Search

Finely preserved fossil assemblages (lagerstätten) provide crucial insights into evolutionary innovations in deep time. We report an exceptionally preserved Early Triassic fossil assemblage, the Guiyang Biota, from the Daye Formation near Guiyang, South China. High-precision uranium-lead dating shows that the age of the Guiyang Biota is 250.83 +0.07/–0.06 million years ago. This is only 1.08 ± 0.08 million years after the severe Permian-Triassic mass extinction, and this assemblage therefore represents the oldest known Mesozoic lagerstätte found so far. The Guiyang Biota comprises at least 12 classes and 19 orders, including diverse fish fauna and malacostracans, revealing a trophically complex marine ecosystem. Therefore, this assemblage demonstrates the rapid rise of modern-type marine ecosystems after the Permian-Triassic mass extinction.

The HA:Tb/Zn synthesized by hydrothermal method synchronously achieved good antibacterial effect, better osteogenic activity, and stable fluorescence.

Machine learning (ML) models are often modelled to predict cancer prognosis but rarely consider spatial factors in a region. Hence this study explored machine learning algorithms utilising Local Government Areas (LGAs) in Queensland, Australia to spatially predict 3- and 5-year prognosis of oral cancer patients and provide clinical interpretability of the predicted outcome made by the ML model.Data from a total of 3,841 oral cancer patients were retrieved from the Queensland Cancer Registry (QCR). Synthesizing minority oversampling technique together with edited nearest neighbours (SMOTE-ENN) was used to pre-process unbalanced datasets. Five ML models: logistic regression, random forest classifier, XGBoost, Gaussian Naïve Bayes and Voting Classifier were trained. Predictive features were age, sex, LGAs, tumour site and differentiation. Outcomes were 3- and 5-year overall survival of patients. Model performances on test set were evaluated using area under the curve and F1 scores. SHapley Additive exPlanations (SHAP) method was applied to the best performing model for model interpretation of the predicted outcome.The Voting Classifier was the best performing model with F1 score of 0.58 and 0.64 for 3- and 5-year overall survival, respectively. Age was the most important feature in the Voting Classifier in 3- and 5-year prognosis prediction. LGAs at diagnosis was the top 3 predictive feature for both 3- and 5-year models.The Voting Classifier demonstrated the best overall performance in classifying both 3- and 5-year overall survival of oral cancer patients in Queensland. SHAP method provided clinical understanding of the predictive features of the Voting Classifier.

Objective: To evaluate the efficacy of Tian dan shu gan rehabilitation exercise in improving the short-term survival quality of patients after percutaneous coronary intervention (PCI) and explore whether patients’ symptoms, physical function, cognitive function, and psychosocial function are improved after this exercise. Methods: Patients with acute myocardial infarction who underwent PCI in Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine from August to November 2020 were selected. A total of 110 patients were selected by the convenience sampling method. Patients in the control group were given routine nursing measures after PCI for coronary heart disease, and patients in the experimental group received Tian dan shu gan rehabilitation exercise in addition to routine nursing. Results: After 3 wk, the quality of life in the experimental group was improved compared with that in the control group, and the differences in symptom scores, physical functions, cognitive functions, and psychosocial functions were statistically significant (P < 0.01). After 3 wk of Tian dan shu gan rehabilitation exercise, patients with body mass index (BMI) between 27 and 29.9 had the highest score of body function, which was statistically significantly better compared with that of other groups (P < 0.001). Patients who had remained bachelors for a long period of time had the highest score of symptoms, which was statistically significant compared with the other groups (P < 0.001). The nursing satisfaction of the experimental group was 96.3%. Conclusions: Tian dan shu gan rehabilitation exercise was effective in improving the short-term quality of life of patients with acute myocardial infarction after PCI, and the nursing satisfaction rate was high, use of which should be further extended to more clinical patients.

Objective: Skin cutaneous melanoma(SKCM) is the most aggressive and complex disease of all skin cancers. The molecular mechanisms of this cancer progression are not well understood. Methods: GEPIA online database was used to validate the differentially expressed genes, from two GEO datasets. The prognostic value was calculated by the Kaplan-Meier method. The expression of TUBB4A in SKCM cell line was verified by RT-qPCR, and the immunohistochemistry of TUBB4A in SKCM and normal skin tissues were gained from Human Protein Atlas. Seven target prediction databases predicted potential microRNAs(miRNAs), and upstream long non-coding RNAs(lncRNAs) were predicted by starBase. The co-expressed gene of TUBB4A was obtained using the two online analysis sites UALCAN and starBase. These co-expressed genes were performed by enrichment analysis and immune infiltration result was obtained by the TIMER2 online database. The receiver operating characteristic(ROC) curve was applied to evaluate the diagnostic value of TUBB4A in the SKCM group and normal skin group, and a new nomogram about TUBB4A was constructed to forecast the survival rate of SKCM patients at 1, 3, and 5 years. Results: Firstly, we found DLL3 and TUBB4A were significantly higher expressed in skin cutaneous melanoma compared with normal skin. Subsequently, by analyzing progress free interval(PFI), disease-specific survival(DSS), and disease-free survival(DFS), only TUBB4A was the most potent gene for inhibiting shin cutaneous melanoma progression. In gene ontology(GO)/ kyoto encyclopedia of genes and genomes(KEGG) analysis, TUBB4A may be a key role in the progression of skin cutaneous melanoma by regulating mitochondrial function and affecting cellular metabolism, possibly related to the immune infiltration of CD4+Th1 cells and NK cells. The upstream non-coding RNA(ncRNA) acts through the SNHG16-hsa-let-7b-5p-TUBB4A axis. Conclusions: In conclusion, we elucidated the regulatory role of the SNHG16-hsa-let-7b-5p-TUBB4A axis in the progression of skin cutaneous melanoma by modulating mitochondrial function to affect cellular metabolism. TUBB4A may be a promising diagnostic biomarker and therapeutic target for skin cutaneous melanoma.

Device-edge co-inference opens up new possibilities for resource-constrained wireless devices (WDs) to execute deep neural network (DNN)-based applications with heavy computation workloads. In particular, the WD executes the first few layers of the DNN and sends the intermediate features to the edge server that processes the remaining layers of the DNN. By adapting the model splitting decision, there exists a tradeoff between local computation cost and communication overhead. In practice, the DNN model is re-trained and updated periodically at the edge server. Once the DNN parameters are regenerated, part of the updated model must be placed at the WD to facilitate on-device inference. In this paper, we study the joint optimization of the model placement and online model splitting decisions to minimize the energy-and-time cost of device-edge co-inference in presence of wireless channel fading. The problem is challenging because the model placement and model splitting decisions are strongly coupled, while involving two different time scales. We first tackle online model splitting by formulating an optimal stopping problem, where the finite horizon of the problem is determined by the model placement decision. In addition to deriving the optimal model splitting rule based on backward induction, we further investigate a simple one-stage look-ahead rule, for which we are able to obtain analytical expressions of the model splitting decision. The analysis is useful for us to efficiently optimize the model placement decision in a larger time scale. In particular, we obtain a closed-form model placement solution for the fully-connected multilayer perceptron with equal neurons. Simulation results validate the superior performance of the joint optimal model placement and splitting with various DNN structures., This paper has been submitted to IEEE Transactions on Wireless Communications

BACKGROUND: Prospective genetic evaluation of patients at our referral research hospital presents clinical research challenges. OBJECTIVE: This study sought not only a single-gene explanation for participants’ immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune-phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: We developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% ≥18 years, and had diverse immune presentations. Overall, 327/1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9/22, 40.9%). One-quarter of the molecular diagnoses (92/361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251/361 (69.5%) of these molecular diagnoses could translate into ≥1 management option. CONCLUSION: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

The search for high-performance functional alloys with improved service life and reliability entails the optimization of their mechanical properties. Recently, the high-entropy alloy (HEA) design concept has found new alloys with excellent mechanical properties. It utilizes multiprincipal elements to yield high configurational entropy of mixing, entailing a large compositional freedom with wide window of opportunities for property exploration. Their functional properties are usually modest when compared to conventional materials. The discovery of HEAs with optimal combination of mechanical and functional properties would be a leap forward in the reliability of functional devices. This review article focuses on magnetocaloric HEAs, the design approaches, and the appropriate analysis methods for their performance. We will highlight the efficient strategic search within the vast HEA space, which has been instrumental for significantly enhancing MCE performance, closing the pre-existing gap between magnetocaloric HEAs and high-performance conventional magnetocaloric materials. Outlook for future directions will also be included. Graphical abstract

Two new withaphysalin-type withanolides (18-O-ethylwithaphysalin R and 5-O-ethylphysaminimin C, 1 and 2), along with twelve known withanolides (3–14), were purified and identified from Physalis peruviana L. The chemical structures of these new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All the obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7. Compound 7 was discovered to exhibit potent activity with an IC50 value of 3.51 µM and compounds 2, 6 and 14 showed weak cytotoxic effect.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphadenopathy, splenomegaly, cytopenias, and other autoimmune manifestations. ALPS is caused by lymphocyte accumulation from defects in FAS-mediated apoptosis. Heterozygous germline or somatic pathogenic single nucleotide variants in FAS are the most common molecular etiology of ALPS. Through the Centralized Sequencing Program at the National Institute of Allergy and Infectious Diseases, we performed exome sequencing on subjects with a clinical diagnosis of ALPS, with a subset receiving copy number variant (CNV) analysis. In this cohort, we identified 3 subjects from unrelated families with CNVs at the FAS locus. One subject had a de novo ∼0.828 Mb copy number loss encompassing all of FAS. The second subject had a maternally inherited ∼1.004 Mb copy number loss encompassing all of FAS. The third subject had a paternally inherited ∼0.044 Mb copy number loss encompassing exons 7 through 9 of FAS. Subjects with deletions in FAS had clinical presentations and biomarker profiles similar to those with ALPS and with germline and somatic FAS variants. We demonstrate that CNV analysis should be pursued if there is clinical and biomarker evidence of ALPS because it can lead to a molecular diagnosis and appropriate treatment when FAS sequencing is inconclusive.

Smartphones have become a popular means to help people cope with stress due to their rich functions (e.g., entertainment) and easy access at anytime and anywhere. However, there is a lack of measures for smartphone coping that capture the specific strategies people use when facing stress or difficulties, especially for adolescents who suffer from psychological stress. This study aimed to develop a smartphone coping scale for adolescents that includes specific strategies. Using both qualitative and quantitative methods, we first implemented focus groups and in-depth interviews to collect qualitative materials on smartphone coping. Then we constructed the initial items of the Smartphone Coping Style Scale accordingly. Second, we conducted exploratory and confirmatory factor analyses in one sample, and then assessed the reliability, stability, construct validity, criterion validity (anxiety/depression), and convergent validity (the Ways of Coping Questionnaire) in another sample. Three independent sub-components of smartphone coping were extracted: solving daily problems, distracting negative emotion, and seeking social support. The developed scale showed favourable levels of reliability, stability, and validity. The developed scale with three different subscales is a validated tool for capturing adolescents’ different smartphone coping styles and should be used separately in practice. Implications and limitations were discussed

Cajaninstilbene acid (CSA), Longistylin A (LLA) and Longistylin C (LLC) are three characteristic stilbenes isolated from pigeon pea, exhibiting antibacterial activities against Staphylococcus aureus and even methicillin-resistant Staphylococcus aureus (MRSA). The results showed that LLA had the highest antibacterial activity against the tested strains following by LLC and CSA. Besides, the results implied that these stilbenes effectively inhibited the levels of adhesion and virulence genes and downregulate the production of ɑ-hemolysin. This study showed that stilbenes from pigeon pea have anti-Staphylococcus potential, and they also inhibited bacterial proliferation, biofilm formation, and key gene expressions related to adhesion and virulence of MRSA. It is the first time that the anti-S. aureus and MRSA activities of the three stilbenes has been systematically reported. These current findings provide insight into the anti-MRSA mechanism of stilbenes from pigeon pea, indicating these compounds may be used as antimicrobial agents or additives for food with health functions, and contribute to the development as well as application of pigeon pea in food science.

Purpose:A phase I clinical trial was conducted to assess the safety and feasibility of iNKT cells combined with PD-1+CD8+ T cells in patients with advanced pancreatic cancer and failing the first-line chemotherapy. Patients and Methods:Fifteen eligible patients were enrolled, of whom nine received at least three cycles of treatment each. In total, 59 courses were administered. Results:Fever was the most common adverse event, peaking at about 2-4 h after cell infusion and reverting within 24 h without treatment in all patients. Influenza-like reactions such as headache, myalgia, and arthralgia were also observed in 4, 4, and 3 of the patients, respectively. Additionally, vomiting and dizziness were prevalent, while abdominal pain, chest pain, rash, and stuffy nose were rare adverse events, each reported in one patient. Side effects above grade 2 were not observed. Two patients achieved partial regression, while one patient experienced disease progression assessed four weeks after the 3rd course. Three patients are still alive at the time of writing and have progression-free survival longer than 12 months. The overall survival time has been extended to over 12 months in six of the nine patients. No constant changes of CD4+T, B, and NK cells were recorded except for elevated CD8+T cells after the 1st course. Conclusions:The combination of autologous iNKT cells and PD-1+CD8+ T cells was a safe therapeutic strategy against advanced pancreatic cancer. The patients exhibited a potentially promising prolonged survival time. Further study appears warranted to evaluate the efficacy of these combined cell infusions in pancreatic cancer.

