Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison of pulsed‐field ablation versus very high power short duration‐ablation for pulmonary vein isolation

The newly introduced nonthermal pulsed field ablation (PFA) is a promising technology to achieve fast pulmonary vein isolation (PVI) with high acute success rates and good safety features. However, previous studies have shown that very high power short duration ablation (VHPSD) is also highly effective and fast to achieve PVI with potentially less arrhythmia recurrence compared to conventional radiofrequency ablation. Data comparing PFA to VHPSD‐PVI is lacking.
Cap Analysis of Gene Expression Clarifies Transcriptomic Divergence Within Monozygotic Twin Pairs

Abstract Phenotypic variation is the result of gene expression based on complex interaction between genetic and environmental factors. It is well known that genetic and environmental factors influence gene expression, but our understanding of their relative importance remains limited. To obtain a hint for the understanding of their contributions, we took advantage of monozygotic twins, as they share genetic and shared environmental factors but differ in nonshared factors, such as environmental differences and stochastic factors. In this study, we performed cap analysis of gene expression on three pairs of twins and clustered each individual based on their expression profiles of annotated genes. The dendrogram of annotated gene transcripts showed a monophyletic clade for each twin pair. We also analyzed the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), given their abundance in the genome. Clustering analyses demonstrated that HERV and LINE expression diverged even within monozygotic twin pairs. Thus, HERVs and LINEs are more susceptible to nonshared factors than annotated genes. Motif analysis of differentially expressed annotated genes suggests that specificity protein/Krüppel-like factor family transcription factors are involved in the expression divergence of annotated gene influenced by nonshared factors. Collectively, our findings suggest that expressions of annotated genes and retrotransposons are differently regulated, and that the expression of retrotransposons is more susceptible to nonshared factors than annotated genes.
Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir

Significance Persistence of a latent reservoir in resting CD4+ T cells is the major barrier to curing HIV-1 infection. Non-human primates infected with simian–human immunodeficiency virus (SHIV) provide a valuable model for cure strategies. As with HIV-1, most SHIV proviruses persisting in animals treated with antiretroviral therapy (ART) are defective and irrelevant to cure. The lack of assays that selectively quantify intact proviruses impeded understanding of reservoir dynamics in this model. Here, we describe an assay for intact SHIV proviruses and use it to define rapid biphasic decay processes during the first year of ART when many interventions are tested. This study provides insights into early decay kinetics of intact SHIV genomes that must be considered in evaluating cure interventions.
Pharmacokinetic considerations for angiogenesis inhibitors used to treat hepatocellular carcinoma: an overview

ABSTRACT Introduction Hepatocellular carcinoma (HCC) is the fifth malignancy in terms of frequency and the fourth malignancy in terms of cancer-related death worldwide. Systemic therapy of advanced HCC has probably gone through the greatest wave of change in the last decade, with the introduction of several anti-angiogenic drugs and immune checkpoint inhibitors, able to significantly improve patients’ prognosis. Areas covered In this review, we summarize the pharmacokinetic characteristic of the antiangiogenic drugs currently approved for the treatment of HCC, from oral tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib) to monoclonal antibodies (bevacizumab and ramucirumab), focusing on the main aspects that differ among compounds from the same class, on factors that can exert an influence on pharmacokinetic parameters and the main issues that could limit their clinical use. Expert opinion Anti-angiogenic drugs have different profiles in terms of bioavailability, metabolism, elimination and interindividual variability in their pharmacokinetics and effectiveness. More studies should be developed to address the intrinsic and extrinsic factors influencing pharmacokinetics parameters to improve the individual therapeutic response and, furthermore, to evaluate the benefit and the harm of systemic therapy for advanced HCC in selected patients with liver impairment.
Paraglacial geomorphology of Quaternary volcanic landscapes in the southern Coast Mountains, British Columbia

Abstract An important paradigm in geomorphology is paraglacial sedimentation, a phrase first used almost 40 years ago to describe reworking of glacial sediment by mass wasting and streams during and after continental-scale deglaciation. The concept has been extended to include non-glacial landforms and landscapes conditioned by glaciation. In this paper we apply the paraglacial concept to volcanoes in southern British Columbia, Canada, that formed, in part, in contact with glacier ice. The Cheekye River basin, a small watershed on the flank of a volcano that erupted against the decaying Cordilleran ice sheet, has a Holocene history marked by an exponential decay in debris-flow activity and sediment yield. Its history is consistent with the primary exhaustion model of the paraglacial cycle. At larger spatial scales, this primary sediment is reworked by rivers and transported downstream and augmented by stochastic geomorphic events. Repeated large landslides from Mount Meager volcano in southern British Columbia have delivered a disproportionate volume of sediment to the fluvial system: although occupying only 2% of the watershed area, 25–75% of the 10 km3 of sediment deposited in Lillooet River valley during the Holocene originated from the volcano. In these cases a significant overall reduction in sediment yield must await the removal, by erosion, of volcanic edifices, a process that could take up to millions of years. These examples of paraglacial activity on Quaternary volcanoes are end members in the spectrum of landscape response to Pleistocene deglaciation.
A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53–/– (NP–/–) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NPmut-AML transcriptome distinct from that of NP–/– cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB–inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.
The 2004 December 26 Indian Ocean tsunami impact on Sri Lanka: cascade modelling from ocean to city scales

SUMMARY The 2004 December 26 Indian Ocean tsunami severely hit Sri Lanka. Although it was not in the direct path of the initial tsunami waves, the western coast was struck by diffracted waves that caused much damage. The numerical model GEOWAVE is used to compute tsunami generation, propagation and inundation from the earthquake source to the Sri Lankan coast. A nested grid system is constructed to increase the resolution until Galle Bay, on the southwestern coast, where a 20 m-grid is used. The six nested topobathymetric grids are interpolated from ETOPO2 and high resolution data, at sea as onshore. Simulation results are compared with tsunami height data from National Oceanic and Atmospheric Administration (NOAA; US) and Geological Survey & Mines Bureau (GSMB; Sri Lanka). When the grid resolution increases, the discrepancy between the model and the data remains, on average, good, whereas its spread increases. We then conclude that the order of magnitude of the tsunami height is consistent from the 180 m-resolution grid, but the spatial imprecision is too high to locally predict reliable water heights. Nevertheless, the comparison between computed time-series of sea surface elevation at the Colombo tide station and tide-gauge data shows a very good agreement as both amplitude, and arrival time of the first wave are well reproduced. When focusing onshore, the modelled inundation limit is compared with the limit measured in the field. With its a priori setup, computed inundation spreads much farther behind the field limit. We then integrate more accurate nearshore conditions into the model. Non-linear shallow water equations are chosen instead of fully non-linear Boussinesq equations; the bottom friction on land is increased to a much higher value than at sea; the buildings cover and the low tide conditions are taken into account in the DEM. The resulting high resolution simulation agrees better with field data, even if discrepancies are still locally observed in places of DEM imprecision and in a river valley. This simulation, however, demonstrates that taking into account nearshore and onshore features may significantly improve tsunami impact assessment.
A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

The transport of drugs into and out of the liver plays a critical role in determining drug disposition and therapeutic ef ﬁ cacy. Competition between drugs or inhibition of transporter function also makes membrane transporters an important site for drug-drug-interactions that can impact therapeutic ef ﬁ cacy and the likelihood of adverse effects. Among the numerous plasma membrane carrier proteins found in the liver, the organic anion transporting polypeptide (OATP; SLCO gene family) transporters are among the most important for many anionic drugs and amphiphilic substrates, including cancer chemotherapeutic agents (Kalliokoski and Niemi, 2009; Tu et al., 2013; van de Steeg et al., 2013). The OATP or SLCO gene family of transporters comprises 11 individual carrier proteins in humans (https://www.guidetopharmacology.org/ GRAC/FamilyDisplayForward? familyId=238). These carriers are further divided into 6 families and 10 sub-families based on amino acid sequence. While they all have in common the properties of 12 transmembrane domains with intracellular termini, multiple glycosylation sites, and the mediation of sodium-independent uptake of various amphiphilic substrates, the different carriers have distinct tissue localizations. There are six OATP proteins that are expressed in the liver, including SLCO1A2, SLCO2A1, and SLCO2B1 (ubiquitously expressed), SLCO1B1 and SLCO1B3 (selectively expressed in the liver), and SLCO4A1 (expressed in the liver as well as the heart, placenta, and lung). The importance of hepatic OATP transporters in drug design and development is highlighted by the recommendations from the U.S. Food and Drug Administration (Food and Drug Administration Center for Drug Evaluation and Research, 2020), European Medicines Agency (European Medicines Agency Committee for Human Medicinal Products, 2012), and Japan Ministry of Health, Labor and Welfare (Ministry of Health, Labour and Welfare Pharmaceuticals and Medical Device Agency,
Effect of intranasal and oral administration of levetiracetam on the temporal and spatial distributions of SV2A in the KA‐induced rat model of SE

To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra‐amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.
Think positive! Resolving human motion ambiguity in the presence of disease threat

ABSTRACT Recently, approach-avoidance tendencies and visual perception biases have been increasingly studied using bistable point-light walkers (PLWs). Prior studies have found a facing-the-viewer bias when one is primed with general threat stimuli (e.g. angry faces), explained by the “error management theory”, as failing to detect a threat as approaching is riskier than the opposite. Importantly, no study has explored how disease threat – linked to the behavioural immune system – might affect this bias. This study aimed to explore whether disease-signalling cues can alter how we perceive the motion direction of ambiguous PLWs. Throughout 3 experiments, participants indicated the motion direction of a bistable PLW previously primed with a control or disease-signalling stimuli – that is, face with a surgical mask (Experiment 1), sickness sound (Experiment 2), or face with a disease cue (Experiment 3). Results showed that sickness cues do not significantly modulate the perception of approach-avoidance behaviours. However, a pattern emerged in Experiments 2 and 3, suggesting that sickness stimuli led to more facing away percepts. Unlike other types of threat, this implies that disease-related threat stimuli might trigger a distinct perceptual bias, indicating a preference to avoid a possible infection source. Nonetheless, this finding warrants future investigations.
Empirical Dynamical System Modeling of ENSO Using Nonlinear Inverse Techniques

Abstract A statistical technique is presented that allows for the empirical derivation of dynamical system equations from data. It is based on multiple nonparametric regression analysis and is applicable to a broad class of physical systems. It is applied to differential delay equations as well as to ordinary differential equations. The aim of this paper is to illustrate this technique in the context of the El Nino–Southern Oscillation (ENSO) phenomenon. A set of reduced models is derived from an intermediate coupled atmosphere–ocean model of the tropical Pacific and from a state-of-the-art coupled general circulation model simulation. The analysis in this paper focuses on the dimensionality issue as well as on the role of nonlinearities. The empirical technique presented in this study helps to identify key ENSO processes and to explain physical peculiarities of ENSO simulations.
Assessing the implementation of inclusion and availability of resources in primary teachers’ colleges: a case of South Western region in Uganda

This study assessed the implementation of inclusion of trainees with special educational needs and availability of resources in primary teachers colleges in Uganda. The study was conducted in the South Western Region in Uganda. Three colleges were selected to be involved in the study. A qualitative research method was used. Data collection strategies that were used are interviews and observation. This study considered independent and dependent variables in the study. The independent variable was availability of resources such as teaching and non teaching staff and material resources: teaching and learning materials and equipment, and physical facilities buildings. The dependent variable was successful implementation of inclusion in primary teachers‟ colleges. The target population that was involved in the study included Principals, Tutors and Student Trainees. Samples of 50 respondents from the three colleges were involved; these included 3 Principals, 15 Tutors and 32 Student trainees. Purposive sampling was used to help the researcher have respondents who would provide the relevant data. The researcher used interviews and observation to collect data from Principals, Tutors and Student trainees of the three colleges in South Western region in Uganda. Data was analyzed descriptively. The study revealed that colleges have resources required for implementation of inclusion which was classified as human and material resources. The study further revealed challenges for successful inclusion that some resources were not accessible to all students, inadequate skills in special needs education among staff, negative attitude and limited funding. Results were summarized according to research questions and recommendations were made that change of attitude is paramount in order to implement inclusion in PTCs, training of tutors in special needs education, appointment of tutors to cater for trainees with special educational needs and provision of ramps to all buildings.
Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis

Emergency granulopoiesis is the enhanced and accelerated production of granulocytes that occurs during acute infection. The contribution of hematopoietic stem cells (HSCs) to this process was reported; however, how HSCs participate in emergency granulopoiesis remains elusive. Here, using a mouse model of emergency granulopoiesis we observe transcriptional changes in HSCs as early as 4 h after lipopolysaccharide (LPS) administration. We observe that the HSC identity is changed towards a myeloid‐biased HSC and show that CD201 is enriched in lymphoid‐biased HSCs. While CD201 expression under steady‐state conditions reveals a lymphoid bias, under emergency granulopoiesis loss of CD201 marks the lymphoid‐to‐myeloid transcriptional switch. Mechanistically, we determine that lymphoid‐biased CD201+ HSCs act as a first response during emergency granulopoiesis due to direct sensing of LPS by TLR4 and downstream activation of NF‐κΒ signaling. The myeloid‐biased CD201− HSC population responds indirectly during an acute infection by sensing G‐CSF, increasing STAT3 phosphorylation, and upregulating LAP/LAP* C/EBPβ isoforms. In conclusion, HSC subpopulations support early phases of emergency granulopoiesis due to their transcriptional rewiring from a lymphoid‐biased to myeloid‐biased population and thus establishing alternative paths to supply elevated numbers of granulocytes.
Mothers' and fathers' experiences of parenting in the fly-in fly-out mode of employment

A qualitative study of mothers' and fathers' experiences of parenting in a fly-in fly-out employment arrangement was undertaken. Eight mothers were interviewed individually to investigate their experiences of parenting. Five fathers also participated in individual interviews to examine their experiences of parenting and to substantiate those of mothers. The findings indicated that mothers were subjected to a range of conditions that would not, in the normal course of events, be experienced by mothers with partners in home-based occupations. These circumstances imposed additional stresses on families, but more particularly on mothers. In family systems theory parental stress inevitably resonates throughout the entire family. Coping strategies may seriously deplete parental resources that could ultimately lead to a breakdown in the marital relationship. Although it was generally perceived that there were no detrimental effects on children's wellbeing overall, some children did manifest negative reactions directly attributed by a parent to father absences. As the scope of this research did not include an examination of differences in maternal coping strategies or specific parenting practices, future research could examine how these factors might account for differences in both mothers' and children's ability to cope. I certify that this thesis does not, to the best of my knowledge and belief: (i) incorporate without acknowledgement any material previously submitted for a degree or diploma in any institution of higher education; (ii) contain any material previously published or written by another person except where due reference is made in the text; or (iii) contain any defamatory material.
Origin of fine-grained granular rocks in layered intrusions

Summary Extremely fine-grained granular rocks are found interleaved with cumulates in some layered differentiated intrusions. The question arises as to whether these can be interpreted as chilled magmas. If this were so it would allow the liquid line of descent to be determined directly. A study of extremely fine-grained granular rocks in the differentiated, layered basic Fongen–Hyllingen complex, Norway, however, showed rocks of this type to be cumulates. Fluctuations in volatile pressure due to crystallization of a hydrous phase may give rise to modal and grain-size variation in layered intrusions.