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With the popularization of the concept of a healthy diet, people are increasingly concerned about food safety. Thermal processing provides foods with desired smell, unique flavor and taste, but also leads to the generation of harmful substances, such as polycyclic aromatic hydrocarbons (PAHs), which are a class of substances with acute toxicity, genotoxicity, carcinogenicity and phototoxicity that exist widely in thermally processed food matrices. Studies have shown that dietary exposure to PAHs accounts for 88%–98% of the total daily exposure of humans to PAHs. Thus, controlling PAHs levels in foods is of great practical importance for reducing the harmful effects brought about by dietary exposure to PAHs. This paper reviews the major generation pathways, deleterious effects and control strategies of PAHs, with a view to providing a reference for research on new control technologies for PAHs in foods.

Abstract Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

[Objective] We aim to establish an efficient and stable genetic transformation system of Lycium ruthenicum and reduce the vitrification rate of the regenerated seedlings in order to promote gene function study and genetic improvement. [Methods] L. ruthenicum leaves were used as explants and Agrobacterium (LBA4404, EHA105) was used to transform L. ruthenicum. By adjusting the types of basic medium and adding plant hormones, we selected the optimal callus-induction medium, differentiation and selection medium, and rooting-induction medium. The transformation rate of L. ruthenicum was increased to over 65%, while the seedling vitrification rate was decreased to below 10%. This combined culture system laid a foundation for the molecular breeding of L. ruthenicum. [Results] (1) The optimal infection concentration of Agrobacterium (OD600) was 0.6 and the infection time was 25 min for the combined culture system of L. ruthenicum. Under this condition, the callus-induction rate was 78.2%-96%; (2) The optimal differentiation and selection medium contained: MS+inositol 50 mg/L+nicotinic acid 0.25 mg/L+vitamin B6 0.25 mg/L+Fe salt storage solution 1 mL/L+glycine 1.0 mg/L+ vitamin B1 0.05 mg/L+6-BA 0.25 mg/L+sucrose 30 g/L+agar 6 g/L+Kanamycin 30 mg/L+Timentin 300 mg/L, pH 6.0. The optimal rooting medium contained: WPM+IBA 0.25 mg/L+sucrose 30 g/L+agar 6 g/L +Kanamycin 30 mg/L+Timentin 300 mg/L, pH 6.0. (3) On the optimal differentiation and selection medium, the seedling vitrification rate infected by Agrobacterium LBA4404-pBI121 was about 65%, while that infected by Agrobacterium EHA105-pBI121 was below 10%. (4) The rooting efficiency of the regenerated seedlings reached 81.2% using a low-salt WPM medium of woody plants. (5) The ratio of the positive callus to the total number of inoculated leaves was used to evaluate the transformation efficiency. Using the optimal transformation system, the transformation rates of Agrobacterium LBA4404-pBI121 and EHA105-pBI121 were 51% and 65.2%, respectively. [Conclusion] The combined culture system of L. ruthenicum leaves can improve transformation rate while reducing seedling vitrification rate.

Abstract Background Xenopus has served as a valuable model system for biomedical research over the past decades. Notably, ADAR was first detected in frog oocytes and embryos as an activity that unwinds RNA duplexes. However, the scope of A-to-I RNA editing by the ADAR enzymes in Xenopus remains underexplored. Results Here, we identify millions of editing events in Xenopus with high accuracy and systematically map the editome across developmental stages, adult organs, and species. We report diverse spatiotemporal patterns of editing with deamination activity highest in early embryogenesis before zygotic genome activation and in the ovary. Strikingly, editing events are poorly conserved across different Xenopus species. Even sites that are detected in both X. laevis and X. tropicalis show largely divergent editing levels or developmental profiles. In protein-coding regions, only a small subset of sites that are found mostly in the brain are well conserved between frogs and mammals. Conclusions Collectively, our work provides fresh insights into ADAR activity in vertebrates and suggest that species-specific editing may play a role in each animal’s unique physiology or environmental adaptation.

