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Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Because of its paramount importance in the successful industrial control strategy of a given heat exchanger network (HEN), the control structure designs for providing appropriate manipulated variable (MV) and controlled variable (CV) pairings have received considerable attention. However, quite frequently HENs with such control structures face the problem of hard constraints, typically holding the HENs at less controlled operating space. So both the MV pairings and the above control pairings should be considered to design a control structure. This paper investigates the systematic incorporation of the two pairings, and presents a methodology for designing such two-tier control structure. This is developed based on the sequential strategy, coupling an indirect-tier with direct-tier control structure design, wherein the intention is realized in the former stage and the latter is implemented for further optimization. The MV identification and pairing are achieved through variations in heat load of heat exchangers to design the indirect-tier control structure. Then the direct-tier control structure is followed the relative gain array (RGA) pairing rules. With the proposed methodology, on the one hand, it generates an explicit connection between the MV pairings and the HEN configuration, and the quantitative interaction measure is improved to avoid the multiple solutions to break the relationship among all the control pairings into individuals; on the other hand, a two-tier control structure reveals control potentials and control system design requirements, this may avoid complex and economically unfavourable control and HEN structures. The application of proposed framework is illustrated with two cases involving the dynamic simulation analysis, the quantitative assessment and the random test.

Adult mammals have limited capacity to regenerate functional cells. Promisingly, in vivo transdifferentiation heralds the possibility of regeneration by lineage reprogramming from other fully differentiated cells. However, the process of regeneration by in vivo transdifferentiation in mammals is poorly understood. Using pancreatic β cell regeneration as a paradigm, we performed a single-cell transcriptomic study of in vivo transdifferentiation from adult mouse acinar cells to induced β cells. Using unsupervised clustering analysis and lineage trajectory construction, we uncovered that the cell fate remodeling trajectory was linear at the initial stage and the reprogrammed cells either evolved to induced β cells or toward a “dead-end” state after day 4.Moreover, functional analyses identified both p53 and Dnmt3a that acted as reprogramming barriers during the process of in vivo transdifferentiation. Collectively, we decipher a high-resolution roadmap of regeneration by in vivo transdifferentiation and provide a detailed molecular blueprint to facilitate mammalian regeneration.

BackgroundThis study aimed to establish an effective model for preoperative prediction of tumor deposits (TDs) in patients with rectal cancer (RC). MethodsIn 500 patients, radiomic features were extracted from magnetic resonance imaging (MRI) using modalities such as high-resolution T2-weighted (HRT2) imaging and diffusion-weighted imaging (DWI). Machine learning (ML)-based and deep learning (DL)-based radiomic models were developed and integrated with clinical characteristics for TD prediction. The performance of the models was assessed using the area under the curve (AUC) over five-fold cross-validation.ResultsA total of 564 radiomic features that quantified the intensity, shape, orientation, and texture of the tumor were extracted for each patient. The HRT2-ML, DWI-ML, Merged-ML, HRT2-DL, DWI-DL, and Merged-DL models demonstrated AUCs of 0.62 ± 0.02, 0.64 ± 0.08, 0.69 ± 0.04, 0.57 ± 0.06, 0.68 ± 0.03, and 0.59 ± 0.04, respectively. The clinical-ML, clinical-HRT2-ML, clinical-DWI-ML, clinical-Merged-ML, clinical-DL, clinical-HRT2-DL, clinical-DWI-DL, and clinical-Merged-DL models demonstrated AUCs of 0.81 ± 0.06, 0.79 ± 0.02, 0.81 ± 0.02, 0.83 ± 0.01, 0.81 ± 0.04, 0.83 ± 0.04, 0.90 ± 0.04, and 0.83 ± 0.05, respectively. The clinical-DWI-DL model achieved the best predictive performance (accuracy 0.84 ± 0.05, sensitivity 0.94 ± 0. 13, specificity 0.79 ± 0.04).ConclusionsA comprehensive model combining MRI radiomic features and clinical characteristics achieved promising performance in TD prediction for RC patients. This approach has the potential to assist clinicians in preoperative stage evaluation and personalized treatment of RC patients.

