Abstract Ova Studija nastaje u vremenu potrebe za rekonstrukcijom, adaptacijom, popravkom i unapređenjem inženjerskog naselja (Bungalovi) Mješovitog Holdinga “ERS” MP a.d. Trebinje ZP “ Hidroelektrane na Drini” a.d. Višegrad, u naselje koje će biti na mapi turističke ponude Višegrada. Turizam Višegrada je u ekspanziji, raste tražnja za turističkom ponudom. Geografski položaj Višegrada, ćuprija na Drini koja je vezana za nobelovca Ivu Andrića, zatim od nedavno Andrićgrad, kao i blizina Zlatibora, doprinose da Višegrad bude veoma interesantna turistička destinacija. Cilj inoviranog naselja jeste profit, koji će ovo preduzeće ostvarivati putem izdavanja bungalova zainteresovanim turistima. Mješoviti Holding “ERS” MP a.d. Trebinje ZP “ Hidroelektrane na Drini”, a.d. Višegrad, uradilo je sve pripreme za adaptaciju istog, tj. naselje se priprema za turističku ponudu. Godina 2023. jeste godina kada se očekuju intezivni radovi na ovom projektu, odnosno godina završetka najvećeg dijela radova. Finansijska sredstva za rekonstrukciju i adaptaciju istih,od strane nadležnih organa ovog preduzeća, odobrena su planom nabavki za 2023. godinu. Ekonomsko finansijska analiza i istraživanje tržišta, kao sastavni dijelovi ove Studije, pokazuju da je racionalno i ekonomski opravdano ulaganje u rekonstrukciju, adaptaciju i popravku bungalova, s ciljem da postanu sastavni dio turističke ponude Višegrada. Na osnovu Studije može se zaključiti da bi bilo neopravdano da naselje služi samo za izdavanje, znajući da je većina gostiju zainteresovana za usluge SPA centra. Zato ova Studija predviđa izgradnju i SPA centra, sa korištenjem termalne vode koja se nalazi u neposrednoj blizini, što zasigurno može biti komparativna prednost ovog naselja.

Background. The arbitrability of administrative contracts contributes to sustainable dispute resolution within the United Nations’ Sustainable Development Goals 16 (SDG 16). However, different regulation of administrative contracts in comparative law affects the arbitrability of the disputes arising out of them. The question arises – is protection deserved if an administrative contract containing an arbitration clause concluded in violation of the administrative law of the governmental body or without a special approval is invalid, unenforceable, or if the company was unaware of such a requirement? This paper analyses the concept of an administrative contract and its arbitrability in Saudi Arabia and comparative law to provide for sustainable solutions. Methods. The analysis of the applicable arbitration and administrative laws and rules is conducted with the normative method to establish the arbitrability of the disputes arising out of administrative contracts and the concept of the administrative contract. The case analysis reveals if the legislative approach causes difficulties in practice. The dogmatic method is applied to link the reasons for legislative and case law development to the current normative solutions in comparative and Saudi law. The conclusions on the existing problems and possible solutions shall be based on the analytical method. Results and Conclusions. Government contracts are of great importance and their exclusion from arbitration contradicts the set goal of sustainable dispute resolution mechanism. Differences in comparative law in terms of the notion of the administrative contract and the arbitrability may diminish the positive effects of arbitration in administrative contracts, as they may endanger equal access to dispute resolution as part of the sustainable development goals, be enforceable, or even cause discrepancies between states that annul the arbitration awards and others that still enforce the awards despite their annulment.

Metals and topological insulators have in common that they cannot be described by exponentially localized wave-functions. Here we establish a relationship between these two seemingly unrelated observations. The connection is explicit in the low-lying states of the spectral localizer of trivial metals, an operator that measures the obstruction to finding localized eigenstates. The low-lying spectrum of the spectral localizer of metals is determined by the zero-mode solutions of Dirac fermions with a varying mass parameter. We use this observation, valid in any dimension, to determine the difference between the localizer spectrum of trivial and topological metals, and conjecture the spectrum of the localizer for fractional quantum Hall edges. Because the localizer is a local real-space operator, it may be used as a tool to differentiate between non-crystalline topological and trivial metals, and to characterize strongly correlated systems, for which local topological markers are scarce.

