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Abstract In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.

Overbank flow in rivers threatens integrity of built elements located in the floodplain. Elements of infrastructure close to the interface between main channel and floodplain are subjected to complex hydrodynamic actions resulting from the obstruction of the shear flow that develops in that interface. In the current paper, the drag forces and the drag coefficient of building-like structures positioned in the interface are investigated. The experimental setup in Laboratorio Nacional de Engenharia Civil (LNEC) involves the placement of an array of square cylinders on the floodplain of a straight compound channel, next to the interface with the main channel. Three-component instantaneous-velocity recordings were performed by means of Acoustic Doppler Velocimetry (ADV) within the boundaries of a considered fluid-control volume encompassing the array, while uniform-flow conditions were established in the channel. The equation of momentum conservation was applied in its integral form in the fluid control-volume towards estimation of the time-averaged drag force at a certain elevation from the floodplain. The drag coefficient is estimated accounting for the typical shear layer at the main-channel/floodplain interface and is compared with coefficients strictly valid for isolated cylinders.

Joint probability analysis is most often conducted within a stationary framework. In the present study a nonstationary bivariate approach is used to investigate the changes in the joint probabilities of extreme wave heights and corresponding storm surges with time. The dependence structure of the studied variables is modelled using copulas. The nonstationary Generalized Extreme Value (GEV) distribution is utilized to model the marginal distribution functions of the variables, within a 40-year moving time window. All parameters of the GEV are tested for statistically significant linear and polynomial trends over time. Then different copula functions are fitted to model the dependence structure of the data. The nonstationarity of the dependence structure of the studied variables is also investigated. The methods and techniques of the present work are implemented to wave height annual maxima and corresponding storm surges at two selected areas of the Aegean Sea. The analysis reveals the existence of trends in the joint exceedance probabilities of the variables, in the most likely events selected for each time interval, as well as in a defined hazard series, such as the water level at the coastline.

Background: The utilization of technology, including robotics and computer navigation, in total hip arthroplasty (THA) has been steadily increasing; however, conflicting data exists regarding its effect on short-term clinical and patient-reported outcomes. Therefore, this study sought to explore the association between different surgical technologies and postoperative outcomes following THA. Methods: We retrospectively reviewed 9892 primary THA cases performed by 62 surgeons from a single institution from September 2017 to November 2022. Three cohorts were created based on the utilization of technology: conventional (no technology), navigation, or robotics. Patient demographics, clinical outcomes, and patient-reported outcome measures were collected over the first 90 days following surgery. This data was compared using analysis of variance and multivariate logistic regressions. In total, 4275 conventional, 4510 navigation, and 1107 robotic cases were included in our analyses. Results: The robotic cohort achieved a perfect Activity Measure for Post-Acute Care (AM-PAC) score earliest (0.1 days, P < .001). After adjusting for potential confounding variables, use of robotic assistance was associated with greater odds of achieving a perfect AM-PAC score on postoperative day 0 (odds ratio 1.6, P < .001) and greater odds of having length of stay shorter than 24 hours (odds ratio 2.3, P < .001) compared to no technology use in THA. Hip dysfunction and Osteoarthritis Outcome Score, Joint Replacement and Patient-Reported Outcomes Measurement Information System Pain Interference scores showed the greatest improvement in the robotic cohort at both 6 weeks and 3 months following surgery. Conclusions: The present study demonstrates favorable clinical and patient-reported outcomes in the first 90 days following surgery for patients undergoing robot-assisted THA compared to conventional and navigation-assisted THA.

Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.

P.M. Pu and Y.M. Liu extended Moore-Smith’s convergence of nets to fuzzy topology and Y.M. Liu provided analogous results to J. Kelley’s classical characterization theorem of net convergence by introducing the notion of fuzzy convergence classes. In a previous paper, the authors of this study provided modified versions of this characterization by using an alternative notion of convergence of fuzzy nets, introduced by B.M.U. Afsan, named fuzzy net ideal convergence. Our main scope here is to generalize and simplify the preceding results. Specifically, we insert the concept of a fuzzy function ideal convergence class, L, on a non-empty set, X, consisting of triads (f,e,I), where f is a function from a non-empty set, D, to the set FP(X) of fuzzy points in X, which we call fuzzy function, e∈FP(X), and I is a proper ideal on D, and we provide necessary and sufficient conditions to establish the existence of a unique fuzzy topology, δ, on X, such that (f,e,I)∈L iff fI-converges to e, relative to the fuzzy topology δ.

Transmembrane protein 106B (TMEM106B), a protein that is localized to the lysosome, is genetically linked to many neurodegenerative diseases and forms fibrils in diseased brains. The reproducibility of TMEM106B research would be enhanced if the community had access to well-characterized anti-TMEM106B antibodies. In this study, we characterized six commercially available TMEM106B antibodies for their performance in Western blot, immunoprecipitation, and immunofluorescence, using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

The expansion of urban areas and the increasing frequency and magnitude of intense rainfall events are anticipated to contribute to the widespread escalation of urban flood risk across the globe. To effectively mitigate future flood risks, it is crucial to combine a comprehensive examination of intense rainfall events in urban areas with the utilization of detailed hydrodynamic models. This study combines extreme value analysis techniques applied to rainfall data ranging from sub-hourly to daily durations with a high-resolution flood modelling analysis at the building level in the centre of Thessaloniki, Greece. A scaling procedure is employed to rainfall return levels assessed by applying the generalised extreme value (GEV) distribution to annual maximum fine-temporal-scale data, and these scaling laws are then applied to more reliable daily rainfall return levels estimated by means of the generalised Pareto distribution (GPD), in order to develop storm profiles with durations of 1 h and 2 h. The advanced flood model, CityCAT, is then used for the simulation of pluvial flooding, providing reliable assessments of building-level exposure to flooding hazards. The results of the analysis conducted provide insights into flood depths and water flowpaths in the city centre of Thessaloniki, identifying major flowpaths along certain main streets resulting in localised flooding, and identifying around 165 and 186 buildings highly exposed to inundation risk in the study area for 50-year storm events with durations of 1 h and 2 h, respectively. For the first time in this study area, a detailed analysis of extreme rainfall events is combined with a high-resolution Digital Terrain Model (DTM), used as an input into the advanced and fully featured CityCAT hydrodynamic model, to assess critical flowpaths and buildings at high flood risk. The results of this study can aid in the planning and design of resilient solutions to combat urban flash floods, as well as contribute to targeted flood damage mitigation and flood risk reduction.

Computer navigation and robotic assistance may reduce total hip arthroplasty (THA) dislocations by improving the accuracy and precision of component positioning. We investigated dislocation rates for THAs using conventional techniques, robotic assistance, and computer navigation, while controlling for surgical approach, dual mobility (DM) use, and fluoroscopic guidance. We reviewed 11,740 primary THAs performed between June 2016 and December 2022, including 5,873 conventional, 1,293 with robotic-arm assistance, and 4,574 with navigation. The approach was posterior in 6,580 (56.0%), anterior in 4,342 (37.0%), and lateral in 818 (7.0%). A DM was used in 10.4%. Fluoroscopy was used in 3,653 cases and only with the anterior approach. Multivariate analyses yielded odds ratios (OR) for dislocation and revision. Additional regression analyses for dislocation were performed for approach and DM. Raw dislocation rates were as follows: conventional 1.2%, robotic 0.4%, navigation 0.9%, anterior with fluoroscopy 0.4%, anterior without fluoroscopy 2.3%, posterior 1.3%, and lateral 0.5%. Upon multivariate analysis, use of robotics was found to be associated with significantly reduced dislocation risk compared to conventional (OR: 0.3), as did anterior (OR: 0.6) compared to posterior approach; navigation and lateral approach were not found to be associated with a significant reduction in risk. For the anterior approach, multivariate analysis demonstrated that fluoroscopy significantly reduced dislocation risk (OR: 0.1), while DM, robotics, and navigation were not significant. For the posterior approach, the dislocation risk was lower with robotics than with conventional (OR: 0.2); the use of navigation or DM did not demonstrate a significant reduction in risk. The use of robotics was associated with a reduction in dislocations for this cohort overall. Further, fluoroscopy in the anterior approach and robotic assistance in the posterior approach were both associated with decreased dislocation risk. The role of imageless computer navigation and DM implants requires further study. [ABSTRACT FROM AUTHOR]