ObjectiveRed blood cell (RBC) parameters are associated with outcomes following aneurysmal subarachnoid hemorrhage (aSAH), but their predictive value remains uncertain. This study aimed to detect the association between RBC parameters and functional outcome in aSAH patients undergoing surgical clipping.MethodsThis retrospective observational study included aSAH patients who underwent surgical clipping at Affiliated Hospital of North Sichuan Medical College between August 2016 and September 2019. The functional outcome following aSAH was assessed by modified Rankin Scale (mRS), and mRS 3–6 was defined as poor functional outcome.ResultsOut of 187 aSAH patients included (62% female, 51–66 years old), 73 patients had poor functional outcome. Multivariate logistic regression of admission parameters showed that World Federation of Neurosurgical Societies (WFNS) grade (odds ratio [95% CI]: 1.322 [1.023–1.707], p = 0.033) and white blood cell (WBC) (odds ratio [95% CI]: 1.136 [1.044–1.236], p = 0.003) were independently associated with poor functional outcome. In postoperative parameters, RBC distribution width (RDW) (odds ratio [95% CI]: 1.411 [1.095–1.818], p = 0.008), mean platelet volume (MPV, odds ratio [95% CI]: 1.253 [1.012–1.552], p = 0.039) and admission WFNS grade (odds ratio [95% CI]: 1.439 [1.119–1.850], p = 0.005) were independently associated with poor functional outcome. The predictive model including WFNS grade, admission WBC, and postoperative RDW and MPV had significantly higher predictive power compared to WFNS grade alone (0.787 [0.722–0.852] vs. 0.707 [0.630–0.784], p = 0.024). The combination of WFNS grade and WBC on admission showed the highest positive predictive value (75.5%) and postoperative RDW and MPV combined with admission WFNS grade and WBC showed the highest negative predictive value (83.7%).ConclusionPostoperative RDW is independently associated with poor functional outcome in aSAH patients undergoing surgical clipping. A combined model containing postoperative RDW may help predict good outcome in patients with aSAH after timely aneurysm clipping.

To establish nutrition knowledge questionnaire items for Chinese adults by Delphi consensus study.The framework system and preliminary items of nutrition knowledge questionnaire were established through literature review and experts consultation, considering the nutrition status and problems of Chinese people. Delphi method was used to conduct consensus analysis with 11 experts in related field involved to determine the nutrition knowledge questionnaire items.The active coefficients of consultation in two rounds were both 100%(11/11), and the authority coefficients of experts were 0.900. The average scores of all items were(4.67±0.28) and(4.80±0.21), the variation coefficients were 0.06 and 0.04, and the Kendall harmony coefficients were 0.261(χ~2=39.645, P=0.004) and 0.324(χ~2=43.122, P=0.001), respectively. After the second round of consultation, all selected items met the inclusion criteria. Finally, 20-item nutrition knowledge questionnaire were determined, including five dimensions of dietary recommendations, food characteristics, nutrition and health, food choices and food safety.The Delphi consensus of nutrition knowledge questionnaire items for Chinese adults were basically achieved.

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

Heat-integrated process synthesis is fundamental to achieve higher energy efficiency. The well-known sequential-conceptual methods have been widely adopted to solve the synthesis problem in a hierarchical manner. However, the natural hierarchy fails to consider complex interactions between the unit operation and the heat integration. To address this issue, a surrogate-based optimization framework is proposed for simultaneous synthesis of chemical process and heat exchanger network. An artificial neural network (ANN)-based surrogate model, derived from the simulation data generated via rigorous mechanism modelling approach, is established for process units to replace their complex realistic models. With surrogate model formulation incorporated into heat integration, an enhanced transshipment-based mixed integer nonlinear programming model is introduced to synthesize heat exchanger network with variable flowrates and temperatures, aiming at the maximized annual profit. Finally, two example studies are investigated to demonstrate the effectiveness of the proposed framework.

Obesity-related muscular dysfunction and relative muscle atrophy affect an increasing number of people. Elucidating the molecular mechanisms of skeletal muscle cell development and growth may contribute to the maintenance of skeletal muscle mass in obesity. Fatty acid translocase (FAT/CD36), as a long-chain fatty acid transport protein, is crucial for lipid metabolism and signaling. CD36 is known to function in myogenic differentiation, and whether it affects the proliferation of skeletal muscle cells and the underlying mechanisms remain unclear. In this study, the effect of CD36 deficiency on skeletal muscle cell viability and proliferation was examined using C2C12 myoblasts. Results showed that the deletion of CD36 enhanced the inhibitory effect of PA on the proliferation and the promotion of apoptosis in skeletal muscle cells. Intriguingly, the silencing of CD36 suppressed cell proliferation by preventing the cell cycle from the G0/G1 phase to the S phase in a cyclin D1/CDK4-dependent manner. Overall, we demonstrated that CD36 was involved in skeletal muscle cell proliferation by cell cycle control, and these findings might facilitate the treatment of obesity-related muscle wasting.

Functional materials with high viscosity and solid materials have received more and more attentions in flexible pressure sensors, which are inadequate in the most used molding method. Herein, laser direct writing (LDW) method is proposed to fabricate flexible piezoresistive sensors with microstructures on PDMS/ MWCNTs composites with an 8% MWCNTs mass fraction. By controlling laser energy, microstructures with different geometries can be obtained, which significantly impacts the performances of the sensors. Subsequently, curved microcones with excellent performance are fabricated under parameters of f = 40 kHz and v = 150 mm·s-1. The sensor exhibits continuous multi-linear sensitivity, ultrahigh original sensitivity of 21.80 % kPa-1, wide detection range of over 20 kPa, response/recovery time of ~100 ms and good cycle stability for more than 1000 times. Besides, obvious resistance variation can be observed when tiny pressure (a peanut of 30 Pa) is applied. Finally, the flexible piezoresistive sensor can be applied for LED brightness controlling, pulse detection and voice recognition.

Ion doping is one of the primary means to enhance the properties of phosphate cathode materials. In this document, the DFT+U method is used to determine the selection of ion doping sites from the energy band perspective and density of state. Further, different contents of niobium-doped LiMn0.6Fe0.4-xNbxPO4(0≤x≤0.2) were obtained by the solid-phase method and synthesized samples were also measured and analyzed. The results show that the ion-doped modification principle is the introduction of impurity bands between the band gaps, and transition metal ions are more inclined to occupy metal sites. LiMn0.6Fe0.25Nb0.15PO4 possesses an excellent electrochemical performance, exhibiting a specific discharge capacity of 156.7 mAh g−1 at 0.2 C. EIS proves that the electrochemical impedance of the sample is significantly reduced, and the lithium-ion diffusion coefficient increase after an appropriate amount of doping.

The possible role of fatty acid translocase (CD36) in the treatment of obesity has gained increasing research interest since researchers recognized its coordinated function in fatty acid uptake and oxidation. However, the effect of CD36 deficiency on intracellular insulin signaling is complex and its impact may depend on different nutritional stresses. Therefore, we investigated the various effects of CD36 deletion on insulin signaling in C2C12 myotubes with or without palmitic acid (PA) overload. In the present work, we reported the upregulated expression levels of CD36 in the skeletal muscle tissues of obese humans and mice as well as in C2C12 myotubes with PA stimulation. CD36 knockdown using RNA interference showed that insulin signaling was impaired in CD36-deficient C2C12 cells in the absence of PA loading, suggesting that CD36 is essential for the maintenance of insulin action, possibly resulting from increased mitochondrial dysfunction and endoplasmic reticulum (ER) stress; however, CD36 deletion improved insulin signaling in the presence of PA overload due to a reduction in lipid overaccumulation. In conclusion, we identified differential roles of CD36 in regulating muscle insulin response under conditions with and without PA overload, which provides supportive evidence for further research into therapeutic approaches to diabetes.

Triethylene glycol (TEG) is widely applied to the removal of water in shale gas. This study presents a framework of economic evaluation and environmental assessment for two TEG-based dehydration approaches, namely, conventional dehydration process and stripping gas dehydration process. The latter one features a higher solvent concentration, at the expense of extra shale gas loss. On the basis of process simulation, the effects of theoretical stage and solvent concentration on economic and environmental performances are investigated for process optimization. A hybrid life cycle inventory (LCI) model that consists of input-output and process-based methods is developed to evaluate the environmental impacts associated with shale gas dehydration. The results show that utility consumption and shale gas loss are dominant sources for the emissions of CO2 and NOx, while soot is mainly derived from embodied emissions. Based on the tradeoff between the total annual cost and environmental impacts, the optimal case with superior economic and environmental performances is acquired. Ultimately, sensitivity analyses are conducted for systematic comparison of two approaches under different compositions of raw shale gas and specifications of water removal.

Background Liver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeting TGF‐β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF‐β/Smad7 signaling. Methods A meta‐analysis was performed to evaluate CKI intervention on viral hepatitis‐induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl4) injection or methionine‐choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF‐β/Smad signaling and typical fibrosis‐related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT‐PCR, Western blotting, RNA‐seq, immunofluorescence, and immunohistochemistry. Results Based on meta‐analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF‐βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI. Conclusions Our results unveil the approach of CKI in rebalancing TGF‐β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis., 1. CKI ‐suppresses liver fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. 2. CKI inhibits HSCs activation by stabilizing the interaction of Smad7/TGFβR1 to rebalance Smad2/Smad3 signaling, acting as an alternative approach to target TGF‐β signaling. 3. High expression of Smad7 and low expression of TGFβR1 in HCC tumors and surrounding normal liver tissues can be tumor suppressive.

Cancers that are histologically defined as the same type of cancer often need a distinct therapy based on underlying heterogeneity; likewise, histologically disparate cancers can require similar treatment approaches due to intrinsic similarities. A comprehensive analysis integrated with drug response data and genomic alterations, particularly to reveal therapeutic concordance mechanisms across histologically disparate tumour subtypes, has not yet been fully exploited.In this study, we used pharmacogenomic profiling data provided from the Cancer Genome Project (CGP) in a systematic in silico investigation of the pharmacological subtypes of cancers and the intrinsic concordance of molecular mechanisms leading to similar therapeutic responses across histologically disparate tumour subtypes. We further developed a novel approach to redefine cell-to-cell similarity and drug-to-drug similarity from the therapeutic concordance, providing a new point of view to study cancer heterogeneity.Our study identified that histologically different tumours, such as malignant melanoma and colorectal adenocarcinoma, could belong to the same pharmacological subtype regarding drug sensitivity to MEK inhibitors, which was determined by their genomic alterations, high occurrence of BRAF or KRAS mutations. Therapeutic concordance for chemotherapy drugs was identified across histologically disparate hematological tumors mainly due to the extraordinary activation of the cell cycle in blood cancers. A subcluster of SCLC had a more similar profile with hematological tumors, and was associated with the malignant phenotype, with a higher level of MYC expression. We developed a website to store and visualize the pharmacological subtypes of drugs, as well as their connected genomic and expression alterations.

In recent years, rehabilitation robot has received great attention. A large number of rehabilitation robots have been developed for gait training and walking assistance, but there are few applications for early rehabilitation after stroke. This paper presents a rehabilitation robot for progressive rehabilitation evaluated by surface electromyography (sEMG) and contact force signal. In order to make the trajectory planning of rehabilitation robot conform to the human bipedal walking, the structure design was based on multi-link. The rehabilitation robot can operate in three modes, each mode provides specific degree of assistance. When subjects doing rehabilitation training by the robot, sEMG from six lower limb muscles was collected to evaluate muscle activation. Meanwhile contact force between rehabilitation robot and subjects was also recorded for analysis. As assistance degree increased, lower limb activation and contact force decreased. It indicated different assistance demand of subjects in progressive treatment. For the rehabilitation robot, specific rehabilitation mode can be selected by subjects with different level dysfunction of lower extremities based on sEMG and contact force.

Human embryonic stem cells (hESCs) derived β cells (SC-β cells) hold great promise for diabetes treatment, yet how to achieve functional maturation of these SC-β cells and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remain elusive. By single cell RNA-seq pseudotime analysis, we revealed that ZnT8 is involved in SC-β cells functional maturation process and its loss of function (LOF) accelerates functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) and enhances proinsulin to insulin conversion efficiency in SC-β cells, both in vitro and in vivo, by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, SC-β cells with ZnT8 LOF are resistant to metabolic stresses induced cell death, as lipotoxicity or glucotoxicity, displaying higher survival. Most importantly, transplantation of SLC30A8-/- SC-β cells into diabetic mice significantly improves glycemia restoration and SC-β cell survival with long-term stability. Therefore, our study offers an advanced cell replacement therapy for diabetes with both improved SC-β cell survival and function against metabolic stress.

Human embryonic stem cell-derived β cells (SC-β cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-β cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-β cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-β cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-β cells that are useful as a potential source for cell replacement therapies.

This work aims to develop and techno-economically analyze a novel coal-based polygeneration process of Molten Carbonate Fuel Cell (MCFC) and methane synthesis with a waste heat recovery system. In this process, the unshifted syngas without entering Rectisol is directly mixed with a part of H2-rich syngas to reduce the energy consumption of Rectisol and flexibly adjust the H/C ratio. An extended Duran-Grossmann (D-G) model for waste heat recovery steam cycle optimization is proposed by conducting Heat Integration among the whole process. According to techno-economic analysis, the annual capital cost of the proposed system is 50,006,000 $, the overall exergy efficiency is 56.3 %. Compared with the base plant, the MCFC with power generation of 16.98 MW is applied instead of the Rankine cycle (RC), which results in a 14 % increase in the efficiency of the power generation system. The major contributions derived from this work are of significant aid in highlighting strong potentials for overall performance enhancement via polygeneration optimization.

Glioblastoma (GBM) is an incurable and highly heterogeneous brain tumor, originating from human neural stem/progenitor cells (hNSCs/hNPCs) years ahead of diagnosis. Despite extensive efforts to characterize hNSCs and end-stage GBM at bulk and single-cell levels, the de novo gliomagenic path from hNSCs is largely unknown due to technical difficulties in early-stage sampling and preclinical modeling. Here, we established two highly penetrant hNSC-derived malignant glioma models, which resemble the histopathology and transcriptional heterogeneity of human GBM. Integrating time-series analyses of whole-exome sequencing, bulk and single-cell RNA-seq, we reconstructed gliomagenic trajectories, and identified a persistent NSC-like population at all stages of tumorigenesis. Through trajectory analyses and lineage tracing, we showed that tumor progression is primarily driven by multi-step transcriptional reprogramming and fate-switches in the NSC-like cells, which sequentially generate malignant heterogeneity and induce tumor phenotype transitions. We further uncovered stage-specific oncogenic cascades, and among the candidate genes we functionally validated C1QL1 as a new glioma-promoting factor. Importantly, the neurogenic-to-gliogenic switch in NSC-like cells marks an early stage characterized by a burst of oncogenic alterations, during which transient AP-1 inhibition is sufficient to inhibit gliomagenesis. Together, our results reveal previously undercharacterized molecular dynamics and fate choices driving de novo gliomagenesis from hNSCs, and provide a blueprint for potential early-stage treatment/diagnosis for GBM.

Type 2 diabetes, characterized by malfunction of pancreatic β cells, is affected by multiple cues including sex differences. Nevertheless, mechanisms of sex differences in type 2 diabetes susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq) technology, we showed that sexual dimorphism of transcriptome exists in both mouse and human β cells, and differs significantly in human under diabetic condition. Our analysis further revealed the existence of sex-dependent type 2 diabetes altered genes in both mice and human beings, suggesting divergences in pathological mechanisms of type 2 diabetes between sexes. Our results indicated that sex should be taken into consideration when treating diabetes, which was further validated by the sex-matched and sex-mismatched islet transplantation in mice. Compared to sex-matched transplants, sex-mismatched transplants showed downregulation of genes involved in the longevity regulating pathway in β cells and led to impaired glucose tolerance in diabetic mice. Taken together, our findings could advance current understanding of type 2 diabetes pathogenesis with sexually dimorphic perspectives and provide new insights to the development of precision medicine.

