MRI-based machine learning radiomics for prediction of HER2 expression status in breast invasive ductal carcinoma.

Background: Human epidermal growth factor receptor 2 (HER2) is a tumor biomarker with significant prognostic and therapeutic implications for invasive ductal breast carcinoma (IDC). Objective: This study aimed to explore the effectiveness of a multisequence magnetic resonance imaging (MRI)-based machine learning radiomics model in classifying the expression status of HER2, including HER2-positive, HER2-low, and HER2 completely negative (HER2-zero), among patients with IDC. Methods: A total of 402 female patients with IDC confirmed through surgical pathology were enrolled and subsequently divided into a training group (n = 250, center I) and a validation group (n = 152, center II). Radiomics features were extracted from the preoperative MRI. A simulated annealing algorithm was used for key feature selection. Two classification tasks were performed: task 1, the classification of HER2-positive vs. HER2-negative (HER2-low and HER2-zero), and task 2, the classification of HER2-low vs. HER2-zero. Logistic regression, random forest (RF), and support vector machine were conducted to establish radiomics models. The performance of the models was evaluated using the area under the curve (AUC) of the operating characteristics (ROC). Results: In total, 4506 radiomics features were extracted from multisequence MRI. A radiomics model for prediction of expression state of HER2 was successfully developed. Among the three classification algorithms, RF achieved the highest performance in classifying HER2-positive from HER2-negative and HER2-low from HER2-zero, with AUC values of 0.777 and 0.731, respectively. Conclusions: Machine learning-based MRI radiomics may aid in the non-invasive prediction of the different expression status of HER2 in IDC.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 µM (IC50 = 27.00 nM, RF = 247.40) and 10 µM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Targeting focal adhesion kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

Strategies that regulate Hippo signaling pathway for novel anticancer therapeutics.

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.

Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.

The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC50s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy.

Regulating Sodium Deposition Behavior by a Triple-Gradient Framework for High-Performance Sodium Metal Batteries.

An efficient method for the synthesis of a self-supporting carbon framework (denoted Gra-GC-MoSe2) is proposed with a triple-gradient structure-in sodiophilic sites, pore volume, and electrical conductivity-which facilitates the highly efficient regulation of Na deposition. In situ and ex situ measurements, together with theoretical calculations, reveal that the gradient distribution of Se heteroatoms in MoSe2, and its derivatives tailor the sodiophilicity, while the gradient distribution of porous nanostructures homogenizes the Na+ diffusion. Therefore, Na deposition occurs from the bottom to the top of the Gra-GC-MoSe2 framework without dendrite formation. In addition, the gradient in electrical conductivity ensures the stripping process does not lead to dead Na. As a result, a Gra-GC-MoSe2 modified Na anode (Na@Gra-GC-MoSe2) shows impressive cycling stability with a high average Coulombic efficiency in an asymmetric cell. In symmetric cells, it also exhibits a long cycling life of 2000 h with a low polarization voltage and works stably even under a large capacity of 10 mAh cm-2. Moreover, a Na@Gra-GC-MoSe2|| Na3V2(PO4)3 full cell delivers a high energy density with an excellent cycling performance.

An Investigation of a Biomimetic Optical System and an Evaluation Model for the Qualitative Analysis of Laser Interference Visual Levels.

To objectively quantify the level of visual interference induced by lasers, we developed a biomimetic optical system designed to emulate human vision. This system is based on an optical model of the eye and synthetic imaging principles, allowing it to generate biomimetic optical images that closely mimic human visual perception. Upon exposure to a 532 nm laser, biomimetic optical images were captured under various ambient lighting conditions. By employing a contrast threshold model for human visual target detection and grayscale hierarchy analysis, we devised an evaluation model to quantify the levels of laser-induced visual interference. The bionic images obtained from our experiments, in conjunction with the constructed model, enabled us to assess the degree of laser-induced visual interference. Our results indicate that this system can effectively substitute the human eye when testing laser imaging effects, with the generated bionic images achieving up to 90% concordance with human vision. The proposed evaluation model facilitates the quantitative analysis of laser-induced visual impairment. This apparatus and evaluation model hold significant promise for the precise quantification of laser-induced visual interference levels.

HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy.

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.

Lithium Superionic Conductive Nanofiber-Reinforcing High-Performance Polymer Electrolytes for Solid-State Batteries.

Although composite solid-state electrolytes (CSEs) are considered promising ionic conductors for high-energy lithium metal batteries, their unsatisfactory ionic conductivity, low mechanical strength, poor thermal stability, and narrow voltage window limit their practical applications. We have prepared a new lithium superionic conductor (Li-HA-F) with an ultralong nanofiber structure and ultrahigh room-temperature ionic conductivity (12.6 mS cm-1). When it is directly coupled with a typical poly(ethylene oxide)-based solid electrolyte, the Li-HA-F nanofibers endow the resulting CSE with high ionic conductivity (4.0 × 10-4 S cm-1 at 30 °C), large Li+ transference number (0.66), and wide voltage window (5.2 V). Detailed experiments and theoretical calculations reveal that Li-HA-F supplies continuous dual-conductive pathways and results in stable LiF-rich interfaces, leading to its excellent performance. Moreover, the Li-HA-F nanofiber-reinforced CSE exhibits good heat/flame resistance and flexibility, with a high breaking strength (9.66 MPa). As a result, the Li/Li half cells fabricated with the Li-HA-F CSE exhibit good stability over 2000 h with a high critical current density of 1.4 mA cm-2. Furthermore, the LiFePO4/Li-HA-F CSE/Li and LiNi0.8Co0.1Mn0.1O2/Li-HA-F CSE/Li solid-state batteries deliver high reversible capacities over a wide temperature range with a good cycling performance.

Transforming Undesired Corrosion Products into a Nanoflake-Array Functional Layer: A Gelatin-Assistant Modification Strategy for High Performance Zn Battery Anodes.

As corrosion products of Zn anodes in ZnSO4 electrolytes, Zn4SO4 (OH)6·xH2O with loose structure cannot suppress persistent side reactions but can increase the electrode polarization and induce dendrite growth, hindering the practical applications of Zn metal batteries. In this work, a functional layer is built on the Zn anode by a gelatin-assistant corrosion and low-temperature pyrolysis method. With the assistant of gelatin, undesired corrosion products are converted into a uniform nanoflake array comprising ZnO coated by gelatin-derived carbon on Zn foil (denoted Zn@ZnO@GC). It is revealed that the gelatin-derived carbons not only enhance the electron conductivity, facilitate Zn2+ desolvation, and boost transport/deposition kinetics, but also inhibit the occurrence of hydrogen evolution and corrosion reactions on the zincophilic Zn@ZnO@GC anode. Moreover, the 3D nanoflake array effectively homogenizes the current density and Zn2+ concentration, thus inhibiting the formation of dendrites. The symmetric cells using the Zn@ZnO@GC anodes exhibit superior cycling performance (over 7000 h at 1 mA cm-2/1 mAh cm-2) and without short-circuiting even up to 25 mAh cm-2. The Zn@ZnO@GC||NaV3O8 full cell works stably for 5000 cycles even with a limited N/P ratio of ≈5.5, showing good application prospects.

Dietary Supplementation of Astragalus membranaceus Extract Affects Growth Performance, Antioxidant Capacity, Immune Response, and Energy Metabolism of Largemouth Bass (Micropterus salmoides).

The present study investigated the effects of Astragalus membranaceus extract (AME) on growth performance, immune response, and energy metabolism of juvenile largemouth bass (Micropterus salmoides). Seven diets containing 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 0.6% AME (Con, AME0.1, AME0.2, AME0.3, AME0.4, AME0.5, and AME0.6 groups) were formulated and fed to M. salmoides for 8 weeks. Final body weight (FBW), feed intake (FI), weight gain (WG), and specific growth rate (SGR) were all significantly higher in AME0.4 group than in Con group (P < 0.05). Feed conversion rate (FCR) was significantly improved in AME0.5 group compared with Con group (P < 0.05). Whole-body crude protein contents were significantly increased in AME0.2 group (P < 0.05). Whole-body crude lipid contents were significantly lower in AME0.2 and AME0.3 groups, while muscle lipid was upregulated by dietary AME (P < 0.05). Hepatic malondialdehyde (MDA) contents were significantly lowered in AME0.3 and AME0.4 groups, and catalase (CAT) activities were significantly increased in AME0.1 and AME0.2 groups (P < 0.05). Plasma aspartate aminotransferase (AST) level was significantly lowered in AME0.5, and AME0.6 groups, and alanine aminotransferase (ALT) level was lowered in AME0.5 groups (P < 0.05). Plasma triglyceride was declined in AME0.6 group, and glucose was decreased by 0.3%-0.5% AME (P < 0.05). Significantly higher hepatocyte diameter, lamina propria width, and submucosal layer thickness were recorded in AME0.6 groups, while the longest villi height was obtained in AME0.2 and AME0.3 groups (P < 0.05). The mRNA expression levels of insulin-like growth factor 1 (igf1) revealed the growth-promoting effect of AME. The anti-inflammatory and antiapoptotic effects of AME were demonstrated by transcription levels of interleukin 8 (il-8), tumor necrosis factor-alpha (tnf-a), caspase, B-cell lymphoma-xl (Bcl-xl), bcl-2 associated x (Bax), and bcl-2-associated death protein (Bad). The transcription levels of lipid metabolism and gluconeogenesis related genes, including acetyl-CoA carboxylase alpha (acc1), fatty acid synthase (fasn), fatty acid binding protein 1 (fabp1), phosphoenolpyruvate carboxykinase 2 (pepck2), and glucose-6-phosphatase catalytic subunit 1a (g6pc), were reduced by AME treatment, while the levels of glycolysis-related genes, including glucokinase (gck) and pyruvate kinase (pk), were the highest in AME0.2 and AME0.3 groups (P < 0.05). According to polynomial regression analysis of SGR, WG, FCR, whole-body crude lipid, MDA, and ALT, the optimal AME supplementation level was estimated to be 0.320%-0.429% of the diet. These results provided insights into the roles of AME in regulating immunity and metabolism, which highly indicated its potential as immunostimulants and metabolic regulators in diverse aquatic animals.

Insight into Sulfur-Containing Zwitter-Molecule Boosting Zn Anode: from Electrolytes to Electrodes.

Numerous organic electrolytes additives have been reported to improve Zn anode performance in aqueous Zn metal batteries (AZMBs). However, the modification mechanism needs to be further revealed in consideration of different environments for electrolytes and electrodes during the charge-discharge process. Herein, sulfur-containing zwitter-molecule (methionine, Met) is used as an additive for ZnSO4 electrolytes. In electrolytes, Met reduces the H2O coordination number and facilitates the desolvation process by virtue of functional groups (─COOH, ─NH2, C─S─C), accelerating Zn2+ transference kinetics and decreasing the amount of active water. On electrodes, Met prefers to adsorb on Zn (002) plane and further transforms into a zincophilic protective layer containing C─SOx─C through an in situ electrochemical oxidization, suppressing H2 evolution/corrosion reactions and guiding dendrite-free Zn deposition. By using Met-containing ZnSO4 electrolytes, the Zn//Zn cells show superior cycling performance under 30 mA cm-2/30 mA h cm-2. Moreover, the full cells Zn//NH4V4O10 full cells using the modified electrolytes exhibit good performance at temperatures from -8 to 60 °C. Notably, a high energy density of 105.30 W h kg-1 can be delivered using a low N/P ratio of 1.2, showing a promising prospect of Met electrolytes additives for practical use.

Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely. METHODS: Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations. RESULTS: Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity. CONCLUSION: FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.

Highly efficient and aberration-free off-plane grating spectrometer and monochromator for EUV-soft X-ray applications.

