Miracle-dz/UniFAR-FTUs huggingface dataset:
TRPML3/BK complex promotes autophagy and bacterial clearance by providing a positive feedback regulation of mTOR via PI3P

Significance Autophagy is a degradation and recycling process that is essential for cellular adaptation to environmental changes, such as nutrient deprivation and bacterial infection. Emerging evidence suggests that endolysosomal Ca2+ release regulates autophagy. However, the endolysosomal Ca2+ release pathway, and its action mechanism and physiopathological significance remain unclear. Here, we report that TRPML3 forms a positive feedback loop with BK channel to facilitate endolysosomal Ca2+ release. TRPML3/BK form another positive feedback loop with mTORC1, a central metabolic sensor, to facilitate autophagy induction via PI3P, an endogenous TRPML3 activator. The two feedback mechanisms amplify autophagy initiation upon nutrient deprivation and bacterial infection. Importantly, TRPML3/BK agonists improve bacterial clearance. This study reveals a mechanism underlying cellular homeostasis upon starvation and bacterial infection.
Kinematics of spatial linkages and its applications to rigid origami

La these conduit une analyse cinematique des mecanismes spatiaux allant de mecanismes spheriques aux mecanismes spatiaux sur-contraints bases sur la methode matricielle D-H et l’applique pour explorer le comportement rigide de pliabilite et de mouvement des modeles d’origami. Dans ce processus, la pliabilite rigide du motif origami en torsion triangulaire est d’abord examinee sur la base de la cinematique du reseau de mecanismes 4 R spheriques et de nouveaux mecanismes 6 R sur-contraints derives par la technique du kirigami. Ensuite, la cinematique du mecanisme de Bricard 6 R plan-symetrique est analysee et ses variations de bifurcation sont discutees. Apres cela, les resultats sont appliques pour etudier le pliage symetrique de l’origami de la waterbomb a six plis a panneau epais, qui est modelise sous laforme d’un reseau de mecanismes de Bricard 6 R plan-symetriques. Le comportement de mouvement de sa tessellation correspondante de feuille de zero-epaisseur est demontre par unreseau de mecanismes 6 R spheriques. Enfin, le comportement de mouvement de la forme cylindrique fermee de l’origami de la waterbomb est analyse a travers une etude parametrique, en le modelisant comme un reseau ferme de mecanismes 6 R spheriques. Ces etudes aident a approfondir la comprehension de la cinematique des mecanismes spatiaux et du mouvement rigide de l’origami, et a jeter les bases des applications techniques des mecanismes spatiaux et des motifs d’origami rigides.
Distributed Robust Learning-Based Backstepping Control Aided With Neurodynamics for Consensus Formation Tracking of Underwater Vessels

This article addresses distributed robust learning-based control for consensus formation tracking of multiple underwater vessels, in which the system parameters of the marine vessels are assumed to be entirely unknown and subject to the modeling mismatch, oceanic disturbances, and noises. Toward this end, graph theory is used to allow us to synthesize the distributed controller with a stability guarantee. Due to the fact that the parameter uncertainties only arise in the vessels’ dynamic model, the backstepping control technique is then employed. Subsequently, to overcome the difficulties in handling time-varying and unknown systems, an online learning procedure is developed in the proposed distributed formation control protocol. Moreover, modeling errors, environmental disturbances, and measurement noises are considered and tackled by introducing a neurodynamics model in the controller design to obtain a robust solution. Then, the stability analysis of the overall closed-loop system under the proposed scheme is provided to ensure the robust adaptive performance at the theoretical level. Finally, extensive simulation experiments are conducted to further verify the efficacy of the presented distributed control protocol.
Feasibility and clinical utility of local rapid Nanopore influenza A virus whole genome sequencing for integrated outbreak management, genotypic resistance detection and timely surveillance

Rapid respiratory viral whole genome sequencing (WGS) in a clinical setting can inform real-time outbreak and patient treatment decisions, but the feasibility and clinical utility of influenza A virus (IAV) WGS using Nanopore technology has not been demonstrated. A 24 h turnaround Nanopore IAV WGS protocol was performed on 128 reverse transcriptase PCR IAV-positive nasopharyngeal samples taken over seven weeks of the 2022–2023 winter influenza season, including 25 from patients with nosocomial IAV infections and 102 from patients attending the Emergency Department. WGS results were reviewed collectively alongside clinical details for interpretation and reported to clinical teams. All eight segments of the IAV genome were recovered for 97/128 samples (75.8 %) and the haemagglutinin gene for 117/128 samples (91.4 %). Infection prevention and control identified nosocomial IAV infections in 19 patients across five wards. IAV WGS revealed two separate clusters on one ward and excluded transmission across different wards with contemporaneous outbreaks. IAV WGS also identified neuraminidase inhibitor resistance in a persistently infected patient and excluded avian influenza in a sample taken from an immunosuppressed patient with a history of travel to Singapore which had failed PCR subtyping. Accurate IAV genomes can be generated in 24 h using a Nanopore protocol accessible to any laboratory with SARS-CoV-2 Nanopore sequencing capacity. In addition to replicating reference laboratory surveillance results, IAV WGS can identify antiviral resistance and exclude avian influenza. IAV WGS also informs management of nosocomial outbreaks, though molecular and clinical epidemiology were concordant in this study, limiting the impact on decision-making.
Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels

Abstract Though the effect of the recently identified mitochondrial NAD+ transporter SLC25A51 on glucose metabolism has been described, its contribution to other NAD+-dependent processes throughout the cell such as ADP-ribosylation remains elusive. Here, we report that absence of SLC25A51 leads to increased NAD+ concentration not only in the cytoplasm and but also in the nucleus. The increase is not associated with upregulation of the salvage pathway, implying an accumulation of constitutively synthesized NAD+ in the cytoplasm and nucleus. This results in an increase of PARP1-mediated nuclear ADP-ribosylation, as well as faster repair of DNA lesions induced by different single-strand DNA damaging agents. Lastly, absence of SLC25A51 reduces both MMS/Olaparib induced PARP1 chromatin retention and the sensitivity of different breast cancer cells to PARP1 inhibition. Together these results provide evidence that SLC25A51 might be a novel target to improve PARP1 inhibitor based therapies by changing subcellular NAD+ redistribution.
Stabilization in a chemotaxis model for virus infection

This paper presents a qualitative analysis of a model describing the time and space dynamics of a virus which migrates driven by chemotaxis. The initial-boundary value problem related to applications of the model to a real biological dynamics is studied in detail. The main result consists in the proof of global existence and asymptotic stability.
Efficacy and Safety of Intravenous Thrombolysis in Patients with Acute Ischemic Stroke and Pre–Existing Disability

Little is known about intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients with pre-existing disability. Disabled patients are often excluded from IVT treatment. Previous studies investigated the role of pre-existing disability on outcomes in AIS patients after IVT. However, no studies have been conducted to date to determine whether IVT may improve clinical outcomes in AIS patients with pre-existing disability. The aim of our study was to evaluate efficacy and safety of IVT in patients with pre-existing moderate and moderately severe disability (pre-stroke modified Rankin Scale score = 3 or 4) affected by AIS. This study was based on a retrospective analysis of a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS from January 2015 to May 2018. The efficacy endpoints were the rate of favorable outcome and rate of major neurological improvement. The safety endpoints were the rate of mortality at three months, presence of intracranial hemorrhage (ICH), and presence of symptomatic intracranial hemorrhage (sICH). The study population included 110 AIS patients with pre-existing moderate and moderately severe disability, 36 of which received (IVT+) and 74 did not receive IVT (IVT−). AIS disabled patients treated with IVT had higher rates of favorable outcome (66.7% vs. 36.5%, p = 0.003) and major neurological improvement (39.4% vs. 17.4%, p = 0.01) compared to non-treated ones. Two in three disabled patients returned to their pre-stroke functional status when treated with IVT. Prevalence of three-month mortality, ICH, and sICH did not differ in the two groups. Disabled patients affected by AIS significantly improved after IVT. Moderate and moderately severe disability alone should not be considered, per se, as a contraindication to IVT treatment.
Multiple repeat elements within the FAM21 tail link the WASH actin regulatory complex to the retromer

The WASH complex controls actin dynamics on endosomes, and its functional mechanism is poorly defined. The WASH complex subunit Fam21 bears many copies of a novel motif that directly interacts with the retromer cargo-selective complex. Endosomal localization of FAM21 requires both the retromer and multivalency of the repeat elements.
THE WHOLE IS GREATER THAN THE SUM OF ITS PARTS – PRICING PRESSURE INDICES FOR MERGERS OF VERTICALLY INTEGRATED FIRMS

The paper analyzes gross upward pricing pressure indices called iGUPPI to assess the effects of a merger between vertically integrated firms where in the downstream market also independent rivals are active. Such indices could be used e.g. to screen mergers between mobile network operators which compete with mobile virtual network operators in the downstream retail market. It is shown that the iGUPPI for the downstream market corresponds to the sum of two well-known upward pricing pressure indices, the GUPPI concept of Salop/Moresi (2009) and the vGUPPI concept of Moresi/Salop (2013). Such a simple decomposition however does not hold for the upstream market a priori. Here, additional effects arise which are not included by the two concepts. Further assumptions on the price reactions of the downstream divisions to increases in the input prices are imposed so that the iGUPPI for the upstream market allows for a decomposition into an upstream market version of the GUPPI and the vGUPPI. JEL–Classifications: L41, L42
Multi‐echo single‐shot spectroscopy combined with simultaneous 2D model fitting for fast and accurate measurement of metabolite‐specific concentrations and T2 relaxation times

The purpose of the current study was to develop a novel single‐voxel MR spectroscopy acquisition scheme to simultaneously determine metabolite‐specific concentrations and transverse relaxation times within realistic clinical scan times. Partly truncated multi‐TE data are acquired as an echo train in a single acquisition (multi‐echo single‐shot [MESS]). A 2D multiparametric model fitting approach combines truncated, low‐resolved short TE data with fully sampled, highly resolved, longer TE data to yield concentration and T2 estimates for major brain metabolites simultaneously. Cramer–Rao lower bounds (CRLB) are used as a measure of performance. The novel scheme was compared with traditional multi‐echo multi‐shot methods. In silico, in vitro, and in vivo experiments support the findings. MESS schemes, requiring only 2 min 12 s for the acquisition of three echo times, provide valid concentration and relaxation estimates for multiple metabolites and outperform traditional methods for simultaneous determinations of metabolite‐specific T2s and concentrations, with improvements ranging from 5% to 30% for T2s and from 10% to 50% for concentrations. However, substantial unsuppressed residual water signals may hamper the method's reproducibility, as observed in an initial experiment setup that prioritizes short TEs with severely truncated acquisition for the benefit of signal‐to‐noise ratio (SNR). Nevertheless, CRLB have been confirmed to be well suited as design criteria, and within‐session repeatability approaches CRLB when residual water is removed in postprocessing by exploiting longer and less truncated data recordings. MESS MRS combined with 2D model fitting promises comparable accuracy, increased precision, or inversely shorter experimental times compared with traditional approaches. However, the optimal design must be investigated as a trade‐off between SNR, the truncation factor, and TE batch selections, all of which influence the robustness of estimations.
Special Section on Mechanism-Based Predictive Methods in Drug Discovery and Development—Editorial

In the current issue of Drug Metabolism and Disposition (DMD), Dr. Yuichi Sugiyama, a highly esteemed scientist in the ﬁ eld of pharmacology and one of the most proli ﬁ c authors in DMD (Ding, 2023), is celebrated for his seminal contributions to the ﬁ elds of physiologically based pharmacokinetics (PBPK) and membrane transporters in a special section authored by him and several of his former trainees, titled “ Mechanism-Based Predictive Methods in Drug Discovery and Development. ” Dr. Sugiyama began his career at the University of Tokyo in 1974 and was mentored by Dr. Manabu Hanano (professor) and Dr. Shoji Awazu (associate professor), where he ﬁ rst encountered the concept of PBPK modeling and, later, mechanism-based pharmacokinetics. He studied hepatology at UCLA from 1979 to 1981 and, after returning to the University of Tokyo, was promoted to associate professor in 1989 and professor in 1991. During his tenure at the University of Tokyo, he trained 79 Ph.D.- and 86 master-level students, and he is now active in various positions in academia and global pharmaceutical industries. After he retired from the University of Tokyo, he continued his scienti ﬁ c pursuits as the head of the Sugiyama Laboratory in the RIKEN Innovation Center in Yokohama and as a professor emeritus at the Innovation base of Josai International University. Throughout his career, Dr. Sugiyama has focused on unraveling the mechanisms underlying the pharmacokinetics of drugs and developing methods for quantitative prediction of their properties. He has covered diverse research areas, including molecular biology, pharmacogenomics, molecular imaging, in silico analysis, and metabolomics. He has developed novel approaches, such as in vitro – in vivo extrapolation, to address uncertainties caused by species differences in drug transport, metabolism, and protein binding. His work on PBPKs has been pivotal for quantitative in vitro
A novel hypoxia‐stimulated lncRNA HIF1A‐AS3 binds with YBX1 to promote ovarian cancer tumorigenesis by suppressing p21 and AJAP1 transcription

Hypoxia is characteristic of the ovarian tumor (OC) microenvironment and profoundly affects tumorigenesis and therapeutic response. Long noncoding RNAs (lncRNAs) play various roles in tumor progression; however, the characteristics of lncRNAs in pathological responses of the OC microenvironment are not entirely understood. Through high‐throughput sequencing, lncRNA expression in hypoxia (1% O2) and normoxia (21% O2) SKOV3 cells was explored and analyzed. The 5′‐ and 3′‐rapid amplification of complementary DNA ends was used to detect the full length of the novel HIF1A‐AS3 transcript. Real‐time quantitative polymerase chain reaction was used to assess HIF1A‐AS3 expression in OC cells and tissues. In vitro and in vivo evaluations of the biological functions of hypoxic HIF1A‐AS3 were conducted. To clarify the underlying mechanisms of HIF1A‐AS3 in hypoxic OC, a dual‐luciferase assay, chromatin immunoprecipitation, RNA pull‐down, RNA immunoprecipitation, and RNA‐sequencing were used. We used high‐throughput sequencing to investigate a novel lncRNA, HIF1A‐AS3, as a hypoxic candidate significantly elevated in OC cells/tissues. HIF1A‐AS3 was predominantly localized in the nucleus and promoted in vitro and in vivo OC growth and tumorigenesis. Hypoxia‐inducible factor 1α bound to hypoxia response elements in the HIF1A‐AS3 promoter region and stimulated its expression in hypoxia. Under hypoxia, HIF1A‐AS3 directly integrated with Y‐Box binding protein 1 and inhibited its ability to bind to the promoters of p21 and AJAP1 to repress their transcriptional activity, thereby promoting hypoxic OC progression. Our results revealed the crucial role and mechanism of the novel hypoxic HIF1A‐AS3 in the oncogenesis of OC. The novel HIF1A‐AS3 could be a crucial biomarker and therapeutic target for future OC treatments.
Decomposing magnetic field measurements into internally and externally sourced components in toroidal plasma devices

The magnetic field on any closed surface can be separated into the component produced by currents in the volume enclosed by the surface and the component produced by currents external to the surface. This decomposition was first discovered by Gauss in 1839, and “Gauss' Algorithm” was used to show that the terrestrial field is sourced from inside the Earth. This magnetic source-decomposition can be used in magnetic confinement fusion to distinguish plasma fields from the fields of external sources using standard magnetic measurements, when no conductors reside in the region between the plasma and the magnetic sensors (otherwise, the internal source is not the plasma alone). Here, Gauss' Algorithm is extended from spherical geometry to cylindrical geometry to decompose fields in the cylindrical tokamak. Demonstrations of the decomposition on DIII-D discharges include the measurement of a rotating tearing mode separate from the induced wall eddy currents and the recovery of a vacuum measurement in the presence of an externally applied 3D field. Anticipated axisymmetric and non-axisymmetric applications, and the requisite diagnostics, are discussed. It is concluded that the ITER magnetic diagnostic design is well suited for many important axisymmetric and non-axisymmetric applications. Future work will extend this decomposition to include fields from halo currents and to generalize it to arbitrary toroidal geometries.The magnetic field on any closed surface can be separated into the component produced by currents in the volume enclosed by the surface and the component produced by currents external to the surface. This decomposition was first discovered by Gauss in 1839, and “Gauss' Algorithm” was used to show that the terrestrial field is sourced from inside the Earth. This magnetic source-decomposition can be used in magnetic confinement fusion to distinguish plasma fields from the fields of external sources using standard magnetic measurements, when no conductors reside in the region between the plasma and the magnetic sensors (otherwise, the internal source is not the plasma alone). Here, Gauss' Algorithm is extended from spherical geometry to cylindrical geometry to decompose fields in the cylindrical tokamak. Demonstrations of the decomposition on DIII-D discharges include the measurement of a rotating tearing mode separate from the induced wall eddy currents and the recovery of a vacuum measurement in the presen.
A comparison of diabetic foot ulcer outcomes using negative pressure wound therapy versus historical standard of care

and their bibliographic details recorded here for information. Margolis DJ, Kantor J, Santanna J, et al. Risk factors for delayed healing of neuropathic diabetic foot ulcers: a pooled analysis. Arch Dermatol 2000;136:1531-5. Armstrong DG, Lavery LA. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet 2005;366:1704-10. Indexing Status Subject indexing assigned by NLM MeSH Aged; Cost-Benefit Analysis; Diabetic Foot /pathology /therapy; Female; Follow-Up Studies; Home Care Services /economics; Humans; Male; Middle Aged; Negative-Pressure Wound Therapy /economics; Retrospective Studies; Time Factors; Treatment Outcome; Wound Healing AccessionNumber 22007001605 Date bibliographic record published 15/08/2007 Date abstract record published 09/08/2008 Powered by TCPDF (www.tcpdf.org) NHS Economic Evaluation Database (NHS EED) Produced by the Centre for Reviews and Dissemination Copyright © 2019 University of York Page: 4 / 4
Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-Mutant Non-Small Cell Lung Cancer

Abstract Background Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. Patients and Methods Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. Results One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). Conclusions We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies.