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With speeding up development of 5 G chips, high-efficient thermal structure and precise management of tremendous heat becomes a substantial challenge to the power-hungry electronics. Here, we demonstrate an interpenetrating architecture of electrocaloric polymer with highly thermally conductive pathways that achieves a 240% increase in the electrocaloric performance and a 300% enhancement in the thermal conductivity of the polymer. A scaled-up version of the device prototype for a single heat spot cooling of 5 G chip is fabricated utilizing this electrocaloric composite and electromagnetic actuation. The continuous three-dimensional (3-D) thermal conductive network embedded in the polymer acts as nucleation sites of the ordered dipoles under applied electric field, efficiently collects thermal energy at the hot-spots arising from field-driven dipolar entropy change, and opens up the high-speed conduction path of phonons. The synergy of two components, thus, tackles the challenge of sluggish heat dissipation of the electroactive polymers and their contact interfaces with low thermal conductivity, and more importantly, significantly reduces the electric energy for switching the dipolar states during the electrocaloric cycles, and increases the manipulable entropy at the low fields. Such a feasible solution is inevitable to the precisely fixed-point thermal management of next-generation smart microelectronic devices. Efficient thermal structure and precise heat management become a substantial challenge for electronics. Here, authors utilize the synergistic effect of classic heat transfer and electrocaloric cooling for fixed-point thermal management of chips.

Anaerobic oxidation of methane (AOM) reduces methane emissions from marine ecosystems but we know little about AOM in rivers, whose role in the global carbon cycle is increasingly recognized. We measured AOM potentials driven by different electron acceptors, including nitrite, nitrate, sulfate, and ferric iron, and identified microorganisms involved across contrasting riverbeds. AOM activity was confined to the more reduced, sandy riverbeds, whereas no activity was measured in the less reduced, gravel riverbeds where there were few anaerobic methanotrophs. Nitrite-dependent and nitrate-dependent AOM occurred in all sandy riverbeds, with the maximum rates of 61.0 and 20.0 nmol CO 2 g −1 (dry sediment) d − 1 , respectively, while sulfate-dependent and ferric iron-dependent AOM occurred only where methane concentration was highest and the diversity of AOM pathways greatest. Diverse Candidatus Methylomirabilis oxyfera ( M. oxyfera )-like bacteria and Candidatus Methanoperedens nitroreducens ( M. nitroreducens )-like archaea were detected in the sandy riverbeds (16S rRNA gene abundance of 9.3 × 10 5 to 1.5 × 10 7 and 2.1 × 10 4 to 2.5 × 10 5 copies g − 1 dry sediment, respectively) but no other known anaerobic methanotrophs. Further, we found M. oxyfera -like bacteria and M. nitroreducens -like archaea to be actively involved in nitrite- and nitrate/ferric iron-dependent AOM, respectively. Hence, we demonstrate multiple pathways of AOM in relation to methane, though the activities of M. oxyfera -like bacteria and M. nitroreducens -like archaea are dominant.

Grafting of C7 from the nonparalyzed to the paralyzed side in patients with arm paralysis resulted in greater improvements in power, spasticity, and function at 12 months than rehabilitation therapy alone, and functional connection to the ipsilateral cerebral hemisphere developed.

The development of multi‐drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5‐FU. Compared with QBC939 cells, a rounder shape, a higher nuclear–cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5‐FU cells. P‐glycoprotein (P‐gp) and β‐catenin were upregulated in QBC939/5‐FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/β‐catenin pathway by β‐catenin siRNA reversed the MDR of QBC939/5‐FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/β‐catenin pathway resulted in upregulation of P‐gp and contributed to MDR of QBC939/5‐FU cells. Extraction of Siamese Crocodile 3 (ESC‐3) bile enhanced the drug sensitivity of QBC939/5‐FU cells to 5‐FU, paralleled with downregulation of β‐catenin and P‐gp. The association of Wnt/β‐catenin pathway and P‐gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/β‐catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.

Long noncoding RNAs (lncRNAs) can compete with endogenous RNAs to modulate the gene expression and contribute to oncogenesis and tumor metastasis. lncRNA NKX2‐1‐AS1 (NKX2‐1 antisense RNA 1) plays a pivotal role in cancer progression and metastasis; however, the contribution of aberrant expression of NKX2‐1‐AS1 and the mechanism by which it functions as a competing endogenous RNA (ceRNA) in gastric cancer (GC) remains elusive. NKX2‐1‐AS1 expression was detected in paired tumor and nontumor tissues of 178 GC patients by quantitative reverse transcription PCR (qRT‐PCR). Using loss‐of‐function and gain‐of‐function experiments, the biological functions of NKX2‐1‐AS1 were evaluated both in vitro and in vivo. Further, to assess that NKX2‐1‐AS1 regulates angiogenic processes, tube formation and co‐culture assays were performed. RNA binding protein immunoprecipitation (RIP) assay, a dual‐luciferase reporter assay, quantitative PCR, Western blot, and fluorescence in situ hybridization (FISH) assays were performed to determine the potential molecular mechanism underlying this ceRNA. The results indicated that NKX2‐1‐AS1 expression was upregulated in GC cell lines and tumor tissues. Overexpression of NKX2‐1‐AS1 was significantly associated with tumor progression and enhanced angiogenesis. Functionally, NKX2‐1‐AS1 overexpression promoted GC cell proliferation, metastasis, invasion, and angiogenesis, while NKX2‐1‐AS1 knockdown restored these effects, both in vitro and in vivo. RIP and dual‐luciferase assays revealed that the microRNA miR‐145‐5p is a direct target of NKX2‐1‐AS1 and that NKX2‐1‐AS1 serves as a ceRNA to sponge miRNA and regulate angiogenesis in GC. Moreover, serpin family E member 1 (SERPINE1) is an explicit target for miR‐145‐5p; besides, the NKX2‐1‐AS1/miR‐145‐5p axis induces the translation of SERPINE1, thus activating the VEGFR‐2 signaling pathway to promote tumor progression and angiogenesis. NKX2‐1‐AS1 overexpression is associated with enhanced tumor cell proliferation, angiogenesis, and poor prognosis in GC. Collectively, NKX2‐1‐AS1 functions as a ceRNA to miR‐145‐5p and promotes tumor progression and angiogenesis by activating the VEGFR‐2 signaling pathway via SERPINE1. This study revealed that NKX2‐1‐AS1 might serve as an independent prognostic biomarker in gastric cancer (GC). NKX2‐1‐AS1 promotes cell proliferation and tumor angiogenesis in GC. Moreover, NKX2‐1‐AS1 directly targets miR‐145‐5p to upregulate SERPINE1 and promote tumor progression and angiogenesis in a VEGFR‐2‐dependent manner.

The process of nitrite-dependent anaerobic methane oxidation (n-damo) was recently discovered and shown to be mediated by \"Candidatus Methylomirabilis oxyfera\" (M. oxyfera). Here, evidence for n-damo in three different freshwater wetlands located in southeastern China was obtained using stable isotope measurements, quantitative PCR assays, and 16S rRNA and particulate methane monooxygenase gene clone library analyses. Stable isotope experiments confirmed the occurrence of n-damo in the examined wetlands, and the potential n-damo rates ranged from 0.31 to 5.43 nmol CO2 per gram of dry soil per day at different depths of soil cores. A combined analysis of 16S rRNA and particulate methane monooxygenase genes demonstrated that M. oxyfera-like bacteria were mainly present in the deep soil with a maximum abundance of 3.2 × 107 gene copies per gram of dry soil. It is estimated that ∼0.51 g of CH4 m-2 per year could be linked to the n-damo process in the examined wetlands based on the measured potential n-damo rates. This study presents previously unidentified confirmation that the n-damo process is a previously overlooked microbial methane sink in wetlands, and n-damo has the potential to be a globally important methane sink due to increasing nitrogen pollution.

BACKGROUNDA previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODSPatients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations' phenotypes over time.RESULTSMultiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSIONThese data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATIONClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDINGSean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST , DAPK1 , CR2 , KIF16B , NPIPB15 , SYTL2 , ZNF91 , and KIAA0586 . With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research. The ChangKang (Heathy Bowel) project was established to collect molecular and clinical information of a thousand Chinese colorectal cancer patients. Here, the authors present the genomic landscape of the ChangKang cohort and find a subgroup of patients defined by abnormal mitochondrial copy numbers.

Background Infective aortitis (IA) with vegetation formation is a rare but potentially life-threatening complication in patients with heart transplantation (HTx). IA caused by Corynebacterium striatum (C. striatum) has scarcely been reported. Herein, we present a case of IA caused by C. striatum in a young man eight months after his second orthotopic HTx. Case presentation We present a case of IA caused by C. striatum in a young man eight months after his second orthotopic HTx. The clinical course was complicated by recurrent fever, persistent bacteremia, anemia, and multiple peripheral arterial embolisms. While transthoracic echocardiography (TTE) revealed normal cardiac valves and endocardium, transesophageal echocardiography (TEE) confirmed an intraluminal mass in the anastomotic site of ascending aortic. The patient declined surgical intervention but responded well to medical therapy. He got resolution of infection following 6 weeks of vancomycin and remained well upon 34 months of follow-up without recurrent fever or new embolic events. Conclusions This case highlights the importance of evaluating the anastomotic site of ascending aortic in the context of bacteremia for HTx recipients, especially when routine TTE shows no valvular or endocardial involvement.

Background Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. Objective The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. Methods Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as ‘proof of concept’ compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. Results The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. Conclusion A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.