Introduction: SETD2, a histone H3-K36 trimethyltransferase, is necessary for regulation of proper intron splicing. SETD2 is frequently inactivated in kidney cancer. We hypothesized that SETD2 deficiency would cause aberrant translation of retained introns (ATaRI) that could serve as potential immunotherapeutic targets in SETD2-mutant states. Methods and Results: We detected increased presence of retained introns in SETD2-mutant vs WT tumors in two publicly available renal cell carcinoma RNA-seq data sets. We hypothesized that if intronic sequences translated into proteins, accumulation of misfolded proteins would activate the Unfolded Protein Response (UPR). The UPR pathway was strongly transcriptionally enriched as measured by GSEA, as were several immunotherapy-relevant pathways, suggesting that tumors are inflamed, possibly related to the antigenic nature of translated introns. To investigate this further, we generated Setd2-isogenic mouse renal cancer cells using CRISPR in the RENCA cell line. RNAseq followed by GSEA confirmed upregulation of UPR pathway transcriptional signature in the Setd2-null condition, supporting our observation in human tumors. Indicators of UPR activation such as cleavage of ATF6 and increase in ATF4 and Xbp1 levels in Setd2 deficient vs. unedited RENCA cells, as well as nuclear translocation of ATF6 in SETD2-mutant human kidney cancer samples validates these findings. We then measured the presence of ATaRI-derived peptides in Setd2-mutant RENCA cells using mass spectrometry, detecting 47 such peptides. Using publicly available proteomics data from one human data set, we preliminarily identified peptides translated from 151 introns that are retained in SETD2-mutant cases. Applying netMHCpan to both the human and murine data, we found that detectable ATaRI peptides were predicted to generate multiple 10-amino acid-long peptides which strongly bind to the 8 murine MHC or to the 20 most common human HLA receptors. We propose that these presentable peptides might activate an immune response to SETD2-mutant renal cell carcinoma. Conclusions: We identified intron retention which may cause activation of the UPR as a feature of SETD2-mutant kidney cancer. ATaRI peptides are detectable and should be presented to the adaptive immune system. These features may represent a new therapeutic vulnerability for exploitation as a rationale for personalized medicine. Citation Format: Marya T. Kozinova, Alexander Metz, Robert Uzzo, Janusz Franco-Barraza, Michael Slifker, Jessica Peskin, Angel Fernández Sanromán, Samra Turajlic, Edna Cukierman, Phillip Phillip Abbosh. SETD2 loss in renal cell carcinoma generates peptides from aberrantly translated retained introns. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6794.

A cosmetologia tornou-se uma ciência multidisciplinar que vem ocupando cada vez mais espaço, estimulando a realização de pesquisas voltadas ao bem-estar dos consumidores. O presente estudo objetivou realizar uma revisão da literatura sobre os aspectos relacionados ao controle de qualidade microbiológico de produtos cosméticos industrializados. Trata-se de uma revisão integrativa com seleção dos estudos nas bases de dados Portal de Periódicos da CAPES, PubMed, Scientific Eletronic Library Online (Scielo), Biblioteca Virtual em Saúde (BVS) e Google Acadêmico, por meio dos Descritores em Ciências da Saúde nos idiomas português e inglês, de 2015 a 2022. A Farmacopeia brasileira foi incorporada como base de informações. Identificou-se que as análises das amostras investigadas (batons, máscaras de cílios, bases faciais, manteiga de cacau, dentre outros) em cada estudo apontaram a presença de microrganismos, sejam bactérias e/ou fungos. Apesar das diretrizes apresentadas na legislação brasileira que dispõem sobre os procedimentos e requisitos para a regularização de produtos de higiene pessoal, cosméticos e perfumes, as pesquisas revelaram, antes ou após o uso de cosméticos, a presença de microrganismos para além dos limites estabelecidos pela ANVISA. Recomenda-se maior rigor no controle de qualidade das indústrias cosméticas e cumprimento das Boas Práticas de Manipulação para a prevenção de riscos à saúde dos usuários de cosméticos industrializados.