Purpose of Review: IgA vasculitis (IgAV), formerly Henoch–Schonlein purpura, is the most common systemic vasculitis in childhood. In adults, however, this condition is poorly understood, yet associated with more severe disease and poorer outcomes. This necessitates the need for early diagnosis and management. Scope of Review: We describe the pathophysiology, clinical manifestations, and diagnosis of IgAV in adults. Poor outcomes are often due to the high frequency of glomerulonephritis in IgAV-IgA vasculitis-associated nephritis (IgAVN). We hence also aim to summarize the latest clinical data regarding treatment strategies in IgAVN. The diagnosis and differentiation in histology between IgAVN and IgA nephropathy (IgAN) remain a challenge. Review of treatment therapies: Pathological mechanisms between IgAVN and IgAN appear to be consistent between the two, and data from IgAN are often extrapolated to IgAVN. The role of various immunosuppression therapies remains controversial, and in this review, we will discuss immunosuppression use and highlight evidence surrounding emerging and promising novel therapies in IgAVN/IgAN. Our aim for this review is to guide future treatment strategies and direct future studies.

English in colleges and universities is an important subject for learning, so it is especially important to evaluate and analyze the quality of teaching English in colleges and universities. This paper constructs the evaluation system of college English teaching quality based on the AHP model, builds the three-level index model of college English teaching quality by combining the relative importance level of Sta, and then carries out the normalization process to determine the importance degree of the indexes at all levels. Combined with factor analysis and data analysis of the results of the expert consultation on the indicator model to measure the factors affecting the quality of teaching in colleges and universities for the overall evaluation and analysis. From the validation data, it can be seen that there are 24 correlation coefficients above 0.5 and 12 above 0.8 in the model influence factor testing. The standardized factor loadings of each potential variable are all greater than 0.75, and the average variance extractions are all greater than 0.65, effectively verifying the internal consistency and convergent validity of the indicator model. In the validation data of the teaching evaluation system, the individual scores of the three-level indicators are all greater than 90, indicating the effectiveness and appropriateness of the teaching evaluation system. The construction of an English teaching quality evaluation system in colleges and universities is conducive to the improvement of teaching management and a more precise grasp of the improvement of teaching quality.

Abstract Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy.

Engineered T cells are used for tumour immunotherapy but can have side effects and need multiple treatment rounds. Here during expansion of T cells from patients, the authors use an inhibitor of the epigenetic regulator G9a/GLP and show that this increases T cell cytotoxic function and tumour reduction in vitro and in vivo respectively.

Land salinization considerably limits crop production. Biological improvement of saline and alkaline land is an important way to achieve efficient land use. It is crucial to study the salt tolerance of halophyte resources in order to explore and improve plant resources through biological improvement. Glaux maritima is a mesophyte halophyte with strong salt tolerance. In this study, we conducted research on the salt tolerance mechanism of G. maritima through phenotypic, physiological, and transcriptomic aspects. The results indicate that leaf cross-sections revealed that G. maritima has a salt gland tissue composed of stalk, collecting, and secretory cells, which are trapped in epidermal cells. At the physiological level, the maximum salt tolerance threshold of G. maritima leaves was 600 mM/L. At this concentration, proline content, relative conductivity, and superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) enzyme activities were maximum. At the transcriptional level, transcriptome data of three experimental groups (N0: 0 mM/L, N3: 600 mM/L, and N4: 800 mM/L) were analyzed, and six essential genes related to proline synthesis and five essential genes related to SOD and CAT enzyme activities were identified. Two genes involved in CAT enzyme activity were also found to play an important role in the MAPK signaling pathway. Trend analysis revealed that the MAPK signaling regulation (37 differentially expressed genes (DEGs)), phytohormone regulation (48 DEGs), glutathione metabolism (8 DEGs), flavonoid and flavonoid biosynthesis (2DEGs), and flavonoid biosynthesis (24 DEGs) pathways played important roles in regulating the salt tolerance of G. maritima. These findings provide valuable information for further studies on the functional characteristics of G. maritima in response to abiotic stress and may contribute to salt resistance breeding of fodder crops for cultivation in saline alkali land.

