Miracle-dz/UniFAR-FTUs huggingface dataset:
The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome

Purpose: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. Experimental Design: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. Results: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. Conclusions: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.
Perceived relative social status and cognitive load influence acceptance of unfair offers in the Ultimatum Game

Participants in the Ultimatum Game will often reject unfair resource allocations at personal cost, reflecting a trade-off between financial gain and maintenance of social standing. Although this rejection behavior is linked to executive control, the exact role of cognitive regulation in relation to status cues is unclear. We propose that the salience of status cues affects how cognitive regulation resolves the conflict between financial gain and social status considerations. Situations that tax executive control by limiting available cognitive resources should increase acceptance rates for unfair offers, particularly when the conflict between economic self-interest and social reputation is high. Here, participants rated their own subjective social status, and then either mentally counted (Load) or ignored (No Load) simultaneously-presented tones while playing two rounds of the Ultimatum Game with an online (sham) “Proposer” of either high or low social status. A logistic regression revealed an interaction of Proposer status with cognitive load. Compared to the No Load group, the Load group showed higher acceptance rates for unfair offers from the high-status Proposer. In contrast, cognitive load did not influence acceptance rates for unfair offers from the low-status Proposer. Additionally, Proposer status interacted with the relative social distance between participant and Proposer. Participants close in social distance to the high-status Proposer were more likely to accept the unfair offer than those farther in social distance, whereas the opposite pattern was observed for offers from the low-status Proposer. Although rejection of unfair offers in the Ultimatum Game has previously been conceptualized as an intuitive response, these results instead suggest it reflects a deliberative strategy, dependent on cognitive resources, to prioritize social standing over short-term financial gain. This study reveals the dynamic interplay of cognitive resources and status concerns within this paradigm, providing new insights into when and why people reject inequitable divisions of resources.
Regeneration after acute kidney injury requires PTIP mediated epigenetic modifications.

Adult renal proximal tubules are composed of terminally differentiated epithelial cells that exhibit few signs of proliferation over time. However, upon acute kidney injury (AKI), surviving epithelial cells can re-enter the mitotic cycle and express genes and proteins coincident with a dedifferentiated, more embryonic phenotype. While a stable, terminally differentiated cellular phenotype is thought to be maintained, at least in part, by epigenetic imprints that impart both active and repressive histone marks, it is unclear whether regenerating cells after injury need to replicate such marks to recover. To test whether renal epithelial cell regeneration is dependent on histone H3K4 methylation, we generated a mouse model that deleted the Paxip1 gene in mature renal proximal tubules. Paxip1 encodes the adaptor protein PTIP, which is part of an Mll3/4 histone H3K4 methyltransferase complex and is essential for embryonic development. Mice with PTIP deletions in the adult kidney proximal tubules were viable and fertile. Upon acute kidney injury, such mice failed to regenerate damaged tubules leading to scarring and interstitial fibrosis. The inability to repair damage was likely due to a failure to re-enter mitosis and reactivate regulatory genes such as Sox9, which is necessary for epithelial cell regeneration. PTIP deletion reduced histone H3K4 methylation in uninjured adult kidneys but did not significantly affect function or the expression of epithelial specific markers. A transient decrease in trimethylation was also observed in controls after AKI but returned to normal after repair. Strikingly, cell lineage tracing revealed that surviving PTIP mutant cells could alter their phenotype and lose epithelial markers. These data demonstrate that PTIP and associated MLL3/4 mediated histone methylation are needed for regenerating proximal tubules and to maintain or reestablish the cellular epithelial phenotype.
Real‐world evidence of secukinumab in psoriasis treatment – a meta‐analysis of 43 studies

