Miracle-dz/UniFAR-FTUs huggingface dataset:
BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia.

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL) such as cytotoxic chemotherapy and alemtuzumab have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and TCR pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify novel combination therapy in this disease. Twenty-four primary T-PLL patient samples were studied using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis ('priming') and the relative dependence of a cell on different anti-apoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis, and predominantly depended on BCL-2 and MCL-1 for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated two patients with refractory T-PLL with the combination of venetoclax and ruxolitinib. We observed a deep response in the JAK3-mutated T-PLL and a stabilization of the unmutated disease. Our functional, precision medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting further exploration of such combinations clinically in T-PLL.
Diffusion-weighted MRI of ischemic stroke at 3T: Value of synthetic b-values.

OBJECTIVES Diffusion-weighted imaging (DWI) plays a crucial role in the diagnosis of ischemic stroke. We assessed the value of computed and acquired high b-value DWI in comparison with conventional b = 1000 s mm-2 DWI for ischemic stroke at 3T. METHODS We included 36 patients with acute ischemic stroke who presented with diffusion abnormalities on DWI performed within 24 h of symptom onset. B-values of 0, 500, 1000 and 2000 s mm-2 were acquired. Synthetic images with b-values of 1000, 1500, 2000 and 2500 s mm-2 were computed. Two readers compared synthetic (syn) and acquired (acq) b = 2000 s mm-2 images with acquired b = 1000 s mm-2 images in terms of lesion detection rate, image quality, presence of uncertain hyperintensities and lesion conspicuity. Readers also selected their preferred b-value. Contrast ratio (CR) measurements were performed. Non-parametrical statistical tests and weighted Cohens' κ tests were computed. RESULTS Syn1000 and syn1500 matched acq1000 images in terms of lesion detection rate, image quality and presence of uncertain hyperintensities but presented with significantly improved lesion conspicuity (p < 0.01) and were frequently selected as preferred b-values. Acq2000 images exhibited a similar lesion detection rate and improved lesion conspicuity (p < 0.01) but worse image quality (p < 0.01) than acq1000 images. Syn2000 and syn2500 images performed significantly worse (p < 0.01) than acq1000 images in most or all categories. CR significantly increased with increasing b-values. CONCLUSION Synthetic images at b = 1000 and 1500 s mm-2 and acquired DWI images at b = 2000 s mm-2 may be of clinical value due to improved lesion conspicuity. ADVANCES IN KNOWLEDGE Synthetic b-values enable improved lesion conspicuity for DWI of ischemic stroke.
Effect of Hearing and Head Protection on the Localization of Tonal and Broadband Reverse Alarms

Objective This study explored the effects of hearing protection devices (HPDs) and head protection on the ability of normal-hearing individuals to localize reverse alarms in background noise. Background Among factors potentially contributing to accidents involving heavy vehicles, reverse alarms can be difficult to localize in space, leading to errors in identifying the source of danger. Previous studies have shown that traditional tonal alarms are more difficult to localize than broadband alarms. In addition, HPDs and safety helmets may further impair localization. Method Standing in the middle of an array of eight loudspeakers, participants with and without HPDs (passive and level-dependent) had to identify the loudspeaker emitting a single cycle of the alarm while performing a task on a tablet computer. Results The broadband alarm was easier to localize than the tonal alarm. Passive HPDs had a significant impact on sound localization (earmuffs generally more so than earplugs), particularly double hearing protection, and level-dependent HPDs did not fully restore sound localization abilities. The safety helmet had a much lesser impact on performance than HPDs. Conclusion Where good sound localization abilities are essential in noisy workplaces, the broadband alarm should be used, double hearing protection should be avoided, and earplug-style passive or level-dependent devices may be a better choice than earmuff-style devices. Construction safety helmets, however, seem to have only a minimal effect on sound localization. Application Results of this study will help stakeholders make decisions that are more informed in promoting safer workplaces.
The Significance of Extra-Cage Bridging Bone via Radiographic Lumbar Interbody Fusion Criterion

Study Design: Prospective observational study. Objectives: We aimed to analysis the distributional patterns of the intra- and extra-cage bridging bone (InCBB and ExCBB) and the significance of ExCBB using suggested lumbar interbody fusion criterion. Methods: This study included the patients with planned single-level transforaminal lumbar interbody fusion. We divided bridging bone into InCBB (in void of right or left cage) and ExCBB (outside of cages; anterior, posterior, intermediate, right, or left) and graded bridging scores from 0 to 2 on postoperative 1-year computed tomography. The fusion was defined as at least having one or more graded 2 and the evaluation were conducted twice by 2 raters. Results: Sixty-five patients were enrolled. All values of intra- and inter-rater reliability in left InCBB, anterior, and posterior ExCBB showed good agreements (≥0.75). Both InCBBs showed similar mean bridging scores (Rt:1.43 vs Lt:1.48), and in ExCBBs, the anterior was the highest (1.43), followed by the posterior (1.14); the right and left were the lowest (0.49 and 0.52 respectively). In subjects determined as fusion (85.4%), complete bridging was observed more in ExCBB (88.8%) than in InCBB (69.9%). Conclusions: Given the higher bridging scores in both InCBBs and Ant. ExCBB, bone grafting is important promoting factor to increase the interbody bridging bone regardless of outside or in void of cages. Based on our suggested criterion, ExCBB has a greater proportion compared to InCBBs for determining the fusion and extra-cage bone grafting should be considered as important procedures for interbody fusion.
SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.
Revealing the changes of IgG subclass‐specific N‐glycosylation in colorectal cancer progression by high‐throughput assay

The changes of glycosylation of different IgG subclass in colorectal cancer (CRC) were rarely investigated. The authors aimed to use a simple and high‐throughput analytical method to explore the changes of subclass‐specific IgG glycosylation in CRC, and to find the specific glyco‐biomarkers for early detection of this disease.
Sampling frequency, duration and the Southern Oscillation influence the ability of long‐term studies to detect sudden change

Ecologists have long acknowledged the importance of context dependency related to position along spatial gradients. It is also acknowledged that broad‐scale climate patterns can directly and indirectly alter population dynamics. What is not often addressed is whether climate patterns such as the Southern Oscillation interact with population‐level temporal patterns and affect the ability of time‐series data, such as long‐term state of the environment monitoring programmes, to detect change. Monitoring design criteria generally focus on number of data points, sampling frequency and duration, often derived from previous information on species seasonal and multi‐year temporal patterns. Our study questioned whether the timing of any changes relative to Southern Oscillation, interacting with species populations dynamics, would also be important. We imposed a series of simulated reductions on macrofaunal abundance data collected regularly over 29 years from two sites, using species selected for observed differences in temporal dynamics. We hypothesized that (1) high within‐year sampling frequency would increase detection ability for species with repeatable seasonality cycles and (2) timing of the reduction in abundance relative to the Southern Oscillation was only likely to affect detection ability for long‐lived species with multi‐year cyclic patterns in abundance. However, regardless of species population dynamics, we found both within‐year sampling frequency and the timing of the imposed reduction relative to the Southern Oscillation Index affected detection ability. The latter result, while apparently demonstrating a confounding influence on monitoring, offers the opportunity to improve our ability to detect and interpret analyses of monitoring data, and thus our ability to make recommendations to managers.
The ASL-LEX 2.0 Project: A Database of Lexical and Phonological Properties for 2,723 Signs in American Sign Language

Abstract ASL-LEX is a publicly available, large-scale lexical database for American Sign Language (ASL). We report on the expanded database (ASL-LEX 2.0) that contains 2,723 ASL signs. For each sign, ASL-LEX now includes a more detailed phonological description, phonological density and complexity measures, frequency ratings (from deaf signers), iconicity ratings (from hearing non-signers and deaf signers), transparency (“guessability”) ratings (from non-signers), sign and videoclip durations, lexical class, and more. We document the steps used to create ASL-LEX 2.0 and describe the distributional characteristics for sign properties across the lexicon and examine the relationships among lexical and phonological properties of signs. Correlation analyses revealed that frequent signs were less iconic and phonologically simpler than infrequent signs and iconic signs tended to be phonologically simpler than less iconic signs. The complete ASL-LEX dataset and supplementary materials are available at https://osf.io/zpha4/ and an interactive visualization of the entire lexicon can be accessed on the ASL-LEX page: http://asl-lex.org/.
Plant egg cell fate determination depends on its exact position in female gametophyte

Significance In a mature female gametophyte of angiosperm, one egg cell and two synergid cells, referred to as the “egg apparatus,” originate from the same functional megaspore. How the egg cell and synergid cells differentiate into distinct cell types has drawn much attention but remains unclear. In this work, a live imaging system was established to visualize nuclear movement and cell specialization in female gametophytes. The final localization of the nuclei before cellularization was found to be critical for determining the cell fates of the egg apparatus. Artificial changes in the nuclear position could produce two functional egg cells. Furthermore, the plant hormone auxin was suggested as a positional cue for egg apparatus specialization. Plant fertilization involves both an egg cell, which fuses with a sperm cell, and synergid cells, which guide pollen tubes for sperm cell delivery. Therefore, egg and synergid cell functional specifications are prerequisites for successful fertilization. However, how the egg and synergid cells, referred to as the “egg apparatus,” derived from one mother cell develop into distinct cell types remains an unanswered question. In this report, we show that the final position of the nuclei in female gametophyte determines the cell fate of the egg apparatus. We established a live imaging system to visualize the dynamics of nuclear positioning and cell identity establishment in the female gametophyte. We observed that free nuclei should migrate to a specific position before egg apparatus specialization. Artificial changing in the nuclear position on disturbance of the actin cytoskeleton, either in vitro or in vivo, could reset the cell fate of the egg apparatus. We also found that nuclei of the same origin moved to different positions and then showed different cell identities, whereas nuclei of different origins moved to the same position showed the same cell identity, indicating that the final positions of the nuclei, rather than specific nucleus lineage, play critical roles in the egg apparatus specification. Furthermore, the active auxin level was higher in the egg cell than in synergid cells. Auxin transport inhibitor could decrease the auxin level in egg cells and impair egg cell identity, suggesting that directional and accurate auxin distribution likely acts as a positional cue for egg apparatus specialization.
Nervonic acid level in cerebrospinal fluid is a candidate biomarker for depressive and manic symptoms: A pilot study

Our previous metabolomics study showed that the plasma nervonic acid levels were higher in patients with major depressive disorder (MDD) than those in healthy controls and patients with bipolar disorder (BD). To examine whether the nervonic acid levels differ in the central nervous system, we investigated the levels in the cerebrospinal fluid (CSF) of patients with MDD, BD, and healthy controls.
Stable reliability diagrams for probabilistic classifiers

Significance Probabilistic classifiers assign predictive probabilities to binary events, such as rainfall tomorrow, a recession, or a personal health outcome. Such a system is reliable or calibrated if the predictive probabilities are matched by the observed frequencies. In practice, calibration is assessed graphically in reliability diagrams and quantified via the reliability component of mean scores. Extant approaches rely on binning and counting and have been hampered by ad hoc implementation decisions, a lack of reproducibility, and inefficiency. Here, we introduce the CORP approach, which uses the pool-adjacent-violators algorithm to generate optimally binned, reproducible, and provably statistically consistent reliability diagrams, along with a numerical measure of miscalibration based on a revisited score decomposition. A probability forecast or probabilistic classifier is reliable or calibrated if the predicted probabilities are matched by ex post observed frequencies, as examined visually in reliability diagrams. The classical binning and counting approach to plotting reliability diagrams has been hampered by a lack of stability under unavoidable, ad hoc implementation decisions. Here, we introduce the CORP approach, which generates provably statistically consistent, optimally binned, and reproducible reliability diagrams in an automated way. CORP is based on nonparametric isotonic regression and implemented via the pool-adjacent-violators (PAV) algorithm—essentially, the CORP reliability diagram shows the graph of the PAV-(re)calibrated forecast probabilities. The CORP approach allows for uncertainty quantification via either resampling techniques or asymptotic theory, furnishes a numerical measure of miscalibration, and provides a CORP-based Brier-score decomposition that generalizes to any proper scoring rule. We anticipate that judicious uses of the PAV algorithm yield improved tools for diagnostics and inference for a very wide range of statistical and machine learning methods.
Distinctiveness of the MMPI-3 Self-Importance and Self-Doubt Scales

Abstract The MMPI-3 is an updated version of the MMPI-2-RF that provides enhanced coverage of constructs related to personality and psychopathology. A new Self-Importance (SFI) scale measures individuals’ beliefs that they possess special qualities. Low SFI scores indicate that test-takers report lacking such attributes. The Self-Doubt (SFD) scale, which was revised from the MMPI-2-RF, also has a self-orientation and measures a lack of self-esteem. The current study used three college student samples to investigate whether MMPI-3 SFI and SFD measure distinct constructs; in other words, are beliefs about self-importance distinct from self-esteem? SFI and SFD scores were conversely but differentially associated with measures of positive valence, self-esteem, and grandiose and vulnerable narcissism. Dominance and regression analyses indicated that SFI scores generally dominated SFD scores in prediction of positive valence and grandiose narcissism (characterized by grandiosity, dominance, aggressiveness). SFD scores generally dominated SFI scores in prediction of self-esteem and vulnerable narcissism (characterized by negative affect, feelings of incompetence, inadequacy). The current findings indicated that self-importance and self-esteem are two distinct constructs and therefore appropriately measured by separate scales.
Adjusting Extracellular pH to Prevent Entry of SARS-CoV-2 into Human Cells.

The frequent outbreaks of life-threatening RNA viruses, including the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose tremendous challenges to humanity. The author proposes that creating a more alkaline extracellular environment that is unsuitable for the fusion between the envelope of SARS-CoV-2 and the host cell membrane is a promising method to prevent the entry of coronaviruses into human cells. The alkaline environment could be achieved by exposing the general public to water-clustered negative air ions (NAIs), both indoors and outdoors, to induce a gradual increase in the pH of the human body. Previous studies have demonstrated that there are no harmful effects of high-concentration NAIs on human health.
Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).
The influence of localized emittants on the concentration of volatile organic compounds in the ambient air measured close to ground level

As part of an investigation into the relationship of volatile organic compounds in ambient air and a nearby refinery, a risk assessment was performed as well as an analysis of the attribution of each source contributing to the emission of pollutants. The compounds under consideration being the alkanes, chlorinated hydrocarbons, aromatics, and aldehydes. Taking into account the sources (refinery and/or traffic) and the possible source-attributable pollutant combinations, locally dependent pollution profiles were observed. While aromatics and aldehydes were distributed relatively uniformly, the combination aromatics and alkanes at several localities pointed clearly to the refinery as the source of the pollution. An analysis of the indoor measurements at a school close to the refinery demonstrated the necessity of identifying the source of the pollutants in order to be able to bring about environmental conditions acceptable to human health. © 1997 by John Wiley & Sons, Inc. Environ Toxicol Water Qual 12: 31–37, 1997
A self-consistent method for X-ray diffraction analysis of multiaxial residual-stress fields in the near-surface region of polycrystalline materials. II. Examples

The application of the formalism for residual-stress gradient evaluation based on the measuring principle of the scattering-vector method, which has been derived in the first paper of this series [Genzel (1999). J. Appl. Cryst. 32, 770–778], is demonstrated by practical examples. Depending on the statistical scattering of the experimental data, either biaxial or even triaxial residual-stress states may be analysed; the latter case yields self-consistently the depth profiles of the in-plane stresses, σ11(τ) and σ22(τ), the normal stress component, σ33(τ), as well as the strain-free lattice spacing, d0(hkl). The results obtained by this new evaluation procedure are compared with those obtained by X-ray stress-gradient analysis performed on the basis of the sin2ψ method.