis indicated that they can competently and independently bind biotin carboxylase (BC), but differ in responses to pH changes representing those in the plastid stroma during light or dark conditions. At pH 7 in phosphate buffer, BADC1 and BADC2 gain an advantage over BCCP1 and BCCP2 in affinity for BC. At pH 8 in KCl solution, however, BCCP1 and BCCP2 had more than 10-fold higher affinity for BC than did BADC1. The pH-modulated shifts in BC preferences for BCCP and BADC partners suggest they contribute to light-dependent regulation of heteromeric ACCase. Using NMR spectroscopy, we found evidence for increased intrinsic disorder of the BADC and BCCPs subunits at pH 7. We propose that this intrinsic disorder potentially promotes fast association with BC through a "fly-casting mechanism." We hypothesize that the pH effects on the BADC and BCCP subunits attenuate ACCase activity by night and enhance it by day. Consistent with this hypothesis, Arabidopsis badc1 badc3 mutant lines grown in a light-dark cycle synthesized more fatty acids in their seeds. In summary, our findings provide evidence that the BADC and BCCP subunits function as pH sensors required for light-dependent switching of heteromeric ACCase activity.Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)- EPH receptor A2 (EPHA2), EGFR-vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2-VEGFR2, EPHA2-fibroblast growth factor receptor 1 (FGFR1), EPHA2-FGFR2, EPHA2-FGFR3, VEGFR2-FGFR1, VEGFR2-FGFR2, and VEGFR2-FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are unavailable. TNBC has a high frequency of tumor protein P53 (P53) and phosphatase and tensin homolog (PTEN) deficiencies, and combined P53/PTEN deficiency is associated with poor prognosis and poor response to anticancer therapies. In this study, we discovered that combined P53/PTEN deficiency in TNBC activates expression of the transcription factor mesenchyme homeobox 1 (MEOX1). We found that MEOX1 is expressed only in TNBC deficient in P53 or PTEN and that its expression is undetectable in luminal A, luminal B, and HER2+ subtypes as well as in normal breast cells with wild type P53/PTEN. Notably, siRNA knockdown of both P53 and PTEN activated MEOX1 expression in breast cancer cells, whereas individual knockdowns of either P53 or PTEN had only minimal effects on MEOX1 expression. MEOX1 knockdown abolished cell proliferation of P53/PTEN-deficient TNBC in vitro and inhibited tumor growth in vivo, but had no effect on the proliferation of luminal and HER2+ cancer cells and of normal breast cells. RNA-Seq and immunoblotting analyses showed that the MEOX1 knockdown decreases expression of tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 5B (STAT5B), and STAT6 in P53- and PTEN-deficient TNBC cells. These results reveal the effects of combined P53/PTEN deficiency on MEOX1 expression and TNBC cell proliferation, suggesting that MEOX1 may serve as a potential therapeutic target for managing P53- and PTEN-deficient TNBC.The accumulation of amyloid Tau aggregates is implicated in Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are known to maintain protein homeostasis. Here we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro We found that this function is mediated by the core chaperone HSC70, assisted by specific co-chaperones, in particular class B J‑domain proteins and a heat shock protein 110 (Hsp110)-type nucleotide exchange factor (NEF). The Hsp70 disaggregation machinery processed recombinant fibrils assembled from all six Tau isoforms as well as sarkosyl-resistant Tau aggregates extracted from cell cultures and human AD brain tissues, demonstrating the ability of the Hsp70 machinery to recognize a broad range of Tau aggregates. However, the chaperone activity released monomeric and small oligomeric Tau species, which induced the aggregation of self-propagating Tau conformers in a Tau cell culture model. We conclude that the activity of the Hsp70 disaggregation machinery is a double-sided sword, as it eliminates Tau amyloids at the cost of generating new seeds.Graded transcription factors are pivotal regulators of embryonic patterning, but whether their role changes over time is unclear. CDK inhibitor A light-regulated protein degradation system was used to assay temporal dependence of the transcription factor Dorsal in dorsal-ventral axis patterning of Drosophila embryos. Surprisingly, the high-threshold target gene snail only requires Dorsal input early but not late when Dorsal levels peak. Instead, late snail expression can be supported by action of the Twist transcription factor, specifically, through one enhancer, sna.distal This study demonstrates that continuous input is not required for some Dorsal targets and downstream responses, such as twist, function as molecular ratchets.Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of Tgm1, Krt16, and Aqp3 In parallel, HDAC3 suppresses expression of inflammatory cytokines through a Rela-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.Introduction Microangiopathic and macroangiopathic complications are the main cause of morbidity and mortality in the diabetic population. Numerous publications have highlighted the role of glycation in the onset of complications of diabetes. In this context, the detection of fructosamine-3-kinase (FN3K)-an enzyme capable of counteracting the effect of hyperglycemia by intervening in protein glycation-has attracted great interest. Several studies have linked FN3K genetic variability to its enzymatic activity and glycated hemoglobin (HbA1c) levels. Here, we investigated the role of FN3K polymorphisms in the development of microvascular and macrovascular complications of diabetes. Research design and methods The anthropometric and biochemical parameters, and any medical history of microangiopathic and macroangiopathic complications, were documented in a sample of 80 subjects with type 2 diabetes. All subjects were screened for FN3K gene and analyzed for the combination of three polymorphisms known to be associated with its enzymatic activity (rs3859206 and rs2256339 in the promoter region and rs1056534 in exon 6). Results The combination of allelic variants of FN3K polymorphisms resulted in 13 distinct genotypic variants within the cohort. Comparison between genotypes showed no significant differences in terms of demographic, anthropometric and biochemical parameters, risk markers and long-term complications, except for a higher age and vitamin E levels associated with the genotype presenting GG at position -385, TT at position -232, and CC at c.900 A. Evaluating the microangiopathic and macroangiopathic complications as a whole, we found that they appeared significantly less present in this genotype compared with all other genotypes (p=0.0306). Conclusions The group of patients carrying the favorable allele for the three polymorphisms of the FN3K gene revealed less severe microangiopathy and macroangiopathy, suggesting a protective role of this genotype against the onset of the complications of diabetes.Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with db/db mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p less then 0.01). Quality assessment suggested that the prior research frequently lacked incorporation of key clinically relevant characteristics. This systematic review suggested that impaired wound healing can be simulated in many different mouse models of diabetes but these require further refinement to become more clinically relevant.Coronavirus disease 2019 (COVID-19) is a serious public health crisis and can have neurologic manifestations. This is a retrospective observational case series performed March 1-31, 2020, at New York University Langone Medical Center campuses. Clinical and imaging data were extracted, reviewed, and analyzed. Two hundred forty-two patients with COVID-19 underwent CT or MRI of the brain within 2 weeks after the positive result of viral testing (mean age, 68.7 ± 16.5 years; 150 men/92 women [62.0%/38.0%]). The 3 most common indications for imaging were altered mental status (42.1%), syncope/fall (32.6%), and focal neurologic deficit (12.4%). The most common imaging findings were nonspecific white matter microangiopathy (134/55.4%), chronic infarct (47/19.4%), acute or subacute ischemic infarct (13/5.4%), and acute hemorrhage (11/4.5%). No patients imaged for altered mental status demonstrated acute ischemic infarct or acute hemorrhage. White matter microangiopathy was associated with higher 2-week mortality (P less then .