The LC3II/LC3I ratio and Atg5 level were upregulated by cGAS overexpression. Under calcification-inducing conditions, HDAC1 deacetylates cGAS and inactivates it. HDAC1 knockdown by short hairpin HDAC1 reversed the cGAS-induced reduction in vascular calcification, as well as in autophagy.

HDAC1-induced cGAS deacetylation enhances vascular calcification and may therefore be a potential therapeutic target.

HDAC1-induced cGAS deacetylation enhances vascular calcification and may therefore be a potential therapeutic target.Should theories of “higher-level” cognitive effects originate in “lower-level” molecular mechanisms? This paper supports reductionist explanations of sensory perception via molecular mechanisms in neurobiology. It shows that molecular and cellular mechanisms must constitute the material foundation to derive better theories and models for neuroscience. In support of “bottom-up theorizing”, I explore the recent application of a new real-time molecular imaging technique (SCAPE microscopy) to mixture coding in olfaction. Seemingly emergent “higher-level” psychological effects in odor perception, irreducible to the physical stimulus, are linked back to underlying molecular mechanisms at the receptor level. The SCAPE study has notable theoretical impact. It provides a possible answer to the neurocomputational challenge in olfaction from combinatorial coding at the periphery how does the brain discriminate different complex mixtures from widespread and overlapping receptor activation? The failure of previous reductionist structure-odor explanations is shown to reside in misconceptualizations of the critical causal elements involved. Causally fundamental features are not of parts independently of a mechanism. Components and their relevant features are units via their causal role within a mechanism. Here, new technologies allow revisiting our understanding of the ontology and levels of organization of a system.Murray’s law, which states that the cube of the radius of a parent vessel equals the sum of the cubes of the radii of the daughter vessels, was originally derived by minimizing the cost of operation of blood flow in a single cylindrical tube. An alternative widely cited derivation by Sherman is based upon the optimization problem of minimizing the total flow resistance subject to a material constraint, and that study claimed that “Conservation of the sum of the cubes of the radii is the condition for minimal resistance whether the parent vessel divides symmetrically or asymmetrically, and whether it divides into two, three, four, or, presumably, any number of daughter vessels.” In this paper we show that Sherman’s analysis is flawed, since with N daughter vessels there are 2N-N-1 sets of vessel radii which satisfy Murray’s law but which do not yield minimal total flow resistance. Moreover, we show that when there are N daughter vessels, each with the same radius, the minimal total flow resistance is an increasing function of N for N⩾1. Since N=1 corresponds to the degenerate case of no branching at all, our result implies that bifurcation (N=2) achieves the minimal total flow resistance. Our analysis thus offers an explanation for the preponderance of bifurcations (as opposed to trifurcations or higher level branchings) in many biological systems.The gene mutation profiles of gastric neuroendocrine neoplasms are incompletely understood. The purpose of this study was to characterize the molecular pathology of poorly differentiated neuroendocrine carcinoma (NEC) and mixed neuroendocrine‒non-neuroendocrine neoplasm (MiNEN) of the stomach. Surgical cases of gastric NEC (n = 7) and MiNEN (n = 6) were examined by clinical review, immunohistochemistry, microsatellite instability (MSI) analysis and whole-exome sequencing. NEC cases consisted of small- (n = 2) and large-cell types (n = 4). All cases of MiNEN were histologically composed of large-cell type NEC and tubular adenocarcinoma. Whole-exome sequencing analysis detected recurrent mutations in TP53 in 8 cases (62%), and they were more frequently observed in MiNEN than in NEC (100% vs. 29%). Frameshift mutations of APC were observed in two cases of MiNEN. One case of large-cell type NEC had a frameshift mutation with loss of heterozygosity in RB1. The other mutated genes (e.g., ARID1 and KRAS) were detected in a single case each. A high level of MSI was confirmed in one case of MiNEN, which harbored mutations in two well-differentiated neuroendocrine tumor (NET)-related genes (MEN1 and ATRX1). In cases of MiNEN, two histological components shared mutations in TP53, APC and ZNF521, whereas alterations in CTNNB1, KMT2C, PTEN and SPEN were observed in neuroendocrine components only. In conclusion, TP53 is a single, frequently mutated gene in gastric NEC and MiNEN, and alterations in other genes are less common, resembling the mutation profiles of gastric adenocarcinomas. Gene mutations frequently observed in well-differentiated NET were uncommon but not entirely exclusive.Neonatal cholestatic liver disease is rarely encountered by pathologists outside of specialized pediatric centers and navigating the long list of potential diseases can be daunting. Elacestrant ic50 However, the differential diagnosis can be rapidly narrowed through open conversations between the pathologist and pediatric gastroenterologist. The dialog should ideally begin before obtaining the liver biopsy and continue through the rendering of the final pathologic diagnosis. Such dialogs are necessary to first ensure the proper handling of the precious sample and then to allow for synthesis of the clinical, laboratory, imaging, and genetic data in the context of the histologic features seen in the liver biopsy. In this review, we aim to provide a broad template on which such dialogs may be based and pitfalls that may be encountered on both the clinical and pathologic sides. This review will focus on non-biliary atresia etiologies of neonatal cholestasis, including select infectious, genetic, and metabolic entities.

The aim of the present study was to assess whether a single measurement of the digital brachial index (DBI; systolic finger pressure/systemic pressure ratio), reflecting the arm’s circulation, was associated with access patency in patients with severe chronic kidney disease scheduled for arteriovenous fistula (AVF) creation.

A bilateral DBI was obtained using digital plethysmography just before construction of the patient’s first AVF from January 2009 to December 2017 at one center. A DBI of 80% to 99% was considered normal, and a DBI of<80% (low) or DBI of ≥100% (high) were considered abnormal. DBI values ipsilateral to the AVF were used for analysis. The primary and secondary access patency rates were calculated using reported standards and compared using standard statistical techniques.

Data sets of 163 patients were obtained (69 women; age, 71± 12years). The median follow-up was 40weeks (range, 0-104weeks; follow-up index, 99%± 1%). Patients with abnormal preoperative DBI values had lower 2-year primary patency rates (low DBI, 25%± 11%; high DBI, 28%± 6%; normal DBI, 49%± 8%; P= .