Search Results (281)

The emergence of human coronaviruses has led to three epidemics or pandemics in the last two decades, collectively causing millions of deaths and thus highlighting a long-term need to identify new antiviral drug targets and develop antiviral therapeutics. In this study, a compound library was screened to uncover novel potential inhibitors of coronavirus replication. Three lead compounds, designated #16-14, #16-23, and #16-24, which were Ixazomib and its analogs, were identified based on their potent antiviral activity and minimal cytotoxicity. These compounds were found to inhibit the immunoproteasome subunit LMP7, a target whose subcellular localization and expression are altered in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-infected Huh7 cells. Yeast two-hybrid assays and co-immunoprecipitation further revealed that LMP7 interacts with the viral proteins Nsp13 and Nsp16. In addition, Nsp13 and Nsp16 disrupted the expression of LMP7 in response to pathogen attacks. Functional studies showed that LMP7 knockout in BEAS-2B-ACE2 cells resulted in enhanced replication of attenuated SARS-CoV-2, highlighting the role of this subunit in restricting viral replication. Taken together, these findings position LMP7 as a novel therapeutic target and highlight Ixazomib and its analogs as potential antiviral agents against current and future coronavirus threats. Full article

Background/Objectives: Epstein–Barr virus (EBV) detection patterns in lymphoproliferative disorders (LPDs) show significant geographical variation worldwide. Regional epidemiological data are essential for understanding viral distribution patterns and developing appropriate clinical surveillance strategies. This study aimed to determine EBV detection frequency in LPDs using available molecular and immunohistochemical methods in Western Mexico. Methods: We conducted a cross-sectional study of 200 formalin-fixed paraffin-embedded tissue samples from patients diagnosed with LPDs (2015–2019) at Hospital Civil de Guadalajara. EBV detection combined with real-time PCR targeting the BNTp143 gene and immunohistochemistry for LMP-1 protein. Cases were classified following current WHO criteria. Statistical analysis included multivariate logistic regression, diagnostic concordance assessment, and age-stratified analysis. Results: EBV detection frequency reached 35.5% overall, with marked differences between neoplastic (53.9%) and reactive LPDs (24.2%) (OR: 3.515; 95% CI: 1.859–6.645, p < 0.001). Hodgkin lymphoma showed the highest detection rate (80.6%), significantly exceeding non-Hodgkin lymphoma (39.3%) (OR: 6.43; 95% CI: 2.08–19.41, p = 0.001). Age-stratified analysis revealed predominant adult involvement (49.1% vs. 22.0% in young adults, p = 0.025). We identified three epidemiological categories based on detection probability patterns. Conclusions: This study represents the first comprehensive molecular and immunohistochemical characterization of Epstein–Barr virus in lymphoproliferative disorders from Western Mexico, establishing distinct epidemiological patterns that align with Latin American regional characteristics. The validated methodology provides a reproducible framework for multi-center studies, while the epidemiological data serve as an essential baseline for future longitudinal research and resource optimization in similar healthcare settings. Full article

This study evaluated the effects of dietary probiotic-fermented corn wet distillers grains (FCWDGs) on finishing pigs. Three Bacillus subtilis strains (CGMCC21218, CCTCC2022073, and CICC10275) were used to ferment corn wet distillers grains, yielding FCWDGs-1, FCWDGs-2, and FCWDGs-3. A total of 128 130-day-old Anqing six white pigs were randomly assigned to four groups: a control group and groups supplemented with 6% FCWDGs-1 (T1), FCWDGs-2 (T2), and FCWDGs-3 (T3). Over a 60-day trial, FCWDGs significantly enhanced growth performance, with T1 and T3 groups showing higher final weight and average daily gain (ADG) compared to the control (p < 0.05), and feed-to-gain ratios were reduced in all treatments (p < 0.05). Loin muscle depth (LMD) was significantly greater in all treatments (p < 0.05), and the lean meat percentage (LMP) was significantly higher in the T1 group (p < 0.05). Antioxidant activity (T-AOC, SOD, and GSH-Px) was enhanced in all treatments, with the highest values observed in the T1 group (p < 0.05). Notably, FCWDGs reduced heavy-metal residues (As, Pb, Cu) in muscle, liver, and kidney tissues, particularly in the T1 group. The results highlight the potential of Bacillus subtilis-fermented FCWDGs to enhance growth performance and carcass traits, and reduce heavy metal accumulation in pig tissues. Full article

