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Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease and Parkinson’s disease. Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.

Selective hydrogenation of nitroarenes to produce functionalized anilines is highly important to synthesize fine and bulk chemicals, but it remains challenging to achieve high selectivity at room temperature. Here, we report that a steric-confinement Rh dual atom catalyst is constructed by anchoring dual Rh atoms on the edge Mo vacancies of thin-layered MoS2nanosheets (Rh2/MoS2dual atom catalyst), which shows excellent catalytic conversion (100%) and selectivity (100%) for the selective hydrogenation of a family of nitroarene derivatives to functionalized anilines at room temperature. Extensive experimental characterizations and theoretical calculations indicate that the steric-confinement Rh2atoms, maintaining an exact metal–metal separation of 3.5 Å, facilitate spatially matched adsorption of the nitro group through a bidentate configuration. This significantly enhances the reactivity of nitro groups and drives the selective synthesis of functionalized anilines. The approach of employing bimetallic atoms to construct edge-confined active sites, as reported in this study, paves the way to develop highly selective catalysts for the targeted hydrogenation of nitroarenes.

AbstractThe effective components and key targets of Shan Zhuyu (Cornus officinalis Sieb.et Zucc, SZY)-ShanYao (Dioscorea opposita Thunb, SY) (SS) in the treatment of Alzheimer’s disease (AD, neurodegenerative disease) were screened by network pharmacology (NP) and molecular docking (MD) technology in this study. We obtained 25 potential bioactive ingredients, 88 putative targets of SS and 4893 related-AD targets. Traditional Chinese Medicine of SS has 77 common targets with AD disease.The network of drug-disease was fabricated 7 key pharmacodynamic components. Interaction network construction and topological analysis yielded, 8 anti-AD targets of SS were filtered. MD investigations showed that bioactive compounds (Hydroxygenkwanin and hancinone C) could stably bind to the key target proteins. 13 pathways related to AD were revealed signaling pathway and functional enrichment analysis. Among them, identified a statistically high significance of the calcium signaling pathway and a variety of calcium channels have been shown to be altered in AD. Our studies confirmed multiple active ingredients, potential targets about pathways of SS, by regulating the active components combined with relevant target proteins in the calcium signaling pathway, which are crucial in the accumulation of neurofbrillary tangles (NFTs) and amyloid-β (Aβ) plaques. Thereby, this furnishes a robust foundation for subsequent experimental studies.

The Ni-coated carbon nanotubes (Ni@CNT) composite was synthesized by the facile “filtration + calcination” of Ni-based metal−organic framework (MOF) precursor and the obtained composite was used as a catalyst for MgH2. MgH2was mixed evenly with different amounts of Ni@CNT (2.5, 5.0 and 7.5, wt.%) through ball milling. The MgH2−5wt.%Ni@CNT can absorb 5.2 wt.% H2at 423 K in 200 s and release about 3.75 wt.% H2at 573 K in 1000 s. And its dehydrogenation and rehydrogenation activation energies are reduced to 87.63 and 45.28 kJ/mol (H2). The in-situ generated Mg2Ni/Mg2NiH4exhibits a good catalytic effect due to the provided more diffusion channels that can be used as “hydrogen pump”. And the presence of carbon nanotubes improves the properties of MgH2to some extent.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109L−1as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

As the most natural and convenient way to communicate with people, speech is always preferred in Human-Computer Interactions. However, voice-based interaction still has several limitations. It raises privacy concerns in some circumstances and the accuracy severely degrades in noisy environments. To address these limitations, silent speech recognition (SSR) has been proposed, which leverages the inaudible information (e.g., lip movements and throat vibration) to recognize the speech. In this paper, we present EarSSR, an earphone-based silent speech recognition system to enable interaction without a need of vocalization. The key insight is that when people are speaking, their ear canals exhibit unique deformation patterns and the corresponding deformation patterns are related to words/letters even without any vocalization. We utilize the built-in microphone and speaker of an earphone to capture the ear canal deformation. Ultrasound signals are emitted and the reflected signals are analyzed to extract the signal features corresponding to speech-induced ear canal deformation for silent speech recognition. We design a two-channel hierarchical convolutional neural network to achieve fine-grained letter/word recognition. Our extensive experiments show that EarSSR can achieve an accuracy of 82% for single alphabetic letter recognition and an accuracy of 93% for word recognition.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg−1·d−1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Pancreatic ductal adenocarcinoma (PDAC) has become a significant health concern with increasing incidence and mortality rates over the past few decades. Researchers have turned their attention to cutting-edge mass spectrometry (MS) technology due to its high-throughput and accurate detection capacity, which plays a vital role in understanding the mechanisms and discovering biomarkers for pancreatic diseases. In this review, we comprehensively investigate various methodologies of quantitative and qualitative proteomics MS technologies, alongside bioinformatical platforms employed in pancreatic cancer research. The integration of these optimized approaches provides novel insights into the molecular mechanisms underlying tumorigenesis and disease progression, ultimately facilitating the discovery of potential diagnostic, prognostic biomarkers, and therapeutic targets. The robust MS-based strategy shows promise in paving the way for early diagnosis and personalized medicine for pancreatic cancer patients.

