Miracle-dz/UniFAR-FTUs huggingface dataset:
Non-Clinical Toxicology Evaluation of the Novel Non-ATP Competitive Oral PI3 Kinase Delta Inhibitor Roginolisib

Roginolisib (IOA-244) is a novel, non-ATP competitive phosphoinositide-3-kinase (PI3K) delta inhibitor that regulates Akt/mTOR signaling. Roginolisib was administered once daily to rats and dogs in dose-range finding (DRF) and 4-week GLP toxicology studies. Free plasma levels of roginolisib exceeded the cellular target engagement IC90 for PI3Kδ for ≥12 hours at doses of 5 mg/kg, the IC90 for PI3Kβ for ≥2 hours at doses ≥15 mg/kg, and the IC50 for PI3Kα for ≥2 hours at dose levels ≥45 mg/kg. Toxicity in rats occurred at doses ≥100 mg/kg. In dogs, we observed dose-dependent skin and gastrointestinal toxicity and doses ≥30 mg/kg had a greater incidence of mortality. Lymphoid tissue toxicity occurred in both species. Toxicities in dogs observed at the ≥15 mg/kg dose, affecting the digestive mucosa, liver, and skin, cleared after treatment cessation. Doses ≤75 mg/kg were tolerated in rats and the no-observed-adverse-effect-level (NOAEL) in rats was 15 mg/kg. Due to mainly epithelial lesions of the skin at 5 mg/kg and necrotizing damage of the intestinal epithelia at ≥15 mg/kg, no NOAEL was determined in dogs. However, the adverse effects observed in dogs at 5 mg/kg were considered monitorable and reversible in patients with advanced malignancies. Furthermore, the PK profile subsequently proved to be a decisive factor for achieving selective PI3Kδ inhibition without the toxicities observed in dogs. As the result of the unique PK profile of roginolisib, patients were able to take daily roginolisib without dose modification and showed pharmacodynamic PI3Kδ inhibition over several months without gastrointestinal or dermatologic toxicities.
Structural characterization of human RPA70N association with DNA damage response proteins

The heterotrimeric Replication protein A (RPA) is the ubiquitous eukaryotic single-stranded DNA (ssDNA) binding protein and participates in nearly all aspects of DNA metabolism, especially DNA damage response. The N-terminal OB domain of the RPA70 subunit (RPA70N) is a major protein-protein interaction element for RPA and binds to more than 20 partner proteins. Previous crystallography studies of RPA70N with p53, DNA2 and PrimPol fragments revealed that RPA70N binds to amphipathic peptides that mimic ssDNA. NMR chemical-shift studies also provided valuable information on the interaction of RPA70N residues with target sequences. However, it is still unclear how RPA70N recognizes and distinguishes such a diverse group of target proteins. Here, we present high-resolution crystal structures of RPA70N in complex with peptides from eight DNA damage response proteins. The structures show that, in addition to the ssDNA mimicry mode of interaction, RPA70N employs multiple ways to bind its partners. Our results advance the mechanistic understanding of RPA70N-mediated recruitment of DNA damage response proteins.
Coronary microvascular dysfunction and heart failure with preserved ejection fraction: what are the mechanistic links?

Purpose of review Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort. Recent findings There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically. Summary CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.
Mechanical ventilation in patients with acute respiratory distress syndrome: current status and future perspectives

ABSTRACT Introduction Although there has been extensive research on mechanical ventilation for acute respiratory distress syndrome (ARDS), treatment remains mainly supportive. Recent studies and new ventilatory modes have been proposed to manage patients with ARDS; however, the clinical impact of these strategies remains uncertain and not clearly supported by guidelines. The aim of this narrative review is to provide an overview and update on ventilatory management for patients with ARDS. Areas covered This article reviews the literature regarding mechanical ventilation in ARDS. A comprehensive overview of the principal settings for the ventilator parameters involved is provided as well as a report on the differences between controlled and assisted ventilation. Additionally, new modes of assisted ventilation are presented and discussed. The evidence concerning rescue strategies, including recruitment maneuvers and extracorporeal membrane oxygenation support, is analyzed. PubMed, EBSCO, and the Cochrane Library were searched up until June 2023, for relevant literature. Expert opinion Available evidence for mechanical ventilation in cases of ARDS suggests the use of a personalized mechanical ventilation strategy. Although promising, new modes of assisted mechanical ventilation are still under investigation and guidelines do not recommend rescue strategies as the standard of care. Further research on this topic is required.
Commentary: The challenges and promises of competitively employing autistic adults in the United States

Current United States statistics suggest that autistic individuals will experience high unemployment and underemployment rates throughout their lives. Furthermore, despite the passage of federal legislation to employ young autistic adults in competitive integrated settings, where they work alongside non‐disabled workers and earn at least minimum wage, most individuals receiving state services still are placed in day programs or sheltered workshops. Since meaningful employment is the most important determinant of life satisfaction, this failure is a critical societal problem, exerting increasing pressure for systems change. But the news is not all bad. Private sector companies have increased their hiring of disabled workers, producing a growing base of expertise in the recruitment, on‐boarding, training, and management of autistic employees. This has led to a growing recognition that autistic individuals can be ideal workers. Autism researchers have advanced the field by investigating these private industry programs as well as conducting efficacy trials of interventions and services that help autistic individuals in the workplace. However, gaps in knowledge persist stemming from the heterogeneity of autistic workers, limited knowledge about those not receiving state services, and a system of federal services that is fragmented, poorly coordinated, difficult to navigate, and over‐taxed. Autism researchers can continue to improve outcomes of autistic workers through investigations of the fit between autistic workers, their preferences, and the characteristics of available jobs, and through effectiveness trails of promising employment interventions and services that promote systems change that help break down the barriers to better integration of existing state services and resources in the United States.
Downclimbing and the evolution of ape forelimb morphologies

The forelimbs of hominoid primates (apes) are decidedly more flexible than those of monkeys, especially at the shoulder, elbow and wrist joints. It is tempting to link the greater mobility of these joints to the functional demands of vertical climbing and below-branch suspension, but field-based kinematic studies have found few differences between chimpanzees and monkeys when comparing forelimb excursion angles during vertical ascent (upclimbing). There is, however, a strong theoretical argument for focusing instead on vertical descent (downclimbing), which motivated us to quantify the effects of climbing directionality on the forelimb kinematics of wild chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys). We found that the shoulders and elbows of chimpanzees and sooty mangabeys subtended larger joint angles during bouts of downclimbing, and that the magnitude of this difference was greatest among chimpanzees. Our results cast new light on the functional importance of downclimbing, while also burnishing functional hypotheses that emphasize the role of vertical climbing during the evolution of apes, including the human lineage.
Weld map tomography for determining local grain orientations from ultrasound

The complex structure of inhomogeneous welds poses a long-standing challenge in ultrasonic non-destructive testing. Elongated grains with spatially varying dominant orientations can distort and split the ultrasonic beam, hindering inspection data interpretation. One way to tackle this problem is to include material information in imaging and signal analysis; however, such information is often only gathered using destructive methods. This paper reports the development of a physics-based weld inversion strategy determining grain orientations using a ray tomography principle. The considered approach does not rely on a macroscopic weld description but may incorporate it to facilitate inversion. Hence, it is more general than other available approaches. The methodology is demonstrated in both numerical and experimental examples. The experimental work focuses on mock-up samples from the nuclear industry and a sample manufactured during this research. The ‘ground truth’ for the latter comes from an EBSD evaluation—the most accurate (yet destructive) examination technique available. Across the considered specimens, our methodology yielded orientation maps with average errors well below 20∘, leading to time-of-flight errors below 0.05 μs. Applying the result from inversion to ultrasonic imaging offered between 5 and 14 dB signal-to-noise ratio improvement for defect signatures.
Empfehlungen für ein körperliches Training zur Sturzprävention bei älteren, selbständig lebenden Menschen

Zusammenfassung Stürze sind der wichtigste Risikofaktor für Frakturen im Alter. Epidemiologische Studien haben viele Risikofaktoren für Stürze identifiziert, die durch strukturiertes körperliches Training beeinflussbar sind. Dieser Artikel beschreibt die Evidenz zu Inhalten, Methoden und Belastungsdosierung eines körperlichen Trainings zur Vermeidung von Stürzen und zur Reduktion des Sturzimpaktes. Die Ergebnisse zeigen hohe Evidenz, dass verglichen mit inaktiven Kontrollgruppen, multimodale Programme, Gleichgewichts-& Funktionstraining und Tai Chi wirksam sind, Stürze zu vermeiden. Insbesondere die Rolle anspruchsvollen Gleichgewichtstrainings kommt hier zum Tragen. Neuere Inhalte/Methodenvariationen sind auch wirksam. Hierzu zählen Stepping und Perturbationstraining. Letzteres scheint auch in kürzeren Zeiträumen beachtliche Effekte zu erzielen. Während einige Programme supervidiert werden müssen, existieren auch wirksame individuelle Heimtrainings. Mit Ausnahme von Perturbationstraining, sollten Programme 3mal/Woche über mind. 3 Monate durchgeführt werden. Ein ggf. periodisiertes, dauerhaftes Training gewährleistet langanhaltende Effekte. Für isoliertes Kraft-, Ausdauer- oder Beweglichkeitstraining, Training im Wasser, Tanzen und interaktive kognitiv-motorische Interventionen liegt keine hinreichende Evidenz vor, um sie als wirksame Trainings in der Sturzprävention zu empfehlen. Jedoch sind sie größtenteils effektiv, um Risikofaktoren zu beeinflussen oder einen Einstieg ins Training zu unterstützen. Limitierte Evidenz existiert für die Beeinflussung des Sturzvorgangs durch Training. Bei gesunden, älteren Menschen sind Sturz-, Abfang-, Abrolltechniken sowie Stepping geeignet, den Impakt selbst-induzierter Stürze zu reduzieren. Keine diesbezüglichen Daten existieren für Verletzungen als Folge echter Stürze.
Varieties of Fluvial Form

Boulder-Bedforms in Jointed-Bedrock Channels. Floods in Central Australia. Flow and Sedimentation at Tributary River. Mouths: A Comparison with Mesotidal Estuaries. Debris Flow and Sheet Flood Fans of the Northern Prince Charles Mountains, East Antarctica. Classifying Bedrock Influenced Semi-Arid River Systems: Extending the Continuum Concept. Bedrock Anastomosing Channel Systems: Morphology and Dynamics of the Sabie River in the Eastern Transvaal Lowveld. Downstream Changes in Valley Confinement as a Control of Floodplain Morphology, Lower Tuross River, NSW, Australia - a Constructivist Approach to Floodplain Analysis. Drainage Evolution and Morphological Development of the Late Cenozoic Sundays River, South Africa. Geomorphology of the Green River in the Eastern Uinta Mountains, Colorado and Utah. The Marmada River, India, through Space and Time. Variability of Fluvial Forms in the Todd River, Central Australia. Anabranching Rivers: Divided Efficiency Leading to Fluvial Diversity. In-Channel Benches: River Adjustment to High Flood Variability. The Fly River, Rapau New Guinea. Inferences about River Dynamics, Floodplain Sedimentation and Fate of Sediment. Downstream Adjustments in Allochthonous Rivers: Western Deccan Trap Upland Region, India. Geomorphology and Coastline Changes of the Lower Yangtze Delta Plain, China. Fluvial Evolution in Areas with Volcanic and Tectonic Activity: The Armeria River (Mexico). Extraterrestrial Fluvial Forms. Channel Planform in Confining Valleys. Alluvial Fan Development in a Hyper-Arid Environment. Sub-Parallel Meander Belts of the Lower Ucayali River in the Upper Amazon Basin - Tectonically Induced Migration or Autocyclic Avulsion? Fluvial Morphology of the Mkuze River Floodplain, Zululand, South Africa. Alluvial Morphology of Channel Bars: A Case Study from Brahmaputra River, Assam.
This Draft : March 2013 Information Acquisition , Noise Trading and Speculation in Double Auction Markets *

This paper analyzes how the size of a double auction market affects information acquisition and trading behavior as well as allocative and informational efficiency. As the main result, this paper shows that with endogenous information if the number of traders and the units a trader is allowed to trade are sufficiently large an efficient equilibrium allocation fails to exist. This inefficiency result is driven by a novel strategic effect that is neither present in an auction where the role of buyers and sellers are assigned exogenously nor in a double auction with exogenous private information. This paper formalizes the notion of how a hedging market becomes a speculative market when the market becomes centralized and large and discusses the link between optimal security design and optimal market design. Journal of Economic Literature Classification Numbers: G14, D82, D83
MRP: An Energy Efficient Network Protocol That Avoids Multiple Encryption in Cloud Computing Environment

To ensure the security of data transmission on the Internet, users usually encrypt the data during the process of sending and receiving data. For example, the commonly used HTTPS protocol verifies the identity of servers through TLS certificates and encrypts communication between browsers and servers. However, the encrypted part of the unstructured data is still re-encrypted by TLS during HTTPS transmission, wasting computing and energy resources. In this paper, we propose an energy efficient network protocol, namely MRP, that avoids multiple encryption. MRP could carry multiple types of application layer protocols, while freely configure the location and encryption approaches of the data that needs to be encrypted. Based on our proposed, users could freely segment application layer data, achieve on-demand encryption of data, reduce encryption costs without compromising user security requirements, avoid redundant double encryption and save energy.
Exploring barriers and enablers to simulation-based training in emergency departments: an international qualitative study (BEST-ED Study)

Introduction Simulation-based training (SBT) has gained significant traction within emergency medicine. The growing body of evidence describes the benefits that SBT can bring. However, identifying barriers and enablers when establishing successful SBT programmes in busy emergency departments (EDs), and ensuring longevity of such programmes, can be difficult. Objective We aim to identify barriers and enablers to SBT in busy EDs. Methods We explored and analysed the thoughts, experience and opinions of professionals involved in SBT and organisational support. 32 participants across 15 international sites were invited to a semistructured interview process. We included participants from a variety of backgrounds, from clinical staff to management staff. Transcribed interview data was classified and coded based on capability, opportunity and motivation behaviour (COM-B) domains and analysed based on theoretical domains framework. Frequency of the most mentioned thematic domain among participants is reported. Results The interview data revealed several common themes, including the following: knowledge and skills (90%), support and leadership (96%), mental barriers (87.5%), local culture (96.6%), dedicated space (65.2%), time constraints (46.8%), social influence (87.5%), education (90.6%), professional development (68.75%), exams (59.3%) and personal goals (93.75%). Management staff was observed to prioritise resource, staffing and flow, while the clinical cohort tended to focus on specialty and personal development when it came to simulation training in the ED. Conclusion Potential barriers and enablers to SBT and in situ simulation for EDs were identified through interviews conducted in this study. The central themes in terms of barriers and enablers were local culture, leadership, individual needs, resources and optimisation. A tailored approach is vital for establishing a successful SBT and in situ simulation programme.
Multi-target Fluid Mixing in MEDA Biochips: Theory and an Attempt toward Waste Minimization

Sample preparation is an inherent procedure of many biochemical applications, and digital microfluidic biochips (DMBs) have proved to be very effective in performing such a procedure. In a single mixing step, conventional DMBs can mix two droplets in a 1:1 ratio only. Due to this limitation, DMBs suffer from heavy fluid wastage and often require a lot of mixing steps. However, the next-generation DMBs, i.e., micro-electrode-dot-array (MEDA) biochips, can realize multiple mixing ratios, which in general helps in minimizing the number of mixing operations. In this article, we present a heuristic-based sample preparation algorithm, specifically a mixing algorithm called Division by Factor Method for MEDA that exploits the mixing models of MEDA biochips. We propose another mixing algorithm for MEDA biochips called Single Target Waste Minimization (STWM), which minimizes the wastage of fluids and determines an efficient mixing graph. We also propose an advanced methodology for multiple target reagent mixing problems called Multi-target Waste Minimization (MTWM), which determines efficient mixing graphs for different target ratios by maximizing the sharing of fluids and minimizing the fluid wastage. Simulation results suggest that the proposed STWM and MTWM methods outperform the state-of-the-art methods in terms of minimizing the amount of fluid wastage, reducing the total usage of reagent fluids, and minimizing the number of mixing operations.
6G Data Analytics Platform for Applying Condition Monitoring in Smart Factory

5G is the new generation of mobile communication and many scientists are doing research on it. Network Data Analytics Function (NWDAF) has been proposed to be a core function in 5G. And the intention is that NWDAF does different analysis tasks on the network data in order to improve the network functionalities and also the third-party applications. Data Science is a field of science which has gained great attention in the last years due to the rising amount of generated data and the necessity to extract information from it. Condition monitoring is an approach to maintain the machinery in industry and especially in the past years using AI/ML methods, scientists could achieve a lot in this field. In this paper we first discuss all the above mentioned topics in more detail, then we propose a data analysis platform using NWDAF in a smart factory scenario. The idea is to apply condition monitoring on the machines’ status which are connected via the 6G network.
A Scoping Survey on Cross-reality Systems

Immersive technologies such as Virtual Reality (VR) and Augmented Reality (AR) empower users to experience digital realities. Known as distinct technology classes, the lines between them are becoming increasingly blurry with recent technological advancements. New systems enable users to interact across technology classes or transition between them—referred to as cross-reality systems. Nevertheless, these systems are not well understood. Hence, in this article, we conducted a scoping literature review to classify and analyze cross-reality systems proposed in previous work. First, we define these systems by distinguishing three different types. Thereafter, we compile a literature corpus of 306 relevant publications, analyze the proposed systems, and present a comprehensive classification, including research topics, involved environments, and transition types. Based on the gathered literature, we extract nine guiding principles that can inform the development of cross-reality systems. We conclude with research challenges and opportunities.