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Abstract Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Abstract Body weight is related to both diabetes and cognitive impairment; however, the associations between body mass index (BMI) and cognitive impairment have been reported less frequently among diabetes patients. A total of 1355 patients with type 2 diabetes aged ≥ 60 years were included in this study. The Montreal Cognitive Assessment (MoCA) was administered to assess participants’ cognitive status. We collected self-reported body weight, weight loss and appetite loss data using questionnaires. Associations between body weight status (in childhood, midlife age, and late life), weight loss, appetite changes and cognitive impairment were explored using logistic regression. Among the participants, 41.7% exhibited cognitive impairment. Overweight in childhood and late life was associated with cognitive impairment among diabetes patients (OR 2.63, 95% CI 1.52–4.55; OR 1.32, 95% CI 1.03–1.69). Diabetes patients with cognitive impairment were more likely to report a body weight decline and appetite reduction in the past three months (OR 4.18, 95% CI 2.61–6.71; OR 4.41, 95% CI 2.67–7.29). Higher BMI, weight loss, and appetite reduction were positively correlated with cognitive impairment. Given the risk of cognitive impairment, we suggest that body weight and BMI decline should be monitored in patients with diabetes.

Abstract It is known that titanium (Ti) implant surfaces exhibit poor antibacterial properties and osteogenesis. In this study, chitosan particles loaded with aspirin, amoxicillin or aspirin + amoxicillin were synthesized and coated onto implant surfaces. In addition to analysing the surface characteristics of the modified Ti surfaces, the effects of the modified Ti surfaces on the adhesion and viability of rat bone marrow-derived stem cells (rBMSCs) were evaluated. The metabolic activities of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilms on the modified Ti surfaces were also measured in vitro. Moreover, S. aureus was tested for its antibacterial effect by coating it in vivo. Using water as the droplet medium, the contact angles of the modified Ti surfaces increased from 44.12 ± 1.75° to 58.37 ± 4.15°. In comparison to those of the other groups tested, significant increases in rBMSC adhesion and proliferation were observed in the presence of aspirin + amoxicillin-loaded microspheres, whereas a significant reduction in the metabolic level of biofilms was observed in the presence of aspirin + amoxicillin-loaded microspheres both in vitro and in vivo. Aspirin and amoxicillin could be used in combination to coat implant surfaces to mitigate bacterial activities and promote osteogenesis.

Objective: Many studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort. Methods: Participants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed. Results: There were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14–1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49–1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9–3.8) for the entire cohort and 9.7 (7.5–12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy. Conclusion: Inclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.

Defective autophagy is linked to proinflammatory diseases. However, the mechanisms by which autophagy limits inflammation remain elusive. Here, we found that the pan-FGFR inhibitor LY2874455 efficiently activated autophagy and suppressed expression of proinflammatory factors in macrophages stimulated by lipopolysaccharide (LPS). Multiplex proteomic profiling identified the immunoproteasome, which is a specific isoform of the 20s constitutive proteasome, as a substrate that is degraded by selective autophagy. SQSTM1/p62 was found to be a selective autophagy-related receptor that mediated this degradation. Autophagy deficiency or p62 knockdown blocked the effects of LY2874455, leading to the accumulation of immunoproteasomes and increases in inflammatory reactions. Expression of proinflammatory factors in autophagy-deficient macrophages could be reversed by immunoproteasome inhibitors, confirming the pivotal role of immunoproteasome turnover in the autophagy-mediated suppression on the expression of proinflammatory factors. In mice, LY2874455 protected against LPS-induced acute lung injury and dextran sulfate sodium (DSS)-induced colitis and caused low levels of proinflammatory cytokines and immunoproteasomes. These findings suggested that selective autophagy of the immunoproteasome was a key regulator of signaling via the innate immune system.

Abstract Background The mechanism of hepatitis B virus (HBV)‐induced carcinogenesis remains an area of interest. The accumulation of hepatitis B surface antigen in the endoplasmic reticulum (ER) of hepatocytes stimulates persistent ER stress. Activity of the unfolded protein response (UPR) pathway of ER stress may play an important role in inflammatory cancer transformation. How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV‐related hepatocellular carcinoma (HCC) is still unclear. Here, we aimed to define the key molecule hyaluronan‐mediated motility receptor (HMMR) in this process and explore its role under ER stress in HCC development. Methods An HBV‐transgenic mouse model was used to characterize the pathological changes during the tumor progression. Proteomics and transcriptomics analyses were performed to identify the potential key molecule, screen the E3 ligase, and define the activation pathway. Quantitative real‐time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines. Luciferase reporter assay, chromatin immunoprecipitation, coimmunoprecipitation, immunoprecipitation, and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress. Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues. Results We found sustained activation of ER stress in the HBV‐transgenic mouse model of hepatitis‐fibrosis‐HCC. HMMR was transcribed by c/EBP homologous protein (CHOP) and degraded by tripartite motif containing 29 (TRIM29) after ubiquitination under ER stress, which caused the inconsistent expression of mRNA and protein. Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR. HMMR could alleviate ER stress by increasing autophagic lysosome activity. The negative correlation between HMMR and ER stress, positive correlation between HMMR and autophagy, and negative correlation between ER stress and autophagy were verified in human tissues. Conclusions This study identified the complicated role of HMMR in autophagy and ER stress, that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression, which could be a novel explanation for HBV‐related carcinogenesis.

Interest in searches for Charged Lepton Flavor Violation (CLFV) has continued in the past few decades since the observation of CLFV would indicate a new physics Beyond the Standard Model (BSM). As several future lepton colliders with high luminosity have been proposed, the search for CLFV will reach an unprecedented level of precision. Many BSM models allow CLFV processes at the tree level, such as the R-parity-violating (RPV) Minimal Supersymmetric Standard Model (MSSM), which is a good choice for benchmarking. In this paper, we perform a detailed fast Monte Carlo simulation study on RPV-induced CLFV processes at future lepton colliders, including a 240 GeV circular electron positron collider (CEPC) and a 6 or 14 TeV Muon Collider. As a result, we found that the upper limits on the τ-related RPV couplings will be significantly improved, while several new limits on RPV couplings can be set, which are inaccessible by low-energy experiments.

Abstract Background To evaluate the quantity and quality of bone in the newly formed edentulous area produced by the orthodontic implant site-switching technique. Methods The bilateral maxillary first premolars of five beagle dogs were extracted and bone defects were created. The right and left sides of the maxilla were randomly divided into control and experimental sides. On the experimental side, the maxillary second premolar was mesially moved into the position of the missing first premolar. On the control side, the second maxillary premolar was extracted. Six months later, the beagles were euthanized. Microcomputer tomography was used to analyze bone microstructure parameters, alveolar bone height and alveolar bone width of the regenerated bone. Histological analysis was performed by staining tissue sections with toluidine blue. Results Median BV/TV values in the experimental group (81.78%) were significantly larger than those in the control group (35.67%; p = 0.04). Median Tb.Sp values in the experimental group (0.14 mm) were significantly lower than those in the control group (0.54 mm; p = 0.04). Median Tb.Th values in the experimental group (0.48 mm) were significantly higher than those in the control group (0.21 mm; p = 0.04). Median Tb.Pf values in the experimental group (0.65/mm) were significantly lower than those in the control group (3.15/mm; p = 0.04). There was no significant difference in the trabecular number (Tb.N) between the two groups (p = 0.23). The median alveolar bone height values in the experimental group (-0.81 mm) were significantly higher than those in the control group (-2.11 mm; p = 0.04) at a distance 5 mm from the mesial CEJ of the third premolar. The median alveolar bone height values in the experimental group (0.45 mm) were significantly higher than those in the control group (-1.70 mm; p = 0.04) at a distance 6 mm from the mesial CEJ of the third premolar. There was no significant difference in alveolar bone width when compared between the two groups (p > 0.05). Conclusions The newly formed edentulous area created by orthodontic treatment had more compact and thicker trabeculae than the extraction socket. Furthermore, the newly formed edentulous area had a greater alveolar bone height available for the placement of implants.

The massive stockpiling of electrolytic manganese residue (EMR) has caused serious environmental pollution. In this study, EMR, coal gangue (CG), and fly ash (FA) were used as raw materials to obtain the optimal mix ratio based on Design-Expert mixture design. The effects of activator modulus, liquid–solid (L/S) ratio, and curing temperature on the mechanical properties of geopolymers were investigated. The results showed that the compressive strength of the prepared geopolymer was 12.0 MPa, and the 28d leaching of Mn was 0.123 mg/L under the conditions of EMR:CG:FA = 0.43:0.34:0.23, L/S = 0.9, a curing temperature of 60 °C, and a curing time of 24 h. This indicates that the geopolymer is an environmentally friendly material with high compressive strength. The mineral composition of the geopolymer is mainly hydrated calcium silicate and geopolymer gel. In addition, a more stable new mineral phase, MnSiO3, was generated. The Fourier transform infrared (FTIR) spectrogram showed that the peak at 1100 m−1 was shifted to 1112 cm−1, which indicated that a geopolymerization reaction had occurred. Through scanning electron microscopy (SEM) and energy dispersive spectrum (EDS) analysis, it was identified that the geopolymerization produced a large amount of amorphous gelatinous substances with a relatively dense structure, the major elements being oxygen, silicon, aluminum, calcium, and sodium.

Abstract Charged lepton flavor violation (CLFV) represents a transition between charged leptons of different generations that violates lepton flavor conservation, which is a clear signature of possible new physics beyond the standard model. By exploiting a typical example model of extra Z′ gauge boson, we perform a detailed comparative study on CLFV searches at several future lepton colliders, including a 240 GeV electron-positron collider and a TeV scale muon collider. Based on detailed signal and background Monte-Carlo studies with fast detector simulations, we derive the potentials in searching for Z′ mediated CLFV couplings with eμ, eτ and μτ of different future colliders. The results are compared with the current and prospect limits set by either low-energy experiments or the high-energy LHC experiments. The sensitivity of the τ related CLFV coupling strength at future lepton colliders will be significantly improved in comparison to the current best constraints and the prospect constraints for the μτ channel.

Covalent organic frameworks (COFs) are an emerging type of crystalline and porous photocatalysts for hydrogen evolution. Here, the authors report a β-ketoamine COF by systematically engineering N-sites, architecture, and morphology for improved water splitting activity.

Zinc (Zn) is an essential trace mineral that is required for plant growth and development. A number of protein transporters, which are involved in Zn uptake, translocation and distribution, are finely regulated to maintain Zn homeostasis in plant. In this study, we functionally characterized an ATP-binding cassette (ABC) transporter gene, OsPDR7, which is involved in Zn homeostasis. OsPDR7 encodes a plasma membrane-localized protein that is expressed mainly in the exodermis and xylem in the rice root. ospdr7 mutants resulted in higher Zn accumulation compared with the wild type. Heterogeneous expression of OsPDR7 in a yeast mutant rescued the Zn-deficiency phenotype, implying transport activity of OsPDR7 to Zn in yeast. However, no ZIP genes except for OsZIP9 showed change in expression profile in the ospdr7 mutants, which suggested that OsPDR7 maintains cellular Zn homeostasis through regulating OsZIP9 expression. RNA-Seq analysis further revealed a set of differentially expressed genes between the wild type and ospdr7 mutants that allowed us to propose a possible OsPDR7-associated signaling network involving transporters, hormone responsive genes, and transcription factors. Our results revealed a novel transporter involved in the regulation of Zn homeostasis and will pave the way toward a better understanding of the fine-tuning of gene expression in the network of transporter genes.

Structured Illumination Microscopy allows for the visualization of biological structures at resolutions below the diffraction limit, but this imaging modality is still hampered by high experimental complexity. Here, the authors present a combination of interferometry and machine learning to construct a structured illumination microscope for super resolution imaging of dynamic sub-cellular biological structures in multiple colors.

Abstract Background Immunotherapy has been proved to have a large effect on extensive‐stage small cell lung cancer, but the role of immunotherapy in limited‐stage small‐cell lung cancer (LS‐SCLC) is still unknown. Methods A retrospective study of six patients with LS‐SCLC who were treated with neoadjuvant chemoimmunotherapy (durvalumab plus etoposide combined with cisplatin) was performed. Patients were evaluated by the safety, feasibility and pathologic responses of neoadjuvant chemoimmunotherapy. Results Neoadjuvant durvalumab combined chemotherapy was associated with few immediate adverse events and did not delay planned surgery. All patients achieved partial pathologic response (pPR) instead of major pathologic response, or pathologic complete response. No association was observed between programmed death‐ligand 1 expression in tumor specimens and the pathologic response. However, tumors with high expression of immune cells such as CD4+ T cells, CD8+ T cells and FoxP3+ Tregs tended to have better pathologic responses than tumors with low expression of immune cells. Conclusions Neoadjuvant durvalumab combined chemotherapy could induce pPR with few side effects in resectable LS‐SCLC. The immune cells in the tumor microenvironment might play an important role in neoadjuvant chemoimmunotherapy in resectable LS‐SCLC.

Electrocatalytic CO2 reduction (ECR) to high value-added chemicals by using renewable electricity presents a promising strategy to realize “carbon neutrality”. However, the ECR system is still limited by its low current density and poor CO2 utilization efficiency. Herein, by using the confinement effect of covalent organic frameworks (COFs) to confine the in-situ growth of metal nanoclusters (NCs), we develop a series of Cu NCs encapsulated on COF catalysts (Cu-NC@COF) for ECR. Among them, Cu-NC@CuPc-COF as a gas diffusion electrode (GDE) achieves a maximum CO2-to-CH4 Faradaic efficiency of 74 ​± ​3% (at −1.0 ​V vs. Reversible Hydrogen Electrode (RHE)) with a current density of 538 ​± ​31 ​mA ​cm−2 (at −1.2 ​V vs. RHE) in a flow cell, making it one of the best among reported materials. More importantly, the current density is much higher than the relevant industrial current density (200 ​mA ​cm−2), indicating the potential for industrial application. This work opens up new possibilities for the design of ECR catalysts that utilize synergistic strategy.

Herein, a wavelength‐selective pyroelectric sensor based on a graphene field‐effect transistor (gFET) with a plasmon‐enhanced pyroelectric gate (PG) is reported. The PG gFET (PG‐gFET) uses a poly(vinylidene fluoride‐co‐trifluoroethylene) or PVDF‐TrFE membrane doped with plasmonic nanoparticles as the gate. Gold nanorods (AuNRs) or silver nanoparticles (AgNPs) are incorporated into the PVDF‐TrFE membrane to enhance the photothermal conversion efficiency of PVDF‐TrFE in a specific narrowband wavelength range. The wavelength‐selective photothermal effect can optically modulate the gate potential of the PG‐gFET; this, in turn, leads to a change in current through the graphene film of the transistor. The PG‐gFET with AuNRs exhibits a maximum responsivity of 0.79 μA mW−1 at the wavelength of 660 nm. Replacing AuNRs with AgNPs in the PVDF‐TrFE membrane results in tuning the plasmonic response of the transistor to 488 nm with a maximum responsivity of 0.68 μA mW−1. When plasmonic nanoparticles are absent from the PVDF‐TrFE membrane, the maximum response wavelength of the transistor is shifted to a midinfrared regime at 3125 nm, which is associated with the CC absorption of PVDF‐TrFE. The ability of the PG‐gFET to selectively respond to different light wavelengths will benefit many fields, including pyroelectric sensors, spectroscopy, and imaging.

Biomass allocation in plants is fundamental for understanding and predicting terrestrial carbon storage. Here, the authors conduct a meta-analysis showing that warming effect on plant root:shoot is influenced by precipitation and the type of mycorrhizal fungi associated.

Up to 50% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) infection, and the surface protein of HBV is essential for the progression of HBV-related HCC. The expression of large HBV surface antigen (LHB) is presented in HBV-associated HCC tissues and is significantly associated with the development of HCC. Gene set enrichment analysis revealed that LHB overexpression regulates the cell cycle process. Excess LHB in HCC cells induced chronic endoplasmic reticulum (ER) stress and was significantly correlated with tumor growth in vivo. Cell cycle analysis showed that cell cycle progression from G1 to S phase was greatly enhanced in vitro. We identified intensive crosstalk between ER stress and cell cycle progression in HCC. As an important regulator of the G1/S checkpoint, p27 was transcriptionally upregulated by transcription factors ATF4 and XBP1s, downstream of the unfolded protein response pathway. Moreover, LHB-induced ER stress promoted internal ribosome-entry-site-mediated selective translation of p27, and E3 ubiquitin ligase HRD1-mediated p27 ubiquitination and degradation. Ultimately, the decrease in p27 protein levels reduced G1/S arrest and promoted the progress of HCC by regulating the cell cycle.

(1) Background: Solanum nigrum L. is a plant of the genus Solanum in the family Solanaceae and is commonly used to treat tumors. Solasonin (SS) is a steroidal alkaloid extracted from Solanum nigrum L. that has anti-colorectal cancer (CRC) activity. (2) Methods: Column chromatography, semi-preparative HPLC and cellular activity screening were used to isolate potential anti-CRC active compounds in Solanum nigrum L., and structure identification using 1H-NMR and 13C-NMR techniques. Expression levels of HDAC in CRC were mined in the UALCAN database. The in vitro effects of SS on SW620 cell line and its mechanism were examined via Western blot, EdU staining, flow cytometry and immunofluorescence. CRC xenograft model and IHC staining were mainly used to evaluate the role of SS in vivo. (3) Results: The results showed that SS was the most potent anti-CRC component in Solanum nigrum L., which induced apoptosis and cell cycle arrest in the SW620 cell line. HDAC was highly expressed in CRC. The treatment of SW620 cell line with SS resulted in a significant downregulation of HDAC, an increase in the level of P53 acetylation and a subsequent increase in the level of P21. The in vivo validation results showed that SS could effectively inhibit CRC growth, which was associated with the downregulation of HDAC. (4) Conclusions: SS treatment for CRC mainly works through the induction of apoptosis and cycle arrest, and its mechanism of action is mainly related to HDAC-induced P53 acetylation, and the HDAC/P53 signaling pathway may be a potential pathway for the treatment of CRC.

Abstract Background Synapses can adapt to changes in the intracerebral microenvironment by regulation of presynaptic neurotransmitter release and postsynaptic neurotransmitter receptor expression following hypoxic ischemia (HI) injury. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) exerts a protective effect on neurons after HI and may be involved in maintaining the function of synaptic networks. In this study, we investigated the changes in the expression of NAAG, glutamic acid (Glu) and metabotropic glutamate receptors (mGluRs), as well as the dynamic regulation of neurotransmitters in the brain after HI, and assessed their effects on synaptic plasticity of the cerebral cortex. Methods Thirty-six Yorkshire newborn pigs (3-day-old, males, 1.0–1.5 kg) were selected and randomly divided into normal saline (NS) group (n = 18) and glutamate carboxypeptidase II inhibition group (n = 18), both groups were divided into control group, 0–6 h, 6–12 h, 12–24 h, 24–48 h and 48–72 h groups (all n = 3) according to different post-HI time. The content of Glu and NAAG after HI injury were detected by 1H-MRS scanning, immunofluorescence staining of mGluRs, synaptophysin (syph) along with postsynaptic density protein-95 (PSD95) and transmission electron microscopy were performed. ANOVA, Tukey and LSD test were used to compare the differences in metabolite and protein expression levels among subgroups. Correlation analysis was performed using Pearson analysis with a significance level of α = 0.05. Results We observed that the NAAG and mGluR3 expression levels in the brain increased and then decreased after HI and was significantly higher in the 12–24 h (P

Abstract The LHCb Collaboration recently gave an update on testing lepton flavour universality with B + → K +ℓ+ℓ − , in which a 3.1 standard deviations from the standard model prediction was observed. The g-2 experiment also reports a 3.3 standard deviations from the standard model on muon anomalous magnetic moment measurement. These deviations could be explained by introducing new particles including leptoquarks. In this paper, we show the possibility to search for heavy spin-1 leptoquarks at a future TeV scale muon collider by performing studies from three channels: 1) same flavour final states with either two bottom or two light quarks, 2) different flavour quark final states, and 3) a so-called “VXS” process representing the scattering between a vector boson and a leptoquark to probe the coupling between leptoquark and tau lepton. We conclude that a 3 TeV muon collider with 3 ab −1 of integrated luminosity is already sufficient to cover the leptoquark parameter space in order to explain the LHCb lepton flavour universality anomaly.

Endogenous single-stranded DNA (essDNA) can form in a mammalian genome as the result of a variety of molecular processes and can both play important roles inside the cell as well as have detrimental consequences to genome integrity, much of which remains to be fully understood. Here, we established the SSiNGLe-P1 approach based on limited digestion by P1 endonuclease for high-throughput genome-wide identification of essDNA regions. We applied this method to profile essDNA in both human mitochondrial and nuclear genomes. In the mitochondrial genome, the profiles of essDNA provide new evidence to support the strand-displacement model of mitochondrial DNA replication. In the nuclear genome, essDNA regions were found to be enriched in certain types of functional genomic elements, particularly, the origins of DNA replication, R-loops, and to a lesser degree, in promoters. Furthermore, interestingly, many of the essDNA regions identified by SSiNGLe-P1 have not been annotated and thus could represent yet unknown functional elements.

The proper replication of mitochondrial DNA is key to the maintenance of this crucial organelle. Multiple studies aimed at understanding the mechanisms of replication of the mitochondrial genome have been conducted in the past several decades; however, while highly informative, they were conducted using relatively low-sensitivity techniques. Here, we established a high-throughput approach based on next-generation sequencing to identify replication start sites with nucleotide-level resolution and applied it to the genome of mitochondria from different human and mouse cell types. We found complex and highly reproducible patterns of mitochondrial initiation sites, both previously annotated and newly discovered in this work, that showed differences among different cell types and species. These results suggest that the patterns of the replication initiation sites are dynamic and might reflect, in some yet unknown ways, the complexities of mitochondrial and cellular physiology. Overall, this work suggests that much remains unknown about the details of mitochondrial DNA replication in different biological states, and the method established here opens up a new avenue in the study of the replication of mitochondrial and potentially other genomes.

Genome duplication supplies raw genetic materials and has been thought to be essential for evolutionary innovation and ecological adaptation. Here, we select Kelch-like (klhl) genes to study the evolution of the duplicated genes in the polyploid Carassius complex, including amphidiploid C. auratus and amphitriploid C. gibelio. Phylogenetic, chromosomal location and read coverage analyses indicate that most of Carassius klhl genes exhibit a 2:1 relationship with zebrafish orthologs and confirm two rounds of polyploidy, an allotetraploidy followed by an autotriploidy, occurred during Carassius evolution. The lineage-specific expansion and biased retention/loss of klhl genes are also found in Carassius. Transcriptome analyses across eight adult tissues and seven embryogenesis stages reveal varied expression dominance and divergence between the two species. The expression of klhls in response to Carassius herpesvirus 2 infection shows different expression changes corresponding to distinct herpesvirus resistances in three C. gibelio gynogenetic clones. Finally, we find that most C. gibelio klhl genes possess three alleles except eight genes that have lost one or two alleles due to genome rearrangement. The allele expression bias is prosperous for Cgklhl genes and varies during embryogenesis owning to the sequential expression manner of the alleles. The current study provides global insights into the genomic and transcriptional evolution of duplicated genes in a given superfamily resulting from multiple rounds of polyploidization.

Abstract This study aimed to compare the therapeutic effects of biplane skin dilator implantation with those of conventional skin dilator implantation in auricular reconstruction. A total of 137 patients with microtia who met the inclusion criteria from January 2020 to April 2021 were retrospectively selected. Sixty-three patients comprised the control group and were implanted with a skin expander using the conventional method. Seventy-four patients comprised the experimental group and were implanted with a skin expander using the biplane method. Non-parametric tests were used to compare the down-moving distance of the skin dilator between the experimental group and the control group. There was a statistically significant difference in the down-moving distance of the skin dilator between the experimental group and the control group (P 0.05). Moreover, there was no significant difference in the satisfaction rate of patients and their families between the experimental group and the control group (P > 0.05). In this study, the treatment effect of biplane skin dilator implantation was better than that of conventional skin dilator implantation.

Abstract Influenza viruses are major respiratory pathogens known to infect human and a variety of animals and are widely prevalent worldwide. Genome structure of influenza D virus (IDV) is identical to that of influenza C virus (ICV), and phylogenetic analyses suggest that IDV and ICV share a common ancestry and high homology. To date, the prevalence of ICV and IDV in China is unclear, but these viruses represent a potential threat to public health due to cross-species transmission and zoonotic potential. To efficiently monitor ICV and IDV, it is necessary to establish a dual detection method to understand their prevalence and conduct in-depth research. A duplex real-time PCR method for the simultaneous detection of ICV and IDV was developed. TaqMan fluorescent probes and specific primers targeting NP gene of ICV and PB1 gene of IDV were designed. This method exhibited good specificity and sensitivity, and the detection limit reached 1 × 101 copies/μL of plasmid standards of each pathogen. Thirty-one clinical swine samples and 10 clinical cattle samples were analyzed using this method. One positive sample of IDV was detected, and the accuracy of clinical test results was verified by conventional PCR and DNA sequencing. The duplex real-time PCR detection method represents a sensitive and specific tool to detect ICV and IDV. It provides technical support for virus research and clinical diagnosis of ICV and IDV. This information will benefit animal and human health.

BackgroundThere is evidence that remote limb ischemic postconditioning (RIPostC) can reduce ischemia-reperfusion injury (IRI) and improve the prognosis of patients with ischemic stroke. However, so far, only few relevant clinical studies have been conducted. Therefore, we carried out a meta-analysis of eligible randomized controlled trials to compare the RIPostC group with a control group (no intervention or sham surgery) in patients with ischemic stroke.MethodsFour English-language publication databases, PubMed, Cochrane, Embase, and Web of Science, were systematically searched up to March 2022. The data were analyzed using Review Manager fixed-effects and random-effects models.ResultsA total of 12 studies were included, and 11 of those were analyzed quantitatively. Compared to controls, The RIPostC group showed significantly reduced NIHHS scores in patients with ischemic stroke, (MD: −1.09, 95% confidence interval [CI]: −1.60, −0.57, P < 0.0001) and improved patients' Montreal Cognitive Assessment (MoCA) scores, (MD: 1.89, 95% CI: 0.78, 3.00, P = 0.0009), Our results showed that RIPostC is safe, (RR = 0.81, 95%CI: 0.61, 1.08, P = 0.15).ConclusionOur meta-analysis showed that RIPostC is safe and effective and has a positive cerebral protective effect in patients with ischemic stroke, which is safe and effective, and future large-sample, multicenter trials are needed to validate the cerebral protective effect of RIPostC.

MicroRNAs are small non-coding RNAs that play important roles in gene regulation by influencing the translation and longevity of various target mRNAs and the expression of various target genes as well as by modifying histones and DNA methylation of promoter sites. Consequently, when dysregulated, microRNAs are involved in the development and progression of a variety of diseases, including cancer, by affecting cell growth, proliferation, differentiation, migration, and apoptosis. Preparations from the dried root and rhizome of Salvia miltiorrhiza Bge (Lamiaceae), also known as red sage or danshen, are widely used for treating cardiovascular diseases. Accumulating data suggest that certain bioactive constituents of this plant, particularly tanshinones, have broad antitumor effects by interfering with microRNAs and epigenetic enzymes. This paper reviews the evidence for the antineoplastic activities of S. miltiorrhiza constituents by causing or promoting cell cycle arrest, apoptosis, autophagy, epithelial-mesenchymal transition, angiogenesis, and epigenetic changes to provide an outlook on their future roles in the treatment of cancer, both alone and in combination with other modalities.

Meniscal injuries caused by trauma, degeneration, osteoarthritis, or other diseases always result in severe joint pain and motor dysfunction. Due to the unique anatomy of the human meniscus, the damaged meniscus lacks the ability to repair itself. Moreover, current clinical treatments for meniscal injuries, including meniscal suturing or resection, have significant limitations and drawbacks. With developments in tissue engineering, biopolymer scaffolds have shown promise in meniscal injury repair. They act as templates for tissue repair and regeneration, interacting with surrounding cells and providing structural support for newly formed meniscal tissue. Biomaterials offer tremendous advantages in terms of biocompatibility, bioactivity, and modifiable mechanical and degradation kinetics. In this study, the preparation and composition of meniscal biopolymer scaffolds, as well as their properties, are summarized. The current status of research and future research prospects for meniscal biopolymer scaffolds are reviewed in terms of collagen, silk, hyaluronic acid, chitosan, and extracellular matrix (ECM) materials. Overall, such a comprehensive summary provides constructive suggestions for the development of meniscal biopolymer scaffolds in tissue engineering.

Abstract Lysine crotonylation has been discovered in histone and non-histone proteins and found to be involved in diverse diseases and biological processes, such as neuropsychiatric disease, carcinogenesis, spermatogenesis, tissue injury, and inflammation. The unique carbon–carbon π-bond structure indicates that lysine crotonylation may use distinct regulatory mechanisms from the widely studied other types of lysine acylation. In this review, we discussed the regulation of lysine crotonylation by enzymatic and non-enzymatic mechanisms, the recognition of substrate proteins, the physiological functions of lysine crotonylation and its cross-talk with other types of modification. The tools and methods for prediction and detection of lysine crotonylation were also described.

Supercritical water oxidation (SCWO) technology has a great potential application for the disposal of liquid hazardous wastes. The feeding process is vital for the safety and normal operation of SCWO. This paper describes the feeding preparation strategy of SCWO with multilevel grouping and programming. Based on the physicochemical properties, the liquid hazardous wastes from various industrial manufacturers were first grouped into acid, neutral and alkaline groups. By mixing between samples, the primary grouping tanks were determined to be acid, alkali, amphoteric reacting, organic and organic high-chlorine liquid wastes. By distributing acid, alkali, amphoteric reacting liquid wastes into organic wastes, three parallel feeding routes are regulated for the homogenizing tank phase, which avoids the reaction between wastes. By calculating with the linear programming optimization model of MATLAB, the waste compatibility ratio of each feeding route was determined to meet the feeding requirements of SCWO. The feeding preparation strategy of this paper provides a practical instruction for the SCWO design and operation. HIGHLIGHTS Supercritical water oxidation (SCWO) technology has great potential application for the disposal of liquid hazardous wastes.; This paper describes the feeding preparation strategy of SCWO with multilevel grouping and programming.; The feeding preparation strategy of this paper provides a practical instruction for the SCWO design and operation.;

Abstract Background Somatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2. Methods Whole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2 −/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis. Results A new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway. Conclusions In our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

Both collagen fibres and nanohydroxyapatite crystals have anisotropic magnetisation, which allows them to be oriented by a high magnetic field. Highly oriented nanohydroxyapatite/collagen composites were prepared using a high magnetic field combined with in situ synthesis. These highly oriented composites were investigated and compared with conventional composites. The results showed that the collagen fibres in the magnetically induced highly oriented nanohydroxyapatite/collagen composites had a preferred orientation and smaller molecular spacing, while the nanohydroxyapatite crystals were tightly adhered along the collagen fibre surface. The magnetically induced composites exhibited superior resistance to swelling and degradation along with high compressive strength. This artificial composite, with a structure and composition similar to natural bone, represents a new idea for improving materials for vertical or horizontal bone augmentation.

Background and AimFew non-invasive models were established to identify patients with non-alcoholic steatohepatitis (NASH). Liver biopsy remains the gold standard in the clinic. Decreased serum ceruloplasmin (CP) is reported in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to develop a non-invasive model incorporating CP for identifying NASH from NAFLD without type 2 diabetes mellitus (T2DM).MethodsA total of 138 biopsy-proven patients with NAFLD without T2DM were enrolled. The CP ratio was calculated for standardization as the CP value divided by the lower limit of normal. The clinical, anthropometric, biochemical, and histological parameters were compared between the low and high CP ratio groups divided by the median value. Multivariate logistic regression analysis was performed to develop a model for identifying NASH in patients with NAFLD.ResultsThe medians of the high (n = 69) and low (n = 69) CP ratio groups were 1.43 (1.28–1.61) and 1.03 (0.94–1.12), respectively. A comparison of the two groups showed that the severity of steatosis, hepatocellular ballooning, inflammation activity, fibrosis, and liver iron deposition decreased along with the CP ratio (p < 0.05). The median CP ratio of patients with NASH was significantly lower than those with NAFL [1.15 (1.01–1.41) vs. 1.33 (1.24–1.54), p = 0.001]. A novel model which consists of the CP ratio, BMI, and aspartate aminotransferase (AST) was developed. The AUCs of the model in discriminating NASH from NAFLD was 0.796 (0.694–0.899) and 0.849 (0.713–0.984) in the training and validation groups, and 0.836 (0.659–1.000), 0.833 (0.705–0.962), and 0.821 (0.612–1.000) in patients with normal serum alanine aminotransferase, AST, and both levels, respectively.ConclusionsDecreased CP ratio is associated with more severe histological activity, a diagnosis of NASH, and hepatic iron deposition among patients with NAFLD without T2DM. The CP ratio model could be served as a non-invasive approach to identifying patients with NASH, which might reduce the need for liver biopsy.

Single-cell RNA sequencing (scRNA-seq) reveals the transcriptome diversity in heterogeneous cell populations as it allows researchers to study gene expression at single-cell resolution. The latest advances in scRNA-seq technology have made it possible to profile tens of thousands of individual cells simultaneously. However, the technology also increases the number of missing values, i. e, dropouts, from technical constraints, such as amplification failure during the reverse transcription step. The resulting sparsity of scRNA-seq count data can be very high, with greater than 90% of data entries being zeros, which becomes an obstacle for clustering cell types. Current imputation methods are not robust in the case of high sparsity. In this study, we develop a Neural Network-based Imputation for scRNA-seq count data, NISC. It uses autoencoder, coupled with a weighted loss function and regularization, to correct the dropouts in scRNA-seq count data. A systematic evaluation shows that NISC is an effective imputation approach for handling sparse scRNA-seq count data, and its performance surpasses existing imputation methods in cell type identification.

Abstract Pseudomonas are ubiquitously occurring microorganisms and are known for their ability to produce antimicrobials. An endophytic bacterial strain NP-1 T, isolated from Eucalyptus dunnii leaves, exhibits antifungal properties against five tested phytopathogenic fungi. The strain is a Gram-negative rod-shaped bacterium containing a single polar flagellum. It is strictly aerobic, grows at 4–37 °C, 2–5% NaCl, and pH 3–7. The 16S rRNA sequence analysis showed that NP-1 T belongs to the Pseudomonas genus. Phylogenetic analysis based on four concatenated partial genes (16S rDNA, gyrB, rpoB and rpoD) and the phylogenomic tree indicated that NP-1 T belongs to Pseudomonas fluorescens lineage but is distinct from any known Pseudomonas species. The G + C mol % of NP-1 T genome is 63.96, and the differences between NP-1 T and related species are larger than 1. The digital DNA-DNA hybridization and tetranucleotide signatures are 23.8 and 0.97, which clearly separates strain NP-1 T from its closest neighbours, Pseudomonas coleopterorum and Pseudomonas rhizosphaerae. Its phenotypic and chemotaxonomic features confirmed its differentiation from related taxa. The results from this polyphasic approach support the classification of NP-1 T as a novel species of Pseudomonas, and the name of Pseudomonas eucalypticola is thus proposed for this strain, whose type is NP-1 T (= CCTCC M2018494T = JCM 33572 T).

The study was conducted to evaluate the effects of Anemoside B4 on diarrhea incidence, serum indices, and fecal microbial of suckling calves. Sixty newborn Chinese Holstein calves with similar body weight (43.7 ± 3.9 kg) were randomly divided into four groups with 15 calves each, fed the diet which was supplied 0 (CON), 15 (A1), 30 (A2), and 45 (A3) mg/day of Anemoside B4, respectively. The trial period is 56 days. The blood and fecal samples were collected at 28 and 56 days of age. Results show that during the whole trial period, the diarrhea incidence in Group A1, A2, and A3 was significantly lower than that in Group CON (p < 0.05). Compared with the Group CON, Anemoside B4 supplementation significantly decreased the contents of serum D-lactic acid and diamine oxidase at 28-day-old (p < 0.05). At 56-day-old, the content of serum D-lactic acid in Group A3 tended to be higher (0.05 < p < 0.01), and the content of serum diamine oxidase in Group A3 increased significantly, in comparison with Group CON (p < 0.05). Group A3 increased the level of Chao1 and Simpson indices at 28-day-old (0.05 < p < 0.01), and Chao1, Observed_species, Shannon, and Simpson indices at 56-day-old (p < 0.05), in comparison to Group CON. Compared with Group CON, 45 mg / day Anemoside B4 supplementation significantly increased the contents of Bacteroidota (at the phylum level), Prevotella (at the genus level) at 28-day-old (p < 0.05), and the content of Sutterella (at the genus level) at 56-day-old (p < 0.05), promoted the processes of energy metabolism, glycan biosynthesis and metabolism, metabolism of cofactors and vitamins (p < 0.05). A positive correlation was observed between Prevotella and metabolism of cofactors and vitamins, energy metabolism, and glycan biosynthesis and metabolism. A positive correlation was observed between Sutterella and energy metabolism. In conclusion, Anemoside B4 could effectively alleviate calf diarrhea, protect the integrity of intestinal mucosa, and change the structure of intestinal microbiota, indicating the potential value of Anemoside B4 in regulating intestinal microbiota and the prevention of intestinal diseases.

Pyroptosis is an inflammatory form of programmed cell death that is involved in various cancers, including hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) were recently verified as crucial mediators in the regulation of pyroptosis. However, the role of pyroptosis-related lncRNAs in HCC and their associations with prognosis have not been reported. In this study, we constructed a prognostic signature based on pyroptosis-related differentially expressed lncRNAs in HCC. A co-expression network of pyroptosis-related mRNAs–lncRNAs was constructed based on HCC data from The Cancer Genome Atlas. Cox regression analyses were performed to construct a pyroptosis-related lncRNA signature (PRlncSig) in a training cohort, which was subsequently validated in a testing cohort and a combination of the two cohorts. Kaplan–Meier analyses revealed that patients in the high-risk group had poorer survival times. Receiver operating characteristic curve and principal component analyses further verified the accuracy of the PRlncSig model. Besides, the external cohort validation confirmed the robustness of PRlncSig. Furthermore, a nomogram based on the PRlncSig score and clinical characteristics was established and shown to have robust prediction ability. In addition, gene set enrichment analysis revealed that the RNA degradation, the cell cycle, the WNT signaling pathway, and numerous immune processes were significantly enriched in the high-risk group compared to the low-risk group. Moreover, the immune cell subpopulations, the expression of immune checkpoint genes, and response to chemotherapy and immunotherapy differed significantly between the high- and low-risk groups. Finally, the expression levels of the five lncRNAs in the signature were validated by quantitative real-time PCR. In summary, our PRlncSig model shows significant predictive value with respect to prognosis of HCC patients and could provide clinical guidance for individualized immunotherapy.

Background Indigo-containing plant tissues change blue after a freezing treatment, which is accompanied by changes in indigo and its related compounds. Phaius flavus is one of the few monocot plants containing indigo. The change to blue after freezing was described to explore the biosynthesis of indigo in P. flavus. Methods In this study, we surveyed the dynamic change of P. flavus flower metabolomics and transcriptomics. Results The non-targeted metabolomics and targeted metabolomics results revealed a total of 98 different metabolites, the contents of indole, indican, indigo, and indirubin were significantly different after the change to blue from the freezing treatment. A transcriptome analysis screened ten different genes related to indigo upstream biosynthesis, including three anthranilate synthase genes, two phosphoribosyl-anthranilate isomerase genes, one indole-3-glycerolphosphate synthase gene, five tryptophan synthase genes. In addition, we further candidate 37 cytochrome P450 enzyme genes, one uridine diphosphate glucosyltransferase gene, and 24 β-D-glucosidase genes were screened that may have participated in the downstream biosynthesis of indigo. This study explained the changes of indigo-related compounds at the metabolic level and gene expression level during the process of P. flavus under freezing and provided new insights for increasing the production of indigo-related compounds in P. flavus. In addition, transcriptome sequencing provides the basis for functional verification of the indigo biosynthesis key genes in P. flavus.

The mechanisms and biological functions of migrating platelets in cancer remain largely unknown. Here, we analyzed platelet infiltration in hepatocellular carcinoma. We detected platelet extravasation in both mouse and human HCC tissues. CX3CL1 directly induced platelet migration, and hypoxia enhanced platelet migration by upregulating CX3CL1 expression. Knocking down CX3CL1 in HCC cells reduced platelet migration in vitro, as well as infiltration of HCC tissue in an orthotopic HCC mouse model. Components of the CX3CR1/Syk/PI3K pathway were essential for CX3CL1‐induced platelet migration. Migrating platelets induced HCC cell apoptosis in vitro, as indicated by a reduced mitochondrial membrane potential and an increased percentage of apoptotic cells. In the orthotopic tumor implantation model, decreased platelet infiltration was associated with accelerated tumor growth. Taken together, our findings indicate that HCC cell‐derived CX3CL1 contributes to tumor infiltration by platelets, which in turn promotes apoptosis of HCC cells.

