In gene expression profiling studies, including single-cell RNAsequencing (scRNA-seq) analyses, the identification and characterization of co-expressed genes provides critical information on cell ...identity and function. Gene co-expression clustering in scRNA-seq data presents certain challenges. We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately, and produce results that substantially limit biological expectations of co-expressed genes. Herein, we present single-cell Latent-variable Model (scLM), a gene co-clustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context. Importantly, scLM can simultaneously cluster multiple single-cell datasets, i.e., consensus clustering, enabling users to leverage single-cell data from multiple sources for novel comparative analysis. scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets. Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of scLM, we apply it to our in-house and public experimental scRNA-seq datasets. scLM identifies novel functional gene modules and refines cell states, which facilitates mechanism discovery and understanding of complex biosystems such as cancers. A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in ...tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1
ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1
ovarian cancer.
► MOF-CJ3 was chosen as a stationary phase to prepare a capillary GC column. ► The column offered good separation of linear and branched alkanes. ► The column offered good separation of aromatic ...positional isomers.
In this work, a tubular metal–organic framework, MOF-CJ3, with a large one-dimensional channel was chosen as stationary phase to prepare a capillary gas chromatographic column via a verified dynamic coating procedure. The column offered good separations of linear and branched alkanes, as well as aromatic positional isomers (ethylbenzene, xylene, cresol, hydroquinone, dichlorobenzene, bromobenzonitrile, chloronitrobenzene, and nitrotoluene) based on a combination of host–guest interactions and adsorption effects. Elution sequence of most of the analytes followed an increasing order of their boiling points, except for the separation of n-heptanes/isooctane, cresol, and hydroquinone isomers. Separation behavior of the column upon different organic substances may be related to the tubular pore structure of MOF-CJ3, in which the van der Waals forces between the alkanes and the hydrophobic inner surfaces might have great effect on separation of n-heptanes and isooctane, whereas the separation of cresol and hydroquinone isomers were affected by (OH⋯O) hydrogen bonds formed between the analytes and the 1,3,5-benzenetricarboxylate ligands on the pore wall. The effects of temperature on separation of aromatic positional isomers were investigated to elucidate entropy and enthalpy controlling of the separation process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant ...population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8
+
T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated
SerpinB2
and
CCL4
transcription, two secretory factors responsible for cancer stemness inhibition and CD8
+
T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.
This study focuses on a novel clutchless and synchronizer-free drive system designed explicitly for pure electric vehicles. In contrast to the majority of previous research that solely considers ...internal excitations, this study not only incorporates various non-linear factors such as time-varying friction forces, time-varying mesh stiffness, and damping associated with internal excitations but also places significant emphasis on analyzing the impact of non-linear external excitations, including road surface unevenness and motor torque fluctuations, on the shifting process of the drive system. Subsequently, a non-linear dynamic model of the shifting process is established. In the modeling process, departing from the traditional two-degree-of-freedom quarter vehicle dynamics model, this study adopts an elastic tire-body and elastic tire-tread tire model, enabling the establishment of a highly accurate multi-degree-of-freedom quarter vehicle dynamics model. The simulation results indicate that road surface roughness and motor torque fluctuation significantly impact the gear-shifting process and the impact of road surface roughness increases with the level of roughness. Moreover, the effect of motor torque fluctuation on the gear-shifting process varies depending on different factors and is not simply additive. Consequently, when formulating and optimizing shifting strategies, it becomes imperative to consider various external factors. The research methodology integrates these factors into the dynamic analysis of the shifting process, providing a theoretical basis for developing effective shifting control strategies while considering external excitations.
Influenza infection continues are a persistent threat to public health. The identification and characterization of human broadly neutralizing antibodies can facilitate the development of antibody ...drugs and the design of universal influenza vaccines. Here, we present structural information for the human antibody PN-SIA28's heterosubtypic binding of hemagglutinin (HA) from circulating and emerging potential influenza A viruses (IAVs). Aside from group 1 and 2 conventional IAV HAs, PN-SIA28 also inhibits membrane fusion mediated by bat-origin H17 and H18 HAs. Crystallographic analyses of Fab alone or in complex with H1, H14, and H18 HA proteins reveal that PN-SIA28 binds to a highly conserved epitope in the fusion domain of different HAs, with the same CDRHs but different CDRLs for different HAs tested, distinguishing it from other structurally characterized anti-stem antibodies. The binding characteristics of PN-SIA28 provides information to support the design of increasingly potent engineered antibodies, antiviral drugs, and/or universal influenza vaccines.
SUMMARY
The Gonghe Basin in the northeast Tibetan Plateau presents significant potential for hot dry rock (HDR) geothermal resources. A 1990 Mw 6.4 earthquake in the basin furthers the need for an ...improved understanding of its sedimentary structure. In this study, we utilize data from a dense seismic array of 88 short-period seismometers deployed at an interstation spacing of approximately 3 km to scrutinize the sedimentary structure of the Gonghe Basin. By analysing teleseismic P waveforms, we identify P-to-S converted waves (Ps wave) originating from the sedimentary basement. We then determine the delay time between the Ps waves and the direct P waves (P wave) through waveform cross-correlation. By integrating this delay time with empirical velocity structure models, HDR borehole data and results from teleseismic receiver function analysis, we derive a sediment thickness model of the Gonghe Basin for the Qabqa geothermal area. Our findings reveal a gradual increase in sediment thickness from around 500 m in the east to approximately 3000 m in the west, which is consistent with other geophysical surveys and borehole data. The thick sediments in the basin could potentially serve as an excellent thermal storage cover for HDR. The strong ground motion simulation using our sediment thickness model shows that thick sediments can amplify seismic waves, increasing the risk of seismic hazards. Moreover, our study indicates that the clear Ps waves can be effectively extracted to construct a dependable sediment thickness model using teleseismic P waves recorded by a short-period dense seismic array.
MicroRNAs are non-coding small RNAs that regulate gene expression by Watson–Crick base pairing to target messenger RNA (mRNA). They are involved in most biological and pathological processes, ...including tumorigenesis. The binding of microRNA to mRNA is critical for regulating the mRNA level and protein expression. However, this binding can be affected by single-nucleotide polymorphisms that can reside in the microRNA target site, which can either abolish existing binding sites or create illegitimate binding sites. Therefore, polymorphisms in microRNA can have a differing effect on gene and protein expression and represent another type of genetic variability that can influence the risk of certain human diseases. Different approaches have been used to predict and identify functional polymorphisms within microRNA-binding sites. The biological relevance of these polymorphisms in predicted microRNA-binding sites is beginning to be examined in large case–control studies.
A pseudorabies virus (PRV) novel virulent variant outbreak occurred in China in 2011. However, little is known about PRV prevention and treatment. Huaier polysaccharide has been used to treat some ...solid cancers, although its antiviral activity has not been reported. Our study confirmed that the polysaccharide can effectively inhibit infection of PRV XJ5 in PK15 cells. It acted in a dose-dependent manner when blocking virus adsorption and entry into PK15 cells. Moreover, it suppressed PRV replication in PK15 cells. In addition, the results suggest that Huaier polysaccharide plays a role in treating PRV XJ5 infection by directly inactivating PRV XJ5. In conclusion, Huaier polysaccharide might be a novel therapeutic agent for preventing and controlling PRV infection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•AST reversed cell injury by repressing ER stress and dysregulation of miR-7 and SNCA•MiR-7 bound to and negative regulated SNCA•MiR-7 inhibition or SNCA overexpression abolished the protective ...effects of AST•AST alleviated neuron injury induced by MPTP through miR-7/SNCA axis in vivo
Parkinson’s disease (PD) is a common neurodegenerative disorder that featured by the loss of dopaminergic neurons. Astaxanthin (AST), an important antioxidant, is demonstrated to be a neuroprotective agent for PD. However, the underlying mechanisms of AST in PD remain largely unclear. In this study, we found that AST treatment significantly not only abolished the cell viability inhibition and apoptosis promotion induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells via inhibiting endoplasmic reticulum (ER) stress, but also reversed the MPP+ caused dysregulation of miR-7 and SNCA expression. MiR-7 knockdown and SNCA overexpression were achieved by treating SH-SY5Y cells with miR-7 inhibitor and pcDNA3.1-SNCA plasmids, respectively. MiR-7 could bind to and negatively regulate SNCA in SH-SY5Y cells. Treated SH-SY5Y cells with miR-7 inhibitor or pcDNA3.1-SNCA abrogated the protective effects of AST on MPP+ induced cytotoxicity. Knockdown of miR-7 aggravated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neuron injury in vivo suggested by athletic performance, histopathological morphology, expression of tyrosine hydroxylase (TH) and TUNEL positvie cells, however, AST treatment could reverse these effects of miR-7 knockdown. Collectively, AST suppressed ER stress and protected against PD-caused neuron damage by targeting miR-7/SNCA axis, implying that AST might be a potential effective therapeutic agent for PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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