Multiorgan-on-a-chip(MOoC)systems are advanced microfluidic devices that integrate multiple organ models into a single modular unit,each composed of cells derived from various tissues or organs.These systems enable in...Multiorgan-on-a-chip(MOoC)systems are advanced microfluidic devices that integrate multiple organ models into a single modular unit,each composed of cells derived from various tissues or organs.These systems enable interorgan communication and accurately replicate physiological conditions,providing a more physiologically relevant modeling framework for constructing disease models and predicting drug efficacy and toxicity.MOoC systems also provide significant advantages in terms of flexibility,cost-effectiveness,and reproducibility,making them valuable tools for drug development and toxicity assessment.In this review,we first provide an overview of the MOoC technology,covering cell sources,stimulations,materials and fabrication techniques,and biosensors.We then examine the application of MOoC systems in disease modeling,focusing on cancer metastasis,metabolic disorders,and cardiovascular disease.We next discuss the use of MOoC systems in drug toxicity evaluation and drug screening,emphasizing their role in providing comprehensive assessments of drug effects.Finally,we address the challenges it faces and the future perspectives of the MOoC technology.展开更多
BACKGROUND Mannosyl-oligosaccharide glucosidase(MOGS)deficiency is an extremely rare type of congenital disorder of glycosylation(CDG),with only 12 reported cases.Its clinical,genetic,and glycomic features are still e...BACKGROUND Mannosyl-oligosaccharide glucosidase(MOGS)deficiency is an extremely rare type of congenital disorder of glycosylation(CDG),with only 12 reported cases.Its clinical,genetic,and glycomic features are still expanding.Our aim is to update the novel clinical and glycosylation features of 2 previously reported patients with MOGS-CDG.CASE SUMMARY We collected comprehensive clinical information,and conducted the immunoglobulin G1 glycosylation assay using nano-electrospray ionization source quadruple time-of-flight mass spectrometry.Novel dysmorphic features included an enlarged tongue,forwardly rotated earlobes,a birth mark,overlapped toes,and abnormal fat distribution.Novel imaging findings included pericardial effusion,a deep interarytenoid groove,mild congenital subglottic stenosis,and laryngomalacia.Novel laboratory findings included peripheral leukocytosis with neutrophil predominance,elevated C-reactive protein and creatine kinase,dyslipidemia,coagulopathy,complement 3 and complement 4 deficiencies,decreased proportions of T lymphocytes and natural killer cells,and increased serum interleukin 6.Glycosylation studies showed a significant increase of hypermannosylated glycopeptides(Glc3Man7GlcNAc2/N2H10 and Man5GlcNAc2/N2H5)and hypersialylated glycopeptides.A compensatory glycosylation pathway leading to an increase in Man5GlcNAc2/N2H5 was indicated with the glycosylation profile.CONCLUSION We confirmed abnormal glycomics in 1 patient,expanding the clinical and glycomic spectrum of MOGS-CDG.We also postulated a compensatory glycosylation pathway,leading to a possible serum biomarker for future diagnosis.展开更多
Experimental rats with root avulsion of the brachial plexus upper trunk were treated with the improved C34 transfer for neurotization of 05-6. Results showed that Terzis grooming test scores were significantly increas...Experimental rats with root avulsion of the brachial plexus upper trunk were treated with the improved C34 transfer for neurotization of 05-6. Results showed that Terzis grooming test scores were significantly increased at 6 months after treatment, the latency of C5-6 motor evoked potential was gradually shortened, and the amplitude was gradually increased. The rate of C3 instead of C5 and the C4 ＋ phrenic nerve instead of C6 myelinated nerve fibers crossing through the anastomotic stoma was approximately 80%. Myelinated nerve fibers were arranged loosely but the thickness of the myelin sheath was similar to that of the healthy side. In clinical applications, 39 patients with root avulsion of the brachial plexus upper trunk were followed for 6 months to 4.5 years after treatment using the improved C3 instead of C5 nerve root transfer and C4 nerve root and phrenic nerve instead of C6 nerve root transfer. Results showed that the strength of the brachial biceps and deltoid muscles recovered to level IIHV, scapular muscle to level Ill-W, latissimus dorsi and pectoralis major muscles to above level Ⅲ, and the brachial triceps muscle to level 0 Ill. Results showed that the improved 03-4 transfer for root avulsion of the brachial plexus upper trunk in animal models is similar to clinical findings and that C3-4 and the phrenic nerve transfer for neurotization of C5-6 can innervate the avulsed brachial plexus upper trunk and promote the recovery of nerve function in the upper extremity.展开更多
Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （AP...Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （APP）. The aspartic protease, β -site APP cleavage enzyme （BACE）, has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases （RTKs）, such as the receptors for epidermal growth factor （EGF） and nerve growth factor （NGF）, in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and A β production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.展开更多
