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Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.

Summary: We developed a method that utilizes fluorescent labeling of nuclear envelopes alongside cytometry sorting for the selective isolation of Purkinje cell (PC) nuclei. Beginning with SUN1 reporter mice, we GFP-tagged envelopes to confirm that PC nuclei could be accurately separated from other cell types. We then developed an antibody-based protocol to make PC nuclear isolation more robust and adaptable to cerebellar tissues of any genotypic background. Immunofluorescent labeling of the nuclear membrane protein RanBP2 enabled the isolation of PC nuclei from C57BL/6 cerebellum. By analyzing the expression of PC markers, nuclear size, and nucleoli number, we confirmed that our method delivers a pure fraction of PC nuclei. To demonstrate its applicability, we isolated PC nuclei from spinocerebellar ataxia type 7 (SCA7) mice and identified transcriptional changes in known and new disease-associated genes. Access to pure PC nuclei offers insights into PC biology and pathology, including the nature of selective neuronal vulnerability. Motivation: Cerebellar Purkinje cells (PCs) play a central role in controlling voluntary movements, coordination, and motor learning. PC degeneration and death are hallmarks of many human neurological disorders, including multiple forms of spinocerebellar ataxia. Unfortunately, PCs comprise a relatively small population of cells in the cerebellum, constituting less than 1% of the total cell count. This makes studying PC-related pathology using omics approaches exceptionally challenging. Here, we introduce a protocol that addresses the need for obtaining pure fractions of PC nuclei for subsequent cell-specific analysis.

Abstract Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA–protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.

Reliable cell labeling and tracking techniques are imperative for elucidating the intricate and ambiguous interactions between mesenchymal stromal cells (MSCs) and tumors. Here, we explore fluorescent photoconvertible nanoengineered vesicles to study mMSC migration in brain tumors. These 3 μm sized vesicles made of carbon nanoparticles, Rhodamine B (RhB), and polyelectrolytes are readily internalized by cells. The dye undergoes photoconversion under 561 nm laser exposure with a fluorescence blue shift upon demand. The optimal laser irradiation duration for photoconversion was 0.4 ms, which provided a maximal blue shift of the fluorescent signal label without excessive laser exposure on cells. Vesicles modified with an extra polymer layer demonstrated enhanced intracellular uptake without remarkable effects on cell viability, motility, or proliferation. The optimal ratio of 20 vesicles per mMSC was determined. Moreover, the migration of individual mMSCs within 2D and 3D glioblastoma cell (EPNT-5) colonies over 2 days and in vivo tumor settings over 7 days were traced. Our study provides a robust nanocomposite platform for investigating MSC–tumor dynamics and offers insights into envisaged therapeutic strategies. Photoconvertible vesicles also present an indispensable tool for studying complex fundamental processes of cell–cell interactions for a wide range of problems in biomedicine.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. ‘Primary pathways’ include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons—all of which have been observed in ALS patients and model systems. ‘Secondary pathways’ include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.

Abstract X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally.

Summary: Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.

Expanding as a result of information and technological progress, the processes of globalization are immersing the material world and the sphere of human relationships in the space of digital technologies. Leading experts note that the world community is on the verge of fundamental changes associated with technological breakthroughs in various fields of knowledge. The article discusses the regional features of digital transformation in the Kabardino-Balkarian Republic. If in developed countries and the most dynamically developing regions of Russia, the transition of society to a new era of digital technologies is a logical, natural, from the point of view of evolutionary development, phenomenon, then what is this process like in traditional societies? This question was central to the present work. The results of the study showed that people rightly point out both the positive and negative aspects of digital transformation. The problem of mass layoffs is relevant. People are afraid that robots and computer programs will force them out of the labor market. This problem is especially acute in such an economically depressed region as the Kabardino-Balkarian Republic. Also, people are concerned about the erosion of the cultural foundations of the titular peoples of the region, as a result of the processes of globalization, which are taking place with particular intensity in the digital world. At the same time, the respondents noted the presence of significant positive aspects of digital transformation. Welfare increases, the solution of many everyday problems is simplified, the quality of human life improves.

Alternative polyadenylation (APA) contributes to the post-transcriptional regulation of most human genes, yet the effects of APA are largely overlooked by conventional transcriptome-wide association studies (TWAS). Here, the authors conduct an APA-TWAS for 11 brain disorders, identifying hundreds of APA-linked disease susceptibility genes.

Quantum computing devices are believed to be powerful in solving the prime factorization problem, which is at the heart of widely deployed public-key cryptographic tools. However, the implementation of Shor’s quantum factorization algorithm requires significant resources scaling linearly with the number size; taking into account an overhead that is required for quantum error correction the estimation is that 20 millions of (noisy) physical qubits are required for factoring 2048-bit RSA key in 8 hours. Recent proposal by Yan et al. claims a possibility of solving the factorization problem with sublinear quantum resources. As we demonstrate in our work, this proposal lacks systematic analysis of the computational complexity of the classical part of the algorithm, which exploits the Schnorr’s lattice-based approach. We provide several examples illustrating the need in additional resource analysis for the proposed quantum factorization algorithm.

Alternating projection onto convex sets (POCS) provides an iterative procedure to find a signal that satisfies two or more convex constraints when the sets intersect. For nonintersecting constraints, the method of simultaneous projections produces a minimum mean square error (MMSE) solution. In certain cases, a minimax solution is more desirable. Generating a minimax solution is possible using dilated POCS. The minimax solution uses morphological dilation of nonintersecting signal convex constraints. The sets are progressively dilated to the point where there is intersection at a minimax solution. Examples are given contrasting the MMSE and minimax solutions in problems of tomographic reconstruction of images. Dilated POCS adds a new imaging modality for image synthesis. Lastly, morphological erosion of signal sets is suggested as a method to shrink the overlap when sets intersect at more than one point.

Objective: To systematically investigate and document the infrastructure, practices, recommendations, and clinical consequences of a structured, organized sports cardiology multidisciplinary team (MDT) for athletes and patients who wish to engage in sports and exercise. Patients and Methods: We established bimonthly sports cardiology MDT meetings, with a permanent panel of experts in sports cardiology, genetics, pediatric cardiology, cardiovascular imaging, electrophysiology, and sports and exercise medicine. Cases were referred nationally or internationally by cardiologists/sports physicians. We retrospectively analyzed all MDT cases (April 10, 2019 through May 13, 2020) and collected clinical follow-up data up to 1 year after the initial review. Results: A total of 115 athletes underwent MDT review; of them, 11% were women, 65% were recreational athletes, and 54% were performing “mixed” type of sports; the mean age was 32±16 years. An MDT review led to a diagnosis revision of “suspected cardiac pathology” to “no cardiac pathology” in 38% of the athletes and increased the number of definitive diagnoses (from 77 to 109; P=.03). We observed fewer “total sports restrictions” (from 6 to 0; P=.04) and more tailored sports advice concerning “no peak load/specific maximum load” (from 10 to 26; P=.02). At the 14±6-month follow-up, 112 (97%) athletes reported no cardiovascular events, 111 (97%) athletes reported no (new) cardiac symptoms, 113 (98%) athletes reported adherence to the MDT sports advice, and no diagnoses were revised. Conclusion: Our experiences with a comprehensive sports cardiology MDT demonstrate that this approach leads to higher percentages of definitive diagnoses and fewer cardiac pathology diagnoses, more tailored sports advice with excellent rates of adherence, and fewer total sports restrictions. Our findings highlight the added value of sports cardiology MDTs for patient and athlete care.

Abstract Besides the broad development of nanotechnological approaches for cancer diagnosis and therapy, currently, there is no significant progress in the treatment of different types of brain tumors. Therapeutic molecules crossing the blood–brain barrier (BBB) and reaching an appropriate targeting ability remain the key challenges. Many invasive and non-invasive methods, and various types of nanocarriers and their hybrids have been widely explored for brain tumor treatment. However, unfortunately, no crucial clinical translations were observed to date. In particular, chemotherapy and surgery remain the main methods for the therapy of brain tumors. Exploring the mechanisms of the BBB penetration in detail and investigating advanced drug delivery platforms are the key factors that could bring us closer to understanding the development of effective therapy against brain tumors. In this review, we discuss the most relevant aspects of the BBB penetration mechanisms, observing both invasive and non-invasive methods of drug delivery. We also review the recent progress in the development of functional drug delivery platforms, from viruses to cell-based vehicles, for brain tumor therapy. The destructive potential of chemotherapeutic drugs delivered to the brain tumor is also considered. This review then summarizes the existing challenges and future prospects in the use of drug delivery platforms for the treatment of brain tumors. Graphical Abstract

Summary: Translocation sequencing can be used to assess mechanisms of DNA repair and identify genome-wide double-strand breaks (DSBs) accessible to DNA repair machinery. Here, we present a protocol for mapping double-strand DNA break sites across the genome with translocation capture sequencing. Bait DSBs are introduced using a Cas9 nuclease and repaired by the host cell, connecting bait DSBs to other DSBs. Repair sites are detected by isolating bait site DNA, cleaving normal sequence to enrich off-site repair, and next-generation sequencing.For complete details on the use and execution of this protocol, please refer to Switonski et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

In the fields of structural and geotechnical engineering, improving the understanding of soil–structure interaction (SSI) effects is critical for earthquake-resistant design. Engineers and practitioners often resort to finite element (FE) software to advance this objective. Unfortunately, the availability of software equipped with boundary representation for absorbing scattered waves and ensuring consistent input ground motion prescriptions, which is necessary for accurately representing SSI effects, is currently limited. To address such limitations, the authors developed Seismo-VLAB (SVL v1.0-stable) an open-source software designed to perform SSI simulations. The methodology considers the integration of advanced techniques, including the domain decomposition method (DDM), perfectly matched layers (PMLs), and domain reduction method (DRM), in addition to parallel computing capabilities to accelerate the solution of large-scale problems. In this work, the authors provide a detailed description of the implementation for addressing SSI modeling, validate some of the SVL’s features needed for such purpose, and demonstrate that the coupled DRM–PML technique is a necessary condition for accurately solving SSI problems. It is expected that SVL provides a significant contribution to the SSI research community, offering a self-contained and versatile alternative. The software’s practical application in analyzing SSI and directionality effects on 3D structures under seismic loading demonstrates its capability to model real-world earthquake responses in structural engineering.

The behavior and migration of human mesenchymal stromal cells (hMSCs) are focal points of research in the biomedical field. One of the major aspects is potential therapy using hMCS, but at present, the safety of their use is still controversial owing to limited data on changes that occur with hMSCs in the long term. Fluorescent photoconvertible proteins are intensively used today as “gold standard” to mark the individual cells and study single-cell interactions, migration processes, and the formation of pure lines. A crucial disadvantage of this method is the need for genetic modification of the primary culture, which casts doubt on the possibility of exploring the resulting clones in personalized medicine. Here we present a new approach for labeling and tracking hMSCs without genetic modification based on the application of cell-internalizable photoconvertible polyelectrolyte microcapsules (size: 2.6 ± 0.5 μm). These capsules were loaded with rhodamine B, and after thermal treatment, exhibited fluorescent photoconversion properties. Photoconvertible capsules demonstrated low cytotoxicity, did not affect the immunophenotype of the hMSCs, and maintained a high level of fluorescent signal for at least seven days. The developed approach was tested for cell tracking for four days and made it possible to trace the destiny of daughter cells without the need for additional labeling.

The flammability of various materials used in industry is an important issue in the modern world. This work is devoted to the study of the effect of flame retardants, graphene and DDM-DOPO (9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide-4,4′-diamino-diphenyl methane), on the flammability of glass-fiber-reinforced epoxy resin (GFRER). Samples were made without additives and with additives of fire retardants: graphene and DDM-DOPO in various proportions. To study the flammability of the samples, standard flammability tests were carried out, such as thermogravimetric analysis, the limiting oxygen index (LOI) test, and cone calorimetry. In addition, in order to test the effectiveness of fire retardants under real fire conditions, for the first time, the thermal structure of downward flame propagation over GFRER composites was measured using thin thermocouples. For the first time, the measured thermal structure of the flame was compared with the results of numerical simulations of flame propagation over GFRER.

Abstract Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

Psychotic episodes are debilitating disease states that can cause extreme distress and impair functioning. There are sex differences that drive the onset of these episodes. One difference is that, in addition to a risk period in adolescence and early adulthood, women approaching the menopause transition experience a second period of risk for new-onset psychosis. One leading hypothesis explaining this menopause-associated psychosis (MAP) is that estrogen decline in menopause removes a protective factor against processes that contribute to psychotic symptoms. However, the neural mechanisms connecting estrogen decline to these symptoms are still not well understood. Using the tools of computational psychiatry, links have been proposed between symptom presentation and potential algorithmic and biological correlates. These models connect changes in signaling with symptom formation by evaluating changes in information processing that are not easily observable (latent states). In this manuscript, we contextualize the observed effects of estrogen (decline) on neural pathways implicated in psychosis. We then propose how estrogen could drive changes in latent states giving rise to cognitive and psychotic symptoms associated with psychosis. Using computational frameworks to inform research in MAP may provide a systematic method for identifying patient-specific pathways driving symptoms and simultaneously refine models describing the pathogenesis of psychosis across all age groups.

Simplifications and theoretical assumptions are usually incorporated into the numerical modeling of structures. However, these assumptions may reduce the accuracy of the simulation results. This problem has led to the development of model-updating techniques to minimize the error between the experimental response and the modeled structure by updating its parameters based on the observed data. Structural numerical models are typically constructed using a deterministic approach, whereby a single best-estimated value of each structural parameter is obtained. However, structural models are often complex and involve many uncertain variables, where a unique solution that captures all the variability is not possible. Updating techniques using Bayesian Inference (BI) have been developed to quantify parametric uncertainty in analytical models. This paper presents the implementation of the BI in the parametric updating of a five-story building model and the quantification of its associated uncertainty. The Bayesian framework is implemented to update the model parameters and calculate the covariance matrix of the output parameters based on the experimental information provided by modal frequencies and mode shapes. The main advantage of this approach is that the uncertainty in the experimental data is considered by defining the likelihood function as a multivariate normal distribution, leading to a better representation of the actual building behavior. The results showed that this Bayesian model-updating approach effectively allows a statistically rigorous update of the model parameters, characterizing the uncertainty and increasing confidence in the model’s predictions, which is particularly useful in engineering applications where model accuracy is critical.

Abstract Identifying state-sensitive measures of perceptual and cognitive processes implicated in psychosis may allow for objective, earlier, and better monitoring of changes in mental status that are predictive of an impending psychotic episode, relative to traditional self-report-based clinical measures. To determine whether a measure of visual perception that has demonstrated sensitivity to the clinical state of schizophrenia in multiple prior studies is sensitive to features of the at-risk mental state, we examined differences between young people identified as being at clinical high risk for psychosis (CHR; n = 37) and non-psychiatric matched controls (n = 29) on the Mooney Faces Test (MFT). On each trial of the MFT, participants report whether they perceive a face in a degraded face image. The CHR group reported perceiving a greater number of faces in both upright and inverted MFT stimuli. Consistent with prior work, males reported more faces on the MFT than females in both conditions. However, the finding of greater reported face perception among CHR subjects was robustly observed in the female CHR group relative to the female control group. Among male CHR participants, greater reported face perception was related to increased perceptual abnormalities. These preliminary results are consistent with a small but growing literature suggesting that heightened perceptual sensitivity may characterize individuals at increased clinical risk for psychosis. Further studies are needed to determine the contributions of specific perceptual, cognitive, and motivational mechanisms to the findings.

Malaria remains a vector-borne infectious disease that is still a major public health concern worldwide, especially in tropical regions. Malaria is caused by a protozoan parasite of the genus Plasmodium and transmitted through the bite of infected female Anopheles mosquitoes. The control interventions targeting mosquito vectors have achieved significant success during the last two decades and rely mainly on the use of chemical insecticides through the insecticide-treated nets (ITNs) and indoor residual spraying (IRS). Unfortunately, resistance to conventional insecticides currently being used in public health is spreading in the natural mosquito populations, hampering the long-term success of the current vector control strategies. Thus, to achieve the goal of malaria elimination, it appears necessary to improve vector control approaches through the development of novel environment-friendly tools. Mosquito microbiota has by now given rise to the expansion of innovative control tools, such as the use of endosymbionts to target insect vectors, known as “symbiotic control.” In this review, we will present the viral, fungal and bacterial diversity of Anopheles mosquitoes, including the bacteriophages. This review discusses the likely interactions between the vector microbiota and its fitness and resistance to insecticides.

Temporal variations in synthetic aperture radar (SAR) backscatter over forests are of concern for any SAR mission with the goal of estimating forest parameters from SAR data. In this article, a densely sampled, two-year long time series of P-band (420 to 450 MHz) boreal forest backscatter, acquired by a tower-based radar, is analyzed. The experiment setup provides time series data at multiple polarizations. Tomographic capabilities allow the separation of backscatter at different heights within the forest. Temporal variations of these multipolarized, tomographic radar observations are characterized and quantified. The mechanisms studied are seasonal variations, effects of freezing conditions, diurnal variations, effects of wind, and the effects of rainfall on backscatter. An emphasis is placed on upper-canopy backscatter, which has been shown to be a robust proxy for forest biomass. The canopy backscatter was more stable than ground-level backscatter during nonfrozen conditions, supporting forest parameter retrieval approaches based on tomography or interferometric ground notching. Large backscatter variations during frozen conditions, which may be detected using cross-polarized backscatter observations, can result in large errors in forest parameter estimates. Diurnal backscatter variations observed during hot periods were likely connected to tree water transport and storage mechanisms. Backscatter changes were also observed during strong winds. These variations were small in comparison to the variations due to freeze-thaw and soil moisture changes and should not result in significant forest parameter estimation errors. The presented results are useful for designing physically based and semiempirical scattering models that account for temporal changes in scattering characteristics.

In this research, two components were developed jointly: On the one hand, an experimental plan was created to obtain specific variables of the concrete and serve as a reference for the second model, a numerical and computational type created to address the variability in parameters, such as the elasticity and flow of coarse aggregate and mortar. The experimental work reproduced a specific gradation with a 1” nominal maximum size TMN on spheroidal-shaped particles. To address the diversity of limestone in the national territory, rocks were extracted from five calcareous areas of the country, which were transformed through different activities from lamination and turning with different bits to being carved into spheres until the reference gradation formed. The next stage consisted of determining the mechanical and stress–strain properties of both the mortar and coarse aggregate. In the case of mortar, the compressive stress was obtained from 50 mm × 50 mm × 50 mm cubes and the modulus of elasticity from 100 mm × 200 mm cylinders; for the coarse aggregate, the compressive stress was obtained through tests on cylinders of the calcareous rock used to form the spherical aggregate particles. The materials were mixed according to a previous proportioning for f′c = 28 MPa and cast in cylinders of 100 mm × 200 mm. Finally, the compressive stress and the modulus of elasticity in these specimens were determined. Separately, a computational model was created to reproduce the experimental model with the same type of materials and load conditions and thereby estimate the compressive stress and modulus of elasticity of the tested material. This model was developed based on finite elements simulating concrete under a two-phase model, in which the coarse aggregate phase was arranged with spheroidal particles that were assembled with the mortar paste, thus finally reproducing a concrete cylinder of 100 mm × 200 mm. Material properties, taken from experimental work, were assigned to these materials. Initially, work was carried out in the elastic range, obtaining, as a result, the modulus of elasticity Ec, and then the specimen was brought to failure, obtaining, as a result, the maximum compressive stress f′c. To attend to the influence of the effect of the mesh size for modeling on the numerical results of both parameters, several simulations were carried out in which mesh sizes of 4.0, 3.5, 3.0, and 2.5 mm were established for the mortar and the coarse aggregate, respectively, for carrying out the modeling. The results in the computational model showed that the compressive stress turned out to be more sensitive than the modulus of elasticity to the variation in the size of the mesh. For the first, the differences between the 4 mm mesh and the 2.5 mm mesh reached 3%, but for the second, the difference only reached 1% between the results for the same meshes. When the results between the experimental and computational models were compared, we found that the experimental values had the best closeness with results in the 2.5 mm mesh.

Complex immunosuppressive therapy is prescribed in medical practice to patients with glomerulonephritis to help them overcome symptoms and prevent chronic renal failure. Such an approach requires long-term systemic administration of strong medications, which causes severe side effects. This work shows the efficiency of polymer capsule accumulation (2.8 ± 0.4 µm) containing labeled etanercept (100 μg per dose) in the kidneys of mice. The comparison of injection into the renal artery and tail vein shows the significant superiority of the intra-arterial administration strategy. The etanercept retention rate of 18% and 8% ID in kidneys was found 1 min and 1 h after injection, respectively. The capsules were predominantly localized in the glomeruli after injection in mice using a model of acute glomerulonephritis. Histological analysis confirmed a significant therapeutic effect only in animals with intra-arterial administration of microcapsules with etanercept. The proposed strategy combines endovascular surgery and the use of polymer microcapsules containing a high molecular weight drug that can be successfully applied to treat a wide range of kidney diseases associated with glomerular pathology.

Abstract Background This article presents examples of how to utilize the research output, to initiate academia-industry interaction, with the ultimate task of launching a new product: a smart heart valve prosthesis for pediatric patients. The article summarizes our efforts in a way that may also be informative to researchers working in fields other than medical devices development. Our task is not to provide a step-by-step guide, but rather to create inspiration, also by describing differences in expectations of business and academic entities. Methods We analyzed market reports, surveyed the scientific literature and conducted interviews with the key players in the field of medical devices. We also obtained a feedback from clinicians, academia and industry-related researchers, technology transfer centres, representatives of public organization and the creators of legislation. Results We have obtained and reported the definitive answers that together constitute a critical review of strategies that should be used by researchers who seek to commercialize the outputs of their research. Conclusion As a result of our investigation, we discovered that the commercialization of research is a complex process, which in some critical aspects does not depend solely on the researcher himself. The most promising ideas, supported by strong experimental evidence, can simply be overlooked by industry representatives, without the proper support of institutions such as a technology transfer centre. Besides, the involvement of scientists in a business project takes them, at least temporarily, outside the regular academic environment, which may cause discomfort and pose a risk to the career path. The limitation to be addressed is the reluctance to report the unsuccessful attempts, which should be considered a legitimate educational experience that ultimately leads to improvement.

Abstract Background Senataxin (SETX) is a DNA/RNA helicase critical for neuron survival. SETX mutations underlie two inherited neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and Amyotrophic Lateral Sclerosis type 4 (ALS4). Methods This review examines SETX key cellular processes and we hypothesize that SETX requires SUMO posttranslational modification to function properly. Results SETX is localized to distinct foci during S‐phase of the cell cycle, and these foci represent sites of DNA polymerase/RNA polymerase II (RNAP) collision, as they co‐localize with DNA damage markers 53BP1 and H2AX. At such sites, SETX directs incomplete RNA transcripts to the nuclear exosome for degradation via interaction with exosome component 9 (Exosc9), a key component of the nuclear exosome. These processes require SETX SUMOylation. SETX was also recently localized within stress granules (SGs), and found to regulate SG disassembly, a process that similarly requires SUMOylation. Conclusion SETX undergoes SUMO modification to function at S‐phase foci in cycling cells to facilitate RNA degradation. SETX may regulate similar processes in non‐dividing neurons at sites of RNAP II bidirectional self‐collision. Finally, SUMOylation of SETX appears to be required for SG disassembly. This SETX function may be crucial for neuron survival, as altered SG dynamics are linked to ALS disease pathogenesis. In addition, AOA2 point mutations have been shown to block SETX SUMOylation. Such mutations induce an ataxia phenotype indistinguishable from those with SETX null mutation, underscoring the importance of this modification.

For years we have investigated the presence and molecular evolution of tuberculosis in Pre Dynastic and Early Dynastic Egyptian mummy material from Abydos (c. 3500-2800 BC), Middle and New Kingdom until the Late Period in Thebes-West (c. 2050 – 500 BC). We have analysed 160 bone and soft tissue samples from different time periods and populations for the occurrence of M. tuberculosis complex DNA. All positive specimens were genetically characterised by spoligotyping and mutation analysis. Molecular analyses revealed excellent state of preservation of the specimens. Research showed a high incidence of M. tuberculosis during all time periods. We further detected specific MTB strain differences with M. africanum in some of the Middle Kingdom samples and “modern” M. tuberculosis strains in the New Kingdom to Late Period material. These results demonstrate that aDNA is excellently preserved in ancient Egyptian mummies allowing the reconstruction of occurrence, frequency, molecular evolution and spread of tuberculosis in Pharaonic populations.

In the necropolis of Thebes-West, Upper Egypt, individuals from various time periods are buried, comprising the Middle Kingdom, the New Kingdom and the Late Period. Previously the bodies had been examined paleopathologically and data of more than 800 individuals had been entered into a data base. We analyzed the data in respect to age distribution, sex, social status and several symptoms that are indicators for distinct disease entities. We identified statistically significant associations of social status with the prevalence of caries. Degenerative diseases and traumas are significantly more frequent in later time periods, whereas severe infectious diseases occur nearby only in the Middle Kingdom. The odds ratio of signs of anaemia for children versus adults was about 3.1 (95% confidence interval 2.2- 4.3), independently of social status and epoch. No differences among time periods, social status and age distribution were found for the occurrence of scurvy and osteopenia. Despite the obstacles of missing data, selection bias through selective burial practices and information bias by contamination of later burials, our results give an insight on disease distribution in ancient Egypt by population based data.

Gynecologic malignancies are among the most common cancers in women worldwide and account for significant morbidity and mortality. Management and consequently overall patient survival is reliant upon early detection, accurate staging and early detection of any recurrence. Ultrasound, Computed Tomography (CT), Magnetic resonance imaging (MRI) and Positron Emission Tomography-Computed Tomography (PET-CT) play an essential role in the detection, characterization, staging and restaging of the most common gynecologic malignancies, namely the cervical, endometrial and ovarian malignancies. Recent advances in imaging including functional MRI, hybrid imaging with Positron Emission Tomography (PET/MRI) contribute even more to lesion specification and overall role of imaging in gynecologic malignancies. Radiomics is a neoteric approach which aspires to enhance decision support by extracting quantitative information from radiological imaging.

The computational underpinnings of positive psychotic symptoms have recently received significant attention. Candidate mechanisms include some combination of maladaptive priors and reduced updating of these priors during perception. A potential benefit of models with such mechanisms is their ability to link multiple levels of explanation, from the neurobiological to the social, allowing us to provide an information processing-based account of how specific alterations in self-self and self-environment interactions result in the experience of positive symptoms. This is key to improving how we understand the experience of psychosis. Moreover, it points us toward more comprehensive avenues for therapeutic research by providing a putative mechanism that could allow for the generation of new treatments from first principles. In order to demonstrate this, our conceptual paper will discuss the application of the insights from previous computational models to an important and complex set of evidence-based clinical interventions with strong social elements, such as coordinated specialty care clinics (CSC) in early psychosis and assertive community treatment (ACT). These interventions may include but also go beyond psychopharmacology, providing, we argue, structure and predictability for patients experiencing psychosis. We develop the argument that this structure and predictability directly counteract the relatively low precision afforded to sensory information in psychosis, while also providing the patient more access to external cognitive resources in the form of providers and the structure of the programs themselves. We discuss how computational models explain the resulting reduction in symptoms, as well as the predictions these models make about potential responses of patients to modifications or to different variations of these interventions. We also link, via the framework of computational models, the patient's experiences and response to interventions to putative neurobiology.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake spontaneously breathing SCA7-266Q knock-in mice at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after the onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia, and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice had profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibited a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation was observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death.

Abstract Radiopharmaceuticals have proven to be effective agents, since they can be successfully applied for both diagnostics and therapy. Effective application of relevant radionuclides in pre-clinical and clinical studies depends on the choice of a sufficient delivery platform. Herein, we provide a comprehensive review on the most relevant aspects in radionuclide delivery using the most employed carrier systems, including, (i) monoclonal antibodies and their fragments, (ii) organic and (iii) inorganic nanoparticles, and (iv) microspheres. This review offers an extensive analysis of radionuclide delivery systems, the approaches of their modification and radiolabeling strategies with the further prospects of their implementation in multimodal imaging and disease curing. Finally, the comparative outlook on the carriers and radionuclide choice, as well as on the targeting efficiency of the developed systems is discussed.

Currently, the livestock industry around the world is not provided with the necessary amount of feed rich in proteins and biologically active substances (BAS) of natural origin. These can be provided with alternative sources like microalgae with chlorella holding a special place due to its unique chemical composition. This paper introduces the research results on the effect of chlorella suspension on the productive and reproductive qualities of geese of various technological groups. It reveals the optimal doses to be included in the poultry diet. Thus, application of chlorella suspension in the feed rations of geese has increased their safety, live weight, egg production and hatching, improved quality indicators of goose semen production, incubation results, yield of commercial replacement birds, indicators of natural resistance, as well as the digestibility of nutrients at lower feed costs per unit of production and higher goose meat quality.

Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal & bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.

Abstract The fragile X premutation is a CGG trinucleotide repeat expansion between 55 and 200 repeats in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene. Human carriers of the premutation allele are at risk of developing the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Characteristic neuropathology associated with FXTAS includes intranuclear inclusions in neurons and astroglia. Previous studies recapitulated these histopathological features in neurons in a knock-in mouse model, but without significant astroglial pathology. To determine the role of astroglia in FXTAS, we generated a transgenic mouse line (Gfa2-CGG99-eGFP) that selectively expresses a 99-CGG repeat expansion linked to an enhanced green fluorescent protein (eGFP) reporter in astroglia throughout the brain, including cerebellar Bergmann glia. Behaviorally these mice displayed impaired motor performance on the ladder-rung test, but paradoxically better performance on the rotarod. Immunocytochemical analysis revealed that CGG99-eGFP co-localized with GFAP and S-100ß, but not with NeuN, Iba1, or MBP, indicating that CGG99-eGFP expression is specific to astroglia. Ubiquitin-positive intranuclear inclusions were found in eGFP-expressing glia throughout the brain. In addition, intracytoplasmic ubiquitin-positive inclusions were found outside the nucleus in distal astrocyte processes. Intriguingly, intranuclear inclusions, in the absence of eGFP mRNA and eGFP fluorescence, were present in neurons of the hypothalamus and neocortex. Furthermore, intranuclear inclusions in both neurons and astrocytes displayed immunofluorescent labeling for the polyglycine peptide FMRpolyG, implicating FMRpolyG in the pathology found in Gfa2-CGG99 mice. Considered together, these results show that Gfa2-CGG99 expression in mice is sufficient to induce key features of FXTAS pathology, including formation of intranuclear inclusions, translation of FMRpolyG, and deficits in motor function.

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = −0.66, p = 0.104, FDR corrected) and global white matter pFA (r = −0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Asiatic wild ass (Kulan, Equus hemionus) population range and numbers became severely reduced and a reintroduction project is currently aiming to re-establish a population in the Central Steppe of Kazakhstan. Pre-emptive deworming is often recommended for equid translocations but eliminating parasites prior to translocation could cause disruptions in a balanced host-parasite relationship, adding an additional stressor to an already stressful intervention involving capture, transport, and adaptation to a new environment. Following a disease risk assessment, we decided against pre-emptive deworming and focused on monitoring the first group of nine translocated kulan in a large acclimatization enclosure prior to release. Over the 5-month acclimatization period, we regularly collected fecal samples and analyzed the shedding intensity of gastro-intestinal parasite eggs, obtained time budgets through behavioral observations, and visually assessed body condition. We identified strongyles (Strongylinae and Cyathostominae) and pinworms (Oxyuris equi) in fecal samples. All individuals shed strongyle eggs and two of the nine individuals had higher shedding intensities, but rarely reached levels for which deworming is recommended. All kulan appeared healthy throughout the observation period, aggressive interactions were very rare, and time budgets were very similar and dominated by feeding. Our results suggest that in translocation projects where the risk of introducing new parasites is minimal, pre-emptive treatment in wild equids can be replaced with non-invasive monitoring during the acclimatization period. We acknowledge that the small number of kulan, the large size of the enclosure, and the low temperatures during the animals stay in the acclimatization enclosure may all have reduced infestation pressure.

Summary: Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells (RGCs). Recent studies have implicated pro-inflammatory microglia, macrophages, and A1 astrocytes in the pathogenesis of neurodegenerative diseases. The role of pro-inflammatory, neurotoxic A1 astrocytes in glaucoma is just beginning to be explored. Using a mouse model of glaucoma, we demonstrate that ocular hypertension is sufficient to trigger production of C1q, interleukin-1α (IL-1α), and tumor necrosis factor α (TNF-α), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulation of these cytokines occurs first in CD11b+ CD11c+ cells followed by CD11b+ CD11c− cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduces A1 astrocyte transformation and RGC death. Together, these results highlight a neuroinflammatory mechanism of glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

Structural Health Monitoring (SHM) is essential to identifying problems that may cause human and material losses produced by disastrous and unexpected structural failures. The dynamic characterization of civil structures adopting SHM systems provides, at a particular moment, accurate information about the current structural response. When considering a proper SHM strategy and affordable economic investment for the maintenance required by structures, it is possible to safeguard the original structural parameters and avoid potential failures. However, traditional SHM systems are not desirable due to the large economic investments involved and demand for exhausting fieldwork. This research presents the design, implementation, and validation of a low-cost SHM system composed of a Wireless Sensor Network (WSN) and a base station in order to identify dynamic properties from the measured structural response. A set of small- and full-scale experimental tests were conducted to validate the WSN system using a wired traditional SHM system. Vibration data recorded through the low-cost SHM system were processed and compared to determine the natural frequencies, mode shapes, and damping properties of different structures by computing modal identification techniques, frequency analysis, and logarithmic decrement. The obtained dynamic characterization results from small- and full-scale experimental testing conclude that the low-cost SHM system can reliably identify the dynamic properties of the tested structures. This proposal provides an inexpensive, functional, and innovative alternative for SHM regarding traditional monitoring systems.