Miracle-dz/UniFAR-FTUs huggingface dataset:
Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out?

Purpose of review The landscape for first-line therapy (1L) of metastatic castration-resistant prostate cancer (mCRPC) is rapidly shifting. In the past 2 years, three phase 3 trials have examined the addition of a poly-ADP ribose polymerase inhibitor (PARPi) to an androgen receptor-signaling inhibitor (ARSI) in 1L. The FDA and the EMA recently considered whether one of these combinations should be approved for “all comers. ” Here, we review the trial designs, assays for homologous recombination repair mutations (HRRm) and BRCA mutations (BRCAm), and predictive capacity of mutational status on treatment efficacy to understand the basis for the FDA decision. Recent findings The phase 3 trials, PROpel, MAGNITUDE, and TALAPRO-2, each compared PARPi and ARSI to placebo (PBO) plus ARSI. PROpel and TALAPRO-2 (cohort 1) included all comers (i.e., no prospective biomarker selection), while MAGNITUDE prospectively assigned patients to HRRm and HRR nonmutated cohorts and TALAPRO-2 (cohort 2) included only those with HRRm. Radiographic progression-free survival (rPFS) was the primary endpoint, and overall survival (OS) was a key secondary endpoint in all trials. Although rPFS with a PARPi and ARSI was improved versus PBO with ARSI, major conclusions differed. Summary The nuances and interpretation of these trials provide an understanding of the rationale for the FDA's decision to restrict the approval of olaparib and abiraterone and prednisone (AAP) as 1L therapy to those with biomarker evidence of BRCAm.
Distinct characteristics of two types of alternative lengthening of telomeres in mouse embryonic stem cells

Abstract Telomere length must be maintained in actively dividing cells to avoid cellular arrest or death. In the absence of telomerase activity, activation of alternative lengthening of telomeres (ALT) allows the maintenance of telomeric length and prolongs the cellular lifespan. Our previous studies have established two types of ALT survivors from mouse embryonic stem cells. The key differences between these ALT survivors are telomere-constituting sequences: non-telomeric sequences and canonical telomeric repeats, with each type of ALT survivors being referred to as type I and type II, respectively. We explored how the characteristics of the two types of ALT lines reflect their fates using multi-omics approaches. The most notable gene expression signatures of type I and type II ALT cell lines were chromatin remodelling and DNA repair, respectively. Compared with type II cells, type I ALT cells accumulated more mutations and demonstrated persistent telomere instability. These findings indicate that cells of the same origin have separate routes for survival, thus providing insights into the plasticity of crisis-suffering cells and cancers.
Inter-Operator Traffic Differentiation based on Multiscale Analysis

Web 2.0 changed the interaction paradigm of Internet users, placing them in a more active role as both producers and consumers of digital contents. This concept has also triggered the appearance of social networks and cloud computing services, which have an increasing contribution to the total traffic amount. The increasing Internet complexity brings new challenges to network operators and managers, which need to understand new applications and know the exact properties of the generated traffic. The ability to accurately map traffic patterns to their corresponding application can be used to build efficient traffic and user profiles, which can be extremely helpful in several critical tasks like network resources optimization, service differentiation and personalization, network management and security. This paper proposes a classification approach that is able to accurately differentiate traffic flows in a core network and associate them with their underlying applications, allowing the construction of accurate traffic and user profiles. By performing a wavelet decomposition and analyzing the obtained scalograms, the captured traffic can be fully characterized in terms of its time and frequency components. As the different frequency components of the traffic are inferred, an appropriate communication profile characteristic of each application type can be defined. This way, it is possible to identify the distinct applications that are being used by the different connected clients and build useful user profiles.
A Constraint on Primordial B-modes from the First Flight of the Spider Balloon-borne Telescope

We present the first linear polarization measurements from the 2015 long-duration balloon flight of Spider, which is an experiment that is designed to map the polarization of the cosmic microwave background (CMB) on degree angular scales. The results from these measurements include maps and angular power spectra from observations of 4.8% of the sky at 95 and 150 GHz, along with the results of internal consistency tests on these data. While the polarized CMB anisotropy from primordial density perturbations is the dominant signal in this region of sky, Galactic dust emission is also detected with high significance. Galactic synchrotron emission is found to be negligible in the Spider bands. We employ two independent foreground-removal techniques to explore the sensitivity of the cosmological result to the assumptions made by each. The primary method uses a dust template derived from Planck data to subtract the Galactic dust signal. A second approach, which constitutes a joint analysis of Spider and Planck data in the harmonic domain, assumes a modified-blackbody model for the spectral energy distribution of the dust with no constraint on its spatial morphology. Using a likelihood that jointly samples the template amplitude and r parameter space, we derive 95% upper limits on the primordial tensor-to-scalar ratio from Feldman–Cousins and Bayesian constructions, finding r < 0.11 and r < 0.19, respectively. Roughly half the uncertainty in r derives from noise associated with the template subtraction. New data at 280 GHz from Spider’s second flight will complement the Planck polarization maps, providing powerful measurements of the polarized Galactic dust emission.
The motion of long drops in rectangular microchannels at low capillary numbers

Drop flow in rectangular microchannels has been utilized extensively in microfluidics. However, the pressure-gradient versus flow-rate relation is still not well understood. We study the motion of a long drop in a rectangular microchannel in the limit the capillary number $Ca\rightarrow 0$ ( $Ca=\unicode[STIX]{x1D707}U/\unicode[STIX]{x1D70E}$ , where $U$ is the constant drop velocity, $\unicode[STIX]{x1D707}$ is the viscosity of the carrier liquid and $\unicode[STIX]{x1D70E}$ is the interfacial tension). In this limit, the moving drop looks like the static drop and has two end caps connected by a long column, which is surrounded by thin films on the microchannel wall and by menisci along the microchannel corners. Integral axial force balances on the drop fluid and on the carrier liquid surrounding the drop relate the carrier-liquid pressure gradient to the drop-fluid pressure gradient and the contact-line drag. The contact-line drag is argued to be the same as that for a long bubble (which has been determined by Wong et al. (J. Fluid Mech., vol. 292, 1995b, pp. 95–110)) if the viscosity ratio $\unicode[STIX]{x1D706}\ll Ca^{-1/3}$ and $\unicode[STIX]{x1D706}\ll L$ , where $\unicode[STIX]{x1D706}=\bar{\unicode[STIX]{x1D707}}/\unicode[STIX]{x1D707}$ , $\bar{\unicode[STIX]{x1D707}}$ is the drop viscosity and $L~(\gg 1)$ is the dimensionless drop length. Thus, the force balances yield one equation relating the two pressure gradients. The two pressure gradients also drive unidirectional flows in the drop and in the corner channels along the long middle column. These coupled flows are solved by a finite-element method to yield another equation relating the two pressure gradients. From the two equations, we determine the pressure gradients and thus the unidirectional velocity fields inside and outside the drop for $\unicode[STIX]{x1D706}=0$ –100 and various microchannel aspect ratios. We find that in the limit $LCa^{1/3}\rightarrow 0$ , the contact-line drag dominates and the carrier liquid bypasses the drop through the corner channels alongside the drop. For $LCa^{1/3}\gg 1$ , the contact-line drag is negligible and the corner fluid is stationary. Thus, the drop moves as a leaky piston. We extend our model to a train of long drops, and compare our model predictions with published experiments.
Genome-wide DNA methylation profiles analysis in primary warm autoimmune hemolytic anemia patients

ABSTRACT Background Autoimmune hemolytic anemia (AIHA) is caused by auto-antibodies, secreted by overactivated B cells, directed against self-red blood cells, resulting in hemolysis. It found that aberrant DNA methylation in B cells can induce the production of autoantibodies. Therefore, we attempted to explore if similar aberrant DNA methylation occur in AIHA patients. Methods A 49-year-old female wAIHA patient and a 47-year-old female healthy control (HC) were enrolled. Peripheral blood (PB) B cells DNA was extracted. After constructing genomic libraries, bisulfite genomic sequencing (BSP) and DNA methylation profiles were analyzed. BSP was verified using PB B cells from 10 patients with hemolysis, 10 patients with hemolytic remission, and 10 healthy controls (HCs) by Methylation-specific PCR. Results Total DNA methylation of whole-genome C bases (4.8%) and CG type bases (76.8%) in wAIHA patient were lower than those in the HC (5.3 and 82.5%, respectively) (p = 0.022 and p < 0.001). DNA methylation of C bases and CG type bases in whole-genome regulatory elements, such as coding sequence, up2Kb and down2Kb in the patient were also lower than those in the HC (p = 0.041, p = 0.038, and p = 0.029). 30,180 DNA-methylated regions (DMRs) on all 23 chromosomes were identified. DMR-related genes were mainly involved in the Rap1, phospholipase D, HIF-1, calcium, vascular endothelial growth factor (VEGF) and Ras signaling pathways. Conclusion The DNA methylation spectrum of B cells in AIHA patients is different from that of HC, and the proportion of hypo-methylation regions is higher than that of HC. DMR-related genes are mainly related to some signaling pathways.
On the Decoupling of Evolutionary Changes in mRNA and Protein Levels

Abstract Variation in gene expression across lineages is thought to explain much of the observed phenotypic variation and adaptation. The protein is closer to the target of natural selection but gene expression is typically measured as the amount of mRNA. The broad assumption that mRNA levels are good proxies for protein levels has been undermined by a number of studies reporting moderate or weak correlations between the two measures across species. One biological explanation for this discrepancy is that there has been compensatory evolution between the mRNA level and regulation of translation. However, we do not understand the evolutionary conditions necessary for this to occur nor the expected strength of the correlation between mRNA and protein levels. Here, we develop a theoretical model for the coevolution of mRNA and protein levels and investigate the dynamics of the model over time. We find that compensatory evolution is widespread when there is stabilizing selection on the protein level; this observation held true across a variety of regulatory pathways. When the protein level is under directional selection, the mRNA level of a gene and the translation rate of the same gene were negatively correlated across lineages but positively correlated across genes. These findings help explain results from comparative studies of gene expression and potentially enable researchers to disentangle biological and statistical hypotheses for the mismatch between transcriptomic and proteomic data.
Chronic spontaneous urticaria: from the hunt for causes and pathogenesis to the identification of different endotypes.

Summary The hunt for the causes and pathogenic mechanisms involved in chronic spontaneous urticaria (CSU) has engaged clinicians and scientists for decades. Although not all aspects of the disease are defined, our knowledge has now improved to the point that we can consider CSU as an umbrella clinical phenotype under which several different endotypes probably exist. The present article will briefly summarize the fascinating history of the progress in our knowledge of this disease.
Mechanical ventilation during pediatric extracorporeal life support

Purpose of review To discuss the role of ventilator induced lung injury (VILI) and patient self-inflicted lung injury in ventilated children supported on extracorporeal membrane oxygenation (ECMO). Recent findings While extracorporeal life support is used routinely used every day around the globe to support neonatal, pediatric, and adult patients with refractory cardiac and/or respiratory failure, the optimal approach to mechanical ventilation, especially for those with acute respiratory distress syndrome (ARDS), remains unknown and controversial. Given the lack of definitive data in this population, one must rely on available evidence in those with ARDS not supported with ECMO and extrapolate adult observations. Ventilatory management should include, as a minimum standard, limiting inspiratory and driving pressures, providing a sufficient level of positive end-expiratory pressure, and setting a low rate to reduce mechanical power. Allowing for spontaneous breathing and use of pulmonary specific ancillary treatment modalities must be individualized, while balancing the risk and benefits. Future studies delineating the best strategies for optimizing MV during pediatric extracorporeal life support are much needed. Summary Future investigations will hopefully provide the needed evidence and better understanding of the overall goal of reducing mechanical ventilation intensity to decrease risk for VILI and promote lung recovery for those supported with ECMO.
ASSESSMENT OF COMPUTER STUDIES TEACHERS’ CONSTRAINTS IN THE USE OF INFORMATION AND COMMUNICATION TECHNOLOGY.

The study investigated Computer Studies Teachers‟ Constraints in the use of Information and Communication Technology (ICT) in Senior Secondary Schools in Bayelsa West Senatorial District in Bayelsa State. The work was undertaken to find out if Computer Studies Teachers‟ constraints in the use of ICT in teaching in Senior Secondary Schools differ significantly with respect to gender, location, experience level and qualification. As a result, the researcher raised nine research questions and also formulated four null hypotheses to guide the study. The variables in the study were systematically reviewed from relevant literatures. An instrument was designed to collect data on the variables and the questionnaire was administered to 104 Computer Studies teachers obtained through simple random sampling of balloting and stratified random sampling. The instrument was validated in its content, face and constructs values. With construct validity a factor loadings matrix ranging from 0.632 to 0.910 in all items. A reliability coefficient of 0.827 was obtained with the use of Cronbach alpha technique. The data collected were analyzed and tested using the t-test statistical analysis at 0.05 level of significance. The findings showed that the four null hypotheses were rejected. This is an indication that Computer Studies teachers‟ constraints in the use of ICT in teaching differed significantly with respect to gender, location, experience level and qualification. From the findings, it was recommended that the National Policy on Education concerning ICT education should be reviewed in line with the New Curriculum for Senior Secondary Schools that made Computer Studies with the use of ICT compulsory and all Policy Statements regarding ICT should be implemented in all levels of the educational system. does not carry weight as expected. Findings revealed that factors like lack of interest by students in learning computer science militate against the teaching of computer 2015).
Recherche de motifs quasi-similaires dans des graphes

Nous decrivons un algorithme base sur des metriques intrinseques de graphes permettant de decouvrir des motifs communs et similaires entre plu- sieurs graphes. Nous montrons des applications a la recherche d? image dans une collection et a l? interpretation de donnees geographiques
Stochastic Gradient Descent with Differentially Private Updates

In recent decades, the amount of data available has grown immensely. A lot of this data may be private or sensitive. Privacy of of this data is very important, which is why algorithms that can operate on this data without violating privacy have become crucial. A framework for designing such algorithms is differential privacy. In this paper we propose differentially private versions of single-point and mini-batch stochastic gradient descent (SGD) and use these for optimizing the objective for logistic regression. We use several data sets of varying sizes to test the algorithms. We conclude that the performance of mini-batch differentially private SGD is very close to non-private SGD, in contrast to single-point differentially private SGD, which does not converge and has a high variance. This holds for both low and high dimensional problems. We also conclude that deciding on hyperparameters is not an easy choice. All the results mentioned before are obtained with doing a single pass through the data sets. We also test the effect of doing multiple passes through the data set for singlepoint differentially private SGD. This decreases the level of privacy and does not increase performance as much as mini-batching does.
Minimal perturbation flows that trigger mean field dynamos in shear flows

Using a variational optimization method we find the smallest flow perturbations that can trigger kinematic dynamo action in Kolmogorov flow. In comparison to previous work, a second-order mean field dynamo model is used to track down the optimal dynamos in the high magnetic Reynolds number limit ( $Rm$ ). The magnitude of minimal perturbation flows decays inversely proportional to the magnetic Reynolds number. We reveal the asymptotic high- $Rm$ structure of the optimal flow perturbation and the magnetic eigenmode. We identify the optimal dynamo as of $\unicode[STIX]{x1D6FC}{-}\unicode[STIX]{x1D6FA}$ type, with magnetic fluctuations that localize on a critical layer.
Unraveling Prevalence and Effects of Deleterious Mutations in Maize Elite Lines across Decades of Modern Breeding

Abstract Future breeding is likely to involve the detection and removal of deleterious alleles, which are mutations that negatively affect crop fitness. However, little is known about the prevalence of such mutations and their effects on phenotypic traits in the context of modern crop breeding. To address this, we examined the number and frequency of deleterious mutations in 350 elite maize inbred lines developed over the past few decades in China and the United States. Our findings reveal an accumulation of weakly deleterious mutations and a decrease in strongly deleterious mutations, indicating the dominant effects of genetic drift and purifying selection for the two types of mutations, respectively. We also discovered that slightly deleterious mutations, when at lower frequencies, were more likely to be heterozygous in the developed hybrids. This is consistent with complementation as a potential explanation for heterosis. Subsequently, we found that deleterious mutations accounted for more of the variation in phenotypic traits than nondeleterious mutations with matched minor allele frequencies, especially for traits related to leaf angle and flowering time. Moreover, we detected fewer deleterious mutations in the promoter and gene body regions of differentially expressed genes across breeding eras than in nondifferentially expressed genes. Overall, our results provide a comprehensive assessment of the prevalence and impact of deleterious mutations in modern maize breeding and establish a useful baseline for future maize improvement efforts.
Effects of tumour heterogeneous properties on modelling the transport of radiative particles

Dose calculation plays a critical role in radiotherapy (RT) treatment planning, and there is a growing need to develop accurate dose deposition models that incorporate heterogeneous tumour properties. Deterministic models have demonstrated their capability in this regard, making them the focus of recent treatment planning studies as they serve as a basis for simplified models in RT treatment planning. In this study, we present a simplified deterministic model for photon transport based on the Boltzmann transport equation (BTE) as a proof‐of‐concept to illustrate the impact of heterogeneous tumour properties on RT treatment planning. We employ the finite element method (FEM) to simulate the photon flux and dose deposition in real cases of diffuse intrinsic pontine glioma (DIPG) and neuroblastoma (NB) tumours. Importantly, in light of the availability of pipelines capable of extracting tumour properties from magnetic resonance imaging (MRI) data, we highlight the significance of such data. Specifically, we utilise cellularity data extracted from DIPG and NB MRI images to demonstrate the importance of heterogeneity in dose calculation. Our model simplifies the process of simulating a RT treatment system and can serve as a useful starting point for further research. To simulate a full RT treatment system, one would need a comprehensive model that couples the transport of electrons and photons.
A hybrid case-based reasoning approach to detecting the optimal solution in nurse scheduling problem

Demand for healthcare is increasing due to a growing and ageing population. Choosing an adequate schedule for medical staff can be a difﬁcult dilemma for managers. The goal of nurse scheduling is to minimize the cost of the staff while maximizing their preferences and the overall beneﬁts for the unit. This paper is focused on a new hybrid strategy based on detecting the optimal solution in nurse scheduling problem. The new proposed hybrid approach is obtained by combining case-based reasoning and general linear empirical model with arbitrary coefﬁcients. The model is tested with original real-world data set obtained from the Oncology Institute of Vojvodina in Serbia.