The continent is the second largest carbon sink on Earth’s surface.With the diversification of vascular land plants in the late Paleozoic,terrestrial organic carbon burial is represented by massive coal formation,whi...The continent is the second largest carbon sink on Earth’s surface.With the diversification of vascular land plants in the late Paleozoic,terrestrial organic carbon burial is represented by massive coal formation,while the development of soil profiles would account for both organic and inorganic carbon burial.As compared with soil organic carbon,inorganic carbon burial,collectively known as the soil carbonate,would have a greater impact on the long-term carbon cycle.Soil carbonate would have multiple carbon sources,including dissolution of host calcareous rocks,dissolved inorganic carbon from freshwater,and oxidation of organic matter,but the host calcareous rock dissolution would not cause atmospheric CO2drawdown.Thus,to evaluate the potential effect of soil carbonate formation on the atmospheric p CO2level,different carbon sources of soil carbonate should be quantitatively differentiated.In this study,we analyzed the carbon and magnesium isotopes of pedogenic calcite veins developed in a heavily weathered outcrop,consisting of limestone of the early Paleogene Guanzhuang Group in North China.Based on the C and Mg isotope data,we developed a numerical model to quantify the carbon source of calcite veins.The modeling results indicate that4–37 wt%of carbon in these calcite veins was derived from atmospheric CO2.The low contribution from atmospheric CO2might be attributed to the host limestone that might have diluted the atmospheric CO2sink.Nevertheless,taking this value into consideration,it is estimated that soil carbonate formation would lower 1 ppm atmospheric CO2within 2000 years,i.e.,soil carbonate alone would sequester all atmospheric CO2within 1 million years.Finally,our study suggests the C–Mg isotope system might be a better tool in quantifying the carbon source of soil carbonate.展开更多
The wake induced vibration(WIV)of a one-and two-degree-of-freedom(1DOF,2DOF)downstream wave-cone cylinder(WCC)behind a stationary equal-size upstream wave-cone cylinder in the staggered arrangement is numerically inve...The wake induced vibration(WIV)of a one-and two-degree-of-freedom(1DOF,2DOF)downstream wave-cone cylinder(WCC)behind a stationary equal-size upstream wave-cone cylinder in the staggered arrangement is numerically investigated at subcritical Reynolds number of 3900 by using shear stressed transfer(SST)k-ωturbulence model.The streamwise pitch ratios(P/Dm)vary from 4 to 6 with a fixed incident angleα=8°.Experimental measurements were also performed for the validation of the present numerical models.It is found that the largest vibration amplitude in crossflow direction occurred at P/Dm=4,Ur=8 with small difference of streamwise vibration at P/Dm=4,6.Different from single wavy-cone cylinder(SWCC),the downstream flexible one of a pair staggered WCCs got larger vibration amplitude during phase switching stage instead of in-phase stage.The upstream wake will suppress the triple frequency of main frequency in the power spectra density(PSD)functions of Cl but stimulate the double one of that.An intriguing vibration mechanism happened in all 2DOF cases where the trajectory of downstream WCC is a significant ellipse rather than a figure of 8.The transformation of phase switching and the variation of the main frequency of drag coefficient(Cd)can be explained by the vortex-shedding modes of downstream WCC.展开更多
Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity.The process is critical for the ecology of the oral microflora and oral health.Although molecular mechanisms for sp...Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity.The process is critical for the ecology of the oral microflora and oral health.Although molecular mechanisms for spacer acquisition are known,it has never been established if this process is associated with the morphological changes of bacteria.In this study,we demonstrated a novel Cas2-induced filamentation phenotype in E.coli that was regulated by co-expression of the Cas1 protein.A 30 amino acid motif at the carboxyl terminus of Cas2 is necessary for this function.By imaging analysis,we provided evidence to argue that Cas-induced filamentation is a step coupled with new spacer acquisition during which filaments are characterised by polyploidy with asymmetric cell division.This work may open new opportunities to investigate the adaptive immune response and microbial balance for oral health.展开更多
Improving vehicle transmission efficiency and reducing vehicle fuel consumption is currently one of the main objectives in the automotive field. Reducing gear churning power losses has significant influence on the dec...Improving vehicle transmission efficiency and reducing vehicle fuel consumption is currently one of the main objectives in the automotive field. Reducing gear churning power losses has significant influence on the decreasing vehicle fuel consumption. Based on the two phase flow theory, a 2D two-phase model of the simplified hypoid gear is established to predict the churning losses in different conditions, the VOF method is introduced to track the volume fraction of the free surface, a standard k-ε model is also built to calculate complex turbulence. The oil distributions at the different rotational speed, the different immersion depth and the different viscosity as well as the churning losses of the hypoid gear are obtained and discussed in detail. In general, the churning power losses increase with the increase of the speed, the immersion depth and the viscosity, while the rotational speed shows the greatest influence on the churning losses. It is hoped that this investigation will be helpful in automotive industry applications.展开更多
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and po...Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC<sub>50</sub> = 3.943 μM) and Molt4 (IC<sub>50</sub> = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC<sub>50</sub>. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.展开更多
Achieving ultra-precise wide-range terahertz(THz)phase modulation has been a long-standing challenge due to the short wavelength and sensitive phase of THz waves.This paper proposes a new ultra-high precision phase co...Achieving ultra-precise wide-range terahertz(THz)phase modulation has been a long-standing challenge due to the short wavelength and sensitive phase of THz waves.This paper proposes a new ultra-high precision phase control method employing a digitally coding needle meta-chip embedded in a waveguide.The needle tips can effectively couple THz waves via the charge aggregation effect.By controlling the Schottky diodes with coding voltages,the charge on each meta-structure part can be tuned to form strong or weak resonances,producing phase shifts.Crucially,the massive charge accumulation and the sub-λ∕10 distance between needle tips lead to near-field coupling among multiple tips.Therefore,modulation of the charge at each tip by multichannel coding voltages enables combined resonance tuning of THz waves,yielding a nonlinear phase superposition.Here,a meta-chip containing 8 needle meta-structure units is demonstrated,which breaks through the precision limitation of independent units and realizes super-resolution precision phase modulation similar to super-resolution imaging.In the 213–227 GHz band,we achieve a phase shift exceeding 180°with 11.25°accuracy,and a phase shift of over 170°with an accuracy of 3°.This super-resolution phase modulation strategy provides a new idea for future highprecision applications of THz integrated systems.展开更多
Pulmonary fibrosis is a devastating lung disease without effective treatment options. Sphingosine-1-phosphate receptor 3 (S1pr3), a receptor for the lipid signaling moleculesphingosine-1-phosphate, has been shown to m...Pulmonary fibrosis is a devastating lung disease without effective treatment options. Sphingosine-1-phosphate receptor 3 (S1pr3), a receptor for the lipid signaling moleculesphingosine-1-phosphate, has been shown to mediate the development of pulmonary fibrosis,although the underlying mechanism is not fully understood. Here, we found increased expression of S1pr3 in the lung during the process of bleomycin-induced pulmonary fibrosis in miceand specific overexpression of S1pr3 in the infiltrated M2 macrophages. We constructed LysM-Cre^(+)/S1pr3^(flox/flox) mice, in which S1pr3 was conditionally depleted in myeloid cells, andthis depletion protected mice from bleomycin-induced lung injury and fibrosis, with reducedM2 macrophage accumulation in the lung. Increased S1pr3 expression was found in bonemarrow-derived macrophages after alternatively activated by IL4 ex vivo, while loss ofS1pr3 attenuated IL-4-induced M2 polarization in bone marrow-derived macrophages by repressing the PI3K/Akt-Stat3 signaling pathway. Moreover, the S1pr3 inhibitors CAY10444 andTY52156 exerted protective effects on pulmonary fibrosis in mice. Taken together, ourresearch showed that inhibition of S1pr3 ameliorates bleomycin-induced pulmonary fibrosisby reducing macrophage M2 polarization via the PI3K/Akt-Stat3 signaling pathway, indicatingthat S1pr3 may be a potential target for pulmonary fibrosis treatment.展开更多
Molecular motions of the luminescent liquid crystals(LLCs)show a significant effect on fluorescent emission and heat generation.In this article,a series of cyanostilbene-based LLCs(CSs:CS1-6,CS1-12,CS2-6 and CS2-12)ar...Molecular motions of the luminescent liquid crystals(LLCs)show a significant effect on fluorescent emission and heat generation.In this article,a series of cyanostilbene-based LLCs(CSs:CS1-6,CS1-12,CS2-6 and CS2-12)are synthesized to investigate how the pho-toluminescence and photothermal effect balanced.Among these materials,the mesogens peripheried by single alkyl chains formed enantiotropic nematic(CS1-6)or smectic C(CS1-12)phase with different alkyl tail lengths.When the single aliphatic chain is re-placed by mini-dendrons,room temperature(RT)monotropic hexagonal columnar phase(CS2-12)or molecular liquid(CS2-6)is formed.The results revealed that all these materials exhibited high efficiency emission with the highest quantum yield reaching 59.0%.The photoluminescence and photothermal effect can be effectively tuned by dispersing CSs into a commercially available RT liquid crystal matrix 8CB,which output significantly improved photothermal conversion efficiency of 63.2%.Furthermore,the pho-tothermal can rapidly trigger the Smectic A-Nematic-Isotropic sequence transitions of 8CB doped with CSs.This work paves a way of adjusting the balance of photoluminescence and photothermal properties of the LLC materials.展开更多
T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poo...T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.展开更多
Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during t...Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].展开更多
ln-situ fabricated perovskite nanocrystals in polymeric matrix provide new generation composite mate- rials for plenty of cutting edge technology. In this work, we report the in-situ fabrication of copper halide perov...ln-situ fabricated perovskite nanocrystals in polymeric matrix provide new generation composite mate- rials for plenty of cutting edge technology. In this work, we report the in-situ fabrication of copper halide perovskite （MA_2CuCI_4, MA：CH_3NH＋3） embedded poly（vinylidene fluoride） （PVDF） composite films. The optimized MA_2CuCI_4/PVDF composite films exhibit greatly enhanced piezo-response in comparasion with pure PVDF films. The enhancements were invesitgated and explained by applying piezo-response force microscopy （PFM） measurements and density functional theory （DFT） caculations. We proposed that the high piezoelectric properties of MA_2CuCI_4/PVDF composite films could be related to the large Cu off-centering displacement, the strong interactions between MA_2CuCI_4 and PVDF as well as large stress concentration around the MA_2CuCI_4 particles in the films. These piezoelectric composite films are expected to be suitable functional materials for flexible and/or wearable niezoelectrics.展开更多
Chirality,which is one of the defining features of biological molecules,plays a critical role in many important life processes.Controlled supramolecular assembly of biomolecules into functional structures with low str...Chirality,which is one of the defining features of biological molecules,plays a critical role in many important life processes.Controlled supramolecular assembly of biomolecules into functional structures with low structural fluidity,e.g.,cytoske-leton filaments[1],flagellar filaments of bacteria[2],and high structural fluidity(e.g.,cell membranes[3]),serves key roles in the correct functioning of biological processes.Inspired by natural supramolecular assembly,a large number of discrete two-and three-dimensional chiral polygons with well-defined shapes have been successfully prepared through self-assembly[4-8].展开更多
We present a facile and controllable method for the large-scale fabrication of highly-ordered octahedral Fe3O4 colloidal ＂single crystals＂ without the assistance of a substrate. Oleic acid is used to reduce the solu...We present a facile and controllable method for the large-scale fabrication of highly-ordered octahedral Fe3O4 colloidal ＂single crystals＂ without the assistance of a substrate. Oleic acid is used to reduce the solubility of the nano-building blocks in colloidal solution and to induce a ＂crystallization＂ process. Our colloidal crystals are of multimicron size and show typical crystallographic characteristics. They have a very robust structure and can serve as a novel ordered magnetic mesoporous material with a relatively narrow pore size distribution. The sample possesses an extremely high Verwey transition temperature （Tv） of 100 K and a high saturation magnetization （Ms） of 86 emu/g at 5 K based on its good crystallinity, as well as the interparticle dipolar interaction behavior arising from its unique structure. Electrochemical measurements have demonstrated the excellent capacity of the mesoporous colloidal crystals when used in lithium-ion batteries.展开更多
Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibit...Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibitors,targeting the key component of super enhancers,in early clinical trials on AML patients,implies the critical role of super enhancers in AML.Here,we review the concept and characteristic of super enhancer,and then summarize the current researches about super enhancers in AML pathogenesis,diagnosis and classification,followed by illustrate the potential super enhancer-related targets and drugs,and propose the future directions of super enhancers in AML.This information provides integrated insight into the roles of super enhancers in this disease.展开更多
Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regener...Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear.SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF,which is essential for kidney and heart fibrosis.We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II(ATII)cells.Moreover,we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO)7-Cre/SMARCA4f/f mice(SOSM4D/D)model,as well as a new SMARCA4-deleted alveolar type II(ATII)-like mle-12 cell line.We found that the bleomycin-induced PF was more aggressive in SOSM4D/D mice.Also,the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro.In addition,we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections.These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells,which might affect the progression of PF.展开更多
基金supported by the National Natural Science Foundation of China(No.32371475)the Natural Science Foundation of Jiangsu Province,Major Project(No.BK20222008).
文摘Multiorgan-on-a-chip(MOoC)systems are advanced microfluidic devices that integrate multiple organ models into a single modular unit,each composed of cells derived from various tissues or organs.These systems enable interorgan communication and accurately replicate physiological conditions,providing a more physiologically relevant modeling framework for constructing disease models and predicting drug efficacy and toxicity.MOoC systems also provide significant advantages in terms of flexibility,cost-effectiveness,and reproducibility,making them valuable tools for drug development and toxicity assessment.In this review,we first provide an overview of the MOoC technology,covering cell sources,stimulations,materials and fabrication techniques,and biosensors.We then examine the application of MOoC systems in disease modeling,focusing on cancer metastasis,metabolic disorders,and cardiovascular disease.We next discuss the use of MOoC systems in drug toxicity evaluation and drug screening,emphasizing their role in providing comprehensive assessments of drug effects.Finally,we address the challenges it faces and the future perspectives of the MOoC technology.
基金Supported by National Science and Technology Major Project,No.2014ZX09101046-004(to Chen L)National Natural Science Foundation of China,Nos.81873543 and 81570468(to Wang JS).
文摘BACKGROUND Mannosyl-oligosaccharide glucosidase(MOGS)deficiency is an extremely rare type of congenital disorder of glycosylation(CDG),with only 12 reported cases.Its clinical,genetic,and glycomic features are still expanding.Our aim is to update the novel clinical and glycosylation features of 2 previously reported patients with MOGS-CDG.CASE SUMMARY We collected comprehensive clinical information,and conducted the immunoglobulin G1 glycosylation assay using nano-electrospray ionization source quadruple time-of-flight mass spectrometry.Novel dysmorphic features included an enlarged tongue,forwardly rotated earlobes,a birth mark,overlapped toes,and abnormal fat distribution.Novel imaging findings included pericardial effusion,a deep interarytenoid groove,mild congenital subglottic stenosis,and laryngomalacia.Novel laboratory findings included peripheral leukocytosis with neutrophil predominance,elevated C-reactive protein and creatine kinase,dyslipidemia,coagulopathy,complement 3 and complement 4 deficiencies,decreased proportions of T lymphocytes and natural killer cells,and increased serum interleukin 6.Glycosylation studies showed a significant increase of hypermannosylated glycopeptides(Glc3Man7GlcNAc2/N2H10 and Man5GlcNAc2/N2H5)and hypersialylated glycopeptides.A compensatory glycosylation pathway leading to an increase in Man5GlcNAc2/N2H5 was indicated with the glycosylation profile.CONCLUSION We confirmed abnormal glycomics in 1 patient,expanding the clinical and glycomic spectrum of MOGS-CDG.We also postulated a compensatory glycosylation pathway,leading to a possible serum biomarker for future diagnosis.
基金supported by the Military Medicine and Health Research Foundation of China,No.06M098, CWS11J240
文摘Experimental rats with root avulsion of the brachial plexus upper trunk were treated with the improved C34 transfer for neurotization of 05-6. Results showed that Terzis grooming test scores were significantly increased at 6 months after treatment, the latency of C5-6 motor evoked potential was gradually shortened, and the amplitude was gradually increased. The rate of C3 instead of C5 and the C4 ＋ phrenic nerve instead of C6 myelinated nerve fibers crossing through the anastomotic stoma was approximately 80%. Myelinated nerve fibers were arranged loosely but the thickness of the myelin sheath was similar to that of the healthy side. In clinical applications, 39 patients with root avulsion of the brachial plexus upper trunk were followed for 6 months to 4.5 years after treatment using the improved C3 instead of C5 nerve root transfer and C4 nerve root and phrenic nerve instead of C6 nerve root transfer. Results showed that the strength of the brachial biceps and deltoid muscles recovered to level IIHV, scapular muscle to level Ill-W, latissimus dorsi and pectoralis major muscles to above level Ⅲ, and the brachial triceps muscle to level 0 Ill. Results showed that the improved 03-4 transfer for root avulsion of the brachial plexus upper trunk in animal models is similar to clinical findings and that C3-4 and the phrenic nerve transfer for neurotization of C5-6 can innervate the avulsed brachial plexus upper trunk and promote the recovery of nerve function in the upper extremity.
基金grants from the Ministry of Science and Technology （2003CB515405, 2005CB522406） the National Natural Science Foundation of China （30021003, 30400230, 30625014）+2 种基金 the Chinese Academy of Sciences （KSCX1- SW, KSCX2-SW） the Ministry of Education, Shanghai Municipal Commission for Science and Technology （06ZR14098） China Post Doctoral Science Foundation, and Shanghai Postdoctoral Science Foundation.
文摘Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （APP）. The aspartic protease, β -site APP cleavage enzyme （BACE）, has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases （RTKs）, such as the receptors for epidermal growth factor （EGF） and nerve growth factor （NGF）, in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and A β production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.
基金funded by the National Key Technology Program during the 13th Five-Year Plan Period (Grant No. 2016ZX05034001-007)National Natural Science Foundation of China (Grant No. 41772359)
文摘The continent is the second largest carbon sink on Earth’s surface.With the diversification of vascular land plants in the late Paleozoic,terrestrial organic carbon burial is represented by massive coal formation,while the development of soil profiles would account for both organic and inorganic carbon burial.As compared with soil organic carbon,inorganic carbon burial,collectively known as the soil carbonate,would have a greater impact on the long-term carbon cycle.Soil carbonate would have multiple carbon sources,including dissolution of host calcareous rocks,dissolved inorganic carbon from freshwater,and oxidation of organic matter,but the host calcareous rock dissolution would not cause atmospheric CO2drawdown.Thus,to evaluate the potential effect of soil carbonate formation on the atmospheric p CO2level,different carbon sources of soil carbonate should be quantitatively differentiated.In this study,we analyzed the carbon and magnesium isotopes of pedogenic calcite veins developed in a heavily weathered outcrop,consisting of limestone of the early Paleogene Guanzhuang Group in North China.Based on the C and Mg isotope data,we developed a numerical model to quantify the carbon source of calcite veins.The modeling results indicate that4–37 wt%of carbon in these calcite veins was derived from atmospheric CO2.The low contribution from atmospheric CO2might be attributed to the host limestone that might have diluted the atmospheric CO2sink.Nevertheless,taking this value into consideration,it is estimated that soil carbonate formation would lower 1 ppm atmospheric CO2within 2000 years,i.e.,soil carbonate alone would sequester all atmospheric CO2within 1 million years.Finally,our study suggests the C–Mg isotope system might be a better tool in quantifying the carbon source of soil carbonate.
基金Project supported by the National Natural Science Foundation of China (Grant Nos.11972268,12372232).
文摘The wake induced vibration(WIV)of a one-and two-degree-of-freedom(1DOF,2DOF)downstream wave-cone cylinder(WCC)behind a stationary equal-size upstream wave-cone cylinder in the staggered arrangement is numerically investigated at subcritical Reynolds number of 3900 by using shear stressed transfer(SST)k-ωturbulence model.The streamwise pitch ratios(P/Dm)vary from 4 to 6 with a fixed incident angleα=8°.Experimental measurements were also performed for the validation of the present numerical models.It is found that the largest vibration amplitude in crossflow direction occurred at P/Dm=4,Ur=8 with small difference of streamwise vibration at P/Dm=4,6.Different from single wavy-cone cylinder(SWCC),the downstream flexible one of a pair staggered WCCs got larger vibration amplitude during phase switching stage instead of in-phase stage.The upstream wake will suppress the triple frequency of main frequency in the power spectra density(PSD)functions of Cl but stimulate the double one of that.An intriguing vibration mechanism happened in all 2DOF cases where the trajectory of downstream WCC is a significant ellipse rather than a figure of 8.The transformation of phase switching and the variation of the main frequency of drag coefficient(Cd)can be explained by the vortex-shedding modes of downstream WCC.
基金supported by the National Science and Technology Major Project(2014ZX09101046-004)the National Natural Foundation of China(31600644)
文摘Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity.The process is critical for the ecology of the oral microflora and oral health.Although molecular mechanisms for spacer acquisition are known,it has never been established if this process is associated with the morphological changes of bacteria.In this study,we demonstrated a novel Cas2-induced filamentation phenotype in E.coli that was regulated by co-expression of the Cas1 protein.A 30 amino acid motif at the carboxyl terminus of Cas2 is necessary for this function.By imaging analysis,we provided evidence to argue that Cas-induced filamentation is a step coupled with new spacer acquisition during which filaments are characterised by polyploidy with asymmetric cell division.This work may open new opportunities to investigate the adaptive immune response and microbial balance for oral health.
文摘Improving vehicle transmission efficiency and reducing vehicle fuel consumption is currently one of the main objectives in the automotive field. Reducing gear churning power losses has significant influence on the decreasing vehicle fuel consumption. Based on the two phase flow theory, a 2D two-phase model of the simplified hypoid gear is established to predict the churning losses in different conditions, the VOF method is introduced to track the volume fraction of the free surface, a standard k-ε model is also built to calculate complex turbulence. The oil distributions at the different rotational speed, the different immersion depth and the different viscosity as well as the churning losses of the hypoid gear are obtained and discussed in detail. In general, the churning power losses increase with the increase of the speed, the immersion depth and the viscosity, while the rotational speed shows the greatest influence on the churning losses. It is hoped that this investigation will be helpful in automotive industry applications.
文摘Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC<sub>50</sub> = 3.943 μM) and Molt4 (IC<sub>50</sub> = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC<sub>50</sub>. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.
基金National Natural Science Foundation of China(62301112,61921002,61931006,62101111,62131007,U20A20212)National Key Research and Development Program of China(2021YFA1401000)+2 种基金Sichuan Province Science and Technology Support Program(2020JDRc0028)Fundamental Research Funds for the Central Universities(ZYGX2020ZB011)“Pioneer”and“Leading Goose”R&D Program of Zhejiang(2023C01139).
文摘Achieving ultra-precise wide-range terahertz(THz)phase modulation has been a long-standing challenge due to the short wavelength and sensitive phase of THz waves.This paper proposes a new ultra-high precision phase control method employing a digitally coding needle meta-chip embedded in a waveguide.The needle tips can effectively couple THz waves via the charge aggregation effect.By controlling the Schottky diodes with coding voltages,the charge on each meta-structure part can be tuned to form strong or weak resonances,producing phase shifts.Crucially,the massive charge accumulation and the sub-λ∕10 distance between needle tips lead to near-field coupling among multiple tips.Therefore,modulation of the charge at each tip by multichannel coding voltages enables combined resonance tuning of THz waves,yielding a nonlinear phase superposition.Here,a meta-chip containing 8 needle meta-structure units is demonstrated,which breaks through the precision limitation of independent units and realizes super-resolution precision phase modulation similar to super-resolution imaging.In the 213–227 GHz band,we achieve a phase shift exceeding 180°with 11.25°accuracy,and a phase shift of over 170°with an accuracy of 3°.This super-resolution phase modulation strategy provides a new idea for future highprecision applications of THz integrated systems.
基金supported by the General Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders(China)(No.GBRP202115)the Chongqing Science and Technology Bureau Major Project(China)(No.cstc2020jcyj-msxmX0782).
文摘Pulmonary fibrosis is a devastating lung disease without effective treatment options. Sphingosine-1-phosphate receptor 3 (S1pr3), a receptor for the lipid signaling moleculesphingosine-1-phosphate, has been shown to mediate the development of pulmonary fibrosis,although the underlying mechanism is not fully understood. Here, we found increased expression of S1pr3 in the lung during the process of bleomycin-induced pulmonary fibrosis in miceand specific overexpression of S1pr3 in the infiltrated M2 macrophages. We constructed LysM-Cre^(+)/S1pr3^(flox/flox) mice, in which S1pr3 was conditionally depleted in myeloid cells, andthis depletion protected mice from bleomycin-induced lung injury and fibrosis, with reducedM2 macrophage accumulation in the lung. Increased S1pr3 expression was found in bonemarrow-derived macrophages after alternatively activated by IL4 ex vivo, while loss ofS1pr3 attenuated IL-4-induced M2 polarization in bone marrow-derived macrophages by repressing the PI3K/Akt-Stat3 signaling pathway. Moreover, the S1pr3 inhibitors CAY10444 andTY52156 exerted protective effects on pulmonary fibrosis in mice. Taken together, ourresearch showed that inhibition of S1pr3 ameliorates bleomycin-induced pulmonary fibrosisby reducing macrophage M2 polarization via the PI3K/Akt-Stat3 signaling pathway, indicatingthat S1pr3 may be a potential target for pulmonary fibrosis treatment.
基金supported bythe National Natural ScienceFoundation of China(Nos.21875143and21875157)the InnovationResearch Foundationof Shenzhen(No.JCYJ20180507182229597)the Natural Science Foundation of Guangdong Province(No.2016-A030312002)and theopen foundation of State Key Laboraatory of Chemical Engineering(No.SKL ChE-20B04).
文摘Molecular motions of the luminescent liquid crystals(LLCs)show a significant effect on fluorescent emission and heat generation.In this article,a series of cyanostilbene-based LLCs(CSs:CS1-6,CS1-12,CS2-6 and CS2-12)are synthesized to investigate how the pho-toluminescence and photothermal effect balanced.Among these materials,the mesogens peripheried by single alkyl chains formed enantiotropic nematic(CS1-6)or smectic C(CS1-12)phase with different alkyl tail lengths.When the single aliphatic chain is re-placed by mini-dendrons,room temperature(RT)monotropic hexagonal columnar phase(CS2-12)or molecular liquid(CS2-6)is formed.The results revealed that all these materials exhibited high efficiency emission with the highest quantum yield reaching 59.0%.The photoluminescence and photothermal effect can be effectively tuned by dispersing CSs into a commercially available RT liquid crystal matrix 8CB,which output significantly improved photothermal conversion efficiency of 63.2%.Furthermore,the pho-tothermal can rapidly trigger the Smectic A-Nematic-Isotropic sequence transitions of 8CB doped with CSs.This work paves a way of adjusting the balance of photoluminescence and photothermal properties of the LLC materials.
基金the National Natural Science Foundation of China(No.82070167,81870126,81900190,81802803)The Chongqing Science and Technology Bureau Major Project,Chongqing,China(No.cstc2020jcyjmsxmX0782).
文摘T-cell acute lymphoblastic leukemia(T-ALL),a heterogeneous hematological malignancy,is caused by the developmental arrest of normal T-cell progenitors.The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease.In this study,we performed multi-omics integration analysis,which included mRNA expression,chromatin accessibility,and gene-dependency database analyses,to identify potential stage-specific druggable targets and repositioned drugs for this disease.This multi-omics integration helped identify 29 potential pathological genes for T-ALL.These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle,hematopoietic stem cell differentiation,and the AMPK signaling pathway.Of these,four known druggable targets(CDK6,TUBA1A,TUBB,and TYMS)showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL.The TUBA1A expression level was higher in the early T cell precursor(ETP)-ALL cells,while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage.CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naıve to maturation stages.Furthermore,mebendazole and gemcitabine,which target TUBA1A and TYMS,respectively,exerted stage-specific inhibitory effects on T-ALL cell lines,indicating their potential stage-specific antileukemic role in T-ALL.Collectively,our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.
文摘Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].
基金supported by the National Key Research and Development Program of China (2017YFB0404603)the National Natural Science Foundation of China (61722502)+1 种基金the support from the National Natural Science Foundation of China (11572040)the Thousand Young Talents Program of China
文摘ln-situ fabricated perovskite nanocrystals in polymeric matrix provide new generation composite mate- rials for plenty of cutting edge technology. In this work, we report the in-situ fabrication of copper halide perovskite （MA_2CuCI_4, MA：CH_3NH＋3） embedded poly（vinylidene fluoride） （PVDF） composite films. The optimized MA_2CuCI_4/PVDF composite films exhibit greatly enhanced piezo-response in comparasion with pure PVDF films. The enhancements were invesitgated and explained by applying piezo-response force microscopy （PFM） measurements and density functional theory （DFT） caculations. We proposed that the high piezoelectric properties of MA_2CuCI_4/PVDF composite films could be related to the large Cu off-centering displacement, the strong interactions between MA_2CuCI_4 and PVDF as well as large stress concentration around the MA_2CuCI_4 particles in the films. These piezoelectric composite films are expected to be suitable functional materials for flexible and/or wearable niezoelectrics.
基金supported by the National Natural Science Foundation of China (21875143 and 21908146)the Innovation Research Foundation of Shenzhen (JCYJ20180507182229597)the Natural Science Foundation of Guangdong Province (2016A030312002)。
文摘Chirality,which is one of the defining features of biological molecules,plays a critical role in many important life processes.Controlled supramolecular assembly of biomolecules into functional structures with low structural fluidity,e.g.,cytoske-leton filaments[1],flagellar filaments of bacteria[2],and high structural fluidity(e.g.,cell membranes[3]),serves key roles in the correct functioning of biological processes.Inspired by natural supramolecular assembly,a large number of discrete two-and three-dimensional chiral polygons with well-defined shapes have been successfully prepared through self-assembly[4-8].
文摘We present a facile and controllable method for the large-scale fabrication of highly-ordered octahedral Fe3O4 colloidal ＂single crystals＂ without the assistance of a substrate. Oleic acid is used to reduce the solubility of the nano-building blocks in colloidal solution and to induce a ＂crystallization＂ process. Our colloidal crystals are of multimicron size and show typical crystallographic characteristics. They have a very robust structure and can serve as a novel ordered magnetic mesoporous material with a relatively narrow pore size distribution. The sample possesses an extremely high Verwey transition temperature （Tv） of 100 K and a high saturation magnetization （Ms） of 86 emu/g at 5 K based on its good crystallinity, as well as the interparticle dipolar interaction behavior arising from its unique structure. Electrochemical measurements have demonstrated the excellent capacity of the mesoporous colloidal crystals when used in lithium-ion batteries.
基金This work was partially supported by the Natural Science Foundation of China(No.82070167,81870126,and 81802803).
文摘Acute myeloid leukemia(AML)is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments.The potent anti-cancer effects of bromodomain and extra-terminal domain(BET)inhibitors,targeting the key component of super enhancers,in early clinical trials on AML patients,implies the critical role of super enhancers in AML.Here,we review the concept and characteristic of super enhancer,and then summarize the current researches about super enhancers in AML pathogenesis,diagnosis and classification,followed by illustrate the potential super enhancer-related targets and drugs,and propose the future directions of super enhancers in AML.This information provides integrated insight into the roles of super enhancers in this disease.
基金This work was supported by the National Natural Science Foundation Committee of China[grant numbers 81373444,81570142,81670018]the Chinese Ministry of Science and Technology[grant number 2016YFA0101300]the Key Grant from the Chongqing Science and Technology Commission[grant number cstc2014yykfC10003].
文摘Alveolar epithelial cells(AECs)injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis(PF).Nevertheless,the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear.SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF,which is essential for kidney and heart fibrosis.We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II(ATII)cells.Moreover,we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO)7-Cre/SMARCA4f/f mice(SOSM4D/D)model,as well as a new SMARCA4-deleted alveolar type II(ATII)-like mle-12 cell line.We found that the bleomycin-induced PF was more aggressive in SOSM4D/D mice.Also,the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro.In addition,we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections.These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells,which might affect the progression of PF.
