Introduction: Klotho acts as a coreceptor for the phosphaturic hormone fibroblast growth factor-23 (FGF-23) and exists in both a membrane-bound and a soluble form (sKlotho) found in blood and urine. Klotho protein is moderately expressed in kidney proximal tubule and more abundant in the distal convolution (DC), which includes the distal convoluted tubule (DCT) and connecting tubule (CNT). However, the function of Klotho in the DC, particularly its role in sKlotho release and regulation of mineral metabolism, remains unclear. Methods: scRNA-seq was performed on isolated mouse DC cells. Four novel gene-modified mouse models were generated with Klotho deleted in the entire DC, the late DCT/CNT, the DCT only, and pan-tubular. Results: Using scRNA-seq on isolated mouse DC tubules, we showed that Klotho is more abundant in the late-DCT/CNT than in the early DCT. The composite data from three DC specific Klotho knockout mice support DC to be the primary source of urinary sKlotho, with 80% coming from the late-DCT/CNT and only 20% from the DCT. Notably, mice lacking Klotho in the entire DC (Kl-KODC) maintained normal serum sKlotho, FGF-23, and phosphate homeostasis. Bulk RNA-seq of isolated fluorescent DC segments from Kl-KODC_Tomato mice revealed suppressed signaling by mitogen activated protein kinase and downregulation of several genes involved in kidney calcium ion handling (Trpv5, Vdr, Pth1r, Klk1). Consistently, the Kl-KODC mice exhibited profound hypercalciuria and reduced bone density. On the other hand, pan-tubular Klotho deficiency in mice led to severe phosphate imbalance and loss of both serum/urine sKlotho. Conclusions: DC-derived Klotho regulates urinary sKlotho levels and controls calcium ion reabsorption, while Klotho in proximal tubule maintains phosphate homeostasis and likely regulates circulating sKlotho levels.

Translocator protein (TSPO) regulates mitochondrial function, inflammation, and oxidative stress; however, its role in acute myocardial injury (MI) remains incompletely understood. While previous studies have examined TSPO ligands in cardiac injury, the interplay between TSPO modulation and nitric oxide (NO) signaling in AMI has not been systematically investigated. The aim of this study was to investigate the effects of TSPO modulation by PK11195, alone or in combination with nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME), on cardiometabolic, inflammatory, oxidative stress, and histopathological parameters in an experimental model of isoprenaline-induced MI in rats. Male Wistar albino rats were divided into four groups: control (C); isoprenaline + saline-treated (ISO); isoprenaline + PK11195-treated (IP); and isoprenaline + PK11195 + L-NAME-treated (IPLN) groups. Isoprenaline administration induced MI, evidenced by elevated cardiac biomarkers, electrocardiographic (ECG) alterations, and histopathological damage. PK11195 treatment significantly attenuated MI and reduced pro-inflammatory cytokine levels while increasing anti-inflammatory cytokine levels, indicating protective effects. Nevertheless, TSPO modulation was associated with adverse metabolic effects, notably elevated fibrinogen and plasma homocysteine levels. Co-administration of L-NAME mechanistically demonstrated that NO availability is essential for PK11195 cardioprotective effects, as NOS inhibition partially abolished cardioprotection and modified oxidative stress parameters. Overall, TSPO modulation exerts complex actions in acute MI through regulating mitochondrial function, inflammatory signaling, and NO pathways, suggesting that TSPO is a potential, multifaceted therapeutic target.

Abstract Fibroblast growth factor receptor 2 (FGFR2) alterations have emerged as an important targetable oncogenic driver in a biologically distinct subset of biliary tract cancers (BTCs), particularly intrahepatic cholangiocarcinoma (iCCA), alongside other actionable genomic events such as IDH1 mutations, BRAF V600E, HER2 amplification and MSI-H. FGFR2 fusions and mutations define a distinct molecular subgroup whose prevalence varies across geographic regions and etiologic backgrounds such as liver fluke–associated disease. Clinical studies of both reversible and irreversible FGFR inhibitors have demonstrated meaningful activity in FGFR2-rearranged iCCA, while also highlighting a characteristic toxicity profile dominated by on-target hyperphosphataemia. Parallel translational work using cfDNA-based liquid biopsy has mapped a spectrum of secondary kinase-domain mutations that underlie acquired resistance, informing the development of next-generation FGFR2-selective inhibitors (eg, lirafugratinib) and combination strategies with EGFR/ERBB blockade. Collectively, these data underscore the need for comprehensive molecular profiling and innovative umbrella trial designs to optimise targeted therapy in this rare, biologically heterogeneous malignancy.

Modification of the contents of alloying elements with a narrower interval of Cr, Ni and Al can be obtained austenitic-martensitic steel 17-7PH which by, a subsequent heat treatment, can have values of mechanical and chemical properties required for components of automotive engine. Studies have confirmed that the rod dimensions 16mm made of steel 17-7PH with modified content of chromium, nickel and aluminum in combination with heat treatment solution annealing and precipitation hardening, gave values of mechanical properties, satisfying the requirements for steel with standard chemical composition.After aging was obtained martensitic austenitic microstru-cture, with a high percentage of martensite with a slight presence of delta ferrite.

This study aims to examine how the design of the work environment and its key dimensions—job design, employee involvement in goal setting and decision-making, as well as teamwork practices and open communication—affect productivity, organizational identification, and workforce stability in organizations in Bosnia and Herzegovina. Using a quantitative research approach and linear regression analysis on a sample of employees from the industrial sector, the results indicate that the work environment exerts a statistically significant and consistent effect on all observed outcomes. Among the analyzed components, employee involvement in decision-making proved to be the most significant factor, indicating that a sense of appreciation and the ability to influence one's own work have a strong effect on employees' motivation, loyalty, and willingness to stay in the organization. The results show that the impact of work environment design on employee performance is largely realized through strengthening employees’ connection to the organization. When the work environment is designed to ensure pleasant working conditions in which employees are actively involved in work processes, it becomes a powerful source of employee motivation and engagement. Therefore, a policy of adequately designing the work environment does not represent merely a short-term solution, but rather a realistic and sustainable approach to strengthening organizational stability and long-term success.

This study explores first-year Electrical Engineering and Computer Science students’ use and perception of artificial intelligence (AI) tools in a programming course, and their preferences for future development. We conducted an anonymous exploratory survey, consisting of items with predefined response options and open-ended items. Responses to the former and open-ended items were analyzed using descriptive statistics and inductive thematic analysis, respectively. Additionally, we clustered students using the Affinity Propagation algorithm based on their expressed preferences for possible improvements of AI tools The findings show that AI tools are not universally effective, with seven student clusters identified based on differing needs and expectations. Students expressed a need for AI tools that offer more detailed error explanations and guidance rather than just delivering correct solutions. The most common concern among students is the provision of correct solutions without adequate explanations of the underlying mistakes, leading to a lack of deeper understanding This study takes an exploratory approach by examining students’ perceptions and preferences for the design and capabilities of AI tools in helping them learn programming. Clustering students by preferences reveals distinct approaches that may be needed for different groups of learners. Given the limited research on such desires or on applying clustering to them, our analysis offers valuable insights into distinct viewpoints that can guide the design of future personalized educational AI tools

Na temelju sačuvanih bilježaka Balda Bogišića i drugih dostupnih izvora rad analizira Bogišićevu ulogu u procesu pregovora o sadržaju bračnog ugovora između crnogorske princeze Jelene Petrović Njegoš i talijanskog prijestolonasljednika Viktora Emanuela III. Pregovori su održani u Rimu u listopadu 1896. godine, a rezultirali su potpisivanjem ugovora čije su odredbe uključivale niz pravnih, dinastičkih i međunarodnih pitanja. U radu se ukazuje na to kako je cijeli proces predstavljao diplomatsku misiju najviše razine u okviru koje su Bogišićev pravni autoritet i diplomatska vještina bili izrazito važni za zaštitu interesa Crne Gore.

