Search Results (1,193)

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL. Full article

Acoustic analysis of voice enables objective assessment of voice to diagnose changes in voice characteristics, and track the progress of therapy. In contrast to subjective assessment, objective measurements provide mathematical results referring to specific parameters and can be analyzed statistically. Changes in the voice of patients with partial deafness (PD) were not widely described in the literature, and recent studies referred to the voice parameters measured in this group of patients only using the multi-dimensional voice program (MDVP) by Kay Pentax. This paper describes the results of acoustic analysis of voice in patients with PD using VOXplot, and compares the results with those achieved with MDVP. Background/Objectives: The purpose of this study was a VOXplot objective analysis of voice in individuals with PD and to assess consistency with results obtained using MDVP and with perceptual assessment. Methods: Voice samples from 22 post-lingual PD individuals were recorded. They included continuous speech (cs) and sustained vowels (sv). The control group consisted of 22 healthy individuals with no history of voice or hearing dysfunction. The samples were analyzed with MDVP followed by VOXplot version 2.0.0 Beta. Statistical analysis was performed using a t-test paired with two samples for means. All individuals were also subjected to a perceptual voice assessment using the GRBAS by Hirano. Results: Differences were observed in 13 VOXplot parameters measured in voice samples of adults with PD compared with those in the control group. Both multiparametric indices, AVQI and ABI, showed a statistical increase. When it comes to MDVP parameters correlating with breathiness, all of them (shim dB, APQ, NHR, SPI, and NSH) increased in patients with partial deafness, reflecting a breathy voice. Only one increase in the SPI was not statistically significant. Seven MDVP parameters correlating with hoarseness were elevated, and five (Jitt%, vF0, Shim dB, APQ, and NHR) showed a statistically significant increase. Correlations were found of VOXplot and MDVP parameters with perceptual voice assessment. Conclusions: Both programs for objective assessment showed voice abnormalities in patients with PD compared with the control groups. There was a poor to moderate level of consistency in the results achieved using both systems. Correlations were also found with GRBAS assessment results. Full article

Drought consequences depend on its type and class and on the preparedness and resistance of communities, which, in turn, depends on the knowledge and capacity to manage this climate disturbance. Therefore, this study aims to assess the drought regime in Southern Africa based on vegetation and meteorological indices. The SPI and SPEI were calculated at different timescales, using ERA5 data for the 1971–2020 period. The results revealed the following: (i) droughts of various classes at different timescales occurred throughout the study period and region; (ii) a greater Sum of Drought Intensity and Number, in all classes, but lower duration and severity of droughts with the SPI than with the SPEI; (iii) drought frequency varies from 1.3 droughts/decade to 4.5 droughts/decade, for the SPI at 12- to 3-month timescales; (iv) the number, duration, severity and intensity of drought present high spatial variability, which tends to decrease with the increasing timescale; (v) the area affected by drought increased, on average, 6.6%/decade with the SPI and 9.1%/decade with the SPEI; and (vi) a high spatial-temporal agreement between drought and vegetation indices that confirm the dryness of vegetation during drought. These results aim to support policymakers and managers in defining legislation and strategies to manage drought and water resources. Full article

This study selected three approved folate sources—folic acid (FA), L-5-methyltetrahydrofolate (MTFA), and calcium 5-methyltetrahydrofolate (CMTFA)—to explore their interaction mechanisms with soy protein isolate (SPI) through spectrofluorometric analysis and molecular docking simulations. We investigated how these interactions influence the structural and physicochemical stability of folates and SPI. Three folates spontaneously bound to SPI, forming complexes, resulting in a decrease of approximately 30 kJ·mol⁻¹ in Gibbs free energy and an association constant (K_a) of 10⁵ L·mol⁻¹. The thermodynamic parameters and molecular docking study revealed the unique binding mechanisms of FA and MTFA with SPI. FA’s planar pteridine ring and conjugated double bonds facilitate hydrophobic interactions, whereas MTFA’s reduced ring structure and additional polar groups strengthen hydrogen bonding. Although the formation of SPI–folate complexes did not result in substantial alterations to the SPI structure, their binding has the potential to enhance both the physical and thermal stability of the protein by stabilizing its conformation. Notably, compared with free FA, the FA-SPI complexes significantly enhanced FA’s stability, exhibiting 71.1 ± 1.2% stability under light conditions after 9 days and 63.2 ± 2.6% stability in the dark after 60 days. In contrast, no similar effect was observed for MTFA. This discrepancy can be ascribed to the distinct degradation pathways of the Fa and MTFA molecules. This study offers both theoretical and experimental insights into the development of folate-loaded delivery systems utilizing SPI as a matrix. Full article

Diagnostics often require specialized equipment and trained personnel in laboratory settings, creating a growing need for point-of-care tests (POCTs). Among the genetic testing methods available, Loop-mediated Isothermal Amplification (LAMP) offers a viable solution for developing genetic POCT due to its compatibility with simplified devices. This study aimed to create a genetic test that integrates all steps from sample processing to analyzing results while minimizing the complexity, handling, equipment, and time required. Several challenges were addressed to achieve this goal: (1) the development of a buffer for bacterial DNA extraction that is compatible with both LAMP and immunochromatographic tests; (2) the adaption of the LAMP protocol for use with the SPID device; and (3) the optimization of the detection protocol for specific test conditions, with a lateral flow immunoassay format selected for its POCT compatibility. Following these developments, the test was validated using Escherichia coli (E. coli) and non-E. coli strains. A portable heating station was also developed to enable amplification without costly equipment. The resulting genetic POCT achieved 100% sensitivity and 85% specificity, with results available in 60 to 75 min. This study demonstrated that our POCT efficiently performs DNA extraction, amplification, and detection for bacterial identification. The test’s simplicity and cost-effectiveness will support its implementation in various settings. Full article

Food poisoning outbreaks frequently involve staphylococcal enterotoxins (SEs). SEs include 33 distinct types and multiple sequence variants per SE type. Various mass spectrometry methods have been reported for the detection of SEs using a conventional bottom-up approach. However, the bottom-up approach cannot differentiate between all sequence variants due to partial sequence coverage, and it requires a long trypsin digestion time. While the alternative top-down approach can theoretically identify any sequence modifications, it generally provides lower sensitivity. In this study, we optimized top-down mass spectrometry conditions and incorporated a fully ¹⁵N-labeled SEA spiked early in the protocol to achieve sensitivity and repeatability comparable to bottom-up approaches. After robust immunoaffinity purification of the SEA, mass spectrometry signals were acquired on a Q-Orbitrap instrument operated in full-scan mode and targeted acquisition by parallel reaction monitoring (PRM), enabling the identification of sequence variants and precise quantification of SEA. The protocol was evaluated in liquid and solid dairy products and demonstrated detection limits of 0.5 ng/mL or ng/g in PRM and 1 ng/mL or ng/g in full-scan mode for milk and Roquefort cheese. The top-down method was successfully applied to various dairy products, allowing discrimination of contaminated versus non-contaminated food, quantification of SEA level and identification of the variant involved. Full article

The aim of this work is to investigate drought variability in Padua, northern Italy, over a nearly 300-year period, from 1725 to 2023. Two well-established and widely used indices are calculated, the standardized precipitation index (SPI) and the standardized precipitation evapotranspiration index (SPEI). They are compatible with a data series starting in the early instrumental period, as both can be estimated using only temperature and precipitation data. The Padua daily precipitation and temperature series from the early 18th century, which were recovered and homogenized with current observations, are used as datasets. The standard approach to estimate SPI and SPEI based on gamma and log-logistic probability distribution functions, respectively, is questioned, assessing the fitting performance of different distributions applied to monthly precipitation data. The best-performing distributions are identified for each index and accumulation period at annual and monthly scales, and their normality is evaluated. In general, they detect more extreme drought events than the standard functions. Moreover, the main statistical values of SPI are very similar, regardless of the approach type, as opposed to SPEI. The difference between SPI and SPEI time series calculated with the best-fit approach has increased since the mid-20th century, in particular in spring and summer, and can be related to ongoing global warming, which SPEI takes into account. The innovative trend analysis applied to SPEI12 indicates a general increasing trend in droughts, while for SPI12, it is significant only for severe events. Summer and fall are the most affected seasons. The critical drought intensity–duration–frequency curves provide an easily understandable relationship between the intensity, duration and frequency of the most severe droughts and allow for the calculation of return periods for the critical events of a certain duration. Moreover, the longest and most severe droughts over the 1725–2023 period are identified. Full article

In the current work, the non-invasive approach of breath analysis is implemented for the first time in an eccentric exercise protocol that investigated the effect of spirulina supplementation on exercise-induced oxidative stress. We assessed whether volatile alkanes in exhaled breath can serve as alternative biomarkers of oxidative stress. A randomized, double-blinded, placebo-controlled, crossover supplementation study was carried out enrolling 14 participants. The volunteers consumed 42 mg·kg⁻¹ body weight of either Spirulina Nigrita^® or maltodextrin, as a placebo, daily for 15 days. Afterward, they followed a damaging eccentric exercise protocol of the upper limbs. Expired breath samples were collected from them just before supplementation (baseline measurement), prior to exercise, and 1 h, 24 h, 48 h, and 72 h after exercise. The samples were analyzed by Gas Chromatography/Mass Spectrometry (GC-MS) coupled with a thermal desorption unit (TDU) to determine the alveolar gradient (AG) of several alkanes, C5–C14, that are known to be related to oxidative stress. Apart from breath analysis, TBARSs were also determined as a crude marker of lipid peroxidation. Two-way repeated measures ANOVA tests were applied to the alkanes’ AGs between the spirulina (SPI) and placebo (PL) groups across time. In the PL group, a trend of increasing almost all alkanes immediately after exercise, with a gradual return to pre-exercise levels up to 72 h later was revealed. A statistically significant time effect was observed for 2-methylhexane, 3-methylhexane, heptane, octane, and undecane. The administration of spirulina appeared to reduce the increases in alkanes after exercise, and a statistically significant attenuation was observed for 2-methylpentane and 2-methylhexane. An examination of TBARSs confirmed that the reduced increases observed in the SPI group were due to changes in lipid peroxidation, while a positive correlation between the iAUC of TBARSs and that of 2-methylhexane and 3-methylhexane was revealed. In conclusion, the analysis of volatile alkanes in exhaled breath may serve as an attractive alternative for assessing redox changes after eccentric exercise compared to traditional blood biomarkers. Full article

Droughts are caused either by a deficiency in precipitation compared to normal levels or by excessive evapotranspiration exceeding long-term averages. Therefore, assessing future drought prevalence based on projected climatic variables is essential for effective drought preparedness. In this study, an ensemble of three Regional Climate Models (REMO2009, RCA4, and CCLM4-8-17) was used for Representative Concentration Pathways (RCP 4.5 and RCP 8.5), covering two future time periods (2025–2069 and 2070–2100). The quantile distribution mapping technique was employed to bias-correct the RCMs. The ensemble of RCMs projected an increase in rainfall, ranging from 40% to 85% under both RCP 8.5 and RCP 4.5. Both RCPs indicated an increase in daily average temperatures. RCP 4.5 projects an increase in average daily temperature by 1% between 2025 and 2069 and 6.5% between 2070 and 2100, while under RCP 8.5, temperatures are expected to rise by 3.7% between 2025 and 2069 and 12.7% between 2070 and 2100. The Standard Precipitation Index (SPI) was used to translate these projected climatic anomalies into future drought prevalence. The results suggest that RCP 4.5 forecasts an 8% increase in drought prevalence, while RCP 8.5 projects an 11% increase in drought frequency, with a greater rise in moderate and severe droughts and a decrease in extreme drought occurrences. Full article

Background: Hepatocellular carcinoma (HCC) is a type of malignant tumor with high morbidity and mortality. Untimely treatment and high recurrence are currently the major challenges for HCC. The identification of potential targets of HCC progression is crucial for the development of new therapeutic strategies. Methods: Bioinformatics analyses have been employed to discover genes that are differentially expressed in clinical cases of HCC. A variety of pharmacological methods, such as MTT, colony formation, EdU, Western blotting, Q-PCR, wound healing, Transwell, cytoskeleton F-actin filaments, immunohistochemistry (IHC), hematoxylin–eosin (HE) staining, and dual-luciferase reporter assay analyses, were utilized to study the pharmacological effects and potential mechanisms of ribonucleotide reductase regulatory subunit M2 (RRM2) in HCC. Results: RRM2 expression is significantly elevated in HCC, which is well correlated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that RRM2 promoted HCC cell growth and metastasis. Mechanistically, RRM2 modulates the EMT phenotype of HCC, and further studies have shown that RRM2 facilitates the activation of the TGF-β/Smad signaling pathway. SB431542, an inhibitor of TGF-β signaling, significantly inhibited RRM2-induced cell migration. Furthermore, RRM2 expression was correlated with diminished survival in HBV-associated HCC patients. RRM2 knockdown decreased the levels of HBV RNA, pgRNA, cccDNA, and HBV DNA in HepG2.2.15 cells exhibiting sustained HBV infection, while RRM2 knockdown inhibited the activity of the HBV Cp, Xp, and SpI promoters. Conclusion: RRM2 is involved in the progression of HCC by activating the TGF-β/Smad signaling pathway. RRM2 increases HBV transcription in HBV-expressing HCC cells. Targeting RRM2 may be of potential value in the treatment of HCC. Full article

The sensitivity of the agricultural production system to short- and long-term climate variations significantly affects the availability and prices of food resources, raising relevant issues of sustainability and food security. Globally, productive systems have adapted to climate change, leading to increased yields over the past century. However, the extent to which these adaptations mitigate the impacts of short-term climate fluctuations, both extreme and ordinary, remains poorly studied. To evaluate the vulnerability of crop yield to short-term climate fluctuations and to determine whether it changes over time, we conducted a statistical analysis focusing on one of the main crops in the Abruzzo region (central Italy) as a case study: grape. The study involves correlation analysis between opportune climatic indices (SPI and SPEI) and grape yield data over the sixty-year period from 1952 to 2014, aimed at evaluating the impact of short-term climatic fluctuations—both extreme and ordinary—on crop yield. Our findings reveal an increasing correlation, mainly in the summer–autumn season, which suggests a rising sensitivity of the productive system over time. The observed increase is indicative of the Abruzzo grape production system’s adaptation to climate change, resulting in higher overall yields but not enhancing the response to short-term climatic fluctuations. Full article

Most wood-based panels were currently prepared using aldehyde-based adhesives, making the development of natural, renewable, and eco-friendly biomass-based adhesives a prominent area of research. Herein, the phenolic resin was modified using a soybean protein isolate (SPI) treated with a NaOH/urea solution through a copolymerization method. The physicochemical properties, chemical structure, bonding properties, and thermal properties of the soybean protein-modified phenolic resin (SPF-U) were analyzed using Fourier transform infrared spectroscopy, thermogravimetric analysis, and formaldehyde emission tests. The results indicated that the molecular structure of the soy protein isolate degraded after NaOH/urea solution treatment, while the gel time was gradually shortened with increasing NaOH/urea solution-treated soy protein isolate (SPI-U) dosages. Although the thermal stability of the soy protein isolate was lower than that of the phenolic resin, the 20% SPF-U resin demonstrated better thermal stability than other modified resins. The PF modified with 30% SPI-U (SPF-U-3) exhibited the lowest curing peak temperature of 139.69 °C than that of the control PF resin. In addition, all modified PF resins exhibited formaldehyde emissions ranging from 0.18 to 0.38 mg/L when the SPI-U dosage varied between 20% and 50%, thereby meeting the E0 plywood grade standard (≤0.5 mg/L). Full article

Drought propagation is a complex process, and understanding the propagation mechanisms of meteorological drought to soil drought is crucial for early warning, disaster prevention, and mitigation. This study focuses on eight tributaries in the upper reaches of the Shiyang River. Based on the Standardized Precipitation Index (SPI) and the Standardized Soil Moisture Index (SSMI), the Drought Propagation Intensity Index (DIP) and Copula function were applied to quantify the intensity and time of drought propagation from meteorological to soil drought and explored the drought propagation patterns at different temporal and spatial scales in these tributaries. Results showed that, in the 0–10 cm soil layer, the propagation intensity of meteorological drought to soil drought was peer-to-peer, with a propagation time of one month. In the middle (10–40 cm) and deep (40–100 cm) soil layers, propagation characteristics differed between the eastern and western tributaries. The western tributaries experienced stronger drought propagation intensity and shorter propagation times (2–4 months), while the eastern tributaries exhibited peer-to-peer propagation intensity with longer times (4–10 months). The large areas of forests and grasslands in the upper reaches of the Shiyang River contributed to strong land–atmosphere interactions, leading to peer-to-peer drought propagation intensity in the 0–10 cm soil layer. The eastern tributaries had extensive cultivated land, where irrigation during meteorological drought enhanced soil moisture, resulting in peer-to-peer propagation intensity in the middle (10–40 cm) and deep (40–100 cm) soil layers. In contrast, the western tributaries, with larger forest areas and widespread permafrost, experienced high water consumption and limited recharge in the 10–40 cm and 40–100 cm soil layers, leading to strong drought propagation. Full article

Ariel (Atmospheric Remote-sensing Infrared Exoplanet Large-survey) is the ESA Cosmic Vision M4 mission, selected in March 2018 and officially adopted in November 2020, whose launch is scheduled by 2029. It aims at characterizing the atmospheres of hundreds of exoplanets orbiting nearby stars by low-resolution primary and secondary transit spectroscopy. The Ariel spacecraft’s operational orbit is baselined as a large-amplitude, eclipse-free halo orbit around the second Lagrangian (L2) point, a virtual point located at about 1.5 million km from the Earth in the anti-Sun direction, as it offers the possibility of long uninterrupted observations in a fairly stable radiative and thermo-mechanical environment. A direct escape injection with a single passage through the Van Allen radiation belts is foreseen. During both the injection trajectory and the final orbit around L2, Ariel will be immersed in and interact with Sun radiation and the plasma environment. These interactions usually result in the accumulation of net electrostatic charge on the external surfaces of the spacecraft, leading to a potentially hazardous configuration for the nominal operation and survivability of the Ariel platform and its payload, as it may induce harmful electrostatic discharges (ESDs). This work presents the latest results collected from surface charging analyses conducted using the SPIS tool of the European SPINE community along the GEO insertion orbit segment and operational orbit. Full article

With the intensification of global warming, droughts and heatwaves occur frequently and widely, which have a serious impact on the healthy growth of vegetation. The challenge is to accurately characterize vegetation vulnerability under compound heat and drought stress using correlation-based methods. This article uses the Haihe River Basin, an ecologically sensitive area known for experiencing droughts nine out of ten years, as an example. Firstly, using daily precipitation and maximum temperature data from 38 meteorological stations in the basin from 1965 to 2019, methods such as univariate linear regression and the Mann–Kendall mutation test were employed to identify the temporal variation patterns of meteorological elements in the basin. Secondly, the Pearson correlation coefficient and other methods were applied to determine the most likely months for compound dry and hot events, and the joint distribution pattern and recurrence period of concurrent high temperature and intense drought events were explored. Finally, a vegetation vulnerability assessment model based on Vine Copula in compound dry and hot climates was constructed to quantify the relationship of the response of watershed vegetation to different extreme events (high temperature, drought, and compound dry and hot climates). The results indicated that the basin’s precipitation keeps decreasing, evaporation rises, and the supply–demand conflict grows more severe. The correlation between the Standardized Precipitation Index (SPI) and Standardized Temperature Index (STI) is strongest at the 3-month scale from June to August. Meanwhile, in most areas of the basin, the Standardized Normalized Difference Vegetation Index (sNDVI) is positively correlated with the SPI and negatively correlated with the STI. Compared to a single drought or high-temperature event, compound dry and hot climates further exacerbate the vegetation vulnerability of the Haihe River Basin. In compound dry and hot climates, the probability of vegetation loss in June, July, and August is as high as 0.45, 0.32, and 0.38, respectively. Moreover, vegetation vulnerability in the southern and northwestern mountainous areas of the basin is higher, and the ecological risk is severe. The research results contribute to an understanding of the vegetation’s response to extreme climate events, aiming to address terrestrial ecosystem risk management in response to climate change. Full article