Enhancing photosynthetic efficiency is a major goal for improving crop yields under agricultural field conditions and is associated with chloroplast biosynthesis and development. In this study, we demonstrate that Golden2-like 1a (BnGLK1a) plays an important role in regulating chloroplast development and photosynthetic efficiency. Overexpressing BnGLK1a resulted in significant increases in chlorophyll content, the number of thylakoid membrane layers and photosynthetic efficiency in Brassica napus, while knocking down BnGLK1a transcript levels through RNA interference (RNAi) had the opposite effects. A yeast two-hybrid screen revealed that BnGLK1a interacts with the abscisic acid receptor PYRABACTIN RESISTANCE 1-LIKE 1–2 (BnPYL1–2) and CONSTITUTIVE PHOTOMORPHOGENIC 9 SIGNALOSOME 5A subunit (BnCSN5A), which play essential roles in regulating chloroplast development and photosynthesis. Consistent with this, BnGLK1a-RNAi lines of B. napusdisplay hypersensitivity to the abscisic acid (ABA) response. Importantly, overexpression of BnGLK1a resulted in a 10% increase in thousand-seed weight, whereas seeds from BnGLK1a-RNAi lines were 16% lighter than wild type. We propose that BnGLK1a could be a potential target in breeding for improving rapeseed productivity. Our results not only provide insights into the mechanisms of BnGLK1a function, but also offer a potential approach for improving the productivity of Brassicaspecies.

The effects of food on the pharmacokinetics (PKs) and safety of 10‐mg rivaroxaban tablets in healthy Chinese subjects were investigated from 1 bioequivalence trial. The bioequivalence trial was designed as randomized, open‐label, 2‐sequence, 4‐period crossover under both fasted and fed conditions. A total of 56 healthy subjects were enrolled, 62.5% were male. These subjects received a single oral 10‐mg dose of rivaroxaban with a 7‐day washout between 4 periods. Serial PK samples were collected and plasma concentrations were analyzed using validated high‐performance liquid chromatography–mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. The BE module of WinNonLin was used for statistical analysis of the maximum concentration (Cmax), the area under the concentration–time curve from zero to the final measurable concentration (AUC0‐t), and the area under the concentration–time curve from time zero to infinity (AUC0‐∞) of rivaroxaban in plasma. Compared with the fasted state, the Cmax, AUC0‐t, and AUC0‐∞of rivaroxaban significantly increased by 47%, 28%, and 26%, respectively, with oral administration of rivaroxaban 10 mg in the fed state. The incidence of adverse events (AEs) was similar between the fasted and fed states, and no serious AEs were observed. Food significantly increased the exposure to rivaroxaban 10 mg in Chinese subjects.

The level of sulfur dioxide (SO2) and viscosity in mitochondria play vital roles in various physiological and pathological processes. Abnormalities in mitochondrial SO2and viscosity are closely associated with numerous biological diseases. It is of great significance to develop novel fluorescence probes for simultaneous detection of SO2and viscosity within mitochondria. Herein, we have developed a water-soluble, mitochondrial-targeted and near-infrared fluorescent probe, CMBT, for the simultaneous detection of SO2and viscosity. The probe CMBTincorporates benzothiazolium salt as a mitochondrial targeting moiety and 7-diethylaminocoumarin as a rotor for viscosity detection, respectively. Based on the prompt reaction between nucleophilic HSO3−/SO32−and the backbone of the benzothiazolium salt derivative, probe CMBTdisplayed high sensitivity and selectivity toward SO2with a limit of detection as low as 0.17 μM. As viscosity increased, the twisted intramolecular charge transfer (TICT) process was restricted, resulting in fluorescence emission enhancement at 690 nm. Moreover, probe CMBTdemonstrated exceptional mitochondrial targeting ability and was successfully employed to image variations of SO2and viscosity in living cells and mice. The work highlights the great potential of the probe as a convenient tool for revealing the relationship between SO2and viscosity in biological systems.

MgH2is considered as a promising hydrogen storage material for its high hydrogen storage capacity, low cost and abundant resource advantages. However, the low kinetics and high enthalpy formation of MgH2limit its wide application. From the perspective of adding catalysts to enhance the hydrogen storage properties of Mg-MgH2, this article elaborated the main catalysts based on Ti and Nb transition elements, including single oxide catalysts, binary oxides catalysts (combined with Ni, Na, Sr, V, etc.), multiple catalysts bound to carbon, and composite catalysts with Ti and Nb elements combined with MXene phase. Moreover, the main pathways of various catalysts to reduce the reaction activity and broaden the hydrogen desorption channel were also analyzed. The Ti-based catalysts can enhance the reactive sites of the matrix by forming multivalent states, while Nb-based catalysts broaden the hydrogen reaction channels by forming tiny Nb. By improving the size structure and enhancing the grain size stability, combined with carbon materials should be the future considerations.

Halide perovskites have shown great potential for X-ray detection in medical imaging and product inspection applications. However, the ion migration in perovskites causes large noise and baseline drift, deteriorating the X-ray detection and imaging performance. Here we adopt the atmosphere-controlled edge-defined film-fed growth (EFG) method to grow high-quality shape-controlled CsPbBr3single crystals (SCs) in an Ar and HBr mixed atmosphere. Compared with the vertical Bridgman (VB)-CsPbBr3SCs, the EFG-CsPbBr3SCs show a much lower trap density, a higher resistivity (1.61 × 1010Ω cm) and a larger ion migration activation energy (0.378 eV), decreasing the leakage current and baseline drift. An X-ray detector based on EFG-CsPbBr3SCs hence exhibits outstanding balanced performance, with a negligible dark-current drift of 1.68 × 10−9μA cm−1s−1V−1, an incredibly low detection limit of 10.81 nGyairs−1and a sensitivity of 46,180 μC Gyair−1cm−2under a high electric field of 5,000 V cm−1. Furthermore, the detector maintains a stable response for 30 days. Our work provides an effective strategy to improve lead-halide perovskite SCs for high-performance X-ray detection and imaging.

Type 2 diabetes mellitus (T2DM) patients exhibit greater susceptibility to vascular calcification (VC), which has a higher risk of death and disability. However, there is no specific drug for VC therapy. NLRP3 inflammasome activation as a hallmark event of medial calcification leads to arterial stiffness, causing vasoconstrictive dysfunction in T2DM. Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), restrains hyperglycemia with definite cardiovascular benefits. Given the anti-inflammatory activity of EMPA, herein we investigated whether EMPA protected against VC in the aorta of T2DM mice by inhibiting NLRP3 inflammasome activation. Since db/dbmice receiving a normal diet developed VC at the age of about 20 weeks, we administered EMPA (5, 10, 20 mg·kg−1·d−1, i.g) to 8 week-old db/dbmice for 12 weeks. We showed that EMPA intervention dose-dependently ameliorated the calcium deposition, accompanied by reduced expression of RUNX2 and BMP2 proteins in the aortas. We found that EMPA (10 mg·kg−1·d−1for 6 weeks) also protected against VC in vitamin D3-overloaded mice, suggesting the protective effects independent of metabolism. We showed that EMPA (10 mg·kg−1·d−1) inhibited the abnormal activation of NLRP3 inflammasome in aortic smooth muscle layer of db/dbmice. Knockout (KO) of NLRP3 significantly alleviated VC in STZ-induced diabetic mice. The protective effects of EMPA were verified in high glucose (HG)-treated mouse aortic smooth muscle cells (MOVASs). In HG-treated NLRP3 KO MOVASs, EMPA (1 μM) did not cause further improvement. Bioinformatics and Western blot analysis revealed that EMPA significantly increased the expression levels of basic helix-loop-helix family transcription factor e40 (Bhlhe40) in HG-treated MOVASs, which served as a negative transcription factor directly binding to the promotor of Nlrp3. We conclude that EMPA ameliorates VC by inhibiting Bhlhe40-dpendent NLRP3 inflammasome activation. These results might provide potential significance for EMPA in VC therapy of T2DM patients.

The integration of aryl diazonium and carbon nanotube chemistries has offered rich and versatile tools for creating nanomaterials of unique optical and electronic properties in a controllable fashion. The diazonium reaction with single-wall carbon nanotubes (SWCNTs) is known to proceed through a radical or carbocation mechanism in aqueous solutions, with deuterated water (D2O) being the frequently used solvent. Here, we show strong water solvent isotope effects on the aryl diazonium reaction with SWCNTs for creating fluorescent quantum defects using water (H2O) and D2O. We found a deduced reaction constant of ∼18.2 times larger value in D2O than in H2O, potentially due to their different chemical properties. We also observed the generation of new defect photoluminescence over a broad concentration range of diazonium reactants in H2O, as opposed to a narrow window of reaction conditions in D2O under UV excitation. Without UV light, the physical adsorption of diazonium on the surface of SWCNTs led to the fluorescence quenching of nanotubes. These findings provide important insights into the aryl diazonium chemistry with carbon nanotubes for creating promising material platforms for optical sensing, imaging, and quantum communication technologies.

In non-small cell lung cancer (NSCLC), the overexpression or abnormal activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and drug resistance. EGFR tyrosine kinase inhibitors (TKIs) are currently the first-line treatment of NSCLC. However, patients inevitably acquired EGFR TKIs resistance mutations, which led to disease progression, so it is urgent to find new treatment. Here, we report that D-mannose up-regulates lysosomal activity by enhancing TFE3-mediated lysosomal biogenesis, thereby increasing the degradation of EGFR and significantly down-regulating its protein level. Therefore, D-mannose significantly inhibited the proliferation, migration and invasion of wild-type EGFR (WT-EGFR) and EGFR mutant cells (E746-A750 deletion, L858R and T790M mutations) in vitro. Oral administration of D-mannose strongly inhibited tumor growth in mice, showing similar effects with osimertinib. Taken together, these data suggest that D-mannose may represent a new strategy for clinical treatment of NSCLC.

The inner rotors of distributed propulsion tilt-wing Unmanned Aerial Vehicles (UAVs) are often folded in the cruising state and deployed in vertical take-off and landing to cope with the huge difference in thrust requirements. However, the blades of the conventional rotor have poor conformality with the nacelle profile, which will greatly increase the drag of the UAV after folding. This paper proposes an integrated method for the design of rotor and nacelle considering geometric compatibility to reduce the drag of the folded rotor and nacelle, so as to further improve the aerodynamic efficiency in cruise while ensuring the rotor efficiency in the vertical flight mode. A geometric mapping model based on nacelle design parameters and rotor design parameters is established, and a parametric model and aerodynamic optimization model of the outer arc airfoil family are developed. In addition, a rotor performance analysis model and a neural network response surface model for nacelle drag prediction that meet the requirements of confidence level are established. Based on the oblique inflow blade element momentum theory method, numerical simulation method, and genetic algorithm, an integrated optimization framework of the design of the conformal rotor and nacelle is built. Then, a geometrically compatible integrated optimization for the rotor and nacelle is carried out with the objective of maximizing energy efficiency in the full mission profile. Finally, a conformal rotor and nacelle design solution is obtained, which satisfies geometric compatibility and thrust constraints while providing high thrust efficiency and low cruising drag. A comparison of the results of the integrated design and the conventional rotor optimization design shows that the drag of the conventional rotor is 3.45 times that of the conformal integrated design in the cruising state, which proves the effectiveness and necessity of the proposed method.

The sympathetic nerve is known to regulate immune responses in autoimmunity. Aberrant T cell immunity plays a vital role in immune thrombocytopenia (ITP) pathogenesis. The spleen is the primary site of platelet destruction. However, little is known whether and how splenic sympathetic innervation and neuroimmune modulation contribute to ITP pathogenesis.

The treatment of spinal cord injury (SCI) is a hot topic in clinic. In this study, female rats were selected and randomly divided into four groups (normal, sham, SCI, and mesenchymal stem cells [MSCs] groups). Hemostatic forceps were used to clamp the spinal cord for 1 min to establish the SCI animal model in rats. The levels of proinflammatory factors in the blood of each group were compared 4 h after operation. The motor function of hind limb was estimated by Basso, Beattie & Bresnahan Locomotor rating scale (BBB scale) at 3 months after surgery, the spinal cord tissue from the experimental area was obtained and stained histologically and immunohistochemically. Basso, Beattie & Bresnahan Locomotor rating scale results indicated that human umbilical cord (HUC) MSCs transplantation could improve the walking ability in rats with the SCI. Human umbilical cord mesenchymal stem cells substantially upregulated the secretion of anti-inflammatory factors and downregulated the secretion of proinflammatory factors, and promoted the repair of the SCI and inhibited the increase of glial cells induced by the SCI. Human umbilical cord mesenchymal stem cells transplantation can partially recovered the motor ability of rats with the SCI through promoting the regeneration of nerve cell and the expression of neural related genes, and inhibiting inflammatory reaction.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, primarily due to its late diagnosis, high propensity to metastasis, and the development of resistance to chemo-/radiotherapy. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are intimately involved in the treatment resistance of pancreatic cancer cells via interacting with critical signaling pathways and may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC.

With the integration of nanotechnology into the medical field at large, great strides have been made in the development of nanomedicines for tackling different diseases, including cancers. To date, various cancer nanomedicines have demonstrated success in preclinical studies, improving therapeutic outcomes, prolonging survival, and/or decreasing side effects. However, the translation from bench to bedside remains challenging. While a number of nanomedicines have entered clinical trials, only a few have been approved for clinical applications. In this review, we highlight the most recent progress in cancer nanomedicine, discuss current clinical advances and challenges for the translation of cancer nanomedicines, and provide our viewpoints on accelerating clinical translation. We expect this review to benefit the future development of cancer nanotherapeutics specifically from the clinical perspective.

•RIPK1/RIPK3 in IECs activates JAK1/STAT1-mediated chemokines and MHC II molecules and triggers an inflammatory cascade.•Nonimmunosuppressive RIPK1 kinase inhibitor Zharp1-211 restores intestinal homeostasis and reduces GVHD without compromising the GVL effect.

Emissions of volatile organic compounds (VOCs) have a substantial impact on the environment, and absorption methods are an important means of dealing with VOCs. In order to screen potential deep eutectic solvents (DESs) as liquid absorbers for capturing xylenes, seven DESs were prepared and were verified by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The melting points of all DESs were well below the melting points of their raw materials, and the water content of all the DESs was less than 0.05 wt %. The viscosities of the seven DESs decreased with increasing temperature. The solubility of o-, m-, and p-xylene in the DESs was determined by the cloud point in the range of 303.15–353.15 K. The tetrabutylammonium bromide-based DESs had the greatest potential to dissolve xylene. Tetrabutylammonium bromide:triethylene glycol (1:4) exhibited the highest solubility for o-, m-, and p-xylene, with the mole fraction solubilities of 0.4075, 0.3754, and 0.3820, respectively (each at 353.15 K). The solubility magnitudes of the three isomers exhibited an overall trend of o-xylene > p-xylene ∼ m-xylene. The experimental solubility data were fitted with the dual-parameter equation and the Apelblat equation; the latter was a better fit.

Enzyme-responsive drug delivery systems have drawn much attention in the field of cancer theranostics due to their high sensitivity and substrate specificity under mild conditions. In this study, an amphiphilic polymer T1is reported, which contains a tetraphenylethene unit and a poly(ethylene glycol) chain linked by an esterase-responsive phenolic ester bond. In aqueous solution, T1formed stable micelles via self-assembly, which showed an aggregation-induced emission enhancement of 32-fold at 532 nm and a critical micelle concentration of 0.53 μM as well as esterase-responsive activity. The hydrophobic drug doxorubicin (DOX) was efficiently encapsulated into the micelles with a drug loading of 21%. In the presence of the esterase, the selective decomposition of drug-loaded T1micelles was observed, and DOX was subsequently released with a half-life of 5 h. In vitro antitumor studies showed that T1@DOXmicelles exhibited good therapeutic effects on HeLa cells, while normal cells remained mostly intact. In vivo anticancer experiments revealed that T1@DOXmicelles indeed suppressed tumor growth and had reduced side effects compared to DOX·HCl. The present work showed the potential clinical application of esterase-responsive drug delivery in cancer therapy.

Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.

The constant emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants indicates the evolution and adaptation of the virus. Enhanced innate immune evasion through increased expression of viral antagonist proteins, including ORF9b, contributes to the improved transmission of the Alpha variant; hence, more attention should be paid to these viral proteins. ORF9b is an accessory protein that suppresses innate immunity via a monomer conformation by binding to Tom70. Here, we solved the dimeric structure of SARS-CoV-2 ORF9b with a long hydrophobic tunnel containing a lipid molecule that is crucial for the dimeric conformation and determined the specific lipid ligands as monoglycerides by conducting a liquid chromatography with tandem mass spectrometry analysis, suggesting an important role in the viral life cycle. Notably, a long intertwined loop accessible for host factor binding was observed in the structure. Eight phosphorylated residues in ORF9b were identified, and residues S50 and S53 were found to contribute to the stabilization of dimeric ORF9b. Additionally, we proposed a model of multifunctional ORF9b with a distinct conformation, suggesting that ORF9b is a fold-switching protein, while both lipids and phosphorylation contribute to the switching. Specifically, the ORF9b monomer interacts with Tom70 to suppress the innate immune response, whereas the ORF9b dimer binds to the membrane involving mature virion assembly. Our results provide a better understanding of the multiple functions of ORF9b.

