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Abstract In the context of four-dimensional N $$ \mathcal{N} $$ = 1 type IIB superstring compactifications, the U-dual completion of the holomorphic flux superpotential leads to four S-dual pairs of fluxes, namely (F, H), (Q, P), (P′, Q′) and (H′, F′). It has been observed that the scalar potentials induced by such generalized superpotentials typically have an enormous amount of terms, making it hard to study any phenomenological aspects such as moduli stabilization. In this regard, we present a set of generic master formulae which not only formulate the scalar potential in a compact way but also enable one to read-off the various scalar potential pieces by simply knowing a set of topological data of the compactifying Calabi Yau and its mirror threefold. We demonstrate the applicability of our master formulae by reading-off the scalar potentials for five explicit models, and using a set of axionic flux combinations we show that 76276 terms arising from the flux superpotential in a 𝕋6 /(ℤ2 × ℤ2)-based model can be equivalently expressed by using 2816 terms, while 11212 terms arising from the flux superpotential in a Quintic-based model can be equivalently expressed by 668 terms! We argue that the master formulae presented in this work can be useful in an analytic exploration of the rich landscape of the non-geometric flux vacua.

This study demonstrates the hydrodynamic performance of a modified NACA 4412 hydrofoil and compares it with the base NACA 4412 hydrofoil in the presence of cavitation. A triangular slot has been introduced at the mid-section of the suction side of the hydrofoil to modify the flow characteristics and assess its effects on the performance at different operational cavitation numbers spanning from 0.8 to 2.5, and at different angles of attack ranging from 4° to 16°. The performance metrics considered include the coefficient of lift, coefficient of drag, and the lift-to-drag ratio. The Reynolds number considered in this study is approximately 1.5 million. The SST k-ω turbulence model, homogeneous mixture multiphase model, and Schnerr& Sauer cavitation model have been employed in this study. At lower cavitation numbers, the modified hydrofoil is better able to control cavitation phenomena compared to the base hydrofoil. However, at higher cavitation numbers, the base hydrofoil exhibits slightly better performance than the modified hydrofoil in terms of lift-to-drag ratio, despite having a lower lift coefficient. Furthermore, the modified hydrofoil demonstrates improved performance at 4°, 8°, and 16° angles of attack, while the base hydrofoil performs better at a 12° angle of attack. It was also observed that stalling occurs at a 16° angle of attack for the base hydrofoil, whereas the modified hydrofoil successfully avoids stalling.

Electric vehicles (EVs) are becoming more popular due to environmental consciousness. The limited availability of charging stations (CSs), compared to the number of EVs on the road, has led to increased range anxiety and a higher frequency of CS queries during trips. Simultaneously, personal data use for analytics is growing at an unprecedented rate, raising concerns for privacy. One standard for formalising location privacy is geo-indistinguishability as a generalisation of local differential privacy. However, the noise must be tuned properly, considering the implications of potential utility losses. In this paper, we introduce the notion of approximate geo-indistinguishability (AGeoI), which allows EVs to obfuscate their query locations while remaining within their area of interest. It is vital because journeys are often sensitive to a sharp drop in quality of service (QoS). Our method applies AGeoI with dummy data generation to provide two-fold privacy protection for EVs while preserving a high QoS. Analytical insights and experiments demonstrate that the majority of EVs get “privacy-for-free” and that the utility loss caused by the gain in privacy guarantees is minuscule. In addition to providing high QoS, the iterative Bayesian update allows for a private and precise CS occupancy forecast, which is crucial for unforeseen traffic congestion and efficient route planning.

BackgroundThe aim of this study was to develop natural language processing (NLP) algorithms to conduct automated identification of incidental durotomy, wound drains, and the use of sutures or skin clips for wound closure, in free text operative notes of patients following lumbar surgery.MethodsA single-centre retrospective case series analysis was conducted between January 2015 and June 2022, analysing operative notes of patients aged >18 years who underwent a primary lumbar discectomy and/or decompression at any lumbar level. Extreme gradient-boosting NLP algorithms were developed and assessed on five performance metrics: accuracy, area under receiver-operating curve (AUC), positive predictive value (PPV), specificity, and Brier score.ResultsA total of 942 patients were used in the training set and 235 patients, in the testing set. The average age of the cohort was 53.900 ± 16.153 years, with a female predominance of 616 patients (52.3%). The models achieved an aggregate accuracy of >91%, a specificity of >91%, a PPV of >84%, an AUC of >0.933, and a Brier score loss of ≤0.082. The decision curve analysis also revealed that these NLP algorithms possessed great clinical net benefit at all possible threshold probabilities. Global and local model interpretation analyses further highlighted relevant clinically useful features (words) important in classifying the presence of each entity appropriately.ConclusionsThese NLP algorithms can help monitor surgical performance and complications in an automated fashion by identifying and classifying the presence of various intra-operative elements in lumbar spine surgery.

Dose limiting cardiotoxicity remains a major limiting factor in the clinical use of several cancer chemotherapeutics including anthracyclines and the antimetabolite 5-fluorouracil (5-FU). Prior work has demonstrated that chemotherapeutics increase expression of R7 family regulator of G protein signaling (RGS) protein-binding partner Gβ5, which drives myocyte cytotoxicity. However, though several R7 family members are expressed in heart, the exact role of each protein in chemotherapy driven heart damage remains unclear. Here, we demonstrate that RGS11, downregulated in the human heart following chemotherapy exposure, possesses potent anti-apoptotic actions, in direct opposition to the actions of fellow R7 family member RGS6. RGS11 forms a direct complex with the apoptotic kinase CaMKII and stress responsive transcription factor ATF3 and acts to counterbalance the ability of CaMKII and ATF3 to trigger oxidative stress, mitochondrial dysfunction, cell death, and release of the cardiokine neuregulin-1 (NRG1), which mediates pathological intercommunication between myocytes and endothelial cells. Doxorubicin triggers RGS11 depletion in the murine myocardium, and cardiac-specific OE of RGS11 decreases doxorubicin-induced fibrosis, myocyte hypertrophy, apoptosis, oxidative stress, and cell loss and aids in the maintenance of left ventricular function. Conversely, RGS11 knockdown in heart promotes cardiac fibrosis associated with CaMKII activation and ATF3/NRG1 induction. Indeed, inhibition of CaMKII largely prevents the fibrotic remodeling resulting from cardiac RGS11 depletion underscoring the functional importance of the RGS11-CaMKII interaction in the pathogenesis of cardiac fibrosis. These data describe an entirely new role for RGS11 in heart and identify RGS11 as a potential new target for amelioration of chemotherapy-induced cardiotoxicity.

AbstractBackground Ursolic acid (UA) is a potent plant-based hepatoprotective agent having poor bioavailability, which hampers its therapeutic efficacy. The present study tries to overcome this limitation by combining it with piperine (PIP), a proven bioenhancer and hepatoprotective agent.Methods The type of interaction (synergism, addition, or antagonism) resulting between UA and PIP was analyzed and quantified by isobologram and combination index analysis. The hepatoprotective activity of UA and PIP was evaluated by measuring the level of hepatic marker enzymes. Pharmacokinetic analysis was carried out to ascertain the improvement of bioavailability.Results The combinations significantly decrease the enzyme levels, which indicate better hepatoprotective activity compared to single drugs. The relative oral bioavailability of UA was increased about tenfold (from AUC0–t =12.78 ± 2.59 µg/h/ml to 125.15 ± 1.84 µg/h/ml) along with the improvement of plasma concentration and elimination half-life.Conclusions The findings indicated that the combination of PIP and UA is an effective strategy in enhancing the bioavailability and hepatoprotective potential of UA.KEY MESSAGESUrsolic acid in a combination with piperine provides a synergistic hepatoprotective effect in carbon tetrachloride induced liver damage in rats.Piperine improves the pharmacokinetic properties of ursolic acid when given in combination.Piperine improves the relative oral bioavailability of ursolic acid by tenfold when combined together.

The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.

Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ5), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ5 in liver. Thus, Gβ5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage.

Cellular phenotypes on bioactive compound treatment are a result of the downstream targets of the respective treatment. Here, a computational approach is taken for downstream subcellular target identification to understand the basis of the cellular response. This response is a readout of cellular phenotypes captured from cell-painting-based light microscopy images. The readouts are morphological profiles measured simultaneously from multiple cellular organelles. Cellular profiles generated from roughly 270 diverse treatments on bone cancer cell line form the high content screen used in this study. Phenotypic diversity across these treatments is demonstrated, depending on the image-based phenotypic profiles. Furthermore, the impact of the treatments on specific organelles and associated organelle sensitivities are determined. This revealed that endoplasmic reticulum has a higher likelihood of being targeted. Employing multivariate regression overall cellular response is predicted based on fewer organelle responses. This prediction model is validated against 1,000 new candidate compounds. Different compounds despite driving specific modulation outcomes elicit a varying effect on cellular integrity. Strikingly, this confirms that phenotypic responses are not conserved that enables quantification of signaling heterogeneity. Agonist-antagonist signaling pairs demonstrate switch of the targets in the cascades hinting toward evidence of signaling plasticity. Quantitative analysis of the screen has enabled the identification of these underlying signatures. Together, these image-based profiling approaches can be employed for target identification in drug and diseased states and understand the hallmark of cellular response.

Cell behavior is controlled through spatio-temporally localized protein activity. Despite unique and often contradictory roles played by Src-family-kinases (SFKs) in regulating cell physiology, activity patterns of individual SFKs have remained elusive. Here, we report a biosensor for specifically visualizing active conformation of SFK-Fyn in live cells. We deployed combinatorial library screening to isolate a binding-protein (F29) targeting activated Fyn. Nuclear-magnetic-resonance (NMR) analysis provides the structural basis of F29 specificity for Fyn over homologous SFKs. Using F29, we engineered a sensitive, minimally-perturbing fluorescence-resonance-energy-transfer (FRET) biosensor (FynSensor) that reveals cellular Fyn activity to be spatially localized, pulsatile and sensitive to adhesion/integrin signaling. Strikingly, growth factor stimulation further enhanced Fyn activity in pre-activated intracellular zones. However, inhibition of focal-adhesion-kinase activity not only attenuates Fyn activity, but abolishes growth-factor modulation. FynSensor imaging uncovers spatially organized, sensitized signaling clusters, direct crosstalk between integrin and growth-factor-signaling, and clarifies how compartmentalized Src-kinase activity may drive cell fate.