Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.

Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.

Microglia in Ischemic Stroke: Pathogenesis Insights and Therapeutic Challenges.

Ischemic stroke is the most common type of stroke, which is the main cause of death and disability on a global scale. As the primary immune cells in the brain that are crucial for preserving homeostasis of the central nervous system microenvironment, microglia have been found to exhibit dual or even multiple effects at different stages of ischemic stroke. The anti-inflammatory polarization of microglia and release of neurotrophic factors may provide benefits by promoting neurological recovery at the lesion in the early phase after ischemic stroke. However, the pro-inflammatory polarization of microglia and secretion of inflammatory factors in the later phase of injury may exacerbate the ischemic lesion, suggesting the therapeutic potential of modulating the balance of microglial polarization to predispose them to anti-inflammatory transformation in ischemic stroke. Microglia-mediated signaling crosstalk with other cells may also be key to improving functional outcomes following ischemic stroke. Thus, this review provides an overview of microglial functions and responses under physiological and ischemic stroke conditions, including microglial activation, polarization, and interactions with other cells. We focus on approaches that promote anti-inflammatory polarization of microglia, inhibit microglial activation, and enhance beneficial cell-to-cell interactions. These targets may hold promise for the creation of innovative therapeutic strategies.

Characterization of diseased primary human hepatocytes in an all-human cell-based triculture system.

Liver diseases, including NAFLD, are a growing worldwide health concern. Currently, there is a lack of suitable in vitro models that sustain basic primary human hepatocyte (PHH) morphology and functionality while supporting presentation of disease-associated phenotypic characteristics such as lipid accumulation and inflammasome activation. In TruVivo, an all-human triculture system (hTCS), basic metabolic functions were characterized in PHHs isolated from normal or diseased livers during two-weeks of culture. Decreases in albumin and urea levels and CYP3A4 activity were seen in diseased-origin PHHs compared to normal PHHs along with higher CYP2E1 expression. Positive expression of the macrophage markers CD68 and CD163 were seen in the diseased PHH preparations. Elevated levels of the pro-inflammatory cytokines IL-6 and MCP-1 and the fibrotic markers CK-18 and TGF-ß were also measured. Gene expression of FASN, PCK1, and G6PC in the diseased PHHs was decreased compared to the normal PHHs. Further characterization revealed differences in lipogenesis and accumulation of intracellular lipids in normal and diseased PHHs when cultured with oleic acid and high glucose. TruVivo represents a promising new platform to study lipogenic mechanisms in normal and diseased populations due to the preservation of phenotypic differences over a prolonged culture period.

Similar incidence of graft glomerulonephritis in recipients with definitively diagnosed glomerulonephritis and those with unknown etiology: a retrospective observational study.

OBJECTIVE: In China, most of the patients who underwent kidney transplants have unknown causes of end-stage renal disease (uESRD). However, little is known regarding the incidence of graft glomerulonephritis (GN) and graft survival in kidney transplant recipients (KTRs) with uESRD. METHODS: In this retrospective cohort study, 473 of the 565 KTRs who underwent kidney transplantation (KTx) from 2015 to 2020 were included. We mainly observed the occurrence of graft GN between uESRD group and definitively diagnosed GN group, and repeatedly compared after propensity score matching (PSM). RESULTS: The median follow-up was 50 months in 473 KTRs, and about 75% of KTRs of native kidney disease of unknown etiology. The total cumulative incidence of graft GN was 17%, and no difference was observed between the definitively diagnosed GN group and the uESRD group (p = 0.76). Further, PSM analysis also showed no difference in the incidence of graft GN between the 2 groups. Multivariable analysis disclosed males (p = 0.001), younger age (p = 0.03), and anti-endothelial cell anti-body (AECA) positive pre-KTx (p = 0.001) were independent risk factors for graft GN. CONCLUSIONS: The incidence of graft GN was similar between uESRD and definitively diagnosed GN group. The allograft survival was also similar between two groups.

Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

A Non-Nucleotide STING Agonist MSA-2 Synergized with Manganese in Enhancing STING Activation to Elicit Potent Anti-RNA Virus Activity in the Cells.

Both Manganese (Mn2+) and MSA-2 can activate the downstream signal pathway through stimulator of interferon genes (STING) and induce the expression of type I interferon, which is important for hosts to protect against DNA viruses. However, its effect on RNA viruses remains unknown. In this study, we used Seneca Valley virus (SVV) as a model RNA virus to investigate the inhibitory effects of Mn2+ and MSA-2 on the virus replication in the porcine cells (PK-15 cells). The results showed that both MSA-2 and Mn2+ were able to inhibit the SVV replication in PK-15 cells. The combination of MAS-2 and Mn2+ could confer better protection against SVV. Further studies showed that MSA-2 and Mn2+ could activate TBK1, IRF3 and NFκB through STING and induce the expression of IFN-ß, IL-6 and TNF-α. The present study confirmed that MSA-2 synergized with Mn2+ in STING activation to generate a better antiviral effect in vitro, which would be helpful for the further development of effective antiviral drugs in the future.

A Method of Water COD Retrieval Based on 1D CNN and 2D Gabor Transform for Absorption-Fluorescence Spectra.

Chemical Oxygen Demand (COD) is one of the indicators of organic pollution in water bodies. The rapid and accurate detection of COD is of great significance to environmental protection. To address the problem of COD retrieval errors in the absorption spectrum method for fluorescent organic matter solutions, a rapid synchronous COD retrieval method for the absorption-fluorescence spectrum is proposed. Based on a one-dimensional convolutional neural network and 2D Gabor transform, an absorption-fluorescence spectrum fusion neural network algorithm is developed to improve the accuracy of water COD retrieval. Results show that the RRMSEP of the absorption-fluorescence COD retrieval method is 0.32% in amino acid aqueous solution, which is 84% lower than that of the single absorption spectrum method. The accuracy of COD retrieval is 98%, which is 15.3% higher than that of the single absorption spectrum method. The test results on the actual sampled water spectral dataset demonstrate that the fusion network outperformed the absorption spectrum CNN network in measuring COD accuracy, with the RRMSEP improving from 5.09% to 1.15%.

A Wafer Pre-Alignment Algorithm Based on Weighted Fourier Series Fitting of Circles and Least Squares Fitting of Circles.

The wafer pre-aligner is a crucial component in the lithography process to correct the wafer center and notch orientation. To improve the precision and the efficiency of pre-alignment, a new method to calibrate the center and the orientation of a wafer based on the weighted Fourier series fitting of circles (WFC) method and the least squares fitting of circles (LSC) method, respectively, is proposed. The WFC method effectively suppressed the influence of the outliers and had high stability compared with the LSC method when fitted to the center of the circle. While the weight matrix degenerated to the identity matrix, the WFC method degenerated into the Fourier series fitting of circles (FC) method. The fitting efficiency of the FC method is 28% higher than that of the LSC method, and the fitting accuracy of the center of the FC method is the same as that of the LSC method. In addition, the WFC method and the FC method perform better than the LSC method in radius fitting. The pre-alignment simulation results showed that the absolute position accuracy of the wafer was ±2 µm, the absolute direction accuracy was 0.01°, and the total calculation time was less than 3.3 s in our platform.

Survival benefits of para-aortic lymphadenectomy in colorectal cancer with clinically suspected para-aortic lymph node metastasis: a meta-analysis and systematic review.

BACKGROUND AND OBJECTIVES: In patients with colorectal cancer and clinically suspected para-aortic lymph node metastasis, the survival benefit of para-aortic lymphadenectomy is unknown. We conducted a meta-analysis and systematic review to investigate it. METHODS: PubMed, Web of Science, and EMBASE were searched until January 2000 to April 2022 to identify studies reporting overall survivals, complication rates, and hazard ratios of prognostic factors in patients with colorectal cancer undergoing para-aortic lymphadenectomy, and those data were pooled. RESULTS: Twenty retrospective studies (1021 patients undergoing para-aortic lymphadenectomy) met the inclusion criteria. Meta-analysis indicates that participants undergoing para-aortic lymphadenectomy were associated with 5-year survival benefit, compared to those not receiving para-aortic lymphadenectomy (odds ratio = 3.73, 95% confidence interval: 2.05-6.78), but there was no significant difference in complication rate (odds ratio = 0.97, 95% confidence interval: 0.46-2.08). Further analysis of para-aortic lymphadenectomy group showed that 5-year survival of the positive group with pathologically para-aortic lymph node metastasis was lower than that of the negative group (odds ratio = 0.19, 95% confidence interval: 0.11-0.31). Moreover, complete resection (odds ratio = 5.26, 95% confidence interval: 2.02-13.69), para-aortic lymph node metastasis (≤4) (hazard ratio = 1.88, 95% confidence interval: 0.97-3.62), and medium-high differentiation (hazard ratio = 2.98, 95% confidence interval: 1.48-5.99) were protective factors for survival. Preoperative extra-retroperitoneal metastasis was associated with poorer relapse-free survival (hazard ratio = 1.85, 95% confidence interval: 1.10-3.10). CONCLUSION: Para-aortic lymphadenectomy had promising clinical efficacy in prolonging survival rather than complication rate in patients with colorectal cancer and clinically diagnostic para-aortic lymph node metastasis. Further prospective studies should be performed. TRIAL REGISTRATION: PROSPERO: CRD42022379276.

Application of immune checkpoint inhibitors in immunotherapy for gastric cancer.

Gastric cancer is the fifth most common cancer worldwide. With the development of immunotherapy, especially the application of immune checkpoint inhibitors (ICIs), the prognosis of advanced gastric cancer has improved. At present, ICIs combined with other therapies or dual ICI strategies in the treatment of advanced gastric cancer have shown clinical effectiveness and controllable safety. In addition, predictive biomarkers facilitate the precise selection of patients. Therefore, it is crucial to explore rational combinations and reliable predictive biomarkers for ICI therapy. This article reviews the recent advances in ICIs and relevant predictive biomarkers in the treatment of gastric cancer.

In recent years, with the application of immunotherapy, clinical efficacy in gastric cancer has been effectively improved. At present, it is encouraging that immunotherapy combined with chemotherapy has become the first choice for the treatment of patients with advanced gastric cancer. However, researchers remain committed to exploring the efficacy of immunotherapy in combination with various therapies. Equally important, the identification of biomarkers can facilitate the selection of patients suitable for immunotherapy. This article summarizes important immunotherapy clinical trials and discusses therapeutic combinations and biomarkers being explored.

Association between cooking fuel and folate insufficiency among pregnant women in Northern China.

This study explored whether using a coal or biomass stove for cooking was associated with a greater risk of red blood cell (RBC) folate insufficiency among pregnant women compared to using clean energy. A researcher-designed questionnaire was used to collect information on exposure-related factors and confounding factors. RBC folate concentrations were examined by microbiological assay. Binary logistic regression analysis was used to identify factors related to RBC folate insufficiency. The use of coal or firewood for cooking was associated with an increased risk of RBC folate insufficiency (<906 nmol/L) compared to gas. In subgroup analyses, associations between the use of polluting cooking fuels and folate insufficiency were positive for both urban and rural residents and statistically significant for rural women. Efforts to promote the use of clean energy and proper ventilation, especially in rural areas, are recommended to improve the health of pregnant women and their offspring.

Characterization of an advanced viable bone allograft with preserved native bone-forming cells.

Bone grafts are widely used to successfully restore structure and function to patients with a broad range of musculoskeletal ailments and bone defects. Autogenous bone grafts are historically preferred because they theoretically contain the three essential components of bone healing (ie, osteoconductivity, osteoinductivity, and osteogenicity), but they have inherent limitations. Allograft bone derived from deceased human donors is one alternative that is also capable of providing both an osteoconductive scaffold and osteoinductive potential but, until recently, lacked the osteogenic component of bone healing. Relatively new, cellular bone allografts (CBAs) were designed to address this need by preserving viable cells. Although most commercially-available CBAs feature mesenchymal stem cells (MSCs), osteogenic differentiation is time-consuming and complex. A more advanced graft, a viable bone allograft (VBA), was thus developed to preserve lineage-committed bone-forming cells, which may be more suitable than MSCs to promote bone fusion. The purpose of this paper was to present the results of preclinical research characterizing VBA. Through a comprehensive series of in vitro and in vivo assays, the present results demonstrate that VBA in its final form is capable of providing all three essential bone remodeling properties and contains viable lineage-committed bone-forming cells, which do not elicit an immune response. The results are discussed in the context of clinical evidence published to date that further supports VBA as a potential alternative to autograft without the associated drawbacks.

The morphology, functionality, and longevity of a novel all human hepatic cell-based tri-culture system.

There remains a significant need for a convenient, phenotypically stable long-term culture platform for primary human hepatocytes (PHHs) for use in pharmacological and toxicological applications. Conventional in vitro models are often inconvenient, burdensome to use, and unable to support a multitude of donor lots or maintain PHH structural and functional properties over extended time. To address these limitations, an all-human cell-based hepatic tri-culture system (HTCS) has been developed comprised of frozen vials of PHHs and feeder cells. Qualified PHHs exhibited healthy morphological characteristics for ≥30 days. Extensive anastomosing networks of bile canaliculi with tight and gap junctions were established early and remained stable and functional throughout the culture period. After 5 culture days, albumin, urea, and basal Phase 1 and Phase 2 metabolic functions were stable for at least 2 weeks and significantly higher in the HTCS PHHs compared to sandwich monoculture PHHs. Induction of CYP functional activity by prototypical receptor agonists was stable after 4 days for at least 2 weeks. Gene expression of Alb and various CYPs in the HTCS PHHs was significantly higher compared to sandwich monoculture PHHs. The HTCS represents a convenient, phenotypically stable, all-human PHH culture platform for pharmacological and toxicological applications.

Poor outcomes of proliferative glomerulonephritis with monoclonal IgG deposits in renal allografts: a retrospective multicenter study.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) in renal allografts is a rare, renal-limited disease. No study has reported the long-term outcomes and prognostic features of PGNMID in renal allografts in the Chinese population. METHODS: We retrospectively included transplant patients diagnosed with PGNMID who underwent renal allograft biopsy at three transplant centers from April 2012 to July 2020. We observed the clinicopathologic features, explored the long-term graft survival, and investigated the characteristics associated with the prognosis. RESULTS: A total of 13 transplant patients with PGNMID were included, out of 3821 biopsies. The mean follow-up time was 55 months since kidney transplantation (KTx). At diagnosis, all patients presented with proteinuria (100%) and most of them with hematuria (92%). IgG3κ (69%) was the main immunofluorescence (IF) subtype. The median graft survival of the total cohort was 17 months from diagnosis and 49 months from kidney transplantation. During follow-up, 9 patients needed dialysis and 2 out of 9 patients who progressed to dialysis died of infection. Primary membranoproliferative glomerulonephritis (MPGN) (P = 0.014) and MPGN pattern at diagnostic biopsy (P < 0.001) were associated with a higher risk of graft loss. CONCLUSIONS: The long-term outcome of allograft PGNMID was relatively poor in the Chinese population. Primary MPGN and MPGN pattern in renal allograft were associated with  poor outcomes.

Exploring the Temporal Correlation of Sarcopenia with Bone Mineral Density and the Effects of Osteoblast-Derived Exosomes on Myoblasts through an Oxidative Stress-Related Gene.

Sarcopenia is an age-related accelerated loss of muscle strength and mass. Bone and muscle are closely related as they are physically adjacent, and bone can influence muscle. However, the temporal association between bone mineral density (BMD) and muscle mass in different regions of the body after adjustment for potential indicators and the mechanisms by which bone influences muscle in sarcopenia remain unclear. Therefore, this study aimed to explore the temporal association between muscle mass and BMD in different regions of the body and mechanisms by which bone regulates muscle in sarcopenia. Here, cross-lagged models were utilized to analyze the temporal association between BMD and muscle mass. We found that low-density lipoprotein (LDL-C) positively predicted appendicular lean mass. Mean whole-body BMD (WBTOT BMD), lumbar spine BMD (LS BMD), and pelvic BMD (PELV BMD) temporally and positively predicted appendicular lean mass, and appendicular lean mass temporally and positively predicted WBTOT BMD, LS BMD, and PELV BMD. Moreover, this study revealed that primary mice femur osteoblasts, but not primary mice skull osteoblasts, induced differentiation of C2C12 myoblasts through exosomes. Furthermore, the level of long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1) was decreased, and the level of lncRNA differentiation antagonizing nonprotein coding RNA (DANCR) was increased in skull osteoblast-derived exosomes, the opposite of femur osteoblast-secreted exosomes. In addition, lncRNA TUG1 enhanced and lncRNA DANCR suppressed the differentiation of myoblasts through regulating the transcription of oxidative stress-related myogenin (Myog) gene by modifying the binding of myogenic factor 5 (Myf5) to the Myog gene promoter via affecting the nuclear translocation of Myf5. The results of the present study may provide novel diagnostic biomarkers and therapeutic targets for sarcopenia.

A Dynamic Constitutive Model and Simulation of Braided CFRP under High-Speed Tensile Loading.

In this study, a dynamic constitutive model for woven-carbon-fiber-reinforced plastics (CFRP) is formulated by combining dynamic tensile test data and fitting curves and incorporating variation rules established for the modulus of elasticity, strength, and fracture strain with respect to the strain rate. The dynamic constitutive model is then implemented with finite element software. The accuracy and applicability of the dynamic constitutive model are evaluated by comparing the numerically predicted load-displacement curves and strain distributions with the test data. The stress distribution, failure factor, modulus, and strength of the material under dynamic tension are also explored. The results show that the response simulated with the dynamic constitutive model is in good agreement with the experimental results. The strain is uniformly distributed during the elastic phase compared with the DIC strain field. Subsequently, it becomes nonuniform when stress exceeds 600 MPa. Then, the brittle fracture occurs. With the increase in the strain rate, the input modulus decreased, and the tensile strength increased. When the displacement was 0.13 mm, the simulation model was damaged at a low strain rate, and the stress value was 837.8 MPa. When it reached the high strain rate of 800 s-1, no failure occurred, and the maximum stress value was 432.5 MPa. For the same specimen, the strain rate was the smallest on both clamped ends, and the modulus and strength were large at the ends and small in the middle. The fitting curve derived from the test data was completely input into the dynamic constitutive model to better capture the dynamic change in the material properties.

The Expression of PPAR Pathway-Related Genes Can Better Predict the Prognosis of Patients with Colon Adenocarcinoma.

The postoperative survival time and quality of life of patients with colon adenocarcinoma (COAD) varies widely. In order to make accurate decisions after surgery, clinicians need to distinguish patients with different prognostic trends. However, we still lack effective methods to predict the prognosis of COAD patients. Accumulated evidences indicated that the inhibition of peroxisome proliferator-activated receptors (PPARs) and a portion of their target genes were associated with the development of COAD. Our study found that the expression of several PPAR pathway-related genes were linked to the prognosis of COAD patients. Therefore, we developed a scoring system (named PPAR-Riskscore) that can predict patients' outcomes. PPAR-Riskscore was constructed by univariate Cox regression based on the expression of 4 genes (NR1D1, ILK, TNFRSF1A, and REN) in tumor tissues. Compared to typical TNM grading systems, PPAR-Riskscore has better predictive accuracy and sensitivity. The reliability of the system was tested on six external validation datasets. Furthermore, PPAR-Riskscore was able to evaluate the immune cell infiltration and chemotherapy sensitivity of each tumor sample. We also combined PPAR-Riskscore and clinical features to create a nomogram with greater clinical utility. The nomogram can help clinicians make precise treatment decisions regarding the possible long-term survival of patients after surgery.

A method based on a one-dimensional convolutional neural network for UV-vis spectrometric quantification of nitrate and COD in water under random turbidity disturbance scenario.

This paper proposed a novel spectrometric quantification method for nitrate and COD concentration in water using a double-channel 1-D convolution neural network for relatively long UV-vis absorption spectra data (2600 points). To improve the model's ability to resist turbidity disturbance, a new dataset augmentation method was applied and the absorption spectra of nitrate and COD under different turbidity disturbances were successfully simulated. Compared to the PLSR model, the value of RRMSEP for the CNN model was reduced from 6.1% to 1.4% in nitrate solution and 4.5% to 1.3% in COD solution. Compared to the PLSR model, the regression accuracy of the CNN model was increased from 56% to 93% in nitrate solution and 68% to 91% in COD solution. The test on the actual solution under different turbidity disturbances shows that the 1D-CNN model had a bias rate of less than 2% in both nitrate and COD solutions, while the worst bias rate in the PLSR method was 15%.

Bayesian Inference of Stochastic Dynamic Models Using Early-Rejection Methods Based on Sequential Stochastic Simulations.

Stochastic modelling is an important method to investigate the functions of noise in a wide range of biological systems. However, the parameter inference for stochastic models is still a challenging problem partially due to the large computing time required for stochastic simulations. To address this issue, we propose a novel early-rejection method by using sequential stochastic simulations. We first show that a large number of stochastic simulations are required to obtain reliable inference results. Instead of generating a large number of simulations for each parameter sample, we propose to generate these simulations in a number of stages. The simulation process will go to the next stage only if the accuracy of simulations at the current stage satisfies a given error criterion. We propose a formula to determine the error criterion and use a stochastic differential equation model to examine the effects of different criteria. Three biochemical network models are used to evaluate the efficiency and accuracy of the proposed method. Numerical results suggest the proposed early-rejection method achieves substantial improvement in the efficiency for the inference of stochastic models.

The Akt pathway mediates the protective effects of myeloid differentiation protein 1 in pathological cardiac remodelling.

AIMS: Myeloid differentiation protein 1 (MD1) was shown to ameliorate pressure overload-induced cardiac hypertrophy and fibrosis by negatively regulating the MEK-ERK1/2 and NF-κB pathways. However, whether MD1 modulates cardiac function and whether the Akt pathway mediates the benefits of MD1 in pressure overload-induced cardiac remodelling remain unclear. METHODS AND RESULTS: Male cardiac-specific transgenic MD1 (MD1-TG) mice, MD1-knockout (KO) mice and wild-type (WT) littermates aged 8-10 weeks were subjected to sham operation and aortic banding (AB) for 4 weeks. Then, left ventricular (LV) hypertrophy, fibrosis and function of the mice were assessed. When compared with WT-AB mice, MD1-TGs showed decreased cross-sectional area (CSA) of cardiomyocytes (P < 0.001), mRNA expression of ß-myosin heavy chain (ß-MHC) (P < 0.02), ratios of heart weight/body weight and heart weight/tibia length (P < 0.04) and collagen volume fraction (P < 0.001). The LV end-diastolic diameter was reduced, and LV ejection fraction and fractional shortening were improved in MD1-TG-AB mice than in WT-AB mice (P < 0.05). In cultured H9C2 cells, adenovirus vector-mediated MD1 overexpression decreased angiotensin II-induced mRNA expression of brain natriuretic peptide (BNP) and ß-MHC and cell CSA (P < 0.002), whereas knockdown of MD1 by shRNA exhibited opposite effects (P < 0.04). Mechanistically, MD1 suppressed pathological cardiac remodelling at least partly by blocking Akt pathway. Akt inactivation by MK2206 largely offset the pro-hypertrophic effects of MD1 deficiency in angiotensin II-stimulated cardiomyocytes. CONCLUSIONS: The Akt pathway mediates the protective effects of MD1 in pressure overload-induced cardiac remodelling in mice. Targeting MD1 may provide therapeutic strategy for the treatment of pathological cardiac remodelling and heart failure.