Natural clays are often employed as substrates for heterogeneous catalysts. However, the direct use of raw clays as catalysts has received less research attention. The objective of the present study was to help fill this gap by investigating catalytic properties of raw pelagic clays (PC) collected from the Indian Ocean. The raw PC were discovered to be efficient catalysts in the reduction of 4-nitrophenol (4-NP) in the presence of NaBH4. The effects of parameters including pH values, dosages of PC, and initial concentration of 4-NP and NaBH4on the conversion or degradation rate of 4-NP have been investigated. The 4-NP was observed to be completely degraded within 480 s under conditions of 0.10 mM 4-NP, 25.0 mM NaBH4, and 0.20 g/L PC at an initial pH value of 7.0. The apparent rate constant was evaluated to be 27.53 × 10–3s–1. Unlike previous pseudo-first order kinetics experiments, the induction period and degradation stages were observed to occur simultaneously during the PC catalysis. The S-shaped kinetics for 4-NP conversion was found to be perfectly matched by Fermi's function, and the enzyme-like catalysis by PC was appointed to describe the kinetics. Species of Fe(III), Mn(IV), and Mn(III) in PC were found to be essential, and were partly reduced to Fe(0) and Mn(II) by NaBH4in our reaction, contributing to rapid conversion of 4-NP to 4-aminophenol (4-AP). The raw PC was converted to magnetic PC (m-PC) particles, which made PC particles separate easily for cycling use. This discovery would also have applications in continuous flow-fluid catalysis.

In this study, 3-carboxyphenylboronic acid (CP)-functionalized amino-modified Fe3O4(Fe3O4@NH2-CP, FNC) magnetic molecularly imprinted polymers (FNC@MIPs) were synthesized and applied for the quick identification and selective separation of luteolin (LTL). The structure and morphology were characterized in detail by Fourier transform-infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and vibrating specimen magnetometry (VSM) methods. The FNC@MIPs had a homogeneous shape, excellent magnetic characteristics, quick binding kinetics, a high adsorption capacity, acceptable selectivity, and stable reusability. The solid-phase extraction parameters and preparation conditions were both optimized. Under optimized conditions, the maximal adsorption capacity was 14.26 mg g−1and the imprinting factor was 3.62. Furthermore, the experimental kinetics data were best fitted with the pseudo-first-order model (R2= 0.9877), and the Langmuir model could describe the adsorption process (R2= 0.9979), suggesting a monolayer covering. The practical application of the sorbent for LTL detection in Lonicera japonicaThunb samples showed recoveries in the range of 84.5–108.7%. Therefore, the strategy offers a fresh avenue for the extraction and purification of LTL.

Damage to peritubular capillaries is a key process that contributes to acute kidney injury (AKI) progression. Vascular endothelial growth factor A (VEGFA) plays a critical role in maintaining the renal microvasculature. However, the physiological role of VEGFA in various AKI durations remains unclear. A severe unilateral ischemia‒reperfusion injury model was established to provide an overview of VEGFA expression and the peritubular microvascular density from acute to chronic injury in mouse kidneys. Therapeutic strategies involving early VEGFA supplementation protecting against acute injury and late anti-VEGFA treatment for fibrosis alleviation were analyzed. A proteomic analysis was conducted to determine the potential mechanism of renal fibrosis alleviation by anti-VEGFA. The results showed that two peaks of extraglomerular VEGFA expression were observed during AKI progression: one occurred at the early phase of AKI, and the other occurred during the transition to chronic kidney disease (CKD). Capillary rarefaction progressed despite the high expression of VEGFA at the CKD stage, and VEGFA was associated with interstitial fibrosis. Early VEGFA supplementation protected against renal injury by preserving microvessel structures and counteracting secondary tubular hypoxic insults, whereas late anti-VEGFA treatment attenuated renal fibrosis progression. The proteomic analysis highlighted an array of biological processes related to fibrosis alleviation by anti-VEGFA, which included regulation of supramolecular fiber organization, cell-matrix adhesion, fibroblast migration, and vasculogenesis. These findings establish the landscape of VEGFA expression and its dual roles during AKI progression, which provides the possibility for the orderly regulation of VEGFA to alleviate early acute injury and late fibrosis.

The stiffness of the extracellular matrix (EM) is known to be associated with tumor metastasis. This study aims to clarify the function and mechanisms of EM stiffness in nasopharyngeal carcinoma (NPC) and to provide a potential therapeutic target for patients with NPC. The NPC cell lines were cultured under varying stiffnesses. Plate cloning, Transwell assays and scratch tests were conducted to compare the phenotypes. Transcriptome sequencing and enrichment analysis were performed to explore the key molecules and the downstream signaling pathways, which were verified via in vitroand in vivoexperiments. Our study showed that the NPC cells cultured on a stiff substrate (50 ​kPa) had greater colony formation, invasion and migration abilities than those cultured on a soft substrate. Transcriptome sequencing showed that a stiff environment induced high expression of fibroblast growth factor 1 (FGF1), which suggested a poor prognosis in various malignancies. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway played an important role in NPC metastasis activated by the FGF1 autocrine pathway in a stiff environment. The increased FGF1 expression was regulated by the transcription factor STAT3, and a positive feedback regulation between them was observed. The use of the JAK inhibitor Ruxolitinib and JAK2 interference inhibited the activation of STAT3. In conclusion, JAK2 activates STAT3/FGF1 positive feedback regulation and promotes NPC metastasis via the PI3K/Akt signaling pathway in a high-stiffness environment. Hence, FGF1 can be used as a potential therapeutic target for patients with NPC.

Metal halide perovskites have emerged as next-generation semiconductors for X-ray detection because of their excellent photoelectric properties. However, severe ion migration in three-dimensional (3D) halide perovskites usually causes dark current drift in radiation detectors, especially in high electric fields. Here, we report a liquid-phase epitaxial method based on inverse-temperature crystallization (ITC), with which a hybrid/all-inorganic 3D perovskite single-crystal heterojunction is constructed, using an orientated CsPbBr3single crystal as a substrate. MAPbBr3–nCln/CsPbBr3single-crystal heterojunctions and single-crystal arrays (through the addition of a mask onto the substrate) with good lattice matching were successfully constructed, laying the foundation for high-performance X-ray detectors. In particular, the MAPbBr3/CsPbBr3heterojunction drastically enhances the X-ray response of the CsPbBr3single crystal, with a record-high sensitivity of 2.0 × 105μC Gyair–1cm–2and lowest detection limit of 96 nGyairs–1for 120 keV hard X-ray detection. Moreover, the dark current drift caused by ion migration is suppressed to 3.92 × 10–4nA cm–1s–1V–1even in a high reverse electric field of −125 V mm–1. Based on the superior detection performance, it is confirmed that a robust and uniform X-ray imaging detector with good resolution was successfully devised using the heterojunction. Our study provides a simple strategy for constructing perovskite single-crystal heterojunction films and arrays that effectively suppress ion migration that otherwise occurs in 3D halide perovskite single crystals to enable the creation of robust ultrasensitive X-ray detection and imaging systems.

Nitrogen-doped carbons (Nano-NC) are often employed as functional supports for boosting oxygen reduction reaction (ORR) over Pt-based catalysts, however, the mechanism of N doping on the adsorption and activation of molecular oxygen on Pt active sites is still not clear. Herein, Nano-NCs as the supports were prepared by a facile NH3antipyretic method, which allowed to tune the kinds of nitrogen species in carbon matrix and their contents by adjusting the NH3antipyretic temperatures. With such an exquisite control, the Pt nanoparticles loaded on the as-obtained Nano-NC showed an optimal Pt particle size (2.10 nm), a higher content of Pt0, a large electrochemically active surface area, and fast electron transport ability. As a consequence, the Pt/Nano-NC-800 catalyst with the optimal N-doping showed an outstanding ORR performance with half-wave potential of 0.80 V vs. RHE, limit diffusion current of 5.37 mA/cm2and improved methanol/CO anti-poisoning, which is superior to the commercial Pt/C catalyst (20%, JM), and most of previously reported Pt-based catalysts. This work may pave a way for the design of the advanced supports for Pt-based catalysts for the ORR applications.

ABSTRACTMCOLN1 and MCOLN3 are two Ca2+release channels residing in the endolysosomal membrane. They are activated by phosphatidylinositol (PtdIns)-3-phosphate (PtdIns3P) and/or PtdIns(3,5)P2. Their activities are also regulated by lumenal pH, with low pH enhancing that of MCOLN1 and high pH increasing that of MCOLN3. Recent studies further suggest that upon starvation, both MCOLN1 and MCOLN3 are activated by a reduction in MTORC1 activity; their activation in turn regulates MTORC1 activity to facilitate macroautophagic/autophagic flux. On the one hand, MCOLN3 appears to be recruited to phagophores where it is activated by PtdIns3P and high pH to inhibit MTORC1 activity using a positive feedback mechanism, thereby increasing autophagy induction. On the other hand, MCOLN1 is activated by PtdIns(3,5)P2and low pH in (auto)lysosomes to increase MTORC1 activity using a negative feedback mechanism, promoting autophagic lysosome reformation. The cell uses the two feedback mechanisms to ensure efficient autophagic flux to survive adverse conditions such as nutrient deprivation and bacterial infection.

We revealed the mechanism of inorganic cesium ion doping on enhancing the proton irradiation resistance of MAPbI3through the combination of experiments and DFT calculations, confirming the potential application prospects of mixed-cation perovskite solar cells in space energy.

The study is aimed to screen the differential expressed genes (DEGs) related to sperm DNA fragmentation in men and provide reference basis of the sperm selection in assisted reproduction based on DNA fragmentation. We evaluated 60 semen samples from patients with high, medium or low sperm DNA fragmentation index (DFI). Using multicolor flow cytometry, we measured the content of reactive oxygen species (ROS), phosphatidylserine (PS) externalization and mitochondrial membrane potential (MMP) in these sperm samples. The results revealed that the more ROS content and PS externalization were detected in the sperm with higher DFI, but there was lower MMP level in the high DFI sperm. Next, we conducted RNA sequencing (RNA-seq) on 3 groups of sperm samples with high, medium and low DFI. Then, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed on DEGs. Furthermore, we utilized qRT-PCR to validated the significantly DEGs from the RNA-seq assay. The transcriptome results showed a total of 5334 DEGs were found in the sperm sample with high, medium and low DFI. According to GO and KEGG analysis 421 down-regulated genes in the high DFI group were related to oxidative stress and spermatogenesis. Thirteen novel genes were also identified that most likely were involved in sperm DNA fragmentation, which were further validated by qRT-PCR. In conclusion, our study suggested that the sperms with highly fragmented DNA were accompanied by down-regulation of a series of genes related to antioxidant and spermatogenesis.

An overview of advanced materials for NH3capture from the aspects of interaction sites and transport pathways is presented.The classifications, working principles, design ideas and structure–property relationships on materials for NH3capture are discussed in detail.The challenges and encouraging outlooks with worthwhile directions for NH3capture are proposed.

