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In this paper, we mainly study the following boundary value problems of fractional discontinuous differential equations with impulses: \begin{document}$ \hskip 3mm \left\{ \begin{array}{lll} _{t}^{C} \mathcal {D}^{\mathfrak{R}}_{0^{+}}\Lambda(t) = \mathcal {E}(t)\digamma(t, \Lambda(t)), \ a.e.\ t\in Q, \\ \triangle \Lambda|_{t = t_{{\kappa}}} = \Phi_{{\kappa}}(\Lambda(t_{{\kappa}})), \ {\kappa} = 1, \ 2, \ \cdots, \ m, \\ \triangle \Lambda'|_{t = t_{{\kappa}}} = 0, \ {\kappa} = 1, \ 2, \ \cdots, \ m, \\ {\vartheta} \Lambda(0)-{\chi} \Lambda(1) = \int_{0}^{1}\varrho_{1}({\upsilon})\Lambda({\upsilon})d{\upsilon}, \\ {\zeta} \Lambda'(0)-\delta \Lambda'(1) = \int_{0}^{1}\varrho_{2}({\upsilon})\Lambda({\upsilon})d{\upsilon}, \end{array}\right. $\end{document} where $ {\vartheta} > {\chi} > 0, \ {\zeta} > \delta > 0 $, $ \Phi_{{\kappa}}\in C(\mbox{ $\mathbb{R}$ }^{+}, \mbox{ $\mathbb{R}$ }^{+}) $, $ \mathcal {E}, \ \varrho_{1}, \ \varrho_{2} \geq 0 $ a.e. on $ Q = [0, 1] $, $ \mathcal {E}, \ \varrho_{1}, \ \varrho_{2} \in L^{1}(0, 1) $ and $ \digamma:[0, 1]\times \mbox{ $\mathbb{R}$ }^{+}\rightarrow \mbox{ $\mathbb{R}$ }^{+} $, $ \mbox{ $\mathbb{R}$ }^{+} = [0, +\infty) $. By using Krasnosel skii's fixed point theorem for discontinuous operators on cones, some sufficient conditions for the existence of single or multiple positive solutions for the above discontinuous differential system are established. An example is given to confirm the main results in the end.

The aim of this discursive representation of the Chinese Dream is to analyze the presentation of the Chinese English-Language press based on the corpus linguistics and critical discourse analysis. The study sought to establish (a) key terms used to discuss the Chinese Dream in the Chinese English-language press (b) the collocation of key terms in the Chinese Dream discourse in the English-language press in China and (c) the frequently used words in the discussion of the Chinese Dream discourse in the English-Language press in China. The findings of this paper give credence to the assertion that powerful officials use media coverage to manipulate other members of the society by providing the information that will work in their favor. Mostly, the Chinese dream has been sold as a dream for all the Chinese people and the President, the Chinese Communist Party, and the party’s general secretary are some of the entities that have been used to give weight to the preposition.

A fundamental feature of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcriptional elongation by sequestering the cyclin dependent kinase 9/cyclin T1 (CDK9/CCNT1) positive transcription elongation factor (P-TEFb) complex. We found that epidermal growth factor signaling induces phosphorylation of the enzyme methyltransferase 3 (METTL3), leading to METTL3-mediated methylation of 7SK. 7SK methylation enhanced its binding to heterogeneous nuclear ribonucleoproteins, causing the release of the HEXIM1 P-TEFb complex subunit1 (HEXIM1)/P-TEFb complex and inducing transcriptional elongation. Our findings establish the mechanism underlying 7SK activation and uncover a previously unknown function for the m 6 A modification in converting growth factor signaling events into a regulatory transcriptional response via an RNA methylation–dependent switch.

In artificial structures of molecular or quantum dot emitters in contact with single-layer graphene (SLG) Förster-type resonant energy transfer (FRET) can occur unconditionally due to the gapless band structure of SLG. A significant breakthrough for applications, however, would be the electrical modulation of FRET between arbitrary FRET pairs, using the SLG to control this process and taking advantage of the particular band structure and the monatomic thickness of SLG, far below the typical Förster radius of a few nanometers. For a proof of concept, we have therefore designed a Sandwich device where the SLG was transferred onto holey Si3N4 membranes and organic molecules were deposited on either side of the SLG. The relative photoluminescence (PL) intensities of donor and acceptor molecules changed continuously and reversibly with the external bias voltage, and a variation of about 6% of FRET efficiency has been achieved. We ascribe the origin of the electrical modulation of FRET to important doping-dependent nonlocal optical effects in the near field of SLG in the visible range.

The diagnosis of primary biliary cholangitis (PBC) in patients with seropositive anti-mitochondrial antibody (AMA) but normal alkaline phosphatase (ALP) depends on a liver biopsy. We aimed to reveal potential serum biomarkers that could suggest the necessity of a liver biopsy in such patients. Retrospective analysis was performed. Subjects who were treatment naive with seropositive AMA but normal ALP and who underwent at least one liver biopsy between 2008 and 2020 were included in this study. Histologic biopsies were evaluated by two experienced pathologists blinded to the serum tests. A total of 115 patients who were treatment naive were included in this study. Of these, 77 patients (67%) exhibited histologic PBC features and nonspecific histologic features were found in the remaining 38 (33%) patients. Multivariate analysis suggested that baseline serum immunoglobulin M (IgM)0.773 × upper limit of normal (ULN) (P 0.001) and age42 years (P = 0.002) were associated with the diagnosis of PBC through liver biopsies. A significant decrease in the median levels of gamma-glutamyl transpeptidase (GGT) and IgM was found in 54 patients with PBC who received ursodeoxycholic acid (UDCA). Conclusion: For patients who were treatment naive with seropositive AMA but normal ALP, baseline serum IgM0.773 × ULN and age42 years were the factors that strongly suggested a diagnosis of PBC. In these patients receiving UDCA, a dynamic monitoring of GGT and IgM might be helpful in evaluating therapeutic responses.

This paper investigates a new class of non-autonomous second-order measure evolution systems involving state-dependent delay and non-instantaneous impulses. We introduce a stronger concept of exact controllability called total controllability. The existence of mild solutions and controllability for the considered system are obtained by applying strongly continuous cosine family and the Mönch fixed point theorem. Finally, an example is used to verify the practical application of the conclusion.

Co1Ni6CH exhibits a good OER activity (η50 = 256 mV, 51 mV/dec) and stability in 1 M KOH with partial phase transformation. Fe impurity in electrolyte can provide more active sites, improve electronic conductivity, and promote stability.

CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal–maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of CD44 expression in mammalian SF and ESF and demonstrate that in the human lineage evolved higher CD44 expression. Isoform expression in cattle and human is very similar suggesting that differences in invasibility are not due to the nature of expressed isoforms. We then asked whether the concerted gene expression increase in both cell types is due to shared regulatory mechanisms or due to cell type-specific factors. Reporter gene experiments with cells and cis-regulatory elements from human and cattle show that the difference of CD44 expression is due to cis effects as well as cell type-specific trans effects. These results suggest that the concerted expression increase is likely due to selection acting on both cell types because the evolutionary change in cell type-specific factors requires selection on cell type-specific functions. This scenario implies that the malignancy enhancing effects of elevated CD44 expression in humans likely evolved as a side-effect of positive selection on a yet unidentified other function of CD44. A possible candidate is the anti-fibrotic effect of CD44 but there are no reliable data showing that humans and primates are less fibrotic than other mammals.

WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout ofWnt5aandWnt5b(Wnt5DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences betweenWnt5DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+T cell GZMB expression in theWnt5DKO mice. In addition, neutrophils from theWnt5DKO colitic mice exert stronger suppression of CD8+T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treatedWnt5DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/CCDH1), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/CCDH1 regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/CCDH1 E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/CCDH1 itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/CCDH1 inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/CCDH1 resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/CCDH1 is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy.

TiO2 nanotube arrays (TiO2 NTs) were regarded as the outstanding semiconductors for the photocatalytic application in waste water treatment and H2 generation, and CdS nanoparticles as the visible light sensitizers were traditionally used to enhance the photocatalytic performance. In this paper, CdS–CuS co-sensitizers were deposited on TiO2 NTs by one-pot hydrothermal method, and the Cu/Cd ratio was changed to adjust the hybrid photocatalyst composition and electron transfer. The photocatalytic data indicated that suitable CdS–CuS composition could effectively enhance the photocatalytic pollutant removal and photocurrent/H2 evolution and the hybrid photocatalyst also exhibited the high stability by the inhibition of CdS photocorrosion. The p-n heterojunction construction of TiO2 NTs/CdS–CuS benefited the solar response, photoelectron separation and photocatalytic reaction, and the photocatalytic mechanism and photoelectron transfer were investigated. The p-n heterojunctional photocatalyst is supposed to apply in environmental remediation and new energy development.

CD8+T cells play an important role in tumor immune surveillance and control. Better understanding of the regulation of their anti-tumor actions and improving their cytotoxic function and persistence will help advancing cancer immunotherapies. Here, we report the development of a step-wise CRISPR knockout (KO) screening strategy under the selection of TGF-β, a clinically relevant immunosuppressive pressure. The screen identifies Cul5 as a negative-feedback regulator of the core signaling pathways, differentiation, and persistence of CD8+T cell. Cul5 KO in mouse CD8+T cells significantly improves their tumor control abilityin vitroandin vivowith significant proteomic alterations that generally enhance TCR and cytokine signaling, effector function, stemness, and survival of CD8+T cell. Mechanistically, Cul5, whose protein content and active, neddylated form increase upon TCR-stimulation, interacts with SOCS-box-containing Pcmtd2 and negatively regulates TCR and IL2/STAT5 signaling by decreasing TCR and IL2 signaling molecules. Moreover, Cul5 KO in human CD8+T cells phenocopies that in mouse CD8+T cells. Furthermore, KO of CTLA4 that is markedly upregulated by Cul5 KO in mouse and human CD8+cells further enhances anti-tumor effect of Cul5 KO, and a neddylation inhibitor enhances CD8 effector activities largely dependently of Cul5. These results together not only reveal a previously unknown negative-feedback regulatory mechanism for CD8+T cells, but also have strong translational implications in cancer immunotherapy.

This paper is mainly concerned with a class of fractionalp,q-difference equations underp,q-integral boundary conditions. Multiple positive solutions are established by using the topological degree theory and Krein–Rutman theorem. Finally, two examples are worked out to illustrate the main results.

Nanofunctional photocatalysts are attractive materials in solar energy transformation for environmental protection and green energy source generation. TiO2 nanoparticles are the most prospective photocatalysts due to the high photoactive property. In this paper, Ag nanoparticle-sensitized TiO2 nanotube arrays (Ag/TiO2 NTAs) were constructed as the photoelectrochemical platform for pollutant removal and hydrogen generation. TiO2 NTAs were firstly obtained by the anodization method, and carbon layer was formed by the hydrothermal carbonization of glucose in different concentrations, and then Ag nanoparticles were deposited by carbon reduction of Ag+. Ag/TiO2 NTAs could effectively decompose organic dye molecules and remove toxic heavy metal ions. The samples also could achieve visible light photocurrent and hydrogen generation. The surface plasmon resonance absorption and electron transfer path of Ag nanoparticles benefit photochemical performance improvement of TiO2 NTAs. The construction of multifunctional platform of Ag/TiO2 NTAs would cause extensive response and focus in the synergistic applications of semiconductor photocatalysts.

The 26S proteasome is a mega-dalton protein complex responsible for the majority of intracellular degradation in eukaryotes. It is composed of two subcomplexes: the 20S core particle and 19S regulatory particle, which form compositionally and structurally heterogeneous proteasome complexes in cells. To fully characterize the 26S proteasome, it is necessary to understand its structural and functional diversities. Multiple mass spectrometric methodologies have been developed in recent years for the study of proteasome structural dynamics, in which biochemically isolated complexes are subjected for analysis. Due to the inherent heterogeneity of proteasome complexes, single-bait affinity purification typically results in a mixture of compositionally heterogeneous complexes regardless of the baits, making accurate assessment of complex-specific conformations and functions challenging. To facilitate complex-centric analysis, we have adopted a bimolecular affinity purification method utilizing a dual-bait cell line expressing a tagged 19S and a tagged 20S subunit to improve the homogeneity of the resulting 26S holocomplexes. To establish the method, four types of purifications were performed and the resulting samples were extensively examined by biochemical analysis and two label-free quantitative MS methods. Our results have demonstrated the effectiveness of this purification strategy to improve complex homogeneity for downstream biochemical and MS characterizations. This strategy will be valuable for facilitating detailed quantitative assessments of complex-specific molecular details under different conditions and can be directly adopted for studying other complexes.

Photocatalytic water splitting for hydrogen production was recognized as an effective strategy to obtain renewable energy for solving the environmental pollution and resource shortage crisis. Herein, we explored the solvothermal deposition method to successfully prepare blanket-like Bi2MoO6 coated on TiO2 nanotube arrays (TiO2 NTA/Bi2MoO6), and the TiO2 NTA/Bi2MoO6 photocatalyst showed outstanding visible light-driven photocatalytic water splitting capacity, and the hydrogen evolution rate achieved 129.26 μmol h-1 cm-2. Moreover, the sample also exhibited high photocatalytic pollutant decomposition performance. The remarkable photocatalytic performance was attributed to the synergistic effect of Bi2MoO6 and TiO2 NTA in the matched energy band location for solar absorption and carrier transportation. The synthesis and photocatalytic water splitting of Bi2MoO6/TiO2 NTA could afford the reproducible lesson for novel resource utilization of semiconductor photocatalysts.

In this work, a green Fe-doped TiO2 photocatalyst was successfully synthesized on Ti mesh through the chemical impregnation and anodization method. The influence of sample Fe-content on the photocatalytic performance was investigated in detail. Ordered TiO2 nanomesh was compactly decorated with nanospheres to form a novel photocatalyst Fe-doped TiO2 with anatase phase. Simultaneously, it exhibits higher light absorption intensity compared to the pristine TiO2 within the visible light range, and its absorption peak has a redshift. The VSM results showed that the sample has excellent magnetic properties. It is hard to achieve magnetic agglomeration after magnetic field removal, which benefits the strong recyclability and reusability of Fe-doped TiO2 photocatalyst. Importantly, this higher visible-light photoresponse of TiO2 was clearly obtained after Fe doping. When the Fe-content was 0.6 wt%, the degradation rate of methylene blue reached 87.9% under simulated sunlight irradiation for 2.5 h. The prepared nanocrystalline photocatalyst demonstrated excellent photocatalysis because of its prominent crystal morphology, strengthen light-absorption capacity, and commendable inhibition recombination of photo-induced electron-hole.

A fundamental facet of cell signaling is the conversion of extracellular signals into adaptive transcriptional responses. The role of RNA modifications in this process is poorly understood. The small nuclear RNA 7SK prevents transcription elongation by sequestering the complex CDK9/CCNT1 (P-TEFb). We discovered that METTL3 methylates 7SK. The m6A methylation of 7SK in turn promotes its binding to heterogeneous nuclear ribonucleoproteins (HNRNPs), with consequent release of the HEXIM1/P-TEFb complex – leading to the induction of growth factor-stimulated transcriptional responses. The methylation of 7SK relies on the activation of METTL3 via phosphorylation downstream of growth factors-signaling pathways such as the epidermal growth factor (EGF). Our findings establish a novel function for the m6A modification in converting growth-factor signaling events to a transcriptional elongation regulatory response via an RNA-methylation-dependent switch.One-Sentence Summarym6A methylation of the non-coding RNA 7SK promotes transcriptional activity upon growth factor stimulation.

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders.Graphical abstract

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomes as reference. Covariation analysis indicates that transcript and protein expression levels and variabilities across mammals remarkably follow functional role, with extracellular matrix–associated expression being the most variable, demonstrating strong transcriptome-proteome coevolution. The biological variability of gene expression is universal at both interindividual and interspecies scales but to a different extent. RNA metabolic processes particularly show higher interspecies versus interindividual variation. Our results further indicate that while the ubiquitin-proteasome system is strongly conserved in mammals, lysosome-mediated protein degradation exhibits remarkable variation between mammalian lineages. In addition, the phosphosite profiles reveal a phosphorylation coevolution network independent of protein abundance.

The smoothened (Smo) receptor facilitates hedgehog signaling between kidney fibroblasts and tubules during acute kidney injury (AKI). Tubule-derived hedgehog is protective in AKI, but the role of fibroblast-derived Smo is unclear. Here, we report that Smo ablation in fibroblasts mitigated tubular cell apoptosis and inflammation, enhanced perivascular mesenchymal activities, and preserved kidney function after AKI. Global proteomics of these kidneys identified extracellular matrix proteins, and nidogen-1 glycoprotein in particular, as key response markers; Intriguingly, Smo was bound to nidogen-1 in cells, suggesting that loss of Smo could impact nidogen-1 accessibility. Phosphoproteomics revealed that the ‘AKI protector’ Wnt pathway was activated in these kidneys, and in vitro and ex vivo, nidogen-1 was able to induce Wnts and repress tubular cell apoptosis. Altogether, our results support that fibroblast-derived Smo dictates AKI fate through cell-matrix interactions, including nidogen-1, and establish a robust resource and path to further dissect AKI pathogenesis.

Fenofibrate (FF) has shown potential benefits in patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid (UDCA). However, the efficacy and safety of FF in patients with cirrhosis remain unclear. To evaluate the efficacy and safety of additional FF therapy in patients with PBC-related cirrhosis with an incomplete response to UDCA, we conducted a retrospective analysis comparing the clinical results of additional FF therapy and continued UDCA monotherapy. A total of 59 patients were included; 27 cases underwent UDCA monotherapy and 32 cases underwent UDCA combined with FF therapy. A significant difference in alkaline phosphatase (ALP) normalization was achieved in the FF group compared to the UDCA group (37% vs. 11%, respectively; p = 0.020). Additional FF therapy was an independent risk factor for ALP normalization (hazard ratio, 7.679; 95% confidence interval, 2.059-28.633; p = 0.003). Hepatic deterioration was experienced by 40% versus 48% (p = 0.562) while 11% vs. 37% (p = 0.111) experienced liver-related mortality or liver transplantation in the FF and UDCA groups, respectively. Compared to UDCA monotherapy, additional FF therapy was associated with lower United Kingdom (UK)-PBC risk score and surrogate serum indices of liver fibrosis. After 12 months of add-on FF therapy, median ALP level and UK-PBC risk score decreased 35% and 52% from baseline (p = 0.001 and 0.210, respectively). Serum aminotransferase, triglyceride, and cholesterol decreased progressively, while total bilirubin, serum creatinine, blood urea, estimated glomerular filtration rate, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 index remained stable in FF-treated cirrhotic cases during follow-up. No significant adverse effects associated with additional FF therapy were observed in our cohort. Conclusion: Additional FF therapy was associated with higher ALP normalization rates and lower UK-PBC risk scores in patients with cirrhotic PBC with an incomplete response to UDCA. In addition, FF therapy seemed safe and well tolerated with a low frequency of adverse effects in patients with cirrhosis.

Background Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. Methods Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. Results MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. Conclusions These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.

The biguanide drug metformin is a safe and widely prescribed drug for type 2 diabetes. Interestingly, hundreds of clinical trials were set to evaluate the potential role of metformin in the prevention and treatment of cancer including colorectal cancer (CRC). To interrogate cell signaling events and networks in CRC and explore the druggability of the metformin-rewired phosphorylation network, we performed a proteomic and phosphoproteomic analysis on a panel of 12 molecularly heterogeneous CRC cell lines. Using in-depth data-independent analysis mass spectrometry (DIA-MS), we profiled a total of 10,142 proteins and 56,080 phosphosites (P-sites) in CRC cells treated with metformin for 30 minutes and 24 hours. Our results indicate that metformin does not directly trigger or inhibit any immediate phosphorylation events. Instead, it primarily remodels cell signaling in the long-term. Strikingly, the phosphorylation response to metformin was highly heterogeneous in the CRC panel, uncovering four groups of metformin responsivity. We further performed a network analysis to systematically estimate kinase/phosphatase activities and reconstruct signaling cascades in each cell line. We created a “MetScore” which catalogs the most consistently perturbed P-sites among CRC cells for future studies. Finally, we leveraged the metformin P-site signature to identify pharmacodynamic interactions revealing a number of candidate metformin-interacting drugs. Together, we provide a data resource using state-of-the-art phosphoproteomics to understand the metformin-induced cell signaling for potential cancer therapeutics.

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomic variability as reference. The co-variation analysis indicates that transcript and protein expression robustness across mammals remarkably follows functional role, with extracellular matrix-associated expressions being most variable, demonstrating strong transcriptome-proteome co-evolution. Interestingly, the variability control of gene expression is universal at both inter-individual and inter-species scales, but of different extent. RNA metabolism processes particularly show the higher inter-species versus inter-individual variations. Our results further uncover that while ubiquitin-proteasome system is extremely conserved in mammals, the lysosome-mediated protein degradation exhibits a remarkable variation between mammalian lineages. Additionally, the phosphosite profiles reveals phosphorylation co-evolution network independent of protein abundance.

This paper is concerned with the existence of mild solutions and approximate controllability for a class of noninstantaneous impulsive fractional neutral measure evolution systems with state-dependent delay. First, the existence of mild solutions for the considered system is obtained by using Kuratowski’s measure of noncompactness and the set contraction fixed point theorem. Next, under the assumption that the correlated linear system is approximately controllable, the approximate controllability of the system is studied. Finally, we present two applications to support the practical usefulness of the study

The data-independent acquisition (DIA) performed in the latest high-resolution, high-speed mass spectrometers offers a powerful analytical tool for biological investigations. The DIA mass spectrometry (DIA-MS) combined with the isotopic labeling approach holds a particular promise for increasing the multiplexity of DIA-MS analysis, which could assist the relative protein quantification and the proteome-wide turnover profiling. However, the wide MS1 isolation windows employed in conventional DIA methods lead to a limited efficiency in identifying and quantifying isotope-labelled peptide pairs through peptide fragment ions. Here, we optimized a high-selectivity DIA-MS named BoxCarmax that supports the analysis of complex samples, such as those generated from Stable isotope labeling by amino acids in cell culture (SILAC) and pulse SILAC (pSILAC) experiments. BoxCarmax enables multiplexed acquisition at both MS1- and MS2- levels, through the integration of BoxCar and MSX features, as well as a gas-phase separation strategy. We found BoxCarmax significantly improved the quantitative accuracy in SILAC and pSILAC samples by mitigating the ratio suppression of isotope-peptide pairs. We further applied BoxCarmax to measure protein degradation regulation during serum starvation stress in cultured cells, revealing valuable biological insights. Our study offered an alternative and accurate approach for the MS analysis of protein turnover and complex samples.

Background and aims There is no data regarding the efficacy and safety of fibrates in patients with decompensated liver disease associated with PBC, as published studies have systematically excluded this population. This study aims to evaluate the efficacy and safety of UDCA in combination with fenofibrate in patients with decompensated liver disease related to UDCA-refractory PBC. Methods We conducted a retrospective analysis comparing the clinical results of additional fenofibrate (FF) therapy and continued UDCA monotherapy in decompensated patients refractory to UDCA. Results Total of 63 patients included: 32 cases underwent UDCA monotherapy and 31 cases underwent UDCA combined with FF therapy. Among UDCA-refractory patients with decompensated cirrhosis, FF add-on therapy for 60 months significantly improved the Mayo risk score, the Globe risk score and the alkaline phosphatase (ALP) normalization rate. Parallel changes in liver transplant-free survival, the UK-PBC risk score and surrogate serum indices of liver fibrosis were consistent with this effect. During follow-up, serum ALP, aminotransferase and gamma-glutamyl transpeptidase decreased significantly, while total bilirubin, albumin, serum creatinine, blood urea, estimated glomerular filtration rate, APRI index, FIB-4 index and Forns index remained stable in FF-treated cases. Only the Globe risk score, not ALP normalization, was independently and negatively associated with improved outcomes on multivariable analysis (odds ratio, 2.934; confidence interval, 1.046-8.235; p = 0.041). No significant adverse effects associated with FF-related symptoms or nephrotoxicity were observed in our cohort. However, decompensated cirrhosis with deteriorated cholestasis should be considered as potential limiting factors for FF therapy. Conclusions Additional FF therapy clearly improves the Mayo risk score, the Globe risk score and the ALP normalization rate in patients with decompensated liver disease related to UDCA-refractory PBC. However, the survival rate was not significantly different between the groups. Decompensated cirrhosis with deteriorated cholestasis should be considered as potential limiting factors for FF therapy.

Immune checkpoint genes (ICGs) have recently been proven to perform instrumental functions in the maintenance of immune homeostasis and represent a promising therapeutic strategy; however, their expression patterns and prognostic values are not fully elucidated in hepatocellular carcinoma (HCC). In this investigation, we focused on establishing and validating a prognostic gene signature to facilitate decision-making in clinical practice. Clinical information, as well as transcriptome data, was obtained from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox method were employed to build a multi-gene signature in the TCGA database, while the ICGC database was used for validation. Subsequently, utilizing the six-gene signature, we were able to categorize patients into high- and low-risk groups. In two cohorts, survival analysis findings revealed a dismal outlook for the high-risk group. The receiver operating characteristic curves were utilized to estimate the gene signature's prediction ability. Moreover, correlation analysis showed high-risk group was linked to advanced pathological stage, infiltration of immune cells and therapeutic response. In summary, this unique gene profile might serve not only as a useful prognostic indicator but also as a marker of therapy responsiveness in HCC.

Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal-maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of

This study investigates the impulsive control for the output tracking of probabilistic Boolean control networks (PBCNs) by the algebraic state-space representation method. Firstly, a novel system with augmented control is established by regarding the impulsive time as a special kind of control, which is equivalent to the considered impulsive PBCN (IPBCN). Secondly, based on the largest control invariant subset, a necessary and sufficient condition is proposed to design impulsive control for the output tracking problem of IPBCNs. Moreover, a constructive method is put forward to design the state feedback controller and state-dependent impulsive time sequence. Finally, an example is given to demonstrate the effectiveness of the obtained results.

The parametric and vibrational characteristics of PZTs (Piezoelectric Transducers) with different diameters before and after coupling are discussed by finite element analysis. It is shown that the vibration stability of the piezoelectric transducer decreases with increasing driving frequency. The PZT's variation of maximum displacement with frequency shows the same trend for different driving conditions according to vibration measurement under conditions of both free and forced vibration (before and after sealing with the pump body). The maximum displacement under forced vibration is less than that under free vibration. The maximum displacement is inversely proportional to the diameter of the transducer and directly proportional to the driving voltage under both free and forced vibration. Micropumps with diffuser/nozzle microvalves are designed and fabricated with different external diameters of the PZTs. Finally, the flow rate and pressure of the micropumps are measured, which are consistent with the vibrational results. Moreover, the maximum displacement is larger under a square-wave driving signal, followed by a sine-wave signal, and then a triangle-wave signal. For a PZT with an external diameter of $12$ mm, the maximum flow rate and pressure value are $150$~$upmu$l/min and $346$ Pa, respectively, under sine-wave driving at $100$ Vpp driving voltage.