Expression patterns of housekeeping genes and tissue-specific genes in black goats across multiple tissues.

Black goats are a significant meat breed in southern China. To investigate the expression patterns and biological functions of genes in various tissues of black goats, we analyzed housekeeping genes (HKGs), tissue-specific genes (TSGs), and hub genes (HUBGs) across 23 tissues. Additionally, we analyzed HKGs in 13 tissues under different feeding conditions. We identified 2968 HKGs, including six important ones. Interestingly, HKGs in grazing black goats demonstrated higher and more stable expression levels. We discovered a total of 9912 TSGs, including 134 newly identified ones. The number of TSGs for mRNA and lncRNA were nearly equal, with 127 mRNA TSGs expressed solely in one tissue. Additionally, the predicted functions of tissue-specific long non-coding RNAs (lncRNAs) targeting mRNAs corresponded with the physiological functions of the tissues.Weighted gene co-expression network analysis (WGCNA) constructed 30 modules, where the dark grey module consists almost entirely of HKGs, and TSGs are located in modules most correlated with their respective tissues. Additionally, we identified 289 HUBGs, which are involved in regulating the physiological functions of their respective tissues. Overall, these identified HKGs, TSGs, and HUBGs provide a foundation for studying the molecular mechanisms affecting the genetic and biological processes of complex traits in black goats.

A disulfide bond mutant of Pseudoalteromonas porphyrae κ-carrageenase conferred improved thermostability and catalytic activity and facilitated its utilization in κ-carrageenan industrial waste residues recycling.

In this study, Discovery Studio was employed to predict the potential disulfide bond mutants of the catalytic domain of Pseudoalteromonas porphyrae κ-carrageenase to improve the catalytic activity and thermal stability. The mutant N205C-G239C was identified with significantly increased catalytic activity toward κ-carrageenan substrate, with activity 4.28 times that of WT. The optimal temperature of N205C-G239C was 55 °C, 15 °C higher than that of WT. For N205C-G239C, the t1/2 value at 50 °C was 52 min, 1.41 times that of WT. The microstructural analysis revealed that the introduced disulfide bond N205C-G239C could create a unique catalytic environment by promoting favorable interactions with κ-neocarratetraose. This interaction impacted various aspects such as product release, water molecule network, thermodynamic equilibrium, and tunnel size. Molecular dynamics simulations demonstrated that the introduced disulfide bond enhanced the overall structure rigidity of N205C-G239C. The results of substrate tunnel analysis showed that the mutation led to the widening of the substrate tunnel. The above structure changes could be the possible reasons responsible for the simultaneous enhancement of the catalytic activity and thermal stability of mutant N205C-G239C. Finally, N205C-G239C exhibited the effective hydrolysis of the κ-carrageenan industrial waste residues, contributing to the recycling of the oligosaccharides and perlite.

Association of the combined stereotactic radiosurgery and embolization strategy and long-term outcomes in brain arteriovenous malformations with a volume >10 ml: A nationwide multicenter observational prospective cohort study.

BACKGROUND: To assess the long-term outcome of large brain arteriovenous malformations (AVMs) (volume > 10 ml) underwent combined embolization and stereotactic radiosurgery (E+SRS) versus SRS alone. METHODS: Patients were recruited from a nationwide multicenter prospective collaboration registry (MATCH study, August 2011-August 2021) and categorized into E+SRS and SRS alone cohorts. Propensity score-matched survival analysis was employed to control for potential confounding variables. The primary outcome was a composite event of non-fatal hemorrhagic stroke or death. Secondary outcomes were favorable patient outcomes, AVM obliteration, favorable neurological outcomes, seizure, worsened mRS score, radiation-induced changes (RIC), and embolization complications. Furthermore, the efficacy of distinct embolization strategies was evaluated. Hazard ratios (HRs) were computed utilizing Cox proportional hazard models. RESULTS: Among 1063 AVMs who underwent SRS with or without prior embolization, 176 patients met the enrollment criteria. Following propensity score matching, the final analysis encompassed 98 patients (49 pairs). Median (interquartile range) follow-up duration for primary outcomes spanned 5.4 (2.7-8.4) years. Overall, the E+SRS strategy demonstrated a trend toward reduced incidence of primary outcomes compared to the SRS alone strategy (1.44 vs 2.37 per 100 patient-years; HR, 0.58 [95 % CI, 0.17-1.93]). Regardless of embolization degree or strategy, stratified analyses further consistently revealed a similar trend, albeit without achieving statistical significance. Secondary outcomes generally exhibited equivalence, but the combined approach showed potential superiority in most measures. CONCLUSIONS: This study suggests a trend toward lower long-term non-fatal hemorrhagic stroke or death risks with the E+SRS strategy when compared to SRS alone in large AVMs (volume > 10 ml).

The improvement and verification of fluid dynamics simulation on temperature uniformity during heat treatment of ring pieces.

The improvement and verification of fluid dynamics simulation on temperature uniformity during the heat treatment of ring pieces are investigated in this study. The accuracy of the temperature field model is validated by comparing the simulation results with the measured temperatures. The findings reveal that the vortex generated near the furnace wall during heat treatment significantly affects the uniformity of the temperature field. To improve this, adjustments are made to the placement of ring pieces based on an experimentally validated fluid dynamics simulation model, and subsequent calculations are performed on this adjusted model. It is observed that these adjustments greatly enhance temperature uniformity in the heating process, with a 39.06 % improvement in medium-temperature zone (732.32-743.69 k) within the furnace compared to the original model. Additionally, surface temperatures of ring pieces in another medium-temperature zone (668.89-691.11 k) show a 34.54 % improvement in comparison to those predicted by the original model.

The changes of tPA/PAI-1 system are associated with the ratio of BDNF/proBDNF in major depressive disorder and SSRIs antidepressant treatment.

Increasing evidence demonstrates that brain-derived neurotrophic factor (BDNF) can be regarded as a biomarker for major depression. Our previous work found that the ratio of mature BDNF (mBDNF) to precursor-BDNF (proBDNF) was a pivotal factor in the pathogenesis of major depressive disorder (MDD). But the mechanism behind the ratio is still obscure. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) both play essential roles in depression by regulating the ratio of BDNF/proBDNF. In present study, we analyzed BDNF, proBDNF, tPA and PAI-1 in the peripheral blood in 57 MDD patients pre- and post-treatment and in 57 healthy controls. We verified that BDNF and tPA levels were significantly decreased, whereas proBDNF and PAI-1 levels elevated obviously in MDD group pre-treatment. And after 4 weeks SSRIs treatment, the BDNF and tPA levels increased while the proBDNF and PAI-1 levels reduced. The MDD pre-treatment group had the lowest ratio of BDNF to proBDNF compared to MDD post-treatment group and control group. Though the ratio of tPA/PAI-1 in MDD pre-treatment had not reached the significance, it was still the lowest one among the three groups. The combination of tPA + PAI + BDNF showed the best diagnostic value for MDD. In summary, our data suggested that the interaction between tPA and PAI-1 implicated to the MDD and the antidepressant treatment which might through regulating the BDNF/proBDNF ratio. The combination of tPA, PAI-1 and BDNF might offer a helpful way for MDD diagnosis.

Waterborne polyurethane nanoparticles incorporating linoleic acid as a potential strategy for controlling antibiotic resistance spread in the mammalian intestine.

Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation in vitro, but its in vivo effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU0.89@LA, WPU0.99@LA, WPU1.09@LA, and WPU1.19@LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU0.99@LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU0.99@LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene (mcr-1) by more than 45.1-fold. In vivo toxicity assessment demonstrated that 10 mg/kg/day WPU0.99@LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU0.99@LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.

Lithiation: A Pathway to Strengthen Sodiophilic Metal Interlayer of 3D Metallic Skeleton for High-Performance Sodium Metal Anodes.

Constructing a three-dimensional (3D) skeleton with a sodiophilic-modified layer (SML) has been proven to be an effective strategy to alleviate excessive volumetric deformation and continuous dendrite growth for sodium (Na) metal anodes. However, the weak binding force and violent reaction between the SML and the 3D skeleton lead to numerous cracks/defects and even pulverization of the SML during repeated Na plating/stripping. Herein, a lithiation pathway is presented to construct a sodiophilic Li-Sn alloy layer onto a 3D copper mesh to strengthen the SML for stable Na metal anodes. The lithiation 3D skeleton exhibits superior sodiophilicity, higher charge-transfer efficiency, and lower ion-diffusion barrier, contributing to the homogenization of ion-electronic flux and Na deposition. Simultaneously, the dense Li-Sn alloy is more stable than the monometal Sn-layer, which effectively prevents damage to the SML and enhances the stability of the SML. As a result, the asymmetrical cell exhibits great performance with a negligible nucleation overpotential and a high average Coulombic efficiency of 99.4%. Moreover, the full cell assembled with Na3V2(PO4)3 cathode delivers superior capacity retention of 91.3% after 1000 cycles at a current of 3C.

Construction of a Multifunctional Upconversion Nanoplatform Based on Autophagy Inhibition and Photodynamic Therapy Combined with Chemotherapy for Antitumor Therapy.

Inhibition of autophagy increases the sensitivity of tumor cells to radiotherapy and chemotherapy and improves the therapeutic effect on tumors. Recently, photodynamic therapy (PDT) combined with chemotherapy has been proven to further improve the efficiency of cancer treatment. As such, combining autophagy inhibition with PDT and chemotherapy may represent a potentially effective new strategy for cancer treatment. However, currently widely studied autophagy inhibitors inevitably produce various toxic side effects due to their inherent pharmacological activity. To overcome this constraint, in this study, we designed an ideal multifunctional upconversion nanoplatform, UCNP-Ce6-EPI@mPPA + NIR (MUCEN). Control, UCNP-EPI@mPPA (MUE), UCNP-EPI@mPPA + NIR (MUEN), Ce6-EPI@mPPA (MCE), Ce6-EPI@mPPA + NIR (MCEN), and UCNP-Ce6-EPI@mPPA (MUCE) groups were set up separately as controls. Based on a combination of autophagy inhibition and PDT, the average particle size of MUCEN was 197 nm, which can simultaneously achieve the double encapsulation of chlorine e6 (Ce6) and epirubicin (EPI). In vitro tests revealed that MUCE was efficiently endocytosed by 4T1 cells under near-infrared light irradiation. Further, in vivo tests revealed that MUCE dramatically inhibited tumor growth. Immunohistochemistry results indicated that MUCE efficiently increased the expression of autophagy inhibitors p62 and LC3 in tumor tissues. The synergistic effect of autophagy inhibition and PDT with MUCE exhibited superior tumor suppression, providing an innovative approach to cancer treatment.

Preparation of micron-sized benzamidine-modified magnetic agarose beads for trypsin purification from fish viscera.

The effective method for trypsin purification should be established because trypsin has important economic value. In this work, a novel and simple strategy was proposed for fabricating micron-sized magnetic Fe3O4@agarose-benzamidine beads (MABB) with benzamidine as a ligand, which can efficiently and selectively capture trypsin. The micro-sized MABB, with clear spherical core-shell structure and average particle size of 6.6 µm, showed excellent suspension ability and magnetic responsiveness in aqueous solution. The adsorption capacity and selectivity of MABB towards target trypsin were significantly better than those of non-target lysozyme. According to the Langmuir equation, the maximum adsorption capacity of MABB for trypsin was 1946 mg g-1 at 25 °C, and the adsorption should be a physical sorption process. Furthermore, the initial adsorption rate and half equilibrium time of MABB toward trypsin were 787.4 mg g-1 min-1 and 0.71 min, respectively. To prove the practicability, MABB-based magnetic solid-phase extraction (MSPE) was proposed, and the related parameters were optimized in detail to improve the purification efficiency. With Tris-HCl buffer (50 mM, 10 mM CaCl2, pH 8.0) as extraction buffer, Tris-HCl buffer (50 mM, 100 mM CaCl2, pH 8.0) as rinsing buffer, acidic eluent (0.01 M HCl, 0.5 M NaCl, pH 2.0) as eluent buffer and alkaline buffer (1 M Tris-HCl buffer, pH 10.0) as neutralization solution, the MABB-based MSPE was successfully used for trypsin purification from the viscera of grass carp (Ctenopharyngodon idella). The molecular weight of purified trypsin was determined as approximate 23 kDa through sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The purified trypsin was highly active from 30 °C to 60 °C, with an optimum temperature of 50 °C, and was tolerant to pH variation, exhibiting 85 % of maximum enzyme activity from pH 7.0 to 10.0. The results demonstrated that the proposed MABB-based MSPE could effectively purify trypsin and ensure the biological activity of purified trypsin. Therefore, we believe that the novel MABB could be applicable for efficient purification of trypsin from complex biological systems.

A Statistical Route to Robust SERS Quantitation Beyond the Single-Molecule Level.

Single-molecule surface-enhanced Raman spectroscopy (SM-SERS) holds great potential to revolutionize ultratrace quantitative analysis. However, achieving quantitative SM-SERS is challenging because of strong intensity fluctuation and blinking characteristics. In this study, we reveal the relation P = 1 - e-α between the statistical SERS probability P and the microscopic average molecule number α in SERS spectra, which lays the physical foundation for a statistical route to implement SM-SERS quantitation. Utilizing SERS probability calibration, we achieve quantitative SERS analysis with batch-to-batch robustness, extremely wide detection range of concentration covering 9 orders of magnitude, and ultralow detection limit far below the single-molecule level. These results indicate the physical feasibility of robust SERS quantitation through statistical route and certainly open a new avenue for implementing SERS as a practical analysis tool in various application scenarios.

Deciphering the Plastome and Molecular Identities of Six Medicinal "Doukou" Species.

The genus Amomum includes over 111 species, 6 of which are widely utilized as medicinal plants and have already undergone taxonomic revision. Due to their morphological similarities, the presence of counterfeit and substandard products remains a challenge. Accurate plant identification is, therefore, essential to address these issues. This study utilized 11 newly sequenced samples and extensive NCBI data to perform molecular identification of the six medicinal "Doukou" species. The plastomes of these species exhibited a typical quadripartite structure with a conserved gene content. However, independent variation shifts of the SC/IR boundaries existed between and within species. The comprehensive set of genetic sequences, including ITS, ITS1, ITS2, complete plastomes, matK, rbcL, psbA-trnH, and ycf1, showed varying discrimination of the six "Doukou" species based on both distance and phylogenetic tree methods. Among these, the ITS, ITS1, and complete plastome sequences demonstrated the highest identification success rate (3/6), followed by ycf1 (2/6), and then ITS2, matK, and psbA-trnH (1/6). In contrast, rbcL failed to identify any species. This research established a basis for a reliable molecular identification method for medicinal "Doukou" plants to protect wild plant resources, promote the sustainable use of medicinal plants, and restrict the exploitation of these resources.

Spatial differentiation characteristics of the Hemiptera insects in China.

The Hemiptera insects are the largest incomplete metamorphosis insect group in Insecta and play a vital role in ecosystems and biodiversity. Previous studies on the spatial distribution of Hemiptera insects mainly focused on a specific region and insect, this study explored the spatial distribution characteristics of Hemiptera insects in China (national scale), and further clarified the dominant factors affecting their spatial distribution. We used spatial autocorrelation analysis, hot spot analysis, and standard ellipse to investigate the spatial distribution characteristics of Hemiptera insects in China. Furthermore, we used geographic detectors to identify the main factors affecting their spatial distribution under China's six agricultural natural divisions and explore the influencing mechanism of dominant factors. The results show that: (i) The spatial differentiation characteristics of Hemiptera insects in China are significant, and their distribution has obvious spatial agglomeration. The Hu Huanyong Line is an important dividing line for the spatial distribution of Hemiptera insects in China. From the city scale, the HH type (high-high cluster) is mainly distributed on both sides of the Hu Huanyong Line. (ii) The hot spots of Hemiptera insects are mainly distributed in southwest China, along the Qinling Mountains, the western side of the Wuyi Mountains, the Yinshan Mountains, the Liupanshan Mountains, the Xuefeng Mountains, the Nanling Mountains, and other mountainous areas. (iii) Under agricultural natural divisions, the influence of natural environmental factors on the spatial distribution of Hemiptera insects is obviously different. Temperature and precipitation are the dominant factors. Natural factors and socio-economic factors have formed a positive reinforcement interaction mode on the spatial distribution of Hemiptera insects. These can provide the decision-making basis for biodiversity conservation and efficient pest control.

Chirality Sensing of Amino Acid Esters by S-2-Methylbutanamido-Substituted m-Phthalic Diamide-Linked Zinc Bisporphyrinate.

To understand the role of an additional coordination site in the linker in chirality sensing, we designed and synthesized an S-2-methylbutanamido-substituted m-phthalic diamide-linked zinc bisporphyrinate, [Zn2(S-MAABis)] and investigated its ability to sense the chirality of amino acid esters. The 1H NMR spectra and the crystal structure showed that the amido oxygen adjacent to the chiral carbon was coordinated with zinc. NMR and UV-vis titration showed that the binding of [Zn2(S-MAABis)] to amino acid esters occurred via two equilibria, forming 1:1 and 1:2 host-guest complexes. The CD spectra suggested that [Zn2(S-MAABis)] can effectively recognize the absolute configuration of amino acid esters. The sign of the CD spectra remained unchanged during the titration, indicating that the corresponding 1:1 and 1:2 host-guest complexes had the same chirality. This is different from previously studied amino-substituted m-phthalic diamide-linked zinc bisporphyrinate [Zn2(AmBis)], which showed chirality inversion during titration. Theoretical calculations indicated that the additional coordination sites (amido or amino) in the 1:1 host-guest complexes played different roles, leading to differences in chirality. Our studies suggest that the introduction of a coordination site can influence the chirality transfer process, but the results of chirality transfers are dependent on the specific binding modes.

Hyperbolic-to-hyperbolic transition at exceptional Reststrahlen point in rare-earth oxyorthosilicates.

Anisotropic optical crystals can exhibit a hyperbolic response within the Reststrahlen band (RB) and support directional polaritonic propagations when interacting with light. Most of the reported low-symmetry optical crystals showcase the evolution from hyperbolic to elliptic dispersion topologies, largely owing to their adjacent RBs being either overlapped or separated. Here, we report an exceptional Reststrahlen point (ERP) in rare-earth oxyorthosilicate Y2SiO5, at which two neighboring RBs almost kiss each other. Consequently, we observe the direct hyperbolic-to-hyperbolic topological transition: the hyperbolic branches close and reopen along with the rotating transverse axis (TA). At such ERP, the TA merges to the direction orthogonal to its proximate phonon mode, mainly due to the interplay between these two non-orthogonal phonon modes. We also find that even with the existence of only one single RB, the TA can rotate in-plane. Our findings are prevalent in isostructural rare-earth oxyorthosilicates, such as Lu2SiO5. The universally underlying physics of ERP and its corresponding special class of rare-earth oxyorthosilicates may offer playgrounds for continuously tuning phonon polariton propagation direction, and broadband controlling light dispersion of polaritonic nanodevices.

Resequencing of reindeer genomes provides clues to their docile habits.

