The methylation inhibitor decitabine (DAC) has great therapeutic value for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, DAC monotherapy is associated with relatively low rates of overall response and complete remission. Previous studies have shown promising results for combination treatment regimens including DAC. Homoharringtonine (HHT), an alkaloid from Chinese natural plants and Cephalotaxus, has demonstrated potential for leukemia treatment. Our studies have suggested that the combination of DAC and HHT has synergistic effects for inhibiting the viability of SKM-1 and Kg-1a cells. This combination leads to enhanced inhibition of colony formation and apoptosis induction compared with DAC alone in SKM-1 but not Kg-1a cells. Only high-dose DAC and HHT significantly up-regulate caspase-3 and caspase-9 and inhibit BCL-XL in the SKM-1 cell line. The combined effects of DAC plus HHT on apoptosis may not only depend on regulation of the apoptosis-related genes we examined but others as well. HHT had no demethylation effects, and HHT in combination with DAC had no enhanced effects on hypomethylation and DNMT1, DNMT3A and DNMT3B mRNA expression in SKM-1 cells. Overall, these results suggest that DAC used in combination with HHT may have clinical potential for MDS treatment.

Depression is a commonly reported co-morbidity during rehabilitation from alcohol use disorders and its presence is associated with an increased likelihood of relapse. Interventions which impede the development of depression could be of potential benefit if incorporated into treatment programs. We previously demonstrated an ameliorative effect of physical exercise on depressive behaviors in a mouse model of alcohol abstinence. Here, we show that environmental enrichment (cognitive and social stimulation) has a similar beneficial effect. The hypothalamic-pituitary-adrenal (HPA) axis is a key physiological system regulating stress responses and its dysregulation has been separably implicated in the pathophysiology of depression and addiction disorders. We performed a series of dexamethasone challenges and found that mice undergoing 2 weeks of alcohol abstinence had significantly greater corticosterone and ACTH levels following a DEX-CRH challenge compared to water controls. Environmental enrichment during alcohol abstinence corrected the abnormal DEX-CRH corticosterone response despite a further elevation of ACTH levels. Examination of gene expression revealed abstinence-associated alterations in glucocorticoid receptor (Gr), corticotrophin releasing hormone (Crh) and pro-opiomelanocortin (Pomc1) mRNA levels which were differentially modulated by environmental enrichment. Overall, our study demonstrates a benefit of environmental enrichment on alcohol abstinence-associated depressive behaviors and HPA axis dysregulation.

Linkage between transmembrane proteins and the spectrin-based cytoskeleton is necessary for membrane elasticity of red blood cells. Mutations of the proteins that mediate this linkage result in various types of hemolytic anemia. Here we report a novel N-ethyl-N-nitrosourea-induced mutation of ankyrin-1, named hema6, which causes hereditary spherocytosis in mice through a mild reduction of protein expression. The causal mutation was traced to a single nucleotide transition located deep into intron 13 of gene Ank1. In vitro minigene splicing assay revealed two abnormally spliced transcripts containing cryptic exons from fragments of Ank1 intron 13. The inclusion of cryptic exons introduced a premature termination codon, which leads to nonsense-mediated decay of the mutant transcripts in vivo. Hence, in homozygous mice, only wild-type ankyrin-1 is expressed, albeit at 70% of the level in wild-type mice. Heterozygotes display a similar hereditary spherocytosis phenotype stemming from intermediate protein expression level, indicating the haploinsufficiency of the mutation. Weakened linkage between integral transmembrane protein, band 3, and underlying cytoskeleton was observed in mutant mice as the result of reduced high-affinity binding sites provided by ankyrin-1. Hema6 is the only known mouse mutant of Ank1 allelic series that expresses full-length canonical ankyrin-1 at a reduced level, a fact that makes it particularly useful to study the functional impact of ankyrin-1 quantitative deficiency.

Many Staphylococcus aureus have lost a major genetic barrier against phage infection, termed clustered regularly interspaced palindromic repeats (CRISPR/cas). Hence, S. aureus strains frequently exchange genetic material via phage-mediated horizontal gene transfer events, but, in turn, are vulnerable in particular to lytic phages. Here, a novel strategy of S. aureus is described, which protects S. aureus against the lytic activity of Podoviridae, a unique family of staphylococcal lytic phages with short, non-contractile tails. Unlike most staphylococcal phages, Podoviridae require a precise wall teichoic acid (WTA) glycosylation pattern for infection. Notably, TarM-mediated WTA α-O-GlcNAcylation prevents infection of Podoviridae while TarS-mediated WTA β-O-GlcNAcylation is required for S. aureus susceptibility to podoviruses. Tracking the evolution of TarM revealed an ancient origin in other staphylococci and vertical inheritance during S. aureus evolution. However, certain phylogenetic branches have lost tarM during evolution, which rendered them podovirus-susceptible. Accordingly, lack of tarM correlates with podovirus susceptibility and can be converted into a podovirus-resistant phenotype upon ectopic expression of tarM indicating that a "glyco-switch" of WTA O-GlcNAcylation can prevent the infection by certain staphylococcal phages. Since lytic staphylococcal phages are considered as anti-S. aureus agents, these data may help to establish valuable strategies for treatment of infections.

Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-catenin. γ-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing γ-catenin in human CML CD34(+) bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that γ-catenin is required for survival of CML LSCs. Pharmacological inhibition of γ-catenin thwarted survival and self-renewal of human CML CD34(+) cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. γ-Catenin inhibition reduced long-term engraftment of human CML CD34(+) cells in NOD.Cg-Prkdc (scid) II2rg (tm1Sug)/JicCrl (NOG) mice. Silencing γ-catenin by shRNA in human primary CD34(+) cells did not alter β-catenin, implying a β-catenin-independent role of γ-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that γ-catenin may be a novel therapeutic target of LSCs, and suppression of γ-catenin by HDACi may explain elimination of CML LSCs.

Abdominal aortic aneurysm (AAA) is a life-threatening condition. A number of studies reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and AAA risk, but substantial controversial findings were observed and the strength of the association remains unclear.

The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that appears to be mechanistically unrelated. Hypopigmentation was rescued by transgenic expression of wild-type Mbtps1, and reciprocal grafting studies showed that normal pigmentation depended upon both cell-intrinsic or paracrine factors, as well as factors that act systemically, both of which are lacking in wrt homozygotes. Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring and partial embryonic lethality (~40%) of zygotic wrt mutant offspring. Mbtps1 is one of two maternal-zygotic effect genes identified in mammals to date. It functions nonredundantly in pigmentation and embryogenesis.

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease worldwide, and it is always regarded as a consequence of a sedentary, food-abundant lifestyle, sitting for an extended time, and a low physical activity level, which often coincide with chronic and long-lasting psychological stress. A Chinese medicine Sinisan (SNS) may be a potential formula for treating this kind of disease.

Chinese adults with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Ph- ALL) have poor outcomes.

Samples from three different mating stages (before, during and after mating) of the Mediterranean fruit fly Ceratitis capitata were used in this experiment. Samples obtained from whole insects were subjected to extraction with the two mixtures of solvents (acetonitrile/water (A) and methanol/acetonitrile/water (B)) and a comparative study of the extractions using the different solvents was performed. Direct immersion-solid phase microextraction (DI-SPME) was employed, followed by gas chromatographic-mass spectrometry analyses (GC/MS) for the collection, separation and identification of compounds. The method was validated by testing its sensitivity, linearity and reproducibility. The main compounds identified in the three different mating stages were ethyl glycolate, α-farnesene, decanoic acid octyl ester, 2,6,10,15-tetramethylheptadecane, 11-tricosene, 9,12-(Z,Z)-octadecadienoic acid, methyl stearate, 9-(Z)-tricosene, 9,11-didehydro-lumisterol acetate; 1,54-dibromotetrapentacontane, 9-(Z)-hexadecenoic acid hexadecyl ester, 9-(E)-octadecenoic acid and 9-(Z)-hexadecenoic acid octadecyl ester. The novel findings indicated that compound compositions were not significantly different before and during mating. However, new chemical compounds were generated after mating, such as 1-iodododecane, 9-(Z)-tricosene and 11,13-dimethyl-12-tetradecen-1-acetate which were extracted with both (A) and (B) and dodecanoic acid, (Z)-oleic acid, octadecanoic acid and hentriacontane which were extracted with (A) and ethyl glycolate, 9-hexadecenoic acid hexadecyl ester, palmitoleic acid and 9-(E)-octadecenoic acid, which were extracted with solvent (B). This study has demonstrated that DI-SPME is useful in quantitative insect metabolomics by determining changes in the metabolic compounds in response to mating periods. DI-SPME chemical extraction technology might offer analysis of metabolites that could potentially enhance our understanding on the evolution of the medfly.

The lack of a general clinic-relevant model for human cancer is a major impediment to the acceleration of novel therapeutic approaches for clinical use. We propose to establish and characterize primary human hepatocellular carcinoma (HCC) xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR) T cells and accelerate the clinical translation of CAR T cells used in HCC.

With the development of the Internet, an increasing number of adolescents play online game excessively, which leads to adverse effects on individuals and society. Previous studies have demonstrated altered gray-matter volume (GMV) in individuals with Internet gaming disorder (IGD), but the relationship between the tendency to IGD and the GMV across whole brain is still unclear in adolescents. In the present study, anatomical imaging with high resolution was performed on 67 male adolescents who played online game; and Young's Internet addiction test (IAT) was conducted to test the tendency to IGD. FMRIB Software Library (FSL) was used to calculate the voxel-based correlations between the GMV and the IAT score after controlling for the age and years of education. The GMVs of the bilateral postcentral gyri (postCG), the bilateral precentral gyri (preCG), the right precuneus, the left posterior midcingulate cortex (pMCC), the left inferior parietal lobe (IPL), and the right middle frontal gyrus (MFG) were negatively correlated with the IAT score. The correlation still existed between the IAT score and the GMVs of the bilateral postCG, the left preCG, the left pMCC, and the right MFG after controlling for the total time of playing online game. When the participants were divided into two groups according to the IAT score, the GMVs of these IAT-related brain regions were lower in high IAT score subgroup (IAT score >50) than in low IAT score subgroup (IAT score ≤50). Our results suggested that the GMVs of brain regions involved in sensorimotor process and cognitive control were associated with the IGD tendency. These findings may lead to new targets for preventing and treating the IGD.

BACKGROUND Dyslipidemia is the most frequent comorbidity in patients with cardiovascular disease. However, studies examining the relationship between blood lipid profiles and AF have produced inconsistent results. MATERIAL AND METHODS A total of 651 patients were enrolled into 3 groups: Healthy controls (n=64), Paroxysmal AF (PAF; n=270), and Continuous AF (CAF; n=317). All enrolled patients underwent routine baseline 12-lead electrocardiography (ECG) and 24-h dynamic ECG along with blood testing, which included the following: complete metabolic panel, hepatic function, renal function, circulating thyroxine, fasting high-density lipoprotein cholesterol (HDL -C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC). RESULTS Patients with AF had significantly higher levels of triglycerides (TG), lower levels of LDL-C-c, and lower levels of HDL-C (p<0.05). TC (OR 0.979, p<0.9247) and TG (OR 0.945, p<0.6496) were negatively and linearly associated with PAF, while TG (OR 0.807, p=0.2042), LDL-C (OR 0.334, p=0.0036), and HDL-C (OR 0.136, p=0.0002) were negatively and linearly associated with CAF. CONCLUSIONS Compared to healthy controls, patients with AF had lower blood lipid levels, especially LDL-c and HDL-c levels. Hypolipoproteinemia may increase patient susceptibility to developing AF.

Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.

Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.

There is currently no treatment available for the cognitive symptoms of schizophrenia, but evidence suggests that selective estrogen receptor modulators (SERMs) may provide relief. Our recent animal model data showed that a lack of female sex hormones in mice impairs the ability of hippocampal neurons to synchronise and generate oscillations within the frequency range of 30-80 Hz (gamma power) leading to cognitive impairment, while both estradiol and the SERM, raloxifene, recovered this. Given that cognitive impairment is accompanied by abnormal gamma power in schizophrenia, this study aimed to determine the effects of raloxifene on gamma power during spatial memory tasks in the prenatal immune challenged (poly-I:C) mouse model with relevance to schizophrenia. Pregnant dams received the viral mimetic poly-I:C (20 mg/kg, i.p.) at gestational day 17. Male and female offspring were treated with placebo or raloxifene implants at adulthood. Local field potentials from the CA1 hippocampus were simultaneously recorded during the Y-maze test of short term spatial memory and the cheeseboard maze test of long-term spatial learning and memory and cognitive flexibility. In female but not male mice, poly I:C exposure reduced gamma power during decision making and prolonged the time spent in the centre (decision making phase) during the Y-maze task. Female poly-I:C exposed mice also showed increased gamma power during acquisition of the cheeseboard long term memory task and perseverative behaviour. Treatment with raloxifene recovered gamma power and decision making deficits in the Y-maze and restored gamma power changes during the cheeseboard maze task as well as perseverative behaviour. Male mice showed no electrophysiological or behavioural effects of poly-I:C or raloxifene treatment. In summary, poly-I:C exposure induced female specific cognitive impairments accompanied by altered neural oscillations in the gamma frequency and raloxifene recovered these abnormalities.

Personalized quality of service (QoS) prediction plays an important role in helping users build high-quality service-oriented systems. To obtain accurate prediction results, many approaches have been investigated in recent years. However, these approaches do not fully address untrustworthy QoS values submitted by unreliable users, leading to inaccurate predictions. To address this issue, inspired by blockchain with distributed ledger technology, distributed consensus mechanisms, encryption algorithms, etc., we propose a personalized QoS prediction method for web services that we call blockchain-based matrix factorization (BMF). We develop a user verification approach based on homomorphic hash, and use the Byzantine agreement to remove unreliable users. Then, matrix factorization is employed to improve the accuracy of predictions and we evaluate the proposed BMF on a real-world web services dataset. Experimental results show that the proposed method significantly outperforms existing approaches, making it much more effective than traditional techniques.

To investigate the relationship between coronary artery calcification and calcium deposition in cardiomyocytes.

Despite advances in the treatment of T‑cell acute lymphoblastic leukemia (T‑ALL), the outcome of T‑ALL treatment remains unsatisfactory, therefore, more effective treatment is urgently required. The present study examined the cytotoxicities of bortezomib in combination with daunorubicin against human Jurkat and Molt‑4 T‑ALL cells and primary T‑ALL cells. Compared with treatment alone, co‑exposure of cells to bortezomib and daunorubicin resulted in a significant increase in cell death in the Jurkat cells, as evidenced by the increased percentage of Annexin V‑positive cells, the formation of apoptotic bodies. In addition, the administration sequence of bortezomib and daunorubicin had an effect on cell viability. Treatment with bortezomib followed by daunorubicin treatment was more effective, compared with treatment with daunorubicin followed by bortezomib. Co-treatment with bortezomib and daunorubicin markedly enhanced the activation of caspase‑3, ‑8 and ‑9, which was reversed by the pan‑caspase inhibitor, Z‑VAD‑FMK. In addition, cotreatment with bortezomib and daunorubicin enhanced the collapse of mitochondrial transmembrane potential and upregulated the proapoptotic protein, B‑cell lymphoma 2 (Bcl‑2)‑interacting mediator of cell death (Bim), but not Bcl‑2 or Bcl‑extra large. Consistent with this, it was demonstrated that cotreatment of bortezomib and daunorubicin efficiently induced apoptosis in primary T‑ALL cells, and cell death was associated with the collapse of mitochondrial transmembrane potential and the upregulation of Bim. Taken together, these findings indicated that the combination of bortezomib and daunorubicin significantly enhanced their apoptosis‑inducing effect in T‑ALL cells, which may warrant further investigation in preclinical and clinical investigations.

Biomedical research often involves conducting experiments on model organisms in the anticipation that the biology learnt will transfer to humans. Previous comparative studies of mouse and human tissues were limited by the use of bulk-cell material. Here we show that transfer learning-the branch of machine learning that concerns passing information from one domain to another-can be used to efficiently map bone marrow biology between species, using data obtained from single-cell RNA sequencing. We first trained a multiclass logistic regression model to recognize different cell types in mouse bone marrow achieving equivalent performance to more complex artificial neural networks. Furthermore, it was able to identify individual human bone marrow cells with 83% overall accuracy. However, some human cell types were not easily identified, indicating important differences in biology. When re-training the mouse classifier using data from human, less than 10 human cells of a given type were needed to accurately learn its representation. In some cases, human cell identities could be inferred directly from the mouse classifier via zero-shot learning. These results show how simple machine learning models can be used to reconstruct complex biology from limited data, with broad implications for biomedical research.