Estimation and Inference for High-Dimensional Generalized Linear Models with Knowledge Transfer.

Transfer learning provides a powerful tool for incorporating data from related studies into a target study of interest. In epidemiology and medical studies, the classification of a target disease could borrow information across other related diseases and populations. In this work, we consider transfer learning for high-dimensional generalized linear models (GLMs). A novel algorithm, TransHDGLM, that integrates data from the target study and the source studies is proposed. Minimax rate of convergence for estimation is established and the proposed estimator is shown to be rate-optimal. Statistical inference for the target regression coefficients is also studied. Asymptotic normality for a debiased estimator is established, which can be used for constructing coordinate-wise confidence intervals of the regression coefficients. Numerical studies show significant improvement in estimation and inference accuracy over GLMs that only use the target data. The proposed methods are applied to a real data study concerning the classification of colorectal cancer using gut microbiomes, and are shown to enhance the classification accuracy in comparison to methods that only use the target data.

Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma.

BACKGROUND: Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear. METHODS: We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target. RESULTS: We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo. CONCLUSIONS: Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

Effects of Three Kinds of Carbohydrate Pharmaceutical Excipients-Fructose, Lactose and Arabic Gum on Intestinal Absorption of Gastrodin through Glucose Transport Pathway in Rats.

BACKGROUND: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway. METHODS: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry. RESULTS: Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability. CONCLUSION: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.

Autonomous Stabilization of Fock States in an Oscillator against Multiphoton Losses.

Fock states with a well-defined number of photons in an oscillator have shown a wide range of applications in quantum information science. Nonetheless, their usefulness has been marred by single and multiphoton losses due to unavoidable environment-induced dissipation. Though several dissipation engineering methods have been developed to counteract the leading single-photon-loss error, averting multiple-photon losses remains elusive. Here, we experimentally demonstrate a dissipation engineering method that autonomously stabilizes multiphoton Fock states against losses of multiple photons using a cascaded selective photon-addition operation in a superconducting quantum circuit. Through measuring the photon-number populations and Wigner tomography of the oscillator states, we observe a prolonged preservation of nonclassical Wigner negativities for the stabilized Fock states |N⟩ with N=1, 2, 3 for a duration of about 10 ms. Furthermore, the dissipation engineering method demonstrated here also facilitates the implementation of a nonunitary operation for resetting a binomially encoded logical qubit. These results highlight potential applications in error-correctable quantum information processing against multiple-photon-loss errors.

Angiogenesis in heterotopic ossification: From mechanisms to clinical significance.

Heterotopic ossification (HO) refers to the formation of pathologic bone in nonskeletal tissues (including muscles, tendons or other soft tissues). HO typically occurs after a severe injury and can occur in any part of the body. HO lesions are highly vascularized. Angiogenesis, which is the formation of new blood vessels, plays an important role in the pathophysiology of HO. Surgical resection is considered an effective treatment for HO. However, it is difficult to completely remove new vessels, which can lead to the recurrence of HO and is often accompanied by significant problems such as intraoperative hemorrhage, demonstrating the important role of angiogenesis in HO. Here, we broadly summarize the current understanding of how angiogenesis contributes to HO; in particular, we focus on new insights into the cellular and signaling mechanisms underlying HO angiogenesis. We also review the development and current challenges associated with antiangiogenic therapy for HO.

Advancing elastomer performance with dynamic bond networks in polymer-grafted single-chain nanoparticles: a molecular dynamics exploration.

This research introduces a method to enhance the mechanical properties of elastomers by grafting polymer chains onto single-chain flexible nanoparticles (SCNPs) and incorporating dynamic functional groups. Drawing on developments in grafting polymers onto hard nanoparticle fillers, this method employs the distinct flexibility of SCNPs to diminish heterogeneity and enhance core size control. We use molecular dynamics (MD) simulations for a mesoscale analysis of structural properties, particularly the effects of dynamic functional group quantities and their distribution. The findings demonstrate that increased quantities of functional groups are correlated with enhanced mechanical strength and toughness, showing improved stress-strain responses and energy dissipation capabilities. Moreover, the uniformity in the distribution of these functional groups is crucial, promoting a more cohesive and stable dynamic bonding network. The insights gained from MD simulations not only advance our understanding of the microstructural control necessary for optimizing macroscopic properties, but also provide valuable guidance for the design and engineering of advanced polymer nanocomposites, thereby enhancing the material performance through strategic molecular design.

A Virus-Inspired Inhalable Liponanogel Induces Potent Antitumor Immunity and Regression in Metastatic Lung Tumors.

Pulmonary delivery of immunostimulatory agents such as poly(I:C) to activate double-stranded RNA sensors MDA5 and RIG-I within lung-resident antigen-presenting cells is a potential strategy to enhance antitumor immunity by promoting type I interferon secretion. However, following pulmonary delivery, poly(I:C) suffers from rapid degradation and poor endosomal escape, thus limiting its potency. Inspired by the structure of a virus that utilizes internal viral proteins to tune the loading and cytosolic delivery of viral nucleic acids, we developed a liponanogel (LNG)-based platform to overcome the delivery challenges of poly(I:C). The LNG consisted of an anionic polymer hyaluronic acid-based nanogel core coated by a lipid shell, which served as a protective layer to stabilize the nanogel core in the lungs. The nanogel core was protonated within acidic endosomes to enhance the endosomal membrane permeability and cytosolic delivery of poly(I:C). After pulmonary delivery, LNG-poly(I:C) induced 13.7-fold more IFNß than poly(I:C) alone and 2-fold more than poly(I:C) loaded in the state-of-art lipid nanoparticles (LNP-poly(I:C)). Moreover, LNG-poly(I:C) induced more potent CD8+ T cell immunity and stronger therapeutic effects than LNP-poly(I:C). The combination of LNG-poly(I:C) and PD-L1 targeting led to regression of established lung metastases. Due to the ease of manufacturing and the high biocompatibility of LNG, pulmonary delivery of LNG may be broadly applicable to the treatment of different lung tumors and may spur the development of innovative strategies for cancer immunotherapy.

Inquiry lipaseoring the mechanism of pancreatic lipase inhibition by isovitexin based on multispectral method and enzyme inhibition assay.

Isovitexin is a main natural flavonoid component in various plants. Currently, the inhibitory effect of isovitexin on pancreatic lipase (PL) and its mechanism have not been elucidated yet. In the present study, we investigated the inhibitory effect of isovitexin on PL, as well as its interaction mechanism, using enzyme inhibition methods, spectroscopic analysis, and molecular simulations. Results showed that isovitexin possessed significant PL inhibitory activity, with IC50 values of 0.26 ± 0.02 mM. The interaction between isovitexin and PL was dominated by static quenching, and mainly through hydrogen bonding and hydrophobic interaction forces. Analysis of fluorescence spectroscopy confirmed that isovitexin binding altered the conformation of the PL. Circular dichroism (CD) spectrum indicated that isovitexin altered the secondary structure of PL by decreasing the α-helix content and increasing the ß-fold content. Molecular simulations further characterize the conformational changes produced by the interaction between isovitexin with PL. The performed study may provide a new insight into the inhibitory mechanism of isovitexin as a novel PL inhibitor.

The Surface Confinement of FeO Assists in the Generation of Singlet Oxygen and High-Valent Metal-Oxo Species for Enhanced Fenton-Like Catalysis.

