Identification and Validation of Garlic (Allium sativum) Metabolites as Quorum Sensing Inhibitors of Bacillus cereus Targeting the PlcR Receptor: An In Silico and In Vitro Study.

This study aimed to investigate the influence of garlic metabolites on the quorum sensing (QS) of Bacillus cereus, a foodborne pathogen that controls its main virulence factor through QS. The QS signal receptor PlcR of B. cereus was targeted by molecular docking with 82 garlic metabolites to identify the most potent QS inhibitors. Five metabolites, quercetin, kaempferol, luteolin, flavone, and rutin, were selected for further evaluation of their impacts on the growth, toxin production, and virulence of B. cereus in vitro. The expression levels of key QS genes were also measured to verify their anti-QS ability. The results revealed that quercetin reduced enterotoxin production by B. cereus but did not affect the QS process at the transcriptional level; flavone and rutin in garlic interfered with the QS of B. cereus by competing with the autoinducing peptide (AIP) PapR7 for the PlcR binding site, resulting in decreased enterotoxin secretion and hemolysis without altering the bacterial growth. Interestingly, luteolin and kaempferol in garlic acted as AIP analogs and bound to PlcR to stimulate the QS process and virulence. Furthermore, kaempferol, luteolin, flavone, and rutin had distinct or opposite interactions with PapR7 at the Gln237 or Tyr275 residues of PlcR, which determined the suppression or enhancement of the QS process. The findings suggested that flavone and rutin were effective compounds to inhibit the QS process in garlic and could be used as alternative methods to control B. cereus.

SAMPL-seq reveals micron-scale spatial hubs in the human gut microbiome.

The local arrangement of microbes can profoundly impact community assembly, function, and stability. To date, little is known about the spatial organization of the human gut microbiome. Here, we describe a high-throughput and streamlined method, dubbed SAMPL-seq, that samples microbial composition of micron-scale sub-communities with split-and-pool barcoding to capture spatial colocalization in a complex consortium. SAMPL-seq analysis of the gut microbiome of healthy humans identified bacterial taxa pairs that consistently co-occurred both over time and across multiple individuals. These colocalized microbes organize into spatially distinct groups or "spatial hubs" dominated by Bacteroideceae, Ruminococceae, and Lachnospiraceae families. From a dietary perturbation using inulin, we observed reversible spatial rearrangement of the gut microbiome, where specific taxa form new local partnerships. Spatial metagenomics using SAMPL-seq can unlock new insights to improve the study of microbial communities.

Residual swin transformer for classifying the types of cotton pests in complex background.

Background: Cotton pests have a major impact on cotton quality and yield during cotton production and cultivation. With the rapid development of agricultural intelligence, the accurate classification of cotton pests is a key factor in realizing the precise application of medicines by utilize unmanned aerial vehicles (UAVs), large application devices and other equipment. Methods: In this study, a cotton insect pest classification model based on improved Swin Transformer is proposed. The model introduces the residual module, skip connection, into Swin Transformer to improve the problem that pest features are easily confused in complex backgrounds leading to poor classification accuracy, and to enhance the recognition of cotton pests. In this study, 2705 leaf images of cotton insect pests (including three insect pests, cotton aphids, cotton mirids and cotton leaf mites) were collected in the field, and after image preprocessing and data augmentation operations, model training was performed. Results: The test results proved that the accuracy of the improved model compared to the original model increased from 94.6% to 97.4%, and the prediction time for a single image was 0.00434s. The improved Swin Transformer model was compared with seven kinds of classification models (VGG11, VGG11-bn, Resnet18, MobilenetV2, VIT, Swin Transformer small, and Swin Transformer base), and the model accuracy was increased respectively by 0.5%, 4.7%, 2.2%, 2.5%, 6.3%, 7.9%, 8.0%. Discussion: Therefore, this study demonstrates that the improved Swin Transformer model significantly improves the accuracy and efficiency of cotton pest detection compared with other classification models, and can be deployed on edge devices such as utilize unmanned aerial vehicles (UAVs), thus providing an important technological support and theoretical basis for cotton pest control and precision drug application.

The significance of consolidation chemotherapy after concurrent chemoradiotherapy in esophageal squamous cell carcinoma: a randomized controlled phase III clinical trial.

BACKGROUND: This study explored the significance of consolidation maintenance chemotherapy after concurrent chemoradiotherapy with different regimens in patients with esophageal squamous cell carcinoma. METHOD: A prospective randomized controlled phase III clinical trial was designed and registered in the China Clinical Trials Registry (Registration number: ChiCTR-TRC-12002719). Survival data were analyzed in terms of intention-to-treat (ITT) and per-protocol (PP) sets for patients undergoing cisplatin and 5-fluorouracil (PF) (group A), or cisplatin and paclitaxel (TP) (group B). RESULTS: The incidence risk of grade III-IV leukopenia in group B was higher than in group A (49.2% vs. 25.5%, p = 0.012). The survival rates at 1, 2, 3, and 5 years were 83.8%, 62.6%, 53.1%, and 41.3%, respectively. Consolidation chemotherapy after concurrent chemoradiation therapy had no benefit on median progression-free survival (PFS) (p = 0.95) and overall survival (OS) (p = 0.809). According to the ITT analysis, the median PFS in group A and group B was 28.6 months and 30.3 months (X2 = 0.242, p = 0.623), while the median OS was 31.0 months and 50.3 months (X2 = 1.25，p = 0.263). For the PP analysis, the median PFS in group A and group B were 28.6 months and 30.3 months (p = 0.584), while the median OS was 31.0 months and 50.3 months (p = 0.259), respectively. Patients receiving consolidation chemotherapy did not show significant OS benefits (46.9 months vs. 38.3 months; X2 = 0.059, p = 0.866). CONCLUSION: Similar PFS and OS were found between PF and TP regimens with concurrent chemoradiotherapy. Consolidation chemotherapy did not show any significant OS benefits.

Intracoronary Versus Intravenous Low-Dose Tirofiban in Patients With ST-Elevation Myocardial Infarction: A Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: This meta-analysis aimed to evaluate the effects of intracoronary (IC) low-dose tirofiban versus intravenous (IV) administration on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: All published randomised controlled trials (RCTs) comparing the effects of IC low-dose tirofiban (a bolus of ≤10 ug/kg) versus IV administration in patients with STEMI were identified by searching PubMed, EMBASE, Cochrane Library, and ISI Web of Science from inception to June 2023, with no language restriction. The risk ratio (RR) with 95% confidence intervals (CI) and the weighted mean difference (WMD) with 95% CI were calculated. RESULTS: Eleven RCTs involving 1,802 patients were included. Compared with the IV group, IC low-dose tirofiban was associated with improved major adverse cardiac events rate (RR 0.595, 95% CI 0.442-0.802; p=0.001), left ventricular ejection fraction (WMD 1.982, 95% CI 0.565-3.398; p=0.006), thrombolysis in myocardial infarction (TIMI) flow grade (RR 1.065, 95% CI 1.004-1.131; p=0.037), and TIMI myocardial perfusion grade (RR 1.194, 95% CI 1.001-1.425; p=0.049). The two groups had no significant difference in bleeding events (RR 0.952, 95% CI 0.709-1.279; p=0.745). CONCLUSIONS: Intracoronary low-dose tirofiban administration may be a safe and effective alternative to IV administration in STEMI patients.

Chronic stress induces wide-spread hyperalgesia: The involvement of spinal CCK1 receptors.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.

Noise-Adaptive State Estimators with Change-Point Detection.

Aiming at tracking sharply maneuvering targets, this paper develops novel variational adaptive state estimators for joint target state and process noise parameter estimation for a class of linear state-space models with abruptly changing parameters. By combining variational inference with change-point detection in an online Bayesian fashion, two adaptive estimators-a change-point-based adaptive Kalman filter (CPAKF) and a change-point-based adaptive Kalman smoother (CPAKS)-are proposed in a recursive detection and estimation process. In each iteration, the run-length probability of the current maneuver mode is first calculated, and then the joint posterior of the target state and process noise parameter conditioned on the run length is approximated by variational inference. Compared with existing variational noise-adaptive Kalman filters, the proposed methods are robust to initial iterative value settings, improving their capability of tracking sharply maneuvering targets. Meanwhile, the change-point detection divides the non-stationary time sequence into several stationary segments, allowing for an adaptive sliding length in the CPAKS method. The tracking performance of the proposed methods is investigated using both synthetic and real-world datasets of maneuvering targets.

Mass Spectrometry-Based Proteomic Analysis of Potential Host Proteins Interacting with N in PRRSV-Infected PAMs.

One of the most significant diseases in the swine business, porcine reproductive and respiratory syndrome virus (PRRSV) causes respiratory problems in piglets and reproductive failure in sows. The PRRSV nucleocapsid (N) protein is essential for the virus' assembly, replication, and immune evasion. Stages in the viral replication cycle can be impacted by interactions between the PRRSV nucleocapsid protein and the host protein components. Therefore, it is of great significance to explore the interaction between the PRRSV nucleocapsid protein and the host. Nevertheless, no information has been published on the network of interactions between the nucleocapsid protein and the host proteins in primary porcine alveolar macrophages (PAMs). In this study, 349 host proteins interacting with nucleocapsid protein were screened in the PRRSV-infected PAMs through a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics approach. Bioinformatics analysis, which included gene ontology annotation, Kyoto Encyclopedia of Genes and Genomes database enrichment, and a protein-protein interaction (PPI) network, revealed that the host proteins interacting with PRRSV-N may be involved in protein binding, DNA transcription, metabolism, and innate immune responses. This study confirmed the interaction between the nucleocapsid protein and the natural immune-related proteins. Ultimately, our findings suggest that the nucleocapsid protein plays a pivotal role in facilitating immune evasion during a PRRSV infection. This study contributes to enhancing our understanding of the role played by the nucleocapsid protein in viral pathogenesis and virus-host interaction, thereby offering novel insights for the prevention and control of PRRS as well as the development of vaccines.

Direct Melt-Calendaring of Highly Textured (Bi,Sb)2Te3 Thick Films: Superior Thermoelectric and Mechanical Performance via Strain Engineering.

The evolutions of chip thermal management and micro energy harvesting put forward urgent need for micro thermoelectric devices. Nevertheless, low-performance thermoelectric thick films as well as the complicated precision cutting process for hundred-micron thermoelectric legs still remain the bottleneck hindering the advancement of micro thermoelectric devices. In this work, an innovative direct melt-calendaring manufacturing technology is first proposed with specially designed and assembled equipment, that enables direct, rapid, and cost-effective continuous manufacturing of Bi2Te3-based films with thickness of hundred microns. Based on the strain engineering with external glass coating confinement and controlled calendaring deformation degree, enhanced thermoelectric performance has been achieved for (Bi,Sb)2Te3 thick films with highly textured nanocrystals, which can promote carrier mobility over 182.6 cm2 V-1 s-1 and bring out a record-high zT value of 0.96 and 1.16 for n-type and p-type (Bi,Sb)2Te3 thick films, respectively. The nanoscale interfaces also further improve the mechanical strength with excellent elastic modules (over 42.0 GPa) and hardness (over 1.7 GPa), even superior to the commercial zone-melting ingots and comparable to the hot-extrusion (Bi,Sb)2Te3 alloys. This new fabrication strategy is versatile to a wide range of inorganic thermoelectric thick films, which lays a solid foundation for the development of micro thermoelectric devices.

M6A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis.

BACKGROUND: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated ß-gal (SA-ß-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. RESULTS: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. CONCLUSION: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.

Shikonin blocks CAF-induced TNBC metastasis by suppressing mitochondrial biogenesis through GSK-3ß/NEDD4-1 mediated phosphorylation-dependent degradation of PGC-1α.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore. METHODS: We investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan-Meier plotter database and clinical breast cancer tissue samples. RESULTS: We demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3ß-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo. CONCLUSIONS: Our findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.

Population structure of Taenioides sp. (Gobiiformes, Gobiidae) reveals their invasion history to inland waters of China based on mitochondrial DNA control region.

Taenioides sp. is a small temperate fish originally known to inhabit muddy bottoms of brackish waters in coastal areas of China. However, it began to invade multiple inland freshwaters and caused severe damage to Chinese aquatic ecosystems in recent years. To investigate the sources and invasive history of this species, we examined the population structure of 141 individuals collected from seven locations based on partial mitochondrial D-loop regions. The results revealed that the genetic diversity gradually decreased from south to north, with the Yangtze River Estuary and Taihu Lake populations possessing the highest haplotype diversity (Hd), average number of differences (k), and nucleotide diversity (π) values, suggesting that they may be the sources of Taenioides sp. invasions. Isolation-by-distance analysis revealed a non-significant correlation (p = 0.166) between genetic and geographic distances among seven populations, indicating that dispersal mediated through the regional hydraulic projects may have played an essential role in Taenioides sp. invasions. The population genetic structure analysis revealed two diverged clades among seven populations, with clade 2 only detected in source populations, suggesting a possible difference in the invasion ability of the two clades. Our results provide insights into how native estuary fish become invasive through hydraulic projects and may provide critical information for the future control of this invasive species.

PRRSV GP5 inhibits the antivirus effects of chaperone-mediated autophagy by targeting LAMP2A.

Autophagy is an important biological process in host defense against viral infection. However, many viruses have evolved various strategies to disrupt the host antiviral system. Porcine reproductive and respiratory syndrome virus (PRRSV) is a typical immunosuppressive virus with a large economic impact on the swine industry. At present, studies on the escape mechanism of PRRSV in the autophagy process, especially through chaperone-mediated autophagy (CMA), are limited. This study confirmed that PRRSV glycoprotein 5 (GP5) could disrupt the formation of the GFAP-LAMP2A complex by inhibiting the MTORC2/PHLPP1/GFAP pathway, promoting the dissociation of the pGFAP-EF1α complex, and blocking the K63-linked polyubiquitination of LAMP2A to inhibit the activity of CMA. Further research demonstrated that CMA plays an anti-PRRSV role by antagonizing nonstructural protein 11 (NSP11)-mediated inhibition of type I interferon (IFN-I) signaling. Taken together, these results indicate that PRRSV GP5 inhibits the antiviral effect of CMA by targeting LAMP2A. This research provides new insight into the escape mechanism of immunosuppressive viruses in CMA. IMPORTANCE: Viruses have evolved sophisticated mechanisms to manipulate autophagy to evade degradation and immune responses. Porcine reproductive and respiratory syndrome virus (PRRSV) is a typical immunosuppressive virus that causes enormous economic losses in the swine industry. However, the mechanism by which PRRSV manipulates autophagy to defend against host antiviral effects remains unclear. In this study, we found that PRRSV GP5 interacts with LAMP2A and disrupts the formation of the GFAP-LAMP2A complex, thus inhibiting the activity of CMA and subsequently enhancing the inhibitory effect of the NSP11-mediated IFN-I signaling pathway, ultimately facilitating PRRSV replication. Our study revealed a novel mechanism by which PRRSV escapes host antiviral effects through CMA, providing a potential host target, LAMP2A, for developing antiviral drugs and contributing to understanding the escape mechanism of immunosuppressive viruses.

Exosomal YB-1 facilitates ovarian restoration by MALAT1/miR-211-5p/FOXO3 axis.

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H2O2 and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO3 levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.

General strategy for developing thick-film micro-thermoelectric coolers from material fabrication to device integration.

Micro-thermoelectric coolers are emerging as a promising solution for high-density cooling applications in confined spaces. Unlike thin-film micro-thermoelectric coolers with high cooling flux at the expense of cooling temperature difference due to very short thermoelectric legs, thick-film micro-thermoelectric coolers can achieve better comprehensive cooling performance. However, they still face significant challenges in both material preparation and device integration. Herein, we propose a design strategy which combines Bi2Te3-based thick film prepared by powder direct molding with micro-thermoelectric cooler integrated via phase-change batch transfer. Accurate thickness control and relatively high thermoelectric performance can be achieved for the thick film, and the high-density-integrated thick-film micro-thermoelectric cooler exhibits excellent performance with maximum cooling temperature difference of 40.6 K and maximum cooling flux of 56.5 W·cm-2 at room temperature. The micro-thermoelectric cooler also shows high temperature control accuracy (0.01 K) and reliability (over 30000 cooling cycles). Moreover, the device demonstrates remarkable capacity in power generation with normalized power density up to 214.0 µW · cm-2 · K-2. This study provides a general and scalable route for developing high-performance thick-film micro-thermoelectric cooler, benefiting widespread applications in thermal management of microsystems.

Downregulation of lysine-specific histone demethylase 1A (KDM1A/LSD1) in medial prefrontal cortex facilitates chronic stress-induced pain and emotional dysfunction in female mice.

Chronic primary pain, characterized by overlapping symptoms of chronic pain, anxiety, and depression, is strongly associated with stress and is particularly prevalent among females. Recent research has convincingly linked epigenetic modifications in the medial prefrontal cortex (mPFC) to chronic pain and chronic stress. However, our understanding of the role of histone demethylation in the mPFC in chronic stress-induced pain remains limited. In this study, we investigated the function of lysine-specific histone demethylase 1A (KDM1A/LSD1) in the context of chronic overlapping pain comorbid with anxiety and depression in female mice. We employed a chronic variable stress model to induce pain hypersensitivity in the face and hindpaws, as well as anxiety-like and depression-like behaviors, in female mice. Our findings revealed that chronic stress led to a downregulation of KDM1A mRNA and protein expression in the mPFC. Notably, overexpressing KDM1A in the mPFC alleviated the pain hypersensitivity, anxiety-like behaviors, and depression-like behaviors in female mice, without affecting basal pain responses or inducing emotional distress. Conversely, conditional knockout of KDM1A in the mPFC exacerbated pain sensitivity and emotional distress specifically in females. In summary, this study highlights the crucial role of KDM1A in the mPFC in modulating chronic stress-induced overlapping pain, anxiety, and depression in females. Our findings suggest that KDM1A may serve as a potential therapeutic target for treating chronic stress-related overlap pain and associated negative emotional disorders.

A deep reinforcement learning algorithm framework for solving multi-objective traveling salesman problem based on feature transformation.

As a special type of multi-objective combinatorial optimization problems (MOCOPs), the multi-objective traveling salesman problem (MOTSP) plays an important role in practical fields such as transportation and robot control. However, due to the complexity of its solution space and the conflicts between different objectives, it is difficult to obtain satisfactory solutions in a short time. This paper proposes an end-to-end algorithm framework for solving MOTSP based on deep reinforcement learning (DRL). By decomposing strategies, solving MOTSP is transformed into solving multiple single-objective optimization subproblems. Through linear transformation, the features of the MOTSP are combined with the weights of the objective function. Subsequently, a modified graph pointer network (GPN) model is used to solve the decomposed subproblems. Compared with the previous DRL model, the proposed algorithm can solve all the subproblems using only one model without adding weight information as input features. Furthermore, our algorithm can output a corresponding solution for each weight, which increases the diversity of solutions. In order to verify the performance of our proposed algorithm, it is compared with four classical evolutionary algorithms and two DRL algorithms on several MOTSP instances. The comparison shows that our proposed algorithm outperforms the compared algorithms both in terms of training time and the quality of the resulting solutions.

Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics.

Tamoxifen (TAM) resistance presents a major clinical obstacle in the management of estrogen-sensitive breast cancer, highlighting the need to understand the underlying mechanisms and potential therapeutic approaches. We showed that dysregulated mitochondrial dynamics were involved in TAM resistance by protecting against mitochondrial apoptosis. The dysregulated mitochondrial dynamics were associated with increased mitochondrial fusion and decreased fission, thus preventing the release of mitochondrial cytochrome c to the cytoplasm following TAM treatment. Dynamin-related GTPase protein mitofusin 1 (MFN1), which promotes fusion, was upregulated in TAM-resistant cells, and high MFN1 expression indicated a poor prognosis in TAM-treated patients. Mitochondrial translocation of MFN1 and interaction between MFN1 and mitofusin 2 (MFN2) were enhanced to promote mitochondrial outer membrane fusion. The interaction of MFN1 and cristae-shaping protein optic atrophy 1 (OPA1) and OPA1 oligomerization were reduced due to augmented OPA1 proteolytic cleavage, and their apoptosis-promoting function was reduced due to cristae remodeling. Furthermore, the interaction of MFN1 and BAK were increased, which restrained BAK activation following TAM treatment. Knockdown or pharmacological inhibition of MFN1 blocked mitochondrial fusion, restored BAK oligomerization and cytochrome c release, and amplified activation of caspase-3/9, thus sensitizing resistant cells to apoptosis and facilitating the therapeutic effects of TAM both in vivo and in vitro. Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance.