Miracle-dz/UniFAR-FTUs huggingface dataset:
Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma–associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.
Non-line-of-sight single-scatter propagation model

A propagation model that describes the temporal characteristics of singly scattered radiation in a homogeneous scattering and absorbing medium is presented. The model generalizes previous results in the area and is used to analyze the angular spectrum of singly scattered energy as well as the impulse-response durations and path losses of short-range non-line-of-sight optical communication systems. It is shown that the angular response starts to drop off significantly at an off-axis angle equal to the receiver half-field of view. It is also shown that lower path losses correspond to longer impulse responses so that a lower available bandwidth is indicated. These results are based on numerical examples motivated by the operation of non-line-of-sight communications links in the middle-ultraviolet wave band.
Using the Grooved Pegboard Test as an Embedded Validity Indicator in a Mixed Neuropsychiatric Sample with Varying Cognitive Impairment: Cross-Validation Problems

Embedded validity indicators (EVIs) derived from motor tests have received less empirical attention than those derived from tests of other neuropsychological abilities, particularly memory. Preliminary evidence suggests that the Grooved Pegboard Test (GPB) may function as an EVI, but existing studies were largely conducted using simulators and population samples without cognitive impairment. In this study we aimed to evaluate the GPB’s classification accuracy as an EVI among a mixed clinical neuropsychiatric sample with and without cognitive impairment. This cross-sectional study comprised 223 patients clinically referred for neuropsychological testing. GPB raw and T-scores for both dominant and nondominant hands were examined as EVIs. A known-groups design, based on ≤1 failure on a battery of validated, independent criterion PVTs, showed that GPB performance differed significantly by validity group. Within the valid group, receiver operating characteristic curve analyses revealed that only the dominant hand raw score displayed acceptable classification accuracy for detecting invalid performance (area under curve [AUC] = .72), with an optimal cut-score of ≥106 seconds (33% sensitivity/88% specificity). All other scores had marginally lower classification accuracy (AUCs = .65–.68) for differentiating valid from invalid performers. Therefore, the GPB demonstrated limited utility as an EVI in a clinical sample containing patients with bona fide cognitive impairment.
Neural representations of the perception of handwritten digits and visual objects from a convolutional neural network compared to humans

We investigated neural representations for visual perception of 10 handwritten digits and six visual objects from a convolutional neural network (CNN) and humans using functional magnetic resonance imaging (fMRI). Once our CNN model was fine‐tuned using a pre‐trained VGG16 model to recognize the visual stimuli from the digit and object categories, representational similarity analysis (RSA) was conducted using neural activations from fMRI and feature representations from the CNN model across all 16 classes. The encoded neural representation of the CNN model exhibited the hierarchical topography mapping of the human visual system. The feature representations in the lower convolutional (Conv) layers showed greater similarity with the neural representations in the early visual areas and parietal cortices, including the posterior cingulate cortex. The feature representations in the higher Conv layers were encoded in the higher‐order visual areas, including the ventral/medial/dorsal stream and middle temporal complex. The neural representations in the classification layers were observed mainly in the ventral stream visual cortex (including the inferior temporal cortex), superior parietal cortex, and prefrontal cortex. There was a surprising similarity between the neural representations from the CNN model and the neural representations for human visual perception in the context of the perception of digits versus objects, particularly in the primary visual and associated areas. This study also illustrates the uniqueness of human visual perception. Unlike the CNN model, the neural representation of digits and objects for humans is more widely distributed across the whole brain, including the frontal and temporal areas.
KIR Allelic Variation and the Remission of Atopic Dermatitis Over Time

Abstract Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in “remission” (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 ∼ 2DS4*001:01 ∼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.
Fourier Transform Infrared Reflection Anisotropy Spectroscopy of Semiconductor Crystals and Structures: Development and Application in the Mid-Infrared

A new method of reflection anisotropy spectroscopy (RAS) with increased mid-IR efficiency owing to the use of a Fourier transform infrared (FT-IR) spectrometer has been developed. An optical setup was implemented using a photoelastic modulator (PEM) to modulate the direction of linear polarization of the probe beam originating from the Michelson interferometer. An original measurement algorithm was proposed to eliminate the influence of spectral inhomogeneity of the PEM efficiency on the obtained spectra using appropriate calibration. It was shown that to preserve the sign of the RAS signal, it is necessary to use a specialized procedure for phase correction of the interferogram registered by the FT-IR spectrometer. In the visible range, good agreement was confirmed between the obtained reflection anisotropy (RA) spectra of a semiconductor crystal and the results of independent measurements using a conventional diffraction-grating spectrometer–based setup. The RA spectrum of a III–V semiconductor heterostructure in the mid-infrared range (λ up to 8 µm) is demonstrated. Application of the developed FT-IR RAS method to layered black phosphorus has enabled characterization of anisotropic interband transitions in this graphene-like semiconductor crystal. Graphical Abstract This is a visual representation of the abstract.
Nelder-Mead simplex modifications for simulation optimization

When the Nelder-Mead method is used to optimize the expected response of a stochastic system e.g., an output of a discrete-event simulation model, the simplex-resizing steps of the method introduce risks of inappropriate termination. We give analytical and empirical results describing the performance of Nelder-Mead when it is applied to a response function that incorporates an additive white-noise error, and we use these results to develop new modifications of Nelder-Mead that yield improved estimates of the optimal expected response. Compared to Nelder-Mead, the best performance was obtained by a modified method, RS + S9, in which a the best point in the simplex is reevaluated at each shrink, step and b the simplex is reduced by 10% rather than 50% at each shrink step. In a suite of 18 test problems that were adapted from the MINPACK collection of NETLIB, the expected response at the estimated optimal point obtained by RS + S9 had errors that averaged 15% less than at the original method's estimated optimal point, at an average cost of three times as many function evaluations. Two well-known existing modifications for stochastic responses, the n + 3-rule and the next-to-worst rule, were found to be inferior to the new modification RS + S9.
Healthcare utilization in Canadian children and young adults with asthma during the COVID-19 pandemic

Literature is limited regarding the COVID-19 pandemic’s impact on health services use in younger Canadian populations with asthma. We utilized health administrative databases from January 2019–December 2021 for a population-based cross-sectional study to identify Ontario residents 0–25 years old with physician-diagnosed asthma and calculate rates of healthcare use. Multivariable negative binomial regression analysis was used to adjust for confounders. We included 716,690 children and young adults ≤25 years. There was a sharp increase of ICS and SABA prescription rates at the start of the pandemic (March 2020) of 61.7% and 54.6%, respectively. Monthly virtual physician visit rates increased from zero to 0.23 per 100 asthma population during the pandemic. After adjusting for potential confounders, rate ratios (RR) with 95% confidence intervals (CI) showed that the pandemic was associated with significant decrease in hospital admissions (RR = 0.21, 95% CI: 0.18–0.24), emergency department visits (RR = 0.35, 95% CI: 0.34–0.37), and physician visits (RR = 0.61, 95% CI: 0.60–0.61). ICS and SABA prescriptions filled also significantly decreased during the pandemic (RR = 0.58, 95% CI: 0.57–0.60 and RR = 0.47, 95% CI: 0.46–0.48, respectively). This Canadian population-based asthma study demonstrated a dramatic decline in physician and emergency department visits, hospitalizations, and medication prescriptions filled during the COVID-19 pandemic. An extensive evaluation of the factors contributing to an 80% reduction in the risk of hospitalization may inform post-pandemic asthma management.
The Orion Molecular Clouds OMC-1 and OMC-2 Mapped in the Far-Infrared Fine-Structure Line Emission of C+ and O0

We have mapped the Orion Molecular Ridge (OMC-1 and OMC-2) in the fine-structure lines [C II] 158 μm and [O I] 63 and 146 μm. The maps cover a region of 7' × 18' (Δα × Δδ) and are fully sampled toward the Orion A H II region/molecular cloud interface. The emission maximum near the molecular region S6/FIR4 arises most probably from a photodissociation region (PDR) on the surface of that molecular condensation. The PDR has column densities that are most likely explained by an edge-on geometry. For the emitting material, we find a temperature between 300 and 500 K, a number density of 3 × 105 cm-3, and O0 and C+ column densities of 1 × 1019 and 4 × 1018 cm-2, respectively. In the Orion Bar region, the northern edge of the Orion interface region, and M43 west we find somewhat lower values for the temperature, number density, and column densities. Furthermore, the ratio of the oxygen to carbon column density is lower in this region and approaches a value of 1.7. The lower ratio could be due to the edge-on geometry and the lower temperature of these regions. In the Dark Lane region we find evidence for cooler oxygen partly absorbing the oxygen line emission from the warmer background material. For the cooler molecular material covering the warm medium in the Dark Lane, we estimate an atomic oxygen abundance [O]/[H] on the order of a few 10-4. In the northern part of OMC-1 the morphology of the [O I] 63 μm emission is consistent with moderately warm oxygen associated with the dense molecular ridge. From the oxygen emission arising from the ridge, we derive an atomic oxygen abundance [O]/[H] > 10-5. The [O I] line emission in OMC-2 may arise partly from the inner parts of the molecular cloud, but emission arising exclusively from PDRs cannot be excluded.
Development and validation of sustainable employability index among older employees

Abstract Background Sustainable employability (SE) has become an important factor for keeping people in the labour market and enabling the extension of working life. Aims We developed and validated an SE index to predict assured workability in 2 years. Additionally, we developed a scoring tool to use in practice. Methods A questionnaire survey of postal employees aged ≥50 years was conducted in 2016 and followed up in 2018 (n = 1102). The data were divided into training and validation sets. The outcome was defined as whether the employees had an assured workability after 2 years or not. Multivariable log-binomial regression was used to calculate the SE index. The area under the curve (AUC) was calculated to assess the discriminative power of the index. Results The probability of assured workability increased with increasing quintiles of the SE index. The highest quintiles of the SE index showed the highest observed and expected assured workability in 2 years. The predictive ability, area under the curve (AUC) for training was 0.79 (95% CI 0.75–0.83) and for validation data was 0.76 (95% CI 0.73–0.80). In the scoring tool, the self-rated health, workability, job satisfaction and perceived employment had the highest contribution to the index. Conclusions The SE index was able to distinguish the employees based on whether they had assured workability after 2 years. The scoring method could be used to calculate the potentiality of future employability among late midlife postal employees.
Compton reflection of gamma rays by cold electrons

Using a Monte Carlo method an approximation was derived to the Green function for the Compton reflection of relativistic photon h nu greater than about m(e) c-sq, by cold electrons, extending previous treatments of this problem for nonrelativistic photons. In Compton reflection, an external flux of photons impinges upon a semiinfinite slab of electrons, gives a portion of its energy to the electrons (or receives energy if the electrons are hotter), and reemerges with an altered spectrum. This Green function may be used to easily calculate the emergent spectrum and albedo for any incident spectrum. Such reprocessing of gamma-rays may be astrophysically important when a source of gamma-rays coexists with a cool, nonrelativistic plasma, such as for nonthermal coronas above accretion disks, high energy emission near the surface of neutron stars, or a chaotic, two-phase medium near the centers of active galaxies. 26 references.
Higher prevalence of idiopathic normal pressure hydrocephalus‐like MRI features in progressive supranuclear palsy: An imaging reminder of atypical parkinsonism

The classic triad of idiopathic normal pressure hydrocephalus (NPH) encompass gait disturbance, cognitive impairment, and urinary incontinence. These symptoms overlap with parkinsonism but with distinct treatment. Lacking applicable differentiation also hampers the prediction to therapeutic response. Here, we try to clarify this issue among different Parkinsonian syndromes and propose some innovative thinking while approaching a patient with parkinsonism and hydrocephalus concomitantly.
N1‐Methylnicotinamide as Biomarker for MATE‐Mediated Renal Drug–Drug Interactions: Impact of Cimetidine, Rifampin, Verapamil, and Probenecid

N1‐methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug–drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma and urine samples of two clinical trials investigating a new probe drug cocktail (consisting of digoxin, metformin, furosemide, and rosuvastatin) dedicated to clinically relevant drug transporters. In trial 1, NMN was investigated after single‐dose treatment with individual cocktail components or after cocktail treatment. In trial 2, NMN was investigated after treatment with cocktail alone or with cocktail + inhibitor (cimetidine, a MATE inhibitor; or rifampin, verapamil, or probenecid, inhibitors of other transporters). In trial 1, NMN kinetics in plasma and urine were essentially not affected by individual cocktail components or after cocktail treatment. In trial 2, NMN renal clearance from 0 to 12 hours (CLR,0–12) geometric mean ratio (GMR) after cocktail + cimetidine vs. cocktail alone was 75% (90% confidence interval (CI): 65–87%). NMN CLR GMR after cocktail + verapamil, + rifampin, or + probenecid vs. cocktail alone was 99% (90% CI: 81–121%), 91% (90% CI: 75–111%), and 107% (90% CI: 91–126%), respectively. Compared with creatinine CLR and creatinine area under the plasma‐concentration time curve, NMN CLR was more specific and more sensitive for renal MATE inhibition. Absence of impact of the cocktail on NMN in trial 1 allows for utilization of NMN in studies using this transporter cocktail. Trial 2 data support that NMN CLR is a specific and sensitive marker for MATE‐mediated renal drug–drug interactions.
Restraint stress during neonatal hypoxia‐ischemia alters brain injury following normothermia and hypothermia

Rodent models of neonatal hypoxic–ischemic (HI) injury require a subset of animals to be immobilized for continuous temperature monitoring during the insult and subsequent treatment. Restrained animals are discarded from the analysis due to the effect of restraint on the brain injury as first demonstrated by Thoresen et al 1996. However, the effects of restraint on responses to hypothermic (HT) post‐insult therapy are not well described. We examine the effects of restraint associated with different probe placements on HI brain injury. We have conducted a meta‐analysis of 23 experiments comparing probe rats (skin n = 42, rectal n = 35) and free‐moving matched non‐probe controls (n = 80) that underwent HI injury (left common carotid artery ligation and 90 min 8% O2) at postnatal day 7 (P7), followed by 5 h of NT (37°C) or HT (32°C). On P14, brain regions were analyzed for injury (by neuropathology and area loss), microglial reactivity and brain‐derived neurotrophic factor (BDNF). HI injury was mitigated in NT skin and rectal probe rats, with greater neuroprotection among the rectal probe rats. Following HT, the skin probe rats maintained the restraint‐associated neuroprotection, while brain injury was significantly exacerbated among the rectal probe rats. Microglial reactivity strongly correlated with the acquired injury, with no detectable difference between the groups. Likewise, we observed no differences in BDNF signal intensity. Our findings suggest a biphasic neuroprotection from restraint stress, which becomes detrimental in combination with HT and the presumed discomfort from the rectal probe. This finding is useful in highlighting unforeseen effects of common experimental designs or routine clinical management.
Effective magnetic moment of magnetic multicore nanoparticles

We carry out Monte Carlo simulations to study the effective magnetic moment mu(eff) in the low-field region of magnetic multicore nanoparticles. Transmission electron microscopy and scanning electron microscopy images show that these particles contain a number of magnetic nanocrystals (MNCs) randomly packed in a single cluster of total volume V(tot). We illustrate how the initial magnetic susceptibility chi(0) of magnetic multicore nanoparticles can be straightforward derived from mu(eff) computed at zero magnetic field. We observe that dipolar interactions between MNCs and polydispersity of the MNCs contribute to increase and to decrease mu(eff)/V(tot), respectively, while magnetic anisotropy of the MNCs does not show any effect. In all three cases, mu(eff)/V(tot) can be described by a linear relation to (mu B/k(B)T)(2) that we analytically derived for low applied fields.
Interferon regulates neural stem cell function at all ages by orchestrating mTOR and cell cycle

Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling also reduces the ability of stem cells to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to progenitor production is not well understood. Here we combine single‐cell transcriptomics, RiboSeq and mathematical models of interferon to show that this pathway is important for proper stem cell function at all ages in mice. Interferon orchestrates cell cycle and mTOR activity to post‐transcriptionally repress Sox2 and induces quiescence. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.