Search Results (3,630)

This study investigates the subsequent stages of recrystallisation in Interstitial-Free (IF) steel subjected to an unconventional continuous annealing process with a controlled thermal gradient. A cold-rolled steel strip was exposed to varying annealing temperatures along its length, enabling the analysis of microstructural evolution during the course of recrystallisation. The microstructure and stored energy were assessed at various positions along the strip using Electron Backscatter Diffraction (EBSD). The results underscore the significant influence of local misorientation and structural inhomogeneity on orientation selection during recrystallisation. The remaining non-recrystallised volume fraction (NRF) strongly correlates with the average misorientation gradient, obeying a phenomenological power-law correspondence with an exponent of ~3.7. This indicates that the recrystallisation process is highly sensitive to small changes in local orientation gradients. These findings highlight the crucial role of stored energy distribution for texture evolution, particularly during the early stages of recrystallisation in continuous annealing. It is observed that g-fiber grains, in comparison to a-fiber grains, are much more susceptible to grain fragmentation and therefore develop more robust intra-granular misorientation gradients, allowing for successful nucleation events to occur. In the present study, these phenomena are documented in a statistically representative manner. These insights are valuable for optimising thermal processing in interstitial-free (IF) steels. Full article

(1) Background: Idiopathic or familial nasal hyperkeratosis (NHK) may be considered a cosmetic issue in its uncomplicated form. Nevertheless, the prevention of secondary lesions could be advised by proper management. (2) Methods: In this multicentre, prospective, open-label pilot study, dogs with familial or idiopathic NHK received a topical emollient balm twice daily for 60 days. Evaluation of the global dermatological score (GDS; 0–12) on D0, D30, and D60 by owners and investigators was the main outcome. The score’s percentage decrease versus D0; the evolution of “dryness”, “lichenification”, “crusts”, and “affected area” (0–3); the correlation between observers and the evaluation of clinical improvement; and animal discomfort rated using a VAS (0–10) during follow-up were analysed. (3) Results: Twenty dogs completed the study. The mean GDS decreased significantly from Day 0 to Day 30 and Day 60 (p < 0.0001), with percentage reductions of 44.9% and 54.5% (investigators) and 54.3% and 62.3% (owners) on Day 30 and Day 60, respectively. Correlations between investigators and owners were significant for dryness, crusts (at Day 60), and the affected area, but not for lichenification. Animal discomfort scores decreased by more than 50% from Day 0. Owners reported high satisfaction with the product (mean score 8.1/10) and no adverse events occurred. (4) Conclusions: This open-label pilot study suggests that the tested balm is well tolerated and may improve clinical signs of NHK in dogs. Given the lack of a control group, small sample size, and absence of blinding, these results should be considered preliminary. Further randomized controlled trials and formal validation of the scoring system are warranted. Full article

Background: Major geopolitical events and structural shocks are thought to play a significant role in shaping HIV epidemics by influencing individual behaviours, reshaping social networks, and impacting HIV prevention and treatment programs. Here, we describe individual-level measures of estimated time since HIV infection (ETI) from viral next-generation sequencing data among female sex workers and their clients in relation to significant geopolitical events in Ukraine. Methods: The Dynamics Study is a cross-sectional integrated biological and behavioural survey conducted among female sex workers and their clients in Dnipro, Ukraine (December 2017 to March 2018). We were able to successfully sequence a portion of the HIV pol gene on dried blood spot specimens among n = 5/9 clients and n = 5/16 female sex workers who tested positive for HIV (total n = 10/25) using an in-house drug resistance genotyping assay. The “HIV EVO” Intrapatient HIV Evolution web-based tool was used to infer ETI from viral diversity. Results: The median ETIs for female sex workers and their clients were 5.4 years (IQR = 2.9, 6.6) and 6.5 years (IQR = 5.4, 10.8), respectively. Nearly all HIV acquisition events (n = 7/10; 70%) were estimated to have occurred between the Great Recession (2008–2009) and the War in Donbas (May 2014–February 2022). In general, ETI suggests that HIV acquisition occurred earlier among clients (2012 [IQR = 2007, 2013]) compared to sex workers (2013 [IQR = 2012, 2016]). Conclusion: Our findings suggest that most HIV acquisition in this small subset of female sex workers and clients living with HIV occurred during periods of economic decline. Molecular studies on timing of HIV acquisition against timing of major geopolitical events offer a novel way to contextualize how such events may shape transmission patterns. Full article

Background: Fetal growth restriction (FGR) is associated with increased perinatal morbidity and mortality, yet optimal intrapartum management remains debated. The contraction stress test (CST) has been proposed as a tool to assess fetal tolerance to labor, but its prognostic value in FGR pregnancies is unclear. This study aimed to evaluate the utility of CST in predicting perinatal outcomes among term fetuses with FGR and to compare these outcomes with those of small-for-gestational-age (SGA) fetuses. Methods: We conducted a retrospective cohort study of term singleton deliveries at a tertiary care center over a two-year period. FGR was defined as birthweight below the 3rd percentile or, prenatally, below the 10th percentile with abnormal Doppler findings. SGA fetuses were defined as birthweights between the 3rd and 10th percentiles. Participants were stratified into the following three groups: (1) FGR with a negative CST result, (2) FGR without CST, and (3) SGA without FGR. The primary outcome was the rate of emergency cesarean delivery. Secondary outcomes included a composite of neonatal adverse events (Apgar score < 7 at 5 min, umbilical cord pH < 7.1, NICU admission, prolonged neonatal hospitalization, intubation, or intraventricular hemorrhage) and a combined metric of neonatal and maternal adverse events. Results: A total of 1688 term singleton pregnancies were included in this analysis, comprising 33 cases of FGR with negative CST results, 275 cases of FGR without CST, and 1123 cases classified as SGA. Emergency cesarean delivery rates were comparable between FGR with negative CST (15.2%) and FGR without CST (14.9%), both were significantly higher than in the SGA group (9.7%, p = 0.025). Composite neonatal adverse events did not differ significantly between the FGR groups (21.2% vs. 24.7%) but were more frequent than in the SGA group (8.1%, p < 0.001). Similarly, the incidence of combined neonatal and maternal adverse events was not different between the FGR groups (30.3% vs. 33.5%) yet exceeded that of the SGA group (15.1%, p < 0.001). Conclusions: In this cohort, a negative CST performed prior to labor induction did not reduce the risk of adverse maternal or neonatal outcomes in pregnancies complicated by FGR. These findings indicate that routine use of CST may offer limited prognostic benefit in the evaluation of term FGR, highlighting the necessity for further studies to establish evidence-based surveillance and management strategies for this high-risk group. Full article

The relationship between concentration and discharge (C/Q) is widely studied to understand the behavior of solute transport in complex natural media during storm events. The causes of C/Q hysteresis are due to the delay between the signals of C and Q at a given observation point. Many indices are used to characterize the C/Q hysteresis curve, like the hysteresis index (HI) and the flushing index (FI). The limitation of relating C/Q hysteresis relationships or indices to storm event parameters is because, in real-world situations, we ignore and do not control storm event parameters. This paper is the first attempt to study the variability of C/Q relationships under a well-known storm event on a controlled experimental channel. We tested nine scenarios where the storm event consisted of a triangular input signal with a constant peak and a variable duration. The main parameter of this study is the storm event duration. We calculated known indices, like the hysteresis index (HI) and the flushing index (FI), and we introduced the following two new indices: the saturation index (SI) and the bisector index (BI). Then we related all calculated indices to the storm duration parameter. The importance of our study is that it presents, for the first time, a quantitative description of how the magnitude of the hysteresis indices varies with the storm duration parameter. We found that the most popular HI index does not follow a monotonic behavior for increasing storm duration. Conversely, the FI index and the two newly introduced indices (SI and BI) follow a monotonic behavior for increasing storm duration according to a Fermi-type function. The SI varies between 0.11 and 0.93, while the BI varies between 1 and 0.32 for an increasing storm event duration. Full article

The analysis of earthquake source mechanisms is key for seismotectonic studies, but it is often limited to traditional methods plagued with issues of precision and automation. This is particularly true in low-seismicity areas with deep and/or hidden seismogenic sources, where the identification of precise source mechanisms is a difficult and non-trivial task. In this study, we present a detailed application of TESLA (Tool for automatic Earthquake low-frequency Spectral Level estimAtion), a novel tool designed to overcome these limitations. We demonstrated TESLA’s effectiveness in defining source mechanism analysis by applying it to seismic sequences that occurred near Asti (AT), in the Monferrato area (Southern Piedmont, Italy). Our analysis reveals that the observed clusters consist of two distinct seismic sequences, occurring in 1991 and 2012, which were activated by the same seismogenic source. We relocated a total of 36 events with magnitudes ranging from 1.1 to 3.7, using a 3D velocity model, and computed 12 well-constrained focal mechanism solutions using the first motion polarities and the low-frequency spectral level ratios. The results highlight a relatively small seismogenic source located at approximately 5 km north of Asti (AT), at a depth of between 10 and 25 km, trending SW–NE with strike-slip kinematics. A smaller cluster of three events shows an activation of a different fault segment at around 60 km of depth, also showing strike-slip kinematics. These findings are in good agreement with the regional stress field acting in the Monferrato area and support the use of investigation tools such as TESLA for microseismicity analysis. Full article

Purpose: Extensive-stage small cell lung cancer (ES-SCLC) has poor prognosis. While immune checkpoint inhibitors (ICIs) with chemotherapy show survival benefits in trials, real-world data from Asia are scarce. This study evaluates real-world efficacy and safety of chemotherapy with or without ICIs in Taiwanese patients with ES-SCLC and identifies survival predictors. Materials and Methods: A retrospective cohort study analyzed 114 patients with ES-SCLC treated between 2017 and 2023 at four Taiwanese medical centers. Patients received first-line chemotherapy alone (n = 68) or with ICIs (atezolizumab, durvalumab, pembrolizumab; n = 46). Primary endpoints were overall survival (OS) and progression-free survival (PFS), assessed via Kaplan–Meier methods and Cox regression. Results: Baseline characteristics were comparable, except poorer ECOG performance (≥2) in the chemotherapy group (27% vs. 9%; p = 0.021). IO–chemotherapy significantly improved OS (16.1 vs. 9.4 months; HR = 0.32, 95% CI: 0.20–0.52; p < 0.001) and PFS (7.8 vs. 5.5 months; HR = 0.40, 95% CI: 0.26–0.63; p < 0.001). Multivariate analysis confirmed IO–chemotherapy as an independent positive predictor (OS adjusted HR = 0.25, 95% CI: 0.14–0.44; PFS adjusted HR = 0.37, 95% CI: 0.22–0.61; both p < 0.001). Skin rash was more common with IO–chemotherapy (24% vs. 3%; p < 0.001). Immune-related adverse events (AEs) correlated with improved survival (median OS: 21.4 months with 1–2 AEs, 16.6 months with 3–4 AEs, 12.5 months without AEs). Conclusion: Immunochemotherapy significantly improves survival in Taiwanese patients with ES-SCLC, with manageable toxicity, supporting ICIs’ incorporation into standard treatment. Full article

Proteolysis-targeting chimera (PROTAC) technology has demonstrated remarkable progress in tumor therapy, attributed to its unique capability of catalytically degrading “undruggable” targets. In the context of the ongoing global health threat posed by the Coronavirus Disease 2019 (COVID-19) pandemic, the application scope of PROTAC technology has been gradually extended to the field of antiviral research. Unlike traditional small molecule inhibitors, PROTAC employs an “event-driven” mechanism to achieve ubiquitination-mediated degradation of target proteins. This approach holds great promise in addressing challenges such as drug resistance, targeting host-dependent factors, and high-mutagenic viral proteins. This article provides a comprehensive review of the application progress of PROTAC technology in antiviral therapy, with a particular emphasis on successful cases across a range of viral pathogens, including Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), influenza virus, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Additionally, it delves into the challenges encountered in this field and ponders future development directions. Through the integration of the latest research findings, this article proposes a dual-target degradation strategy based on the host–pathogen interaction interface. These proposals aim to offer theoretical support for the clinical translation of antiviral PROTACs. Full article

Prime editing (PE), a novel “search-and-replace” genome editing technology, demonstrates significant potential for crop genetic improvement due to its precision and versatility. However, since its initial application in plants, PE technology has consistently faced challenges of low and variable editing efficiency, representing a major bottleneck hindering its broader application. Therefore, this study conducted a systematic review following the PRISMA 2020 guidelines. We systematically searched databases—Web of Science, PubMed, and Google Scholar—for studies published up to June 2025 focusing on enhancing PE performance in crops. After a rigorous screening process, 38 eligible primary research articles were ultimately included for comprehensive analysis. Our analysis revealed that early PE systems such as PE2 could perform diverse edits, including all 12 base substitutions and small insertions or deletions (indels), but their efficiency was highly variable across species, targets, and edit types. To overcome this bottleneck, researchers developed four major optimization strategies: (1) engineering core components such as Cas9, reverse transcriptase (RT), and editor architecture; (2) enhancing expression and delivery via optimized promoters and vectors; (3) improving reaction processes by modulating DNA repair pathways or external conditions; and (4) enriching edited events through selectable or visual markers. These advancements broadened PE’s targeting scope with novel Cas9 variants and enabled complex, kilobase-scale DNA insertions and rearrangements. The application of PE technology in plants has evolved from basic functional validation, through systematic optimization for enhanced efficiency, to advanced stages of functional expansion. This review charts this trajectory and clarifies the key strategies driving these advancements. We posit that future breakthroughs will increasingly depend on synergistically integrating these strategies to enable the efficient, precise, and predictable application of PE technology across diverse crops and complex breeding objectives. This study provides an important theoretical framework and practical guidance for subsequent research and application in this field. Full article

Background/Objectives: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have achieved clinical success but face drawbacks such as poor oral bioavailability, limited tumor penetration, and immune-related adverse events. Small-molecule inhibitors present a promising alternative that may overcome these challenges. Methods: Here, an integrated computational framework combining ligand-based pharmacophore modeling and structure-based molecular docking was utilized to screen a comprehensive library consisting of traditional Chinese medicine-derived compounds and clinically approved drugs. The binding affinity between identified candidate compounds and PD-L1 was quantitatively assessed using bio-layer interferometry (BLI). In vitro cytotoxicity assays were conducted on A549 human lung carcinoma and LLC mouse lung carcinoma cell lines. In vivo antitumor efficacy was evaluated in LLC tumor-bearing mice through measurement of tumor growth inhibition, serum cytokine levels (IFN-γ and IL-4) by ELISA, and expression levels of IFN-γ and granzyme B (GZMB) within tumor tissues via immunohistochemistry. Results: In vitro, anidulafungin exhibited anti-tumor effects against both human lung cancer A549 cells and mouse Lewis lung carcinoma (LLC) tumor cells, with IC₅₀ values of 170.6 µg/mL and 160.9 µg/mL, respectively. The BLI analysis revealed a dissociation constant (K_D) of 76.9 μM, indicating a high affinity of anidulafungin for PD-L1. In vivo, anidulafungin significantly increased serum levels of IFN-γ and IL-4 in tumor-bearing mice and elevated expression of IFN-γ and granzyme B (GZMB) in tumor tissues, confirming its immune-mediated anti-tumor effects. Conclusions: Anidulafungin represents a promising small-molecule PD-L1 inhibitor, demonstrating significant anti-tumor potential via immune activation and highlighting the feasibility of repurposing approved drugs for cancer immunotherapy. Full article

The Sultanate of Oman boasts remarkable biodiversity, exemplified by such species as the Arabian leopard (Panthera pardus nimr) and the Arabian oryx (Oryx leucoryx), national symbols that highlight the extensive conservation efforts required to protect the country’s natural heritage. During decades, Omani authorities have taken significant measures to safeguard wildlife and preserve the natural environment. A sanctuary dedicated to the reintroduction of the Arabian Oryx, after extinction in nature in 1972, was established in 1980 in the Al Wusta Governorate under the patronage of the Royal Diwan and currently administrated by the recently established Environment Authority. During the almost 40 years since the reintroduction and the creation of the sanctuary, the oryx population has grown slowly but constantly. In 2021, the sanctuary hosted 738 oryx, allowing the start of the reintroduction of the species into the natural environment. Small groups of animals were released into the wild in selected areas. No animal health adverse events were recorded, and mortality was generally due to injuries received as a consequence of fighting, in particular during mating season. Standard veterinary care, including control of internal and external parasites, was regularly provided. In some occasions, immunization against certain diseases, such as clostridial infections, pasteurellosis, or mycoplasmosis, was also applied. In 2023, an FMD outbreak in cattle reported in Dhofar, about 500 km from the Al Wusta sanctuary, motivated specific prophylactic actions to prevent the risk of diffusion to oryx. From December 2023 to January 2024, an immunization program was undertaken using an FMD vaccine against serotypes A, O, and SAT 1, mostly in male oryx, while pregnant oryx were avoided for abortion risk due to handling. The following year, in January 2025, a severe outbreak occurred in oryx herds held in the sanctuary. The rapid onset and the spread of clinical symptoms among animals (100% morbidity in the second day after the first appearance of signs in some individuals) were suggestive of a highly contagious disease. The animals suffered from severe depression and inappetence, rapidly followed by abundant salivation, erosions of the oral mucosa and tongue, and diarrhea, with a short course characterized by prostration and death of the animal in the most severe cases. Therapeutical attempts (administration of antibiotics and rehydration) were mostly ineffective. Laboratory investigations (ELISA and PCR) ruled out contagious bovine pleuropneumonia (CBPP), Johne’s disease and Peste des petits ruminants (PPR). Both serology and antigen detection showed positiveness to foot-and-mouth disease (FMD). Out of a total population of 669 present in the sanctuary at the beginning of the outbreak, 226 (33.78%) oryx died. Despite the vaccinal status, the 38.49% of dead animals resulted being vaccinated against FMD. Taking into account the incalculable value of the species, the outbreak represented a very dangerous event that risked wiping out the decades of conservation efforts. Therefore, all the available means, such as accrued biosecurity and adequate prophylaxis, should be implemented to prevent the recurrence of such health risks. The delicate equilibrium of wild fauna in Oman requires study and support for an effective protection, in line with the national plan “Vision 2040”, targeting the inclusion of the Sultanate within the 20 best virtuous countries for wildlife protection. Full article

Wildfires are becoming more frequent and widespread, posing a threat to European ecosystems. Recent findings quantified a large fraction of Europe’s burnt areas within Natura 2000 protected area sites. This study analyzed total wildfire events and burnt areas in Greece. The frequency of protected area burn percentages per fire event and their trend over time were quantified. The mean protected area percentage of burn per fire event across other Mediterranean countries was compared. Results indicated an increase in the total number of wildfire events over time, while total burnt area was highest in recent years but generally varied. Forest-type vegetation burn exhibits no trend over time with the exception being that the transitional vegetation percentage of burn per wildfire is increasing, while agricultural land is decreasing. The protected area percentage of burn per wildfire is not related with total area burn. The majority of the high percentage protected area burns derive mainly from small or medium total area burn wildfires. More than a third of wildfires burned exclusively (100%) Natura protected area surfaces. Protected area percent per burn is increasing over time. This increase is not related to the increased total burnt area. Protected area percent per burn is considerably higher in Greece in comparison to Italy, Spain, and Portugal. Protected area percent per burn is increasing over time in Greece and with a slower slope in Portugal, while it has no monotonic trend in Italy and Spain. Reserves face increasing burn frequency, necessitating effective management strategies to conserve them. Climate change exacerbates total wildfires or surface area burned but cannot entirely explain the steep increase in protected area percent per burn. While a legislative framework preventing arson exists, management measures need to further improve the efficacy and clarity of legislation. High-power electricity networks and wind and solar energy facilities are often causes of wildfires and should receive low priority or not be licensed in Natura areas. Full article

Powerful jetted radio sources for which the luminosity in directed kinetic energy has been empirically determined, independent of assumptions, are considered. The total outflow lifetime of each source determined in the context of detailed cosmological studies was found to depend only upon the luminosity in directed kinetic energy (L). The distributions of L, total outflow lifetime, and total outflow energy each have a broad range of values, as do the supermassive black hole masses. The total outflow energy relative to the black hole mass is a small number with a small dispersion. Three explanations of these remarkable results are considered. This could indicate (1) the efficiencies with which black hole irreducible mass is increased and spin mass energy is extracted during the outflow event, (2) that the merger of two supermassive black holes occurs over a timescale commensurate with the independently determined outflow lifetime and that these mergers lead to the production of the low-frequency gravitational wave background, or (3) that feedback shuts off black hole accretion due to energy injected into the ambient medium. Full article

Background/Objectives: Advances in understanding immune checkpoint pathways and tumor immune biology have enabled the development of immune checkpoint inhibitors (ICIs), particularly targeting the PD-1/PD-L1 axis, which has transformed cancer immunotherapy. While they have shown remarkable success in various cancer types, including melanoma, non-small cell lung cancer, and gastrointestinal malignancies, variability in patient response, immune-related adverse events (irAEs), and resistance mechanisms remain significant. This review aims to evaluate clinical pharmacology, mechanisms of action, resistance pathways, and pharmacogenomic influences shaping interindividual responses to ICIs. Methods: This comprehensive review synthesizes current literature on FDA-approved ICIs, exploring their clinical use, underlying biological mechanisms, and emerging pharmacogenomic data. It also assesses key biomarkers such as tumor mutational burden (TMB), microsatellite instability (MSI), HLA diversity, and epigenetic factors influencing ICI efficacy and safety. Results: We outline key mechanisms contributing to ICI resistance, including T cell dysfunction, altered antigen presentation, and immunosuppressive tumor microenvironment components. Furthermore, we highlight promising pharmacogenomic findings, including single-nucleotide polymorphisms (SNPs) in PD-1/PD-L1 and immune-regulatory genes, offering predictive and prognostic utility. Variability in PD-L1 expression and the role of epigenetic modifications are also addressed as challenges in treatment optimization. Conclusions: Interindividual variability in ICI response underscores the need for biomarker-driven strategies. By integrating pharmacogenomic insights with clinical pharmacology, future approaches may support more personalized and effective use of ICIs. Combination therapies and novel modalities hold promise for overcoming resistance, enhancing therapeutic efficacy, and enabling precision oncology. Full article

Extremely persistent flash heavy rainfalls (EPHRs) over the Sichuan Basin in China are influenced by both multiscale weather systems and complex underlying surfaces, making it difficult to understand the favorable dynamic mechanisms and to further improve operational numerical forecasting skills. In this study, EPHRs from 2010 to 2024 are objectively identified and then classified into three categories based on the SOM method. Precipitating characteristics for each category are further investigated from the perspective of the diurnal cycle and spatial features with the use of rain-gauge-based observations. Evaluations of the ERA5 reanalysis dataset, MSWX bias-corrected meteorological product, and CMORPH satellite-based precipitation product are performed to determine their capabilities in representing precipitating characteristics of different EPHR categories at different stages. The following results are obtained. During EPHR events, CMORPH outperforms MSWX and ERA5 in capturing heavy precipitation distribution, diurnal cycles, and evolution over the central basin. Both MSWX and ERA5 miss the central precipitation core, with MSWX showing premature peaks and ERA5 generating secondary evening peaks while overestimating precipitation duration. During events influenced by small-scale weather systems, all three products exhibit minimal false alarms but show the largest errors in intensity and diurnal variation. Under certain circulation types, MSWX and ERA5 significantly underestimate precipitation development with comparable metrics, while CMORPH achieves superior accuracy in precipitation intensity and correlations, yet it underestimates nighttime precipitation occurrences in steep western terrain. This study may help to facilitate not only theoretical studies but also numerical model developments for precipitation extremes. Full article