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Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC. The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

Abstract Background We conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. Exploratory objectives included correlative studies of immune marker expression, tumor evolution, and immune infiltration in response to treatment. Patients and Methods Adult patients with histologically confirmed BTC were enrolled and received oxaliplatin and pembrolizumab on day 1 of cycles 1-6. Capecitabine was administered orally twice daily as intermittent treatment, with the first dose on day 1 and the last dose on day 14 of cycles 1-6. Starting on cycle 7, pembrolizumab monotherapy was continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, tolerability, feasibility, and response rate. Immunohistochemistry (IHC) for PD-L1 and immune infiltrates was analyzed in paired tumor biopsies, as well as bulk transcriptome and exome profiling for five patients and single-cell RNA sequencing for one partial responder. Results Eleven patients enrolled, three of whom had received no prior systemic therapy. Treatment was well tolerated, and the most common treatment-related grade 3 or 4 adverse events were lymphocytopenia, anemia, and decreased platelet count. Three patients (27.3%) achieved a partial response, and six (54%) had stable disease. The disease control rate was 81.8%. The median PFS was 4.1 months with a 6-month PFS rate of 45.5%. Molecular profiling suggests qualitative differences in immune infiltration and clonal evolution based on response. Conclusion Capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. This study highlights a design framework for the precise characterization of individual BTC tumors. Trial Registration This study was registered in ClinicalTrials.gov (NCT03111732). This article reports results of a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin in patients with advanced biliary tract carcinoma to assess response rate and clinical efficacy.

The cyanobacterium Trichodesmium fixes as much as half of the nitrogen (N2) that supports tropical open-ocean biomes, but its growth is frequently limited by iron (Fe) availability1,2. How future ocean warming may interact with this globally widespread Fe limitation of Trichodesmium N2 fixation is unclear3. Here, we show that the optimum growth temperature of Fe-limited Trichodesmium is ~5 °C higher than for Fe-replete cells, which results in large increases in growth and N2 fixation under the projected warmer Fe-deplete sea surface conditions. Concurrently, the cellular Fe content decreases as temperature rises. Together, these two trends result in thermally driven increases of ~470% in Fe-limited cellular iron use efficiencies (IUEs), defined as the molar quantity of N2 fixed by Trichodesmium per unit time per mole of cellular Fe (mol N2 fixed h–1 mol Fe–1), which enables Trichodesmium to much more efficiently leverage the scarce available Fe supplies to support N2 fixation. Modelling these results in the context of the IPCC representative concentration pathway (RCP) 8.5 global warming scenario4 predicts that IUEs of N2 fixers could increase by ~76% by 2100, and largely alleviate the prevailing Fe limitation across broad expanses of the tropical Pacific and Indian Oceans. Thermally enhanced cyanobacterial IUEs could increase future global marine N2 fixation by ~22% over the next century, and thus profoundly alter the biology and biogeochemistry of open-ocean ecosystems.

Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1 -deficient mice, we found that Sirt1 and Period 2 ( Per2 ) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1 -deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2 , the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.

A low-profile broadband circularly polarized (CP) crossed-dipole antenna is proposed. In this antenna, the dipole uses a fractal-based structure with multiple similar patches for obtaining broadband CP radiation and impedance matching. The incorporation of the crossed-dipole antenna with four triangular parasitic patches improves both the impedance and axial ratio (AR) bandwidths. Four parasitic coupled inverted-L metal plates are loaded on the ground plane to significantly enhance the AR bandwidth and reduce the antenna profile. The measured results are in agreement with the simulations, which demonstrates that the proposed antenna has a low profile of 0.18 λ 0 , a − 10 dB impedance bandwidth of 91% (2.78–7.42 GHz), a 3 dB AR bandwidth of 81.5% (2.99–7.1 GHz), and a good right hand circular polarization (RHCP) radiation pattern with an average gain of 7.9 dBi over the whole operating band.

Background HIF-1α is thought to be a novel regulator which contributes to carcinogenesis. However, the mechanism underlying the effect of HIF-1α in gliomas remains largely unknown. Methods In the research, we demonstrate that HIF-lα mRNA and protein levels are elevated in glioma cells. The colony formation assays, transwell assays, and wound-healing assays showed that overexpression of HIF-1α promoted proliferation and invasion of glioma cells. Results Overexpression of HIF-lα also increased the expression of inflammatory factors related to pyrolysis (TNF-α, IL-10, and IL-1β) and protein related to pyrolysis signal pathway (NLRP3, ASC, caspase-1, GSDMD, and GSDME). Conclusions Therefore, we speculate that HIF-1α promotes the proliferation and invasion of glial cells by regulating pyrolysis pathway. These results might provide a novel strategy and target for treatment of glioma.

Background Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. Methods We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. Results The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P  < 0.05), and 80% of the patients had a clear history of exposure to cattle and sheep. Moreover, 19 (54%) cases were hospitalized with FUO, among which the patients with epidemiological histories were significantly more than those without ( P  < 0.05). The incidence of toxic hepatitis in FUO patients was higher than that in non-FUO patients (89% vs. 50%, P  < 0.05). Meanwhile, the misdiagnosis rate was considerably higher in the FUO group than in the non-FUO group (100% vs. 63%; P  < 0.05). Conclusion Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.

To enhance the gravimetric specific capacity of Lithium-Sulfur battery electrodes, it is significant to develop a host material capable of accommodating sufficient sulfur. This host not only provides a space for binding of Li and S elements, but also effectively suppresses the dissolution of lithium polysulfide in the electrolyte, avoiding capacity loss. Herein, a composite carrier consisting of CeO 2 nanoparticles, sulfur, and Ti 3 C 2 T F was prepared through the hydrothermal method and the ball-milling method. This hierarchical structure enables efficient sulfur entrapment and dynamic storage. Benefiting from these structural advantages, the composite with 60.2 wt% sulfur exhibits an outstanding initial discharge capacity of 1714.57 mAh g ‐1 at 1C. Remarkably, after 1000 cycles, it maintains a reversible capacity of 1714.41 mAh g ‐1 , corresponding to a capacity retention of 99.94%. The composite material incorporating carbon nanotubes (CNTs) offers a higher initial discharge capacity (2211.28 mAh g ‐1 ), yet under identical cycling conditions, its capacity retention rate is 99.92% (2209.55 mAh g ‐1 ).

Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC-specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs.

Background Stroke and its related complications, place significant burdens on human society in the twenty-first century, and lead to substantial demands for upper limb rehabilitation. To fulfill the rehabilitation needs, human–machine interaction (HMI) technology strives continuously. Depends on the involvement of subject, HMI strategy can be classified as passive or active. Compare to passive modalities, active strategies are believed to be more effective in promoting neuroplasticity and motor recovery for post-stroke survivors in sub-acute and chronic phase. However, post-stroke survivors usually experience weak upper arms, limited range of motion (ROM) and involuntary excessive movement patterns. Distinguishing between complex subtle motion intentions and excessive involuntary movements in real-time remains a challenge in current research, which impedes the application of active HMI strategies in clinical practice. Method An Up-limb Rehabilitation Device and Utility System (UarDus) is proposed along with 3 HMI strategies namely robot-in-charge, therapist-in-charge and patient-in-charge. Based on physiological structure of human upper-limb and scapulohumeral rhythm (SHR) of shoulder, a base exoskeleton with 14 degrees of freedoms (DoFs) is designed as foundation of the 3 strategies. Passive robot-in-charge and therapist-in-charge strategies provides fully-assisted rehabilitation options. The active patient-in-charge strategy incorporates data acquisition matrices and a new deep learning model, which is developed based on Convolutional Neural Network (CNN) and Transformer structure, aims to capture subtle motion intentions. Motors’ current is monitored and the surge in the current is identified adopting Discrete Wavelet Transform (DWT) method for safety concerns. Results Kinematically, the work space of the base exoskeleton is presented first. Utilizing motion capture technology, the glenohumeral joint (GH) centers of both human and exoskeleton exhibit well-matched motion curves, suggesting a comfortable dynamic wear experience. For robot-in-charge and therapist-in-charge strategy, the desired and measured angle-time curve present good correlation, with low phase difference, which serve the purpose of real-time control. Featuring the patient-in-charge strategy, Kernel Density Estimation (KDE) result suggesting reasonable sensor-machine-human synergy. Applying K-fold (K = 10) cross-validation method, the classification accuracy of the proposed model with outstanding response time achieves an average of 99.7% for the designated 15 actions, signifies its capability for subtle motion intention recognition in real-time. Additionally, signal surge is easily identified with DWT. Conclusions An upper-limb exoskeleton hardware device named UarDus is constructed, along with three HMI modalities, offering both passive and active rehabilitation approaches. The proposed system is validated through a proof-of-concept study on a subject who underwent a craniotomy for a hemorrhagic stroke, demonstrating the possibility for post-stroke individuals to engage in safe, personalized rehabilitation training in real-time, with a dynamically comfortable wear experience.