In many areas of oncology, we lack sensitive tumor-burden monitoring to guide critical decision making. While circulating tumor DNA (ctDNA) promises to enable disease monitoring, this approach is limited by the sparsity of ctDNA in the plasma. To overcome this challenge, error-corrected deep targeted sequencing has been proposed. Nonetheless, this framework is limited by the low number of genomic equivalents (GEs, ~103/mL of plasma), imposing a ceiling on effective sequencing depth. We have previously shown that genome-wide mutational integration through plasma whole genome sequencing (WGS) can sever the dependency between available GEs and assay sensitivity (Zviran et al, 2020). In this approach, tumor-informed mutational profiles are applied to plasma WGS, allowing detection of tumor fractions as low as 10−5. However, the higher cost of WGS limits practical depth of coverage (20-30X) and may limit broad adoption. Lower costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (1USD/Gb, Almogy et al, 2022) to plasma from 7 patients with metastatic cancer at ~115x coverage depth. Read depth profiling and error rates were comparable between matched Ultima and standard platform datasets. Integration of deep learning architectures for signal to noise enrichment (Widman et al, biorxiv, 2022) with deeper WGS coverage enabled ctDNA detection at the parts per million range. We reasoned that lower sequencing cost can be harnessed for duplex error-corrected WGS. Proof-of-concept experiments in mouse PDX samples showed ~1,500x decrease in errors. Applied to the plasma of stage IV melanoma patients (n=5), we obtained error rates ~10−7. We used this approach to tackle the challenging context of cancer monitoring in early-stage melanoma without matched tumor sequencing. While in uncorrected WGS, de novo mutation calling yielded limited ability to detect melanoma specific mutations, duplex-corrected WGS allowed us to harness melanoma mutational signatures for disease monitoring without matched tumor profiling. Analytic validation of our assay showed sensitive and specific cancer detection when the concentration of ctDNA was at 10−4 concentrations. Applied to a cohort of stage III melanoma patients with negative ctDNA detection using previously described methods, we detected ctDNA in all cases (n=4), demonstrating enhanced sensitivity using duplex WGS. These data demonstrate the exciting potential of low cost WGS for ultra-sensitive ctDNA cancer monitoring. In the tumor-informed setting, deeper sequencing increased sensitivity for mutational profile detection. Moreover, the application of duplex error-correction at genome scale allowed for sensitive cancer monitoring without matched tumor profiles. We envision that the era of low-cost sequencing will empower ultra-sensitive cancer monitoring via WGS, with transformative impact on cancer care. Citation Format: Alexandre P. Cheng, Adam J. Widman, Anushri Arora, Itai Rusinek, William F. Hooper, Rebecca Murray, Daniel Halmos, Theophile Langanay, Giorgio Inghirami, Soren Germer, Melissa Marton, Adrienne Helland, Rob Furatero, Jaime McClintock, Lara Winterkorn, Zoe Steinsnyder, Yohyoh Wang, Srinivas Rajagopalan, Asrar I. Alimohamed, Murtaza S. Malbari, Ashish Saxena, Margaret K. Callahan, Dennie T. Frederick, Lavinia Spain, Ariel Jaimovich, Doron Lipson, Samra Turajlic, Michael C. Zody, Nasser K. Altorki, Jedd D. Wolchok, Michael A. Postow, Nicolas Robine, Genevieve Boland, Dan A. Landau. Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5709.

Topological insulators are described by topological invariants that can be computed by integrals over momentum space, but also as traces over local, real-space topological markers. These markers are useful to detect topological insulating phases in disordered crystals, quasicrystals and amorphous systems. Among these markers, only the spectral localizer operator can be used to distinguish topological metals, that show zero-modes of the localizer spectrum. However, it remains unclear whether trivial metals also display zero-modes, and if their localizer spectrum is distinguishable from topological ones. Here, we show that trivial metals generically display zero-modes of the localizer spectrum. The localizer zero-modes are determined by the zero-mode solutions of a Dirac equation with a varying mass parameter. We use this observation, valid in any dimension, to determine the difference between the localizer spectrum of trivial and topological metals, and conjecture the spectrum of the localizer for fractional quantum Hall edges. Because the localizer is a local, real-space operator, it may be used as a tool to differentiate between non-crystalline topological and trivial metals, and characterize strongly correlated systems, for which local topological markers are scarce.

Analysis and modeling of wireless communication systems are dependent on the validity of the wide-sense stationarity uncorrelated scattering (WSSUS) assumption. However, in high-mobility scenarios, the WSSUS assumption is approximately fulfilled just over a short time period. This paper focuses on the stationarity evaluation of high-mobility multi-band channels. We evaluate the stationarity time, the time over which WSSUS is fulfilled approximately. The investigation is performed over real, measured high-mobility channels for two frequency bands, 2.55 and 25.5 GHz. Furthermore, we demonstrate the influence of the user velocity on the stationarity time. We show that the stationarity time decreases with increased relative velocity between the transmitter and the receiver. Furthermore, we show the similarity of the stationarity regions between sub-6 GHz and mmWave channels. Finally, we demonstrate that the sub-6 GHz channels are characterized by longer stationarity time.

Quality of Experience (QoE) multidimensional concept is the key for successful delivery of multimedia services. Higher user requirements for new experiences such as augmented reality, virtual reality, and future 6G services set higher requirements for QoE. A more complex QoE space requires the use of data mining methods in order to process the data for better QoE prediction. The increased dimensionality of the QoE space becomes a limiting factor for achieving the desired QoE prediction accuracy. Existing studies considering the QoE multidimensional concept with approaches that overcome the challenge of increased QoE space dimensionality are of great importance for future research. Accordingly, this article aims to review the applications of Feature Selection (FS) methods in video QoE modeling. It provides a comprehensive overview of the existing studies with the categorization and review of applied FS methods with reference to the data collection and data modeling steps. The analysis included 71 studies which provides overview of the FS methods applications in video QoE modeling depending on the input Influence Factor (IF) dimension sizes, type of IFs, QoE prediction methods used and QoE evaluation type. Our review revealed the advantages of using FS methods in video QoE modeling, frequency of application of FS methods with potential of applying more FS methods in a series or a parallel, gives an overview of the achieved dimensionality reduction degree for different methods, and provides insights in opportunities for researchers for applying FS methods on complex multidimensional QoE space.

Mass spectrometry analysis can be performed by introducing samples directly to mass spectrometry, allowing the increase of the analysis throughput; however, some disadvantages of direct-to-mass spectrometry analysis include susceptibility to matrix effects and risk of instrument contamination from inadequate sample preparation. Solid-phase microextraction is one of the most suitable sample preparation methods for direct-to-mass spectrometry analysis, as it offers matrix-compatible coatings which ensure analyte enrichment with minimal or no interference from matrix. One of the ways solid-phase microextraction can be coupled directly to mass spectrometry is via a microfluidic open interface. This manuscript reports improvements made to the initial microfluidic open interface design, where the system components have been simplified to mostly commercially available materials. In addition, the analysis of samples has been automated by implementing software that fully controls the analysis workflow, where the washing procedure is optimized to completely reduce the carryover. Herein, the extraction and desorption time profiles from thin and thick SPME devices was studied where the overall workflow consisted of high-throughput sample preparation of 1.3 min per 96 samples and <1 min per sample instrumental analysis.

The focus of this study is on the significance of location in establishing distribution centers. The key question when selecting a location is regarding which location would contribute the most to the growth of a company’s business through the establishment of distribution centers. To answer this question, we conducted research in the Brčko District of BiH in order to determine the best location for a distribution center using expert decision-making based on linguistic values. In order to use these values when selecting locations, a fuzzy set was formed using the IMF SWARA (Improved Fuzzy Stepwise Weight Assessment Ratio Analysis) and fuzzy CRADIS (Compromise Ranking of Alternatives from Distance to the Ideal Solution) methods. The IMF SWARA method was utilized to determine the weights of the criteria, and the fuzzy CRADIS method was employed to rank the locations based on expert ratings. The location for the construction of distribution centers at Bodarište was rated the worst, while the McGowern Base location was rated the best. Based on these findings, the research question was answered, and it was demonstrated that fuzzy methods could be utilized in the selection of distribution center locations. Hence, we recommend that future research be performed on the application of fuzzy methods in the expert selection of potential sites for distribution centers.

We consider the problem of adaptive stabilization for discrete-time, multi-dimensional linear systems with bounded control input constraints and unbounded stochastic disturbances, where the parameters of the system are unknown. To address this challenge, we propose a certainty-equivalent control scheme combining online parameter estimation with saturated linear control. We establish the existence of a high probability stability bound on the closed-loop system, under additional assumptions on the system and noise processes. Numerical examples are presented to illustrate our results.

The marine environment has a significant impact on life on Earth. Organisms residing in it are vital for the ecosystem but also serve as an inexhaustible source of biologically active compounds. Herein, the biodiversity of two brown seaweeds, Dictyota dichotoma and Dictyota fasciola from the Adriatic Sea, was evaluated. The aim of the study was the determination of differences in compound composition while comparing their activities, including antioxidant, antimicrobial, and enzyme inhibition, in connection to human digestion, dermatology, and neurological disorders. Chemical analysis revealed several terpenoids and steroids as dominant molecules, while fucoxanthin was the main identified pigment in both algae. D. dichotoma had higher protein, carbohydrate, and pigment content. Omega-6 and omega-3 fatty acids were identified, with the highest amount of dihomo-γ-linolenic acid and α-linolenic acid in D. dichotoma. Antimicrobial testing revealed a dose-dependent inhibitory activity of methanolic fraction against Escherichia coli and Staphylococcus aureus. Moderate antioxidant activity was observed for both algae fractions, while the dietary potential was high, especially for the D. fasciola dichloromethane fraction, with inhibition percentages of around 92% for α-amylase and 57% for pancreatic lipase at 0.25 mg/mL. These results suggest that Dictyota species might be a potent source of naturally derived agents for obesity and diabetes.