The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity. Untargeted mass spectrometry-based proteomics revealed that MLN4924 and CSN5i-3 substantially alter the microglial proteome, including inflammation-related proteins. Applying these drugs and mimicking microglial and endothelial inflammation as well as ischemic neuronal stress by TNF and oxygen-glucose-deprivation/reoxygenation (OGD/RO) treatment, respectively, we could link CSN5/CSN-mediated cullin deNEDDylation to reduction of microglial inflammation, attenuated cerebral endothelial inflammation, improved barrier integrity, as well as protection from ischemic stress-induced neuronal cell death. Specifically, MLN4924 reduced phagocytic activity, motility, and inflammatory cytokine expression of microglial cells, and this was linked to inhibition of inflammation-induced NF-κB and Akt signaling. Inversely, Csn5 knockdown and CSN5i-3 increased NF-κB signaling. Moreover, MLN4924 abrogated TNF-induced NF-κB signaling in cerebral microvascular endothelial cells (hCMECs) and rescued hCMEC monolayers from OGD/RO-triggered barrier leakage, while CSN5i-3 exacerbated permeability. In an ex vivo organotypic brain slice model of ischemia/reperfusion stress, MLN4924 protected from neuronal death, while CSN5i-3 impaired neuronal survival. Neuronal damage was attributable to microglial activation and inflammatory cytokines, as indicated by microglial shape tracking and TNF-blocking experiments. Our results indicate a protective role of the CSN in neuroinflammation via brain-resident cell types involved in ischemic brain disease and implicate CSN activity-mimicking deNEDDylating drugs as potential therapeutics.

In terms of both developed and developing countries, banking regulations have a very important place for regulatory authorities and investors. The study aims to examine the effects of regulations on banking performance and profitability. The effects of regulatory indicators such as capital adequacy, liquidity, and total provisions on the return on assets of banks are examined. In this study, Annual data set of 53 banks operating in selected Balkan countries and Turkey was constructed for the study, and analysis estimation using the System Generalized Moments Method (SGMM) were carried out. In addition, GDP, Inflation, Total Assets, and Budget deficits are used as control variables. According to the findings obtained from the study, it has been ascertained that the primary determinant impacting the return on assets is capital adequacy as per the regulatory criterion. Apart from this, it has been concluded that liquidity, which is one of the other regulatory indicators, has a positive and a negative effect on its counterparts in terms of its effects on return on assets. According to the research analysis applied in the study, it has been concluded that the regulatory indicators increase the profitability of capital adequacy and liquidity.

Brief tools are necessary to identify adolescents at greatest risk for ART non-adherence. From the WHO’s HEADSS/HEADSS+ adolescent wellbeing checklists, we identify constructs strongly associated with non-adherence (validated with viral load). We conducted interviews and collected clinical records from a 3-year cohort of 1046 adolescents living with HIV from 52 South African government facilities. We used least absolute shrinkage and selection operator variable selection approach with a generalized linear mixed model. HEADSS constructs most predictive were: violence exposure (aOR 1.97, CI 1.61; 2.42, p < 0.001), depression (aOR 1.71, CI 1.42; 2.07, p < 0.001) and being sexually active (aOR 1.80, CI 1.41; 2.28, p < 0.001). Risk of non-adherence rose from 20.4% with none, to 55.6% with all three. HEADSS+ constructs were: medication side effects (aOR 2.27, CI 1.82; 2.81, p < 0.001), low social support (aOR 1.97, CI 1.60; 2.43, p < 0.001) and non-disclosure to parents (aOR 2.53, CI 1.91; 3.53, p < 0.001). Risk of non-adherence rose from 21.6% with none, to 71.8% with all three. Screening within established checklists can improve identification of adolescents needing increased support. Adolescent HIV services need to include side-effect management, violence prevention, mental health and sexual and reproductive health.