We demonstrate a novel flat-field, dual-optic imaging EUV-soft X-ray spectrometer and monochromator that attains an unprecedented throughput efficiency exceeding 60% by design, along with a superb spectral resolution of λ/Δλ > 200 accomplished without employing variable line spacing gratings. Exploiting the benefits of the conical diffraction geometry, the optical system is globally optimized in multidimensional parameter space to guarantee optimal imaging performance over a broad spectral range while maintaining circular and elliptical polarization states at the first, second, and third diffraction orders. Moreover, our analysis indicates minimal temporal dispersion, with pulse broadening confined within 80 fs tail-to-tail and an FWHM value of 29 fs, which enables ultrafast spectroscopic and pump-probe studies with femtosecond accuracy. Furthermore, the spectrometer can be effortlessly transformed into a monochromator spanning the EUV-soft X-ray spectral region using a single grating with an aberration-free spatial profile. Such capability allows coherent diffractive imaging applications to be conducted with highly monochromatic light in a broad spectral range and extended to the soft X-ray region with minimal photon loss, thus facilitating state-of-the-art imaging of intricate nano- and bio-systems, with a significantly enhanced spatiotemporal resolution, down to the nanometer-femtosecond level.

The quantitative parameters derived from IDEAL-IQ in the lumbar vertebrae of healthy children: a pilot study of bone development.

Background: Early childhood bone development affects that of bone disease in adolescence and adulthood. Many diseases can affect the cancellous bone or bone marrow. Therefore, it is of great significance to quantify the bone development of healthy children. The evaluation methods of bone development include bone age (BA) assessment and dual-energy X-ray bone mineral densitometry (DXA), both of which have strong subjectivity. The present study was conducted to improve our understanding of the bone development of healthy children using the quantitative parameters derived from iterative decomposition of water and fat with echo asymmetry and least squares estimation quantification (IDEAL-IQ) sequence. Methods: Our study enrolled healthy children between January 2022 to December 2022 consecutively in Children's Hospital of Shanxi. The inclusion criteria were as follows: (I) age ≤18 years; (II) no contraindications (surgical and interventional devices for ferromagnetic materials, cardiac implantable electronic devices, cochlear implants, insulin pumps, dental implants containing metal or alloy) to magnetic resonance imaging (MRI) scan. The exclusion criteria were as follows: (I) previous malignant disease, (II) previous chemoradiotherapy, (III) previous spine surgery, (IV) previous or acute vertebral compression fracture, (V) artifacts present in images. Participants underwent MRI scans using IDEAL-IQ sequence in the lumbar vertebrae. The IDEAL-IQ parameters [proton density fat fraction (PDFF), 1/T2* (R2*)] were obtained. The factor analysis of variance was applied to compare the differences of PDFF and R2* in different lumbar vertebral groups. The Kruskal-Wallis H test or Mann-Whitney U test was applied to compare the differences of quantitative data among different gender or age groups. Spearman correlation analysis was applied to study the relationship among the age, PDFF, and R2*. Results: A total of 145 participants (76 males, 69 females) were evaluated. There were no significant differences in PDFF and R2* of different lumbar vertebrae (PPDFF=0.338, PR2*=0.868). The average age was 36 [13-72] months. They were assigned into 4 groups (0-11, 12-35, 36-71, and 72-144 months). As the age increased, the average PDFF and R2* both increased significantly (rPDFF=0.659, rR2*=0.359, P<0.001). There were significant statistical differences in PDFF and R2* between the 4 age groups (ZPDFF=46.651, ZR2*=27.537, P<0.001). Moreover, the PDFF was also positively correlated with R2* (r=0.576, P<0.001). No association was found between the gender and PDFF, R2* (PPDFF=0.949, PR2*=0.177). Conclusions: The quantitative parameters derived from IDEAL-IQ in the lumbar vertebrae of healthy children will improve our understanding of bone development and provide a basis for further exploring the diseases that affect children's bone development.

Construction of LncRNA-Related ceRNA Networks in Longissimus Dorsi Muscle of Jinfen White Pigs at Different Developmental Stages.