Halide perovskites are promising candidates for soft X-ray detection (<80 keV) owing to their high X-ray absorption coefficient, resistivity, and mobility lifetime product. However, the lack of large high-quality single crystals (SCs) renders it challenging to manufacture robust hard X-ray imaging systems (>100 keV) with a low detection limit and stable dark current. Herein, high-quality inch-size two-dimensional (2D) Cs3Bi2Br9(CBB) single crystals are grown from a melt via the Bridgman method. The crystal quality is enhanced by eliminating inclusions of CsBr-rich phases and restraining the trap-state density, leading to an enhanced resistivity of 1.41 × 1012Ω cm and a mobility lifetime product of 8.32 × 10–4cm2V–1. The Au/CBB/Au single-crystal device exhibits a high sensitivity of 1705 μC Gyair–1cm–2in all-inorganic bismuth-based perovskites and an ultralow detection limit of 0.58 nGyairs–1in all of the bismuth-based perovskites for 120 keV hard X-ray detection. The CBB detector exhibits high work stability with an ultralow dark current drift of 2.8 × 10–10nA cm–1s–1V–1and long-term air environment reliability under a high electric field of 10 000 V cm–1owing to the ultrahigh ionic activation energy of the 2D structure. The proposed robust imaging system based on CBB SC is a promising tool for X-ray medical imaging and diagnostics.

Two-dimensional (2D) metal–organic framework (MOF) nanosheets, with largely exposed surface area and highly accessible active sites, have emerged as a novel kind of sensing material. Here, a luminescent 2D MOF nanosheet was designed and synthesized by a facile top-down strategy based on a three-dimensional (3D) layered MOF {[Zn(H2L)(H2O)2]·H2O}n(Zn-MOF; H4L = 3,5-bis(3′,5′-dicarboxyphenyl)-1H-1,2,4-triazole). With a large π-conjugated system and rigid planar structure, ligand H4L was elaborately selected to construct the bulk Zn-MOF, which can be readily exfoliated into 2D nanosheets, owing to the weak interlayer interactions and easy-to-release H2O molecules in the interspaces of 2D layers. Given the great threat posed to the ecological environment by anti-inflammatory drugs and pesticides, the developed luminescent Zn-MOFnanosheets were utilized to determine these organic pollutants, achieving highly selective and sensitive detection of diclofenac sodium (DCF) and tetramethylthiuram disulfide (TMTD). Compared to the detection limits of 3D Zn-MOF(7.72 ppm for DCF, 6.01 ppm for TMTD), the obviously lower detection limits for 2D Zn-MOFnanosheets toward DCF (0.20 ppm) and TMTD (0.18 ppm) further revealed that the largely exposed surface area with rigid planar structure and ultralarge π-conjugated system greatly accelerated electron transfer, which brought about a vast improvement in response sensitivity. The remarkable quenching performance for DCF and TMTD stems from a combined effect of photoinduced electron transfer and competitive energy absorption. The possible sensing mechanism was systematically investigated by the studies of powder X-ray diffraction, UV–vis, luminescence lifetime, and density functional theory calculations.

Four novel pyrazole-benzene carboxamide derivatives 2a~2dwere synthesized and characterized by NMR, HRMS spectral method and X-ray diffraction analysis, and were further conducted for screening the anti-fungal/anti-oomycete activity. Compound 2dcrystallizes as monoclinic space group P21/cwith a= 42.260(4), b= 5.3751(4), c= 8.0129(9) Å, β= 92.958(10)°, V= 1817.7(3) Å3, Z= 4, Mr= 385.41, Dc= 1.408 Mg/m3, S= 1.087, µ = 0.773 mm−1, F(000) = 808, the final R= 0.0763 and wR= 0.2136 for 2657 observed reflections (I >2σ(I)). The preliminary antifungal assay indicates that the title compounds show fair to excellent anti-fungal/anti-oomycete activity toward four plant fungi and two crop oomycetes. Among them, compound 2bexhibits the strongest in vitroanti-B. cinereaeffects (EC50 = 1.61 mg/L). In vivotest presents compound 2bdisplays considerable protective and curative effects to tomato fruits infected by B. cinerea. These results indicate that compound 2bwould be potential fungicides leads for further development.

Objective: Thyroid hormones (THs) regulate multiple physiological activities in the liver, including cellular metabolism, differentiation, and cell growth, and play important roles in the pathogenesis of hepatocellular carcinoma (HCC). Thyroid peroxidase (TPO) is a key molecule involved in the THs synthesis and signaling pathway. As an epigenetic modification, DNA methylation has a critical role in tumorigenesis with diagnostic potential. However, the connection between THs and DNA methylation has been rarely investigated. Methods: The methylation of key TH-related genes was analyzed by in-house epigenome-wide scanning, and we further analyzed the methylation levels of the TPOpromotor in 164 sample pairs of HCC and adjacent non-cancerous tissues by Sequenom EpiTYPER assays, and evaluated their clinical implications. Results: We identified that the methylation of the TPOpromoter was downregulated in the HCC tissues (P&lt;0.0001) with a mean difference ranging from 18.5% to 22.3%. This methylation pattern correlated with several clinical factors, including a multi-satellite tumor, fibrous capsule, and the presence of tumor thrombus. The receiver operator characteristic (ROC) curve analysis further confirmed that the percent methylated reference (PMR) values for TPOwere predictive of the tumor [the area under the curve (AUC) ranged from 0.755 to 0.818] and the thrombosis in the HCC patients (the AUC ranged from 0.706 to 0.777). Conclusion: These findings demonstrated that epigenetic alterations of TPO, as indicated by the PMR values, were a potential biomarker for HCC patients with tumor thrombosis.

A simple hydrothermal method was employed to synthesize BiVO4supported on reduced graphene oxide (BiVO4/RGO) composite photocatalyst to enhance photocatalytic activity of BiVO4for degradation of dye wastewater under visible light. The prepared photocatalysts were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-Vis DRS and photocurrent measurements. The photocatalytic performances of the BiVO4/RGO composite were evaluated by degradation of Orange II (AO7) under visible light irradiation (λ > 420 nm). A series of experiments were carried out to evaluate the effects of various factors on removal efficiency of AO7. The results show that the BiVO4/RGO composite exhibited much higher photocatalytic activity than pure BiVO4. The highest removal efficiency of AO7 was obtained, and reach 100% after 150 min when the doping content, pH value, catalyst dosage was GB30 (30 mg of GO corresponds to 1 mmol of BiVO4), pH = 9 and 200 mg, respectively. The free radical trapping experiments show that •O2-played the most important role in the degradation of AO7. The enhanced catalytic activity of the BiVO4/RGO composite can be attributed to the RGO. As an electron acceptor and transporter, RGO can effectively promote charge transfer in composite and inhibit the recombination of photo-induced electron-hole pairs.

