Miracle-dz/UniFAR-FTUs huggingface dataset:
iPSC-Derived Hereditary Breast Cancer Model Reveals the BRCA1-Deleted Tumor Niche as a New Culprit in Disease Progression

Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/− who, based on their family histories, were at a high risk for cancer. Using peripheral blood mononuclear cells (PBMCs) of these two affected family members and two normal (BRCA1+/+) individuals, we established a number of iPSC clones via non-integrating Sendai virus-based delivery of the four OCT4, SOX2, KLF4, and c-MYC factors. Induced mesenchymal stem cells (iMSCs) were generated and used as normal and pathological stromal cells. In transcriptome analyses, BRCA1+/− iMSCs exhibited a unique pro-angiogenic signature: compared to non-mutated iMSCs, they expressed high levels of HIF-1α, angiogenic factors belonging to the VEGF, PDGF, and ANGPT subfamilies showing high angiogenic potential. This was confirmed in vitro through the increased capacity to generate tube-like structures compared to BRCA1+/+ iMSCs and in vivo by a matrigel plug angiogenesis assay where the BRCA1+/− iMSCs promoted the development of an extended and organized vessel network. We also reported a highly increased migration capacity of BRCA1+/− iMSCs through an in vitro wound healing assay that correlated with the upregulation of the periostin (POSTN). Finally, we assessed the ability of both iMSCs to facilitate the engraftment of murine breast cancer cells using a xenogenic 4T1 transplant model. The co-injection of BRCA1+/− iMSCs and 4T1 breast cancer cells into mouse mammary fat pads gave rise to highly aggressive tumor growth (2-fold increase in tumor volume compared to 4T1 alone, p = 0.01283) and a higher prevalence of spontaneous metastatic spread to the lungs. Here, we report for the first time a major effect of BRCA1 haploinsufficiency on tumor-associated stroma in the context of BRCA1-associated cancers. The unique iMSC model used here was generated using patient-specific iPSCs, which opens new therapeutic avenues for the prevention and personalized treatment of BRCA1-associated hereditary breast cancer.
Antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease

Objective Approximately 10% of patients with myocardial infarction (MI) have no obstructive coronary artery disease. The prognosis and role of intensified antiplatelet therapy in those patients were evaluated. Methods We analysed data from the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organisation to Assess Strategies in Ischaemic Symptoms trial randomising patients with ACS referred for early intervention to receive either double-dose (600 mg, day 1; 150 mg, days 2–7; then 75 mg/day) or standard-dose (300 mg, day 1; then 75 mg/day) clopidogrel. Outcomes in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) versus those with obstructive coronary artery disease (CAD) and their relation to standard-dose versus double-dose clopidogrel were evaluated. The primary outcome was cardiovascular (CV) death, MI or stroke at 30 days. Results We included 23 783 patients with MI and 1599 (6.7%) with MINOCA. Patients with MINOCA were younger, presented more frequently with non-ST-segment elevation MI and had fewer comorbidities. All-cause mortality (0.6% vs 2.3%, p=0.005), CV mortality (0.6% vs 2.2%, p=0.006), repeat MI (0.5% vs 2.3%, p=0.001) and major bleeding (0.6% vs 2.4%, p<0.0001) were lower among patients with MINOCA than among those with obstructive CAD. Among patients with MINOCA, 2.1% of patients in the double-dose clopidogrel group and 0.6% in the standard-dose group experienced a primary outcome (HR 3.57, 95% CI 1.31 to 9.76), whereas in those with obstructive CAD, rates were 4.3% and 4.7%, respectively (HR 0.91, 95% CI 0.80 to 1.03; p value for interaction=0.011). Conclusions Patients with MINOCA are at lower risk of recurrent CV events compared with patients with MI with obstructive CAD. Compared with a standard clopidogrel-based dual antiplatelet therapy (DAPT) regimen, an intensified dosing strategy appears to offer no additional benefit with a signal of possible harm. Further randomised trials evaluating the effects of potent DAPT in patients with MINOCA are warranted. Trial registration number NCT00335452.
Dairy Caretaker Perspectives on Performing Euthanasia as an Essential Component of Their Job

