Search Results (524)

The kisspeptin/kisspeptin receptor (KISS1/KISS1R) system has emerged as a vital regulator of various physiological processes, including cancer progression, metabolic function, and reproduction. KISS1R, a member of the G protein-coupled receptor family, is crucial for regulating the hypothalamic/pituitary/gonadal axis. A growing number of KISS1R agonists are currently being investigated in clinical trials, whereas the number of antagonists remains limited. Most existing ligands are synthetic peptides, with only a few small-molecule compounds, such as musk ambrette, having been identified. In this article, we provide an overview of the KISS1/KISS1R system and its involvement in diseases such as reproductive disorders, cancer, diabetes, and cardiovascular disease. We also highlight the various technologies used to identify KISS1R ligands, including radioligand binding assays, calcium flux assays, IP1 formation assays, ERK phosphorylation assays, qRT-PCR, and AI-based virtual screening. Furthermore, we discuss the latest advances in identifying KISS1R agonists and antagonists, highlighting ongoing challenges and future directions in research. These insights lay the groundwork for future research aimed at leveraging this system for developing innovative therapeutic strategies across a range of medical conditions. Full article

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed^® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future. Full article

Background/Objectives: Part-to-whole object completion and search guidance by salient, integrated objects has been proposed to require attentional resources, as shown by studies of neglect patients suffering from right-parietal brain damage. The current study was performed to provide further causal evidence for the link between attention and object integration. Methods: Healthy observers detected targets in the left and/or right hemifields, and these targets were in turn embedded in various Kanizsa-type configurations that systematically varied in the extent to which individual items could be integrated into a complete, whole object. Moreover, repetitive transcranial magnetic stimulation (rTMS) was applied over the right intraparietal sulcus (IPS) and compared to both active and passive baseline conditions. Results: The results showed that target detection was substantially facilitated when the to-be detected item(s) were fully embedded in a salient, grouped Kanizsa figure, either a unilateral triangle or a bilateral diamond. However, object groupings in one hemifield did not facilitate target detection to the same extent when there were bilateral targets, one inside the (triangle) grouping and the other outside of the grouped object. These results extend previous findings from neglect patients. Moreover, a subgroup of observers was found to be particularly sensitive to IPS stimulation, revealing neglect-like extinction behavior with the single-hemifield triangle groupings and bilateral targets. Conversely, a second subgroup showed the opposite effect, namely an overall, IPS-dependent improvement in performance. Conclusions: These explorative analyses show that the parietal cortex, in particular IPS, seems to modulate the processing of object groupings by up- and downregulating the deployment of attention to spatial regions were to-be-grouped items necessitate attentional resources for object completion. Full article

Background: Resistance to antipsychotic treatment in patients suffering from schizophrenia is linked to immune system disequilibrium. One effective therapeutic option for treatment-resistant schizophrenia is electroconvulsive therapy (ECT); however, its impact on cytokines remains poorly understood. The aim of this study is to evaluate the impact of ECT on cytokines (IL-1β, IP-10, IL-17, TNFα, IL-10, and soluble receptor for IL-2 (sIL-2R)) in TRS patients. Additionally, correlations between cytokine concentrations and schizophrenia symptoms severity are explored. Methods: Cytokine and receptor concentrations were measured in eight TRS patients before and after ECT and in 13 healthy participants from control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of the symptoms. Results: Before ECT, TRS patients exhibited significantly higher concentrations of IL-1ß, IL-10, IL-17, and IP-10 compared to the control group, whereas no significant differences were observed in sIL-2R and TNF-α. In the TRS patients, ECT induced a significant reduction in IL-10, IL-17 and IP-10 levels, while IL-1β, TNF-α, and sIL-2R remained unchanged compared to pre-ECT. ECT also led to clinical improvement in schizophrenia symptoms, as measured by PANSS. Furthermore, correlations between cytokine levels and PANSS results were found. Conclusions: The above results suggest that clinical improvement in TRS patients following ECT is associated with immune modulation, especially with the steadiness between pro- and anti-inflammatory systems. However, further research is required to elucidate these mechanisms in greater detail. Full article

Background: Frontal sinus inverted papilloma (IP) is a particularly rare form of IP and its management is challenging, with a high rate of recurrence. Objectives: Our aim was to evaluate the recurrence rate of frontal sinus IP after surgery and compare this rate according to the surgical modality (purely endoscopic sinus surgery vs. a combined/open approach). Design: A systematic review without meta-analysis conducted by a working group of the Young Otolaryngologists of the International Federation of Otorhinolaryngological Societies (yo-IFOS). Data Sources and Methods: A systematic analysis of the literature was performed and reported following the criteria laid down in the SWiM guidelines. The review was registered on Prospero, a dedicated software was used for screening (Covidence), and R (v.4.2.2) was used for statistical analysis. Eligible articles were studies reporting at least five cases of frontal sinus IP surgically treated. Results: A total of 2925 studies were identified based on the MeSH equation, and 39 studies were included (n = 642 patients). Among the studies included, the recurrence rate was 18.4% (118/642) with a mean time to recurrence of 25.6 (±11.7) months. The difference between surgical modalities was not statistically significant in terms of recurrence rate (14.7% vs. 16.5%; p = 0.675). Conclusions: The recurrence rate of frontal sinus IP is not different between surgical modalities. However, it does not reduce the need for a tailored therapeutic strategy, as other factors also need to be considered (time to recurrence, complications, quality of life) when choosing the most appropriate approach. Full article

This study investigated the control of porosity during gas metal arc welding with pulsed arc (GMAW-P) of complex-phase 780 (CP780) galvanized steel. Due to the Zn coating on this type of steel, porosity forms during welding as a result of Zn vaporization. The objective was to optimize the welding parameters to minimize porosity with a design of experiments using an L9 orthogonal array to analyze the effects of peak current (I_p), pulse time (t_p), and pulse frequency (f) in high-speed welding conditions. The results showed that porosity was significantly reduced with a peak current of 313 A, a frequency of 10 Hz, and a pulse time of 10 ms, achieving ~0% porosity in the validation welding trials. A microstructural analysis identified allotriomorphic ferrite, Widmanstätten ferrite, acicular ferrite, bainite, and martensite in the heat-affected zone (HAZ). A predictive model to anticipate the percentage of porosity with an R² of 99.97% was developed, and an ANOVA determined the peak current as the most critical factor in porosity formation. Full article

Background: The oviduct is an organ that participates in multiple critical reproductive processes and provides essential nutritional support while maintaining a specialized microenvironment. It is particularly vulnerable to damage following heat stress-induced hyperthermia. Therefore, mitigating heat-induced damage to oviduct epithelial cells while preserving their physiological integrity under hyperthermia represents a critical therapeutic goal. Objective: This study aims to simulate the cellular damage state in yak oviduct epithelial cells (YOECs) under thermal challenge by increasing the incubation temperature of cultured cells, while observing changes in cellular injury upon supplementation with 17β-estradiol (E₂), in order to explore the underlying cellular regulatory mechanisms involved. Results: After 48 h of exposure to 41 °C, YOECs exhibited elevated HSP70 and HSP90 protein expression levels, reduced OVGP1 protein expression, and increased apoptotic cells. Compared to the 41 °C group, the E₂ + 41 °C group displayed decreased HSP70 protein levels, increased OVGP1 protein expression, and reduced apoptotic cell numbers. Additionally, changes in endoplasmic reticulum calcium ion (ER-Ca²⁺) distribution and fluorescence intensity variations in ER-Ca²⁺ regulatory proteins SERCA and IP3R3 were analyzed in the 37 °C, 41 °C, and E₂ + 41 °C groups. The ER-Ca²⁺ distribution pattern in the E₂ + 41 °C group remained similar to that of the 37 °C group. However, the fluorescence intensity levels of SERCA and IP3R3 proteins in the E₂ + 41 °C group did not recover to levels comparable to the 37 °C group. Conclusion: These findings suggest that E₂ may mitigate thermal challenge-induced cellular damage in YOECs by maintaining ER-Ca²⁺ homeostasis, thereby preserving cellular functionality under elevated temperatures. Full article

In this study, the methods of tangential magnetic field (TMF), magnetic Barkhausen noise (MBN), and incremental permeability (IP) were employed for in the simultaneous, quantitative prediction of target properties (bidirectional residual stress, surface hardness, and case depth) in the 45 steel plate. The bidirectional magnetic signals and target properties were measured experimentally. The results of Pearson correlation analyses revealed that most parameters of the MBN and IP signals are strongly correlated with both residual stress and surface hardness under the influence of multiple target properties. The multiple linear regression (MLR) model demonstrated highly accurate quantitative prediction of residual stress and hardness in the y-direction. However, the simultaneous prediction of residual stress and case depth in the x-direction proved less effective than expected. To address this limitation, an inversion method was developed based on the regression model with the single parameter as the dependent variable and the target properties as the independent variable. By incorporating known magnetic parameters and target properties, the model effectively determined the unknown target properties. After applying the method, the coefficient of determination (R²) for x-direction residual stress increased from 0.89 to 0.96 and the absolute error (AE) of case depth decreased from 0.10 mm to 0.04 mm for case depths below 0.15. Full article

Bis-(o-dipheylphosphinophenyl)amine, a tridentate (PNP) chelating ligand, and several of their Rare Earth (RE) metal complexes, [bis-(o-dipheylphosphinophenyl)amido]-RER₂, {[(C₆H₅)₂P-o-(C₆H₄)]₂NMR₂ (R = -CH₂-o-(C₆H₄)NMe₂: M = Y, 1; Nd, 2; Gd, 3;), are prepared in high yields. When activated with the strong Lewis acid MMAO-7, all these complexes exhibit catalytic activity toward the polymerization of isoprene (IP) in non-protic hydrocarbons. While the Nd complex (2) showed moderate activity and stereoselectivity, the Y and Gd complexes (1 and 3) exhibited extremely high catalytic efficiency in IP homo-polymerization, and produced polyisoprene rubber (PI) with 95% to over 99% cis-1,4 stereoselectivity and narrow polydispersity indices (<2.0). Moreover, under industrially relevant conditions, complex 3 can catalyze IP to produce ultrahigh molecular weight PI (UHMW-PI, MW up to 1200–2600 kg/mol) rubber with a very narrow polydispersity index (PDI ca. 1.1–1.6), a high-performance elastomeric material mimic of natural rubber (NR). Full article

Background and Objectives: Aging-related bone loss still lacks interventions. As bone marrow-derived mesenchymal stem cells (BMSCs) undergo aging, R-loop-induced DNA replication stress impairs the osteogenic ability of BMSCs. High-mobility group A-2 (Hmga2) acts as a DNA-binding protein, and the understanding of its underlying mechanisms is crucial for developing effective preventive and therapeutic strategies. Materials and Methods: Aging mice were used as the experimental model, and mouse BMSCs were isolated from their femurs. Hmga2 was achieved through specific gene delivery methods. R-loop formation was detected using dot blotting, chromatin immunoprecipitation (ChIP), and DNA–RNA immunoprecipitation (DRIP) assays. Osteogenic differentiation was evaluated. Results: R-loops were highly accumulated in aging BMSCs. Notably, the key regulator Hmga2 reversed the accumulation of R-loops in aging BMSCs. Hmga2 overexpression significantly decreased the senescence and improved the osteogenic differentiation of aging mBMSCs. Mechanistically, R-loop-forming sequence (RLFS) regions were confirmed in key osteogenesis-related genes, including runt-related transcription factor 2 (Runx2). Hmga2 bound to the RLFS region of Runx2 and promoted its expression by reducing the R-loop level. More, Hmga2 treatment delivered via the AAV system effectively decreased bone loss in aging mice and increased the serum bone turnover biomarkers and collagen remodeling. Conclusions: Our study demonstrates that Hmga2 acts as an activator of aging BMSCs, significantly promoting their osteogenic ability by eliminating the aging-induced DNA replication stress caused by R-loops. Our findings provide new insights into the mechanisms of aging-related bone loss, suggesting that Hmga2 may be a new strategy for alleviating the bone loss phenotype in aging individuals. Full article

Background and aims: The CC5, CXC3, and CC2 chemokines (CK) are known to play a role in the pathogenesis of autoimmune hepatitis (AIH). However, no data are available on their potential utility as markers of disease progression or response to treatment. Material and methods: We analyzed their role as markers of remission in a population of patients with AIH. We retrospectively investigated the kinetics of RANTES (CCL5), IP-10 (CXCL10), and MCP-1 (CCL2) in 48 patients with AIH at the time of treatment initiation and also in 32 at biochemical, clinical and histological remission. Forty-nine healthy donors (HDs) served as controls. Results: At baseline, IP-10 and MCP-1 levels were higher in AIH patients than in HDs (261 vs. 101 pg/mL and 689 vs. 330 pg/mL, p < 0.01), and RANTES levels showed no differences. Correlations were observed between RANTES and IgG concentrations (r = 0.36 p = 0.04) and between IP-10 and Ishak’s grade (r = 0.52 p = 0.02). At remission, in 32 patients, while IP-10 and MCP-1 values showed a significant decrease from baseline reaching HD levels (261 vs. 106 pg/mL and 689 vs. 387 pg/mL, p < 0.01), RANTES did not. However, two kinetics patterns emerged, with 20 patients showing lower and 12 higher baseline RANTES values compared to HDs (29,450 pg/mL and 70,960 pg/mL vs. 52,010 pg/mL, p < 0.01). The former required longer treatment to reach remission and had higher Ishak’s grades than the latter (p < 0.01). Conclusions: RANTES, IP-10, and MCP-1 may help in predicting response to treatment and stable remission and in supporting the decision if and when to discontinue immune suppressive therapy. Full article

(1) Background: Natural-looking dental restorations require careful selection of the restorative material, with color and translucency characteristics similar to the natural dental structures. (2) Objectives: This research aimed to evaluate if there is compatibility regarding the color and translucency between different commercial RBCs in different layering recipes. (3) Methods: Sixty 1 mm thick disk specimens were produced from three different RBCs: ESS (Essentia-GC), BEG (Brilliant Ever Glow-Coltene), and IPS (IPS Empress Direct-Ivoclar Vivadent). Three different opacities and translucencies (enamel, dentin, and opaque shades) from each system were used in four recipes (R1-enamel, R2-dentin, R3-enamel and dentin, R4-enamel, dentin, and opaque) to obtain single-, double-, and triple-layered samples, respecting the anatomical layering technique. CIE L*, a*, b*, C*, h⁰ coordinates were recorded, and the relative translucency parameter (RTP₀₀) was calculated. Further, the color differences (ΔE₀₀) and the difference in translucencies ΔRTP₀₀ were analyzed between the materials and between the layered recipes. (4) Results: The CIE L* and h° color coordinates and RTP₀₀ showed significant differences among all three RBCs for all four recipes (p < 0.001). The decreasing order of translucency for each recipe was R1: ESS > BEG > IPS, R2 and R3: BEG > IPS > ESS, R4: BEG > ESS > IPS. Important differences were found in color and translucency among the recipes for each of the three RBCs tested (p < 0.001). The decreasing order of translucency for the tested RBCs was ESS: R1 > R3 > R4 > R2, BEG and IPS: R1 > R3 > R2 > R4. (5) Conclusions: No significant compatibility was observed in color and translucency among different layering recipes of the same composite materials nor between similar layering recipes when using different composites. The color differences between materials were more significant than the differences in translucency for each recipe. Full article

We investigated the cellular and neurophysiological mechanisms underlying the pro-cognitive effects of 5-HT4R activation in hippocampal–prefrontal pathways. Our findings show that, in addition to pyramidal neurons, 30–60% of parvalbumin+ interneurons in the CA1, CA3, and dentate gyrus (DG) of the hippocampus and the anterior cingulate (ACC), prelimbic (PL), and infralimbic (IL) regions of the prefrontal cortex co-express 5-HT4Rs. Additionally, 15% of somatostatin+ interneurons in CA1 and CA3 express 5-HT4Rs. Partial 5-HT4R agonist RS-67333 (1 mg/kg, i.p.) exerted anxiolytic effects and ameliorated short-term (3-min) and long-term (24-h) memory deficits in a mouse model of schizophrenia-like cognitive impairment induced by sub-chronic phencyclidine (sPCP) but did not enhance memory in healthy mice. At the neurophysiological level, RS-67333 normalized sPCP-induced disruptions in hippocampal–prefrontal neural dynamics while having no effect in healthy animals. Specifically, sPCP increased delta oscillations in CA1 and PL, leading to aberrant delta–high-frequency coupling in CA1 and delta–high-gamma coupling in PL. RS-67333 administration attenuated this abnormal delta synchronization without altering phase coherence or signal directionality within the circuit. Collectively, these results highlight the therapeutic potential of 5-HT4R activation in pyramidal, parvalbumin+, and somatostatin+ neurons of hippocampal–prefrontal pathways for mitigation of cognitive and negative symptoms associated with schizophrenia. Full article

Objectives: Ischemic stroke is a severe neurological disorder with high morbidity, mortality, and disability rates, posing a substantial burden on patients, families, and healthcare systems. Soy isoflavone (SI), a naturally occurring phytoestrogen, has demonstrated promising neuroprotective effects. This study aimed to evaluate the anti-stroke efficacy of SI and elucidate its underlying mechanisms through integrated phytochemical profiling, network pharmacology, and both in vitro and in vivo experimental validation. Methods: Active constituents of SI were extracted via reflux and identified using liquid chromatography–mass spectrometry (LC-MS). Network pharmacology was employed to predict therapeutic targets and signaling pathways. The neuroprotective effects of SI were first assessed in PC12 cells subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) injury in vitro. For in vivo evaluation, transient cerebral ischemia–reperfusion injury was induced using the bilateral common carotid artery occlusion (BCCAO) model in adult male ICR rats (27.3 ± 1.8 g; 6–8 weeks old), obtained from the Shanghai Experimental Animal Center, Chinese Academy of Sciences. Forty-eight rats were randomly assigned into four groups (n = 12): sham, model (BCCAO), SI-treated (100 mg/kg, oral gavage for 5 days), and edaravone (EDA)-treated (10 mg/kg, i.p., positive control). All procedures were approved by the Institutional Animal Care and Use Committee of Changchun Normal University (Approval No. 2024003, 13 March 2024) and conducted in accordance with the NIH guidelines and ARRIVE 2.0 reporting standards. Results: In vitro, SI significantly enhanced PC12 cell viability from 57.23 ± 2.88% to 80.76 ± 4.43% following OGD/R. It also reduced intracellular Ca²⁺ by 58.42%, lactate dehydrogenase (LDH) release by 37.67%, caspase-3 activity by 55.05%, and reactive oxygen species (ROS) levels by 74.13% (p < 0.05). A flow cytometry analysis revealed that OGD/R increased the apoptosis rate from 5.34% (control) to 30.85% (model group), which was significantly attenuated by SI treatment, especially in the 560 µg/mL group (20.00%), followed by the 140 and 280 µg/mL groups. In vivo, SI improved neurological scores from 8.3 ± 1.09 to 6.8 ± 1.68, reduced cerebral infarction volume by 18.49%, and alleviated brain edema by 10.42% (p < 0.05). SI also decreased malondialdehyde (MDA) and LDH levels by 31.15% and 39.46%, respectively, while increasing the activity of antioxidant enzymes: superoxide dismutase (SOD) by 11.70%, catalase (CAT) by 26.09%, and glutathione peroxidase (GSH-px) by 27.55% (p < 0.01). Scratch assay results showed that SI restored the impaired migratory ability of the OGD/R-treated PC12 cells, further supporting its role in cellular repair. A Western blot analysis demonstrated the upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1) and the downregulation of Kelch-like, ECH-associated protein 1 (Keap1) in the cerebral ischemia–reperfusion model. Conclusions: These findings indicate that soy isoflavone confers significant neuroprotective effects against cerebral ischemia–reperfusion injury by enhancing endogenous antioxidant defense mechanisms, reducing oxidative stress, inhibiting apoptosis, and promoting cell migration. The protective effects are likely mediated through the activation of the Nrf2/Keap1 signaling pathway, supporting the therapeutic potential of SI in ischemic stroke treatment. Full article

This retrospective study analyzed SARS-CoV-2 Omicron variability since its emergence, focusing on immunocompromised (IPs) and non-immunocompromised adult people (NIPs). Phylogenetic analysis identified at least five major Omicron lineage groups circulating in Central Italy, from December 2021 to December 2023: (a) BA.1 (34.0%), (b) BA.2 + BA.4 (25.8%), (c) BA.5 + BF (10.8%), (d) BQ + BE + EF (9.2%), and (e) Recombinants (20.2%). The BA.2 + BA.4 lineages were more common in IPs compared to NIPs (30.9% vs. 17.8%, respectively; p = 0.011); conversely, Recombinants were less prevalent in IPs than in NIPs (16.0% vs. 27.1%, respectively; p = 0.018). High-abundant single nucleotide polymorphisms (SNPs; prevalence ≥ 40%) and non-synonymous SNPs (prevalence ≥ 20%) increased during the emergence of new variants, rising from BA.1 to Recombinants (54 to 92, and 43 to 70, respectively, both p < 0.001). Evaluating the genetic variability, 109 SNPs were identified as being involved in significant positive or negative associations in pairs (phi > 0.70, p < 0.001), with 19 SNPs associated in 3 distinct clusters (bootstrap > 0.96). Multivariate regression analysis showed that hospitalization was positively associated with one specific cluster, including S686R and A694S in Spike and L221F in Nucleocapsid (AOR: 2.74 [95% CI: 1.13–6.64, p = 0.025]), and with increased age (AOR:1.03 [95% CI: 1.00–1.06], p = 0.028). Conversely, negative associations with hospitalization were observed for female gender and previous vaccination status (AORs: 0.34 [95% CI: 0.14–0.83], p = 0.017 and 0.19 (95% CI: 0.06–0.63, p = 0.006, respectively). Interestingly, the S686R SNP located in a furin cleavage site suggests its potential pathogenetic role. The results show how Omicron genetic diversification significantly influences disease severity and hospitalization, together with age, sex, and vaccination status as key factors. Full article