Expression of costimulatory receptor (A. ICOS and 4-1BB) and checkpoint ligands (B. CTLA-4 and PD-1) are assessed in expanded PD-1+CD8+ T cell products (n=5). Expression of CXCR4 and CXCR3 on PD-1+CD8+ T cells pre- and post-expansion are assessed by flow cytometry, and shown in C and D respectively (n=5).

Proliferation curve of iNKT cells of P001 (A) and P002 (B) during expansion ex vivo. Curves representing iNKT cells expanded in later courses is shown in darker color.

Change of tumor markers recorded over time during treatment.

Count of CD8+T cell and iNKT cell products in each course

Representativeness of Study Participants

Heatmap shows the frequencies of the top 50 TCR clones in CD8+T cells in cell products pre-infusion and PBMCs four weeks post infusion. Scale bar, %.

Gating strategy to detect CD4+ T, CD8+ T, B and NK cells by flow cytometry. Only living cells were included in the analysis (A). Changing in percentages of CD4+ T, CD8+ T, B, and NK cells during treatment are shown in panels B, C, D and E respectively.

Purpose:A phase I clinical trial was conducted to assess the safety and feasibility of iNKT cells combined with PD-1+CD8+ T cells in patients with advanced pancreatic cancer and failing the first-line chemotherapy. Patients and Methods:Fifteen eligible patients were enrolled, of whom nine received at least three cycles of treatment each. In total, 59 courses were administered. Results:Fever was the most common adverse event, peaking at about 2-4 h after cell infusion and reverting within 24 h without treatment in all patients. Influenza-like reactions such as headache, myalgia, and arthralgia were also observed in 4, 4, and 3 of the patients, respectively. Additionally, vomiting and dizziness were prevalent, while abdominal pain, chest pain, rash, and stuffy nose were rare adverse events, each reported in one patient. Side effects above grade 2 were not observed. Two patients achieved partial regression, while one patient experienced disease progression assessed four weeks after the 3rd course. Three patients are still alive at the time of writing and have progression-free survival longer than 12 months. The overall survival time has been extended to over 12 months in six of the nine patients. No constant changes of CD4+T, B, and NK cells were recorded except for elevated CD8+T cells after the 1st course. Conclusions:The combination of autologous iNKT cells and PD-1+CD8+ T cells was a safe therapeutic strategy against advanced pancreatic cancer. The patients exhibited a potentially promising prolonged survival time. Further study appears warranted to evaluate the efficacy of these combined cell infusions in pancreatic cancer.

Background Cantharidin (CTD) is a major ingredient of cantharis (Mylabris phalerata Pallas) and has been used extensively in traditional Chinese medicines. It has been shown to exhibit anticancer activity in multiple types of cancer, especially hepatocellular carcinoma (HCC). However, there is no systematic study on the relationships among the regulatory networks of its targets in HCC therapy. We focused on histone epigenetic regulation and the influence of CTD on the immune response in HCC. Methods We performed a comprehensive analysis of novel CTD targets in HCC based on network pharmacology and RNA-seq approaches. The mRNA levels of target genes were analyzed by qRT-PCR, and the corresponding protein levels were confirmed using enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining (IHC). ChIP-seq data were visualized by IGV software. The associations of gene transcript levels with the cancer immune score and infiltration level were investigated using TIMER. In vivo, the H22 mouse model of hepatocellular carcinoma was established by treatment with CTD and 5-Fu. The immune cell proportions in the blood were elevated in model mice, as shown by flow cytometry. Results We identified 58 targets of CTD, which were involved in various pathways in cancer, including apoptosis, the cell cycle, EMT and immune pathways. Moreover, we found that 100 EMT-related genes were differentially expressed after CTD treatment in HCC cells. Interestingly, our results confirmed that the EZH2/H3K27me3 -related cell cycle pathway is a therapeutic target of CTD in antitumour. In addition, we evaluated the influence of CTD on the immune response. Our data showed that the significantly enriched gene sets were positively correlated with the chemokine biosynthetic and chemokine metabolic modules. The proportions of CD4+/CD8 + T cells and B cells were increased, but the proportion of Tregs was decreased after treatment with CTD in vivo. Moreover, we found that the expression of the inflammatory factor and immune checkpoint genes PD­1/PD-L1 was significantly reduced in the mouse model. Conclusion We performed a novel integrated analysis of the potential role of CTD in HCC treatment. Our results provide innovative insight into the mechanism by which cantharidin exerts antitumour effects by regulating target genes expression to mediate apoptosis, EMT, cell cycle progression and the immune response in HCC. Based on the effect of CTD on the immune response, it can be used as a potential effective drug to activate antitumour immunity for the treatment of liver cancer.

Background Hepatitis B virus (HBV)-encoded X antigen, HBx, assists in the development of hepatocellular carcinoma (HCC) through complex mechanisms. Our results provide new insights into the EZH2 epigenetic repression of let-7c that promotes HCC migration induced by HBx. Thus, let-7c and HMGA2 represent key diagnostic markers and potential therapeutic targets for the treatment of HBV-related HCC. Results We investigated the epigenetic regulation of let-7c, an important representative miRNA in liver tumor metastasis, in human HCC cells to verify the effect of HBx. Based on quantitative PCR (qPCR) of mRNA isolated from tumor and adjacent non-tumor liver tissues of 24 patients with HBV-related HCC, EZH2 expression was significantly overexpressed in most HCC tissues (87.5%). We executed a miRNA microarray analysis in paired HBV-related HCC tumor and adjacent non-tumorous liver tissue from six of these patients and identified let-7c, miR-199a-3p, and miR-99a as being downregulated in the tumor tissue. Real-time PCR analysis verified significant downregulation of let-7c and miR-99a in both HepG2X and Hep3BX cells, which stably overexpress HBx, relative to parental cells. HBX enhanced EZH2 expression and attenuated let-7c expression to induce HMGA2 expression in the HCC cells. Knockdown of HMGA2 significantly downregulated the metastatic potential of HCC cells induced by HBx. Conclusions The deregulation of let-7c expression by HBx may indicate a potential novel pathway through deregulating cell metastasis and imply that HMGA2 might be used as a new prognostic marker and/or as an effective therapeutic target for HCC.

Introduction: Fu-Fang-Jin-Qian-Cao is a Chinese herbal preparation used to treat urinary calculi. Fu-Fang-Jin-Qian-Cao can protect renal tubular epithelial cells from calcium oxalate-induced renal injury by inhibiting ROS-mediated autopathy. The mechanism still needs further exploration. Metabonomics is a new subject; the combination of metabolomics and network pharmacology can find pathways for drugs to act on targets more efficiently Methods: Comprehensive metabolomics and network pharmacology to study the mechanism of Fu-Fang-Jin-Qian-Cao inhibiting autophagy in calcium oxalate-induced renal injury. Based on UHPLC-Q-TOF-MS, combined with biochemical analysis, a mice model of Calcium oxalate-induced renal injury was established to study the therapeutic effect of Fu-Fang-Jin-Qian-Cao. Based on the network pharmacology, the target signaling pathway and the protective effect of Fu-Fang-Jin-Qian-Cao on Calcium oxalate-induced renal injury by inhibiting autophagy were explored. Autophagy-related proteins LC3-II, BECN1, ATG5, and ATG7 were studied by immunohistochemistry. Results: Combining network pharmacology and metabolomics, 50 differential metabolites and 2482 targets related to these metabolites were found. Subsequently, the targets enriched in PI3K-Akt, MAPK and Ras signaling pathways. LC3-II, BECN1, ATG5 and ATG7 were up-regulated in Calcium oxalate-induced renal injury. All of them could be reversed after the Fu-Fang-Jin-Qian-Cao treatment. Conclusions: Fu-Fang-Jin-Qian-Cao can reverse ROS-induced activation of the MAPK signaling pathway and inhibition of the PI3K-Akt signaling pathway, thereby reducing autophagy damage of renal tubular epithelial cells in Calcium oxalate-induced renal injury.

PurposeThough copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.MethodsWe performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.ResultsOf the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.ConclusionPairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

Adults with Hirschsprung disease (HD), unaffected parents of children with HD, and affected adults with an affected child completed a cross-sectional survey with open-ended questions about greatest needs at diagnosis and at current time, greatest challenges encountered, and any benefits of having HD or having a child with HD. In the 297 respondents, information and good medical care were common needs at diagnosis and at the time of survey, but the information needed evolved with time. Managing ongoing symptoms was a frequently cited need and challenge, along with managing medical care and the social and emotional impact of HD. Perceived benefits included empathy for others and new perspectives on life. The needs and challenges identified in this study can guide healthcare providers in discussions with families. Provision of information, recommendations, and referrals based on each individual family's needs can support families with HD throughout the lifecycle and facilitate adaptation.