Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia

The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.
Instrument Choice and the Effectiveness of International Sanctions: A Simultaneous Equations Approach

The literature on economic sanctions suggests that the choice of policy instrument, for example trade sanctions, financial sanctions, or military intervention, is endogenous to the political process and, in particular, to the policy outcome sought by the sanctioner. But the choice of instrument also affects the outcome of the sanctions. Therefore, the sanctions policy outcome and the probabilities of the sanctioner's adoption of different sanctions instruments are jointly determined. To capture this endogeneity, multivariate probit and logit models are estimated using data from Hufbauer, Schott & Elliott, with the random utilities to the sanctioner of choosing military action, trade sanctions, and financial sanctions as dependent variables. The expected probabilities of choosing these alternatives are then incorporated as explanatory variables in predicting the success of the sanctions in attaining their political objectives. This procedure generates simultaneous estimates of the determinants of both instrument choice and sanctions success. The empirical results indicate that military force is less likely to be used against an economically healthy and politically stable target than against a more vulnerable target. However, military action is encouraged by third-country assistance to the sanctioned country and by a high cost of sanctions to the sanctioner. Financial sanctions are more likely to be used against a target that receives third-country support but are less likely against an economically healthy country. Sanctions success is positively correlated with the degree of warmth in relations between sanctioner and target prior to the sanctions; negatively correlated with the size of the sanctioner relative to the target; and negatively correlated with the economic health and political stability of the target. There is no evidence that third-country assistance to the target diminishes the effectiveness of sanctions or that the cost of sanctions to either the target or the sanctioner has a strong effect on the sanctions outcome.
Psychometric Properties of the HADS Measure of Anxiety and Depression Among Multiple Sclerosis Patients in Croatia

Depression and anxiety are common complaints in patients with multiple sclerosis (MS). The study objective was to investigate the factor structure, internal consistency, and correlates of the Croatian version of the Hospital Anxiety and Depression Scale (HADS) in patients with MS. A total of 179 patients with MS and 999 controls were included in the online survey. All subjects completed the HADS and self-administered questionnaires capturing information of demographic, education level, disease-related variables, and the Multiple Sclerosis Impact Scale-29 (MSIS-29). Psychometric properties were examined by estimating the validity, reliability, and factor structure of the HADS in patients with MS. The two HADS subscales (anxiety and depression) had excellent internal consistencies (Cronbach’s α value 0.82–0.83), and factor analysis confirmed a two-factor structure. The convergent validity of the HADS subscales appeared to be good due to the significant correlations between HADS and MSIS-29. Receiver operating characteristic (ROC) analysis indicates that the HADS subscales have a significant diagnostic validity for group differentiation. Hierarchical regression analysis using MSIS-29 subscales as criterion variables showed consistent evidence for the incremental validity of the HADS. The HADS is a reliable and valid self-assessment scale in patients with MS and is suggested to be used in clinical monitoring of the psychiatric and psychological status of patients with MS.
Bone Turnover Markers in Response to Ultrasound-Guided Microwave Ablation for Primary Hyperparathyroidism

Objective To assess the efficacy and safety of ultrasound-guided microwave ablation (MWA) in the treatment of primary hyperparathyroidism (PHPT), and to investigate whether MWA can improve the bone turnover and renal function. Methods A total of 20 consecutive PHPT patients with 21 parathyroid lesions treated with MWA in our center from May 2019 to March 2021 were recruited in this study. Serum parathyroid hormone (PTH), calcium and phosphorus levels before MWA and at 20 minutes, 4 hours, 1 day, 3 months, 6 months and 12 months after MWA were measured. Bone turnover biomarkers, renal function and lesion volume with volume reduction rate (VRR) before MWA and at the last follow-up were compared. Any complication related with MWA was evaluated. The technical and clinical success rates of MWA in the treatment of PHPT were calculated. Clinical success was defined as normal serum PTH and calcium without PHPT-associated manifestations at more than 6 months after ablation. Technical success was defined as complete ablation indicated by immediate postoperative contrast-enhanced ultrasound. Results The serum PTH, calcium and phosphorus levels at their respective follow-up time points dropped significantly after MWA (P <0.05). The volume of parathyroid lesions at the final examination was significantly reduced, compared with pre-ablation volume (P <0.001), with a median VRR reaching 89%. The technical and clinical success rates were 100% and 63.6%, respectively. Substantial changes of bone turnover biomarkers were observed before and after MWA (P <0.05), but the differences in renal function were not statistically significant. No major complications were reported in all cases. Pre-MWA serum PTH, lesion volume, maximum diameter of lesion and ablation time were significantly different between patients with successful and failed MWA. Conclusions PHPT can be effectively and safely treated by ultrasound-guided MWA, as proven by drop in serum PTH and reduction in the volume of parathyroid adenomas. Besides, MWA can impede bone remodeling to suppress hyperparathyroidism in the condition of PHPT.
A First in Human Trial Implanting Microalgae Shows Safety of Photosynthetic Therapy for the Effective Treatment of Full Thickness Skin Wounds

Insufficient oxygen supply represents a relevant issue in several fields of human physiology and medicine. It has been suggested that the implantation of photosynthetic cells can provide oxygen to tissues in the absence of a vascular supply. This approach has been demonstrated to be successful in several in vitro and in vivo models; however, no data is available about their safety in human patients. Here, an early phase-1 clinical trial (ClinicalTrials.gov identifier: NCT03960164, https://clinicaltrials.gov/ct2/show/NCT03960164) is presented to evaluate the safety and feasibility of implanting photosynthetic scaffolds for dermal regeneration in eight patients with full-thickness skin wounds. Overall, this trial shows that the presence of the photosynthetic microalgae Chlamydomonas reinhardtii in the implanted scaffolds did not trigger any deleterious local or systemic immune responses in a 90 days follow-up, allowing full tissue regeneration in humans. The results presented here represent the first attempt to treat patients with photosynthetic cells, supporting the translation of photosynthetic therapies into clinics. Clinical Trial Registration: www.clinicaltrials.gov/ct2/show/NCT03960164, identifier: NCT03960164.
Do Differences in Latitudinal Distributions of Species and Organelle Haplotypes Reflect Thermal Reaction Norms Within the Emiliania/Gephyrocapsa Complex?

The cosmopolitan phytoplankter Emiliania huxleyi contrasts with its closest relatives that are restricted to narrower latitudinal bands, making it interesting for exploring how alternative outcomes in phytoplankton range distributions arise. Mitochondrial and chloroplast haplogroups within E. huxleyi are shared with their closest relatives: Some E. huxleyi share organelle haplogroups with Gephyrocapsa parvula and G. ericsonii which inhabit lower latitudes, while other E. huxleyi share organelle haplogroups with G. muellerae, which inhabit high latitudes. We investigated whether the phylogeny of E. huxleyi organelles reflects environmental gradients, focusing on the Southeast Pacific where the different haplogroups and species co-occur. There was a high congruence between mitochondrial and chloroplast haplogroups within E. huxleyi. Haplogroup II of E. huxleyi is negatively associated with cooler less saline waters, compared to haplogroup I, both when analyzed globally and across temporal variability at the small special scale of a center of coastal upwelling at 30° S. A new mitochondrial haplogroup Ib detected in coastal Chile was associated with warmer waters. In an experiment focused on inter-species comparisons, laboratory-determined thermal reaction norms were consistent with latitudinal/thermal distributions of species, with G. oceanica exhibiting warm thermal optima and tolerance and G. muellerae exhibiting cooler thermal optima and tolerances. Emiliania huxleyi haplogroups I and II tended to exhibit a wider thermal niche compared to the other Gephyrocapsa, but no differences among haplogroups within E. huxleyi were found. A second experiment, controlling for local adaptation and time in culture, found a significant difference between E. huxleyi haplogroups. The difference between I and II was of the expected sign, but not the difference between I and Ib. The differences were small (≤1°C) compared to differences reported previously within E. huxleyi by local adaptation and even in-culture evolution. Haplogroup Ib showed a narrower thermal niche. The cosmopolitanism of E. huxleyi might result from both wide-spread generalist phenotypes and specialist phenotypes, as well as a capacity for local adaptation. Thermal reaction norm differences can well explain the species distributions but poorly explain distributions among mitochondrial haplogroups within E. huxleyi. Perhaps organelle haplogroup distributions reflect historical rather than selective processes.
Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.
Early Life Experiences Moderate the Relationship Between Genetic Risk of Autism and Current and Lifetime Mental Health

Although individuals with autism are at greater risk of mental health challenges than others, we know little about the relationship between the mental health of older adults (50+) and autism because they are less likely to be diagnosed. Identifying the risk and protective factors that are associated with mental health can increase educational awareness, inform clinical practice, and provide information to help diagnose and treat older adults with autism. This study used longitudinal panel data of the 2008–2016 waves of the Health and Retirement Study. It estimated individual random-effect models by interacting a genetic propensity toward autism and early life experiences to test whether the latter has a moderating effect on the relationships between genetics and the Center for Epidemiologic Studies Depression (CES-D) score, self-reported depression, and history of psychiatric problems. Results suggest that individuals with a higher genetic propensity for autism are less likely to develop psychiatric problems if they report a positive maternal relationship early in life. Further, a combined effect of police encounters early in life and genetic risk for autism is associated with higher CES-D scores, increased odds of self-reported depression, and a history of psychiatric problems. Clinical applications of these findings include the need to establish and support high-quality relationships by addressing both child and caregiver needs. Further, these findings support the need to design and implement proactive interventions to teach police and autistic individuals how to successfully navigate these encounters.
Early-Time Non-Equilibrium Pitch Angle Diffusion of Electrons by Whistler-Mode Hiss in a Plasmaspheric Plume Associated with BARREL Precipitation

In August 2015, the Balloon Array for Radiation belt Relativistic Electron Losses (BARREL) observed precipitation of energetic ( < 200 keV) electrons magnetically conjugate to a region of dense cold plasma as measured by the twin Van Allen Probes spacecraft. The two spacecraft passed through the high density region during multiple orbits, showing that the structure was spatial and relatively stable over many hours. The region, identified as a plasmaspheric plume, was filled with intense hiss-like plasma waves. We use a quasi-linear diffusion model to investigate plume whistler-mode hiss waves as the cause of precipitation observed by BARREL. The model input parameters are based on the observed wave, plasma and energetic particle properties obtained from Van Allen Probes. Diffusion coefficients are found to be largest in the same energy range as the precipitation observed by BARREL, indicating that the plume hiss waves were responsible for the precipitation. The event-driven pitch angle diffusion simulation is also used to investigate the evolution of the electron phase space density (PSD) for different energies and assumed initial pitch angle distributions. The results show a complex temporal evolution of the phase space density, with periods of both growth and loss. The earliest dynamics, within the ∼5 first minutes, can be controlled by a growth of the PSD near the loss cone (by a factor up to ∼2, depending on the conditions, pitch angle, and energy), favored by the absence of a gradient at the loss cone and by the gradients of the initial pitch angle distribution. Global loss by 1-3 orders of magnitude (depending on the energy) occurs within the first ∼100 min of wave-particle interaction. The prevalence of plasmaspheric plumes and detached plasma regions suggests whistler-mode hiss waves could be an important driver of electron loss even at high L-value (L ∼6), outside of the main plasmasphere.
Pathogen-Host Interaction Repertoire at Proteome and Posttranslational Modification Levels During Fungal Infections

Prevalence of fungal diseases has increased globally in recent years, which often associated with increased immunocompromised patients, aging populations, and the novel Coronavirus pandemic. Furthermore, due to the limitation of available antifungal agents mortality and morbidity rates of invasion fungal disease remain stubbornly high, and the emergence of multidrug-resistant fungi exacerbates the problem. Fungal pathogenicity and interactions between fungi and host have been the focus of many studies, as a result, lots of pathogenic mechanisms and fungal virulence factors have been identified. Mass spectrometry (MS)-based proteomics is a novel approach to better understand fungal pathogenicities and host–pathogen interactions at protein and protein posttranslational modification (PTM) levels. The approach has successfully elucidated interactions between pathogens and hosts by examining, for example, samples of fungal cells under different conditions, body fluids from infected patients, and exosomes. Many studies conclude that protein and PTM levels in both pathogens and hosts play important roles in progression of fungal diseases. This review summarizes mass spectrometry studies of protein and PTM levels from perspectives of both pathogens and hosts and provides an integrative conceptual outlook on fungal pathogenesis, antifungal agents development, and host–pathogen interactions.
Challenges of machine learning-based RUL prognosis: A review on NASA's C-MAPSS data set

The estimation of a system's or a component's remaining useful life (RUL) is considered the most complex task in predictive maintenance, at the same time the most beneficial one. In this brief review paper, we survey the state-of-the-art in machine learning-based RUL prognosis based on research on NASA's C-MAPSS data set. We identify the frequently used models, comparatively evaluate model performance and survey the used feature extraction methods. As a main contribution, we formulate challenges in the field, independently of the C-MAPSS data set. Among the challenges are interpretability, model uncertainty and domain adaptation, i.e. transfer learning. The identified challenges may serve to identify potential research directions, in order to further push the field of machine learning applied to RUL prognosis.
Exact analysis for basic single-rate cyclic executives

The academic interest in cyclic executives for multitasking in hard real-time systems decreased significantly during the past decades. Moreover, cyclic executives are hardly addressed in contemporary text books, if at all. Cyclic executives are still in use, however, and there is therefore a need for analysis techniques for these executives. In this document, we consider two basic cyclic executives, i.e. a single-rate AFAP (as fast as possible) and a single-rate time-driven AFAP cyclic executive, scheduling a given sequence of independent hard real-time polling tasks in a single-processor system. We present exact analysis for both cyclic executives and discuss their relative strengths and weaknesses in terms of jitter, energy efficiency, and schedulability. Unlike existing approaches, which typically take periodic tasks as a starting point for cyclic executives and focus on schedulability of tasks, we take the schedulability of the system as a starting point, i.e. whether or not the system meets its deadlines. In particular, we do not assume periods and deadlines for tasks.
Vulnerability Maps for Reinforced Concrete Structures for Mexico City's Metropolitan Area under a Design Earthquake Scenario

This paper presents vulnerability maps for reinforced concrete moment frames (RCMFs) in Mexico City's Metropolitan Area (MCMA) for a Ms =8.1 earthquake scenario assessing peak nonlinear dynamic responses using the concept of displacement ductility demand spectra (DDDS). The considered earthquake scenario is the 1985 Michoacán Earthquake. Artificial and recorded ground motions were used. Takeda model was used to simulate nonlinear behavior of RCMFs. Seismic strength for existing RCMFs structures was estimated according to the nominal strength required by versions of Mexico's Federal District Code (MFDC) that were effective before the 1985 earthquake. Overstrength sources for RCMFs were also evaluated. With all of this information, DDDS were obtained for different sites in MCMA. Later, vulnerability maps based on contours of equal displacement ductility demands and nonlinear displacements for a given structural period and a version of MFDC were defined. These vulnerability maps were compared with the geographic area of severe structural damage and collapses mapped during the 1985 earthquake. Based on the results of this study, it is believed that this procedure can be useful to forecast demands for different structural systems for a given earthquake scenario, being therefore potentially useful for urban planning of cities located in zones of high seismic risk.
What Matters Most in Life? A German Cohort Study on the Sources of Meaning and Their Neurobiological Foundations in Four Age Groups

Existing work in the field of positive psychology suggests that people can draw meaning from a variety of sources. The present study aimed to identify the most important sources of meaning and to explore the role of age and neural adaptation processes in this context. As part of a large German cohort study, 1,587 individuals between 12 and 94 years were asked to provide a maximum of five responses to the question “What matters most to you in life? ” We divided the study population into four age groups and analyzed the obtained answers qualitatively and quantitatively using (1) word clouds and (2) frequency comparisons based on a summarizing content analysis. A chi-squared test was used to test the observed differences between age groups. Identified sources of meaning could be clustered into 16 main and 76 subcategories, with relationships (by 90% of respondents) and health and well-being (by 65% of respondents) being the most frequently named main categories, followed by a good living environment (by 28%), (leisure) time (by 26%), and work (by 24%). The study revealed some remarkable age-related patterns. While the importance of partnership increased with age, social networks were less important to older individuals. We also found that, for example, the importance of self-realization, success and career decreased with age, while the opposite was true for life satisfaction and peace and harmony. Security was most important to individuals in the two middle age groups between 30 and 69 years. The study advances our understanding of meaning across various ages by showing that individuals of different ages perceive different things as meaningful to them. Interpreting our results in the light of a neurobiological model of motivation systems, we argue that neural adaptation processes may play an important role in the (changing) perceptions of meaning throughout life.