The treatment effect across ASPECTS in acute ischemic stroke: Analysis from the AcT Trial.

BACKGROUND: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication. AIMS: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase versus Alteplase. METHODS: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed effects logistic regression was used to assess the association of ASPECTS [continuous and categorical (0-4 vs. 5-7 vs. 8-10)] with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity. RESULTS: Of the 1577 patients in the trial, 901 patients (56.3%) (median age 75 years [IQR 65-84], 50.8% females, median NIHSS 14 [IQR 17-19]) with anterior circulation stroke were included. mRS 0-1 at 90d was achieved in 1/14 (0.3%), 43/160 (14.7%) and 252/726 (85.1%) in the ASPECTS 0-4, 5-7 and 8-10 groups respectively. Every 1-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in EVT treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P interaction 0.75). There was no significant interaction by thrombolytic type with any other outcome. CONCLUSIONS: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase.

Partial asynchrony of coniferous forest carbon sources and sinks at the intra-annual time scale.

As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels.

FInCH: FIJI plugin for automated and scalable whole-image analysis of protein expression and cell morphology.

Study of morphogenesis and its regulation requires analytical tools that enable simultaneous assessment of processes operating at cellular level, such as synthesis of transcription factors (TF), with their effects at the tissue scale. Most current studies conduct histological, cellular and immunochemical (IHC) analyses in separate steps, introducing inevitable biases in finding and alignment of areas of interest at vastly distinct scales of organization, as well as image distortion associated with image repositioning or file modifications. These problems are particularly severe for longitudinal analyses of growing structures that change size and shape. Here we introduce a python-based application for automated and complete whole-slide measurement of expression of multiple TFs and associated cellular morphology. The plugin collects data at customizable scale from the cell-level to the entire structure, records each data point with positional information, accounts for ontogenetic transformation of structures and variation in slide positioning with scalable grid, and includes a customizable file manager that outputs collected data in association with full details of image classification (e.g., ontogenetic stage, population, IHC assay). We demonstrate the utility and accuracy of this application by automated measurement of morphology and associated expression of eight TFs for more than six million cells recorded with full positional information in beak tissues across 12 developmental stages and 25 study populations of a wild passerine bird. Our script is freely available as an open-source Fiji plugin and can be applied to IHC slides from any imaging platforms and transcriptional factors.

Relationship between thermal stability of collagens and the fraction of hydrophobic residues in their molecules.

In this study, a database of the thermal stability of collagens and their synthetic analogues has been compiled taking into account literature sources. In total, our database includes 1200 records. As a result of a comparative theoretical analysis of the collected experimental data, the relationship between the melting temperature (Tm) or denaturation temperature (Td) of collagens and the fraction of hydrophobic residues (f) in their molecules has been established. It is shown that this relationship is linear: the larger the f value, the higher the denaturation or melting temperature of a given collagen.

Time-reflection of microwaves by a fast optically-controlled time-boundary.

When an electromagnetic (EM) wave propagates in a medium whose properties are varied abruptly in time, the wave experiences refractions and reflections known as time-refractions and time-reflections, both manifesting spectral translation as a consequence of the abrupt change of the medium and the conservation of momentum. However, while the time-refracted wave continues to propagate with the same wave-vector, the time-reflected wave propagates backward with a conjugate phase despite the lack of any spatial interface. Importantly, while time-refraction is always significant, observing time-reflection poses a major challenge - because it requires a large change in the medium occurring within a single cycle of the EM wave. For that reason, time-reflection of EM waves was observed only recently. Here, we present the observation of microwave pulses at the highest frequency ever observed (0.59 GHz), and the experimental evidence of the phase-conjugation nature of time-reflected waves. Our experiments are carried out in a periodically-loaded microstrip line with optically-controlled picosecond-switchable photodiodes. Our system paves the way to the experimental realization of Photonic Time-Crystals at GHz frequencies.

Assessing the prevalence of obesity in a Russian adult population by six indices and their associations with hypertension, diabetes mellitus and hypercholesterolaemia.

