Whole-genome sequencing of allotetraploid bermudagrass reveals the origin of Cynodon and candidate genes for salt tolerance.

Bermudagrass (Cynodon dactylon) is a globally distributed, extensively used warm-season turf and forage grass with high tolerance to salinity and drought stress in alkaline environments. However, the origin of the species and genetic mechanisms for salinity tolerance in the species are basically unknown. Accordingly, we set out to study evolution divergence events in the Cynodon genome and to identify genes for salinity tolerance. We developed a 604.0 Mb chromosome-level polyploid genome sequence for bermudagrass 'A12359' (n = 18). The C. dactylon genome comprises 2 complete sets of homoeologous chromosomes, each with approximately 30 000 genes, and most genes are conserved as syntenic pairs. Phylogenetic study showed that the initial Cynodon species diverged from Oropetium thomaeum approximately 19.7-25.4 million years ago (Mya), the A and B subgenomes of C. dactylon diverged approximately 6.3-9.1 Mya, and the bermudagrass polyploidization event occurred 1.5 Mya on the African continent. Moreover, we identified 82 candidate genes associated with seven agronomic traits using a genome-wide association study, and three single-nucleotide polymorphisms were strongly associated with three salt resistance genes: RAP2-2, CNG channels, and F14D7.1. These genes may be associated with enhanced bermudagrass salt tolerance. These bermudagrass genomic resources, when integrated, may provide fundamental insights into evolution of diploid and tetraploid genomes and enhance the efficacy of comparative genomics in studying salt tolerance in Cynodon.

fastCCLasso: a fast and efficient algorithm for estimating correlation matrix from compositional data.

MOTIVATION: The composition and structure of microbial communities on the body surface are closely related to human health. The interaction relationship among microbes can help us understand the formation of the microecological environment and the biological mechanism by which microorganisms influence host health. With the help of high-throughput sequencing technologies, microbial abundances in a natural environment can be directly measured without the isolation of microorganisms in culture. Sequencing experiments in microbiome studies can measure the relative abundance of microbes, which is called compositional data. Although there are already many methods for correlation analysis for compositional data, the computation time or accuracy still needs to be improved for current microbiome studies. RESULTS: We develop a fast and efficient algorithm, called fastCCLasso, based on a penalized weighted least squares for inferring the correlation structure of microbes from compositional data in microbiome studies. We perform a large number of numerical experiments and the simulation results show that fastCCLasso outperforms its competitors in edge detection for inferring the correlation network. We also apply fastCCLasso for estimating microbial networks in microbiome studies and fastCCLasso provides a conservative network with comparable false discovery counts that are derived from shuffled data. AVAILABILITY AND IMPLEMENTATION: FastCCLasso is open source and freely available from https://github.com/ShenZhang-Statistics/fastCCLasso under GNU LGPL v3.

Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine abstinence mice.

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.

Multipiezo Effect in Altermagnetic V2SeTeO Monolayer.

Strain engineering has been used as an efficient method to modulate various properties of quantum materials and electronic devices. One may establish piezo effects based on a disciplined response to the strain in multifunctional nanosystems. Inspired by a recent theoretical proposal on the interesting piezomagnetism and C-paired valley polarization in the V2Se2O monolayer, we predict a stable altermagnetic Janus monolayer V2SeTeO using density functional theory calculations. It exhibits a novel "multipiezo" effect combining piezoelectricity, piezovalley, and piezomagnetism. Most interestingly, the valley polarization and the net magnetization under strain in V2SeTeO exceed these in V2Se2O, along with the additional large piezoelectric coefficient. The "multipiezo" effect makes Janus monolayer V2SeTeO as a tantalizing material for potential applications in nanoelectronics, optoelectronics, spintronics, and valleytronics.

Layer-Number-Dependent Magnetism in the Co-Doped van der Waals Ferromagnet Fe3GaTe2.