Optimizing the metabolizable protein level in ruminant diets represents a promising strategy to increase nitrogen use efficiency and mitigate environmental pollution. This study explored the impacts of varying metabolizable protein (MP) levels on amino acid (AA) balance, nitrogen (N) utilization, and the ruminal microbiota in Hu lambs. Fifty-four female Hu lambs of 60 d old, with an average body weight (BW) of 18.7 ± 2.37 kg, were randomly allocated to three dietary MP groups: (1) low MP (LMP, 7.38% of DM), (2) moderate MP (MMP, 8.66% of DM), and (3) high MP (HMP, 9.93% of DM). Three lambs with similar BW within each group were housed together in a single pen, serving as one experimental replicate (n = 6). The feeding trial lasted for 60 days with 10 days for adaptation. The final BW of lambs in the MMP and HMP groups increased (p < 0.05) by 5.64% and 5.26%, respectively, compared to the LMP group. Additionally, lambs fed the MMP diet exhibited an 11.6% higher (p < 0.05) average daily gain than those in the LMP group. Increasing dietary MP levels enhanced (p < 0.05) N intake, urinary N, retained N, and percent N retained, but decreased apparent N digestibility (p < 0.05). Urinary uric acid, total purine derivatives, intestinally absorbable dietary protein, microbial crude protein, intestinally absorbable microbial crude protein, and actual MP supply all increased (p < 0.05) with higher MP values in the diet. The plasma concentrations of arginine, lysine, methionine, phenylalanine, threonine, aspartic acid, proline, total essential AAs, and total nonessential AAs were the lowest (p < 0.05) in the LMP group. In the rumen, elevated MP levels led to a significant increase (p < 0.05) in the ammonia N content. The relative abundances of Candidatus_Saccharimonas, Ruminococcus, and Oscillospira were the lowest (p < 0.05), whereas the relative abundances of Terrisporobacter and the Christensenellaceae_R-7_group were the highest (p < 0.05) in the MMP group. In conclusion, the moderate dietary metabolizable protein level could enhance growth performance, balance the plasma amino acid profiles, and increase nitrogen utilization efficiency in Hu lambs, while also altering the rumen bacterial community by increasing beneficial probiotics like the Christensenellaceae_R-7_group. Full article

Liquid metals (LMs), with their unique combination of high electrical conductivity and mechanical deformability, have emerged as promising materials for stretchable electronics and biointerfaces. However, the practical application of bulk LMs in wearable sensors has been hindered by processing challenges and low stability. To overcome these limitations, liquid metal particles (LMPs) encapsulated by native oxide shells have gained attention as versatile and stable fillers for stretchable and conductive composites. Recent advances have focused on the development of LM-based hybrid composites that combine LMPs with metal, carbon, or polymeric fillers. These systems offer enhanced electrical and mechanical properties and can form conductive networks without the need for additional sintering processes. They also impart composites with multiple functions such as self-healing, electromagnetic interference shielding, and recyclability. Hence, the present review summarizes the fabrication methods and functional properties of LM-based composites, with a particular focus on their applications in wearable sensing. In addition, recent developments in the use of LM composites for physical motion monitoring (e.g., strain and pressure sensing) and electrophysiological signal recording (e.g., EMG and ECG) are presented, and the key challenges and opportunities for next-generation wearable platforms are discussed. Full article

The electricity market can optimize the resource allocation in power systems by calculating the market clearing problem. However, in the market clearing process, various market operation requirements must be considered. These requirements might cause the obtained power system dispatch instructions to deviate from the optimal solutions of original market clearing problems, thereby compromising the economic properties of locational marginal price (LMP). To mitigate the adverse effects of such optimality limitations, this paper proposes a pricing method for improving economic properties under the optimality limitation of power system dispatch instructions. Firstly, the underlying mechanism through which optimality limitations lead to economic property distortions in the electricity market is analyzed. Secondly, an analytical framework is developed to characterize economic properties under optimality limitations. Subsequently, an optimization-based electricity market pricing model is formulated, where price serves as the decision variable and economic properties, such as competitive equilibrium, are incorporated as optimization objectives. Case studies show that the proposed electricity market pricing method effectively mitigates the economic property distortions induced by optimality limitations and can be adapted to satisfy different economic properties based on market preferences. Full article

Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, the ER manages protein folding and redox balance, while lysosomes regulate autophagy and degradation. Cancer cells, however, are frequently exposed to elevated levels of reactive oxygen species (ROS), which disrupt protein folding in the ER and damage lysosomal membranes and enzymes, promoting dysfunction. Persistent OS activates the unfolded protein response (UPR) and contributes to lysosomal membrane permeabilization (LMP), leading to pro-survival autophagy or cell death depending on the context and on the modulation of pathways like PERK, IRE1, and ATF6. Cancer cells exploit these pathways by enhancing their tolerance to OS and shifting UPR signaling toward survival. Moreover, lysosomal impairment due to ROS accumulation compromises autophagy, resulting in the buildup of damaged organelles and further amplifying oxidative damage. This vicious cycle of ROS-induced ER stress and lysosomal dysfunction contributes to tumor progression, therapy resistance, and metabolic adaptation. Thus, targeting lysosomal and ER stress responses offers potential as cancer therapy, particularly in increasing oxidative stress and promoting apoptosis. This review explores the interconnected roles of lysosomal dysfunction, ER stress, and OS in cancer, focusing on the mechanisms driving their crosstalk and its implications for tumor progression and therapeutic resistance. Full article

Background/Objectives: Premature ovarian insufficiency (POI) is a leading cause of hypoestrogenism in women under the age of 40 years and is associated with an increased risk of impaired bone health. Early diagnosis and timely hormonal intervention are essential to prevent irreversible bone loss. However, diagnostic delay is not uncommon in clinical practice. Methods: We conducted a retrospective analysis of 168 women diagnosed with POI or early menopause (EM) between 2017 and 2024 at a tertiary gynecological endocrinology unit. Bone mineral density (BMD) and T-score were assessed by dual-energy X-ray absorptiometry (DXA) at the time of diagnosis in 125 patients, of whom 116 had secondary amenorrhea. The interval between the last menstrual period (LMP) and diagnosis was used to assess the impact of diagnostic delay. The patients were further stratified by serum estradiol (E2) levels and body mass index (BMI). Results: At the time of diagnosis, 43.1% of patients had osteopenia, and 10.3% had osteoporosis. A statistically significant negative correlation was observed between time to diagnosis and BMD (r = −0.225, p = 0.022), with a similar trend seen for T-score (r = −0.211, p = 0.031). In patients with E2 ≤ 5 ng/L, the association was stronger (BMD: r = −0.401, p = 0.026). Lower E2 levels tended to be associated with poorer bone health in women with a BMI < 25 kg/m², whereas no such trend was observed in those with a higher BMI. Conclusions: Our findings indicate that diagnostic delay in POI is associated with deterioration in bone health, particularly in lean patients and those with severe hypoestrogenism. These results underscore the importance of early recognition and timely initiation of hormone therapy to preserve bone mass and reduce long-term skeletal complications. Full article

Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC’s anti-cancer activities, providing an integrative framework to bridge preclinical evidence with future clinical application. We delineate the pleiotropic mechanisms by which OC modulates cancer hallmarks, including lysosomal membrane permeabilization (LMP)-mediated apoptosis, the inhibition of key oncogenic signaling pathways (c-MET/STAT3, PAR-2/TNF-α, COX-2/mPGES-1), the suppression of epithelial-to-mesenchymal transition (EMT), angiogenesis, and metabolic reprogramming. Furthermore, this review uniquely highlights the emerging role of OC in modulating drug resistance mechanisms by downregulating efflux transporters and sensitizing tumors to chemotherapy, targeted therapies, and immunotherapies. We also examine OC’s bidirectional interaction with gut microbiota, underscoring its systemic immunometabolic effects. A major unmet need addressed by this review is the lack of consolidated knowledge regarding OC’s pharmacokinetic limitations and drug–drug interaction potential in the context of polypharmacy in oncology. We provide an in-depth analysis of OC’s poor bioavailability, extensive first-pass metabolism, and pharmacogenomic interactions, and systematically compile preclinical evidence on advanced delivery platforms—including nanocarriers, microneedle systems, and peptide–drug conjugates—designed to overcome these barriers. By critically evaluating the mechanistic, pharmacological, and translational dimensions of OC, this review advances the field beyond isolated mechanistic studies and offers a strategic blueprint for its integration into precision oncology. It also identifies key research gaps and outlines the future directions necessary to transition OC from a nutraceutical of dietary interest to a viable adjunctive therapeutic agent in cancer treatment. Full article

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8⁺ T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8⁺ T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC. Full article

In this paper, four kinds of flooding systems, high-molecular-weight polymer (HMP), low-molecular-weight polymer (LMP), hydrophobic association polymer (HAP), and LMP/petroleum sulfonate (PS), are preferred. By comparing the static performance, their good basic characteristics as an oil displacement system are clarified. The application concentration range of the polymer solution is optimized and designed in combination with core injectivity experiments and mobility control theory. The oil displacement system and its injection volume have been optimized via three parallel core flooding experiments. The results show that the increase of the polymer molecular weight and the association will enhance the viscosity-increasing performance, viscosity stability, viscoelasticity, and hydrodynamic characteristic size of the solution. According to whether the injection pressure curve reaches equilibrium and the time required for equilibrium, the matching relationship between the polymer and the reservoir can be divided into plugging, flow difficulty and flow smoothly. Based on the mobility control theory, the minimum mobility of the target core occurs when the water saturation is 30–40%. Therefore, the polymer formulation for the application of combined cores with viscosities of 50 mD, 210 mD, and 350 mD is set at 1500 mg/L for LMP and 800 mg/L for MAP. HAP has the best profile improvement effect, but its lowest EOR is 9.68%, which mainly acts on high-permeability layers; LMP can produce more remaining oil in middle-permeability layers, and its EOR can reach 12.01%; LMP/PS can give full play to the oil displacement performance of the polymer and the oil washing ability of the surfactant, and its highest EOR is 21.32%. Meanwhile, the emulsification effect also makes the profile improvement last longer. According to the EOR efficiency and final oil recovery, the optimal injection volume of LMP/PS can be designed to be 0.6–0.7 PV. Full article

Background: Failure to accurately estimate gestational age remains an important dilemma for optimal evidence-based antenatal care. Currently, when the last menstrual period (LMP) is unknown, ultrasonography measurement is the best method for estimating gestational age (GA). This study aims to assess the feasibility and accuracy of ultrasonography measurement of the transverse cerebellar diameter (TCD) to deduce fetal GA after 13 weeks of gestation. Methods: A prospective study was conducted on 384 normal singleton pregnancies. Demographic information and biometric measurements, including TCD, were collected using a data sheet. The data were then analyzed using SPSS version 27, DATAtab, and the R program. Results: The study found a strong significant association between GA based on TCD and the LMP, GA based on femur length (FL), GA based on biparietal diameter (BPD), GA based on abdominal circumference (AC), and GA based on the average gestational age (AVG) (r = 0.976, 0.970, 0.966, 0.968, and 0.984, respectively, p < 0.001). Furthermore, there was perfect agreement between GA estimated using TCD and GA based on LMP, with a mean difference of 0.41 weeks and upper and lower limits of agreement of −1.43 to 2.26 weeks. Conclusions: Ultrasonography measurements of the TCD accurately predict gestational age with excellent concordance with GA based on the LMP, FL, AC, and BPD. TCD can be used as a reliable estimator of GA in the second and third trimesters of pregnancy with the benefit of its brain-sparing effect in fetuses of fetal intrauterine growth restriction pregnancies. Combining TCD with FL, BPD, and AC provides the most accurate method of GA prediction. Full article

Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, has been robustly linked to the pathogenesis of nasopharyngeal carcinoma (NPC). The mechanism of EBV-induced NPC involves complex interactions between viral proteins and host cell pathways. This review aims to comprehensively outline the mechanism of EBV-induced NPC and the latest advances in targeted EBV vaccines for prophylaxis and treatment. This review explores the intricate molecular mechanisms by which EBV contributes to NPC pathogenesis, highlighting viral latency, genetic and epigenetic alterations, and immune evasion strategies. It emphasizes the pivotal role of key viral proteins, including EBNA1, LMP1, and LMP2A, in carcinogenesis. Subsequently, the discussion shifts towards the development of targeted EBV vaccines, including preventive vaccines aimed at preventing primary EBV infection and therapeutic vaccines aimed at treating diagnosed EBV-related NPC. The review underscores the challenges and future directions in the field, stressing the importance of developing innovative vaccine strategies and combination therapies to improve efficacy. This review synthesizes current insights into the molecular mechanisms of EBV-induced NPC and the development of EBV-targeted vaccines, highlighting the potential use of mRNA vaccines for NPC treatment. Full article

To enhance Lactobacillus paracei F50 viability during spray drying and long-term storage, this study evaluates whey protein (WP) crosslinked with four polysaccharides (κ-carrageenan (KC), xanthan gum (XG), low-methoxyl pectin (LMP), sodium alginate (SA)) for the first time as protective matrices for L. paracasei F50 during spray drying. The four kinds of crosslinked wall materials were compared by various characterization methods. Among them, the WP-κ-carrageenan (WP-KC) composite exhibited optimal performance, forming a uniform microcapsule with high colloidal stability. After spray drying, WP-KC achieved the highest viable cell density (9.62 lg CFU/g) and survival rate (91.85%). Notably, WP-KC maintained viability above 8.68 lg CFU/g after 120 days of storage at 4 °C, surpassing other formulations. Structural analysis showed that the WP-KC microcapsule was completely encapsulated without breaking or leaking and confirmed the molecular interaction between WP and KC. Under the condition of high temperatures (≤142.63 °C), the wall material of the microcapsule does not undergo any endothermic or exothermic process and is in a state of thermodynamic equilibrium, with excellent stability and good dispersion. Additionally, microcapsules exhibited enhanced resistance to thermal stress (55–75 °C) and UV irradiation, higher than that of free cells. These results highlight WP-KC as an industrially viable encapsulation system for improving probiotic stability in functional foods, offering critical insights into polysaccharide–protein interactions for optimized delivery systems. Full article

Classic Hodgkin lymphoma (cHL) in patients with immune deficiency/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein–Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1/2A) exploit immune vulnerabilities to activate NF-κB, rewire tumor microenvironments (TME), and evade immune surveillance. EBV-positive cHL, prevalent in immunosuppressed populations, exhibits distinct molecular hallmarks, including reduced somatic mutations, unique HLA associations, and profound PD-L1-mediated immune suppression, that diverge from EBV-negative cases reliant on genetic aberrations. Despite advances in combined antiretroviral therapy, HIV co-infection exacerbates pathogenesis, M2 macrophage dominance, and T-cell exhaustion, while links to other viruses remain ambiguous. Current therapies fail to adequately target these viral and immune complexities, leaving patients with poorer outcomes. This review synthesizes insights into EBV’s etiological role, immune contexture disparities, and the genetic–environmental interplay shaping cHL heterogeneity. The WHO classification highlights the need to reclassify EBV-associated cHL as a distinct subset, integrating viral status and immune biomarkers into diagnostic frameworks. Urgent priorities include global epidemiological studies to clarify causal mechanisms, development of virus-targeted therapies (e.g., EBV-specific T-cell strategies, PD-1/CTLA-4 blockade), and personalized regimens for immune-dysregulated cohorts. Full article