OBJECTIVES Aortic stenosis (AS) is the most common valvular heart disease, with transcatheter aortic valve implantation (TAVI) now preferred for select severe cases. This study evaluated the early safety and performance of the new Myval Octacor Transcatheter Heart Valve (THV) (Meril Life Sciences), for which limited clinical data exist. METHODS The authors retrospectively analyzed 43 consecutive patients with severe AS who underwent TAVI using the Myval Octacor THV at a tertiary cardiac center. Primary outcomes included all-cause mortality, stroke, major vascular complications, conduction abnormalities, new pacemaker implantation, paravalvular leak, and valve failure at 30 days follow-up. RESULTS The median age was 81 years (IQR: 7), and 22 patients (51.2%) were female. Coronary artery disease was present in 24 (55.8%). Technical success rate was 100%. Mean pressure gradient decreased significantly post-procedure (55 mm Hg [IQR: 24] vs 5 mm Hg [IQR: 2]; P ≤ .001). No in-hospital deaths occurred. Two patients (4.7%) received permanent pacemakers during hospitalization, and 3 (7.0%) required pacemakers within a week because of conduction issues. Two patients (4.7%) experienced Bleeding Academic Research Consortium Type 3a bleeding. At 30 days, 42 patients remained in follow-up (98%), with 55% improved to New York Heart Association Class I. No vascular complications, stroke, acute kidney injury, valve thrombosis, or endocarditis occurred. One patient had valve failure from a significant paravalvular leak and 1 noncardiac death occurred 2 weeks post-discharge. CONCLUSIONS Early outcomes suggest that the Myval Octacor THV is a safe and effective option for TAVI in severe AS; however, larger studies with longer follow-up are required.

Background/Objectives: Venous thromboembolism (VTE) is a common and clinically significant complication in patients with metastatic colorectal cancer (mCRC). Tumor sidedness and molecular alterations such as RAS and BRAF mutations are established prognostic factors in mCRC; however, their role in VTE risk stratification remains unclear. This study aimed to evaluate the association between primary tumor sidedness, KRAS/NRAS/BRAF mutational status, and VTE occurrence in patients with mCRC treated in the outpatient setting. Methods: This multicenter ambispective observational study included 224 patients with mCRC treated with first-line chemotherapy with or without targeted therapy. All patients had known KRAS/NRAS/BRAF statuses. The primary endpoint was the association between tumor sidedness and VTE risk. Secondary endpoints included associations between oncogenic mutations and VTE, subgroup analyses according to tumor localization and mutational status, and overall survival (OS). Multivariate logistic regression was used to identify independent predictors of VTE. Results: After a median follow-up of 21 months, VTE occurred in 23.3% of patients. The incidence of VTE was significantly higher in right-sided colorectal cancer (RCRC) compared with left-sided colorectal cancer (LCRC) (41.0% vs. 17.6%, p < 0.001). Although KRAS/NRAS and BRAF mutations were more frequent in RCRC, mutational status was not independently associated with VTE. In multivariate analysis, right-sided tumor location remained a strong predictor of VTE (OR 5.2; 95% CI 1.9–14.1; p = 0.001), along with anti-EGFR therapy. The Khorana score classified most patients as low risk and did not reliably identify those who developed VTE. VTE occurrence was not significantly associated with OS, whereas right-sided tumor location was associated with inferior survival. Conclusions: Right-sided tumor location is an independent predictor of VTE in patients with mCRC and confers a high absolute thrombotic risk not captured by the Khorana score. Incorporating tumor sidedness into VTE risk assessment may improve identification of patients who could benefit from primary thromboprophylaxis.

Background Functional dyspepsia (FD) is a common gastrointestinal (GI) disorder which significantly impacts quality of life and subjective well-being (SWB). Psychosocial factors have been linked to FD symptoms, which places this disorder among the “disorders of gut-brain interaction.” Recent studies suggest notable sex differences in symptom expression and the level of disruption of daily activities. This study aims to explore the impact of sex on associations between psychological factors and SWB in individuals with FD. Methods The study included 191 adults referred to their first endoscopic examination of the upper GI tract due to dyspeptic symptoms. Patients completed validated measures assessing GI symptoms, GI and extra-GI comorbidities, health-related habits, psychological traits (somatization, stress resilience), and indicators of SWB (life satisfaction, positive and negative experiences). Multiple regression and hierarchical block regression analyses were conducted to identify predictors of SWB and to examine the potential moderating role of sex and psychological factors. Subsequently, path analysis was conducted to explore potential causal pathways among sex, psychological variables and SWB. Results Participants displayed relatively homogeneous characteristics according to sex. Two main subgroups were identified: a larger group of highly educated, working-age individuals and a smaller group of older adults (>60 years) with higher comorbidity levels. Psychological factors, stress resilience and somatization emerged as the strongest predictors of SWB, while health and lifestyle factors had modest effects. Sex was identified as a significant determinant of SWB in the complex hierarchical model, but only after controlling for somatization and stress-resilience. The path model indicated that other sex-related factors may also influence SWB. Conclusion Results pointed toward the need to involve psychological constructs like somatization and stress resilience in studies examining SWB in individuals with FD. The importance was highlighted of examining the gender-related (socially conditioned) factors associated with SWB, and the need to separately assess these factors in older and younger individuals with FD (<60, ≥60). The study revealed a complex interactive network between age, gender, and SWB-related factors, supporting the biopsychosocial model of FD. However, identifying a suitable methodological framework to elucidate these complex relationships remains a challenge.

In this paper, we propose a simple and experimentally feasible method to suppress non-dipole effects in strong-field ionization by introducing a weak bichromatic control field polarized along the laser-field propagation direction. Within the framework of the non-dipole strong-field approximation, we derive the form of this control field and demonstrate that it compensates the leading magnetic-field-induced drift in the photoelectron momentum distribution. Numerical simulations for helium atom show that the control field restores the dipole-like photoelectron spectrum and electron trajectories for both direct and rescattered electrons. While residual non-dipole contributions remain in the ionization matrix element and rescattering action, their influence on the observables is minor. The proposed approach provides a transparent means of isolating and controlling non-dipole effects and offers new opportunities for exploring their role in complex field configurations as well as in strong-field electron dynamics.

Background/Objectives. Ebstein’s anomaly (EA), which accounts for fewer than 1% of congenital heart diseases, and atrioventricular canal defect (AVCD), present in approximately 4–5% of cases, exceptionally coexist, with this combination observed in fewer than 0.5% of patients with AVCD. We aim to report the oldest documented case of a 45-year-old female with the exceptionally rare combination of complete AVCD, EA, and right ventricular hypoplasia and to provide a concise review of these anomalies. Case presentation. Diagnosed in early childhood with a complete AVCD, pulmonary stenosis, and right ventricular (RV) hypoplasia, the patient underwent palliative surgical intervention with a modified Blalock–Taussig shunt at the age of 10 but did not receive subsequent regular follow-up. Over the ensuing 35 years, she remained largely untreated until presentation at 45 years of age with progressive exertional dyspnea, central cyanosis, and palpitations, corresponding to NYHA class III. Comprehensive multimodal imaging, including transthoracic echocardiography and cardiac magnetic resonance, revealed a complete AVCD with moderate-to-severe mitral regurgitation secondary to an anterior mitral leaflet cleft, severe tricuspid regurgitation, RV hypoplasia, and hallmark features of EA. Given the complex cardiac anatomy and the elevated surgical risk, the patient was considered inoperable, and a strategy of conservative management with multidisciplinary follow-up was implemented. Conclusions. This case highlights the exceptional longevity of a patient with the rare coexistence of complete AVCD, EA, and RV hypoplasia, surviving 45 years from diagnosis despite limited early intervention. It underscores the importance of lifelong follow-up in complex congenital heart disease and illustrates the role of multimodal imaging in assessing anatomy and guiding management when surgical options are high-risk or not feasible.