The development of skeletal muscle in pigs might determine the quality of pork. In recent years, long non-coding RNAs (lncRNAs) have been found to play an important role in skeletal muscle growth and development. In this study, we investigated the whole transcriptome of the longissimus dorsi muscle (LDM) of Jinfen White pigs at three developmental stages (1, 90, and 180 days) and performed a comprehensive analysis of lncRNAs, mRNAs, and micro-RNAs (miRNAs), aiming to find the key regulators and interaction networks in Jinfen White pigs. A total of 2638 differentially expressed mRNAs (DE mRNAs) and 982 differentially expressed lncRNAs (DE lncRNAs) were identified. Compared with JFW_1d, there were 497 up-regulated and 698 down-regulated DE mRNAs and 212 up-regulated and 286 down-regulated DE lncRNAs in JFW_90d, respectively. In JFW_180d, there were 613 up-regulated and 895 down-regulated DE mRNAs and 184 up-regulated and 131 down-regulated DE lncRNAs compared with JFW_1d. There were 615 up-regulated and 477 down-regulated DE mRNAs and 254 up-regulated and 355 down-regulated DE lncRNAs in JFW_180d compared with JFW_90d. Compared with mRNA, lncRNA has fewer exons, fewer ORFs, and a shorter length. We performed GO and KEGG pathway functional enrichment analysis for DE mRNAs and the potential target genes of DE lncRNAs. As a result, several pathways are involved in muscle growth and development, such as the PI3K-Akt, MAPK, hedgehog, and hippo signaling pathways. These are among the pathways through which mRNA and lncRNAs function. As part of this study, bioinformatic screening was used to identify miRNAs and DE lncRNAs that could act as ceRNAs. Finally, we constructed an lncRNA-miRNA-mRNA regulation network containing 26 mRNAs, 7 miRNAs, and 17 lncRNAs; qRT-PCR was used to verify the key genes in these networks. Among these, XLOC_022984/miR-127/ENAH and XLOC_016847/miR-486/NRF1 may function as key ceRNA networks. In this study, we obtained transcriptomic profiles from the LDM of Jinfen White pigs at three developmental stages and screened out lncRNA-miRNA-mRNA regulatory networks that may provide crucial information for the further exploration of the molecular mechanisms during skeletal muscle development.

Longitudinal Position and Cancer Risk in the United States Revisited.

The debate over daylight saving time (DST) has surged, with interests in the effects of sunlight exposure on health. Prior studies simulated DST and standard time conditions by analyzing different locations within time zones and neighboring areas across time zone borders. We analyzed cancer incidence rates from various longitudinal positions within time zones and at time zone borders in the contiguous United States. Using data from State Cancer Profiles (2016-2020), we analyzed total cancer of 19 types and specific rates for eight cancers, adjusted for age and includes all demographics. log-linear regression is used to replicate a previous study, and spatial regression models are employed to explore discontinuities at borders. Cancer rate differences lack statistical significance within time zones and near borders for total cancer and most individual cancers. Exceptions included breast, prostate, and liver and bile duct cancers, which exhibited significant relationships with relative position at the 95% significance level. Breast and liver and bile duct cancers saw decreases, while prostate cancer incidence increased from west to east within time zones. Relative position does not have a significant impact on cancer incidence, hence cancer development in general. Isolated exceptions may warrant further investigation as more data become available. Our findings challenge prior research, revealing numerous inconsistencies. These disparities urge a reconsideration of the potential disparities in human health associated with DST and standard time. They offer insights contribute to the ongoing discussion surrounding the retention or abandonment of DST. SIGNIFICANCE: In this article, we investigate the relation between the epidemiology of cancer incidence in the United States and time zone-related longitudinal positions. Our results differ from previous research, which were based on a subset of our data, and show that the time zone effect on cancer incidence rate is not significant. Our research provides implications on the implementation of DST by suggesting that there is no cancer-risk associated reason to prefer one time over the other. Our study also uses regression discontinuity design using natural splines, a more advanced statistical method, to increase robustness of our result. Our findings challenge prior research, revealing numerous inconsistencies. These disparities urge a reconsideration of the potential disparities in human health associated with DST and standard time. They offer insights contribute to the ongoing discussion surrounding the retention or abandonment of DST.

Discovery of novel cMET-targeting antibody Fab drug conjugates as potential treatment for solid tumors with highly expressed cMET.

BACKGROUND: Solid tumors are becoming prevalent affecting both old and young populations. Numerous solid tumors are associated with high cMET expression. The complexity of solid tumors combined with the highly interconnected nature of the cMET/HGF pathway with other cellular pathways make the pursuit of finding an effective treatment extremely challenging. The current standard of care for these malignancies is mostly small molecule-based chemotherapy. Antibody-based therapeutics as well as antibody drug conjugates are promising emerging classes against cMET-overexpressing solid tumors. RESEARCH DESIGN AND METHODS: In this study, we described the design, synthesis, in vitro and in vivo characterization of cMET-targeting Fab drug conjugates (FDCs) as an alternative therapeutic strategy. The format is comprised of a Fab conjugated to a potent cytotoxic drug via a cleavable linker employing lysine-based and cysteine-based conjugation chemistries. RESULTS: We found that the FDCs have potent anti-tumor efficacies in cancer cells with elevated overexpression of cMET. Moreover, they demonstrated a remarkable anti-tumor effect in a human gastric xenograft mouse model. CONCLUSIONS: The FDC format has the potential to overcome some of the challenges presented by the other classes of therapeutics. This study highlights the promise of antibody fragment-based drug conjugate formats for the treatment of solid tumors.

Effects of dietary supplementation of Bacillus subtilis DSM 32315 on growth, immune response and acute ammonia stress tolerance of Nile tilapia (Oreochromis niloticus) fed with high or low protein diets.

Aquatic animals have benefited from Bacillus subtilis-based probiotics over the past few decades. This study evaluated the effects of B. subtilis DSM 32315 probiotics as a feed additive on growth, immune response and resistance to acute ammonia challenge in Nile tilapia. Specifically, four supplemental levels (0%, 0.1%, 0.2%, and 0.3%) of B. subtilis probiotics were tested under two dietary protein levels (32% and 28%). Five replicate tanks were randomly allotted to each dietary treatment, with each tank containing 30 Nile tilapia. After 8 weeks of feeding, Nile tilapia in each tank were exposed to 43.61 mg/L of total ammonia nitrogen for 48 h. The results revealed that reducing protein levels from 32% to 28% did not affect growth performance or antioxidant capacity. However, the low protein diet tended to induce an inflammatory effect shown by increased expressions of TGF-ß and IFN-γ genes (P < 0.05) in the liver. The impact was alleviated by the probiotic supplementation. Compared with the non-supplemented group, 0.1% probiotic supplementation remarkably increased plasma lysozyme activity, total antioxidant capacity and complement C3 and interleukin-10 mRNA levels (P < 0.05) in the 28% protein diet, while higher supplementation of probiotics (0.3%) was shown to be beneficial for the high protein diet (32%). In both the dietary protein levels, 0.1% supplementation of probiotics promoted the antioxidant capacity of Nile tilapia before exposure to ammonia stress but higher probiotic supplementation (0.3%) proved to be necessary under ammonia stress as evidenced by higher fish survival rate. Results exhibited that supplementation with B. subtilis probiotics had a better effect on the intestinal morphology (villi height and width) regardless of protein levels. In conclusion, dietary supplementation of B. subtilis DSM 32315 probiotics at 0.1% in the low protein diet and up to 0.3% in the high protein diet showed beneficial effects on the growth, immunity, and antioxidant capacity of Nile tilapia. Under ammonia stress conditions, the higher supplementation of B. subtilis DSM 32315 probiotics at 0.3% improves stress tolerance of Nile tilapia despite the two dietary protein levels (32%; 28%).

Low distortion reversible database watermarking based on hybrid intelligent algorithm.

In many fields, such as medicine and the computer industry, databases are vital in the process of information sharing. However, databases face the risk of being stolen or misused, leading to security threats such as copyright disputes and privacy breaches. Reversible watermarking techniques ensure the ownership of shared relational databases, protect the rights of data owners and enable the recovery of original data. However, most of the methods modify the original data to a large extent and cannot achieve a good balance between protection against malicious attacks and data recovery. In this paper, we proposed a robust and reversible database watermarking technique using a hash function to group digital relational databases, setting the data distortion and watermarking capacity of the band weight function, adjusting the weight of the function to determine the watermarking capacity and the level of data distortion, using firefly algorithms (FA) and simulated annealing algorithms (SA) to improve the efficiency of the search for the location of the watermark embedded and, finally, using the differential expansion of the way to embed the watermark. The experimental results prove that the method maintains the data quality and has good robustness against malicious attacks.