Search Results (258)

CC chemokine receptor 2 (CCR2) has been linked to many inflammatory and immune diseases, making it a relevant drug target. Yet, all CCR2 antagonists developed so far have failed in clinical trials; thus, novel strategies are needed to target this receptor. Targeted protein degradation represents a novel approach to inhibit protein function by hijacking the cellular degradation machinery, such as the proteasome, to degrade the protein of interest. Here, we aimed to determine the amenability of CCR2 to chemically induced degradation by using a CCR2 fusion protein containing a HaloTag7 and HiBiT tag (CCR2-HaloTag-HiBiT). After characterization of the CCR2 construct, we used luminescence-based assays and immunofluorescence to quantify CCR2 levels, as well as a label-free, phenotypic assay to investigate the functional effect of CCR2 degradation. Treatment with HaloPROTAC3, which selectively degrades HaloTag fusion proteins, led to concentration- and time-dependent degradation of CCR2-HaloTag-HiBiT. HaloPROTAC3 induced degradation via the proteasome, as degradation was fully blocked with proteasomal inhibitors. Finally, functional assays showed that degradation of CCR2-HaloTag-HiBiT leads to a reduced functional response after agonist stimulation. Overall, our results indicate that CCR2 is amenable to targeted degradation, paving the way for the future development of CCR2 chemical degraders. Full article

P2A (Power to ammonia) is one of the important ways of large-scale consumption of renewable energy, and one of the important technological routes for the chemical industry to realize low-carbon and clean development. The new off-grid energy power to hydrogen ammonia system lacks the support of large power grids due to the complex mathematical model of the system, more variables, and cumbersome constraints, which leads to model solving difficulties, and the production simulation results obtained suffer from the problems of low economic efficiency and high new energy power abandonment rate. To address the shortcomings of the algorithm, which converges slowly and easily falls into the local optimum when solving the model, this paper applies the Sparrow Search Algorithm (SSA) to the problem of economic optimization of new energy hydrogen synthesis and ammonia system scheduling. Firstly, based on the characteristics of wind and light, the operating characteristics of an electrolyzer, and the characteristics of an electrochemical energy storage device, and taking the economic optimization of the electric hydrogen synthesis ammonia system as the objective function, the economic optimization scheduling model of an off-grid new energy electric hydrogen synthesis ammonia system is established for 24 h production simulation. Secondly, the model is solved based on the sparrow search algorithm, and the speed of solving and the economic benefits of the system are analyzed in comparison with the conventional algorithm. Finally, the proposed off-grid wind-powered hydrogen synthesis ammonia system based on the sparrow search algorithm is verified to achieve the optimal operation of the 24 h production simulation through an actual example in the Daan area of Baicheng City, Jilin Province, which shows that the optimized system has better economic efficiency and the new energy is completely consumed, thus verifying the reasonableness and validity of the algorithm proposed in this article. Full article

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results: A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group (p < 0.01), and had a better ECOG performance status (p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% (p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02–1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20–3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74–1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% (p < 0.01). Conclusions: Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment. Full article

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n = 558). Our PH cohort (n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time. Full article

Lyssaviruses are neurotropic viruses capable of inducing fatal encephalitis. While rabies virus has been successfully eradicated in Belgium, the prevalence of other lyssaviruses remains uncertain. In this study, we conducted a survey on live animals and passive surveillance to investigate the presence of lyssaviruses in Belgium. In 2018, a total of 113 saliva samples and 87 blood samples were collected from bats. Saliva was subjected to RT-qPCR to identify lyssavirus infections. Additionally, an adapted lyssavirus neutralisation assay was set up for the detection of antibodies neutralising EBLV-1 in blood samples. Furthermore, we examined 124 brain tissue samples obtained from deceased bats during passive surveillance between 2016 and 2018. All saliva samples tested negative for lyssaviruses. Analysis of the blood samples uncovered the presence of lyssavirus-neutralising antibodies in five bat species and 32% of samples with a wide range depending on bat species, suggesting past exposure to a lyssavirus. Notably, EBLV-1 was detected in brain tissue samples from two Eptesicus serotinus specimens collected in 2016 near Bertrix and 2017 near Étalle, confirming for the first time the presence of EBLV-1 in Belgium and raising awareness of the potential risks associated with this species of bats as reservoirs of the virus. Full article

Metformin is the most widely used drug in type 2 diabetes. Regular metformin use has been associated with changes in concentrations of amino acids. In the present study, we used valid stable-isotope labeled GC-MS methods to measure amino acids and metabolites, including creatinine as well as malondialdehyde (MDA), as an oxidative stress biomarker in plasma, urine, and dialysate samples in a patient at admission to the intensive care unit and during renal replacement treatment because of metformin-associated lactic acidosis (MALA, 21 mM lactate, 175 µM metformin). GC-MS revealed lower concentrations of amino acids in plasma, normal concentrations of the nitric oxide (NO) metabolites nitrite and nitrate, and normal concentrations of MDA. Renal tubular reabsorption rates were altered on admission. The patient received renal replacement therapy over 50 to 70 h of normalized plasma amino acid concentrations and their tubular reabsorption, as well as the tubular reabsorption of nitrite and nitrate. This study indicates that GC-MS is a versatile analytical tool to measure different classes of physiological inorganic and organic substances in complex biological samples in clinical settings such as MALA. Full article

The KM3NeT Collaboration is building an underwater neutrino observatory at the bottom of the Mediterranean Sea, consisting of two neutrino telescopes, both composed of a three-dimensional array of light detectors, known as digital optical modules. Each digital optical module contains a set of 31 three-inch photomultiplier tubes distributed over the surface of a 0.44 m diameter pressure-resistant glass sphere. The module also includes calibration instruments and electronics for power, readout, and data acquisition. The power board was developed to supply power to all the elements of the digital optical module. The design of the power board began in 2013, and ten prototypes were produced and tested. After an exhaustive validation process in various laboratories within the KM3NeT Collaboration, a mass production batch began, resulting in the construction of over 1200 power boards so far. These boards were integrated in the digital optical modules that have already been produced and deployed, which total 828 as of October 2023. In 2017, an upgrade of the power board, to increase reliability and efficiency, was initiated. The validation of a pre-production series has been completed, and a production batch of 800 upgraded boards is currently underway. This paper describes the design, architecture, upgrade, validation, and production of the power board, including the reliability studies and tests conducted to ensure safe operation at the bottom of the Mediterranean Sea throughout the observatory’s lifespan. Full article

Ovarian follicular fluid (FF) has a direct impact on oocyte quality, playing key roles in fertilization, implantation, and early embryo development. In our recent study, we found FF thromboxane (TX) to be a novel factor inversely correlated with oocyte maturation and identified thrombin, transforming growth factor β (TGFβ), TNF-α, and follicular granulosa cells (GCs) as possible contributors to FF TX production. Therefore, this study sought to investigate the role of TGFβ3 in regulating TX generation in human ovarian follicular GCs. TGFβ3 was differentially and significantly present in the FF of large and small follicles obtained from IVF patients with average concentrations of 68.58 ± 12.38 and 112.55 ± 14.82 pg/mL, respectively, and its levels were correlated with oocyte maturity. In an in vitro study, TGFβ3 induced TX generation/secretion and the converting enzyme-COX-2 protein/mRNA expression both in human HO23 and primary cultured ovarian follicular GCs. While TGFβRI and Smad2/3 signaling was mainly required for COX-2 induction, ERK1/2 appeared to regulate TX secretion. The participation of Smad2/3 and COX-2 in TGFβ3-induced TX generation/secretion could be further supported by the observations that Smad2/3 phosphorylation and nuclear translocation and siRNA knockdown of COX-2 expression compromised TX secretion in GCs challenged with TGFβ3. Taken together, the results presented here first demonstrated that FF TGFβ3 levels differ significantly in IVF patients’ large preovulatory and small mid-antral follicles and are positively associated with oocyte maturation. TGFβ3 can provoke TX generation by induction of COX-2 mRNA/protein via a TGFβR-related canonical Smad2/3 signaling pathway, and TX secretion possibly by ERK1/2. These imply that TGFβ3 is one of the inducers for yielding FF TX in vivo, which may play a role in folliculogenesis and oocyte maturation. Full article

We investigated the electronic structure of Mg-, Si-, and Zn-doped four-faceted [001]- and [110]-oriented SnO₂ nanowires using first-principles calculations based on the linear combination of atomic orbitals (LCAO) method. This approach, employing atomic-centered Gaussian-type functions as a basis set, was combined with hybrid density functional theory (DFT). Our results show qualitative agreement in predicting the formation of stable point defects due to atom substitutions on the surface of the SnO₂ nanowire. Doping induces substantial atomic relaxation in the nanowires, changes in the covalency of the dopant–oxygen bond, and additional charge redistribution between the dopant and nanowire. Furthermore, our calculations reveal a narrowing of the band gap resulting from the emergence of midgap states induced by the incorporated defects. This study provides insights into the altered electronic properties caused by Mg, Si, and Zn doping, contributing to the further design of SnO₂ nanowires for advanced electronic, optoelectronic, photovoltaic, and photocatalytic applications. Full article

