Effective Manipulation of a Colossal Second-Order Transverse Response in an Electric-Field-Tunable Graphene Moiré System.

The second-order nonlinear transport illuminates a frequency-doubling response emerging in quantum materials with a broken inversion symmetry. The two principal driving mechanisms, the Berry curvature dipole and the skew scattering, reflect various information including ground-state symmetries, band dispersions, and topology of electronic wave functions. However, effective manipulation of them in a single system has been lacking, hindering the pursuit of strong responses. Here, we report on the effective manipulation of the two mechanisms in a single graphene moiré superlattice, AB-BA stacked twisted double bilayer graphene. Most saliently, by virtue of the high tunability of moiré band structures and scattering rates, a record-high second-order transverse conductivity ∼ 510 µm S V-1 is observed, which is orders of magnitude higher than any reported values in the literature. Our findings establish the potential of electrically tunable graphene moiré systems for nonlinear transport manipulations and applications.

Efficacy and Safety of Dupilumab in Chinese Elderly Patients with Atopic Dermatitis: A Real-World Study.

INTRODUCTION: With the aging of the population in China, the prevalence of atopic dermatitis (AD) is high in elderly patients. These patients usually have more comorbidities and they need more effective and safer treatments. Dupilumab is an anti-interleukin-4 (IL-4) receptor monoclonal antibody which was approved for the treatment of moderate-to-severe AD. METHODS: Elderly patients (60 years or older) with moderate-to-severe AD who treated with dupilumab were included. Eczema Area and Severity Index (EASI) score, Peak Pruritus Numerical Rating Scale (PP-NRS), EASI-50, EASI-75, and EASI-50 were evaluated. The efficacy in subgroups was also investigated. RESULTS: Fifty-eight patients were enrolled. The EASI score and PP-NRS score were significantly reduced at weeks 4, 16, 28, and 52. 91.2% and 79.4% of the patients achieved EASI-50 and EASI-75 at week 16, respectively. 95.8% and 87.5% patients achieved EASI-50 and EASI-75 at week 52, respectively. Adverse events were reported in 10 (17.2%) patients, and no severe adverse event was reported. Male, older age, and moderate AD (EASI <21) were related to better efficacy. CONCLUSIONS: This study demonstrated that dupilumab is effective and safe in elderly patients with AD.

Mechanochemical Thioglycolate Modification of Microscale Zero-Valent Iron for Superior Heavy Metal Removal.

Microscale zero-valent iron (mZVI) is widely used for water pollutant control and environmental remediation, yet its reactivity is still constrained by the inert oxide shell. Herein, we demonstrate that mechanochemical thioglycolate (TG) modification can dramatically enhance heavy metal (NiII, CrVI, CdII, PbII, HgII, and SbIII) removal rates of mZVI by times of 16.7 to 88.0. Compared with conventional impregnation (wet chemical process), this dry mechanochemical process could construct more robust covalent bonding between TG and the inert oxide shell of mZVI through its electron-withdrawing carboxylate group to accelerate the electron release from the iron core, and more effectively strengthen the surface heavy metal adsorption through metal(d)-sulfur(p) orbital hybridization between its thiol group and heavy metal ions. Impressively, this mechanochemically TG-modified mZVI exhibited an unprecedented NiII removal capacity of 580.4 mg Ni g-1 Fe, 17.1 and 9.5 times those of mZVI and wet chemically TG-modified mZVI, respectively. Its application potential was further validated by more than 10 days of stable groundwater NiII removal in a column flow reactor. This study offers a promising strategy to enhance the reactivity of mZVI, and also emphasizes the importance of the modification strategy in optimizing its performance for environmental applications.

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

Hhex and Prox1a synergistically dictate the hepatoblast to hepatocyte differentiation in zebrafish.

The specification of endoderm cells to prospective hepatoblasts is the starting point for hepatogenesis. However, how a prospective hepatoblast gains the hepatic fate remains elusive. Previous studies have shown that loss-of-function of either hhex or prox1a alone causes a small liver phenotype but without abolishing the hepatocyte differentiation, suggesting that absence of either Hhex or Prox1a alone is not sufficient to block the hepatoblast differentiation. Here, via genetic studies of the zebrafish two single (hhex-/- and prox1a-/-) and one double (hhex-/-prox1a-/-) mutants, we show that simultaneous loss-of-function of the hhex and prox1a two genes does not block the endoderm cells to gain the hepatoblast potency but abolishes the hepatic differentiation from the prospective hepatoblast. Consequently, the hhex-/-prox1a-/- double mutant displays a liverless phenotype that cannot be rescued by the injection of bmp2a mRNA. Taken together, we provide strong evidences showing that Hhex teams with Prox1a to act as a master control of the differentiation of the prospective hepatoblasts towards hepatocytes.

Impaired cell-cell communication and axon guidance because of pulmonary hypoperfusion during postnatal alveolar development.

BACKGROUND: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. METHODS AND RESULTS: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell-cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. CONCLUSIONS: This study suggested that promoting cell-cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion-induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion.

Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases.

H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC50 = 9.32 µM) and A18 (IC50 = 5.83 µM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo, and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy-d-glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases.

Effects of Florfenicol on Intestinal Histology, Apoptosis and Gut Microbiota of Chinese Mitten Crab (Eriocheir sinensis).

Excessive use of antibiotics in aquaculture causes residues in aquatic animal products and harms human health. However, knowledge of florfenicol (FF) toxicology on gut health and microbiota and their resulting relationships in economic freshwater crustaceans is scarce. Here, we first investigated the influence of FF on the intestinal health of Chinese mitten crabs, and then explored the role of bacterial community in FF-induced intestinal antioxidation system and intestinal homeostasis dysbiosis. A total of 120 male crabs (48.5 ± 4.5 g) were experimentally treated in four different concentrations of FF (0, 0.5, 5 and 50 µg/L) for 14 days. Responses of antioxidant defenses and changes of gut microbiota were assessed in the intestine. Results revealed that FF exposure induced significant histological morphology variation. FF exposure also enhanced immune and apoptosis characteristics in the intestine after 7 days. Moreover, antioxidant enzyme catalase activities showed a similar pattern. The intestinal microbiota community was analyzed based on full-length 16S rRNA sequencing. Only the high concentration group showed a marked decrease in microbial diversity and change in its composition after 14 days of exposure. Relative abundance of beneficial genera increased on day 14. These findings illustrate that exposure to FF could cause intestinal dysfunction and gut microbiota dysbiosis in Chinese mitten crabs, which provides new insights into the relationship between gut health and gut microbiota in invertebrates following exposure to persistent antibiotics pollutants.

Outness and its correlates among gay and bisexual men attending university in China: a cross-sectional study.

BACKGROUND: Disclosure of sexual orientation to others (outness) might be associated with sexual and mental health among gay and bisexual men (GBM) attending university. We aimed to characterise outness and investigate factors correlated with outness among GBM attending university in China. METHODS: Between September 2018 and March 2019, GBM attending university were recruited in six cities in China. Information on sociodemographic characteristics, outness and sexual behaviours were collected using a self-administered questionnaire. Each participant was tested for HIV/STIs. Correlates of outness were assessed using multivariable logistic regression. RESULTS: A total of 400 GBM attending university were recruited, of whom 251 (62.8%) had disclosed their sexual orientation. Men who served as student leaders (adjusted odds ratio [AOR]=2.28, 95% CI: 1.46-3.54) and donated blood (AOR 1.85, 95% CI: 1.05-3.24) were more likely to disclose their sexual orientation, whereas men who had sex with a female (AOR 0.19, 95% CI: 0.05-0.74) and had group sex (AOR 0.52, 95% CI: 0.30-0.89) were less likely to disclose their sexual orientation. Mental health status, HIV/STI infections were not associated with outness. CONCLUSIONS: GBM attending university who disclosed their sexual orientation were more likely to be involved with student work and less likely to engage in high-risk sexual behaviours. More attention and education could focus on non-disclosing GBM men attending university through peer education or other ways.

LncRNA TTN-AS1 acts as a tumor promoter in gallbladder carcinoma by regulating miR-107/HMGA1 axis.

BACKGROUND: The incidence of gallbladder carcinoma (GBM) in China has increased in recent years. Here, the functional mechanism of lncRNA TTN-AS1 in GBC was preliminary elucidated. METHODS: The expression levels of lncRNA TTN-AS1, miR-107, and HMGA1 in tissues and cell lines were assessed by RT-qPCR. Cell proliferation was measured by MTT assays. Cell invasion and migration abilities were evaluated by Transwell assays. The relationship between miR-107 and lncRNA TTN-AS1 or HMGA1 was confirmed by luciferase reporter assay. RESULTS: Upregulation of lncRNA TTN-AS1 and downregulation of miR-107 were detected in GBC. Furthermore, the expressions between TTN-AS1 and miR-107 were mutually inhibited in GBC. Functionally, lncRNA TTN-AS1 promoted cell viability and motility in GBC by sponging miR-107. In addition, miR-107 directly targets HMGA1. And HMGA1 can be positively regulated by lncRNA TTN-AS1 in GBC. Furthermore, HMGA1 promoted GBC progression by interacting with lncRNA TTN-AS1/miR-107 axis. CONCLUSION: LncRNA TTN-AS1 acted as a tumor promoter in GBC by sponging miR-107 and upregulating HMGA1.

A Systematical Survey on the TRP Channels Provides New Insight into Its Functional Diversity in Zhikong Scallop (Chlamys farreri).

Transient receptor potential (TRP) channel plays a significant role in mediating various sensory physiological functions. It is widely present in the vertebrate and invertebrate genomes and can be activated by multiple compounds, messenger molecules, temperature, and mechanical stimulation. Mollusks are the second largest phylum of the animal kingdom and are sensitive to environmental factors. However, the molecular underpinnings through which mollusks sense and respond to environmental stimulus are unknown. In this study, we systematically identified and characterized 17 TRP channels (C.FA TRPs, seven subfamilies) in the genome of the Zhikong scallop (Chlamys farreri). All C.FA TRPs had six transmembrane structures (TM1-TM6). The sequences and structural features of C.FA TRPs are highly conserved with TRP channels of other species. Spatiotemporal expression profiling suggested that some C.FA TRPs participated in the early embryonic development of scallops and the sensory process of adult tissues. Notably, the expression of C.FA TRPM3 continuously increased during developmental stages and was highest among all C.FA TRPs. C.FA TRPC-α was specifically expressed in eyes, which may be involved in light transmission of scallop eyes. Under high temperature stress, C.FA TRPA1 and C.FA TRPA1-homolog upregulated significantly, which indicated that the TRPA subfamily is the thermoTRPs channel of scallops. Our results provided the first systematic study of TRP channels in scallops, and the findings will provide a valuable resource for a better understanding of TRP evolution and function in mollusks.

Sensitive and selective monitoring of the DNA damage-induced intracellular p21 protein and unraveling the role of the p21 protein in DNA repair and cell apoptosis by surface plasmon resonance.

The cyclin-dependent kinase inhibitor p21 protein is a critical regulator that mediates various biological activities, such as cell cycle progression, apoptosis, and cellular senescence. As a DNA damage-inducing agent, doxorubicin could reactivate the transcriptional activity of p53 and modulate the p21 protein level. In this work, sensitive and selective monitoring of the intracellular p21 protein in doxorubicin-treated breast cancer cells was conducted using surface plasmon resonance (SPR). The fluidic channels were pre-immobilized with double stranded (ds) DNA/proliferating cell nuclear antigen (PCNA) for the capture of the p21 protein. The incorporation of the anti-p21 antibody-streptavidin conjugate pre-formed between streptavidin and biotinylated anti-p21 antibody that specifically recognizes the p21 protein leads to signal amplification. The detection limit of 0.85 pM for the p21 protein was lower than that using the commercial enzyme-linked immunosorbent assay (ELISA) kit. The treatment of MCF-7 breast cancer cells with wild-type p53 by various doses of doxorubicin leads to differences in the extent of DNA damage. Low-level DNA damage by low-dose doxorubicin up-regulates the p21 level, and p21 exerts its anti-apoptotic function, causing p53-dependent cell cycle arrest and DNA repair. However, massive DNA damage by high-dose doxorubicin represses the expression of the p21 protein through increased proteasome activity, leading to cell apoptosis. The proposed method is sensitive, selective and label-free, holding great promise for the assay of the DNA damage-induced intracellular p21 protein and understanding of p21 protein-mediated cell cycle arrest, DNA repair, and cell apoptosis.

