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Background: The problem of venous thromboembolic events (VTE) after incisional hernia repair remains relevant. According to the literature the frequency of VTE ranges from 0.2 to 4.2%. The data on risk factors of VTE in this cohort of patients are scarce. Aim of our study is to find frequency and risk factors for VTE development in patients who underwent surgery for incisional ventral hernia. Materials and methods: There were 240 patients enrolled in our retrospective study. We included patients, who were operated for incisional hernia in Saveljev University Surgery Clinic from January 2018 to December 2019. Compression duplex ultrasound of lower extremity veins was performed within median 3 days (min 1 day, max 7 days) after surgery for all participants. The primary endpoint was the occurrence of the VTE event, including deep venous thrombosis (DVT) and pulmonary embolism (PE). Results: VTE was detected in 19 patients, which accounted for 7.9% in analyzed cohort. All patients received standard pharmacological prophylaxis. There were 3 (1.3%) proximal, 16 (6.7%) distal DVT, in one patient (0.4%) distal thrombosis was complicated by symptomatic pulmonary embolism. In multivariate Cox proportional hazard model was found that component separation (HR 3.99, 95% CI 1.14–14.0, p = 0.03), duration of operation in hours (HR 1.67. 95% CI 1.13–2.5, p = 0.011) and body mass index (HR 1.13, 95% CI 1.02–1.2, p = 0.02) were statistically significant risk factors. Conclusion: The incidence of postoperative VTE in patients after incisional hernia repair is high with a predominant distal DVT as a thrombotic event. Component separation, duration of operation and body mass index are statistically significant factors of VTE in patients undergoing surgery for incisional hernia. [ABSTRACT FROM AUTHOR]

Several years ago a series of powerful millisecond radio bursts with close dispersion measures was detected toward the galaxy M31. Taking the hypothesis about the possible association of these radio bursts with a magnetar in M31 as a starting point, we have searched for periodic X-ray signal sources using data from the XMM-Newton X-ray telescope. As a result of our data analysis, we have identified a signal from the already known periodic X-ray source 3XMM J004301.4+413017, an accreting pulsar in a binary system. However, we have failed to detect new candidates. In particular, we have revealed no object that could be associated with the hypothetical magnetar responsible for the observed radio bursts that could have a luminosity erg s . [ABSTRACT FROM AUTHOR]

Purpose: To find out the prevalence and risk factors for abdominal wall hernias in the general Russian population.Methods: 783 residents of Kryukovo rural community (Central Russia) of 10 > years were enrolled. Medical history was taken and clinical examination was performed documenting hernia presence. Ultrasound examination was performed in inconclusive situations. We considered residents with hernias at the time of examination, as well as those who had previously undergone hernia repair, to be hernia positive.Results: There were 298 (38%) men and 485 (62%) women (mean age 49.3). Abdominal wall hernias have been found in 20.9% of population. 31.2% of men and 14.6% of women were affected (p < 0.0001). Umbilical hernias was found in 10.2%, groin hernias in 8.3%, incisional in 2.4% of residents. 72% of individuals with hernia reported local pain. 70% had never asked for medical advice before, 30% had undergone hernia repair before. Male gender, age, family history were confirmed as risk factors for any hernia with OR 3.9, 1.03 and 2.7, respectively (p < 0.01). For groin hernias male gender, age, family history and rough labour were confirmed with ORs 9.2, 1.03, 2.9 (p < 0.01) and 2.1 (p < 0.05). Risk factors for umbilical hernias were male gender with OR 2.2 (p < 0.01), age, family history and BMI with ORs 1.02, 1.8 and 1.08 (p < 0.05).Conclusions: This study is the first to demonstrate prevalence of abdominal wall hernias and its risk factors in Russia. The results confirm that hernias are common in a general population pointing the need for improvement of surgical activity. [ABSTRACT FROM AUTHOR]

We studied the effects of single nucleotide polymorphisms in the promoter regions of matrix metalloproteinase genes rs1799750 (-1607dupG) MMP1, rs243865 ( C-1306T) MMP2, rs3025058 ( -1171dupA) MMP3, and rs11568818 ( A-181G) MMP7 on the risk of varicose vein of the lower extremities in ethnical Russians, residents of the Russian Federation. We genotyped 536 patients with this pathology and 273 healthy participants without history of chronic venous disease. Association was examined using logistic regression analysis. None of the studied polymorphisms showed statistically significant association with the risk of varicose veins of the lower extremities. Our results provide evidence that these polymorphisms are not involved in the pathogenesis of varicose veins and cannot serve as markers of predisposition to this pathology. [ABSTRACT FROM AUTHOR]

The structure and properties of graphene, which is a two-dimensional layer of carbon atoms with a hexagonal crystal lattice, are considered. Graphene is a zero bandgap semiconductor with a nondissipative motion of Dirac electron-hole pairs, which provides a charge mobility of μ ∼ 10 cm V s. Methods of their production are considered. It is shown that graphenes are the most promising materials for application as nanoelectromechanical transducers and ultracapacitors. [ABSTRACT FROM AUTHOR]

We analyzed associations between single nucleotide polymorphisms (SNP) rs13155212 and rs7704267 in the AGGF1 gene (angiogenic factor with G patch and FHA domains 1) and the risk of risk of varicose veins of the legs in ethnic Russians. Frequencies of alleles, genotypes, and haplotypes were estimated in the sample of patients with this disease (474 patients) and in the control group of participants (478 volunteers) without a history of chronic venous disease. None of the studied polymorphisms was associated with the risk of this pathology. The whole AGGF1 gene sequence lies in a single block of high linkage disequilibrium, and both studied polymorphic variants are representative of all other SNP within this region. From these results, a conclusion was made that AGGF1 gene polymorphism does not affect the risk of varicose veins of the legs in ethnic Russians, or its contribution is low and can be revealed only after analysis of larger cohorts. [ABSTRACT FROM AUTHOR]

Automated search for star clusters in J, H, K s data from 2MASS catalog has been performed using the method developed by Koposov et al. (2008). We have found and verified 153 new clusters in the interval of the galactic latitude −24° < b < 24°. Color excesses E( B − V), distance moduli and ages were determined for 130 new and 14 yet-unstudied known clusters. In this paper, we publish a catalog of coordinates, diameters, and main parameters of all the clusters under study. A special web-site available at has been developed to facilitate dissemination and scientific usage of the results. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid α-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa−/−). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641±190% of normal (Gaa+/+) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa−/− control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.Gene Therapy (2005) 12, 1405–1409. doi:10.1038/sj.gt.3302550; published online 26 May 2005 [ABSTRACT FROM AUTHOR]

Astrocyte to neuron reprogramming has been performed using viral delivery of neurogenic transcription factors in GFAP expressing cells. Recent reports of off-target expression in cortical neurons following adeno-associated virus (AAV) transduction to deliver the neurogenic factors have confounded our understanding of the efficacy of direct cellular reprogramming. To shed light on potential mechanisms that may underlie the neuronal off-target expression of GFAP promoter driven expression of neurogenic factors in neurons, two regionally distinct cortices were compared—the motor cortex (MC) and medial prefrontal cortex (mPFC)—and investigated: (1) the regional tropism and astrocyte transduction with an AAV5-GFAP vector, (2) the expression of Gfap in MC and mPFC neurons; and (3) material transfer between astrocytes and neurons. Using a Cre-based system (AAV5-hGFAP-Cre; Rosa26R-tdTomato reporter mice), regional differences were observed in tdTomato expression between the MC and mPFC. Interestingly, this correlated with the presence of a greater expression of Gfap mRNA in neurons in the mPFC. Additionally, intercellular material transfer of Cre and tdTomato was observed between astrocytes and neurons in both regions, albeit at very low frequencies. Our study highlights regionally distinct variation in neurons that warrants consideration when designing genetic constructs for gene therapies targeting astrocytes including astrocyte to neuron reprogramming. [ABSTRACT FROM AUTHOR]

This article presents an analysis of the results of a study on a promising method for producing functionally graded composite materials using "cold" gas dynamic spraying technology. In particular, for the Al–Al2O3 composite, the influence of the ceramic component content on the change in the coefficient of thermal linear expansion is determined. The results can be used in the design and creation of materials in thermally loaded components to reduce stresses by adjusting thermal gaps. [ABSTRACT FROM AUTHOR]

A study is performed of the temperature dependences of the Hall coefficient, specific electrical resistance, and saturation magnetization for Fe60Co20Si8B12 and Fe58Co20Si12B10 alloys in amorphous and crystalline states. The relationship between these parameters is established and explained from the viewpoint of the theory of the anomalous Hall effect. Coefficients of the parameter of spin–orbital interaction are estimated on the basis of experimental data. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated virus type 2 (rAAV) vectors have recently been used to achieve long-term, high level transduction in vivo. Further development of rAAV vectors for clinical use requires significant technological improvements in large-scale vector production. In order to facilitate the production of rAAV vectors, a recombinant herpes simplex virus type I vector (rHSV-1) which does not produce ICP27, has been engineered to express the AAV-2 rep and cap genes. The optimal dose of this vector, d27.1-rc, for AAV production has been determined and results in a yield of 380 expression units (EU) of AAV-GFP produced from 293 cells following transfection with AAV-GFP plasmid DNA. In addition, d27.1-rc was also efficient at producing rAAV from cell lines that have an integrated AAV-GFP provirus. Up to 480 EU/cell of AAV-GFP could be produced from the cell line GFP-92, a proviral, 293 derived cell line. Effective amplification of rAAV vectors introduced into 293 cells by infection was also demonstrated. Passage of rAAV with d27.1-rc results in up to 200-fold amplification of AAV-GFP with each passage after coinfection of the vectors. Efficient, large-scale production (>109 cells) of AAV-GFP from a proviral cell line was also achieved and these stocks were free of replication-competent AAV. The described rHSV-1 vector provides a novel, simple and flexible way to introduce the AAV-2 rep and cap genes and helper virus functions required to produce high-titer rAAV preparations from any rAAV proviral construct. The efficiency and potential for scalable delivery of d27.1-rc to producer cell cultures should facilitate the production of sufficient quantities of rAAV vectors for clinical application. [ABSTRACT FROM AUTHOR]

Conventional methods for rAAV purification that are based on cesium chloride ultracentrifugation have often produced vector preparations of variable quality and resulted in significant loss of particle infectivity. We report here several novel purification strategies that involve the use of non-ionic iodixanol gradients followed by ion exchange or heparin affinity chromatography by either conventional or HPLC columns. These methods result in more than 50% recovery of rAAV from a crude lysate and routinely produce vector that is more than 99% pure. More importantly, the new purification procedures consistently produce rAAV stocks with particle-to-infectivity ratios of less than 100, which is significantly better than conventional methods. The new protocol increases the overall yield of infectious rAAV by at least 10-fold and allows for the complete purification of rAAV in 1 working day. Several of these methods should also be useful for large-scale production. [ABSTRACT FROM AUTHOR]

Macroscopic fractal aggregates of cobalt are obtained by thermal evaporation of cobalt metal in an argon atmosphere and subsequent deposition on a silicon substrate heated to 1000 K. It is established that the fractal structure is formed by diffusion-limited aggregation of cobalt particles. The macroscopic fractal cobalt aggregates are ferromagnetic. © 1997 American Institute of Physics. [ABSTRACT FROM AUTHOR]

The experimental results on the turbulent flow structure in a lattice matrix cell, which is a region between intersecting ribs on the opposite walls of a flat channel, are presented. The angle between the ribs was 2β = 60°, 90° and 120°; the Reynolds number calculated from the average velocity and hydraulic diameter of the channel was varied in the range Re = (1–7)·104. The aerodynamic characteristics of the flow inside a lattice matrix cell placed in a rectangular channel with a cross section of 20×150 mm and a length of 400 mm were measured using a two-component laser Doppler anemometer (LDA). The flow structure was studied in individual cells of 15×15 mm, formed by crossing ribs on the opposite channel walls. The complex three-dimensional structure of the flow in the matrix cells and strong turbulence of the flow in the near-wall regions are shown. The installation of ribs leads to a significant increase in hydraulic losses, especially at large crossing angles. [ABSTRACT FROM AUTHOR]

We have studied the effective density, electric conductivity, and thermo emf of compacted carbon nanotubes (NTs) and nanowhiskers (NWs). The effective densities of NTs and NWs are 1.6 and 2.8g/cm3 respectively. The thermo emf of compacted NWs (33μV/K) and NTs (7–8μV/K) make it possible to use these materials in sensors of molecular gases and biological objects. It is also recommended to introduce NWs and NTs as fillers into glue compositions possessing increased strength and electric conductivity, which are necessary for gluing metals. © 2005 Pleiades Publishing, Inc. [ABSTRACT FROM AUTHOR]

The concept of steady-state solutions to the Navier–Stokes equation is defined. Such solutions extend the notion of stationary ones, diminish exponentially over time, and have a fixed spatial field of velocities and constant pressure in the absence of external fields. A way of constructing these solutions is considered, and the problem of Taylor vortices is solved. A mathematical model of a tornado is proposed, within which a steady-state solution is obtained as an eigenfunction of the problem in the form of a vortex. A model for the formation of the structure of a gas cloud is proposed, based on the Navier–Stokes equation. It is shown that spiral arms arise from flows of gas moving outward, due to the Coriolis force. It is proved that the number of arms is even and their structure is independent of the angular velocity of rotation. We obtain a formula for the twist angle of the spirals, depending on the cloud parameters for when . [ABSTRACT FROM AUTHOR]

We have obtained macroscopic fractal aggregates of fullerite ranging in size from 100 to 400 μm. The fractal structure of fullerite is formed by microscopic (30–100 nm) fullerite crystals in the presence of a temperature gradient under conditions of diffusion-limited aggregation. © 1998 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Recent advancements have focused on enhancing factor VIII half-life and refining its delivery methods, despite the well-established knowledge that factor VIII deficiency is the main clotting protein lacking in hemophilia. Consequently, both viral and non-viral delivery systems play a crucial role in enhancing the quality of life for hemophilia patients. The utilization of viral vectors and the manipulation of non-viral vectors through targeted delivery are significant advancements in the field of cellular and molecular therapies for hemophilia. These developments contribute to the progression of treatment strategies and hold great promise for improving the overall well-being of individuals with hemophilia. This review study comprehensively explores the application of viral and non-viral vectors in cellular (specifically T cell) and molecular therapy approaches, such as RNA, monoclonal antibody (mAb), and CRISPR therapeutics, with the aim of addressing the challenges in hemophilia treatment. By examining these innovative strategies, the study aims to shed light on potential solutions to enhance the efficacy and outcomes of hemophilia therapy. [ABSTRACT FROM AUTHOR]

Experimental data on the self-organization of massive fractal granules with a total volume of up to 1.1 cm3 consisting of carbon nanofibers with transverse dimensions within 50–70 nm and a length of up to 1000 nm are presented. The fractal granules have a density of 1.3 g/cm3, an elastic modulus of 37.4 MPa, and a fractal dimension of D = 2.95. The resistivity of this material is about three orders of magnitude greater than the values typical of pyrolytic graphite. The surface layers in the fractal granule are characterized by a Seebeck coefficient of about S ∼ 24 μV/K, whereas the bulk regions have S ∼ 11 μV/K. [ABSTRACT FROM AUTHOR]

The structure and thermo emf of nanotubular and fractal carbon layers deposited from an electric discharge plasma were studied. The thermo emf of such nanotubular and fractal deposits is almost tenfold higher as compared to that of polycrystalline carbon, which is explained by the nanostructural state of carbon in the deposits studied. [ABSTRACT FROM AUTHOR]

Among the several animal models of α-synucleinopathies, the well-known viral vector-mediated delivery of wild-type or mutated (A53T) α-synuclein requires new tools to increase the lesion in mice and follow up in vivo expression. To this end, we developed a bioluminescent expression reporter of the human A53T-α-synuclein gene using the NanoLuc system into an AAV2/9, embedded or not in a fibroin solution to stabilise its expression in space and time. We first verified the expression of the fused protein in vitro on transfected cells by bioluminescence and Western blotting. Next, two groups of C57Bl6Jr mice were unilaterally injected with the AAV-NanoLuc-human-A53T-α-synuclein above the substantia nigra combined (or not) with fibroin. We first show that the in vivo cerebral bioluminescence signal was more intense in the presence of fibroin. Using immunohistochemistry, we find that the human-A53T-α-synuclein protein is more restricted to the ipsilateral side with an overall greater magnitude of the lesion when fibroin was added. However, we also detected a bioluminescence signal in peripheral organs in both conditions, confirmed by the presence of viral DNA corresponding to the injected AAV in the liver using qPCR. [ABSTRACT FROM AUTHOR]

The silicon carbide particles with solid fractal formed in an electric arc discharge plasma exhibit anomalous optical properties. In the 360-475 nm wavelength range, the level of light absorption in the fractal structures of silicon carbide is 15-30 times that in single-crystalline SiC samples. [ABSTRACT FROM AUTHOR]

High-temperature internal friction in an amorphous CuTi alloy is investigated. Exponential regions with different activation energies are observed on the dependence of internal friction on temperature on both sides of the glass transition temperature. An exponential increase in the background of internal friction with temperature in both sites is associated with the migration of vacancy-like defects in the amorphous structure under the influence of mechanical stresses, while frozen defects of constant concentration migrate to the glass transition temperature. After the transition to a state of thermodynamic equilibrium, the concentration the number of migrating defects increases exponentially. Based on the experimental results of measuring the high-temperature background, estimates of the activation energy of migration and the formation of vacancies of similar defects in the amorphous structure of the alloy under study are made. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this systematic review was to assess the inheritance of groin hernias. Methods: The primary outcome was to assess the inheritance based on the family history of groin hernias. We included studies that reported family history in patients with groin hernias, assessed the development of groin hernias in patients with a positive family history, or assessed the development of groin hernias in twins. Searches were conducted in PubMed, EMBASE, and Cochrane CENTRAL in November 2021. Results were synthesized narratively and with meta-analyses. Results: Twenty-two studies with unique participants were included. While two twin studies did not show convincing results of a genetic origin in children, database studies with low risk of bias showed that a positive history in parents or siblings increased the risk of inguinal hernia in children, and the risk was highest between mothers and daughters and between sisters. In adults, patients with inguinal hernia had higher odds of having a positive family history compared with patients without groin hernia (odds ratio 5.3, 95% confidence interval 3.3–8.7), and a nationwide study found the highest risk of inguinal hernia repair when a sister had been repaired compared with a brother. This study also found that having a sibling repaired for a groin hernia increased the risk of femoral hernia repair. Conclusion: Despite studies being heterogeneous, there is overwhelming evidence that a positive family history is a risk factor for developing inguinal hernia in both children and adults, seemingly with a pronounced female–female inheritance pattern. [ABSTRACT FROM AUTHOR]

Purpose of Review: Recombinant adeno-associated virus (rAAV) is the commonest viral vector used in gene therapies. With the increase in the number of such therapies being employed in human clinical trials and approved clinical use, the associated adverse events are increasingly observed. Hepatotoxicity is the most common adverse event. Recent Findings: Although mild in most, hepatotoxicity may affect gene therapy efficacy, lead to acute liver failure, death and persisting hepatitis necessitating prolonged use of immunosuppressants. There has been an increase in the referrals of such cases to hepatologists. Summary: There is a lack of good quality evidence on the use of reactive immunosuppressants. There is a need to devise empiric protocols to diagnose and treat hepatotoxicity based on the side-effect profile of individual gene therapy, the present understanding of immunological basis of hepatotoxicity, the experience with various immunosuppressants in other disorders and the unique challenges and requirements of gene therapy. [ABSTRACT FROM AUTHOR]

New experimental results are presented to show that when graphite is sputtered in an electric arc, a carbon deposit having a fractal structure is formed on the cathode. The superior microhardness and high microporosity indicate that this fractal carbon deposit may have applications in engineering. [ABSTRACT FROM AUTHOR]

A long-distance manned flight, for example, to the Moon or Mars, requires an efficient and reliable system of water recovery from wastewater. The vapor compression distiller (VCD) designed for use in a near-Earth orbit and installed on the International Space Station (ISS) does not meet the requirements for deep space flights for several reasons: it has a low recovery rate (up to 85%) and low processing rate (1.5 kg/h); the compressor it uses to reduce the specific power consumption has a complex design, and peristaltic pumps used for pumping liquids have multiple flaws. These shortcomings cannot be eliminated unless the distiller is fundamentally redesigned, and thus such distiller cannot be used in long-term space missions. Therefore, alternative options must be considered. One candidate for the primary distillation for space applications is centrifugal multiple effect distiller (CMED) with a thermoelectric heat pump (THP) used as power source. This article describes the research process and the main characteristics of a three-stage and a five-stage CMED systems with THP, demonstrating their advantages. It is shown that it is possible to obtain up to 7 kg/h of distillate from urine. The effect of heat pump power on its efficiency (COP) and specific power consumption of the distiller is shown. The possibility of reducing the specific power consumption by 20–30% is shown. [ABSTRACT FROM AUTHOR]

We report the results of optical spectroscopy of eight highly variable X-ray sources—AGN candidates from all-sky survey of the eROSITA telescope of the Spectrum-Roentgen-Gamma Space Observatory—performed with the TDS spectrograph (3600–7500 Å, ) attached to the 2.5-m telescope of the Caucasian Mountain Observatory of Sternberg Astronomical Institute of M.V. Lomonosov Moscow State University. We determined the redshifts of the sources from the emission and absorption lines in their spectra. At least five objects can be classified as Seyfert galaxies. We performed pilot infrared photometry of three distant quasars with using the ASTRONIRCAM camera and show that on the " " diagram the distant quasars studied can be confidently distinguished from Galactic red and brown dwarfs. This result proves the possibility of preliminary classification of distant X-ray quasar candidates by their IR colors for further detailed spectroscopic study on large telescopes. [ABSTRACT FROM AUTHOR]

A survey conducted by the Therapeutic Product Immunogenicity (TPI) community within the American Association of Pharmaceutical Scientists (AAPS) posed questions to the participants on their immunogenicity risk assessment strategies prior to clinical development. The survey was conducted in 2 phases spanning 5 years, and queried information about in silico algorithms and in vitro assay formats for immunogenicity risk assessments and how the data were used to inform early developability effort in discovery, chemistry, manufacturing and control (CMC), and non-clinical stages of development. The key findings representing the trends from a majority of the participants included the use of high throughput in silico algorithms, human immune cell-based assays, and proteomics based outputs, as well as specialized assays when therapeutic mechanism of action could impact risk assessment. Additional insights into the CMC-related risks could also be gathered with the same tools to inform future process development and de-risk critical quality attributes with uncertain and unknown risks. The use of the outputs beyond supporting early development activities was also noted with participants utilizing the risk assessments to drive their clinical strategy and streamline bioanalysis. [ABSTRACT FROM AUTHOR]

The maximum eccentricity method (MEM, (Dvorak et al. in Astron Astrophys 426(2):L37–L40, 2004)) is a standard tool for the analysis of planetary systems and their stability. The method amounts to estimating the maximal stretch of orbits over sampled domains of initial conditions. The present paper leverages on the MEM to introduce a sharp detector of separatrices and chaotic seas. After introducing the MEM analogue for nearly-integrable action-angle Hamiltonians, i.e., diameters, we use low-dimensional dynamical systems with multi-resonant modes and junctions, supporting chaotic motions, to recognise the drivers of the diameter metric. Once this is appreciated, we present a second-derivative-based index measuring the regularity of this application. This quantity turns to be a sensitive and robust indicator to detect separatrices, resonant webs and chaotic seas. We discuss practical applications of this framework in the context of N-body simulations for the planetary case affected by mean-motion resonances, and demonstrate the ability of the index to distinguish minute structures of the phase space, otherwise undetected with the original MEM. [ABSTRACT FROM AUTHOR]

Gene transfer with high doses of adeno-associated viral (AAV) vectors has resulted in serious adverse events and even death of the recipients. Toxicity could most likely be circumvented by repeated injections of lower and less toxic doses of vectors. This has not been pursued as AAV vectors induce potent neutralizing antibodies, which prevent cell transduction upon reinjection of the same vector. This review discusses different types of immune responses against AAV vectors and how they offer targets for the elimination or inhibition of vector-specific neutralizing antibodies. Such antibodies can be circumvented by using different virus serotypes for sequential injections, they can be removed by plasmapheresis, or they can be destroyed by enzymatic degradation. Antibody producing cells can be eliminated by proteasome inhibitors. Drugs that inhibit T-cell responses, B-cell signaling, or presentation of the vector's antigens to B cells can prevent or reduce induction of AAV-specific antibodies. Combinations of different approaches and drugs are likely needed to suppress or eliminate neutralizing antibodies, which would then allow for repeated dosing. Alternatively, novel AAV vectors with higher transduction efficacy are being developed and may allow for a dose reduction, although it remains unknown if this will completely address the problem of high-dose adverse events. [ABSTRACT FROM AUTHOR]

Neurons are highly interwoven to form intricate neural circuits that underlie the diverse functions of the brain. Dissecting the anatomical organization of neural circuits is key to deciphering how the brain processes information, produces thoughts, and instructs behaviors. Over the past decades, recombinant viral vectors have become the most commonly used tracing tools to define circuit architecture. In this review, we introduce the current categories of viral tools and their proper application in circuit tracing. We further discuss some advances in viral tracing strategy and prospective innovations of viral tools for future study. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the few malignancies that includes vaccination as a treatment modality. Elements of an effective cancer vaccine should include the ability to elicit a Type I T-cell response and target multiple antigenic proteins expressed early in the disease. Using existing gene datasets encompassing normal prostate tissue and tumors with Gleason Score ≤ 6 and ≥ 8, 10 genes were identified that were upregulated and conserved in prostate cancer regardless of the aggressiveness of disease. These genes encoded proteins also expressed in prostatic intraepithelial neoplasia. Putative Class II epitopes derived from these proteins were predicted by a combination of algorithms and, using human peripheral blood, epitopes which selectively elicited IFN-γ or IL-10 dominant antigen specific cytokine secretion were determined. Th1 selective epitopes were identified for eight antigens. Epitopes from three antigens elicited Th1 dominant immunity in mice; PSMA, HPN, and AMACR. Each single antigen vaccine demonstrated significant anti-tumor activity inhibiting growth of implanted Myc-Cap cells after immunization as compared to control. Immunization with the combination of antigens, however, was superior to each alone in controlling tumor growth. When vaccination occurred simultaneously to tumor implant, multiantigen immunized mice had significantly smaller tumors than controls (p = 0.002) and a significantly improved overall survival (p = 0.0006). This multiantigen vaccine shows anti-tumor activity in a murine model of prostate cancer. [ABSTRACT FROM AUTHOR]

A series of new paramagnetic six-coordinate gallium complexes based on 3,6-di-tert-butyl-o-benzoquinone with N-donor ligands, such as pyridine (Py), 2,2′-dipyridyl (2,2′-dipy), and 4,4′-di-tert-butyl-2,2′-dipyridyl (But-dipy), were synthesized and structurally characterized. The molecular structures of the synthesized compounds were established by single-crystal X-ray diffraction. The complexes with bidentate N-donor ligands have the cis arrangement of the o-quinone ligands, whereas the compound with coordinated pyridine molecules has the trans arrangement of the diolate moieties. The synthesized compounds are characterized by spin density delocalization between the differently charged redox-active ligands. Regardless of the metal coordination environment, the near-IR region of the electronic absorption spectra of all the synthesized complexes show a low-intensity charge-transfer band between the catecholate and o-semiquinolate ligands, which was confirmed by DFT calculations. [ABSTRACT FROM AUTHOR]

Genome editing through adeno-associated viral (AAV) vectors is a promising gene therapy strategy for various diseases, especially genetic disorders. However, homologous recombination (HR) efficiency is extremely low in adult animal models. We assumed that increasing AAV transduction efficiency could increase genome editing activity, especially HR efficiency, for in vivo gene therapy. Firstly, a mouse phenylketonuria (PKU) model carrying a pathogenic R408W mutation in phenylalanine hydroxylase (Pah) was generated. Through co-delivery of the general AAV receptor (AAVR), we found that AAVR could dramatically increase AAV transduction efficiency in vitro and in vivo. Furthermore, co-delivery of SaCas9/sgRNA/donor templates with AAVR via AAV8 vectors increased indel rate over 2-fold and HR rate over 15-fold for the correction of the single mutation in PahR408W mice. Moreover, AAVR co-injection successfully increased the site-specific insertion rate of a 1.4 kb Pah cDNA by 11-fold, bringing the HR rate up to 7.3% without detectable global off-target effects. Insertion of Pah cDNA significantly decreased the Phe level and ameliorated PKU symptoms. This study demonstrates a novel strategy to dramatically increase AAV transduction which substantially enhanced in vivo genome editing efficiency in adult animal models, showing clinical potential for both conventional and genome editing-based gene therapy. [ABSTRACT FROM AUTHOR]

The Ariel mission will characterise the chemical and thermal properties of the atmospheres of about a thousand exoplanets transiting their host star(s). The observation of such a large sample of planets will allow to deepen our understanding of planetary and atmospheric formation at the early stages, providing a truly representative picture of the chemical nature of exoplanets, and relating this directly to the type and chemical environment of the host star. Hence, the accurate and precise determination of the host star fundamental properties is essential to Ariel for drawing a comprehensive picture of the underlying essence of these planetary systems. We present here a structured approach for the characterisation of Ariel stars that accounts for the concepts of homogeneity and coherence among a large set of stellar parameters. We present here the studies and benchmark analyses we have been performing to determine robust stellar fundamental parameters, elemental abundances, activity indices, and stellar ages. In particular, we present results for the homogeneous estimation of the activity indices S and log (R HK ′) , and preliminary results for elemental abundances of Na, Al, Mg, Si, C, N. In addition, we analyse the variation of a planetary spectrum, obtained with Ariel, as a function of the uncertainty on the stellar effective temperature. Finally, we present our observational campaign for precisely and homogeneously characterising all Ariel stars in order to perform a meaningful choice of final targets before the mission launch. [ABSTRACT FROM AUTHOR]

Abstract—In our work, we carry out a structural-spectroscopic study of AlGaN/GaN epitaxial layers grown by molecular-beam epitaxy with nitrogen-plasma activation on a hybrid substrate containing layers of silicon carbide and porous silicon. Using X-ray diffractometry, Raman and photoluminescence spectroscopy, it is shown that thin films formed on a hybrid substrate have minimal residual stresses and intense photoluminescence. [ABSTRACT FROM AUTHOR]

Abstract—Our work reports on the influence of etching modes and their combination on the design, microstructural and optical properties of compliant substrates based on porous silicon. It is shown on the basis of the data of a set of microstructural and spectroscopic methods of analysis that at constant lattice parameters, the magnitude of residual stresses, the size of crystallites, the volume of the crystalline fraction, as well as the reflectivity and energy of direct transitions in the porous silicon layer depend on the combination of etching modes, but do not always correlate with the value of the layer porosity calculated from the analysis of SEM images. [ABSTRACT FROM AUTHOR]

The internal friction spectra of cured epoxy T-107 and a fiberglass reinforced plastic based on it are studied. In the temperature dependence of mechanical losses, β and γ relaxation maxima are found below the glass transition temperature with activation energies of Eβ = 0.30 ± 0.05 eV and Eγ = 0.18 ± 0.04 eV, respectively. The first maximum is associated with the vibrations of the defective oxygen atoms of the epoxy groups of the polymer network, and the second maximum is attributed to the vibrations of the lateral OH groups of the main polymer network. The internal friction of the epoxy polymer in the region of α relaxation process has been studied. In this region, two segments with an intersection point at the glass transition temperature are seen in the temperature dependence of the internal friction in coordinates lnQ−1 vs. 1/T. The high temperature segment of the internal friction background is used to estimate the energies of migration and formation of vacancy-like defects in the amorphous matrix of glass reinforced plastics, which are associated with delocalized oxygen and equal to Em = 0.72 ± 0.05 eV and Ev = 1.41 ± 0.06 eV, respectively. [ABSTRACT FROM AUTHOR]

Given the recent success of gene therapy modalities and the growing number of cell and gene-based therapies in clinical development across many different therapeutic areas, it is evident that this evolving field holds great promise for the unmet medical needs of patients. The recent approvals of Luxturna® and Zolgensma® prove that recombinant adeno-associated virus (rAAV)-based gene therapy is a transformative modality that enables curative treatment for genetic disorders. Over the last decade, Takeda has accumulated significant experience with rAAV-based gene therapies, especially in the early stage of development. In this review, based on the learnings from Takeda and publicly available information, we aim to provide a guiding perspective on Drug Metabolism and Pharmacokinetics (DMPK) substantial role in advancing therapeutic gene therapy modalities from nonclinical research to clinical development, in particular the characterization of gene therapy product biodistribution, elimination (shedding), immunogenicity assessment, multiple platform bioanalytical assays, and first-in-human (FIH) dose projection strategies. [ABSTRACT FROM AUTHOR]

Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (β3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of β3AR overexpression on AS-induced HF. Selective β3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human β3AR in the heart (c-hβ3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human β3AR before AS induction. Moreover, AAV9-hβ3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated β3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hβ3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that β3AR overexpression might have translational potential as a therapeutic strategy in AS–induced HF. [ABSTRACT FROM AUTHOR]

The reaction of cobalt(ii) iodide with 1,4-bis(2,4,6-trimethylphenyl)-1,4-diazabuta-1,3-diene (Mes-DAD) in anhydrous acetonitrile afforded the mononuclear complex [CoI2(Mes-DAD)] (1). The crystal structure of the complex was established by single-crystal X-ray diffraction. The phase purity was confirmed by powder X-ray diffraction. The zero-field splitting parameter (D = 17.2 cm−1) and the intermolecular exchange coupling parameter (zJ = −0.78 cm−1) were determined from magnetochemical studies of complex 1 in a direct current magnetic field of 5 kOe in the temperature range of 2–300 K. Magnetic measurements in an alternating magnetic field showed the absence of slow relaxation of the magnetization. [ABSTRACT FROM AUTHOR]

The growth of GaN films on preliminarily treated Si(001) substrates by chloride–hydride vapor-phase epitaxy through a buffer layer is reported. It is demonstrated that the use of the technology proposed in the study brings about the formation of a Si transition sublayer in the Si substrate, so that further growth on this sublayer provides the formation of columnar GaN grains, between which there is a thin interlayer of the AlN phase. The epitaxial GaN film possesses low residual stresses, which is reflected in high-intensity luminescence. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Connective tissue disorders may contribute to pelvic floor disorders (PFDs). Like PFDs, abdominal wall hernias are more common in patients with systemic connective tissue disorders. We conducted this study to explore the possible association between PFDs and hernias in adult women. Methods: We obtained the data for this study from a study of PFDs among parous women. At enrollment, stress urinary incontinence (SUI), overactive bladder (OAB), and anal incontinence (AI) were assessed using the Epidemiology of Prolapse and Incontinence Questionnaire (EPIQ) and pelvic organ prolapse (POP) was assessed through the Pelvic Organ Prolapse Quantification (POP-Q) examination. Participants were asked to report hernia surgery and list their hernia types. We compared the prevalence of PFDs in those with and without hernias using chi-square test. We used multiple regression analysis to adjust for obstetric and sociodemographic variables. Results: Among 1529 women, 79 (5.2%) reported history of hernia surgery. The prevalence of POP was 7.6% (6 cases) vs. 7.4% (107 cases), the prevalence of SUI was 7.6% (6 cases) vs. 9.9% (144 cases), the prevalence of OAB was 7.6% (6 cases) vs. 5.7% (83 cases), and the prevalence of AI was 7.6% (6 cases) vs. 10.8% (156 cases) in those with hernias compared to those without hernias, respectively. None of these differences were statistically significant. There was no association between hernias and PFDs after adjustment for type of delivery, number of deliveries, age group, primary racial background, weight category, and smoking status. Conclusion: In this study, we could not find any association between hernias and PFDs. [ABSTRACT FROM AUTHOR]

Abstract—This work studies the candidate double and multiple open clusters (OCs) in the galactic sector from l = 240° to l = 270°, which contains the Vela-Puppis star formation region. To do that, we have searched the most recent and complete catalogues of OCs by hand to get an extensive list of 22 groups of OCs involving 80 candidate members. Gaia EDR3 has been used to review some of the candidate OCs and look for new OCs near the candidate groups. Gaia data also permitted filtering out most of the field sources that are not member stars of the OCs. The plotting of combined color-magnitude diagrams of candidate pairs has allowed, in several cases, endorsing or discarding their link. The most likely systems are formed by OCs less than 0.1 Gyr old, with only one eccentric OC in this respect. No probable system of older OCs has been found. Preliminary estimations of the fraction of known OCs that form part of groups (9.4 to 15%) support the hypothesis that the Galaxy and the Large Magellanic Cloud are similar in this respect. The results indicate that OCs are born in groups like stars are born in OCs. [ABSTRACT FROM AUTHOR]

Coagulation factors are produced from hepatocytes, whereas production of coagulation factor VIII (FVIII) from primary tissues and cell species is still controversial. Here, we tried to characterize primary FVIII-producing organ and cell species using genetically engineered mice, in which enhanced green fluorescent protein (EGFP) was expressed instead of the F8 gene. EGFP-positive FVIII-producing cells existed only in thin sinusoidal layer of the liver and characterized as CD31high, CD146high, and lymphatic vascular endothelial hyaluronan receptor 1 (Lyve1)+. EGFP-positive cells can be clearly distinguished from lymphatic endothelial cells in the expression profile of the podoplanin− and C-type lectin-like receptor-2 (CLEC-2)+. In embryogenesis, EGFP-positive cells began to emerge at E14.5 and subsequently increased according to liver maturation. Furthermore, plasma FVIII could be abolished by crossing F8 conditional deficient mice with Lyve1-Cre mice. In conclusion, in mice, FVIII is only produced from endothelial cells exhibiting CD31high, CD146high, Lyve1+, CLEC-2+, and podoplanin− in liver sinusoidal endothelial cells. [ABSTRACT FROM AUTHOR]