Recently, van der Waals (vdW) antiferromagnets have been proposed to be crucial for spintronics due to their favorable properties compared to ferromagnets, including robustness against magnetic perturbation and high frequencies of spin dynamics. High-performance and energy-efficient spin functionalities often depend on the current-driven manipulation and detection of spin states, highlighting the significance of two-dimensional metallic antiferromagnets, which have not been much explored due to the lack of suitable materials. Here, we report a new metallic vdW antiferromagnet obtained from the ferromagnet Fe3GaTe2 by cobalt (Co) doping. Through the layer-number-dependent Hall resistance and magnetoresistance measurements, an evident odd-even layer-number effect has been observed in its few-layered flakes, suggesting that it could host an A-type antiferromagnetic structure. This peculiar layer-number-dependent magnetism in Co-doped Fe3GaTe2 helps unravel the complex magnetic structures in such doped vdW magnets, and our finding will enrich material candidates and spin functionalities for spintronic applications.

Room-Temperature Highly Efficient Nonvolatile Magnetization Switching by Current in van der Waals Fe3GaTe2 Devices.

The ability to manipulate magnetic states by a low electric current represents a fundamental desire in spintronics. In recent years, two-dimensional van der Waals (vdW) magnetic materials have attracted an extensive amount of attention due to their appreciable spin-orbit torque effect. However, for most known vdW ferromagnets, their relatively low Curie temperatures (TC) limit their applications. Consequently, low-power vdW spintronic devices that can operate at room temperature are in great demand. In this research, we fabricate nanodevices based on a solitary thin flake of vdW ferromagnet Fe3GaTe2, in which we successfully achieve nonvolatile and highly efficient magnetization switching by small currents at room temperature. Notably, the switching current density and the switching power dissipation are as low as 1.7 × 105 A/cm2 and 1.6 × 1013 W/m3, respectively, with an external magnetic field of 80 Oe; both are much reduced compared to those of conventional magnet/heavy metal heterostructure devices and other vdW devices.

Tunable Magnetism in Atomically Thin Itinerant Antiferromagnet with Room-Temperature Ferromagnetic Order.

Addressing the need for modulated spin configurations is crucial, as they serve as the foundational building blocks for next-generation spintronics, particularly in atomically thin structures and at room temperature. In this work, we realize intrinsic ferromagnetism in monolayer flakes and tunable ferro-/antiferromagnetism in (Fe0.56Co0.44)5GeTe2 antiferromagnets. Remarkably, the ferromagnetic ordering (≥1 L) and antiferromagnetic ordering (≥4 L) remain discernible up to room temperature. The TC (∼310 K) of the monolayer flakes sets a record high for known exfoliated monolayer van der Waals magnets. Within the framework of A-type antiferromagnetism, a notable odd-even layer-number effect at elevated temperatures (T = 150 K) is observed. Of particular interest is the strong ferromagnetic order in even-layer flakes at low temperatures. The intricate interplay among magnetic field strength, layer number, and temperature gives rise to a diverse array of phenomena, holding promise not only for new physics but also for practical applications.

SEPHS1 attenuates intervertebral disc degeneration by delaying nucleus pulposus cell senescence through the Hippo-Yap/Taz pathway.

Nucleus pulposus cell (NPC) senescence is a major cause of intervertebral disc degeneration (IVDD). Oxidative stress and reactive oxygen species (ROS) play critical roles in regulating cell senescence. Selenophosphate synthetase 1 (SEPHS1) was reported to play an important role in mitigating oxidative stress in an osteoarthritis (OA) model by reducing the production of ROS, thereby, delaying the occurrence and development of osteoarthritis. In this study, we explored the, hitherto unknown, role of SEPHS1 in IVDD in vitro and in vivo using an interleukin-1ß (IL-1ß)-induced NPC senescence model and a rat needle puncture IVDD model, respectively. SEPHS1 delayed NPC senescence in vitro by reducing ROS production. Age-related dysfunction was also ameliorated by the overexpression of SEPHS1 and inhibition of the Hippo-Yap/Taz signaling pathway. In vivo experiments revealed that the overexpression of SEPHS1 and inhibition of Hippo-Yap/Taz alleviated IVDD in rats. Moreover, a selenium (Se)-deficient diet and lack of SEPHS1 synergistically aggravated IVDD progression. Taken together, our results demonstrate that SEPHS1 plays a significant role in NPC senescence. Overexpression of SEPHS1 and inhibition of Hippo-Yap/Taz can delay NPC senescence, restore the balance of extracellular matrix metabolism, and attenuate IVDD. SEPHS1 could be a promising therapeutic target for IVDD.NEW & NOTEWORTHY Selenophosphate synthetase 1 (SEPHS1) deficiency leads to an increase in reactive oxygen species levels and in the subsequent activation of the Hippo-Yap/Taz signaling pathway. In the rat model of intervertebral disc degeneration (IVDD), overexpression of SEPHS1 and inhibition of Hippo-YAP/Taz mitigated the progression of disc degeneration indicating the involvement of SEPHS1 in IVDD. SEPHS1 is a promising therapeutic target for IVDD.

Comparative proteomics in tall fescue to reveal underlying mechanisms for improving Photosystem II thermotolerance during heat stress memory.

BACKGROUND: The escalating impacts of global warming intensify the detrimental effects of heat stress on crop growth and yield. Among the earliest and most vulnerable sites of damage is Photosystem II (PSII). Plants exposed to recurring high temperatures develop heat stress memory, a phenomenon that enables them to retain information from previous stress events to better cope with subsequent one. Understanding the components and regulatory networks associated with heat stress memory is crucial for the development of heat-resistant crops. RESULTS: Physiological assays revealed that heat priming (HP) enabled tall fescue to possess higher Photosystem II photochemical activity when subjected to trigger stress. To investigate the underlying mechanisms of heat stress memory, we performed comparative proteomic analyses on tall fescue leaves at S0 (control), R4 (primed), and S5 (triggering), using an integrated approach of Tandem Mass Tag (TMT) labeling and Liquid Chromatography-Mass Spectrometry. A total of 3,851 proteins were detected, with quantitative information available for 3,835 proteins. Among these, we identified 1,423 differentially abundant proteins (DAPs), including 526 proteins that were classified as Heat Stress Memory Proteins (HSMPs). GO and KEGG enrichment analyses revealed that the HSMPs were primarily associated with the "autophagy" in R4 and with "PSII repair", "HSP binding", and "peptidase activity" in S5. Notably, we identified 7 chloroplast-localized HSMPs (HSP21, DJC77, EGY3, LHCA4, LQY1, PSBR and DEGP8, R4/S0 > 1.2, S5/S0 > 1.2), which were considered to be effectors linked to PSII heat stress memory, predominantly in cluster 4. Protein-protein interaction (PPI) analysis indicated that the ubiquitin-proteasome system, with key nodes at UPL3, RAD23b, and UCH3, might play a role in the selective retention of memory effectors in the R4 stage. Furthermore, we conducted RT-qPCR validation on 12 genes, and the results showed that in comparison to the S5 stage, the R4 stage exhibited reduced consistency between transcript and protein levels, providing additional evidence for post-transcriptional regulation in R4. CONCLUSIONS: These findings provide valuable insights into the establishment of heat stress memory under recurring high-temperature episodes and offer a conceptual framework for breeding thermotolerant crops with improved PSII functionality.

DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma.

BACKGROUND: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. METHODS: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. RESULTS: We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3ß collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. CONCLUSIONS: Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.

Isolation and characterization of a novel rodent hepevirus in long-tailed dwarf hamsters (Cricetulus longicaudatus) in China.

Hepeviruses have been identified in a broad range of animal hosts, including mammals, birds, and fish. In this study, rodents (n=91) from seven different species and ten pikas (Ochotona curzoniae) were collected in Qinghai Province, China. Using transcriptomic sequencing and confirmatory molecular testing, hepeviruses were detected in 27 of 45 (60 %) long-tailed dwarf hamsters (Cricetulus longicaudatus) and were undetected in other rodents and pika. The complete genome sequences from 14 representative strains were subsequently obtained, and phylogenetic analyses suggested that they represent a novel species within the genus Rocahepevirus, which we tentatively designated as Cl-2018QH. The virus was successfully isolated in human hepatoma (Huh-7) and murine fibroblast (17 Cl-1) cell lines, though both exhibited limited replication as assayed by detection of negative-sense RNA intermediates. A129 immunodeficient mice were inoculated with Cl-2018QH and the virus was consistently detected in multiple organs, despite relatively low viral loads. In summary, this study has described a novel rodent hepevirus, which enhances our knowledge of the genetic diversity of rodent hepeviruses and highlights its potential for cross-species transmission.

Fast-Responsive HClO-Activated Near-Infrared Fluorescent Probe for In Vivo Diagnosis of Inflammatory Bowel Disease and Ex Vivo Optical Fecal Analysis.

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease, whose etiology is intimately related to the overproduction of hypochlorous acid (HClO). Optical monitoring of HClO in the living body favors real-time diagnosis of inflammatory diseases. However, HClO-activated near-infrared (NIR) fluorescent probes with rapid response and high inflammatory cell uptake are still lacking. Herein, we report an activatable acceptor-π-acceptor (A-π-A)-type NIR fluorescent probe (Cy-DM) bearing two d-mannosamine groups for the sensitive detection of HClO in early IBD and stool testing. Once reacted with HClO, nonfluorescent Cy-DM could be turned on within 2 s by generating a donor-π-acceptor (D-π-A) structure due to the enhanced intramolecular charge transfer mechanism, showing intense NIR fluorescence emission at 700 nm and a large Stokes shift of 115 nm. Moreover, it was able to sensitively and selectively image exogenous and endogenous HClO in the lysosomes of living cells with a detection limit of 0.84 µM. More importantly, because of the d-mannosamine modification, Cy-DM was efficiently taken up by inflammatory cells in the intestine after intravenous administration, allowing noninvasive visualization of endogenous HClO in a lipopolysaccharide-induced IBD mouse model with a high fluorescence contrast of 6.8/1. In addition, water-soluble Cy-DM has also been successfully applied in ex vivo optical fecal analysis, exhibiting a 3.4-fold higher fluorescence intensity in the feces excreted by IBD mice. We believe that Cy-DM is promising as an invaluable tool for rapid diagnosis of HClO-related diseases as well as stool testing.

Anion Structure Regulation of Cobalt Silicate Hydroxide Endowing Boosted Oxygen Evolution Reaction.

Transition metal silicates (TMSs) are attempted for the electrocatalyst of oxygen evolution reaction (OER) due to their special layered structure in recent years. However, defects such as low theoretical activity and conductivity limit their application. Researchers always prefer to composite TMSs with other functional materials to make up for their deficiency, but rarely focus on the effect of intrinsic structure adjustment on their catalytic activity, especially anion structure regulation. Herein, applying the method of interference hydrolysis and vacancy reserve, new silicate vacancies (anionic regulation) are introduced in cobalt silicate hydroxide (CoSi), named SV-CoSi, to enlarge the number and enhance the activity of catalytic sites. The overpotential of SV-CoSi declines to 301 mV at 10 mA cm-2 compared to 438 mV of CoSi. Source of such improvement is verified to be not only the increase of active sites, but also the positive effect on the intrinsic activity due to the enhancement of cobalt-oxygen covalence with the variation of anion structure by density functional theory (DFT) method. This work demonstrates that the feasible intrinsic anion structure regulation can improve OER performance of TMSs and provides an effective idea for the development of non-noble metal catalyst for OER.

Van der Waals Transition Metal Carbo-Chalcogenides: Theoretical Screening and Charge Storage.

High-rate lithium/sodium ion batteries or capacitors are the most promising functional units to achieve fast energy storage that highly depends on charge host materials. Host materials with lamellar structures are a good choice for hybrid charge storage hosts (capacitor or redox type). Emerging layered transition metal carbo-chalcogenides (TMCC) with homogeneous sulfur termination are especially attractive for charge storage. Using density functional theory calculations, six of 30 potential TMCC are screened to be stable, metallic, anisotropic in electronic conduction and mechanical properties due to the lamellar structures. Raman, infrared active modes and frequencies of the six TMCC are well assigned. Interlayer coupling, especially binding energies predict that the bulk layered materials can be easily exfoliated into 2D monolayers. Moreover, Ti2S2C, Zr2S2C are identified as the most gifted Li+/Na+ anode materials with relatively high capacities, moderate volume expansion, relatively low Li+/Na+ migration barriers for batteries or ion-hybrid capacitors. This work provides a foundation for rational materials design, synthesis, and identification of the emerging 2D family of TMCC.

Piezocatalysis for Chemical-Mechanical Polishing of SiC: Dual Roles of t-BaTiO3 as a Piezocatalyst and an Abrasive.

Chemical mechanical polishing (CMP) offers a promising pathway to smooth third-generation semiconductors. However, it is still a challenge to reduce the use of additional oxidants or/and energy in current CMP processes. Here, a new and green atomically smoothing method: Piezocatalytic-CMP (Piezo-CMP) is reported. Investigation shows that the Piezo-CMP based on tetragonal BaTiO3 (t-BT) can polish the rough surface of a reaction sintering SiC (RS-SiC) to the ultra-smooth surface with an average surface roughness (Ra) of 0.45 nm and the rough surface of a single-crystal 4H-SiC to the atomic planarization Si and C surfaces with Ra of 0.120 and 0.157 nm, respectively. In these processes, t-BT plays a dual role of piezocatalyst and abrasive. That is, it piezo-catalytically generates in-situ active oxygen species to selectively oxidize protruding sites of SiC surface, yielding soft SiO2, and subsequently, it acts as a usual abrasive to mechanically remove these SiO2. This mechanism is further confirmed by density functional theory (DFT) calculation and molecular simulation. In this process, piezocatalytic oxidation is driven only by the original pressure and friction force of a conventional polishing process, thus, the piezo-CMP process do not require any additional oxidant and energy, being a green and effective polishing method.

Analysis of bistatic multiphoton quantum radar cross section for the cylindrical surface.

A closed-form model of bistatic multiphoton quantum radar cross section (QRCS) for the cylindrical surface, the main structure of typical aircraft, especially missiles, is established to analyze the system and scattering characteristics. The influence of curvature of the three-dimensional target on QRCS is analyzed. By comparing and analyzing the bistatic multiphoton QRCS for a cylinder and a rectangular plate, we find that the QRCS for the convex surface target is the extension of the QRCS for the planar target with inhomogeneous atomic arrangement intervals and patterns. The characteristics of cylindrical QRCS are discussed by combining the transceiver system and the photon number of the transmitted signal, and the influences of the cylindrical radius, cylindrical length, and incident photon number on QRCS are analyzed. The bistatic results provide guidance on potential strong scattering directions for the target under various directions of photon incidence. Compared with the plane target, the cylindrical target amplifies scattering intensity near the target surface at the scattering angle side in the bistatic system. A bistatic multiphoton quantum radar system can achieve sharpening and amplification of the main lobe of the QRCS for a cylinder in an extensive scattering angle range. Bistatic multiphoton quantum radar has better visibility for the cylinder with a smaller length. These characteristics will provide prior information for research in many fields, such as photonic technology, radar technology, and precision metrology.

Myricetin ameliorates polycystic ovary syndrome in mice by brown adipose tissue activation.

In brief: Brown adipose tissue impaired in polycystic ovary syndrome (PCOS) plays a crucial role in the treatment of PCOS. This study shows that myricetin potently improves PCOS by activating brown adipose tissue (BAT). Abstract: PCOS is a complex endocrine disease characterized by hyperandrogenism, anovulation and polycystic ovary, and is often accompanied by metabolic disorder such as insulin resistance. BAT has been considered as a promising target for the treatment of obesity and other metabolic disease. In this study, we showed that 3 weeks of myricetin (a compound from natural product) treatment improved metabolic capacity and insulin sensitivity by activating BAT in dehydroepiandrosterone (DHEA)-induced PCOS mice. Furthermore, increased number of corpus luteum and decreased cystic formation were observed in PCOS mice. With the hormone levels such as luteinizing hormone (LH) were reversed, estrous cycle was also normalized after myricetin treatment. Eventually, myricetin markedly improved reproductive defects in PCOS mice. In short, our results suggest that myricetin treatment dramatically ameliorates ovarian dysfunction and metabolic disturbances in PCOS and provides a novel perspective for the treatment of PCOS.

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

Simultaneous variable selection and estimation in semiparametric regression of mixed panel count data.

Mixed panel count data represent a common complex data structure in longitudinal survey studies. A major challenge in analyzing such data is variable selection and estimation while efficiently incorporating both the panel count and panel binary data components. Analyses in the medical literature have often ignored the panel binary component and treated it as missing with the unknown panel counts, while obviously such a simplification does not effectively utilize the original data information. In this research, we put forward a penalized likelihood variable selection and estimation procedure under the proportional mean model. A computationally efficient EM algorithm is developed that ensures sparse estimation for variable selection, and the resulting estimator is shown to have the desirable oracle property. Simulation studies assessed and confirmed the good finite-sample properties of the proposed method, and the method is applied to analyze a motivating dataset from the Health and Retirement Study.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.