The growing prevalence of bacterial and viral infections, highlighted by the recent COVID-19 pandemic, urgently calls for new antimicrobial strategies. To this end, we have synthesized and characterized a novel fatty acid epoxy-ester plasticizer for polymers, named GDE. GDE is not only sustainable and user-friendly but also demonstrates superior plasticizing properties, while its epoxy components improve the heat stability of PVC-based matrices. A key feature of GDE is its ability to confer antimicrobial properties to surfaces. Indeed, upon contact, this material can effectively kill enveloped viruses, such as herpes simplex virus type 1 (HSV-1) and the β-coronavirus prototype HCoV-OC43, but it is ineffective against nonenveloped viruses like human adenovirus (HAdV). Further analysis using transmission electron microscopy (TEM) on HSV-1 virions exposed to GDE showed significant structural damage, indicating that GDE can interfere with the viral envelope, potentially causing leakage. Moreover, GDE demonstrates antibacterial activity, albeit to a lesser extent, against notorious pathogens such as Staphylococcus aureus and Escherichia coli. Overall, this newly developed plasticizer shows significant potential as an antimicrobial agent suitable for use in both community and healthcare settings to curb the spread of infections caused by microorganisms contaminating physical surfaces. Full article

The scientific and reasonable division of geographical units of cultivated land reserve resource areas is an important foundation for comprehensive land consolidation (CLC). Saline–alkali land is an important cultivated land reserve resource, and is significant for ensuring food security. This paper constructs a two-level land consolidation index system for cultivated land reserve resource areas. The Kruskal graph theory clustering algorithm was used to divide the study area into four types of ecological zones. On the basis of ecological zones, the study area was further divided into three types of consolidation units. Finally, the spatial relationship between ecological zoning and land use types was clarified, and the classification distribution of land consolidation potential was determined through an analysis of the CLC of two-level geographical units. Da’an City, Jilin province, China, was selected as the study area. The results of this study show the following: (1) In Da’an City, the conservation priority areas are concentrated in the north, the development priority areas are concentrated in the central and southern areas, and the comprehensive upgrade areas and adjustment rebuilding areas are in the transition zones. (2) The CLC potential trend is low in the north but high in the south in Da’an City. This paper proposes a framework for a geographical unit delineation method for saline–alkali-enriched cultivated land reserve resource zones, and analyzes the spatial layout of ecological protection demands and land consolidation potential in Da’an City. The results and conclusions of this study will provide a reference for CLC in cultivated land reserve resource areas. Full article

A theoretical analysis is presented for a recently proposed high-speed µ-OLED optically pumped organic laser. We confirm that for this configuration, the laser threshold is reached at a lower current density than in the case of a direct-electrically pumped organic laser diode while generating pulses of order $15 \mathrm{n}\mathrm{s}$ duration. With a validated model for the electrically pumped organic light-emitting diode (OLED), we simulate the generation of light pulses. This light is fed into the organic laser section, where it optically pumps the emitting organic medium. The full model includes field-enhanced Langevin recombination in the OLED, Stoke-shifted reabsorption in both the OLED and organic laser, and an optical cavity in the latter. We numerically demonstrate $2 \mathrm{G}\mathrm{H}\mathrm{z}$ modulation and conjecture the feasibility of $~0.025 \mathrm{M}\mathrm{b}/\mathrm{s}$ data transmission with this device. Full article

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes. Full article

Shortening the aging duration and enhancing the functional components of garlic present significant technical challenges that need to be addressed. Thus, this study aimed to evaluate the potential role of pulsed electric field (PEF) treatment, a novel nonthermal food processing method, in promoting and enhancing the functional attributes of aged garlic. Our results showed that 2–4 kV/cm PEF pretreatment increased S-allyl cysteine (SAC), total polyphenol (TPC), and flavonoid contents (TFC) compared with un-pretreated garlic during aging. The browning and texture-softening were also significantly improved during processing time, though the latter showed no significant difference from the eighth day to the end of the aging process. The principal component analysis results showed that PEF positively affects the SAC and TFC formations without adverse effects. Among the PEF pretreatments, 3 kV/cm is the most effective in enhancing functional component production compared with the other PEF pretreatments. Therefore, PEF pretreatment is a time-saving process that promotes and enhances the functionality of aged garlic. Full article

Bardet–Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration with additional extra-ocular manifestations, including obesity, intellectual disability, kidney disease, polydactyly and other skeletal abnormalities. We observed an Israeli patient with autosomal recessive apparently non-syndromic rod–cone dystrophy (RCD). Extra-ocular findings were limited to epilepsy and dental problems. Genetic analysis with a single molecule molecular inversion probes-based panel that targets the exons and splice sites of 113 genes associated with retinitis pigmentosa and Leber congenital amaurosis revealed a homozygous rare missense variant in the BBS9 gene (c.263C>T;p.(Ser88Leu)). This variant, which affects a highly conserved amino acid, is also located in the last base of Exon 3, and predicted to be splice-altering. An in vitro minigene splice assay demonstrated that this variant leads to the partial aberrant splicing of Exon 3. Therefore, we suggest that this variant is likely hypomorphic. This is in agreement with the relatively mild phenotype observed in the patient. Hence, the findings in our study expand the phenotypic spectrum associated with BBS9 variants and indicate that variants in this gene should be considered not only in BBS patients but also in individuals with non-syndromic IRD or IRD with very mild extra-ocular manifestations. Full article