Binders are critical components used in the preparation of a range of extraction devices, including solid-phase microextraction (SPME) devices. While the main role of a binder is to affix the sorbent particles to the selected support, it is critical to select the optimal binder to ensure that it does not negatively impact the coating's particle sorption capability. This work presents the first comprehensive investigation of the interactions between binders and solid sorbent particles as these interactions can significantly impact the performance of the coating. Specifically, the findings presented herein provide a better understanding of the extraction mechanisms of composite coatings and new rules for predicting the particle adhesion forces and binder distribution in the coating. The influence of binder chemistry on coating performance is investigated by examining a selection of the most used binders, namely, polydimethylsiloxane (PDMS), polyacrylonitrile (PAN), poly(vinylidene difluoride) (PVDF), polytetrafluoroethylene amorphous fluoroplastics (PTFE AF 2400), and polybenzimidazole (PBI). The solid particles (e.g., hydrophilic-lipophilic balanced (HLB) and C18) used in this work were selected for their ability to provide optimal extraction coverage for a broad range of analytes. The results show that PDMS does not change the properties of the solid particles and that the binder occupies a negligible volume due to shrinking after polymerization, resulting in the solid particles making up most of the coating volume. Hence, the coating sorption characteristics correspond closely to the properties of the selected solid particles. On the other hand, the results also showed that PTFE AF 2400 can interact with the active surface of the sorbent, leading to the deactivation of the sorbent particles. Therefore, the extraction performance and permeability coefficients decrease as the size of the penetrant increases, indicating a rigid porous structure. The results of this study can aid in the optimization of SPME devices as they provide reference values that can be used to determine the optimal binder and the sorbent affinity for the targeted compounds. Finally, the present work also provides the broader scientific community with a strategy for investigating the properties of sorbent particle/binder structures and defines the characteristics of a good coating/membrane by analyzing all parameters such as kinetics, thermodynamic equilibria, and morphology.

Background Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. Methods C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) (“CPI”) or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2−/− and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment. Results Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+ T cells and CCR2+ monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+ T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis. Conclusion This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+ monocyte interaction with tissue-destructive CD8+ T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.

Abstract Recent advances in surgical technology and innovative techniques have revolutionized surgical gynecology, including transcervical hysteroscopic procedures. Surgical lasers (Nd-Yag, Argon, diode, and CO2 lasers) have been promoted to remove a variety of gynecological pathologies. For hysteroscopic surgery, the diode laser represents the most versatile and feasible innovation, with simultaneous cut and coagulate action, providing improved hemostasis compared with CO2 laser. The newest diode laser devices exhibit increased power and a dual wavelength, to work precisely with reduced thermal dispersion and minimal damage to surrounding tissues. Their efficacy and safety have been validated both in the hospitals as well as in the office setting. Updated evidence reports that several hysteroscopic procedures, including endometrial polypectomies, myomectomies and metroplasties can be successfully performed with a diode laser. Therefore, this review aimed to give a deeper understanding of the role of laser energy in gynecology and subsequently in hysteroscopy in order to safely incorporate this technology into clinical practice.

The aim of this work is to investigate the impact of geometry on the mechanical stability of characteristic structural solutions of plates for internal bone fixation using the finite element method (FEM). Based on the realistic construction of plates for internal bone fixation, 3D geometric and FEM models were formed, and then structural analysis was carried out in the CAD/CAE system CATIA V5. Five different types of plates for internal bone fixa - tion were tested under two types of loads: axial pressure and torque in the case of application to the femur. During the structural analysis, stresses and displacements were monitored at characteristic points of the structure. The most attention was paid to the relative displacements of the bone model fragments, because the stiffness of the plates for the internal fixation of the bone was determined based on them. At the end of the paper, the results of all analyzed plates are presented, their mutual comparison as well as the conclusion in which, based on everything done, it was stated which plate would be the most favorable solution for a given case of bone fracture.

Field research conducted in the Peripanonian part of Bosnia and Herzegovina resulted in new and noteworthy records for the genus Lindernia. For the first time, alien L. dubia was recorded in Bosnia and Herzegovina, and new localities of threatened L. procumbens were also discovered. Individuals of both species grew in wetland vegetation of the class Isoëto-Nanojuncetea. The paper presents data on the morphology, ecology and distribution of species of the genus Lindernia. The alien status of L. dubia in Bosnia and Herzegovina is determined as the initial phase of naturalisation. The threatened status of L. procumbens in Bosnia and Herzegovina is assessed as endangered. These results contribute to a better knowledge of the flora and vegetation of ephemeral wetlands in Bosnia and Herzegovina, as well as the Balkans, which are still not sufficiently explored.

An adult female hedgehog Erinaceus roumanicus, was found in a city traffic zone with serious injuries, most likely from a vehicle impact. Rapid diagnostics, including X-ray imaging, were performed at the veterinarian clinic to rescue the animal. Due to multiple traumatic injuries and poor prognosis, the animal was anesthetized for blood sampling and then euthanized. Polycythaemia, platelet aggregation, rare megakaryoblasts, neutrophilia, lymphocytosis, and a high red blood cell (RBC) and white blood cell (WBC) count were found in peripheral blood. Eosinophilia and the physiological phenomenon of emperipolesis were detected in the femur bone marrow, while the liver biopsy confirmed the extramedullary haematopoiesis (EMH). It has been noted that acute hypovolemic shock results in rapid changes in haematological and biochemical parameters. Given the increased vulnerability of small mammal fauna due to expanding urbanization, this finding may significantly improve care for their welfare and conservation.

U današnje vrijeme stariji ljudi su često percipirani kroz prizmu onoga što više ne mogu da rade, umjesto shvatanja starijih osoba kao svojevrsnih potencijala i resursa koji se još uvijek mogu razvijati i doprinositi društvenoj zajednici. Upravo iz ovih razloga jako je važno raditi na povećanju svijesti društa o mogućnostima ali i potrebama starih osoba koje nisu u mogućnosti sebi obezbijediti. Postoje različiti oblici zaštite ove populacije. Jedan od pristupa jeste i intitucionalni smještaj, koji pruža veliki broj usluga starijim osobama uključujući, zdravstvnu, socijalnu i psihološku podršku tokom dužeg vremenskog perioda. Cilj rada je ispitati nivo funkcionalnih kompetencija i smislenih aktivnosti kao važnih indikatora kvalitete života osoba smještenih u Dom penzionera, Tuzla. Za potrebe istraživanja uzorkom je obuhvaćeno ukupno 35 (N=35) osoba, od čega je 12 (N=12) ispitanika muškog, dok je 23 (N=23) ispitanika ženskog spola. Starosna dob ispitanika kreće se od od 65 do 90 godina starosti. Istraživanje je trajalo od januara do aprila 2023. godine, bilo je anonimno i na dobrovoljnoj osnovi. Mjerni instrument korišten u istraživanju je dio Ljestvice procjene kvalitete života među korisnicima domova za starije (Quality Of Life (QOL) Upitnik), verzija 2.0 (Kane, 2001). Ljestivca je Likertovog tipa. Podaci su obrađeni metodom deskriptivne statistike. Rezultati istraživanja pokazali su da je korisnicima starijm osobama koje su na institucionalnom smještaju potrebno više podrške u ostvarivanju funkcionalnih kompetencija i smislenih aktivnosti. Većina ispitanika navodi da bi njihov kvalitet života poboljšalo kada bi češće izlazili vani i provodili vrijeme na otvorenom prostoru.

Upon entering a home for the elderly, a person may feel rejected by their relatives and friends. That is why the support of the social pedagogue is very important for them when they enter the institution, the way of communication, familiarization with the rights and obligations in the institution, but their better functioning. The aim of the paper is to examine the role of the social pedagogue in relation to other employees in institutions for housing the elderly, and to examine the significance of the social pedagogue for the functioning and assistance in the adaptation of users when entering an institution for the housing of the elderly. 100 respondents participated in the research. For the purposes of the research, two measuring instruments were used: the Multidimensional Scale of Perceived Social Support - MSPSS and the HCAHPS Survey. The results of the research show that the social pedagogue is an important support link for the elderly, and that he has the competencies and knowledge to work with the elderly, considering their personality structure. The results of the t-test (t=4.778; df=87; p=0.000) show that there is a statistically significant difference in relation to the adaptation of users and the professional competence of social pedagogues who play a crucial role in facilitating the adaptation of users of the home.

U radu su predstavljene vannastavne aktivnosti učenika u svim osnovnim i srednjim školama Kantona Sarajevo. Autori iznose podatke o nazivima aktivnosti, broju učenika koji su uključeni u ovaj vid odgojno-obrazovnog rada s posebnim osvrtom na uključenost učenika s teškoćama u razvoju. Cilj rada je prezentirati ulogu i značaj vannastavnih aktivnosti za učenike kao pozitivan i dobar primjer provođenja slobodnog vremena, koje, pritom, trebaju biti dostupne i prilagođene potrebama i interesovanjima svakog djeteta u našim školama. Institut za razvoj preduniverzitetskog obrazovanja Kantona Sarajevo u tom smislu pravi iskorak. Donošenjem dokumenta Opća metodologija o registraciji vannastavnih i posebnih programa ciljano i sistemski djeluje, prilagođavajući vannastvne aktivnosti podjednako svim učenicima. U zaključnim razmatranjima autori ističu kako vannastavne aktivnosti u školama nisu u dovoljnoj mjeri dostupne učenicima s teškoćama u razvoju. U skladu s time preporučuju i adekvatna rješenja za njihovo uključivanje u sve vannastavne aktivnosti shodno djetetovim mogućnostima.

Izvršne funkcije (IF) su svrsihodne ka cilju usmjerene aktivnosti. Razvojni profil djeteta predškolske dobi kreira se procjenom kroz pet razvojnih područja: kognitivno, komunikacijsko, socioemocionalno, fizičko i adaptivno ponašanje. Cilj ovog istraživanje je utvrditi uticaj različitih komponenti IF na razvojne domene djece sa poteškoćama u razvoju predškolske dobi (DPR) i uporediti ih sa djecom neurotipičnog razvoja (DTR), te ispitati uticaj socioekonomskog statusa porodice na razvoj IF. Metode: Uzorak je obuhvatio 120 djece iz redovnnih i specijaliziranih predškolskih ustanova iz Bosne i Hercegovine. Starosna dob djece je pet i šest godina. Socioekonoomski status je ispitan kroz stručnu spremu roditelja i uzorak čine roditelji DPR i to 28 roditelja sa visokom stručnom spremom (VSS) i 32 roditelja sa srednjom stručnom spremom (SSS), te roditelji DTR 25 roditelja sa VSS i 35 roditelja sa SSS. Instrumenti: Profili djece ispitani su Razvojnom procjenom male djece (Developmental Assessment of Young Children, DAYC-2, Swartmiller 2014), a izvršne funkcije pomoću predškolske verzije Inventara za procjenu izvršnih funkcija (Behavior Rating Inventory of Executive Functions; BRIEF-a, Giola et al., 2003). Dobijeni rezultati ukazuju na postojanje značajno nižih statističkih povezanosti IF sa domenima razvoja kod DPR u odnosu na TPR. Kod DPR postoji statistički značajna povezanost u korist roditelja sa VSS u komponentama: preusmjeravanje (t=-2,53; p=0,01), emocionalna kontrola (t=-2,46; p=0,01), a kod DTR inhibicija (t=2,26; p=0,02), emocionalna kontrola (t=2,26; p=0,05) i radna memorija (t=2,51; p=0,01). Zaključak: Istraživanje pokazuju različitu povezanost IF i razvojnih domena kod DPR i DTR. Djeca višeg socioekonomskog statusa pokazuju povezanost sa više komponenti IF.

As the field of special education continually evolves, special education teachers must stay current with emerging trends and engage in ongoing professional development. The present review aims to synthesize existing research on the professional development of special education teachers. A search was conducted using the Web of Science and Scopus databases to locate relevant articles. In total, 63 articles satisfied the inclusion requirements for this review. We identified several important topics related to the professional development of special education teachers, including inclusive education, assistive technologies collaboration with other professionals, and instructional methods. The findings from this review have the potential to guide the design and implementation of tailored professional development programs and inform policy decisions related to the ongoing education of special education teachers.

Cancer is an evolutionary process, and an evolutionary framework can be used to decipher cancer initiation, progression and treatment resistance. In the context of VHL disease with repeat evolution of malignancies across different tissue contexts we can examine the factors that constrain tumour evolution. In the largest analysis of VHL-related tumours to date (1321 tumours across 132 patients), we observe the second hits on the background of germline VHL mutation vary and include loss of chromosome 3p, narrow deletion of VHL locus, VHL mutation or methylation. Pheochromocytomas and paragangliomas (PPGL) and solid renal tumours show a higher frequency of 3p loss, while pancreatic neuroendocrine tumors (PNETs) and renal cysts, exhibited a higher frequency of somatic VHL mutations, without 3p loss. Tumour size and progression were contingent on the nature of the second hit, suggesting potential evolutionary "dead-ends" where the tumor initiating event does not involve 3p loss. The type of germline VHL mutation (whether a complete deletion or missense) determined the distribution of cancers and their burden, but beyond this, multiple renal tumours in individual patients did not converge onto the same trajectory. This observation suggests that following malignant transformation evolutionary contingency and chance dominate tumour evolution. Metastases from renal tumours were driven by loss of chromosomes 9p and 14q, reminiscent of sporadic renal tumours, suggesting that acquisition of metastatic competence is associated with a high degree of bottlenecking and highlighting these events as important targets for metastasis prevention. Citation Format: Scott Shepherd, Alex Coulton, Cathy Vocke, Chris Ricketts, Marston Linehan, Samra Turajlic. The cell of origin is the dominant constraint in evolution of VHL related neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA025.