Education in modern business conditions plays a strategic role in the development of knowledge-based and innovation-driven societies. Investment in education represents one of the key determinants of democratization and the economic empowerment of individuals. The goal of contemporary education is to strengthen professional knowledge and to develop key competencies, including digital skills, which enable individuals to be prepared for new professional challenges and actively participate in current socio-economic trends. This paper aims to analyse, through conducted empirical research, the impact of formal education and acquired digital competencies on employability in the Republic of Serbia. Special emphasis is placed on the relationship between the level of education, digital literacy, and employment opportunities, to provide recommendations for improving educational policies and professional training programs.

Sustainable innovation is important in Albania, a small transition economy facing pressures from digitalization, the green transition, and increased competition. Yet the country’s innovation system is still developing, and academia–business linkages remain weak. This article investigates how academia–business (A2B) collaboration contributes to firms’ sustainable innovation, addressing the lack of quantitative evidence from a country in the Western Balkans context. Building on innovation systems and resource-based perspectives, A2B cooperation is conceptualized as a multidimensional latent construct, capturing types of collaboration, key actors, and organizational drivers. Using survey data from 298 firms operating in Albania, collected in 2025, the study applies Covariance-Based Structural Equation Modeling (CB-SEM) to test whether the intensity and quality of A2B cooperation are linked to sustainable innovation outcomes. The findings indicate that collaboration is still limited and inconsistent, dominated by student internships and sporadic joint projects. However, the CB-SEM results confirm that more intensive and better-structured cooperation is strongly associated with higher levels of sustainable innovation. The study offers one of the first CB-SEM-based quantitative assessments of A2B collaboration and sustainable innovation in Albania and provides policy implications for strengthening innovation-oriented partnerships in transition economies.

Background: While rescue stenting (RS) is a recognized bailout strategy following failed endovascular thrombectomy (EVT) for acute ischemic stroke with large vessel occlusion (AIS-LVO), first-line stenting (FLS) has emerged as a potential alternative to avoid vascular injury and improve outcomes. However, direct comparisons between these strategies remain limited. We conducted a comparative analysis of FLS versus RS using data from a large, multicenter international registry to evaluate their relative safety and effectiveness. Methods: We conducted a comparative analysis of FLS versus RS using data from the RESISTANT registry, a multicenter, international, retrospective cohort of AIS patients treated with intracranial stenting during EVT (2016-2023). Patients were categorized by stenting strategy: FLS (stent placed without prior thrombectomy) or RS (stent placed after failed thrombectomy). The primary effectiveness outcome was functional independence (modified Rankin Scale [mRS] 0-2) at 90 days; the primary safety outcome was symptomatic intracranial hemorrhage (sICH). Propensity score inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences. Results: Among 827 patients, 723 were in the RS cohort (median age 67 years [IQR 59-77], 64.2% male) and 104 in the FLS cohort (median age 65.5 years [IQR 58.8-77], 72.1% male). Using FLS as the reference strategy, IPTW=adjusted analyses did not detect significant differences in functional independence (OR=0.64; 95% CI 0.38-1.07) or sICH (OR=0.93; 95% CI 0.34-2.59). No significant differences were observed in secondary outcomes including successful reperfusion, mortality, or procedural complications. In the anterior circulation cohort (n=589), outcomes were likewise comparable (functional independence: OR=0.62; 95% CI 0.60-1.25; sICH: OR=0.81; 95% CI 0.30-2.18). Similarly, in the posterior circulation cohort (n=234), no significant differences were found (functional independence: OR=0.82; 95% CI 0.32-2.10; sICH: OR=0.81; 95% CI 0.30-2.18). Conclusions: In this study, no significant differences in safety or effectiveness were detected between FLS and RS strategies during EVT for AIS. Prospective, randomized trials are needed to better define optimal treatment approaches.