Transition metal compounds (TMCs) have long been potential candidate catalysts in persulfate-based advanced oxidation process (PS-AOPs) due to their Fenton-like catalyze ability for radical generation. However, the mechanism involved in TMCs-catalyzed nonradical PS-AOPs remains obscure. Herein, the growth of FeO on the Fe3O4/carbon precursor is regulated by restricted pyrolysis of MIL-88A template to activate peroxymonosulfate (PMS) for tetracycline (TC) removal. The higher FeO incorporation conferred a 2.6 times higher degradation performance than that catalyzed by Fe3O4 and also a higher interference resistance to anions or natural organic matter. Unexpectedly, the quenching experiment, probe method, and electron paramagnetic resonance quantitatively revealed that the FeO reassigned high nonradical species (1O2 and FeIV═O) generation to replace original radical system created by Fe3O4. Density functional theory calculation interpreted that PMS molecular on strongly-adsorbed (200) and (220) facets of FeO enjoyed unique polarized electronic reception for surface confinement effect, thus the retained peroxide bond energetically supported the production of 1O2 and FeIV═O. This work promotes the mechanism understanding of TMCs-induced surface-catalyzed persulfate activation and enables them better perform catalytic properties in wastewater treatment.

Development and validation of prognostic nomograms for adult with papillary renal cell carcinoma: A retrospective study.

OBJECTIVE: The aim of the study was to create two consensus nomograms for predicting Overall Survival (OS) and Cancer-Specific Survival (CSS) in adults with papillary Renal Cell Carcinoma (pRCC). METHODS: Using the Surveillance, Epidemiology, and End Results databases, a retrospective analysis of 1,074 adults with pRCC from 2004 to 2015 was performed. These patients were then randomly divided into two independent cohorts with a ratio of 7:3 (training cohort: 752; validation cohort: 322). In a retrospective analysis of 752 patients from the training cohort, independent prognostic variables affecting OS and CSS were found. R software was used to create prognostic nomograms based on the findings of Cox regression analysis. The performance of the nomograms was assessed using the Concordance Index (C-index), the Area Under Curve (AUC), a calibration curve, and Decision Curve Analysis (DCA). Data from the 107 postoperative pRCC patients at the Affiliated Hospital of Xuzhou Medical University were used for external validation of the nomogram. RESULTS: For OS and CSS, the C-indices and AUCs of the training cohort and the validation cohort indicated that the model had excellent discrimination. The DCA demonstrated that the model was clinically applicable, and the calibration curves in the internal and external validations showed that the model's accuracy was high. CONCLUSION: The authors developed and validated a prognostic nomogram that accurately predicted the 3-, 5-, and 8-year OS and CSS of adults with pRCC. Clinicians can use this knowledge to direct the clinical management and counseling of patients with pRCC.

Loss of GCN5L1 exacerbates damage in alcoholic liver disease through ferroptosis activation.

BACKGROUND AND AIMS: Iron overload, oxidative stress and ferroptosis are associated with liver injury in alcohol-associated liver disease (ALD), however, the crosstalk among these regulatory pathways in ALD development is unclear. METHODS: ALD mouse model and general control of amino acid synthesis 5 like 1 (GCN5L1) liver knockout mice were generated to investigate the role of GCN5L1 in ALD development. Proteomic screening tests were performed to identify the key factors mediating GCN5L1 loss-induced ALD. RESULTS: Gene Expression Omnibus data set analysis indicates that GCN5L1 expression is negatively associated with ALD progression. GCN5L1 hepatic knockout mice develop severe liver injury and lipid accumulation when fed an alcohol diet. Screening tests identified that GCN5L1 targeted the mitochondrial iron transporter CISD1 to regulate mitochondrial iron homeostasis in ethanol-induced ferroptosis. GCN5L1-modulated CISD1 acetylation and activity were crucial for iron accumulation and ferroptosis in response to alcohol exposure. CONCLUSION: Pharmaceutical modulation of CISD1 activity is critical for cellular iron homeostasis and ethanol-induced ferroptosis. The GCN5L1/CISD1 axis is crucial for oxidative stress and ethanol-induced ferroptosis in ALD and is a promising avenue for novel therapeutic strategies.

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear. AIM: To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance. METHODS: Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance. RESULTS: LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo. CONCLUSION: The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

Compilation of a self-management assessment scale for postoperative patients with aortic dissection.

Objective: The aim of this research was to compile a self-management assessment scale for patients with aortic dissection (AD). The questionnaire is useful in making the patient aware of the need for post-operative care in order to contribute to improving the outcome and quality of life. Methods: The initial version of the "postoperative self-management assessment scale for patients with aortic dissection" was developed using the Delphi expert consultation method based on qualitative research results, consultation of self-management-related literature, reference to the existing self-management scale, and self-efficacy theory, combined with the disease characteristics of AD. By using the convenience sampling method, a total of 201 patients with AD who had undergone surgery were selected as the research participants. The initial version of the scale was used for follow-up investigation, and the scale entries were evaluated and exploratory factor analysis carried out to form the formal version of the "postoperative self-management assessment scale for patients with aortic dissection." A total of 214 patients with AD after surgery were selected as the research participants. The formal version of the scale was used for follow-up investigation, and its reliability and validity were evaluated. Results: The formal version of the scale had 6 dimensions and 35 entries. The Cronbach's α coefficient for the total scale was 0.908, the split-half reliability was 0.790, and the test-retest reliability after 2 weeks was 0.471. The content validity index of the total scale was 0.963. Exploratory factor analysis yielded six common factors, and the cumulative contribution rate of variance was 66.303%. Confirmatory factor analysis showed that except for the incremental fit index, Tucker-Lewis index, and comparative fit index >0.85, slightly lower than 0.90, χ 2/df <3, root mean square of approximation <0.08, parsimonious goodness-of-fit index, and parsimonious normed fit index >0.50; all other model fitting requirements were satisfied, indicating that the model fitting was acceptable. Conclusion: We compiled the postoperative self-management assessment scale for patients with AD, which has demonstrated excellent reliability and validity and can be used as a tool to evaluate the postoperative self-management level in patients with aortic dissection.

A new generation of structural biologists in China.

We have asked young scientists who spoke at our recent Cell Symposium "Structural biology from the nanoscale to cellular mesoscale" in Huangshan, China to tell us more about themselves and their exciting research in this collection of Voices.

FeSe2 and Its Composites for Pollutants Removal: Synthesis, Mechanisms, and Application Potential.

In recent years, the research of FeSe2 and its composites in environmental remediation has been gradually carried out. And the FeSe2 materials show great catalytic performance in photocatalysis, electrocatalysis, and Fenton-like reactions for pollutants removal. Therefore, the studies and applications of FeSe2 materials are reviewed in this work, including the common synthesis methods, the role of Fe and Se species as well as the catalyst structure, and the potential for practical environmental applications. Hereinto, it is worth noting in particular that the lower-valent Se (Se2- ), unsaturated Se (Se- ), and Se vacancies (VSe ) can play different roles in promoting pollutants removal. In addition, the FeSe2 material also demonstrates high stability, reusability, and adaptability over a wider pH range as well as universality to different pollutants. In view of the overall great properties and performance of FeSe2 materials compared with other typical Fe-based materials, it deserves and needs further research. And finally, this paper presents some challenges and perspectives in future development, looking forward to providing helpful guidance for the subsequent research of FeSe2 and its composites for environmental application.

Utilizing physician modified fenestration on the castor branched stent technique for reconstruction of an isolated left vertebral artery on the aortic arch.

The study aimed to provide physician modified fenestration (PMF) on a single-branched stent for the aortic arch (Castor) to protect the isolated left vertebral artery (ILVA) during thoracic endovascular aortic repair (TEVAR). Patients who underwent TEVAR involving ILVA reconstruction through PMF performing on the Castor branched stent were included in a retrospective, multi-centre study from June 2018 to December 2022. In these patients, all proximal landing zones of "Castor" were positioned in Ishimaru zone 2a. A total of twenty-five patients met the inclusion criteria and the achievement rate showed 25/25 (100%) success in them. The twenty-five patients had a median follow-up length of 28.5 ± 14.6 months. One patient (4.0%) suffered from postoperative ischemic stroke before discharge. One patient (4.0%) died from a hemodialysis-related brain hemorrhage before discharge on the 29th day after the procedure. One patient died of advanced liver cancer in the 33th month after discharge. Aortic rupture, stroke or spinal cord injury did not occur throughout the follow-up period after discharge. Two patients (8.0%) experienced endoleak at the fenestration, however, resulting in only one's necessity for reintervention. Notably, the procedure effectively maintained ILVAs patency for all patients during follow up. According to our preliminary findings, performing a TEVAR under local anaesthesia using PMF on a Castor branched stent for ILVA preservation appeared practical, secure, and effective.

Dataset on the tested and simulated response of thick cold-formed circular hollow sections under cyclic loading.

This article describes a dataset used to calibrate a finite element model of a thick circular hollow section (CHS) with varying d/t (diameter to thickness) ratio under cyclic loading which may be used as a computational model validation benchmark by researchers working on similar problems in structural and mechanical engineering. The test data consists of seven cold-formed S335J2H steel CHS tube specimens tested to buckling failure in low-cycle fatigue under a three-point bending arrangement, instrumented with discrete strain gauges, displacement transducers and string potentiometers together with continuous surface deformation fields obtained by two pairs of digital image correlation (DIC) cameras. 'Half-cycle' material data from the uniaxial tensile testing of dog-bone coupons is also provided. Comparisons between measured and simulated entities such as midspan forces, moments, displacements and mean curvatures can be obtained with MATLAB processing scripts. Complete ABAQUS model input files are also provided to aid in benchmarking.

Three new species of Cortinarius section Delibuti (Cortinariaceae, Agaricales) from China.

Three new species of CortinariussectionDelibuti, namely C.fibrillososalor, C.pseudosalor, and C.subtropicus are described as new to science based on morphological and phylogenetic evidences. Cortinariuspseudosalor is extremely morphologically similar to C.salor, but it differs from the latter by smaller coarsely verrucose basidiospores. Cortinariusfibrillososalor can be easily differentiated by its fibrillose pileus. The pileus of C.subtropicus becomes brown without lilac tint at maturity comparing with other members of section Delibuti. A combined dataset of ITS and LSU sequences was used for phylogenetic analysis. The phylogenetic reconstruction of section Delibuti revealed that these three new species clustered and formed independent lineages with full support respectively. A key to the three new species and related species of section Delibuti is provided in this work.

circNINL facilitates aerobic glycolysis, proliferation, invasion, and migration in lung cancer by sponging miR-3918 to mediate FGFR1 expression.

Previously characterized as an oncogenic player in breast cancer, the function of circular RNA NINL (circNINL) in lung cancer (LC) remained elusive. This study aimed to delineate the biological role of circNINL in LC and to unveil its potential molecular mechanisms. We discovered elevated expression levels of circNINL and Fibroblast Growth Factor Receptor 1 (FGFR1) concomitant with diminished expression of microRNA-3918 (miR-3918) in LC specimens. Knockdown of circNINL led to a marked decrease in cell proliferation, migration, invasion, and aerobic glycolysis, alongside an upsurge in apoptosis in LC cells. Either downregulation of miR-3918 or overexpression of FGFR1 mitigated the suppressive impact of circNINL knockdown on LC pathogenesis. Mechanistic studies validated that circNINL served as a competitive endogenous RNA for miR-3918, thus influencing FGFR1 expression. Further, in vivo experiments using nude mouse xenograft models underscored that silencing circNINL substantially curtailed tumor growth in LC. Collectively, these findings illuminate that circNINL exacerbates LC malignancy via the miR-3918/FGFR1 axis, a process integrally linked with the activation of aerobic glycolysis.