The notion of convergence wins its own important part in the branch of Topology. Convergences in metric spaces, topological spaces, fuzzy topological spaces, fuzzy metric spaces, partially ordered sets (in short, posets), and fuzzy ordered sets (in short, fosets) develop significant chapters that attract the interest of many studies. In particular, statistical and ideal convergences play their own important role in all these areas. A lot of studies have been devoted to these special convergences, and many results have been proven. As a consequence, the necessity to produce and extend new results arises. Since there are many results on different kinds of convergences in different areas, we present a review paper on this research topic in order to collect the most essential results, which leads us to provide open questions for further investigation. More precisely, we present and gather definitions and results which have been proven for different kinds of convergences, mainly on statistical/ideal convergences, in metric spaces, topological spaces, fuzzy topological spaces, fuzzy metric spaces, posets, and fosets. Based on this presentation, we provide new open problems for further investigation on related topics. The study of these problems will create new “roads”, enriching the branch of convergences in the field of Topology.

The notion of sequential convergence in fuzzy partially ordered sets, under the name oF-convergence, is well known. Our aim in this paper is to introduce and study a notion of net convergence, with respect to the fuzzy order relation, named o-convergence, which generalizes the former notion and is also closer to our sense of the classic concept of "convergence". The main result of this article is that the two notions of convergence are identical in the area of complete F-lattices.

In this study lock-exchange experiments are performed in a tank of rectangular upper cross section and a lower vegetated valley of trapezoidal shape to study the effect of drag resistance, due to vegetation, on gravity currents. Many natural and man-made channels are approximately trapezoidal. For the simulation of the vegetation the bed is covered by flexible grass vegetation (height of vegetation, hv=2.0cm) of different submergence ratio hν/H (hν=height of vegetation, H=water depth). The motion of the gravity current is monitored with a digital video of high definition, the front velocity is measured and the height of the front is captured. Twenty four experiments are performed, twelve inside the trapezoidal section (H/Htr=0.4, 0.6 or 0.8) and twelve over the trapezoidal section (H/Htr=1.2, 1.4 or 1.6). The initial Reynolds number, based on the height of the valley and the reduced gravity, is greater than 10000 for all cases indicating that the gravity currents are turbulent. Results are compared with those of similar experiments without vegetation (Keramaris and Prinos, 2010) and hence the effect of the vegetation drag resistance on the motion of the current is investigated. The main conclusion of this study is that the shape of the tank plays a significant role in the propagation of gravity currents. The presence of trapezoidal increases the velocity of gravity currents in comparison with triangular or orthogonal shape.

In this study the generalized extreme value (GEV) distribution function was used to assess nonstationarity in annual maximum wave heights for selected locations in the Greek Seas, both in the present and future climates. The available significant wave height data were divided into groups corresponding to the present period (1951–2000), a first future period (2001–2050), and a second future period (2051–2100). For each time period, the parameters of the GEV distribution were specified as functions of time-varying covariates and estimated using the conditional density network (CDN). For each location and selected time period, a total number of 29 linear and nonlinear models were fitted to the wave data, for a given combination of covariates. The covariates used in the GEV-CDN models consisted of wind fields resulting from the Regional Climate Model version 3 (RegCM3) developed by the International Center for Theoretical Physics (ICTP) with a spatial resolution of 10 km × 10 km, after being processed using principal component analysis (PCA). The results obtained from the best fitted models in the present and future periods for each location were compared, revealing different patterns of relationships between wind components and extreme wave height quantiles in different parts of the Greek Seas and different periods. The analysis demonstrates an increase of extreme wave heights in the first future period as compared with the present period, causing a significant threat to Greek coastal areas in the North Aegean Sea and the Ionian Sea.

Turbulent flow in compound open channels is studied numerically with nonlinear k-[Epsilon] turbulence models of low-Reynolds type. Emphasis is given to the flow characteristics and the performance of the models for conditions of low relative depths (up to 0.2547) for which the interaction between main channel and flood plain flow is significant. Experiments and computations indicate that the velocities follow the law of the wall in the interaction region even for such low relative depths. Secondary currents are predicted by a modified version of a previous model; however, the predicted currents are not as strong as the experimental ones. Turbulent shear stresses and especially [Mathematical Expression Omitted], which is significant for low relative depths, are predicted reasonably by the model, except in the interaction region in the main channel. The turbulent intensities v[prime] and w[prime] are captured by the model while u[prime] is underestimated. A depth-averaged analysis identifies two basic mechanisms that influence the variation of the bed shear stress and suggests a means of assessing the contribution of each mechanism to the deviation of the bed shear stress from its respective two-dimensional value.

The effects of wall suction on the structure of fully developed pipe flow are studied numerically by solving the Reynolds averaged Navier-Stokes equations. Linear and nonlinear k-[Epsilon] or k-[Omega] low-Re models of turbulence are used for 'closing' the system of the governing equations. Computed results are compared satisfactorily against experimental measurements. Analytical results, based on boundary layer assumptions and the mixing length concept, provide a law of the wall for pipe flow under the influence of low suction rates. The analytical solution is found in satisfactory agreement with computed and experimental data for a suction rate of A = 0.46 percent. For the much higher rate of A = 2.53 percent the above assumptions are not valid and analytical velocities do not follow the computed and experimental profiles, especially in the near-wall region. Near-wall velocities, as well as the boundary shear stress, are increased with increasing suction rates. The excess wall shear stress, resulting from suction, is found to be 1.5 to 5.5 times the respective one with no suction. The turbulence levels are reduced with the presence of the wall suction. Computed results of the turbulent shear stress [bar uv] are in close agreement with experimental measurements. The distribution of the turbulent kinetic energy k is predicted better by the k-[Omega] model of Wilcox (1993). Nonlinear models of the k-[Epsilon] and k-[Omega] type predict the reduction of the turbulence intensities u[prime], v[prime], w[prime], and the correct levels of v[prime] and w[prime] but they underpredict the level of u[prime].

The effects of bed suction on the structure of turbulent open-channel flow are studied numerically by solving the Reynolds-averaged Navier-Stokes equations. Two low-R turbulence models of the k-[Epsilon] type are used for 'closing' the system of equations. The models of Nagano and Hishida and of Launder and Sharma give similar predictions for suction rates up to 9% against experimental measurements performed by Maclean. The bed-suction effects on the mean flow characteristics are found to be significant within the suction region. The near-bed velocities are increased with increasing suction rate, as well as the bed shear stress. The law of the wall with suction, developed by Stevenson, is found to be applicable for low rates of bed suction up to 0.3%. The excess bed shear stress, resulting from suction, is calculated in the order of three to eight times the respective one with no suction. The turbulence levels are greatly reduced with increasing suction rate and a new normalization of the turbulence characteristics is satisfactory for suction rates up to 0.3%.

The double spiral system was proposed as an alternative to the separate-channel method. The separate-channel method results in an overestimation of the total discharge in main channels and floodplains. The double spiral system considers the interaction between the main channel and the floodplain. The system lessens the additional energy needed to drive a certain discharge at a flow cross section, resulting in a lower flow depth.