Reindeer have long been served as vital subsistence resources for inhabitants of Arctic and subarctic regions owing to their domestication. However, the evolutionary relationships and divergence times among different reindeer populations, genetic traits that distinguish domesticated reindeer, and factors that contribute to their relative docility compared with that of other Cervidae specie, remain unclear. In this study, we sequenced the genomes of 32 individuals from wild and domestic reindeer populations that inhabit Arctic and subarctic regions. We found that reindeer experienced 2 or more independent domestication events characterized by weak artificial selection pressure and limited significant differences in genomic parameters between wild and domestic populations. Alterations in conserved noncoding elements in the reindeer genomes, particularly those associated with nervous system development, may have contributed to their domestication by rendering the nervous system less responsive. Together, our results suggest that inherent species-specific traits, rather than intense artificial selection, may have played a significant role in the relatively docile behavior of reindeer and offer valuable insights into the domestication process of these animals.

Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer.

The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.

Meta-Genomic Analysis of Different Bacteria and Their Genomes Found in Raw Buffalo Milk Obtained in Various Farms Using Different Milking Methods.

Milking methods have significant impacts on the microbiological composition, which could affect the quality of raw buffalo milk. Hence, the current study was conducted on the impact of milking methods on microorganisms in buffalo tank raw milk from 15 farms in Guangxi, China. The farms were divided into two groups based on the milking method: mechanical milking (MM, n = 6) and hand milking (HM, n = 9). Somatic cell counts, bacterial cell counts and nutrients of the raw buffalo milk samples were analyzed. The comparison of raw buffalo milk samples was analyzed using metagenomic sequencing to detect any differences between the two groups. There was no significant difference in the basic nutritional compositions and somatic cell count of raw buffalo milk between the two milking methods. However, the HM samples had significantly higher bacterial counts and diversity compared to the MM samples. The results showed that Staphylococcus spp., Klebsiella spp., Streptococcus spp., and Pseudomonas spp. were the major microbes present in canned raw buffalo milk. However, the differences between the two milking methods were the relative abundance of core microorganisms and their potential mastitis-causing genera, including the content of antibiotic-resistance genes and virulence genes. Our study revealed that Staphylococcus spp. and Streptococcus spp. were significantly more abundant in the MM group, while Klebsiella spp. was more abundant in the HM group. Regardless of the milking method used, Pseudomonas spp. was identified as the primary genus contributing to antibiotic resistance and virulence genes in canned raw buffalo milk. These findings affirm that there are differences in the microbial and genomic levels in canned raw milk. To prove the functional roles of the discovered genes and how these genes affect milk quality, further research and experimental validation are necessary.

Simvastatin Inhibits the Formation of NETs by the Mac-1 Pathway to Reduce Hepatic Ischemia-Reperfusion Injury under High-Fat Conditions.

BACKGROUND: Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI. METHODS: An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms. RESULTS: Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia. CONCLUSIONS: Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.

Cross-Species Prediction of Transcription Factor Binding by Adversarial Training of a Novel Nucleotide-Level Deep Neural Network.

Cross-species prediction of TF binding remains a major challenge due to the rapid evolutionary turnover of individual TF binding sites, resulting in cross-species predictive performance being consistently worse than within-species performance. In this study, a novel Nucleotide-Level Deep Neural Network (NLDNN) is first proposed to predict TF binding within or across species. NLDNN regards the task of TF binding prediction as a nucleotide-level regression task, which takes DNA sequences as input and directly predicts experimental coverage values. Beyond predictive performance, it also assesses model performance by locating potential TF binding regions, discriminating TF-specific single-nucleotide polymorphisms (SNPs), and identifying causal disease-associated SNPs. The experimental results show that NLDNN outperforms the competing methods in these tasks. Then, a dual-path framework is designed for adversarial training of NLDNN to further improve the cross-species prediction performance by pulling the domain space of human and mouse species closer. Through comparison and analysis, it finds that adversarial training not only can improve the cross-species prediction performance between humans and mice but also enhance the ability to locate TF binding regions and discriminate TF-specific SNPs. By visualizing the predictions, it is figured out that the framework corrects some mispredictions by amplifying the coverage values of incorrectly predicted peaks.

Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. RESULTS: A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. CONCLUSION: The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.