Cell therapy is an emerging and promising regenerative approach by cell replacement for the treatment of diseases or injuries. Hydrogels, featuring high biocompatibility, tunable physicochemical properties, controllable structures, and multiple functionalization possibilities, have been developed as most-frequently-used cell reservoirs. Aiming at treating diseases or injuries with high efficiency, a series of porous and responsive hydrogels have been fabricated for the encapsulation of therapeutic cells. These cell-laden hydrogels have been applied in a broad range of pre-clinical researches of which results have demonstrated hopeful prospects in cell therapy. In this review, we highlight the recent progress of porous and responsive hydrogels used for cell encapsulation towards cell therapy. The hydrogels used for cell therapy are firstly classified. The porosity fabrication strategies of hydrogels are summarized and discussed. The responsive functionalities of hydrogels are surveyed, focusing on temperature-sensitivity, photo-sensitivity, pH-responsivity and biomolecule-sensitivity. Moreover, preclinical researches of hydrogels towards cell therapy, including the treatment of several diseases, such as diabetes mellitus, cancer, neuro disorders, cardiac diseases and bone injuries are discussed.

The use of physical barriers, such as nanofiber membranes, is a potential method to prevent adhesion formation after surgery. In this study, we fabricated electrospun composite poly(ethylene glycol) (PEG)/poly(lactic-co-glycolic) (PLGA) nanofibrous membrane to prevent abdomen adhesion; this composite acts as a barrier between cecum and the surrounding tissues without interrupting mass transfer and cecum healing. PEG/PLGA nanofibrous membranes consisting of 0% (P0), 5% (P1), 10% (P2), 15% (P3), 20% (P4), and 25% (P5) PEG were prepared, and their physicochemical properties were characterized. The P0 shows the highest thermostability, whereas P1 exhibited the most homogenous morphology, the narrowest diameter distribution, and the largest ultimate stress and strain. In vitro cell adhesion and proliferation tests using fibroblasts indicate that all nanofibrous membranes inhibited cell proliferation, with P1 showing the lowest degree of cell attachment. In vivo application of nanofibrous membranes on the repaired site of rat cecum model demonstrated that all of the membranes prevent adhesion formation to a certain extent. We concluded based on gross observation, histological analysis, and functional assays that P1 served as an effective anti-adhesion membrane after cecum surgery in a clinical setting.

Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genesGlucose 6 phosphatase(G6Pase) andPhosphoenolpyruvate carboxykinase(Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genesAcyl-coenzyme A oxidase(Aox) andCarnitine palmitoyltransferase 1a(Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuatesAoxandCpt1aexpression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation.

This paper describes a novel under-actuated lower limb rehabilitation training robot, which can resolve the problem of joint neutrality of the existing lower limb rehabilitation training robots. The presented under-actuated robot system has four linear drives and the linear motion can be transformed into the flexion and extension of lower limbs in the sagittal plane through human-machine connection mechanism. Human-machine coupling model is built, and then forward and inverse kinematic analysis is carried out. Besides, the online identification method of human parameters and connection parameters in coupling system is studied. Finally, based on the above research, the trajectory planning algorithm is studied, and the correctness of the algorithm is verified by simulation.

Compared with direct utilisation as fuel, the downstream processing of shale gas shows great potential in economic competitiveness, in which methanol is a particularly important product. This study simulates a technical route for producing methanol from shale gas, which is evaluated from the points of economic, exergy and environment. The economic target is estimated by purchased cost curves, while exergy analysis demonstrates the distribution of exergy destruction. A hybrid LCI (Life cycle inventory) model is established to assess pollutant emissions by sources. The results show that methane reforming features the highest capital cost, while methanol synthesis requires the highest operating cost. The reaction systems account for 73.3 % of total exergy destruction. Electricity consumption dominates the environmental impacts of the whole process.

The automatic detection of nuclei in pathological images plays an important role in diagnosis and prognosis of cancers. Most nuclei detection algorithms are based on the assumption that the nuclei center should have larger responses than their surroundings in the probability map of the pathological image, which in turn transforms the detection or localization problem into finding the local maxima on the probability map. However, all the existing studies used regression algorithms to determine the probability map, which neglect to take the spatial contiguity within the probability map into consideration. In order to capture the higher-order consistency within the generated probability map, we propose an approach called Residual Attention Generative Adversarial Network (i.e., RAGAN) for nuclei detection. Specifically, the objective function of the RAGAN model combines a detection term with an adversarial term. The adversarial term adopts a generator called Residual Attention U-Net (i.e., RAU-Net) to produce the probability maps that cannot be distinguished by the ground-truth. Based on the adversarial model, we can simultaneously estimate the probabilities of many pixels with high-order consistency, by which we can derive a more accurate probability map. We evaluate our method on a public colorectal adenocarcinoma images dataset with 29756 nuclei. Experimental results show that our method can achieve the F1 Score of 0.847 (with a Precision of 0.859 and a Recall of 0.836) for nuclei detection, which is superior to the conventional methods.

In fMRI analysis, the scientist seeks to aggregate multi-subject fMRI data so that inferences shared across subjects can be achieved. The challenge is to eliminate the variability of anatomical structure and functional topography of the human brain, which calls for aligning fMRI data across subjects. However, the existing methods do not exploit the geometry of the stimuli, which can be inferred by using certain domain knowledge and then serve as a priori. In this paper, such geometry is encoded in a graph matrix, and we propose an algorithm named Graph Hyperalignment for leveraging it. Specifically, a kernel-based optimization is developed to allow for non-linear feature extraction. To tackle overfitting caused by the high-spatial-and-low-temporal resolution of fMRI, the data in the new feature space are assumed to lie in a low-dimensional affine subspace, which can be implicitly integrated into the proposed optimization. Unlike other iterative existing methods, GHA reaches an optimal solution directly. Examining over four real datasets, Graph Hyperaligment achieves superior results to other methods.

Aggregating multi-subject functional magnetic resonance imaging (fMRI) data is indispensable for generating valid and general inferences from patterns distributed across human brains. The disparities in anatomical structures and functional topographies of human brains warrant aligning fMRI data across subjects. However, the existing functional alignment methods cannot handle well various kinds of fMRI datasets today, especially when they are not temporally-aligned, i.e., some of the subjects probably lack the responses to some stimuli, or different subjects might follow different sequences of stimuli. In this paper, a cross-subject graph that depicts the (dis)similarities between samples across subjects is used as a priori for developing a more flexible framework that suits an assortment of fMRI datasets. However, the high dimension of fMRI data and the use of multiple subjects makes the crude framework time-consuming or unpractical. To address this issue, we further regularize the framework, so that a novel feasible kernel-based optimization, which permits nonlinear feature extraction, could be theoretically developed. Specifically, a low-dimension assumption is imposed on each new feature space to avoid overfitting caused by the highspatial-low-temporal resolution of fMRI data. Experimental results on five datasets suggest that the proposed method is not only superior to several state-of-the-art methods on temporally-aligned fMRI data, but also suitable for dealing `with temporally-unaligned fMRI data., Comment: 17 pages, 10 figures, Proceedings of the Association for the Advancement of Artificial Intelligence (AAAI-20)

Human-machine interface (HMI) is the link between Exoskeleton and wearer, and the study of wearing comfort of HMI is of great significance for Exoskeleton robots. On the basis of the analysis of HMI mechanism model, this paper proposes an evaluating method of wearing comfort. By measuring the force of HMI mechanism and combining the wearer's subjective feeling, wearing comfort model is built. Finally, the rationality of wearing comfort model is verified by experimental research.

Coal-based chemical production processes bring severe greenhouse gas emissions. As a significant clean and energy-efficient technology, the polygeneration process has attracted increasing attentions due to its higher energy efficiency, lower production cost and fewer emissions. Towards this end, this work aims to develop a novel coal-based polygeneration process of carbon-capture coal-to-methanol/power and molten carbonate fuel cell (CTMP-MCFC). In the proposed process, coal is first converted to crude syngas. Afterwards, one part of the crude gas is shifted to H2-rich gas, where a part of H2-rich gas goes into the anode of MCFC, and another part of the H2-rich gas mixed with the rest of unshifted syngas goes into the methanol synthesis (MS) unit. The unreacted syngas out of the MS is then sent into the gas turbine (GT) for power generation. The exhausted gas out of the GT goes into the cathode of MCFC for CO2 and O2 supply and CO2 is enriched to the anode for carbon capture simultaneously. Ultimately, waste heat recovery steam cycle at three levels is proposed for global waste heat recovery. An extended pinch-based Duran-Grossmann (D-G) model is introduced to optimize the waste heat utilization. Sensitivity analysis is conducted to investigate the interactive effects of key parameters in MCFC. A comprehensive techno-economic and carbon footprint performance assessment is performed to verify the feasibility of the proposed polygeneration process. Compared with the base plant, carbon footprint shows the great ability to reduce carbon emissions of the proposed system. The product cost of CTMP-MCFC is 12.47 $/GJ and reduced by 1.68%. The exergy efficiency of CTMP-MCFC is improved by 8.53% and the units with the maximum exergy losses are also identified for further energy conservation. The derived significant contributions of this work highlight strong potentials for the overall performance enhancement via an MCFC-integrated polygeneration process.

The downstream production from shale gas to methanol has attracted attention in recent years. However, the traditional thermodynamic modeling method cannot precisely predict process performances. To this end, kinetics-based reaction models of methane reforming and methanol synthesis are developed for a rigorous simulation of this route. The evaluation of process performance is addressed from the perspectives of economics and environment. Then, the effects of reacting temperature and pressure on production cost and pollutant emissions are investigated in the interest of process optimization. The results demonstrate that an increased temperature enhances the conversion of methane in partial oxidation reforming, leading to superior performance in both economics and environment. It is also found that the reforming pressure for lower production cost and emissions tends to increase as temperature elevates. The results shows that the lowest production cost is 58.13 $/t methanol, while the lowest emissions of CO2, SO2, NOx and soot are 124.7 kg/t, 0.181 kg/t, 0.226 kg/t and 0.054 kg/t. Ultimately, a trade-off between the contradictory economic and environmental targets is conducted to acquire the optimal operating condition. The method developed in this study provides guidance to the design and optimization for downstream process of shale gas.

As a sort of emerging unconventional energy, shale gas has extensive market outlook by virtue of its enormous reserves, and concerns for shale gas exploitation and processing have been raised nowadays. Raw shale gas must be processed to achieve certain specifications before it can be transmitted in pipelines or utilized by consumers. Sweetening is a gas conditioning process to decrease the concentration of acid gases such as hydrogen sulfide and carbon dioxide which are not preferred in sales gas in consideration of heating value specification and corrosion prevention. However, the after-treatment of acid gases is not discussed in many research of sweetening process. In this paper, a flowsheet of shale gas sweetening process is established using Aspen Plus v8.6. Dissolution of light gases and weak electrolyte, absorption of acid gases and reactions in electrolyte solution are considered simultaneously in process modelling. Diethanolamine (DEA) solution is employed as the solvent to separate acid gases from raw shale gas. The optimal feed stage of rich solvent regeneration and reflux ratio of regenerator are analysed to optimize the sweetening flowsheet. A three-stage Claus process is simulated coupling with shale gas sweetening process to convert hydrogen sulfide in acid gas to element sulphur for pollution reduction. A principle is proposed to determine the operating temperature of each Claus reactor which is a decisive parameter on sulfur recovery efficiency and performance of Claus process. Ultimately, the sulfur recovery efficiency of the three-stage Claus process proposed in this paper is 97.35 %. The effectivity of the principle is confirmed by the results reported in literatures. Energy synthesis is then adopted to integrate sweetening process with Claus process in both mass and energy flow. The coupled process provides with more streams than a single sweetening or Claus process, promoting the reasonability of energy utilization. Streams are extracted and matched for heat exchanger network (HEN) synthesis to reduce the energy consumption and total annual cost of the whole process.

Direct reprogramming is a promising approach for regenerative medicine whereby one cell type is directly converted into another without going through a multipotent or pluripotent stage. This reprogramming approach has been extensively explored for the generation of functional insulin-secreting cells from non-beta-cells with the aim of developing novel cell therapies for the treatment of people with diabetes lacking sufficient endogenous beta-cells. A common approach for such conversion studies is the introduction of key regulators that are important in controlling beta-cell development and maintenance. In this review, we will summarize the recent advances in the field of beta-cell reprogramming and discuss the challenges of creating functional and long-lasting beta-cells.

We proposed a hybrid powered ankle exoskeleton. It can be able to supply positive mechanical power to the user during the swing phase of gait. The hybrid powered ankle exoskeleton was composed of a pair of compressed springs and a cable-driven actuator fasted to the shin. It was lightweight, and permitted the cable-driven actuator to provide the forces at the biological level to the ankle joint. Meanwhile the compressed spring also provide power (the power is different according to ankle angles.) to the ankle joint. The hybrid powered ankle exoskeleton was driven by the lithium battery attached to the waist and controlled by motor controller fixed on the transmission. By analyzing the characteristic of the lower limbs motion, the kinematics of the exoskeleton is analyzed and the dynamic model of the lower limb is built. Velocity-force control strategy aims at the change of the angle position. Based on the normal gait, the kinematics simulation of the ankle was built in MATLAB/Simulink.

Body weight support (BWS) system is increasingly used in conjunction with treadmills to assist the patients with neurological impairments. Owing to lower limbs of the patients unable to bear the whole weight during the rehabilitation training, some weight can be removed to help the patients recover the basic walking ability gradually. Therefore, considering the man-machine relationship and the effects of the rehabilitation, a wire-driven BWS system is designed. The main unit of the system is an active closed-loop controlled drive to generate the exact desired force. The force acted on the body is through the adjustment of the length of the rope which is connected to the harness worn by the patient. The structure designed in the research is easy to operate to realize the goal of the rehabilitation. To verify the effectiveness and practicability of the BWS system, some experiments have been curried out. From the results, not only the constant unloading force can be realized, but also the response time is limited in a small range which can bring a positive effect on correcting gait, improving balance and reducing muscle spasms. Also, compared to the traditional body weight support system, such as static system or passive elastic system, it has the advantages of the fast response, small errors and constant unloading force.

In the brain, the serotonergic neurons located in the raphe nucleus are the unique resource of the neurotransmitter serotonin, which plays a pivotal role in the regulation of brain development and functions. Dysfunction of the serotonin system is present in many psychiatric disorders. Lack of in vitro functional human model limits the understanding of human central serotonergic system and its related diseases and clinical applications. Previously, we have developed a method generating human serotonergic neurons from induced pluripotent stem cells (iPSCs). In this study, we analyzed the features of these human iPSCs-derived serotonergic neurons both in vitro and in vivo. We found that these human serotonergic neurons are sensitive to the selective neurotoxin 5, 7-Dihydroxytryptamine (5,7-DHT) in vitro. After being transplanted into newborn mice, the cells not only expressed their typical molecular markers, but also showed the migration and projection to the host’s cerebellum, hindbrain and spinal cord. The data demonstrate that these human iPSCs-derived neurons exhibit the typical features as the serotonergic neurons in the brain, which provides a solid foundation for studying on human serotonin system and its related disorders.

Due to the difference between kinematics of human joints and exoskeleton joints, joint misalignment may be brought about by human-machine interface (HMI). Joint misalignment may lead to undesired interaction forces, if not copped with properly, e.g. in the HMI mechanism with straps. In this paper, firstly the interaction forces caused by joint misalignment in HMI mechanism with straps are studied. Then, a compliant HMI mechanism which consists of passive mechanical linkages is presented and Degrees of Freedom (DOFs) of the whole human-machine system are analyzed. A simulation model of human-machine system is established for analyzing the interaction forces in the compliant HMI mechanism. Finally, comparative results were obtained to demonstrate that the constraint forces can be decreased greatly with sufficient driving forces simultaneously by using of the compliant HMI mechanism.

To generate new beta cells after birth is a key focus of regenerative medicine, which could greatly aid the major health burden of diabetes. Beta-cell regeneration has been described using four different approaches: (1) the development of beta cells from putative precursor cells of the adult pancreas, which is termed neogenesis, (2) replication of existing beta cells, (3) differentiation from embryonic or induced pluripotent stem cells, and (4) reprogramming of non-beta cells to beta cells. Studies from the authors' laboratory have shown that beta-cell reprogramming can be achieved by transduction of adult pancreatic tissues with viral constructs containing the three developmentally important transcription factors Pdx1, Ngn3, and MafA. This protocol outlines the generation of a polycistronic construct containing the three transcription factors, the expansion and purification of the polycistronic virus, and in vivo transduction for acinar to beta-cell reprogramming in adult mice. The ultimate goal is to generate beta-like cells that resemble as closely as possible endogenous beta cells in phenotype and function for potential translational applications. © 2017 by John Wiley & Sons, Inc.

Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet-like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.

The TNF–JNK pathway is a highly conserved signaling pathway that regulates a wide spectrum of biological processes including cell death and migration. To further delineate this pathway, we carried out a genetic screen for dominant modifiers of the cell death phenotype triggered by ectopic expression of Eiger (Egr), the Drosophila TNF ortholog. Here we show that Bendless (Ben), an E2 ubiquitin-conjugating enzyme, modulates Egr-induced JNK activation and cell death through dTRAF2. Furthermore, Ben physically interacts with dTRAF2 and regulates Egr-induced dTRAF2 polyubiquitination. Finally, Ben is required for JNK-dependent tumor progression, cell migration, oxidative stress resistance and longevity. Our results indicate that Ben constitutes an essential component of the evolutionarily conserved TNF–JNK pathway that modulates cell death and invasion, tumor progression, stress response and lifespan in metazoans.

Fatty acid oxidation and subsequent ketogenesis is one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions. Fasting hormone glucagon has been shown to stimulate ketone body production through activation of PPARα; however, the signal pathway linking glucagon to PPARα is largely undiscovered. Here we report that a SIK2-p300-PPARα cascade mediates glucagon’s effect on ketogenesis. p300 interacts with PPARα through a conserved LXXLL motif and enhances its transcriptional activity. SIK2 disrupts p300-PPARα interaction by direct phosphorylation of p300 at Ser89, which in turn decreases PPARα-mediated ketogenic gene expression. Moreover, SIK2 phosphorylation defective p300 (p300 S89A) shows increased interaction with PPARα and abolishes suppression of SIK2 on PPARα-mediated ketogenic gene expression in liver. Taken together, our results unveil the signal pathway that mediates fasting induced ketogenesis to maintain hepatic lipid homeostasis.

SummaryWe discovered a class of naturally occurring human proteins with unusually high net positive charge that can potently deliver proteins in functional form into mammalian cells both in vitro and also in murine retina, pancreas, and white adipose tissues in vivo. These findings represent diverse macromolecule delivery agents for in vivo applications, and also raise the possibility that some of these human proteins may penetrate cells as part of their native biological functions.

During apoptosis, dying cells are swiftly removed by phagocytes. It is not fully understood how apoptotic cells are recognized by phagocytes. Here we report the identification and characterization of the Caenorhabditis elegans ttr-52 gene, which encodes a transthyretin-like protein and is required for efficient cell corpse engulfment. The TTR-52 protein is expressed in, and secreted from, C. elegans endoderm and clusters around apoptotic cells. Genetic analysis indicates that TTR-52 acts in the cell corpse engulfment pathway mediated by CED-1, CED-6 and CED-7 and affects clustering of the phagocyte receptor CED-1 around apoptotic cells. TTR-52 recognizes surface-exposed phosphatidylserine (PtdSer) in vivo and binds to both PtdSer and the extracellular domain of CED-1 in vitro. TTR-52 is therefore the first bridging molecule identified in C. elegans that mediates recognition of apoptotic cells by crosslinking the PtdSer 'eat me' signal with the phagocyte receptor CED-1.