Miracle-dz/UniFAR-FTUs huggingface dataset:
Germline DDX41 mutations define a significant entity within adult MDS/AML patients.

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients which we classified as causal (n=21) or unknown significance (n=7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. Median age was 69 years, most patients were males (79%). Only 9 patients (27%) had a family history of hematological malignancy, while 15 (46%) had personal history of cytopenias years prior to MDS/AML diagnosis. Most patients had normal karyotype (85%) and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n=9) or azacitidine (n=11) had an overall response rate of 100% and 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent pre-existing cytopenias, additional somatic DDX41 mutation and relatively good outcome.
A Case of Non-Operative Management of Atraumatic Splenic Hemorrhage Due to Snakebite Venom-Induced Consumption Coagulopathy

Patient: Male, 62 Final Diagnosis: Splenic hemorrhage Symptoms: Hypotension • syncope Medication: — Clinical Procedure: Splenic artery angio-embolization Specialty: Critical Care Medicine Objective: Rare disease Background: Snakebite envenoming results from injection of a mixture different toxins following snakebite. Coagulopathy and life-threatening hemorrhage can occur, or venom-induced consumption coagulopathy (VICC). A rare case is presented of spontaneous splenic hemorrhage due to VICC that was successfully treated by non-surgical splenic artery embolization. Case Report: A 62-year-old man was admitted to the emergency department after an episode of dizziness and loss of consciousness following a snakebite. He was transferred to our hospital with hypotension and an abnormal blood coagulation test. On admission, he was hypotensive, with reduced hemoglobin and hematocrit levels, but did not complain of abdominal pain. The occult source of bleeding was identified by abdominal computed tomography (CT) as splenic hemorrhage. Treatment began with the administration of antivenom and blood transfusion. Splenic artery angio-embolization was performed to control the bleeding and was without complication. Conclusions: Snakebite envenoming associated with VICC is a serious and life-threatening condition. Because of the possibility of associated occult bleeding from internal organs or blood vessels, imaging studies should be performed as soon as possible. For patients who are hemodynamically stabilized and have atraumatic hemorrhage from the spleen, non-operative treatment using angio-embolization may be performed with intensive monitoring and follow-up.
Fenretinide via NOXA Induction, Enhanced Activity of the BCL-2 Inhibitor Venetoclax in High BCL-2–Expressing Neuroblastoma Preclinical Models

Recurrent high-risk neuroblastoma is a childhood cancer that often fails to respond to therapy. Fenretinide (4-HPR) is a cytotoxic retinoid with clinical activity in recurrent neuroblastoma and venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2). We evaluated activity of 4-HPR + ABT-199 in preclinical models of neuroblastoma. Patient-derived cell lines and xenografts from progressive neuroblastoma were tested. Cytotoxicity was evaluated by DIMSCAN, apoptosis by flow cytometry, and gene expression by RNA sequencing, quantitative RT-PCR, and immunoblotting. 4-HPR + ABT-199 was highly synergistic against high BCL-2–expressing neuroblastoma cell lines and significantly improved event-free survival of mice carrying high BCL-2–expressing patient-derived xenografts (PDX). In 10 matched-pair cell lines [established at diagnosis (DX) and progressive disease (PD) from the same patients], BCL-2 expression in the DX and PD lines was comparable, suggesting that BCL-2 expression at diagnosis may provide a biomarker for neuroblastomas likely to respond to 4-HPR + ABT-199. In a pair of DX (COG-N-603x) and PD (COG-N-623x) PDXs established from the same patient, COG-N-623x was less responsive to cyclophosphamide + topotecan than COG-N-603x, but both DX and PD PDXs were responsive to 4-HPR + ABT-199. Synergy of 4-HPR + ABT-199 was mediated by induction of NOXA via 4-HPR stimulation of reactive oxygen species that induced expression of ATF4 and ATF3, transcription factors for NOXA. Thus, fenretinide + venetoclax is a synergistic combination that warrants clinical testing in high BCL-2–expressing neuroblastoma.
Does Perpetrator Occupation Affect Classification of Sexual Assault?

Classification of sexual assault varies based on the characteristics of the victim, perpetrator, and event. However, most studies focus on the individual characteristics of participants asked to classify the assault, the victims’ characteristics, or the event; few have examined variations in the perpetrator. Therefore, this study examined whether the occupation of the perpetrator affected the classification of the event as sexual assault. Participants included a primarily White female sample of undergraduate students (n = 401) at a south-Atlantic university. They completed a paper-and-pencil survey containing an ambiguous sexual assault encounter where the occupation of the perpetrator (athlete, reporter, college student, or politician) was randomly varied. Participants were asked to classify whether the encounter was sexual assault and what an appropriate punishment might be. Additional measures included the Illinois Rape Myth Acceptance Scale (IRMA) and questions about personal experience with sexual assault. Overall, most participants labeled the encounter as sexual assault, indicating that college students are aware of the legal parameters for providing consent. However, this classification occurred differentially based on the occupation of the perpetrator. Participants were most likely to label the athlete as committing sexual assault, followed by the college student, politician, and reporter, respectively. Females and those who reject rape myths were more likely to label the scenario as sexual assault. A “personal apology” and a “sexual rehabilitation program” were the most common punishments selected for the perpetrator. These findings highlight potential concerns and the need for additional training when college students adjudicate sexual assault reports and determine appropriate consequences.
Methylophiopogonanone B of Radix Ophiopogonis protects cells from H2O2-induced apoptosis through the NADPH oxidase pathway in HUVECs

Methylophiopogonanone B (MO-B), which belongs to a group of homoisoflavonoids, present in Ophiopogon japonicus, has been identified as an active component with antioxidative and anti-tumor properties. The present study investigated whether MO-B may exert protective effects on human umbilical vein endothelial cells (HUVECs) against H2O2-induced injury in vitro, and whether the MO-B effects may be modulated by the NADPH pathway. HUVECs were treated with MO-B in the presence or absence of H2O2. Malondialdehyde (MDA), reactive oxygen species (ROS) levels, and superoxide dismutase (SOD) activity were analyzed to evaluate cell injury and the antioxidative potential of MO-B. The results revealed that MO-B inhibited the production of MDA and ROS, but enhanced SOD activity. Furthermore, MO-B could alleviate H2O2-induced apoptosis in HUVECs, which is consistent with the expression of apoptosis-associated genes and proteins in cells, including Bax/Bcl-2 and caspase-3. To explore the potential mechanism, the present study investigated the effects of MO-B on NADPH-related signaling via the analysis of neutrophil cytochrome b light chain (p22phox) expression, which is the membrane-associated subunit of NADPH oxidase. MO-B could improve the survival of endothelial cells and therefore may be a potential drug in the treatment of cardiovascular diseases.
Corneal refractive surgery combined with simultaneous corneal cross‐linking: Indications, protocols and clinical outcomes—A review

Corneal refractive surgery is one of the most common approaches for correction of refractive errors. Combined corneal refractive surgery and corneal cross‐linking (CXL) has been proposed as a method to achieve better refractive stability and to prevent iatrogenic corneal ectasia. However, there are concerns regarding its indications, surgical safety, standardization of protocols and long‐term effect on corneal tissue. This review article aims to discuss the current knowledge and recent updates on combination of CXL and refractive surgery.
Health Benefits of β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Addition to Physical Exercise in Older Adults: A Systematic Review with Meta-Analysis

Both regular exercise training and beta-hydroxy-beta-methylbutyrate (HMB) supplementation are shown as effective treatments to delay or reverse frailty and reduce cognitive impairment in older people. However, there is very little evidence on the true benefits of combining both strategies. The aim of this meta-analysis was to quantify the effects of exercise in addition to HMB supplementation, on physical and cognitive health in older adults. Data from 10 randomized controlled trials (RCTs) investigating the effect of HMB supplementation and physical function in adults aged 50 years or older were analyzed, involving 384 participants. Results showed that HMB supplementation in addition to physical exercise has no or fairly low impact in improving body composition, muscle strength, or physical performance in adults aged 50 to 80 years, compared to exercise alone. There is a gap of knowledge on the beneficial effects of HMB combined with exercise to preserve cognitive functions in aging and age-related neurodegenerative diseases. Future RCTs are needed to refine treatment choices combining HMB and exercises for older people in particular populations, ages, and health status. Specifically, interventions in older adults aged 80 years or older, with cognitive impairment, frailty, or limited mobility are required.
Nutritional Potential and Toxicological Evaluation of Tetraselmis sp. CTP4 Microalgal Biomass Produced in Industrial Photobioreactors

Commercial production of microalgal biomass for food and feed is a recent worldwide trend. Although it is common to publish nutritional data for microalgae grown at the lab-scale, data about industrial strains cultivated in an industrial setting are scarce in the literature. Thus, here we present the nutritional composition and a microbiological and toxicological evaluation of Tetraselmis sp. CTP4 biomass, cultivated in 100-m3 photobioreactors at an industrial production facility (AlgaFarm). This microalga contained high amounts of protein (31.2 g/100 g), dietary fibres (24.6 g/100 g), digestible carbohydrates (18.1 g/100 g) and ashes (15.2 g/100 g), but low lipid content (7.04 g/100 g). The biomass displayed a balanced amount of essential amino acids, n-3 polyunsaturated fatty acids, and starch-like polysaccharides. Significant levels of chlorophyll (3.5 g/100 g), carotenoids (0.61 g/100 g), and vitamins (e.g., 79.2 mg ascorbic acid /100 g) were also found in the biomass. Conversely, pathogenic bacteria, heavy metals, cyanotoxins, mycotoxins, polycyclic aromatic hydrocarbons, and pesticides were absent. The biomass showed moderate antioxidant activity in several in vitro assays. Taken together, as the biomass produced has a balanced biochemical composition of macronutrients and (pro-)vitamins, lacking any toxic contaminants, these results suggest that this strain can be used for nutritional applications.
Three‐dimensional computed tomographic examination of pelvic cavity in Van Cats and its morphometric investigation

This study was carried out to determine the morphometric values of the pelvic cavity, the cranial and caudal pelvic aperture by three‐dimensional (3D) reconstruction of the images obtained by computed tomography in adult Van Cats and to show the differences between these indicators in both genders. A total of 16 adult Van Cats, eight male and eight female, were used in the study. Animals were anesthetized with ketamine–xylazine combination and were scanned by computerized tomography. Images of the pelvic cavity were obtained. Three‐dimensional reconstruction of the pelvis was performed with three‐dimensional modelling program. Measurements of the diameters of the pelvic cavity, the cranial and caudal pelvic aperture were calculated from these images, and statistical analyzes were performed. Three‐dimensional modelling of the pelvic cavity of Van Cats were examined between males and females. The results showed that there were significant (p < .05) differences between measurement of the pelvic inclination, the medial transverse diameter, the caudal transverse diameter and the angle between ischiatic arch. In addition, the correlations between age and weight were found statistically significant (p < .05) with the dorsal transverse diameter, the intermediate transverse diameter and the caudal transverse diameter in males. On the other hand, the correlations of age were statistically significant (p < .01) with the cranial pelvic aperture and the caudal pelvic aperture in females. In conclusion, some biometric values of pelvic cavity were observed to be statistically different in Van Cats.
A Reversible Phase Transition of 2D Coordination Layers by B–H∙∙∙Cu(II) Interactions in a Coordination Polymer

Materials that combine flexibility and open metal sites are crucial for myriad applications. In this article, we report a 2D coordination polymer (CP) assembled from CuII ions and a flexible meta-carborane-based linker [Cu2(L1)2(Solv)2]•xSolv (1-DMA, 1-DMF, and 1-MeOH; L1: 1,7-di(4-carboxyphenyl)-1,7-dicarba-closo-dodecaborane). 1-DMF undergoes an unusual example of reversible phase transition on solvent treatment (i.e., MeOH and CH2Cl2). Solvent exchange, followed by thermal activation provided a new porous phase that exhibits an estimated Brunauer-Emmett-Teller (BET) surface area of 301 m2 g−1 and is capable of a CO2 uptake of 41 cm3 g−1. The transformation is reversible and 1-DMF is reformed on addition of DMF to the porous phase. We provide evidence for the reversible process being the result of the formation/cleavage of weak but attractive B–H∙∙∙Cu interactions by a combination of single-crystal (SCXRD), powder (PXRD) X-ray diffraction, Raman spectroscopy, and DFT calculations.
Adaptive Neural Network Finite-Time Control for Multi-Input and Multi-Output Nonlinear Systems With Positive Powers of Odd Rational Numbers

This article investigates the adaptive neural network (NN) finite-time output tracking control problem for a class of multi-input and multi-output (MIMO) uncertain nonlinear systems whose powers are positive odd rational numbers. Such designs adopt NNs to approximate unknown continuous system functions, and a controller is constructed by combining backstepping design and adding a power integrator technique. By constructing new iterative Lyapunov functions and using finite-time stability theory, the closed-loop stability has been achieved, which further verifies that the entire system possesses semiglobal practical finite-time stability (SGPFS), and the tracking errors converge to a small neighborhood of the origin within finite time. Finally, a simulation example is given to elaborate the effectiveness and superiority of the developed.
An update on the management of low risk differentiated thyroid cancer.

Low risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6-18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg-antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.
Seawater-buffered diagenesis, destruction of carbon isotope excursions, and the composition of DIC in Neoproterozoic oceans

Significance Carbonate sediments of Neoproterozoic age exhibit large secular excursions of carbon isotope composition outside the range of modern seawater dissolved inorganic carbon (DIC), but their origins are controversial. We show that in a Neoproterozoic carbonate platform in Namibia, such excursions disappear on the flanks of the platform, where compositions are more compatible with modern seawater. We attribute the observed spatial variation to early fluid-buffered alteration on the flanks of the platform, where seawater invaded the sediment in response to geothermal porewater convection. Accordingly, the isotope excursions in the platform interior are decoupled from open-ocean DIC, which remained close to the modern range. Our interpretation is testable and, if confirmed, has important ramifications for the origins of ancient carbon isotope excursions. Carbonate sediments of nonglacial Cryogenian (659 to 649 Ma) and early Ediacaran (635 to 590 Ma) age exhibit large positive and negative δ13Ccarb excursions in a shallow-water marine platform in northern Namibia. The same excursions are recorded in fringing deep-sea fans and in carbonate platforms on other paleocontinents. However, coeval carbonates in the upper foreslope of the Namibian platform, and to a lesser extent in the outermost platform, have relatively uniform δ13Ccarb compositions compatible with dissolved inorganic carbon (DIC) in the modern ocean. We attribute the uniform values to fluid-buffered diagenesis that occurred where seawater invaded the sediment in response to geothermal porewater convection. This attribution, which is testable with paired Ca and Mg isotopes, implies that large δ13Ccarb excursions observed in Neoproterozoic platforms, while sedimentary in origin, do not reflect the composition of ancient open-ocean DIC.
EZH2 Supports Osteoclast Differentiation and Bone Resorption Via Epigenetic and Cytoplasmic Targets

Key osteoclast (OCL) regulatory gene promoters in bone marrow–derived monocytes harbor bivalent histone modifications that combine activating Histone 3 lysine 4 tri‐methyl (H3K4me3) and repressive H3K27me3 marks, which upon RANKL stimulation resolve into repressive or activating architecture. Enhancer of zeste homologue 2 (EZH2) is the histone methyltransferase component of the polycomb repressive complex 2, which catalyzes H3K27me3 modifications. Immunofluorescence microscopy reveals that EZH2 localization during murine osteoclastogenesis is dynamically regulated. Using EZH2 knockdown and small molecule EZH2 inhibitor GSK126, we show that EZH2 plays a critical epigenetic role in OCL precursors (OCLp) during the first 24 hours of RANKL activation. RANKL triggers EZH2 translocation into the nucleus where it represses OCL‐negative regulators MafB, Irf8, and Arg1. Consistent with its cytoplasmic localization in OCLp, EZH2 methyltransferase activity is required during early RANKL signaling for phosphorylation of AKT, resulting in downstream activation of the mTOR complex, which is essential for induction of OCL differentiation. Inhibition of RANKL‐induced pmTOR‐pS6RP signaling by GSK126 altered the translation ratio of the C/EBPβ‐LAP and C/EBPβ‐LIP isoforms and reduced nuclear translocation of the inhibitory C/EBPβ‐LIP, which is necessary for transcriptional repression of the OCL negative‐regulatory transcription factor MafB. EZH2 in multinucleated OCL is primarily cytoplasmic and mature OCL cultured on bone segments in the presence of GSK126 exhibit defective cytoskeletal architecture and reduced resorptive activity. Here we present new evidence that EZH2 plays epigenetic and cytoplasmic roles during OCL differentiation by suppressing MafB transcription and regulating early phases of PI3K‐AKT–mTOR‐mediated RANKL signaling, respectively. Consistent with its cytoplasmic localization, EZH2 is required for cytoskeletal dynamics during resorption by mature OCL. Thus, EZH2 exhibits complex roles in supporting osteoclast differentiation and function. © 2019 American Society for Bone and Mineral Research.
Estimation of the Mitochondrial Membrane Potential Using Fluorescence Lifetime Imaging Microscopy

Monitoring of cell metabolism represents an important application area for fluorescence lifetime imaging microscopy (FLIM). In particular, assessment of mitochondrial membrane potential (MMP) in complex three‐dimensional multicellular in vitro, ex vivo, and in vivo models would enable improved segmentation and functional discrimination of cell types, directly report on the mitochondrial function and complement the quenched‐phosphorescence detection of cellular O2 and two‐photon excited FLIM of endogenous NAD(P)H. Here, we report the green and orange‐emitting fluorescent dyes SYTO and tetramethylrhodamine methyl ester (TMRM) as potential FLIM probes for MMP. In addition to nuclear, SYTO 16 and 24 dyes also display mitochondrial accumulation. FLIM with the culture of human colon cancer HCT116 cells allowed observation of the heterogeneity of mitochondrial polarization during the cell cycle progression. The dyes also demonstrated good performance with 3D cultures of Lgr5‐GFP mouse intestinal organoids, providing efficient and quick cell staining and compatibility with two‐photon excitation. Multiplexed imaging of Lgr5‐GFP, proliferating cells (Hoechst 33342‐aided FLIM), and TMRM‐FLIM allowed us to identify the population of metabolically active cells in stem cell niche. TMRM‐FLIM enabled to visualize the differences in membrane potential between Lgr5‐positive and other proliferating and differentiated cell types. Altogether, SYTO 24 and TMRM dyes represent promising markers for advanced FLIM‐based studies of cell bioenergetics with complex 3D and in vivo models. © 2019 International Society for Advancement of Cytometry