Miracle-dz/UniFAR-FTUs huggingface dataset:
Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine (5′DFCR), 5′-deoxy-5-fluorouridine (5′DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5′DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5′DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5′DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.
Safety and efficacy of induction immunochemotherapy with rituximab, methotrexate, ifosfamide, and vincristine (R‐MIV) in patients with primary CNS lymphoma including recent COVID‐19 pandemic experience

Clinical data on primary central nervous system (CNS) lymphoma (PCNSL) patients is mostly generated from prospective studies, and many frail real‐world patients are not included. Recently,the diagnosis and treatment of PCNSL patients was confounded by the COVID‐19 pandemic. In particular, treatment with high‐dose cytarabine was linked to increased risk of pneumonia and virus persistence. We report on outcome of the induction regimen R‐MIV (rituximab, methotrexate, ifosfamide, and vincristine) involving intensive administration of high‐dose methotrexate (3.5 g/m2) with ifosfamide, every 2 weeks and rituximab once per week for six doses. The median age and performance status (PS) for 64 patients was 58 years and 2 (PS 3; 22%) respectively. The overall response rate by magnetic resonance imaging/computed tomography (MRI/CT) was 73% (n = 46/63), with an additional 17.5% (n = 11/63) patients without measurable disease at baseline. Grade 3–4 haematological toxicity was low for R‐MIV (neutropenia: 25% and thrombocytopenia: 1%). Three patients (4.7%) died from treatment‐related toxicity. Co‐existence of SARS‐CoV‐2 infection with cytomegalovirus reactivation and the varicella‐zoster virus in two patients was fatal. Fifty patients (78%) were eligible for consolidation. Median progression‐free and overall survival were not reached (median follow‐up: 44 months). In conclusion, the R‐MIV regimen is feasible in routine practice, effective and safe, even during the COVID‐19 pandemic.
Ice particle concentrations in clouds

Abstract Measurements and observations have been made on the development of ice in 90 cumulus (cumulus and cumulonimbus) and 72 stratiform (altocumulus, altostratus, nimbostratus, stratocumulus, and stratus) clouds. Ice particle concentrations significantly in excess of those to be expected from ice nucleus measurements (i.e., ice enhancement) were measured in 42 of the cumuliform and 36 of the stratiform clouds. For the complete data set, and for cloud top temperatures (TT) between −6° and −32°C, the maximum concentrations of ice particles (Imax in L−1) in the clouds were essentially independent of TT(r=0.32). However, Imax was strongly dependent on the broadness of the cloud droplet size distribution near cloud top. If the breadth of the droplet size distribution is measured by DT, such that the cumulative concentration of droplets with diameters ≥DT exceeds a prescribed value, then for −32≤TT≤−6°C:where n=8.4 and DO=18.5 μm for the cumuliform clouds and n=6.6 and DO=19.4 μm for the stratiform clouds. W.
Stochasticity may generate coherent motion in bird flocks

Murmurations along with other forms of flocking have come to epitomize collective animal movements. Most studies into these stunning aerial displays have aimed to understand how coherent motion may emerge from simple behavioral rules and behavioral correlations. These studies may now need revision because recently it has been shown that flocking birds, like swarming insects, behave on the average as if they are trapped in elastic potential wells. Here I show, somewhat paradoxically, how coherent motion can be generated by variations in the intensity of multiplicative noise which causes the shape of a potential well to change, thereby shifting the positions and strengths of centres of attraction. Each bird, irrespective of its position in the flock will respond in a similar way to such changes, giving the impression that the flock behaves as one, and typically resulting in scale-free correlations. I thereby show how correlations can be an emergent property of noisy, confining potential wells. I also show how such wells can lead to high density borders, a characteristic of flocks, and I show how they can account for the complex patterns of collective escape patterns of starling flocks under predation. I suggest swarming and flocking do not constitute two distinctly different kinds of collective behavior but rather that insects are residing in relatively stable potential wells whilst birds are residing in unstable potential wells. It is shown how, dependent upon individual perceptual capabilities, bird flocks can be poised at criticality.
Genetic algorithms as applied to the numerical computation of electromagnetic scattering by weakly nonlinear dielectric cylinders

This paper deals with the application of an optimization procedure based on a genetic algorithm (GA) to the prediction of the electromagnetic fields scattered by weakly nonlinear dielectric objects. Starting by an integral approach and describing the nonlinearities of the constitutive parameters by the Volterra-type integrals, the nonlinear scattering problem is numerically solved by an iterative procedure developed for the minimization of a suitable defined cost function. A GA is applied in order to deal with a large number of unknowns related to the harmonic components of the nonlinear internal electromagnetic field. In a preliminary stage, the behavior of typical parameters of the GA is analyzed; then numerical solutions are carried out and compared with those provided by other methods. Finally, some considerations are made concerning the rate of convergence of the iterative procedure.
Antenatal corticosteroids‐to‐delivery interval associates cord blood S100B levels

Antenatal corticosteroids (ACS) are recommended for women at risk of preterm birth before 34 weeks' gestation. However, adverse effects of ACS on the fetal brain have also been reported. The time interval from ACS administration to delivery (ACS‐to‐delivery interval) might alter the effect of ACS on the fetal brain. This study aimed to evaluate the effect of ACS‐to‐delivery interval on cord blood S100 calcium‐binding protein B (S100B) levels as a biomarker of brain damage.
Optimization of Microchannel Heat Sinks Using Genetic Algorithm

In this study, a genetic algorithm is employed to minimize the entropy generation rate in microchannel heat sinks. The entropy generation rate allows the combined effects of thermal performance and pressure drop to be assessed simultaneously as the heat sink interacts with the surrounding flow field. Previously developed models for the heat transfer, pressure drop and entropy generation rate are used in the optimization procedure. The results of optimization are compared with existing results obtained by the Newton–Raphson method. It is observed that the GA gives better overall performance of the microchannel heat sinks.
Turbulent flame–wall interaction: a direct numerical simulation study

A turbulent flame–wall interaction (FWI) configuration is studied using three-dimensional direct numerical simulation (DNS) and detailed chemical kinetics. The simulations are used to investigate the effects of the wall turbulent boundary layer (i) on the structure of a hydrogen–air premixed flame, (ii) on its near-wall propagation characteristics and (iii) on the spatial and temporal patterns of the convective wall heat flux. Results show that the local flame thickness and propagation speed vary between the core flow and the boundary layer, resulting in a regime change from flamelet near the channel centreline to a thickened flame at the wall. This finding has strong implications for the modelling of turbulent combustion using Reynolds-averaged Navier–Stokes or large-eddy simulation techniques. Moreover, the DNS results suggest that the near-wall coherent turbulent structures play an important role on the convective wall heat transfer by pushing the hot reactive zone towards the cold solid surface. At the wall, exothermic radical recombination reactions become important, and are responsible for approximately 70% of the overall heat release rate at the wall. Spectral analysis of the convective wall heat flux provides an unambiguous picture of its spatial and temporal patterns, previously unobserved, that is directly related to the spatial and temporal characteristic scalings of the coherent near-wall turbulent structures.
Radio Continuum-H2O Maser Systems in NGC 2071: H2O Masers Tracing a Jet (IRS 1) and a Rotating Proto-Planetary Disk of Radius 20 AU (IRS 3)

We have observed simultaneously the 1.3 cm continuum and H2O maser emission toward the core of the star-forming region NGC 2071 using the Very Large Array in its A configuration. Two 1.3 cm continuum sources have been detected in the region, coinciding with the infrared sources IRS 1 and IRS 3, respectively. The radio emission in IRS 3 is consistent with an ionized thermal bipolar radio jet. Two clusters of H2O maser spots are detected, one associated with IRS 1 (22 spots) and the other one associated with IRS 3 (13 spots). The H2O maser distribution in IRS 1 seems to be tracing at scales of 300 AU the larger scale H2 outflow observed at a few thousands of AU from the exciting source. On the other hand, the H2O masers in IRS 3 are distributed as an apparent disk of ≃0. ″05 (≃20 AU) radius, oriented almost perpendicular to the major axis of the radio jet. There is a clear velocity gradient (≃0.35 km s-1 AU-1) along the major axis of the H2O maser distribution, which can be gravitationally bound by a central mass of ≃1 M☉. These results, together with the low-mass and early evolutionary stage of IRS 3, suggest that masers around this source are tracing a rotating proto-planetary disk within a proto-solar-like system. This represents direct kinematic evidence of the smallest rotating circumstellar disk ever observed around a young stellar object (YSO). We discuss the dichotomy of H2O masers tracing either outflows or disks around YSOs, based on the evolutionary scheme proposed in our earlier work. We suggested that systems in which H2O masers trace disks are less evolved than those in which masers trace outflows. In this scheme, IRS 3 would then represent a relatively less evolved object than IRS 1. This prediction is consistent with independent infrared observations showing that IRS 3 is at an earlier phase of evolution.
Diminished Repetition Suppression Reveals Selective and Systems-Level Face Processing Differences in ASD

Repeated exposure to a stimulus results in reduced neural response, or repetition suppression, in brain regions responsible for processing that stimulus. This rapid accommodation to repetition is thought to underlie learning, stimulus selectivity, and strengthening of perceptual expectations. Importantly, reduced sensitivity to repetition has been identified in several neurodevelopmental, learning, and psychiatric disorders, including autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by challenges in social communication and repetitive behaviors and restricted interests. Reduced ability to exploit or learn from repetition in ASD is hypothesized to contribute to sensory hypersensitivities, and parallels several theoretical frameworks claiming that ASD individuals show difficulty using regularities in the environment to facilitate behavior. Using fMRI in autistic and neurotypical human adults (females and males), we assessed the status of repetition suppression across two modalities (vision, audition) and with four stimulus categories (faces, objects, printed words, and spoken words). ASD individuals showed domain-specific reductions in repetition suppression for face stimuli only, but not for objects, printed words, or spoken words. Reduced repetition suppression for faces was associated with greater challenges in social communication in ASD. We also found altered functional connectivity between atypically adapting cortical regions and higher-order face recognition regions, and microstructural differences in related white matter tracts in ASD. These results suggest that fundamental neural mechanisms and system-wide circuits are selectively altered for face processing in ASD and enhance our understanding of how disruptions in the formation of stable face representations may relate to higher-order social communication processes. SIGNIFICANCE STATEMENT A common finding in neuroscience is that repetition results in plasticity in stimulus-specific processing regions, reflecting selectivity and adaptation (repetition suppression [RS]). RS is reduced in several neurodevelopmental and psychiatric conditions including autism spectrum disorder (ASD). Theoretical frameworks of ASD posit that reduced adaptation may contribute to associated challenges in social communication and sensory processing. However, the scope of RS differences in ASD is unknown. We examined RS for multiple categories across visual and auditory domains (faces, objects, printed words, spoken words) in autistic and neurotypical individuals. We found reduced RS in ASD for face stimuli only and altered functional connectivity and white matter microstructure between cortical face-recognition areas. RS magnitude correlated with social communication challenges among autistic individuals.
Transitive inference and the testing effect: Retrieval practice impairs transitive inference

There is substantial interest in the extent to which the testing effect (the finding that retrieval practice enhances memory) extends to more complex forms of learning, especially those entailing greater element interactivity. Transitive inference (TI) requires just such interactivity, in which information must be combined across multiple learning elements or premises to extract an underlying structure. Picklesimer et al. provided preliminary evidence that retrieval practice fails to enhance, and actually disrupts, TI. This study assessed the generality of that result. The current experiments employed a seven- or eight-element TI paradigm in which participants initially learned a set of premise pairs (e.g., A > B, B > C, and C > D) and then engaged in either restudy or retrieval practice of the premise pairs before taking a final test that assessed memory for the original premise pairs and one’s ability to make TIs (e.g., to infer that B > D). Experiments 1 and 2 used pictorial materials and simultaneous presentation of premises during learning, a form of presentation that has induced testing effects on other forms of inference. For TI, the results were unchanged from Picklesimer et al.—TI was worse for retrieval practice than restudy. Experiment 3 used verbal materials and likewise found worse TI for retrieval practice. A small-scale meta-analysis combining the current experiments with those of Picklesimer et al. revealed a significant negative testing effect on TI (d = −0.37). Although retrieval practice enhances many aspects of memory, this fundamental aspect of human reasoning may be impaired by retrieval practice.
Evidence for wind and accretion in the Herbig Be star HD 100546 from FUSE observations

We present the first far-UV spectra of the Herbig Be star HD 100546, observed by the Far Ultraviolet Spectroscopic Explorer (FUSE )a s part of theCircumstellar Disks team program. We identified and analyzed numerous narrow absorption lines of circumstellar origin. Intense, broad and fairly asymmetric emission lines of C  ,C  ,O  and S  were also detected, spanning temperatures up to 3 × 10 5 K. Comparison of the spectra recorded two years apart reveals strong spectral variations, not only in the emission lines but also in the circumstellar lines of N  ,N  ,O  ,A r and Fe . The varying absorption lines of N  and O  exhibit the largest velocity width, from −200 to +320 km s −1 , relative to the star's rest-frame. Variations on a timescale of an hour occurred only in the N  resonance triplet and O  ( 1 D) lines. The spectroscopic variability highlighted by these two observations and the line profile analysis reveal signatures of both outflow and infall processes, which appear to be related in this system. We suggest that these spectral signatures originate in a stellar magnetosphere, which likely interacts with the innermost part of the star's circumstellar disk. This interpretation can account for the main features observed in the spectrum of HD 100546: variable emission and absorption lines as well as suspected continuum variation.
Association of eGFR and mortality with use of a joint model: results of a nationwide study in Iceland

ABSTRACT Objectives Prior studies on the association of estimated glomerular filtration rate (eGFR) and mortality have failed to include methods to account for repeated eGFR determinations. The aim of this study was to estimate the association between eGFR and mortality in the general population in Iceland employing a joint model. Methods We obtained all serum creatinine and urine protein measurements from all clinical laboratories in Iceland in the years 2008–16. Clinical data were obtained from nationwide electronic medical records. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and categorized as follows: 0–29, 30–44, 45–59, 60–74, 75–89, 90–104 and >104 mL/min/1.73 m2. A multiple imputation method was used to account for missing urine protein data. A joint model was used to assess risk of all-cause mortality. Results We obtained 2 120 147 creatinine values for 218 437 individuals, of whom 84 364 (39%) had proteinuria measurements available. Median age was 46 (range 18–106) years and 47% were men. Proteinuria associated with increased risk of death for all eGFR categories in persons of all ages. In persons ≤65 years, the lowest risk was observed for eGFR of 75–89 mL/min/1.73 m2 without proteinuria. For persons aged >65 years, the lowest risk was observed for eGFR of 60–74 mL/min/1.73 m2 without proteinuria. eGFR of 45–59 mL/min/1.73 m2 without proteinuria did not associate with increased mortality risk in this age group. eGFR >104 mL/min/1.73 m2 associated with increased mortality. Conclusions These results lend further support to the use of age-adapted eGFR thresholds for defining chronic kidney disease. Very high eGFR needs to be studied in more detail with regard to mortality.
Risks of snakebite and challenges to seeking and providing treatment for agro-pastoral communities in Tanzania

Background Continuous occurrence of snakebite incidences and the vulnerability of some communities remain a critical problem in sub-Saharan Africa. Despite causing permanent disability to almost half a million people annually and numerous deaths, snakebite and associated complications are still largely neglected. This study aimed at elucidating risk factors associated with snakebite cases, treatment availability and case management practices for vulnerable agro-pastoralist communities in Northern Tanzania. Methods Data was collected in the Monduli (Arusha region) and the Simanjiro (Manyara region) districts in Tanzania. Interviews with 101 snakebite victims or their guardians and 13 health professionals from 3 health centers in the districts were conducted. Additionally, case records of patients admitted between 2007 and 2019 to the Meserani Snakebite Clinic were obtained. Results This study showed that appropriate treatment for snakebite including anti-venom, is difficult to access and that snakebite incidences were significantly linked to factors such as gender, age, socio-economic activity, season of the year, and whether being at home or out in the fields. Anti-venom and trained health professionals were only available at the Meserani Snake Park Clinic. Men were bitten most often (χ2 = 62.08, df = 4, p-value < 0.0001). Overall, adults between the ages of 18 and 60 years (χ2 = 62.08, df = 4, p-value < 0.0001) received most bites, usually while outdoors herding cattle in the dry season. A significant majority of victims looked for traditional treatment first (52.7%, χ2 = 29.541, df = 2, p-value = 0.0001). The results of this study present crucial information on what is needed to improve the accessibility to appropriate treatment after a snakebite among agro-pastoral communities. Conclusion The situation regarding morbidity and mortality due to the inaccessibility of common treatment for snakebite in northern Tanzania is challenging. Reliance on traditional medicine exacerbates the situation. There is dire need to involve affected communities, researchers, the government, clinicians and the public in general, to work together and take part in the global snakebite initiative. Communities and health professionals recognise the underlying challenges and have valuable suggestions on how to improve the situation.
An Overview of Gene Editing Modalities and Related Non-clinical Testing Considerations

Gene therapy has become an important modality for a wide range of therapeutic indications with a rapid increase in the number of therapeutic candidates being developed in this field. Understanding the molecular biology underlying the gene therapy is often critical to develop appropriate safety assessment strategies. We aimed to discuss some of the commonly used gene therapy modalities and common preclinical toxicology testing considerations when developing gene therapies. Non-viral gene delivery methods such as electroporation, microinjection, peptide nanoparticles and lipid nanoparticles are deployed as innovative molecular molecular construct which are included in the design of novel gene therapies and the associated molecular biology mechanisms have become relevant knowledge to non-clinical toxicology. Viral gene delivery methodologies including Adenovirus vectors, Adeno-Associated virus vectors and Lentivirus gene therapy vectors have also advanced considerably across numerous therapeutic areas, raising unique non-clinical toxicology and immunological considerations. General toxicology, biodistribution and tumorigenicity are the pillars of non-clinical safety testing in gene therapies. Evaluating the tumorigenicity potential of a gene editing therapy often leverages molecular pathology while some translational challenges remain. Toxicology study design is entering a new era where science-driven customized approaches and program specific considerations have become the norm.