Clinical relevance of eosinophils, basophils, serum total IgE level, allergen-specific IgE, and clinical features in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory disease with diverse clinical features. Although AD is diagnosed mainly by clinical features, the laboratory abnormalities can be found in most patients and may be of diagnostic value. However, few studies have been performed on the clinical significance of laboratory abnormalities in adult and adolescent AD. METHODS: Adult and adolescent patients with AD were included in this study. The questionnaire and dermatological examination were completed by investigators. Laboratory tests included complete blood count, serum total IgE, and allergen-specific IgE. RESULTS: A total of 473 patients were recruited and 396 of them were diagnosed as AD. Increased serum total IgE level, peripheral eosinophils, and basophils were seen more frequently in AD patients than in non-AD patients (P < .05). Positive aeroallergens were seen more in AD patients than in non-AD patients (P < .05). Both total serum IgE level (R = .286, P < .001) and peripheral eosinophils (R = .444, P < .001) significantly correlated with EASI score. Serum total IgE level and extrinsic type AD decreased with age. Patients with elevated serum total IgE are more likely to have a personal history of atopic diseases (P = .014). AD-associated symptoms (such as flexural dermatitis, white dermographism, and anterior neck folds) are more frequently observed in AD patients with high serum IgE or eosinophilia (P < .05). CONCLUSION: The serum total IgE level, allergen-specific IgE, peripheral eosinophils, and basophils are important for the diagnosis of AD. And they are associated with the severity, age groups, and clinical manifestations.

Real-time surface plasmon resonance monitoring of site-specific phosphorylation of p53 protein and its interaction with MDM2 protein.

Phosphorylation serves as an important post-translational modification implicated in cellular signaling and regulation. In this work, real-time monitoring of site-specific phosphorylation of p53 protein by several protein kinases, followed by its interaction with MDM2 protein was conducted using surface plasmon resonance (SPR). The binding of phosphorylated p53 to MDM2 yields a smaller SPR signal in comparison with that in the case of unphosphorylated p53 protein. Three specific protein kinases were involved in the in situ phosphorylation of the surface-confined p53 protein, and the binding kinetics between the phosphorylated p53 and MDM2 protein was monitored. The results indicate that phosphorylation of Ser15 and Ser37 at the p53 transactivation domain 1 (TAD1) by DNA-dependent protein kinase (DNA-PK) is critical for inhibiting the p53-MDM2 interaction, and the weaker binding affinity is most likely caused by the hydrophobicity change in the vicinity of the MDM2-binding motif or phosphorylation-induced p53 conformational change. In contrast, phosphorylation of Ser46 at the p53 TAD2 domain by c-Jun NH2-terminal kinase 2α2 (JNK2α2) exerts a weaker influence on the binding affinity, whereas phosphorylation of Ser376 and Ser378 at the C-terminus of p53 by protein kinase C (PKC) appears to have little effect. The feasibility of the method for the screening of the DNA-PK inhibitor and the inhibitor of p53-MDM2 interaction has been demonstrated and the half-maximal inhibitory concentration (IC50) values of wortmannin and Nutlin-3 (21 nM and 83 nM, respectively) were highly comparable with those obtained by other methods. The proposed method holds great promise for monitoring protein phosphorylation and unraveling the post-translational modification mechanism.

Dual-channel surface plasmon resonance monitoring of intracellular levels of the p53-MDM2 complex and caspase-3 induced by MDM2 antagonist Nutlin-3.

MDM2 can mediate the degradation of tumor suppressor p53 through an autoregulatory feedback loop, in which MDM2 abolishes wild-type p53 function and accelerates malignant transformation. However, the incorporation of MDM2 antagonist Nutlin-3 could reactivate the transcriptional activity of p53, up-regulate caspase-3, and induce apoptosis. In this work, the simultaneous and label-free monitoring of p53-MDM2 complex and caspase-3 levels in cancer cells before and after Nutlin-3 treatment was conducted using dual-channel surface plasmon resonance (SPR). The p53-MDM2 complex was captured in one fluidic channel covered with consensus double-stranded (ds)-DNA, while the other channel was pre-immobilized with caspase-3-specific biotinylated DEVD-containing peptides. To amplify the SPR signals, the attachment of streptavidin (SA)-conjugated anti-MDM2 antibody in both channels was achieved. The signal diversity before and after Nutlin-3 treatment is indicative of the difference in the levels of the intracellular p53-MDM2 complex and caspase-3. The limit of detection for p53-MDM2 and caspase-3 down to 4.54 pM and 0.03 ng mL-1, respectively, was attained. Upon treatment with Nutlin-3, MCF-7 cancer cells with wild-type p53 showed decreased expression of the p53-MDM2 complex and an increased caspase-3 level, while MDA-MB-231 cancer cells with mutant p53 exhibited an elevated caspase-3 level and unchanged p53-MDM2 complex expression. The apoptosis of MCF-7 and MDA-MB-231 cancer cells upon Nutlin-3 treatment follows a p53-dependent and a p53-independent pathway, respectively. The proposed method is sensitive, selective and label-free, holding great promise for assaying intracellular p53-MDM2 complex and caspase-3 levels and differentiating Nutlin-3-mediated p53-dependent or p53-independent apoptotic pathways.