Real‐world evidence (RWE) meta‐analyses provide valuable insights from patients in routine clinical practice. Secukinumab, the first fully human monoclonal antibody that neutralizes IL‐17A, has shown long‐lasting effectiveness and safety in plaque psoriasis (PsO). Since its licence approval in 2015, many RWE studies have been published. The objective of this study was to review all available literature on RWE studies with secukinumab and the secukinumab arm of comparator studies in patients with moderate‐to‐severe PsO to evaluate its effectiveness, drug survival and safety. https://www.embase. com and https://clinicaltrials.gov databases were searched using prespecified inclusion criteria between 1 January 2015 and 31 May 2019. Using a meta‐package and R statistical software to analyse data, key outcomes were measured at 3, 6 and 12 months. PASI and DLQI score data were recorded for patients who remained on secukinumab treatment. Overall, 43 studies were included. Drug survival was 90% at 3 and 6 months, and 80% at 12 months. At 12 months, 8% of patients had discontinued treatment due to lack of effectiveness. At 3, 6 and 12 months, Psoriasis Area and Severity Index (PASI) 90 scores were as follows: 50%, 53% and 60%, and PASI 100 scores were 36%, 46% and 51%, respectively. At 3, 6 and 12 months, 57%, 55% and 65% of patients achieved a Dermatology Life Quality Index (DLQI) score of 0 or 1, respectively. Adverse events were consistent with rates observed in clinical trials with no new safety signals. This meta‐analysis strengthens existing evidence on the clinical effectiveness of secukinumab in patients with moderate‐to‐severe PsO, demonstrating high drug survival rates, high levels of patient‐reported outcomes, and good tolerance.
Gender specific pharmacokinetic and pharmacodynamic considerations for antimuscarinic drugs for overactive bladder treatment

ABSTRACT Introduction: Overactive bladder (OAB) has a heterogeneous presentation that varies between individuals and by gender. Treatment with antimuscarinic medications is standard first line pharmacotherapy for most patients with OAB. However, gender specific differences in the pharmacokinetics and pharmacodynamics of antimuscarinic therapy are often overlooked and not discussed. Areas covered: This review will explore differences by gender between the presentation and treatment of OAB. We will discuss the differences between sexes in terms of lower urinary tract anatomy, muscarinic receptors, and hormone variation. The effect of antimuscarinics on males and females as well as adherence and persistence patterns will be reviewed in order to fully review all available literature on the gender specific pharmacokinetic and pharmacodynamic considerations for antimuscarinic use in the treatment of OAB. Expert opinion: Despite extensive research into various antimuscarinic formulations and therapeutic regimens for the treatment of OAB, identification of gender specific pharmacokinetic and pharmacodynamics considerations remains scant. As our knowledge and understanding of OAB, muscarinic receptors, and antimuscarinic medications evolve, we will hopefully be better able to understand and implement gender-specific and genomic-sprecific treatment regimens and considerations for improved clinical outcomes.
Expression of Hematopoietic Stem and Endothelial Cell Markers in Canine Hemangiosarcoma

Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs. Neoplastic canine cells expressed EC markers and a myeloid marker, but expressed HSC markers less consistently. The canine tumor expression results were then compared to previously published immunoreactivity results for these markers in human and mouse HSAs. There are 2 noteworthy differences across species: (1) most human HSAs had HSC marker expression, indicating that they were comprised of tumor cells that were less differentiated than those in canine and mouse tumors; and (2) human and canine HSAs expressed a late-stage EC maturation marker, whereas mouse HSAs were negative, suggesting that human and canine tumors may retain greater differentiation potential than mouse tumors. These results indicate that HSA development is variable across species and that caution is necessary when discussing translation of carcinogenic risk from animal models to humans.
Establishment of a novel culture method for maintaining intestinal stem cells derived from human induced pluripotent stem cells

ABSTRACT The small intestine plays an important role in the pharmacokinetics of orally administered drugs due to the presence of drug transporters and drug-metabolizing enzymes. However, few appropriate methods exist to investigate intestinal pharmacokinetics. Induced pluripotent stem (iPS) cells can form various types of cells and represent a potentially useful tool for drug discovery. We previously reported that differentiated enterocytes from human iPS cells are useful for pharmacokinetic studies; however, the process is time and resource intensive. Here, we established a new two-dimensional culture method for maintaining human iPS-cell-derived intestinal stem cells (ISCs) with differentiation potency and evaluated their ability to differentiate into enterocytes exhibiting appropriate pharmacokinetic function. The culture method used several factors to activate signalling pathways required for maintaining stemness, followed by differentiation into enterocytes. Functional evaluation was carried out to verify epithelial-marker expression and inducibility and activity of metabolic enzymes and transporters. Our results confirmed the establishment of an ISC culture method for maintaining stemness and verified that the differentiated enterocytes from the maintained ISCs demonstrated proper pharmacokinetic function. Thus, our findings describe a time- and cost-effective approach that can be used as a general evaluation tool for evaluating intestinal pharmacokinetics. Summary: This study describes a novel two-dimensional culture method for maintaining intestinal stem cells (ISCs) derived from human iPS cells. The enterocytes differentiated from maintained ISCs showed pharmacokinetics functions.
Enantio‐ and Diastereoselective Synthesis of Homopropargyl Amines by Copper‐Catalyzed Coupling of Imines, 1,3‐Enynes, and Diborons

Abstract An efficient, enantio‐ and diastereoselective, copper‐catalyzed coupling of imines, 1,3‐enynes, and diborons is reported. The process shows broad substrate scope and delivers complex, chiral homopropargyl amines; useful building blocks on the way to biologically‐relevant compounds. In particular, functionalized homopropargyl amines bearing up to three contiguous stereocenters can be prepared in a single step.
Complete Genome Sequence of Sinorhizobium meliloti Strain AK21, a Salt-Tolerant Isolate from the Aral Sea Region

We report here the complete genome sequence of the salt-tolerant Sinorhizobium meliloti strain AK21, isolated from nodules of Medicago sativa L. subsp. ambigua inhabiting the northern Aral Sea Region. This genome (7.36 Mb) consists of a chromosome and four accessory plasmids, two of which are the symbiotic megaplasmids pSymA and pSymB. ABSTRACT We report here the complete genome sequence of the salt-tolerant Sinorhizobium meliloti strain AK21, isolated from nodules of Medicago sativa L. subsp. ambigua inhabiting the northern Aral Sea Region. This genome (7.36 Mb) consists of a chromosome and four accessory plasmids, two of which are the symbiotic megaplasmids pSymA and pSymB.
Behavioural responses in a congested sea: an observational study on a coastal nest-guarding fish

Abstract The deleterious effects of anthropogenic noise on animal communication are nowadays recognised, not only in urban environments but also in terrestrial habitats and along coasts and in open waters. Yet, the assessment of short- and long-term exposure consequences of anthropogenic noise in marine organisms remains challenging, especially in fish and invertebrates. Males of the Mediterranean damselfish Chromis chromis vocalise and perform visual displays (multimodal communication) to attract mates. The frequency-range of courtship vocalisations overlaps with low-frequency noise generated by maritime activities, resulting in a reduced detection distance among conspecifics. We quantified the number of courtship-related visual displays performed by males living in areas with different levels of maritime traffic. We also tried to manipulate ambient noise in the field to test male short-term response to increased noise levels. Males living in busier areas (near to a harbour) performed significantly more visual displays than those living in less congested areas. When exposed to artificially-increased ambient noise level (playback of boat noise), males did not adjust the number of visual displays accordingly. Yet, we note how assessing the actual effect of maritime traffic in marine populations in their natural environments is particularly difficult, as the effects of boat noise cannot be easily disentangled from a variety of other intrinsic or environmental factors, discussed in the paper. We thus present suggestions to obtain more robust analyses of variations of courtship behaviours in territorial fishes. We hope this will facilitate a further understanding of the potential long-term effects of anthropogenic noise, whose analyses should be prioritised in the context of environmental impact assessment, resource management and biodiversity conservation.
What drives economic growth sustainability? Evidence from Indonesia

This paper analyzes the determinants of economic growth sustainability in Indonesia. Based on annual data 1971-2017, this research applies the vector error correction model (VECM) to estimate the dynamic effects of the inflation rate, tax ratio, government spending, broad money, and exchange rate on economic growth. The findings present the existence of long-run equilibrium in a set of those variables. Specifically, the price level and fiscal policy have positive impact on economic growth sustainability. We also find that the effect of monetary policy on economic growth is neutral. The monetary authority should strengthen the impact of monetary variables on economic growth. The exchange rate is part of international factors that threats the economic growth sustainability. It implies that economic growth sustainability is closely related to the international financial sector. Therefore, the central bank should control the exchange rate variable at the safety level to maintain economic growth sustainability.
Child Abuse and Neglect, Posttraumatic Stress Disorder

Angelo P Giardino, MD, PhD, Clinical Associate Professor, Department of Pediatrics, Baylor College of Medicine; Medical Director, Texas Children's Health Plan, Inc Toi Blakley Harris, MD,, Assistant Professor and Director of Diversity and Education, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Founder and Director, Texas Regional Psychiatry Minority Mentor Network; Eileen R Giardino, PhD, RN, MSN, FNP-BC, ANP-BC, Associate Professor of Nursing, Department of Acute and Continuing Care, University of Texas Health Sciences Center Houston School of Nursing Updated: Jul 28, 2009
Protective role of vitamin-D on chronic stress induced-learning and memory deficits in rats

كچ ي هد :فده ازفا بجوم سرتسا ي ش اهر ي ش تروکوکولگ ي ئوک ي د اه تسلاپ رد للاتخا و ي س ي ت ي نورون ب اه ه ه رد صوصخ ي پمکوپ هک هدش م ي و هظفاح رد للاتخا هب رجنم دناوت ي گدا ي ر ي . دوش نآ زا و هک اج ي مات ي ن D تظفاحم شقن س رب هدننک ي متس بصع ي و هتشاد گ ي هدنر اه ي ه رد نآ ي پمکوپ وتب دراد لامتحا ،دنراد روضح دنا فنم تارثا لباقم رد ي زم سرتسا تظفاحم شقن نم ا هدننک ي اف . دنک ربانب ا ي ،ن ا فده ي ن سررب ،هعلاطم ي تظفاحم تارثا ي و ي مات ي ن D للاتخا رب ي گدا ي ر ي شان هظفاح و ي گرزب شوم رد نمزم سرتسا زا امزآ ي هاگش ي تسا هدوب . شور و داوم :اه شوم =دادعت( ،اه 78 هورگ هب يفداصت تروص هب ،) اه ي اب مادک ره( لرتنک و سرتسا 3 ز ي ر )هورگ سقت ي م . دندش ح سرتسا هورگ رد ي تاناو تدم هب 28 زور ،زور ي 3 دودحم سرتسا تحت تعاس هورگ . دنتفرگ رارق هدننک للاح هتفه رد راب ود اه و ي مات ي ن D ي ا و ي مات ي ن D ( زود ود رد μg/kg 10 ي ا 5 ) قافص لخاد تروص هب ي رد ي تفا تروک حطس سپس . دندرک ي نورتسوک امسلاپ يي زرا ي با ي ارب . دش ي شجنس ي گدا ي ر ي نومزآ هظفاح و اه ي بآ زام ي زارتحا سپس و ي غ ي ر دش ماجنا لاعف . هتفاي :اه تروک رتلااب حطس سرتسا هورگ ي نورتسوک ( دنداد ناشن نوخ رد لرتنک هورگ هب تبسن ار 0001 / 0 P< .) تست رد بآ زام ي روم ي س هورگ مامت رد ار وکس لحم اه 4 شزومآ زور ي دا ( دنتفرگ 0001 / 0 = P ) اضف هظفاح تست يي ناشن مک نامز تدم هدنهد رت سر ي ند ارب وکس لحم هب ي شوم اه ي د سرتسا ي هد لااب زود . دوب ي و ي مات ي ن D پ بجوم ي اد دش وکس رتدوز ندرک ( 0002 / 0 = P .) رد زارتحا تست ي غ ي ر مک نامز تدم لرتنک هورگ هب تبسن سرتسا هورگ لاعف رت ي حان رد ي ه رات ي ک دوب ( 0997 / 0 = P ) رد ي تفا و ي مات ي ن
Gestión de la Dimensión Social de la Sostenibilidad en los Códigos de Edificación = Building Codes and the Management of Sustainability´s Social Dimension

De acuerdo con la definicion propuesta por las Naciones Unidas, el desarrollo sostenible se basa en tres dimensiones interrelacionadas: medio ambiente, economia y sociedad. A lo largo de las ultimas tres decadas, la industria de la construccion ha adoptado esta definicion centrandose principalmente en la dimension medioambiental, descuidando la dimension social. Al comparar ambas dimensiones, los parametros medioambientales son medibles mediante unidades cuantitativas, lo que ha hecho posible su incorporacion en los codigos de edificacion a nivel internacional. Sin embargo, la dificultad para establecer valores cuantitativos adecuados a los parametros sociales ha obstaculizado su incorporacion en los codigos. Para facilitar la incorporacion de factores sociales dentro de la industria de la edificacion, se propone un enfoque teorico como base para desarrollar sistemas de valoracion cuantitativos de los aspectos sociales en la edificacion. Abstract As defined by the United Nations, a sustainable development relies on three interrelated dimensions: environment, economy, and society. Throughout the last three decades, the building industry has adopted the philosophy of sustainable development by focusing on the environmental dimension, but neglecting the social dimension. When comparing both dimensions, environmental parameters are measurable by quantitative units, which have made their implementation in mandatory building codes feasible. However, the challenging nature to provide appropriate quantitative standards for social parameters prevented their incorporation in building codes. To promote the development of social sustainability within the building industry, this paper aimed to provide a preliminary approach to develop standards that addressed social aspects and health within indoor built environments, so that their incorporation in building codes may be feasible in the near future
Evaluation du traitement antibiotique des infections de prothèse vasculaire à Staphylococcus aureus : apport d'un modèle murin

Les infections de protheses vasculaires (IPV) sont des maladies particulierement graves. Malgre une frequence finalement assez importante, elles demeurent mal connues. Staphylococcus aureus en est l’agent responsable principal. Les donnees concernant le traitement antibiotique a administrer pour ces infections sont excessivement pauvres. L’objectif de notre travail etait donc de comparer l’efficacite de differents protocoles d’antibiotherapie a l’aide de divers modeles experimentaux d’IPV. Six souches differentes de S. aureus ont ete evaluees : 3 sensibles (SAMS) et 3 resistants a la meticilline (SARM). Nous avons compare les concentrations minimales inhibitrices et eradicatrices (CMIB et CMEB) au sein du biofilm obtenues avec des techniques classiques sur polystyrene a ceux obtenus a l’aide d’un modele original in vitro sur Dacron® (dCMIB et dCMEB) ®. Nous avons ensuite utilise un modele original d’infection de Dacron chez la souris pour comparer l’efficacite de differents protocoles therapeutiques. Enfin nous avons visualise l’effet de ces antibiotiques in vivo par microscopie confocale. Nous avons montre que les mesures classiques de CMIB et CMEB obtenues sur polystyrene pouvaient surestimer la baisse d’efficacite des antibiotiques dans le biofilm et que des mesures sur le materiel d’interet pouvaient etre plus pertinentes. Dans notre modele in vivo, la daptomycine pouvait etre superieure que les comparateurs pour certaines souches de SARM et de SAMS mais pas pour toutes. Par contre, si l’ajout de rifampicine etait benefique pour la cloxacilline et la vancomycine, cela n’etait pas le cas pour la daptomycine. Enfin, nous avons visualises des effets totalement differents sur le biofilm selon les antibiotiques utilises mais egalement selon les souches testees. Nos modeles ont permis d’obtenir des informations nouvelles concernant l’antibiotherapie des IPV qui, nous l’esperons, permettront d’aider a la prise en charge des patients.