Increasing nitrogen (N) rate could accelerate the decomposition of crop residues, and then improve crop yield by increasing N availability of soil and N uptake of crops. However, it is not clear whether N rate and plant density should be modified after a long period of cotton stubble return with high N rate. This study seeks to assess the effects of N rate and plant density on cotton yield, N use efficiency, leaf senescence, soil inorganic N, and apparent N balance in cotton stubble return fields in Liaocheng, China, in 2016 and 2017. Three plant densities 5.25 (D5.25), 6.75 (D6.75) and 8.25 (D8.25) plants m−2and five N rates 0 (N0), 105 (N105), 210 (N210), 315 (N315), and 420 (N420) kg ha−1were investigated. Compared to the combination used by local farmers (D5.25N315), a 33.3% N reduction and a 28.6% increase in plant density (D6.75N210) can maintain high cotton yield, while a 66.7% N reduction at 6.75 plants m−2(D6.75N105) can only achieve high yield in the first year. Biological yield increased with the increase of N rate and plant density, and the highest yield was obtained under 420 kg N ha−1at 8.25 plants m−2(D8.25N420) across the two years under investigation. Compared to D5.25N315, N agronomic efficiency (NAE) and N recovery efficiency (NRE) in D6.75N210increased by 30.2 and 54.1%, respectively, and NAE and NRE in D6.75N105increased by 104.8 and 88.1%, respectively. Soil inorganic N decreased sharply under 105 kg N ha−1, but no change was found under 210 kg N ha−1at 6.75 plants m−2. N deficit occurred under 105 kg N ha−1, but it did not occurr under 210 kg N ha−1at 6.75 plants m−2. Net photosynthetic rate and N concentration of leaves under N rate ranging from 210 to 420 kg ha−1were higher than those under N rate of 0 or 105 kg N ha−1at all three densities. The findings suggest that D6.75N210is a superior combination in cotton stubble retaining fields in the Yellow River Valley and other areas with similar ecologies.

The optical properties of two Re(CO)3(bpy)Cl complexes in which the bpy is substituted with two donor (triphenylamine, TPA, ReTPA2) as well as both donor (TPA) and acceptor (benzothiadiazole, BTD, ReTPA-BTD) groups are presented. For ReTPA2the absorption spectra show intense intraligand charge-transfer (ILCT) bands at 460 nm with small solvatochromic behavior; for ReTPA-BTD the ILCT transitions are weaker. These transitions are assigned as TPA → bpy transitions as supported by resonance Raman data and TDDFT calculations. The excited-state spectroscopy shows the presence of two emissive states for both complexes. The intensity of these emission signals is modulated by solvent. Time-resolved infrared spectroscopy definitively assigns the excited states present in CH2Cl2to be MLCT in nature, and in MeCN the excited states are ILCT in nature. DFT calculations indicated this switching with solvent is governed by access to states controlled by spin–orbit coupling, which is sufficiently different in the two solvents, allowing to select out each of the charge-transfer states.

The direct‐to‐consumer genetic testing (DTC‐GT) industry has exploded in recent years, initiated by market pioneers from the United States and quickly followed by companies from Europe and Asia. In addition to their primary objective of providing ancestry and health information to customers, DTC‐GT services have emerged as a valuable data resource for large‐scale population and genetics studies. We assessed DTC‐GT market leaders in the U.S. and China, user participation in research, and academic reports based on this information. We also investigated DTC‐GT end‐user value by tracing key updates of companies provided via health risk reports and evaluating their predictive power. We then assessed the replicability of several genome‐wide association studies (GWAS) based on a Chinese DTC‐GT biobank. As recent entrants to the market, Chinese DTC‐GT service providers have published less academic research than their Western counterparts; however, a larger proportion of Chinese users consent to participate in research projects. Dramatic increases in user volume and resultant report updates led to reclassification of some users’ polygenic risk levels, but within a reasonable scale and with increased predictive power. Replicability among GWAS using the Chinese DTC‐GT biobank varied by studied trait, population background, and sample size. We speculate that the rapid growth in DTC‐GT services, particularly in non‐Caucasian populations, will yield an important and much‐needed resource for biobanking, large‐scale genetic studies, clinical trials, and post‐clinical applications. Author summary:Direct‐to‐consumer genetic testing in China has exploded over the past five years. Chinese DTC‐GC users are overwhelmingly willing to participate in research initiated by service providers. As most of these users are non‐Caucasian, we evaluated the reliability of GWAS‐derived polygenic disease reports using populations of predominantly European ancestry and found that prediction power increased alongside new GWAS loci integration. In assessing the outcomes of different GWAS, replicability varied among studies with different ethnic backgrounds and sample sizes. We speculate that Chinese DTC‐GT databases represent valuable biobanks for genetic studies and clinical applications.

In this paper, we investigate periodic solutions of a beam equation with jumping nonlinearity. Such a nonlinearity describes the restoring force acting on the bridge due to the possible slackening of the stays of the suspension bridge. By analyzing the beam operator, we find that there is a strictly positive eigenfunction. Thus, for the external force which is a linear combination of the positive eigenfunction and the eigenfunction corresponding to the first negative eigenvalue, using the critical point theory and Brouwer degree theory, we obtain some results on the multiplicity of periodic solutions when the nonlinearity crosses the first negative eigenvalue.