Search Results (1,706)

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (−45.17 and −23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (−4.81 and −7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (−27.95 and −12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (−3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD. Full article

This study investigated the impact of harvest season and extraction method on the yield, composition, and bioactivity of essential oils (EOs) from wild Rosmarinus officinalis L. plants collected in Algeria. Oils were obtained by hydro distillation (HD), steam distillation (SD), and microwave-assisted distillation (MD) across four seasons and characterized by GC–MS. Camphor, α-pinene, camphene, and 1,8-cineole were consistently dominant, with spring oils, particularly those extracted by microwave-assisted distillation, showing the highest enrichment in oxygenated monoterpenes (up to 59.6%). Functional assays revealed clear seasonal variation, whereas spring oils exhibited the strongest antioxidant capacity, with a FRAP value of 4.63 µg/mL, approaching that of the synthetic standard BHA (6.89 µg/mL), alongside notable anti-inflammatory effects. Antimicrobial screening indicated selective inhibition of Escherichia coli and Candida albicans, while Pseudomonas aeruginosa and Bacillus subtilis remained resistant. Acute toxicity evaluation confirmed safety at 2000 mg/kg. These findings demonstrate that ecological timing and extraction strategy critically determine rosemary EO properties and establish quantitative benchmarks for their pharmaceutical and industrial valorization. Full article

This study evaluates the technical and economic feasibility of liquid polymer emulsions as substitutes for powder polymers in polymer flooding applications, particularly in space-constrained, low-permeability reservoirs in Austria. Rheological tests determined that target viscosities of 20 mPa·s at 20 °C and a shear rate of 7.94 s⁻¹ were achieved using concentrations of 1200 ppm for liquid polymer 1 (LP1), 2250 ppm for liquid polymer 2 (LP2), and 1200–1400 ppm for powder polymers. Injectivity tests revealed that liquid polymers encountered challenges in 60 mD and 300 mD core plugs, with pressure stabilization not achieved at injection rates of 1–2.5 ft/day. Powder polymers demonstrated stable injectivity, with powder polymer 1 (PP1) showing an optimal performance at 10 ft/day and a low residual resistance factor (RRF). Two-phase core floods using PP1 and powder polymer 2 (PP2) at 1 ft/day yielded incremental oil recovery factors of approximately 5%, with a maximum of 8% observed for higher viscosity slugs. Economic analysis indicated that over a 3-year horizon, liquid polymers are 30% cheaper than powder polymer Option 1 but 100% more expensive than Option 2. Over a 10-year horizon, liquid polymers are 50% more expensive than both powder polymer options. Although liquid polymers offer logistical advantages, they are unsuitable for low-permeability reservoirs. Powdered polymers, particularly PP1, are recommended for pilot implementation due to superior injectivity, mechanical stability, and recovery performance. Full article

Background/Objectives: The gluten-free diet (GFD) may be anti-inflammatory in treating Hashimoto’s thyroiditis (HT), but the studies are inconsistent. Methods: To determine the effects of the GFD in non-celiac HT, we included randomized controlled trials from the following databases: Cochrane Central, Embase, Lilacs, Medline, Scopus, and Web of Science. The study was registered at Prospero (no. CRD42024566034). The outcomes assessed included free triiodothyronine (fT3), free tetraiodothyronine (fT4), thyroid stimulating hormone (TSH), Anti-thyroid Peroxidase (TPO), anti-thyroglobulin (Tg), C-reactive protein (CRP), body weight (BW), body mass index (BMI) and adverse effects. Sensitivity, subgroup, meta-regression, bias risk, and evidence analyses’ certainty were also assessed. Results: Only three studies were meta-analyzed, comprising 110 participants. The pooled data revealed the evidence was very uncertain about the effect of GFD compared to the control group on mean differences (MD) of TSH (MD −0.63 uIU/mL; 95% CI −1.63 to 0.36; p = 0.21), fT3 (MD −0.18 pg/mL; 95% CI −0.50 to 0.14; p = 0.28), fT4 (MD −0.33 ng/dL; 95% CI −0.89 to 0.23; p = 0.24), anti-Tg (MD −10.07 IU/mL; 95% CI −17.73 to −2.42; p = 0.010), anti-TPO (MD 76.19 IU/mL; 95% CI 46.86 to 108.51; p < 0.00001), CRP (MD −0.12 IU/mL; 95% CI −0.30 to 0.07), BW (MD −1.46 kg; 95% CI −6.70 to 3.77), and BMI (MD −1.80 kg/m2; 95% CI −3.30 to −0.31). The quality of evidence was rated as having serious methodological concerns to extremely serious imprecision. Conclusions: The GFD decreased anti-Tg and increased the anti-TPO levels, both significantly. There were no significant results on fT3, fT4, and TSH. Full article

Background/Objectives: Moyamoya angiopathy is a progressive occlusive cerebrovascular disorder and a relevant cause of pediatric stroke. While most published data originate from Asian and North American populations, reports from South America remain scarce. This study aimed to characterize the clinical, angiographic, and functional outcomes of pediatric patients with Moyamoya disease (MMD) or Moyamoya syndrome (MMS) who underwent indirect revascularization in a Brazilian cohort, and to contextualize these findings within the international literature. Methods: We retrospectively reviewed all patients under 18 years of age who underwent indirect bypass (EDAS/EDAMS) for MMD or MMS at a tertiary pediatric center in Curitiba, Brazil, between 2009 and 2023. Demographic, clinical, and angiographic data were analyzed, including postoperative Matsushima grading, and functional outcomes assessed by the modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS). All eligible patients received perioperative aspirin (3–5 mg/kg/day). Results: Fourteen patients (64% female; mean age 9.9 years) were included: 43% with MMD and 57% with MMS. Hemiparesis (86%), seizures (57%), and cognitive impairment (57%) were the most common symptoms. Most were classified as Suzuki stages II–III. All underwent indirect revascularization; 79% received bilateral procedures. Angiographic follow-up (14 hemispheres) showed good collateral formation (Matsushima grade A: 43%; B: 57%). Complications occurred in three patients (21%), and two (14%)—both MMD—developed new postoperative ischemic strokes despite receiving aspirin therapy. At 3.5 years of mean follow-up, the mean mRS was 1.9 ± 0.8 and the GOS was 4.0 ± 0.3. Conclusions: Indirect revascularization in this Brazilian pediatric cohort was feasible and safe, yielding outcomes comparable to international series. Collateral development correlated with functional improvement. These exploratory findings emphasize the importance of early diagnosis, standardized perioperative care, and long-term follow-up, and highlight the need for multicenter collaboration in Latin America. Full article

Background/Objectives: The Mediterranean diet (MD) has been associated with favorable metabolic outcomes in the general population. However, evidence of these associations among thyroid cancer survivors remains limited. This study examined whether higher MD adherence at diagnosis is associated with longitudinal changes in insulin resistance and lipid profiles in patients with papillary thyroid cancer (PTC). Methods: We analyzed 345 Korean patients aged ≥20 years with histologically confirmed PTC at a tertiary hospital between April 2023 and March 2024. MD adherence at baseline (diagnosis) was assessed using the Korean Mediterranean Diet Adherence Screener and categorized into tertiles. Changes in body mass index (BMI), hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), metabolic score for insulin resistance (METS-IR), homeostasis model assessment of β-cell function (HOMA-β), and triglyceride-glucose (TyG) index were evaluated between baseline and one year post-diagnosis. A stratified analysis was conducted according to BMI (<25 vs. ≥25 kg/m²). Results: During the one-year follow-up, patients with PTC experienced significant reductions in BMI, HbA1c, METS-IR, HOMA-β, triglycerides, LDL-cholesterol, and the TyG index, whereas HDL-cholesterol levels increased. Patients in the high MD adherence group showed decreased HOMA-IR and increased HDL-cholesterol levels compared to those in the low adherence groups. In BMI-stratified analyses, reductions in insulin and HOMA-IR were observed only among patients with obesity in the high MD adherence group. Conclusions: Higher adherence to the MD at diagnosis was associated with decreases in insulin resistance markers and an increase in HDL-cholesterol levels among patients with PTC during the first year after diagnosis. Full article

This study investigates the effect of pyrite content on the flocculation and sedimentation of clay-based tailings composed of kaolin, quartz, and pyrite in seawater at pH 8. A high-molecular-weight anionic hydrolyzed polyacrylamide (SNF 704) was used in batch settling tests, supported by floc characterization with FBRM, zeta potential measurements, and molecular dynamics (MD) simulations. Results showed that increasing pyrite content reduced the maximum floc size and increased the fraction of unflocculated fines, particularly at 10 g/t dosage. Although the fractal dimension remained nearly constant (1.92–1.97 at 10 g/t and 2.05–2.08 at 30 g/t), floc density increased linearly with pyrite proportion due to its higher specific gravity. Zeta potential analysis confirmed strong polymer–pyrite interactions, with charge inversion from +5.3 to −4.5 mV, while MD simulations indicated that adsorption occurs mainly through aliphatic chain segments, in contrast to hydrogen bonding observed for quartz and kaolinite. These findings demonstrate that pyrite affects flocculation dynamics both by its density and by specific polymer–surface interactions, directly influencing floc size, density, and sedimentation performance in seawater thickening systems. Full article

Background: Treosulfan combined with fludarabine (FluTreo) has emerged as a reduced-toxicity alternative to conventional myeloablative conditioning in allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) and related myeloid malignancies. Purpose: This study evaluates the safety, engraftment kinetics, and long-term outcomes of the FluTreo FT14 regimen in a real-world adult cohort. Materials and Methods: We conducted a prospective cohort study of 186 consecutive adults (18–70 years) undergoing allo-HCT between January 2015 and December 2024. Eligible diagnoses included de novo or secondary AML, myelodysplastic syndrome, and myelofibrosis. All received peripheral blood stem cells from matched or mismatched unrelated donors, HLA-matched siblings, or haploidentical relatives. The FT14 protocol comprised fludarabine 150 mg/m² over five days and treosulfan 42 g/m² over three days, with rabbit antithymocyte globulin (5 mg/kg) for unrelated grafts. Primary endpoints were neutrophil and platelet engraftment, donor chimerism, incidence of acute and chronic graft-versus-host disease (GVHD), overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM). Kaplan–Meier, Cox regression, and Fine and Gray models were applied. Results: Median age was 59 years; diagnoses included de novo AML (43%), secondary AML (16%), MDS (25%), and MF (16%). Neutrophil and platelet engraftment medians were 10 and 12 days, respectively. Full donor chimerism (≥99%) was achieved by day 31. Grade III conditioning-related toxicity occurred in 3.2% of cases. Five-year cumulative incidences of grade II–IV acute GVHD and moderate/severe chronic GVHD were 37.6% and 30.6%. Median follow-up was 16.3 months; relapse occurred in 25.3%. Five-year OS and DFS were 71% and 49% overall (75.8% and 59% in CR1), with TRM of 15.3%. Disease relapse and acute GVHD independently predicted inferior OS, and acute GVHD predicted TRM. Conclusions: The FluTreo FT14 regimen achieves rapid engraftment, universal high donor chimerism, low severe toxicity, and durable survival, supporting its use as a myeloablative, reduced-toxicity conditioning option in myeloid malignancies. Full article

In this study, a comprehensive approach to the taxonomy and the distribution areas of Cornus mas (commonly known as cornelian cherry) is presented, considering the superior valorization of bioactive compounds through co-microencapsulation in a unique matrix combination, together with probiotic bacteria. According to the phytochemical profile, the whole plant of cornelian cherry includes 101 chemical compounds, classified as follows: polyphenols, terpenoids, carotenoids, vitamins, carbohydrates, acids, and hydrocarbons. In general, the bioactive compounds are highly sensitive to digestion and external factors, such as oxygen, pH, temperature, etc. In order to improve the bioaccesibility and the storage stability of the polyphenols, a solid–liquid ultrasound assisted method was applied to deliver an anthocyanin-enriched extract, which was microencapsulated together with Lacticaseibacillus casei (L. casei) by freeze-drying in a unique combination of whey protein isolate (WPI) and maltodextrin (MD) as wall materials. Two powders were obtained, with and without the probiotic bacteria. The data obtained in this study showed a high encapsulation efficiency (82.16–88.95%) of anthocyanins, whereas for L. casei, the microencapsulation efficiency reached 80%. The co-microencapsulated powder showed a viable cell count of 3.80·10⁹ CFU/g dry matter (D.M.). The microencapsulated powders showed a significant amount of total polyphenols (8.30–13.00 mg of gallic acid equivalent per gram D.M.). Furthermore, the in vitro digestibility of the anthocyanins highlighted the protective effect of the microencapsulation matrix in the stomach, whereas a slow release was observed in the simulated intestinal conditions. Furthermore, after 21 days of storage, the lactic acid bacteria viability was high (2.53 × 10⁹ CFU/g dry matter), which confirmed the functionality and the nutraceutical value of the co-microencapsulated powder. Full article

Human immunodeficiency virus (HIV-1) and SARS-CoV-2 continue to co-burden global health, motivating discovery of broad-spectrum small molecules. Conessine, a steroidal alkaloid, has reported membrane-active and antimicrobial properties but remains underexplored as a dual antiviral chemotype. To interrogate conessine’s multi-target antiviral potential against key enzymatic and entry determinants of HIV-1 and SARS-CoV-2 and to benchmark performance versus approved comparators. Eight targets were modeled: HIV-1 reverse transcriptase (RT, 3V81), protease (PR, 1HVR), integrase (IN, 3LPT), gp120–gp41 trimer (4NCO); and SARS-CoV-2 main protease (M^pro, 6LU7), papain-like protease (PL^pro, 6W9C), RNA-dependent RNA polymerase (RdRp, 7BV2), spike RBD (6M0J). Ligands (conessine; positive controls: dolutegravir for HIV-1, nirmatrelvir for SARS-CoV-2) were prepared with standard protonation, minimized, and docked using AutoDock Vina v 1.2.0exhaustiveness 4; 20 poses). Binding modes were profiled in 2D/3D. Protocol robustness was verified by re-docking co-crystallized ligands (RMSD ≤ 2.0 Å). Atomistic MD (explicit TIP3P, OPLS4, 300 K/1 atm, NPT; 50–100 ns) assessed pose stability (RMSD/RMSF), pocket compaction (Rg, volume), and interaction persistence; MM/GBSA provided qualitative energy decomposition. ADMET was predicted in silico. Conessine showed coherent, hydrophobically anchored binding across both viral panels. Best docking scores (kcal·mol⁻¹) were: HIV-1—PR −6.910, RT −6.672, IN −5.733; SARS-CoV-2—spike RBD −7.025, M^pro −5.745, RdRp −5.737, PL^pro −5.024. Interaction maps were dominated by alkyl/π-alkyl packing to catalytic corridors (e.g., PR Ile50/Val82, RT Tyr181/Val106; M^pro His41/Met49; RBD L455/F486/Y489) with occasional carbon-/water-mediated H-bonds guiding orientation. MD sustained low ligand RMSD (typically ≤1.6–2.2 Å) and damped RMSF at catalytic loops, indicating pocket rigidification; MM/GBSA trends (≈ −30 to −40 kcal·mol⁻¹, dispersion-driven) supported persistent nonpolar stabilization. Benchmarks behaved as expected: dolutegravir bound strongly to IN (−6.070) and PR (−7.319) with stable MD; nirmatrelvir was specific for M^pro and displayed weaker, discontinuous engagement at PL^pro/RdRp/RBD under identical settings. ADMET suggested conessine has excellent permeability/BBB access (high logP), but liabilities include poor aqueous solubility, predicted hERG risk, and CYP2D6 substrate dependence.Conessine operates as a hydrophobic, multi-target wedge with the most favorable computed engagement at HIV-1 PR/RT and the SARS-CoV-2 spike RBD, while maintaining stable poses at M^pro and RdRp. The scaffold merits medicinal-chemistry optimization to improve solubility and de-risk cardiotoxicity/CYP interactions, followed by biochemical and cell-based validation against prioritized targets. Full article

Low-permeability reservoirs play a crucial role in global energy supply, yet their efficient development is hindered by complex seepage mechanisms and strong nonlinear flow behavior. This study systematically investigates the characteristics of oil–water relative permeability curves and the associated non-Darcy flow phenomena in low-permeability sandstone reservoirs. Through unsteady-state water flooding experiments on native cores with permeabilities ranging from 2.99 to 34.40 mD, we analyzed the influence of permeability on relative permeability curves and categorized the water-phase curves into concave-downward and linear types. A dynamic quasi-threshold pressure gradient model was established, incorporating the corrected permeability and water saturation. Furthermore, a novel relative permeability calculation model was derived by integrating the threshold pressure gradient into the non-Darcy flow framework. Validation against the traditional Johnson–Bossler–Naumann (JBN) method demonstrated that the proposed model more accurately captures the flow behavior in low-permeability media, showing lower oil-phase permeability and higher water-phase permeability. The findings provide a reliable theoretical basis for optimizing water flooding strategies and enhancing recovery in low-permeability reservoirs. Full article

Chronic pain is a serious health issue, often irrationally managed by conventional analgesics. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), also effective in neuropathic and musculoskeletal pain, but the molecular mechanism of its analgesic action is still unclear. Here, we examined whether Duloxetine exerts pleiotropic effects by directly targeting phosphorylated STAT3 (pSTAT3), a key regulator of neuroinflammation and pain sensitization. Molecular docking showed that Duloxetine binds with pSTAT3 with binding energy −5.83 kcal/mol. Ruxolitinib, a JAK/STAT inhibitor used as reference, showed binding energy of −6.19 kcal/mol. Molecular dynamics (MD) simulations confirmed stable Duloxetine–pSTAT3 complexes, while MM-PBSA free energy analysis revealed more favorable binding for Duloxetine (ΔG = −15.17 kJ·mol⁻¹) than Ruxolitinib (ΔG = −12.98 kJ·mol⁻¹) for pSTAT3. In-vitro analyses, Western blot showed that Duloxetine significantly reduced IL-6–induced STAT3 and pSTAT3 expression in C2C12 cells in a dose-dependent manner (6.4 and 12.8 μM, *** p < 0.0001), although Ruxolitinib produced a stronger suppression. Transcriptomic analysis revealed Duloxetine-specific enrichment of mitochondrial, oxidative phosphorylation, and synaptic pathways, distinct from the immune-suppressive influence of Ruxolitinib. RNA-seq further revealed that STAT3 transcript abundance remains constant under all treatment conditions, indicating that post-transcriptional or post-translational mechanisms, such as phosphorylation-dependent activation, may be involved rather than transcriptional modulation of STAT3 in action of Ruxolitinib and Duloxetine and the formation of novel STAT3 indicating enhanced transcript diversity. The rMATS splicing analysis confirmed dose-dependent modulation, with Duloxetine promoting mild exon skipping at 6.4 μM (IncLevel 0.90 → 0.80) and recovery at 12.8 μM (0.85 → 0.86), while Ruxolitinib induced stronger exon inclusion (0.85 → 1.00,0.94), with broader transcript suppression at 6.4 μM and 12.8 μM, respectively. These findings establish Duloxetine as a dual-action therapeutic that combines neurotransmitter reuptake inhibition with pSTAT3 suppression and isoform-level transcriptomic modulation. This pleiotropic mechanism provides a rationale for its durable analgesic effects and supports repurposing in STAT3-associated disorders. Full article

To address the limitation that single-index evaluation fails to fully reflect the development performance of reservoirs of different types and at various development stages, a multi-index comprehensive evaluation system featuring the workflow of “index screening–weight determination–model evaluation–strategy guidance” was established. Firstly, the grey correlation analysis method (with a correlation degree threshold set at 0.65) was employed to screen 12 key evaluation indicators, including reservoir physical properties (porosity, permeability) and development dynamics (recovery factor, water cut, well activation rate). Subsequently, the fuzzy analytic hierarchy process (FAHP, for subjective weighting, with the consistency ratio (CR) of expert judgments < 0.1) was coupled with the attribute measurement method (for objective weighting, with information entropy redundancy < 5%) to determine the indicator weights, thereby balancing the influences of subjective experience and objective data. Finally, two evaluation models, namely the fuzzy comprehensive decision-making method and the unascertained measurement method, were constructed to conduct evaluations on 308 reservoirs in the Liaohe Oilfield (covering five major categories: integral medium–high-permeability reservoirs, complex fault-block reservoirs, low-permeability reservoirs, special lithology reservoirs, and thermal recovery heavy oil reservoirs). The results indicate that there are 147 high-efficiency reservoirs categorized as Class I and Class II in total. Although these reservoirs account for 47.7% of the total number, they control 71% of the geological reserves (154,548 × 10⁴ t) and 78% of the annual oil production (738.2 × 10⁴ t) in the oilfield, with an average well activation rate of 65.4% and an average recovery factor of 28.9. Significant quantitative differences are observed in the development characteristics of different reservoir types: Integral medium–high-permeability reservoirs achieve an average recovery factor of 37.6% and an average well activation rate of 74.1% by virtue of their excellent physical properties (permeability mostly > 100 mD), with Block Jin 16 (recovery factor: 56.9%, well activation rate: 86.1%) serving as a typical example. Complex fault-block reservoirs exhibit optimal performance at the stage of “recovery degree > 70%, water cut ≥ 90%”, where 65.6% of the blocks are classified as Class I, and the recovery factor of blocks with a “good” rating (42.3%) is 1.8 times that of blocks with a “poor” rating (23.5%). For low-permeability reservoirs, blocks with a rating below medium grade account for 68% of the geological reserves (8403.2 × 10⁴ t), with an average well activation rate of 64.9%. Specifically, Block Le 208 (permeability < 10 mD) has an annual oil production of only 0.83 × 10⁴ t. Special lithology reservoirs show polarized development performance, as Block Shugu 1 (recovery factor: 32.0%) and Biantai Buried Hill (recovery factor: 20.4%) exhibit significantly different development effects due to variations in fracture–vug development. Among thermal recovery heavy oil reservoirs, ultra-heavy oil reservoirs (e.g., Block Du 84 Guantao, with a recovery factor of 63.1% and a well activation rate of 92%) are developed efficiently via steam flooding, while extra-heavy oil reservoirs (e.g., Block Leng 42, with a recovery factor of 19.6% and a well activation rate of 30%) are constrained by reservoir heterogeneity. This system refines the quantitative classification boundaries for four development levels of water-flooded reservoirs (e.g., for Class I reservoirs in the high water cut stage, the recovery factor is ≥35% and the water cut is ≥90%), as well as the evaluation criteria for different stages (steam huff and puff, steam flooding) of thermal recovery heavy oil reservoirs. It realizes the transition from traditional single-index qualitative evaluation to multi-index quantitative evaluation, and the consistency between the evaluation results and the on-site development adjustment plans reaches 88%, which provides a scientific basis for formulating development strategies for the Liaohe Oilfield and other similar oilfields. Full article

ERK5, a member of the MAP kinase family, has been implicated in several cancer types due to its role in regulating cell proliferation, survival, and migration. In this study, structure-based virtual screening was employed, followed by cell assays, and molecular dynamics simulations to identify novel ERK5 inhibitors. A commercially available library of 1.6 million compounds was subjected to a three-stage docking process (HTVS, SP, and XP), using the docking module in Schrodinger Maestro, yielding 40 candidates with superior docking scores compared to the co-crystallized ligand. These compounds were then tested for antiproliferative activity using an MTT assay in A549 and H292 lung cancer cell lines. Among the hits, STK038175, STK300222, and GR04 showed significant activity with IC₅₀ values of ranging from 10 to 25 µM. Western blot analysis revealed that STK300222 at 50 µM reduced the phosphorylation of ERK5 downstream targets similarly to a known inhibitor, while wound healing assays confirmed a dose-dependent decrease in cell migration. Molecular dynamics simulations of 200 ns further demonstrated that all three compounds form stable complexes with ERK5 that are comparable to the co-crystallized ligand in 5BYZ. The MD simulations also revealed strong electrostatic and solvation interactions observed for STK300222 and GR04 particularly. Furthermore, by calculating the MM-GB/SA scores from the MD trajectories, the binding affinities of the three hits, along with the co-crystallized ligand in 5BYZ, were re-scored. Although the co-crystallized ligand had the highest MM-GB/SA score at −38.96 Kcal mol⁻¹, STK300222 had a comparable score of −35.45 Kcal mol⁻¹. These results highlight STK300222 and GR04 as promising candidates for further optimization and in vivo validation as ERK5 inhibitors. Full article

Quantifying and removing urbanization-induced biases in existing precipitation datasets is critical for climate change detection, model assessment, and attribution studies in Northwest China (NWC). The precipitation observational stations of NWC were divided into rural (reference) stations and urban stations using the percentage of urban areas calculated from the land use/land cover (LULC) satellite data of the European Space Agency (ESA) Climate Change Initiative (CCI) Land Cover project. The annual extreme precipitation index series for urban stations (all stations) and rural stations from 1961 to 2022 were calculated based on the categorization of meteorological stations, and the urbanization effects and their contributions to precipitation index series were quantitatively evaluated through estimating trends in the difference series between all stations and the rural stations. The results showed that the urbanization effect varies among different regions and indices. The R10mm, R95pTOT, R99pTOT, and PRCPTOT indices in the sampled urban areas of NWC exhibited statistically significant negative urbanization effects, reaching −0.075 days decade⁻¹, −0.038 % decade⁻¹, −0.024 % decade⁻¹, and −0.035 % decade⁻¹, respectively. However, the R95pTOT, SDII, CDD, and CWD indices at the urban station of the largest city, Urumqi, have been significantly positively affected by urbanization, which is inconsistent with the sampled urban areas of NWC, where the urbanization effect reached 0.069 % decade⁻¹, 0.054 mm·d⁻¹ decade⁻¹, 2.319 days decade⁻¹, and 0.112 days decade⁻¹, respectively. Our analysis shows that the previously reported regional increase in total precipitation and extremes has been underestimated due to the negative urbanization effects in the precipitation data series of urban stations. Full article