Simple Summary Although on-farm euthanasia is a critical component of dairy management and provides a way to alleviate animal suffering, little is known about dairy caretaker perspectives on their role in euthanasia, their comfort level with the procedures, and the impact of practicing euthanasia on their wellbeing and mental health. Thematic analysis of focus groups and interviews of Colorado dairy caretakers revealed a human–animal bond and empathy toward animals in all participants. Training practices were varied and correlated with knowledge about euthanasia procedures and language used to discuss euthanasia. Participants reported that little communication about the stress related to performing euthanasia occurred on the farm, and there was no awareness of mental health resources available to caretakers. Testing of interventions that can support animal caretakers by reducing euthanasia-related stress and improving emotional wellbeing, and efforts to increase awareness of mental health recourses are clear needs for dairy operations. Abstract The objectives of this study were to identify caretakers’ perceptions and stressors related to performing on-farm euthanasia as well as potential ideas for intervention strategies to alleviate negative effects of performing euthanasia on caretaker well-being. Additionally, we aimed to determine how euthanasia methods, procedures, and training correlate with dairy caretakers’ attitudes toward performing on-farm euthanasia and their job satisfaction and sense of well-being. Thirty-eight dairy caretakers (19 workers, 15 supervisors, 3 owners, 1 veterinarian) participated in focus groups or interviews conducted and recorded on five Northern Colorado dairies. Thematic analysis of focus group and interview transcripts revealed seven recurring themes. Variation in available training and euthanasia protocols among dairy farms was evident. There was a lack of awareness regarding available mental health resources and little communication between farm personnel about euthanasia-related stress. Training was correlated with caretaker knowledge about euthanasia procedures and the language used to refer to euthanasia. Human-animal bonds and empathy toward animals were evident in participants regardless of training, job position, or dairy experience. Interventions such as training programs, mental health resources, and other support systems should be tested for effectiveness in addressing euthanasia-related stressors, improving euthanasia decision-making and practice, and increasing animal wellbeing on dairy farms.
K3326X and Other C-Terminal BRCA2 Variants Implicated in Hereditary Cancer Syndromes: A Review

Simple Summary The cancer associated protein BRCA2 is the subject of intense continual study. Because of this, new insights into the relation of specific variants of this gene and cancer are regularly generated. These discoveries shed light on cancer risk and management for patients carrying these mutations. Additionally, new techniques for variant discovery and investigation are developed and tested, further enhancing scientific and clinical understanding of this key protein. In this review we will investigate the recent literature associated with variants in the C-terminus of BRCA2 and their effect on health and cancer predisposition. Abstract Whole genome analysis and the search for mutations in germline and tumor DNAs is becoming a major tool in the evaluation of risk as well as the management of hereditary cancer syndromes. Because of the identification of cancer predisposition gene panels, thousands of such variants have been catalogued yet many remain unclassified, presenting a clinical challenge for the management of hereditary cancer syndromes. Although algorithms exist to estimate the likelihood of a variant being deleterious, these tools are rarely used for clinical decision-making. Here, we review the progress in classifying K3326X, a rare truncating variant on the C-terminus of BRCA2 and review recent literature on other novel single nucleotide polymorphisms, SNPs, on the C-terminus of the protein, defined in this review as the portion after the final BRC repeat (amino acids 2058–3418).
A lower-than-expected saltation threshold at Martian pressure and below

Significance Reproducing aeolian transport of grains in low-pressure conditions, we have discovered a saltation regime where the transport threshold is significantly lower than one would expect from the extrapolation of what is observed in ambient conditions. This regime is relevant for the Martian environment, where the observed wind-blown bedforms reveal aeolian sediment transport as a major geomorphic agent shaping the landscape of the planet. This surprising result reveals the existence of yet-unknown processes and provides a challenge for our fundamental understanding of sediment transport on planetary bodies in general. We also reproduce bedforms analogous to small (decimeter-scale) Martian impact ripples, whose photographs taken by NASA’s Curiosity rover were a surprise and could be used as proxies to estimate sand fluxes remotely. Aeolian sediment transport is observed to occur on Mars as well as other extraterrestrial environments, generating ripples and dunes as on Earth. The search for terrestrial analogs of planetary bedforms, as well as environmental simulation experiments able to reproduce their formation in planetary conditions, are powerful ways to question our understanding of geomorphological processes toward unusual environmental conditions. Here, we perform sediment transport laboratory experiments in a closed-circuit wind tunnel placed in a vacuum chamber and operated at extremely low pressures to show that Martian conditions belong to a previously unexplored saltation regime. The threshold wind speed required to initiate saltation is only quantitatively predicted by state-of-the art models up to a density ratio between grain and air of 4×105 but unexpectedly falls to much lower values for higher density ratios. In contrast, impact ripples, whose emergence is continuously observed on the granular bed over the whole pressure range investigated, display a characteristic wavelength and propagation velocity essentially independent of pressure. A comparison of these findings with existing models suggests that sediment transport at low Reynolds number but high grain-to-fluid density ratio may be dominated by collective effects associated with grain inertia in the granular collisional layer.
Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout

Significance Histone H3Q5ser and H3K4me3 can coexist as a dual modification pattern to regulate active gene transcription. However, the molecular impact of H3Q5ser on H3K4me3 recognition and catalysis remains largely unexplored. Here, we profile the influence of H3Q5ser on H3K4 methylation readers, writers, and erasers. Interestingly, all tested H3K4me3 readers bind H3K4me3Q5ser. Furthermore, while the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, corresponding H3K4 methylation erasers are profoundly inhibited by the presence of the mark. Collectively, this work suggests that H3Q5ser plays an augmenting role when coupled with the installation of H3K4 methylation so as to potentiate downstream outputs via chromatin readers and erasers. The present work exemplifies the importance of modification crosstalk in gene regulation. Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3–H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.
Effective Negative Diffusion of Singlet Excitons in Organic Semiconductors

Using diffraction-limited ultrafast imaging techniques, we investigate the propagation of singlet and triplet excitons in single-crystal tetracene. Instead of an expected broadening, the distribution of singlet excitons narrows on a nanosecond time scale after photoexcitation. This narrowing results in an effective negative diffusion in which singlet excitons migrate toward the high-density region, eventually leading to a singlet exciton distribution that is smaller than the laser excitation spot. Modeling the excited-state dynamics demonstrates that the origin of the anomalous diffusion is rooted in nonlinear triplet–triplet annihilation (TTA). We anticipate that this is a general phenomenon that can be used to study exciton diffusion and nonlinear TTA rates in semiconductors relevant for organic optoelectronics.
Optimizing the Context of Support to Improve Outcomes of Internet-Based Self-help in Individuals With Depressive Symptoms: Protocol for a Randomized Factorial Trial

Background Internet-based self-help interventions for individuals with depressive symptoms, in which the main component is often a web-based self-help program, have been shown to be efficacious in many controlled trials. However, there are also trials on self-help programs showing no significant effect when delivered in routine care, and some studies report high dropout and low adherence rates. Research suggests that these findings do not emerge primarily due to the specific content of a self-help program. It seems more important how a program is embedded in the context of human and automated support before and during the use of a self-help program. Objective This study aims to better understand the effects of 4 supportive contextual factors on outcomes of and adherence to a web-based self-help program for depressive symptoms. In a factorial experiment, 2 of 4 supportive factors, for which there is evidence for their role on outcomes and adherence, are realized during the intervention—personal guidance and automated email reminders. The other 2 factors are realized before the intervention—a diagnostic interview and a preintervention module aimed at increasing the motivation to use the program with motivational interviewing techniques. Methods The study is a full factorial randomized trial. Adults with mild to moderate depressive symptoms (Patient Health Questionnaire–9 score: 5-14) are recruited from the community through the internet and conventional media. All participants receive access to a web-based self-help program based on problem-solving therapy. They are randomized across 4 experimental factors, each reflecting the presence versus absence of a supportive factor (guidance, automated reminders, diagnostic interview, preintervention module) resulting in a 16-condition balanced factorial design. The primary outcome is depressive symptoms at 10 weeks post assessment. Secondary outcomes include adherence to the program, anxiety, stress, health-related quality of life, possible negative effects, and treatment satisfaction. Potential moderators and mediators (eg, treatment expectancy, problem-solving skills, working alliance with the study team) will also be investigated. Results Ethical approval was received on January 20, 2020. The study was initiated in February 2020, and 240 participants have been enrolled in the study as of November 1, 2020. Recruitment for a total of 255 participants is ongoing. Data collection is expected to be completed by May 2021. Conclusions A better understanding of relevant supportive factors in the dissemination of web-based interventions is necessary to improve outcomes of and adherence to web-based self-help programs. This study may inform health care systems and guide decisions to optimize the implementation context of web-based self-help programs for depressive symptoms. Trial Registration ClinicalTrials.gov NCT04318236; https://clinicaltrials.gov/ct2/show/NCT04318236 International Registered Report Identifier (IRRID) DERR1-10.2196/21207
Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft‐versus‐host disease prophylaxis

Graft‐versus‐host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo‐HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex‐vivo T cell cultures and in patients given RAPA plus tacrolimus as GVHD prophylaxis after nonmyeloablative allo‐HCT. We demonstrate that RAPA mitigates GVHD by decreasing T cell engraftment and differentiation, inhibiting CD8+ T cell activation and increasing the long‐term IL‐2 secretion, thereby supporting regulatory T cell (Treg) proliferation. In contrast, graft‐versus‐leukemia effects were not abrogated, as RAPA‐treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re‐stimulation. Importantly, we found that RAPA impact on Treg and CD8+ T cells was closely dependent upon IL‐2 signaling and that therapeutic options interfering with IL‐2, such as calcineurin inhibitors, antagonize the IL‐2‐dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5‐azacytidine.
Reconstitution of Human Necrosome Interactions in Saccharomyces cerevisiae

The necrosome is a large-molecular-weight complex in which the terminal effector of the necroptotic pathway, Mixed Lineage Kinase Domain-Like protein (MLKL), is activated to induce necroptotic cell death. The precise mechanism of MLKL activation by the upstream kinase, Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) and the role of Receptor Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in mediating MLKL activation remain incompletely understood. Here, we reconstituted human necrosome interactions in yeast by inducible expression of these necrosome effectors. Functional interactions were reflected by the detection of phosphorylated MLKL, plasma membrane permeabilization, and reduced proliferative potential. Following overexpression of human necrosome effectors in yeast, MLKL aggregated in the periphery of the cell, permeabilized the plasma membrane and compromised clonogenic potential. RIPK1 had little impact on RIPK3/MLKL-mediated yeast lethality; however, it exacerbated the toxicity provoked by co-expression of MLKL with a RIPK3 variant bearing a mutated RHIM-domain. Small molecule necroptotic inhibitors necrostatin-1 and TC13172, and viral inhibitors M45 (residues 1–90) and BAV_Rmil, abated the yeast toxicity triggered by the reconstituted necrosome. This yeast model provides a convenient tool to study necrosome protein interactions and to screen for and characterize potential necroptotic inhibitors.
Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis

Abstract Objectives To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods In two 52-week phase 1 b trials, s.c. -TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. Results Study participants were 51 sJIA patients and 52 pJIA patients aged 1–17 years who received s.c. -TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v. -TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c. -TCZ and i.v. -TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v. -TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. Conclusion s.c. -TCZ provides exposure and risk/benefit profiles similar to those of i.v. -TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279
Evaluation of soil texture data for estimating soil water retention curve

The soil water retention curve (SWRC) is one of the basic characteristics used in determining soil hydraulic properties, including unsaturated hydraulic conductivity. As its measurement is time consuming and difficult, much effort has been expended to develop indirect methods, such as pedotransfer functions and empirical relationships, to estimate SWRC. In this study, three methods were evaluated based on estimation of retention models parameters and, consequently, the soil water retention curve. For this purpose, soil data collected from three data bases, totaling 72 soil samples with 11 different textures, were used in this study. The statistical parameters such as: MR (mean of residual), RE (relative error), RMSE (root mean square error), AIC (Akaike’s information criterion) and GMER (geometric mean error ratio) showed that the Saxton et al. (1986) method estimates the soil water retention curve better than the other methods.Key words: Pedotransfer function, soil texture, soil water retention curve