The sex of organ geometry.

Organs have a distinctive yet often overlooked spatial arrangement in the body1-5. We propose that there is a logic to the shape of an organ and its proximity to its neighbours. Here, by using volumetric scans of many Drosophila melanogaster flies, we develop methods to quantify three-dimensional features of organ shape, position and interindividual variability. We find that both the shapes of organs and their relative arrangement are consistent yet differ between the sexes, and identify unexpected interorgan adjacencies and left-right organ asymmetries. Focusing on the intestine, which traverses the entire body, we investigate how sex differences in three-dimensional organ geometry arise. The configuration of the adult intestine is only partially determined by physical constraints imposed by adjacent organs; its sex-specific shape is actively maintained by mechanochemical crosstalk between gut muscles and vascular-like trachea. Indeed, sex-biased expression of a muscle-derived fibroblast growth factor-like ligand renders trachea sexually dimorphic. In turn, tracheal branches hold gut loops together into a male or female shape, with physiological consequences. Interorgan geometry represents a previously unrecognized level of biological complexity which might enable or confine communication across organs and could help explain sex or species differences in organ function.

Variational Sparse Bayesian Learning for Estimation of Gaussian Mixture Distributed Wireless Channels.

In this paper, variational sparse Bayesian learning is utilized to estimate the multipath parameters for wireless channels. Due to its flexibility to fit any probability density function (PDF), the Gaussian mixture model (GMM) is introduced to represent the complicated fading phenomena in various communication scenarios. First, the expectation-maximization (EM) algorithm is applied to the parameter initialization. Then, the variational update scheme is proposed and implemented for the channel parameters' posterior PDF approximation. Finally, in order to prevent the derived channel model from overfitting, an effective pruning criterion is designed to eliminate the virtual multipath components. The numerical results show that the proposed method outperforms the variational Bayesian scheme with Gaussian prior in terms of root mean squared error (RMSE) and selection accuracy of model order.

Structure-Based Discovery and Characterization of a Preclinical Drug Candidate for the Treatment of HIV-1 Infection.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) area key component of the current HIV-1 combination drug regimens. Although they exhibit potent anti-HIV-1 activity and modest toxicity, the emergence of mutant strains limits their application in clinical. Our previous research efforts contributed to the identification of compound K-5a2, which exhibits nanomolar activity in HIV-1-infected MT-4 cells. In this study, K-5a2 was shown to have a high level of anti-HIV-1 activity against various lab-adapted strains and clinical isolate strains, being comparable to ETR. Moreover, we showed the feasibility of K-5a2 as a preclinical anti-HIV-1 candidate by establishing its synergistic or additive anti-HIV-1 activity in combination with other representative anti-HIV-1 drugs and candidates. In addition, K-5a2 exhibited no inhibitory activity to the primary CYP isoforms and favorable pharmacokinetics. Taken together, its robust anti-HIV-1 potency, synergistic or additive effects with other anti-HIV drugs, and favorable pharmacokinetic and safety profiles make K-5a2 a potent alternative drug for HIV/AIDS treatment.

Ligustrazine Suppresses Platelet-Derived Growth Factor-BB-Induced Pulmonary Artery Smooth Muscle Cell Proliferation and Inflammation by Regulating the PI3K/AKT Signaling Pathway.

Pulmonary arterial hypertension (PAH) is a serious pulmonary vascular disease. Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role in the course of this disease. Ligustrazine is an alkaloid monomer extracted from the rhizome of the herb Ligusticum chuanxiong. It is often used to treat cardiovascular diseases, but its effect on PAH has rarely been reported. This study aims to explore the protective effect and mechanism of ligustrazine on PAH. In the in vivo experiment, monocrotaline (MCT) was used to induce PAH in rats, and then ligustrazine (40, 80, 160 mg/kg/day) or sildenafil (25 mg/kg/day) was administered. Four weeks later, hemodynamic changes, right ventricular hypertrophy index, lung morphological characteristics, inflammatory factors, phosphoinositide 3-kinase (PI3K), and AKT expression were evaluated. In addition, primary rat PASMCs were extracted by the tissue adhesion method, a proliferation model was established with platelet-derived growth factor-BB (PDGF-BB), and the cells were treated with ligustrazine to investigate its effects on cell proliferation, inflammation, and cell cycle distribution. The results indicate that ligustrazine can markedly alleviate right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling, and inflammation caused by MCT, and that it decreased PI3K and AKT phosphorylation expression. Moreover, ligustrazine can inhibit the proliferation and inflammation of PASMCs and arrest the progression of G0/G1 to S phase through the PI3K/AKT signaling pathway. Therefore, we conclude that ligustrazine may inhibit the proliferation and inflammation of PASMCs by regulating the activation of the PI3K/AKT signaling pathway, thereby attenuating MCT-induced PAH in rats. Collectively, these findings suggest that ligustrazine may be a promising therapeutic for PAH.

Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load.

Hepatolenticular degeneration (HLD) is an autosomal recessive genetic disease caused by the toxic accumulation of copper in the liver. Excessive copper will disrupt the redox balance in cells and tissues, causing ischemia, hypoxia, and inflammation. Acid-sensitive ion channel 1a is a cationic channel activated by extracellular acid and allowing Ca2+ and Na+ to flow into cells. Its expression appears in inflammation, arthritis, fibrotic tissue, and damaged environment, but its role in hepatolenticular degeneration has not been studied. This study established a Wistar rat model of high copper accumulation and used CuSO4 to induce the activation of HSC-T6 in an in vitro experiment. In vivo, Wistar rats were examined to determine the serum copper concentration, serum ALT and AST activities, and liver copper accumulation, and liver tissue HE staining and immunohistochemical analyses were conducted. The expression of ASIC1a, α-SMA, Collagen-Ι, GRP78, XBP1, ATP7B, and CCS were detected. Besides, immunofluorescence technology can detect the expression of the phosphorylated protein in vitro. It is suggested that ASIC1a is involved in the quality control of the endoplasmic reticulum, which degrades mutant ATP7B and increases the accumulation of copper. After blocking or silencing the expression of ASIC1a, ELISA can detect the level of inflammatory factors, the expression of endoplasmic reticulum stress-related factors, and ATP7B was improved in a higher copper environment reduction of copper deposition was observed in liver Timm's staining. Collectively, we conclude that ASIC1a is involved in the HSC activation induced by copper accumulation and promotes the occurrence of hepatolenticular fibrosis.

ASIC1a inhibits cell pyroptosis induced by acid-induced activation of rat hepatic stellate cells.

The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis-associated speck-like protein, gasdermin D, caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor 3, and apoptosis-associated speck-like protein (ASC) decreased, while the level of α-smooth muscle actin and collagen-I increased upon introduction of ASIC1a into an acid-induced model. Inhibition or silencing of ASIC1a and the use of Ca2+ -free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis.

Synthesis and crystal structure of 6-fluoro-3-hydroxypyrazine-2-carboxamide.

As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O-H(•••)O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions.