Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Antibody Nanotweezer Constructing Bivalent Transistor-Biomolecule Interface with Spatial Tolerance.

Establishing a multivalent interface between the biointerface of a living system and electronic device is vital to building intelligent bioelectronic systems. How to achieve multivalent binding with spatial tolerance at the nanoscale remains challenging. Here, we report an antibody nanotweezer that is a self-adaptive bivalent nanobody enabling strong and resilient binding between transistor and envelope proteins at biointerfaces. The antibody nanotweezer is constructed by a DNA framework, where the nanoscale patterning of nanobodies along with their local spatial adaptivity enables simultaneous recognition of target epitopes without binding stress. As such, effective binding affinity increases by 1 order of magnitude compared with monovalent antibody. The antibody nanotweezer operating on transistor offers enhanced signal transduction, which is implemented to detect clinical pathogens, showing ∼100% overall agreement with PCR results. This work provides a perspective of engineering multivalent interfaces between biosystems with solid-state devices, holding great potential for organoid intelligence on a chip.

Prevention and treatment of HPV-related cancer through a mRNA vaccine expressing APC-targeting antigen.

Persistent human papillomavirus (HPV) infection is associated with multiple malignancies. Developing therapeutic vaccines to eliminate HPV-infected and malignant cells holds significant value. In this study, we introduced a lipid nanoparticle encapsulated mRNA vaccine expressing tHA-mE7-mE6. Mutations were introduced into E6 and E7 of HPV to eliminate their tumourigenicity. A truncated influenza haemagglutinin protein (tHA), which binds to the CD209 receptor on the surface of dendritic cells (DCs), was fused with mE7-mE6 in order to allow efficient uptake of antigen by antigen presenting cells. The tHA-mE7-mE6 (mRNA) showed higher therapeutic efficacy than mE7-mE6 (mRNA) in an E6 and E7+ tumour model. The treatment resulted in complete tumour regression and prevented tumour formation. Strong CD8+ T-cell immune response was induced, contributing to preventing and curing of E6 and E7+ tumour. Antigen-specific CD8+ T were found in spleens, peripheral blood and in tumours. In addition, the tumour infiltration of DC and NK cells were increased post therapy. In conclusion, this study described a therapeutic mRNA vaccine inducing strong anti-tumour immunity in peripheral and in tumour microenvironment, holding promising potential to treat HPV-induced cancer and to prevent cancer recurrence.

Spatially and Temporally Resolved Dynamic Response of Co-Based Composite Interface during the Oxygen Evolution Reaction.

Interfacial interaction dictates the overall catalytic performance and catalytic behavior rules of the composite catalyst. However, understanding of interfacial active sites at the microscopic scale is still limited. Importantly, identifying the dynamic action mechanism of the "real" active site at the interface necessitates nanoscale, high spatial-time-resolved complementary-operando techniques. In this work, a Co3O4 homojunction with a well-defined interface effect is developed as a model system to explore the spatial-correlation dynamic response of the interface toward oxygen evolution reaction. Quasi in situ scanning transmission electron microscopy-electron energy-loss spectroscopy with high spatial resolution visually confirms the size characteristics of the interface effect in the spatial dimension, showing that the activation of active sites originates from strong interfacial electron interactions at a scale of 3 nm. Multiple time-resolved operando spectroscopy techniques explicitly capture dynamic changes in the adsorption behavior for key reaction intermediates. Combined with density functional theory calculations, we reveal that the dynamic adjustment of multiple adsorption configurations of intermediates by highly activated active sites at the interface facilitates the O-O coupling and *OOH deprotonation processes. The dual dynamic regulation mechanism accelerates the kinetics of oxygen evolution and serves as a pivotal factor in promoting the oxygen evolution activity of the composite structure. The resulting composite catalyst (Co-B@Co3O4/Co3O4 NSs) exhibits an approximately 70-fold turnover frequency and 20-fold mass activity than the monomer structure (Co3O4 NSs) and leads to significant activity (η10 ∼257 mV). The visual complementary analysis of multimodal operando/in situ techniques provides us with a powerful platform to advance our fundamental understanding of interfacial structure-activity relationships in composite structured catalysts.

CHMP5 attenuates osteoarthritis via inhibiting chondrocyte apoptosis and extracellular matrix degradation: involvement of NF-κB pathway.

BACKGROUND: Osteoarthritis (OA), the most common joint disease, is linked with chondrocyte apoptosis and extracellular matrix (ECM) degradation. Charged multivesicular body protein 5 (CHMP5), a member of the multivesicular body, has been reported to serve as an anti-apoptotic protein to participate in leukemia development. However, the effects of CHMP5 on apoptosis and ECM degradation in OA remain unclear. METHODS: In this study, quantitative proteomics was performed to analyze differential proteins between normal and OA patient articular cartilages. The OA mouse model was constructed by the destabilization of the medial meniscus (DMM). In vitro, interleukin-1 beta (IL-1ß) was used to induce OA in human chondrocytes. CHMP5 overexpression and silencing vectors were created using an adenovirus system. The effects of CHMP5 on IL-1ß-induced chondrocyte apoptosis were investigated by CCK-8, flow cytometry, and western blot. The effects on ECM degradation were examined by western blot and immunofluorescence. The potential mechanism was explored by western blot and Co-IP assays. RESULTS: Downregulated CHMP5 was identified by proteomics in OA patient cartilages, which was verified in human and mouse articular cartilages. CHMP5 overexpression repressed cell apoptosis and ECM degradation in OA chondrocytes. However, silencing CHMP5 exacerbated OA chondrocyte apoptosis and ECM degradation. Furthermore, we found that the protective effect of CHMP5 against OA was involved in nuclear factor kappa B (NF-κB) signaling pathway. CONCLUSIONS: This study demonstrated that CHMP5 repressed IL-1ß-induced chondrocyte apoptosis and ECM degradation and blocked NF-κB activation. It was shown that CHMP5 might be a novel potential therapeutic target for OA in the future.

Machine Learning-Based Integrated Multiomics Characterization of Colorectal Cancer Reveals Distinctive Metabolic Signatures.

The metabolic signature identification of colorectal cancer is critical for its early diagnosis and therapeutic approaches that will significantly block cancer progression and improve patient survival. Here, we combined an untargeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry and the machine learning approach to analyze metabolites in 173 pairs of cancer samples and matched normal tissue samples to build robust metabolic signature models for diagnostic purposes. Screening and independent validation of metabolic signatures from colorectal cancers via machine learning methods (Logistic Regression_L1 for feature selection and eXtreme Gradient Boosting for classification) was performed to generate a panel of seven signatures with good diagnostic performance (the accuracy of 87.74%, sensitivity of 85.82%, and specificity of 89.66%). Moreover, seven signatures were evaluated according to their ability to distinguish between cancer and normal tissues, with the metabolic molecule PC (30:0) showing good diagnostic performance. In addition, genes associated with PC (30:0) were identified by multiomics analysis (combining metabolic data with transcriptomic data analysis) and our results showed that PC (30:0) could promote the proliferation of colorectal cancer cell SW480, revealing the correlation between genetic changes and metabolic dysregulation in cancer. Overall, our results reveal potential determinants affecting metabolite dysregulation, paving the way for a mechanistic understanding of altered tissue metabolites in colorectal cancer and design interventions for manipulating the levels of circulating metabolites.

Strongly-Interacted NiSe2/NiFe2O4 Architectures Built Through Selective Atomic Migration as Catalysts for the Oxygen Evolution Reaction.

The interactions between the catalyst and support are widely used in many important catalytic reactions but the construction of strong interaction with definite microenvironments to understand the structure-activity relationship is still challenging. Here, strongly-interacted composites are prepared via selective exsolution of active NiSe2 from the host matrix of NiFe2O4 (S-NiSe2/NiFe2O4) taking advantage of the differences of migration energy, in which the NiSe2 possessed both high dispersion and small size. The characteristics of spatially resolved scanning transmission X-ray microscopy (STXM) coupled with analytical Mössbauer spectra for the surface and bulk electronic structures unveiled that this strongly interacted composite triggered more charge transfers from the NiSe2 to the host of NiFe2O4 while stabilizing the inherent atomic coordination of NiFe2O4. The obtained S-NiSe2/NiFe2O4 exhibits overpotentials of 290 mV at 10 mA cm-2 for oxygen evolution reaction (OER). This strategy is general and can be extended to other supported catalysts, providing a powerful tool for modulating the catalytic performance of strongly-interacted composites.

Electron Accumulation Induced by Electron Injection-Incomplete Discharge on NiFe LDH for Enhanced Oxygen Evolution Reaction.

Optimizing the local electronic structure of electrocatalysts can effectively lower the energy barrier of electrochemical reactions, thus enhancing the electrocatalytic activity. However, the intrinsic contribution of the electronic effect is still experimentally unclear. In this work, the electron injection-incomplete discharge approach to achieve the electron accumulation (EA) degree on the nickel-iron layered double hydroxide (NiFe LDH) is proposed, to reveal the intrinsic contribution of EA toward oxygen evolution reaction (OER). Such NiFe LDH with EA effect results in only 262 mV overpotential to reach 50 mA cm-2, which is 51 mV-lower compared with pristine NiFe LDH (313 mV), and reduced Tafel slope of 54.8 mV dec-1 than NiFe LDH (107.5 mV dec-1). Spectroscopy characterizations combined with theoretical calculations confirm that the EA near concomitant Vo can induce a narrower energy gap and lower thermodynamic barrier to enhance OER performance. This study clarifies the mechanism of the EA effect on OER activity, providing a direct electronic structure modulation guideline for effective electrocatalyst design.

Analogous Chain Selenite Chlorides Ba2M(SeO3)2Cl2 (M = Cu2+, Ni2+, Co2+, Mn2+) and Pb2Cu(SeO3)2Cl2 with Tunable Spin S: Syntheses and Characterizations.

A series of analogous chain selenite chlorides Ba2M(SeO3)2Cl2 (M = Cu 1, Ni 2, Co 3, Mn 4) and Pb2Cu(SeO3)2Cl2 5 with tunable spin S from S = 1/2 to S = 5/2 have been hydrothermally synthesized and characterized. These analogues crystallized in the orthorhombic Pnnm space group (monoclinic P21/n space group for 5) all containing M2+-SeO3-M2+ spin chains, which are further separated by the Ba2+ ions (Pb2+ for 5). The magnetic susceptibility results of 1, 2, and 5 show broad maxima around 80.0, 18.9, and 78.0 K, respectively, indicating good one-dimensional (1D) magnetism. Meanwhile, no long-range order (LRO) is observed down to 2 K for both 1 and 5, while the isostructural compounds 2, 3, and 4 exhibit LRO at 3.4 K, 10.8 K, and 5.7 K, respectively, which are further confirmed by the heat capacity and electron spin resonance results, as well as the observed spin-flop transitions in the M-H curves measured at 2 K below TN. The magnetizations of 1-5 at 7 T are still far from saturation. In addition, thermal stability and FT-IR and UV-vis-NIR spectroscopy of 1-5 are reported.

MSRB2 Ameliorates H2O2-induced Chondrocyte Oxidative Stress and Suppresses Apoptosis in Osteoarthritis.

BACKGROUND: Chondrocyte oxidative stress and apoptosis are critical factors contributing to the pathogenesis of osteoarthritis (OA). Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cells from oxidative stress and is involved in apoptosis. This study aimed to investigated the expression of MSRB2 in articular cartilage tissues and elucidated its effect on H2O2-stimulated chondrocytes. METHODS: Human chondrocytes were cultured in Dulbecco's modified Eagle's medium (DMEM)/F12. MSRB2 overexpression in chondrocytes was achieved by transfecting with an MSRB2 overexpression plasmid. Western blot, quantitative RT-PCR, Immunofluorescence staining, and TUNEL assay were employed in this study. RESULTS: MSRB2 expression was found to be reduced in OA patients. Furthermore, overexpression of MSRB2 in H2O2-induced chondrocytes mitigated apoptosis and enhanced cell viability. Elevated MSRB2 expression diminished chondrocyte ROS contents, decreased cytochrome C (Cyc) in the cytoplasm, and regulated mitochondrial membrane potential to maintain mitochondrial homeostasis. Interestingly, knockdown of charged multivesicular body protein 5 (CHMP5) led to a decreased inMSRB2 expression in chondrocytes. Additionally, protein levels of CHMP5 and MSRB2 were reduced in H2O2-stimulated chondrocytes, and silencing CHMP5 reduced MSRB2 expression. Knockdown of CHMP5 increased cleaved caspase-3 expression in H2O2-induced chondrocytes and elevated TUNEL-positive chondrocytes. CONCLUSION: MSRB2 decreased in OA, and overexpression of MSRB2 alleviated oxidative stress and apoptosis of chondrocyte.

A novel human single-domain antibody-drug conjugate targeting CEACAM5 exhibits potent in vitro and in vivo antitumor activity.

Leveraging the specificity of antibody to deliver cytotoxic agent into tumor, antibody-drug conjugates (ADCs) have become one of the hotspots in the development of anticancer therapies. Although significant progress has been achieved, there remain challenges to overcome, including limited penetration into solid tumors and potential immunogenicity. Fully human single-domain antibodies (UdAbs), with their small size and human nature, represent a promising approach for addressing these challenges. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycosylated cell surface protein that rarely expressed in normal adult tissues but overexpressed in diverse cancers, taking part in tumorigenesis, progression, and metastasis. In this study, we investigated the therapeutic potential of UdADC targeting CEACAM5. We performed biopanning in our library and obtained an antibody candidate B9, which bound potently and specifically to CEACAM5 protein (KD = 4.84 nM) and possessed excellent biophysical properties (low aggregation tendency, high homogeneity, and thermal stability). The conjugation of B9 with a potent cytotoxic agent, monomethyl auristatin E (MMAE), exhibited superior antitumor efficacy against CEACAM5-expressing human gastric cancer cell line MKN-45, human pancreatic carcinoma cell line BxPC-3 and human colorectal cancer cell line LS174T with IC50 values of 38.14, 25.60, and 101.4 nM, respectively. In BxPC-3 and MKN-45 xenograft mice, administration of UdADC B9-MMAE (5 mg/kg, i.v.) every 2 days for 4 times markedly inhibited the tumor growth without significant change in body weight. This study may have significant implications for the design of next-generation ADCs.

Multifunctional nano-in-micro delivery systems for targeted therapy in fundus neovascularization diseases.

Fundus neovascularization diseases are a series of blinding eye diseases that seriously impair vision worldwide. Currently, the means of treating these diseases in clinical practice are continuously evolving and have rapidly revolutionized treatment opinions. However, key issues such as inadequate treatment effectiveness, high rates of recurrence, and poor patient compliance still need to be urgently addressed. Multifunctional nanomedicine can specifically respond to both endogenous and exogenous microenvironments, effectively deliver drugs to specific targets and participate in activities such as biological imaging and the detection of small molecules. Nano-in-micro (NIM) delivery systems such as metal, metal oxide and up-conversion nanoparticles (NPs), quantum dots, and carbon materials, have shown certain advantages in overcoming the presence of physiological barriers within the eyeball and are widely used in the treatment of ophthalmic diseases. Few studies, however, have evaluated the efficacy of NIM delivery systems in treating fundus neovascular diseases (FNDs). The present study describes the main clinical treatment strategies and the adverse events associated with the treatment of FNDs with NIM delivery systems and summarizes the anatomical obstacles that must be overcome. In this review, we wish to highlight the principle of intraocular microenvironment normalization, aiming to provide a more rational approach for designing new NIM delivery systems to treat specific FNDs.

Manipulating the Spin State of Spinel Octahedral Sites via a π-π Type Orbital Coupling to Boost Water Oxidation.

Spin state is often regarded as the crucial valve to release the reactivity of energy-related catalysts, yet it is also challenging to precisely manipulate, especially for the active center ions occupied at the specific geometric sites. Herein, a π-π type orbital coupling of 3d (Co)-2p (O)-4f (Ce) was employed to regulate the spin state of octahedral cobalt sites (CoOh) in the composite of Co3O4/CeO2. More specifically, the equivalent high-spin ratio of CoOh can reach to 54.7 % via tuning the CeO2 content, thereby triggering the average eg filling (1.094) close to the theoretical optimum value. The corresponding catalyst exhibits a superior water oxidation performance with an overpotential of 251 mV at 10 mA cm-2, rivaling most cobalt-based oxides state-of-the-art. The π-π type coupling corroborated by the matched energy levels between Ce t1u/t2u-O and CoOh t2g-O π type bond in the calculated crystal orbital Hamilton population and partial density of states profiles, stimulates a π-donation between O 2p and π-symmetric Ce 4fyz 2 orbital, consequently facilitating the electrons hopping from t2g to eg orbital of CoOh. This work offers an in-depth insight into understanding the 4f and 3d orbital coupling for spin state optimization in composite oxides.

Tensile Strain-Mediated Spinel Ferrites Enable Superior Oxygen Evolution Activity.

Exploring efficient strategies to overcome the performance constraints of oxygen evolution reaction (OER) electrocatalysts is vital for electrocatalytic applications such as H2O splitting, CO2 reduction, N2 reduction, etc. Herein, tunable, wide-range strain engineering of spinel oxides, such as NiFe2O4, is proposed to enhance the OER activity. The lattice strain is regulated by interfacial thermal mismatch during the bonding process between thermally expanding NiFe2O4 nanoparticles and the nonexpanding carbon fiber substrate. The tensile lattice strain causes energy bands to flatten near the Fermi level, lowering eg orbital occupancy, effectively increasing the number of electronic states near the Fermi level, and reducing the pseudoenergy gap. Consequently, the energy barrier of the rate-determining step for strained NiFe2O4 is reduced, achieving a low overpotential of 180 mV at 10 mA/cm2. A total water decomposition voltage range of 1.52-1.56 V at 10 mA/cm2 (without iR correction) was achieved in an asymmetric alkaline electrolytic cell with strained NiFe2O4 nanoparticles, and its robust stability was verified with a voltage retention of approximately 99.4% after 100 h. Furthermore, the current work demonstrates the universality of tuning OER performance with other spinel ferrite systems, including cobalt, manganese, and zinc ferrites.

MMP9-Responsive Graphene Oxide Quantum Dot-Based Nano-in-Micro Drug Delivery System for Combinatorial Therapy of Choroidal Neovascularization.

Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the "inflammation-MMP9-angiogenesis" cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV.

Palmitoyl transferases act as novel drug targets for pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. METHODS: Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. RESULTS: ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. CONCLUSION: This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.

Palbociclib enhances the effect of doxorubicin-induced apoptosis in activated B-cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma around the world. While R-CHOP has significantly improved patient outcomes, a subset of patients still has poor outcome. Here, the oncogenic roles of cyclin dependent kinase 4/6 (CDK4/6)-Cyclin D (CCND) signaling axis in DLBCL and its potential mechanism were investigated to explore the possibility of targeting CDK4/6-CCND signaling axis for DLBCL therapy. The transcription levels, functional enrichment analysis, mutation analysis, and prognostic values were performed via the Oncomine, GEPIA, UALCAN, cBioPortal, and Metascape and GenomicScape databases. Expression of CDK4/6-CCND signaling axis in DLBCL patients and DLBCL cell lines was evaluated by qRT-PCR. Additionally, the impact of CDK4/6-CCND signaling axis on cell viability and apoptosis in DLBCL cell lines were evaluated in vitro . The transcription levels of CDK4/6-CCND signaling were increased in DLBCL patients. Meanwhile, in Gene Expression Omnibus dataset, the expression of CDK4 and CCND2 was higher in ABC-DLBCL, whereas the expression of CCND1 and CCND3 was higher in GCB-DLBCL. Moreover, according to the results of qRT-PCR, the expression of CDK4/6-CCND signaling axis in ABC-DLBCL cell line is higher than that in GCB-DLBCL cell lines. Prognostic analysis indicated that upregulation of CDK4, CCND2, and CCND3 was significantly associated with poor survival. Cell function experiments showed that palbociclib could enhance the apoptosis-promoting and cell viability-inhibiting effects of doxorubicin on ABC-DLBCL (SU-DHL-2) cells. Doxorubicin accumulation experiment showed that palbociclib promoted doxorubicin accumulation in ABC-DLBCL cells. Additionally, Western blot analysis demonstrated that palbociclib prevented antiapoptotic protein BCL2 expression in ABC-DLBCL cell line. Our study provides novel insights into targeted therapies for ABC-DLBCL patients.

A robust sparse identification method for nonlinear dynamic systems affected by non-stationary noise.

In the field of science and engineering, identifying the nonlinear dynamics of systems from data is a significant yet challenging task. In practice, the collected data are often contaminated by noise, which often severely reduce the accuracy of the identification results. To address the issue of inaccurate identification induced by non-stationary noise in data, this paper proposes a method called weighted ℓ1-regularized and insensitive loss function-based sparse identification of dynamics. Specifically, the robust identification problem is formulated using a sparse identification mathematical model that takes into account the presence of non-stationary noise in a quantitative manner. Then, a novel weighted ℓ1-regularized and insensitive loss function is proposed to account for the nature of non-stationary noise. Compared to traditional loss functions like least squares and least absolute deviation, the proposed method can mitigate the adverse effects of non-stationary noise and better promote the sparsity of results, thereby enhancing the accuracy of identification. Third, to overcome the non-smooth nature of the objective function induced by the inclusion of loss and regularization terms, a smooth approximation of the non-smooth objective function is presented, and the alternating direction multiplier method is utilized to develop an efficient optimization algorithm. Finally, the robustness of the proposed method is verified by extensive experiments under different types of nonlinear dynamical systems. Compared to some state-of-the-art methods, the proposed method achieves better identification accuracy.

A comprehensive assessment of runoff dynamics in response to climate change and human activities in a typical karst watershed, southwest China.

The Chengbi River Basin is a typical karst watershed in Southwest China. Understanding the effects of climate change (CC) and human activities (HAs) on hydrological process is important for regional water resources management and water security. However, a comprehensive assessment of the effects of CC and HAs on runoff dynamics at different time scales in the Chengbi River Basin is still lacking. To address these needs, we used Budyko Mezentsev-Choudhurdy-Yang and Slope change ratio of accumulative quantity methods to assess the contribution of the changing environment to annual and intra-annual runoff changes in the Chengbi River Basin. The results indicated that annual runoff time series was divided into the base phase Ta (1980-1996) and the change phase Tb (1997-2019). Compared to the natural status in Ta, the relative contributions of CC and HAs to the runoff increase in Tb were 154.86% and -54.86%. In addition, the shift in intra-annual runoff occurred in 2007 and was mainly caused by HAs, with a contribution rate of 76.22%. The increase in annual runoff in Tb could be attributed to the positive contribution of rainfall. Changes in rainfall and reservoir construction altered the original state of intra-annual runoff. Furthermore, the high degree of heterogeneity in the surface karst zone increased the runoff coefficient. The spatial unsaturation of the subsurface water-bearing media and rainfall patterns caused a significant lag effect in the response of surface runoff to rainfall. This study can help researchers and policy makers to better understand the response of karst runoff to changing environment and provide insights for future water resources management and flood control measures.

Metabolic-Dysregulation-Based iEESI-MS Reveals Potential Biomarkers Associated with Early-Stage and Progressive Colorectal Cancer.

The application of rapid and accurate diagnostic methods can improve colorectal cancer (CRC) survival rates dramatically. Here, we used a non-targeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry (iEESI-MS) to detect metabolite ions associated with the progression of CRC from 172 tissues (45 stage I/II CRC, 41 stage III/IV CRC, and 86 well-matched normal tissues). A support vector machine (SVM) model based on 10 differential metabolite ions for differentiating early-stage CRC from normal tissues was built with a good prediction accuracy of 92.6%. The biomarker panel consisting of lysophosphatidylcholine (LPC) (18:0) has good diagnostic potential in differentiating early-stage CRC from advanced-stage CRC. We showed that the down-regulation of LPC (18:0) in tumor tissues is associated with CRC progression and related to the regulation of the epidermal growth factor receptor. Pathway analysis showed that metabolic pathways in CRC are related to glycerophospholipid metabolism and purine metabolism. In conclusion, we built an SVM model with good performance to distinguish between early-stage CRC and normal groups based on iEESI-MS and found that LPC (18:0) is associated with the progression of CRC.