ObjectivesIn this study, we compared the cost-effectiveness comparison of the active surveillance (AS) and early surgery (ES) approaches for papillary thyroid microcarcinoma (PTMC) from the perspective of the Chinese healthcare system.MethodsWe performed a cost-effectiveness analysis using a Markov model of PTMC we developed to evaluate the incremental cost-effectiveness ratio of AS and ES. Our reference case was of a 40-year-old woman diagnosed with unifocal (

Over 90% of the U.S. adult population suffers from tooth structure loss due to caries. Most of the mineralized tooth structure is composed of dentin, a material produced and mineralized by ectomesenchyme derived cells known as odontoblasts. Clinicians, scientists, and the general public share the desire to regenerate this missing tooth structure. To bioengineer missing dentin, increased understanding of human tooth development is required. Here we interrogate at the single cell level the signaling interactions that guide human odontoblast and ameloblast development and which determine incisor or molar tooth germ type identity. During human odontoblast development, computational analysis predicts that early FGF and BMP activation followed by later HH signaling is crucial. Here we generate a differentiation protocol based on this sci-RNA-seq analysis to produce mature hiPSC derived odontoblasts in vitro (iOB). Further, we elucidate the critical role of FGF signaling in odontoblast maturation and its biomineralization capacity using the de novo designed FGFR1/2c isoform specific minibinder scaffolded as a C6 oligomer that acts as a pathway agonist. Using computational tools, we show on a molecular level how human molar development is delayed compared to incisors. We reveal that enamel knot development is guided by FGF and WNT in incisors and BMP and ROBO in the molars, and that incisor and molar ameloblast development is guided by FGF, EGF and BMP signaling, with tooth type specific intensity of signaling interactions. Dental ectomesenchyme derived cells are the primary source of signaling ligands responsible for both enamel knot and ameloblast development.

Abstract Kinase inhibitors often exert on/off-target effects, and efficient data analysis is essential for assessing these effects on the proteome. We developed a workflow for rapidly performing such a proteomic assessment, termed as kinase inhibitor proteome impact analysis (KOPI). We demonstrate KOPI’s utility with staurosporine (STS) on the leukemic K562 cell proteome. We identified systematically staurosporine’s non-kinome interactors, and showed for the first time that it caused paradoxical hyper- and biphasic phosphorylation.

Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.

Summary: Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.

Copeptin (C-terminal fragment of pro-arginine vasopressin) levels change as fasting plasma glucose (FPG) and blood pressure change. To explore the clinical significance of changes in copeptin levels in development of type 2 diabetes mellitus (T2DM), we enrolled patients undergoing physical health examinations who met diagnostic criteria for prediabetes and T2DM. Subjects were divided into eight subgroups based on FPG levels and presence or absence of hypertension, including: a normal group (NGT), FPG

Objectives: To examine the prevalence and characteristics of HIV-tuberculosis (TB) co-infected patients in Singapore, an intermediate TB-burden country.Methods: Retrospective data across 11 years was obtained from the National University Hospital (NUH), a quaternary hospital and the National Centre for Infectious Diseases (NCID), the national HIV center.Results: From December 2005 to December 2016, 4015 HIV-infected patients were managed at NUH and NCID, of whom, respectively, 48 and 272 were diagnosed with active TB disease. Only 2 patients (0.6%) were screened for latent TB infection on HIV diagnosis. Mean CD4 count at TB diagnosis was 125.0 ± 153.9 cells/mm3. More patients with HIV diagnosed ≥6 weeks before TB (41%) were associated with CD4 counts >200 cells/mm3 than patients with TB diagnosed ≥6 weeks before HIV (2%). Of 124 (38.6%) HIV-TB patients with CD4 count ≤50 cells/mm3, only 18 (14.2%) started anti-retroviral therapy (ART) in

Abstract Background Correction surgery for cleft palate is recommended between 9 and 18 months of age. Patients suffer from acute pain after palatoplasty. Clinicians are hesitant to use opioids for analgesia concerning the potential high risk of respiratory adverse events. Intravenous ibuprofen perhaps be a suitable adjuvant to pain relief. We try to assess whether preoperative administration of intravenous ibuprofen can decrease opioid requirements following cleft palate repair in infants. Methods This single center prospective randomized clinical trial was performed from February to April 2021 at Department of Anesthesiology in Shanghai Children’s Medical Center. Forty patients ASA I-II, aged 9–24 months with isolated cleft palate and undergoing palatoplasty were randomized in a 1:1 ratio to receive either a single dose of 10 mg/kg ibuprofen intravenously or normal saline at induction. Children and infants postoperative pain scale (CHIPPS) was used for pain assessment. Those patients CHIPPS pain score equal or higher than 4 received analgesic rescue with titrating intravenous fentanyl 0.5 μg/kg and repeated in 10 min if required. The primary outcome was the amount of postoperative fentanyl used for rescue analgesia in postanesthesia care unit (PACU). Results Patients (n = 20 in each group) in IV-Ibuprofen group required less postoperative fentanyl than those in placebo group (p

Anti-Ro52 autoantibody, also known as anti-TRIM21 autoantibody, is one of the widespread autoantibodies in connective tissue diseases(CTD). It was first detected in the patients of Sjögren's syndrome(SS), which had long been considered as an unknown component of anti-SS/Ro autoantibodies. With the development of molecular biology technology, antibodies against Ro52 are considered as independent auto-antibodies. However, there is still some uncertainty about the clinical applications. Recent studies have found that various connective tissue diseases can be positive for anti-Ro52 antibodies alone or in combination with other ones, leading to clinical manifestations or prognosis heterogeneity.

Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.

Multiple pathologies and non-pathological factors can disrupt the function of the non-regenerative human salivary gland including cancer and cancer therapeutics, autoimmune diseases, infections, pharmaceutical side effects, and traumatic injury. Despite the wide range of pathologies, no therapeutic or regenerative approaches exist to address salivary gland loss, likely due to significant gaps in our understanding of salivary gland development. Moreover, identifying the tissue of origin when diagnosing salivary carcinomas requires an understanding of human fetal development. Using computational tools, we identify developmental branchpoints, a novel stem cell-like population, and key signaling pathways in the human developing salivary glands by analyzing our human fetal single-cell sequencing data. Trajectory and transcriptional analysis suggest that the earliest progenitors yield excretory duct and myoepithelial cells and a transitional population that will yield later ductal cell types. Importantly, this single-cell analysis revealed a previously undescribed population of stem cell-like cells that are derived from SD and expresses high levels of genes associated with stem cell-like function. We have observed these rare cells, not in a single niche location but dispersed within the developing duct at later developmental stages. Our studies introduce new human-specific developmental paradigms for the salivary gland and lay the groundwork for the development of translational human therapeutics.

Abstract The slime of velvet worms (Onychophora) is a strong and fully biodegradable protein material, which upon ejection undergoes a fast liquid‐to‐solid transition to ensnare prey. However, the molecular mechanisms of slime self‐assembly are still not well understood, notably because the primary structures of slime proteins are yet unknown. Combining transcriptomic and proteomic studies, the authors have obtained the complete primary sequences of slime proteins and identified key features for slime self‐assembly. The high molecular weight slime proteins contain cysteine residues at the N‐ and C‐termini that mediate the formation of multi‐protein complexes via disulfide bonding. Low complexity domains in the N‐termini are also identified and their propensity for liquid‐liquid phase separation is established, which may play a central role in slime biofabrication. Using solid‐state nuclear magnetic resonance, rigid and flexible domains of the slime proteins are mapped to specific peptide domains. The complete sequencing of major slime proteins is an important step toward sustainable fabrication of polymers inspired by the velvet worm slime.

In order to implement the educational policy in the new era, the paper proposes to reconstruct the teaching content system of basic computer courses. It aims to form an employment ability tree that can benchmark the actual job demands with the guidance of the precise connection between the supply side of talent training and the future demand side of enterprises. Starting from the preset training needs of technical talents on autonomous controllable platforms in China, and faced with the practical problems by the teaching of basic computer courses, the teaching content is reconstructed by the three-step method of “update - feedback - continuous learning”. In the process of concrete implementation, the knowledge map of “point, line and plane” is established and the PDCA cycle model of “plan-do-check-action” is adopted to implement teaching; Bring together, build and share high-quality curriculum resources to improve teaching quality. Highquality course resources are gathered, built and shared to improve the teaching quality.

Post-translational modifications on nucleosomal histones represent a key epigenetic regulatory mechanism to mediate the complex gene expression, DNA replication, and cell cycle changes that occur in embryonic cells undergoing lineage specification, maturation, and differentiation during development. Here, we investigated the dynamics of 13 key histone marks in epidermal cells at three distinct stages of embryonic skin development and identified significant changes that corresponded with the maturation of the proliferative basal epidermal cells and terminally differentiated cells in the stratified layers. In particular, H3K4me3 and H3K27ac were accumulated and became more prominent in the basal cells at later stages of epidermal development, while H3K27me3 was found to be low in the basal cells but highly enriched in the differentiated suprabasal cell types. Constitutive heterochromatin marked by H4K20me3 was also significantly elevated in differentiated epidermal cells at late gestation stages, which exhibited a concomitant loss of H4K16 acetylation. These differential chromatin profiles were established in the embryonic skin by gestation day 15 and further amplified at E18 and in postnatal skin. Our results reveal the dynamic chromatin states that occur as epidermal progenitor cells commit to the lineage and differentiate into the different cells of the stratified epidermis and provide insight to the underlying epigenetic pathways that support normal epidermal development and homoeostasis.

Abstract Background Cardiopulmonary bypass (CPB) with high-priming volume can significantly activate the inflammatory response and increse the usage of packed red blood cells (PRBCs). As risks and complications related to transfusions are increasing, many cardiac centers are focusing on reducing the priming volume of CPB. In our center, efforts have also been made to reduce the priming volume, and the effects of CPB with low-priming volume on clinical outcomes in children undergoing congenital heart disease (CHD) surgery were investigated in this study to provide referential experiences for pediatric CPB. Methods The clinical case data of 158 children undergoing CHD surgery with CPB were collected. The children were divided into the low-priming-volume group (group A, n = 79) and the traditional group (group B, n = 79) according to the priming volume. The amount of PRBCs transfused, the postoperative hematological test results and the clinical outcomes of the two groups were compared by the independent sample t-test or the chi-square test. Results The amount of PRBCs transfused during CPB and during the whole operation were significantly lower in group A than in group B (p

Amino acids modified hydroxyapatite (AA/HAP) composites were synthesized in the presence of different concentrations of serine (Ser), aspartic acid (Asp) and glutamic acid (Glu). The composites were characterized by Fourier transform infrared spectrometer, X-ray diffractometer (XRD) and transmission electron microscope (TEM), and were evaluated in the in vitro remineralization of acid-etched bovine enamel. The results show that amino acids (AA)can interfere with the growth of HAP crystal plane, resulting in the increase of the solubility and decrease of the ordered structure of the HAP crystals. XRD patterns and TEM analysis show that AA has a significant inhibitory effect on the[100] crystalline direction of HAP.Meanwhile, the HAP composites modified by AA have refined crystalline size when compared with the HAP without AA. The cytotoxicity of the materials was evaluated by CCK-8 assay and the results show that the relative cell activity of AA/HAP composites is better than the HAP. Field emission scanning electron microscope images show that the HAP without amino acids and the HAP modified with two different concentrations of amino acids both can repair the surface lesions of bovine enamel. While only the AA/HAP synthesized in the presence of 10 mmol·L-1 Ser, Asp and Glu generates a dense remineralization layer with a thickness of approximately 22 μm in the subsurface restoration, and obtains the best surface microhardness recovering.

Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2–/– organoids and blocked via treatment with de novo–designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.

The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here, we describe a new mouse model to investigate the consequences of RB depletion and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to Rb knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo. Author summary The retinoblastoma protein (RB) is a central regulator of the cell cycle. Functional inactivation of RB leads to unchecked proliferation and is a frequent occurrence in human cancer. Experiments with pre-clinical models have clearly demonstrated that loss of RB is a strong promoter of cancer development. However, the mechanisms through which RB carries out its tumor suppressor function remain only partly understood. Here, we describe a new genetically engineered mouse model in which RB expression can be turned on or off. Using this controllable RB knock-down system, we investigated both the consequences of RB loss in normal cells and its re-expression in cancer cells. We found that long-term RB knock-down in mice leads to the development of pituitary and thyroid tumors, recapitulating previously reported phenotypes of Rb knockout mice, thus validating this new mouse model. Notably, re-expression of RB in pituitary tumors initiated by loss of RB was sufficient to block tumor growth, indicating that these tumors are still dependent on RB loss for their expansion.

Insufficient delivery of systemically administered anticancer drugs to tumors can compromise therapeutic efficacy and develop drug delivery-based therapeutic resistance. Nanotherapeutics such as PEGylated liposomal doxorubicin (PLD) are designed to preferentially accumulate in tumors utilizing enhanced permeation and retention effect. However, their antitumor effects and resulting clinical outcomes are modest and heterogeneous among tumors. Here, we aimed to investigate whether the amount and efficacy of PLD delivered to tumors are tumor site dependent. We established orthotopic primary tumor or liver metastases models of murine breast cancer using 4 T1 cells. PLD showed significant therapeutic effects against tumors that grew in primary mammary sites but not in the liver. We found that differences in therapeutic efficacy were not because of the intrinsic biological resistance of cancer cells but rather were associated with tumor site-dependent differences in transport properties, such as the amount of PLD delivery, blood vessel function, relative vascular permeability, and mechanical pressure in tumors. Thus, transport properties in tumor is site dependent and can be used as phenotypic surrogate markers for tumor drug delivery and therapeutic efficacy.

Amino acids modified hydroxyapatite (AA/HAP) composites were synthesized in the presence of different concentrations of serine (Ser), aspartic acid (Asp) and glutamic acid (Glu). The composites were characterized by Fourier transform infrared spectrometer, X-ray diffractometer (XRD) and transmission electron microscope (TEM), and were evaluated in the in vitro remineralization of acid-etched bovine enamel. The results show that amino acids (AA)can interfere with the growth of HAP crystal plane, resulting in the increase of the solubility and decrease of the ordered structure of the HAP crystals. XRD patterns and TEM analysis show that AA has a significant inhibitory effect on the[100] crystalline direction of HAP.Meanwhile, the HAP composites modified by AA have refined crystalline size when compared with the HAP without AA. The cytotoxicity of the materials was evaluated by CCK-8 assay and the results show that the relative cell activity of AA/HAP composites is better than the HAP. Field emission scanning electron microscope images show that the HAP without amino acids and the HAP modified with two different concentrations of amino acids both can repair the surface lesions of bovine enamel. While only the AA/HAP synthesized in the presence of 10 mmol·L-1 Ser, Asp and Glu generates a dense remineralization layer with a thickness of approximately 22 μm in the subsurface restoration, and obtains the best surface microhardness recovering.

LncRNA H19 has been shown to be aberrantly expressed in different cancers. Here, the authors show that H19 lncRNA is downregulated in pituitary adenomas and H19 is able to impede pituitary tumorigenesis via disruption of 4E-BPB1 and Raptor interaction to inhibit the phosphorylation of 4E-BP1.

Although influenza can lead to significant morbidity and mortality in solid organ transplant recipients, its vaccination rate among solid organ transplant recipients remains low. This study evaluates influenza vaccination among solid organ transplant recipients and compares rates before and after introducing a one-stop influenza vaccination service. In a prospective study on influenza vaccination among solid organ transplant recipients followed up from December 2014 to February 2015, 308 solid organ transplant recipients were surveyed, of which 25.0% received their annual influenza vaccination previously. Of those who have not, 60.6% were vaccinated after the education. We found most solid organ transplant recipients to be unaware of the importance of annual influenza vaccination (66.7%). Recipients with a shorter number of years post-transplant (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.91–0.99) and a history of diabetes (OR 0.48, 95% CI 0.23–0.94) were more likely to receive vaccination. The incidence of influenza infection post-implementation was lower (4.9%, 2.6%; P =0.668). Solid organ transplant recipients who had had been vaccinated were associated with a lower incidence of influenza (OR 0.19, 95% CI 0.04–0.99). We conclude that the implementation of the one-stop influenza vaccination service had increased the vaccination uptake rate among solid organ transplant recipients by addressing the barriers and increasing accessibility.

Many environmental factors such as temperature or food level may influence growth and mortality risks of ectothermic vertebrates in both aquatic and terrestrial habitats. In this study, plasticity in growth rates, survival, larval period, and size at metamorphosis were examined in Bufo gargarizans gargarizans larvae under different combinations of temperature and food level. Our results showed that larvae metamorphosed at an older age when reared at 17.3°C. A significant interaction between food level and temperature revealed that the food level has obviously affected length of larval period when tadpoles raised at 17.3 °C, but not at 27.3 or 31.3 °C. Also, we found clear evidence that growth rates are influenced by both temperature and food level. Interestingly, tadpoles reared at 17.3 °C had larger size at metamorphosis than those reared at other temperatures, suggesting that B. g. gargarizans larvae reared at cold temperatures have a longer developmental period but they are also larger as metamorphs than conspecifics reared at warmer temperatures. Therefore, the global climate change or local manipulations of the environment may promote growth and development of B. g. gargarizans larvae, but not large size at metamorphosis.

The calcium sulfate/strontium-doped β-tricalcium phosphate composite spherical pellets was fabricated, using the calcium sulfate/strontium-doped β-TCP as raw material, and through the stirring spray drying method, and then composite spherical pellets were combined with silica gel, porous silica gel/calcium sulfate/strontium-doped β-tricalcium phosphate scaffold was obtained by stacking aggregation method in the mould. The XRD, SEM and FT-IR, etc are employed to examine the chemical composition, composite morphology and structure characteristics, and the degradability, porosity, mechanical properties and cytotoxicity of the scaffolds materials were studied. The results reveal that the composite porous scaffolds have irregular pore structure with pore size between 0.2-1.0mm, and they have a large number of micropores on each of the composite spherical pellets, with the aperture between 50-200μm. Moreover, the porosity of the composite scaffolds is about 62%, which can meet the requirements of scaffolds for bone tissue engineering in porosity; the cytotoxicity tests show the composite scaffolds have no cytotoxic effect and it has good degradation. Therefore, it has good application prospect in bone tissue engineering of the bone defect repair of non-bearing site.

The clutch engagement control is a main factor which influences the power interruption time and shock during mode transformation of hybrid electric vehicles. The key is how to be adaptive to the abrasion in the course of usage and change of working condition. For this purpose,an online adaptive optimal control method based on data-driven and torque estimation is presented. The clutch model is updated online by Artificial Neural Network and clutch torque is estimated by Kalman Filtering in real time to solve clutch parametric dynamic uncertainty. Then an object function is formulated to reduce impact and shorten engagement time integrally,combined with a combination optimization algorithm to obtain the optimal outlet valve duty ratio sequence and optimal engagement time. Meanwhile,clutch speed synchronization is accomplished by engine target speed trajectory tracking control. Test results show that the proposed method can be applied on-board in real time and can restrain impact and decrease engagement time effectively in comparison to other control methods.