Abstract Background Stem cells, including induced pluripotent stem cells (iPSCs), have tremendous potential in health care, though with several significant limitations. Each of the limitations, including immunogenicity, may block most of the therapeutic potentials. Beta2 microglobulin (B2M) and MHC II transactivator (CIITA) are critical for MHC I and II, respectively. MHCs are responsible for immunogenic recognition. Methods B2M and CIITA were knocked out from human iPSCs, either separately or simultaneously. The effects of single or dual knockout of B2M and CIITA on iPSC properties were evaluated in a xenogeneic model of human-to-monkey transplantation. Results B2M or CIITA knockout in human induced pluripotent stem cells (iPSCs) diminishes the expression of MHC I or II alleles, respectively, without changing iPSC pluripotency. Dual knockout was better than either single knockout in preserving the ability of human iPSCs to reduce infiltration of T and B lymphocytes, survive, and promote wound healing in monkey wound lesions. The knockouts did not affect the xenogeneic iPSC-induced infiltration of macrophages and natural killer cells. They, however, decreased the iPSC-promoted proliferation of allogeneic peripheral blood mononuclear cells and T lymphocytes in vitro, although not so for B lymphocytes isolated from healthy human donors. Although the dual knockout cells survived long enough for suiting therapeutic needs, the cells eventually died, possibly due to innate immune response against them, thereby eliminating long-term risks. Conclusions Having these iPSCs with diminished immunogenicity-recognizable to allogeneic recipient may provide unlimited reproducible, universal, standardized “ready-to-use” iPSCs and relevant derivatives for clinical applications.

Anomalies from the LHCb lepton flavour universality and Fermilab muon anomalous magnetic moment show tantalizing hints of possible new physics from the lepton sectors. Due to its large mass and shorter lifetime than muon, the tau lepton is believed to couple more to possible new physics beyond the Standard Model. Traditionally, tau leptons are probed through their decay products due to tau’s short lifetime. On the other hand, at a high energy scale, a large fraction of tau leptons could be boosted to a much longer lifetime and fly a visible distance from several centimetres up to kilometer length scale yet very informative to new physics beyond the standard model or high energy cosmic rays. In this article, we investigate rare, yet promising, tau-physics phenomena, where long-lived taus are exploited either as a microscope (for the measurement of tau’s anomalous magnetic moment to an unprecedented level of accuracy) or as a macroscope (for the detection of 1 TeV to 1 PeV cosmic neutrinos).

Background Members of the plant-specific YABBY gene family are thought to play an important role in the development of leaf, flower, and fruit. The YABBY genes have been characterized and regarded as vital contributors to fruit development in Arabidopsis thaliana and tomato, in contrast to that in the important tropical economic fruit star fruit (Averrhoa carambola), even though its genome is available. Methods In the present study, a total of eight YABBY family genes (named from AcYABBY1 to AcYABBY8) were identified from the genome of star fruit, and their phylogenetic relationships, functional domains and motif compositions, physicochemical properties, chromosome locations, gene structures, protomer elements, collinear analysis, selective pressure, and expression profiles were further analyzed. Results Eight AcYABBY genes (AcYABBYs) were clustered into five clades and were distributed on five chromosomes, and all of them had undergone negative selection. Tandem and fragment duplications rather than WGD contributed to YABBY gene number in the star fruit. Expression profiles of AcYABBYs from different organs and developmental stages of fleshy fruit indicated that AcYABBY4 may play a specific role in regulating fruit size. These results emphasize the need for further studies on the functions of AcYABBYs in fruit development.

Summary: Background: Diabetes is a major health concern and is influenced by lifestyle, which can be affected by the neighbourhood environment. Specifically, a fast-food environment can influence eating behaviours and thus diabetes prevalence. Therefore, our aim was to assess the relationship between fast-food environment and diabetes prevalence for urban and rural environments in the Netherlands, using multiple indicators and buffer sizes. Methods: In this cross-sectional study, data on a nationwide sample of adults older than 19 years in the Netherlands were taken from the 2012 Dutch national health survey (from Public Health Monitor), in which participants were surveyed on topics related to health and lifestyle behaviour. Fast-food outlet exposures were determined within street-network buffers of 100 m, 400 m, 1000 m, and 1500 m around residential addresses. For each of these buffers, three indicators were calculated: presence (yes or no) of fast-food outlets, fast-food outlet density, and ratio. Logistic regression analyses were carried out to assess associations of these indicators with diabetes, adjusting for potential confounders and stratifying into urban and rural areas. Findings: 387 195 adults were surveyed, 284 793 of whom were included in the study. 22 951 (8%) reported having diabetes. Fast-food outlet exposures were positively associated with diabetes prevalence. We did not observe large differences between urban and rural areas. The effect estimates were small for all indicators. For example, in the 400 m buffer in the urban environment, the odds ratio (OR) for having diabetes among people with a fast-food outlet present compared with those without, was 1·006 (95% CI 1·003–1·009) using the presence indicator. The presence indicator showed higher effect estimates and the most consistent results across buffer sizes (ranging from OR 1·005 [95% CI 1·000–1·010] with the 1000 m buffer to 1·016 [1·005–1·028] with the 1500 m buffer in urban areas and from 1·002 [0·998–1·005] with the 1500 m buffer to 1·009 [1·006–1·018] with the 100 m buffer in rural areas) compared with the density and ratio indicators. Interpretation: The results confirm the evidence that the fast-food outlet environment is a diabetes risk factor. All data included were at the individual level and the variability was ensured by the spatial distribution and number of participants. In this study, we only accounted for residential exposure because we were unable to account for exposure outside the residential environment. The findings of this study encourage local governments to consider the potential adverse effects of fast-food exposures and aim at minimising unhealthy food access. Funding: Global Geo Health Data Centre, Utrecht University, Netherlands.

Abstract Background TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. Objective Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real‐world healthcare setting. Methods Case–control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow‐up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. Results A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non‐white. The independent predictors of TdP were potassium concentration 480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in‐hospital and 1‐year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. Conclusions These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.