Penile pyoderma gangrenosum: Successful treatment with thalidomide.

Pyoderma gangrenosum (PG) is a rare ulcerating inflammatory neutrophilic dermatosis. Different clinical manifestations have been described, including ulcerative, pustular and bullous, and vegetative variants. Classic PG usually occurs on the lower extremities (~70% of cases) but can also involve the hands, head, neck, and scrotum. Genital involvement of PG has rarely been reported. Treatment of the genital PG is usually difficult and resistance to conventional therapeutic regimens was frequently observed. The present authors reported a 16-year-old male patient who presented with progressive genital ulceration for 3 weeks. He was treated successfully low dose thalidomide (50 mg/d) and minocycline.

Heterostructured n-ZnO@p-CuO nanosheets filled in a polymer matrix for enhanced electrostatic energy storage performance.

Metallized film capacitors use plastic films as the dielectric spacer, and these polymer films generally have low dielectric constants. To boost the electrostatic energy storage density of a film capacitor, advanced high-k films with high electrical breakdown strength and low dielectric loss are highly desired. Herein, polymer nanocomposite films were made by filling ZnO@CuO nanosheets into poly(vinylidene fluoride-co-hexafluoropropylene) [P(VDF-HFP)]. The n-type ZnO nanosheets are synthesized in an aqueous solution. Through a calcination process, thin layers of p-type CuO are coated over the ZnO nanosheets. Compared to pure P(VDF-HFP) and ZnO/P(VDF-HFP) films, the ZnO@CuO/P(VDF-HFP) films exhibit higher dielectric constant and higher breakdown strength. The optimal content of ZnO@CuO nanosheet in the polymer matrix is determined to be 3 wt%, which leads to a dielectric constant of 15.6 at 1 kHz and the highest energy density of 5.6 J cm-3. The efficacy of ZnO@CuO nanosheets in enhancing the dielectric performance of the polymer nanocomposite is elucidated in detail. This research provides a scalable and low-cost strategy to produce polymer nanocomposite films with high capacitive energy storage performance.

Transcriptome-associated metabolomics reveals the molecular mechanism of flavonoid biosynthesis in Desmodium styracifolium (Osbeck.) Merr under abiotic stress.

The primary pharmacological components of Desmodium styracifolium (Osbeck.) Merr. are flavonoids, which have a broad range of pharmacological effects and are important in many applications. However, there have been few reports on the molecular mechanisms underlying flavonoid biosynthesis in the pharmacodynamic constituents of D. styracifolium. Flavonoid biosynthesis in D. styracifolium pharmacodynamic constituents has, however, been rarely studied. In this study, we investigated how salt stress, 6-BA (6-Benzylaminopurine) treatment, and PEG 6000-simulated drought stress affect flavonoid accumulation in D. styracifolium leaves. We integrated metabolomics and transcriptomic analysis to map the secondary metabolism regulatory network of D. styracifolium and identify key transcription factors involved in flavonoid biosynthesis. We then constructed overexpression vectors for the transcription factors and used them to transiently infiltrate Nicotiana benthamiana for functional validation. This experiment confirmed that the transcription factor DsMYB60 promotes the production of total flavonoids in Nicotiana tabacum L. leaves. This study lays the foundation for studying flavonoid biosynthesis in D. styracifolium at the molecular level. Furthermore, this study contributes novel insights into the molecular mechanisms involved in the biosynthesis of active ingredients in medicinal plants.