Representations and cohomologies of modified λ-differential Hom-Lie algebras

In this paper, we introduce the concept and representations of modified $\lambda$-differential Hom-Lie algebras. We then develop the cohomology of modified $\lambda$-differential Hom-Lie algebras with coefficients in a suitable representation. As applications, abelian extensions and skeletal modified $\lambda$-differential Hom-Lie 2-algebras are characterized in terms of cohomology groups

Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview

Despite the clear benefits demonstrated by immunotherapy, there is still an inevitable off-target effect resulting in serious adverse immune reactions. In recent years, the research and development of Drug Delivery System (DDS) has received increased prominence. In decades of development, DDS has demonstrated the ability to deliver drugs in a precisely targeted manner to mitigate side effects and has the advantages of flexible control of drug release, improved pharmacokinetics, and drug distribution. Therefore, we consider that combining cancer immunotherapy with DDS can enhance the anti-tumor ability. In this paper, we provide an overview of the latest drug delivery strategies in cancer immunotherapy and briefly introduce the characteristics of DDS based on nano-carriers (liposomes, polymer nano-micelles, mesoporous silica, extracellular vesicles, etc.) and coupling technology (ADCs, PDCs and targeted protein degradation). Our aim is to show readers a variety of drug delivery platforms under different immune mechanisms, and analyze their advantages and limitations, to provide more superior and accurate targeting strategies for cancer immunotherapy

End-To-End Semi-supervised Learning for Differentiable Particle Filters

Recent advances in incorporating neural networks into particle filters provide the desired flexibility to apply particle filters in large-scale real-world applications. The dynamic and measurement models in this framework are learnable through the differentiable implementation of particle filters. Past efforts in optimising such models often require the knowledge of true states which can be expensive to obtain or even unavailable in practice. In this paper, in order to reduce the demand for annotated data, we present an end-to-end learning objective based upon the maximisation of a pseudo-likelihood function which can improve the estimation of states when large portion of true states are unknown. We assess performance of the proposed method in state estimation tasks in robotics with simulated and real-world datasets.Comment: Accepted in ICRA 202

Cyclohexadione-aniline conjugate inhibits proliferation of melanoma cells via upregulation of Mek 1/2 kinase activity

Purpose: To investigate the antiproliferative effect of cyclohexadione-aniline conjugate (CHAC) on melanoma cells, and the mechanism of action involved. Methods: Human melanoma cell lines (B16 F1 and A375) were used in this study. The cells were cultured in RPMI 1640 medium supplemented with 10 % fetal bovine serum (FBS) and 1 % penicillin/streptomycin at 37 °C in a humidified atmosphere of 5 % CO2 and 95 % air. After attaining 70 - 80 % confluency, the cells were treated with serum-free medium and graded concentrations of CHAC (10 – 60 μM) for 24 h. Normal cell culture without CHAC served as control group. B16 F1 and A375 cells were used in logarithmic growth phase in this study. Cell viability and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphe¬nyltetrazolium bromide (MTT) and flow cytometric assays, respectively. Western blotting was used to assess the levels of protein expression of X linked inhibitor of apoptosis (XIAP), survivin, p-Erk 1/2, and p-Mek 1/2. Results: Treatment of B16 F1 and A375 cells with CHAC led to significant and concentrationdependent reductions in their viability (p < 0.05). The proliferation of B16 F1 cells decreased from 93.41 to 32.87 %, while that of A375 cells was reduced from 95.23 to 36.50 %. Treatment of B16 F1 cells with CHAC significantly and concentration-dependently increased the population of cells in G0/G1 phase, and significantly reduced cell proportion in S and G2/M phases (p < 0.05). It also significantly and concentration-dependently promoted apoptosis in B16 F1 cells (p < 0.05). CHAC treatment significantly and concentration-dependently down-regulated the expressions of XIAP and survivin proteins (p < 0.05). Exposure of B16 F1 cells to CHAC significantly and concentration-dependently upregulated the expression of p-Mek 1/2, but down-regulated p-Erk 1/2 protein expression (p < 0.05). Densitometric analysis revealed that the expression of p-Mek 1/2 was increased from 12 to 91 %. Conclusion: The results of this study indicate that CHAC inhibits the proliferation of melanoma cells via upregulation of Mek 1/2 kinase activity, and therefore may find application in the management of melanoma

Using noble gases to trace groundwater evolution and assess helium accumulation in Weihe Basin, central China

The severe shortage of helium resources is an impending global problem. However, the helium accumulation processes and conditions favorable for helium enrichment in reservoirs remain poorly understood, which makes helium exploration challenging. Noble gases are good tracers of subsurface fluids provenance, migration and storage, as well as indicators of the nature and quantity of associated phases. In this study the variation of major gases and noble gases data in Weihe Basin provide us with an excellent opportunity to understand the groundwater evolution and helium accumulation processes. Twelve gas samples collected from wellheads of geothermal wells can be classified into three groups, in which Group A has high concentrations of N2 (58.57% - 91.66%) and He (0.32% - 2.94%); Group B has high contents of CH4 (52.94% and 69.50%) and low concentrations of He (0.057% and 0.062%); Group C has a high content of CH4 (71.70%) and He (2.11%). Helium isotopic ratios are predominantly radiogenic in origin and therefore crustally derived. Measured elemental ratios of noble gases are compared with multiple fractionation models for Group A and B samples, implying that open system heavy oil-water fractionation with excess heavy noble gases has occurred in the basin with Voil/Vwater ratios of 0.06-0.18. The amount of helium in Group A and B samples requires the release of all 4He produced in the crust since 0.30Ma-1.98Ma into the groundwater. The Group C sample requires an additional He flux from adjacent granitic bodies. The accumulation of helium and hydrocarbon in the Weihe Basin can be explained by a 4-stage process. Accumulation of commercially viable helium requires high He flux from source rocks, the existence of a free gas phase of major gas components (CH4 in most cases, N2 or CO2) and minimal major gas addition after formation of the free gas phase

MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK

Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues (p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis (p < 0.05) and good prognosis (p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro. miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC

Differences in subthalamic oscillatory activity in the two hemispheres associated with severity of Parkinson’s disease

BackgroundIt is well known that motor features of Parkinson’s disease (PD) commonly begin on one side of the body and extend to the other side with disease progression. The onset side generally remains more severely affected over the course of the disease. However, the pathophysiology underlying the asymmetry of motor manifestations remains unclear. The purpose of the present study is to examine whether alterations in neuronal activity in the subthalamic nucleus (STN) associate with PD severity.MethodsMicroelectrode recording was performed in the STN during targeting for 30 patients in the treatment of deep brain stimulation. The mean spontaneous firing rate (MSFR), power density spectral analysis, and correlations were calculated. Characteristics of subthalamic oscillatory activity were compared between two hemispheres. UPDRS III scores during “Off” and “On” states were obtained for the body side of initial symptoms (BSIS) and the body side of extended symptoms (BSES).ResultsThere were significant differences of MSFR (41.3 ± 11.0 Hz vs 35.2 ± 10.0 Hz) and percentage of ß frequency oscillatory neurons (51.3% vs 34.9%) between BSIS and BSES. The percentage of ß frequency oscillatory neurons correlated with the bradykinesia/rigidity scores for both sides (p < 0.05). In contrast, the percentage of tremor frequency oscillatory neurons was significantly higher in the BSES than that in the BSIS. In particular, these neurons only correlated with the tremor scores of the BSES (p < 0.05).ConclusionThe results suggest that increased neuronal firing rate and ß frequency oscillatory neurons in the STN are associated with contralateral side motor severity and its progression. Tremor frequency oscillatory neurons are less observed in the STN of the BSIS suggesting that ß oscillatory activity dominates and tremor frequency oscillatory activity reciprocally declines

Leveraging genomic annotations and pleiotropic enrichment for improved replication rates in schizophrenia GWAS

Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic (“z-score”) of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a “relative enrichment score” for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3

CXCR4 involvement in neurodegenerative diseases

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases

Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.

BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. CONCLUSIONS: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD