In a bucolic idyll, a terrorist agonizes over the act of violence he is about to commit. On a remote island in the South Pacific, the investigation of a case of mass suicide reveals further ...mysteries. In a far-flung colony, a cynical trio sends an unwitting man into the wilderness in search of a chimera. Mixing romance and high adventure, intrigue and the fantastic, these magnificent tales by one of Russia's most enduringly popular writers deftly probe the depths of human nature and desire. Fandango and Other Stories presents a selection of essential short fiction by Alexander Grin, Russia's counterpart to Robert Louis Stevenson, Edgar Allan Poe, and Alexandre Dumas. By turns a sailor, a dockworker, a vagrant, a gold prospector, a lumberjack, a soldier, a deserter, an agitator, an exile, a prisoner, and a runaway, Grin wrote seven novels and over three hundred short stories that transport the reader to a realm of pure art and imagination. His ingenious plots explore conflicts of the individual and society in a romantic world populated by a cast of eccentric, cosmopolitan characters.Fandango and Other Stories includes works drawn from across the entirety of Grin's varied career to encompass the range and sophistication of his writing. Bryan Karetnyk's elegant translations bring Grin's distinctive voice to a new generation of readers.
The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion ...of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the μ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2μ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.
Background Objective and quantifiable markers are crucial for developing novel therapeutics for mental disorders by 1) stratifying clinically similar patients with different underlying ...neurobiological deficits and 2) objectively tracking disease trajectory and treatment response. Schizophrenia is often confounded with other psychiatric disorders, especially bipolar disorder, if based on cross-sectional symptoms. Awake and sleep EEG have shown promise in identifying neurophysiological differences as biomarkers for schizophrenia. However, most previous studies, while useful, were conducted in European and American populations, had small sample sizes, and utilized varying analytic methods, limiting comprehensive analyses or generalizability to diverse human populations. Furthermore, the extent to which wake and sleep neurophysiology metrics correlate with each other and with symptom severity or cognitive impairment remains unresolved. Moreover, how these neurophysiological markers compare across psychiatric conditions is not well characterized. The utility of biomarkers in clinical trials and practice would be significantly advanced by well-powered transdiagnostic studies. The Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project aims to address these questions through a large, multi-center cohort study involving East Asian populations. To promote transparency and reproducibility, we describe the protocol for the GRINS project. Methods The research procedure consists of an initial screening interview followed by three subsequent sessions: an introductory interview, an evaluation visit, and an overnight neurophysiological recording session. Data from multiple domains, including demographic and clinical characteristics, behavioral performance (cognitive tasks, motor sequence tasks), and neurophysiological metrics (both awake and sleep electroencephalography), are collected by research groups specialized in each domain. Conclusion Pilot results from the GRINS project demonstrate the feasibility of this study protocol and highlight the importance of such research, as well as its potential to study a broader range of patients with psychiatric conditions. Through GRINS, we are generating a valuable dataset across multiple domains to identify neurophysiological markers of schizophrenia individually and in combination. By applying this protocol to related mental disorders often confounded with each other, we can gather information that offers insight into the neurophysiological characteristics and underlying mechanisms of these severe conditions, informing objective diagnosis, stratification for clinical research, and ultimately, the development of better-targeted treatment matching in the clinic. Keywords: Neurophysiological mechanism, Biomarkers, Sleep EEG, Event-related potential, Brain dynamics, Psychiatric disorders, Schizophrenia, Bipolar disorder
Context. The evolution of massive stars is strongly influenced by internal mixing processes such as semiconvection, convective core overshooting, and rotationally induced mixing. None of these ...processes are currently well constrained. Aims. We investigate models for massive stars in the Small Magellanic Cloud (SMC), for which stellar-wind mass loss is less important than for their metal-rich counterparts. We aim to constrain the various mixing efficiencies by comparing model results to observations. Methods. For this purpose, we use the stellar-evolution code MESA to compute more than 60 grids of detailed evolutionary models for stars with initial masses of 9…100 M⊙, assuming different combinations of mixing efficiencies of the various processes in each grid. Our models evolve through core hydrogen and helium burning, such that they can be compared with the massive main sequence and supergiant population of the SMC. Results. We find that for most of the combinations of the mixing efficiencies, models in a wide mass range spend core-helium burning either only as blue supergiants, or only as red supergiants. The latter case corresponds to models that maintain a shallow slope of the hydrogen/helium (H/He) gradient separating the core and the envelope of the models. Only a small part of the mixing parameter space leads to models that produce a significant number of blue and red supergiants, which are both in abundance in the SMC. Some of our grids also predict a cut-off in the number of red supergiants above log L/L⊙ = 5…5.5. Interestingly, these models contain steep H/He gradients, as is required to understand the hot, hydrogen-rich Wolf-Rayet stars in the SMC. We find that unless it is very fast, rotation has a limited effect on the H/He profiles in our models. Conclusions. While we use specific implementations of the considered mixing processes, they comprehensively probe the two first-order structural parameters, the core mass and the H/He gradient in the core-envelope interface. Our results imply that in massive stars, mixing during the main-sequence evolution leads to a moderate increase in the helium core masses, and also that the H/He gradients above the helium cores become very steep. Our model grids can be used to further refine the various mixing efficiencies with the help of future observational surveys of the massive stars in the SMC, and thereby help to considerably reduce the uncertainties in models of massive star evolution.
This book proposes a multidisciplinary assessment of the impact of complex diversity on language politics and policies, analysing how the legacies of the old interact with the challenges of the new. ...Its main focus is on the interplay of multilingualism on the one hand, and the dynamics of transnationalism, globalisation, and Europeanisation on the other. This interplay confronts contemporary societies with unprecedented questions, as they face the need to come to grips with increasingly varied and pervasive manifestations of linguistic and cultural diversity. This volume develops an integrative approach that identifies the key social and political dimensions at hand, offering an innovative contribution to the ongoing conversation on the manifestations and management of multilingualism.
Microstate analysis is a promising technique for analyzing high-density electroencephalographic data, but there are multiple questions about methodological best practices. Between and within ...individuals, microstates can differ both in terms of characteristic topographies and temporal dynamics, which leads to analytic challenges as the measurement of microstate dynamics is dependent on assumptions about their topographies. Here we focus on the analysis of group differences, using simulations seeded on real data from healthy control subjects to compare approaches that derive separate sets of maps within subgroups versus a single set of maps applied uniformly to the entire dataset. In the absence of true group differences in either microstate maps or temporal metrics, we found that using separate subgroup maps resulted in substantially inflated type I error rates. On the other hand, when groups truly differed in their microstate maps, analyses based on a single set of maps confounded topographic effects with differences in other derived metrics. We propose an approach to alleviate both classes of bias, based on a paired analysis of all subgroup maps. We illustrate the qualitative and quantitative impact of these issues in real data by comparing waking versus non-rapid eye movement sleep microstates. Overall, our results suggest that even subtle chance differences in microstate topography can have profound effects on derived microstate metrics and that future studies using microstate analysis should take steps to mitigate this large source of error.
Female Sprague-Dawley rats were used as models of moderate contusion spinal cord injury to evaluate the efficiency of single systemic (intravenous) infusion of human mononuclear cord blood cells for ...restoration of the motor function of hind limbs. The dynamics of recovery of hind limb motor function was assessed using a specially designed method based on calculation of selective dispersion and amplitude-dependent dispersion of hind limbs joint angles measured in the swimming test. The obtained data suggest that systemic application of human mononuclear cord blood cells significantly (
p
<0.05) promoted recovery of hind limb motor function in the animal models of contusion spinal cord injury of moderate severity in comparison with control animals (without cell therapy).
Extrauterine leiomyoma is a rare benign tumor, originating from smooth muscle cells, most often localized in the uterus. Extrauterine localization of leiomyoma is extremely rare. The presence of a ...neoplasm near the urethra always poses a challenge for differential diagnosis. Variety of pathologies sharing similar clinical findings requires further diagnostic testing and doctor alertness. We present the clinical case of urethral leiomyoma in a female patient aged 42 years complaining of frequent urination and vulval mass. The patient underwent neoplasm removal with further histologic examination revealing urethral leiomyoma. The article features the diagnosis and treatment of this rare pathology.
A series of novel conjugates of cobalt bis(dicarbollide) and
-dodecaborate with curcumin were synthesized by copper(I)-catalyzed azide-alkyne cycloaddition. These conjugates were tested for ...antibacterial activity. It was shown that all derivatives are active when exposed to
ATCC 10702 and are not active against Gram-negative microorganisms and
at the maximum studied concentration of 1000 mg/L. The conjugate of alkynyl-curcumin with azide synthesized from the tetrahydropyran derivative of cobalt bis(dicarbollide) exhibited activity against Gram-positive microorganisms:
ATCC 29213,
ATCC 29212 and the clinical isolate MRSA 17, that surpassed curcumin by 2-4 times.
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Hydrophobic bacteriochlorin based photosensitizer (PS) can be effectively immobilized on MNP covered by human serum albumin (HSA). PS loading into MNP protein shell allows ...solubilizing PS in water solution without altering its photodynamic activity. MNP@PS can serve as diagnostic tool for tracking PS delivery to tumor tissues by MRI.
Immobilization on MNP-HSA-PEG was performed by adding PS solution in organic solvents with further purification. MNP@PS were characterized by DLS, HAADF STEM and AFM. Absorbance and fluorescence measurements were used to assess PS photophysical properties before and after immobilization. MNP@PS internalization into CT26 cells was investigated by confocal microscopy in vitro and MRI/IVIS were used for tracking MNP@PS delivery to tumors in vivo.
MNP@PS complexes were stable in water solution and retained PS photophysical activity. The length of side chain affected MNP@PS size, loading capacity and cell internalization. In vitro testing demonstrated MNP@PS delivery to cancer cells followed by photoinduced toxicity. In vivo studies confirmed that as-synthetized complexes can be used for MRI tracking over drug accumulation in tumors.
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