The anthropometric index that best predicts cardiometabolic risk remains inconclusive. This study therefore assessed the prevalence of obesity using six indices and compared their associations with obesity-related cardiometabolic disorders. We determined obesity prevalence according to body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio (WHtR), body fat percentage and fat mass index (FMI) using data from the Know Your Heart study (n = 4495, 35-69 years). The areas under the receiver operating characteristic curves (AUCs) provided predictive values of each index for detecting the presence of hypertension, hypercholesterolaemia and diabetes. Age-standardised obesity prevalence significantly varied according to anthropometric index: from 17.2% (FMI) to 75.8% (WHtR) among men and from 23.6% (FMI) to 65.0% (WHtR) among women. WHtR had the strongest association with hypertension (AUC = 0.784; p < 0.001) and with a combination of disorders (AUC = 0.779; p < 0.001) in women. In women, WHtR also had the largest AUCs for hypercholesterolaemia, in men - for hypertension, diabetes and a combination of disorders, although not all the differences from other obesity indices were significant. WHtR exhibited the closest association between hypertension and a combination of disorders in women and was non-inferior compared to other indices in men.

Meso-Macroporous Hydroxyapatite Powders Synthesized in Polyvinyl Alcohol or Polyvinylpyrrolidone Media.

Mesoporous hydroxyapatite (HA) is widely used in various applications, such as the biomedical field, as a catalytic, as a sensor, and many others. The aim of this work was to obtain HA powders by means of chemical precipitation in a medium containing a polymer-polyvinyl alcohol or polyvinylpyrrolidone (PVP)-with concentrations ranging from 0 to 10%. The HA powders were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, atomic emission spectroscopy with inductively coupled plasma, electron paramagnetic resonance, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The specific surface area (SSA), pore volume, and pore size distributions were determined by low-temperature nitrogen adsorption measurements, and the zeta potential was established. The formation of macropores in powder agglomerates was determined using SEM and TEM. The synthesis in 10% PVP increased the SSA from 101.3 to 158.0 m2/g, while the ripening for 7 days led to an increase from 112.3 to 195.8 m2/g, with the total pore volume rising from 0.37 to 0.71 cm3/g. These materials could be classified as meso-macroporous HA. Such materials can serve as the basis for various applications requiring improved textural properties and may lay the foundation for the creation of bulk 3D materials using a technique that allows for the preservation of their unique pore structure.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

Stereotactic Ablative Radiotherapy for Oligoprogressive Cancers: Results of the Randomized Phase II STOP Trial.

PURPOSE: This trial examined if patients with ≤5 sites of oligoprogression benefit from the addition of stereotactic ablative radiotherapy (SABR) to standard of care (SOC) systemic therapy. METHODS: We enrolled patients with 1-5 metastases progressing on systemic therapy, and after stratifying by type of systemic therapy (cytotoxic vs. non-cytotoxic), randomized 1:2 between continued SOC treatment vs. SABR to all progressing lesions plus SOC. The trial was initially limited to non-small cell lung cancer but was expanded to include all non-hematologic malignancies to meet accrual goals. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), lesional control, quality of life, adverse events (AEs), and duration of systemic therapy post-randomization. RESULTS: Ninety patients with 127 oligoprogressive metastases were enrolled across 8 Canadian institutions, with 59 randomized to SABR and 31 to SOC. Median age was 67 years and 39 (43%) were female. The most common primary sites were lung (44%), genitourinary (23%) and breast (13%). Protocol adherence in the SOC arm was suboptimal, with 11 patients (35%) either receiving high-dose/ablative therapies (conflicting with trial protocol) or withdrawing from the study. Median follow-up was 31 months. There was no difference in PFS between arms (median PFS 8.4 months in the SABR arm vs. 4.3 months in the SOC arm but curves cross and 2-year PFS was 9% vs. 24% respectively, p=0.91). Median OS was 31.2 months vs. 27.4 months, respectively (p=0.22). Lesional control was superior with SABR (70% vs. 38% respectively, p=0.0015). There were 2 (3.4%) grade 3 and no grade 4/5 AEs attributable to SABR. CONCLUSION: SABR was well-tolerated with superior lesional control but did not improve PFS or OS. Accrual to this study was difficult, and the results may have been impacted by an unwillingness to forgo ablative treatments on the SOC arm. (NCT02756793).

Laser fragmentation of amorphous and crystalline selenium of various morphologies and assessment of their antioxidant and protection properties.

Introduction: The process of laser-induced breakdown of amorphous and crystalline selenium nanoparticles (Se NPs) of various shapes during nanosecond laser fragmentation of aqueous colloidal solutions of nanoparticles with different concentrations has been studied. Methods: The methods of studying the characteristics of plasma and acoustic oscillations induced by optical breakdown are applied. The methods of assessing the concentration of hydrogen peroxide and hydroxyl radicals, the amount of long-lived reactive species of protein and 8-oxoguanine are applied. Results: It has been established that in the process of laser fragmentation of selenium nanoparticles at a wavelength of 532 nm, corresponding to the maximum absorption of selenium, the highest probability of breakdown, the number of plasma flashes, their luminosity and the amplitude of acoustic signals are achieved at concentrations of the order of 109 NPs/mL. It has been shown that the use of selenium nanoparticles of various shapes and structures leads to a change in the photoacoustic signal during laser-induced breakdown. When crystalline selenium nanoparticles are irradiated, the intensity of the photoacoustic response during breakdown turns out to be greater (1.5 times for flash luminosity and 3 times for acoustics) than when amorphous particles are irradiated at the same concentration. It has been shown that selenium nanoparticles exhibit significant antioxidant properties. Selenium nanoparticles effectively prevent the formation of reactive oxygen species (ROS) during water radiolysis, eliminate radiation-induced long-lived reactive species of protein, and reduce the radiation-chemical yield of a key marker of oxidative DNA damage - 8-oxoguanine. Discussion: In general, the intensity of processes occurring during laser fragmentation of amorphous and crystalline selenium nanoparticles differs significantly. The antioxidant properties are more pronounced in amorphous selenium nanoparticles compared to crystalline selenium nanoparticles.

Erratum: Nuclear Charge Radii of Silicon Isotopes [Phys. Rev. Lett. 132, 162502 (2024)].

This corrects the article DOI: 10.1103/PhysRevLett.132.162502.

Dual-Functional Implant Based on Gellan-Xanthan Hydrogel with Diopside, BMP-2 and Lysostaphin for Bone Defect Repair and Control of Staphylococcal Infection.

A new dual-functional implant based on gellan-xanthan hydrogel with calcium-magnesium silicate ceramic diopside and recombinant lysostaphin and bone morphogenetic protein 2 (BMP-2)-ray is developed. In this composite, BMP-2 is immobilized on microparticles of diopside while lysostaphin is mixed directly into the hydrogel, providing sustained release of BMP-2 to allow gradual bone formation and rapid release of lysostaphin to eliminate infection immediately after implantation. Introduction of diopside of up to 3% (w/v) has a negligible effect on the mechanical properties of the hydrogel but provides a high sorption capacity for BMP-2. The hydrogels show good biocompatibility and antibacterial activity. Lysostaphin released from the implants over a 3 h period efficiently kills planktonic cells and completely destroys 24 h pre-formed biofilms of Staphylococcus aureus. Furthermore, in vivo experiments in a mouse model of critically-sized cranial defects infected with S. aureus show a complete lack of osteogenesis when implants contain only BMP-2, whereas, in the presence of lysostaphin, complete closure of the defect with newly formed mineralized bone tissue is observed. Thus, the new implantable gellan-xanthan hydrogel with diopside and recombinant lysostaphin and BMP-2 shows both osteogenic and antibacterial properties and represents a promising material for the treatment and/or prevention of osteomyelitis after bone trauma.

Hemal sinus basal laminae contact sites: a possible route between gonadal lumen and myoepithelial cells in the gonad of the sea star Patiria pectinifera.

Sea stars are a group of marine invertebrates suitable for studying the hormonal regulation of reproduction and spawning. In spite of substantial progress in understanding how various substances such as 1-methyladenine act in their gonads, there are still many gaps concerning the fine details of their action. One such gap is how the gonadal wall contraction is induced. Recent literature data suggest that, upon 1-methyladenine stimulation, some cells within the gonadal lumen produce non-neuronal acetylcholine that, upon contact with the gonadal wall, induces contraction of myoepithelial cells. Our ultrastructural study of the gonads in the sea star Patiria pectinifera has shown, for the first time, that there are sites where the basal laminae bordering the hemal sinus directly contact one another and appear at this contact site as a single entity. These contact sites are often associated with hemidesmosome-like junctions that anchor male accessory cells or female follicle cells on one side of the site and myoepithelial cells on the opposite. We suggest that contraction-inducing substance is secreted from an accessory or follicle cell, passes through a basal lamina contact site, and on the opposite side of the contact site acts on a myoepithelial cell to induce its contraction.

Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss.

Autosomal dominant hearing loss is represented by a large number of genetically determined forms. Over 50 genes associated with dominant nonsyndromic hearing impairments were described. Pathogenic variants in the CEACAM16 gene lead to the development of DFNA4B hearing loss. Currently, 8 pathogenic variants in this gene have been described. The objective of this study was to study the audiological and molecular genetic characteristics of a large family with CEACAM16-associated autosomal dominant nonsyndromic hearing loss. A detailed anamnesis was collected, and a comprehensive audiological examination was performed for 21 family members. Genetic testing was performed, including whole-genome sequencing for the proband's son and Sanger sequence analysis for the proband and for all available family members. In a large Russian family, including 5 generations, an autosomal dominant type of slowly progressing nonsyndromic late-onset hearing loss was observed. Eleven family members suffer from hearing impairment, which starts with tinnitus and threshold increase at high frequencies, since the age of 5-20 years. Hearing loss slowly progresses with age in each person and is similar to age-related hearing loss. We have detected the novel likely pathogenic variant с.419С>T (p.(Thr140Ile)) in exon 3 of the CEACAM16 gene, which segregates with late-onset nonsyndromic hearing loss in this family. The clinical data obtained in the examined family correspond with the phenotype in previously described cases. In general, the study widened the mutation spectrum of the gene, allowing to carry out medical genetic counseling and to answer the questions about the hearing impairment prognosis for future generations.

Flow Activation Energy of High-Concentration Monoclonal Antibody Solutions and Protein-Protein Interactions Influenced by NaCl and Sucrose.

The solution viscosity and protein-protein interactions (PPIs) as a function of temperature (4-40 °C) were measured at a series of protein concentrations for a monoclonal antibody (mAb) with different formulation conditions, which include NaCl and sucrose. The flow activation energy (Eη) was extracted from the temperature dependence of solution viscosity using the Arrhenius equation. PPIs were quantified via the protein diffusion interaction parameter (kD) measured by dynamic light scattering, together with the osmotic second virial coefficient and the structure factor obtained through small-angle X-ray scattering. Both viscosity and PPIs were found to vary with the formulation conditions. Adding NaCl introduces an attractive interaction but leads to a significant reduction in the viscosity. However, adding sucrose enhances an overall repulsive effect and leads to a slight decrease in viscosity. Thus, the averaged (attractive or repulsive) PPI information is not a good indicator of viscosity at high protein concentrations for the mAb studied here. Instead, a correlation based on the temperature dependence of viscosity (i.e., Eη) and the temperature sensitivity in PPIs was observed for this specific mAb. When kD is more sensitive to the temperature variation, it corresponds to a larger value of Eη and thus a higher viscosity in concentrated protein solutions. When kD is less sensitive to temperature change, it corresponds to a smaller value of Eη and thus a lower viscosity at high protein concentrations. Rather than the absolute value of PPIs at a given temperature, our results show that the temperature sensitivity of PPIs may be a more useful metric for predicting issues with high viscosity of concentrated solutions. In addition, we also demonstrate that caution is required in choosing a proper protein concentration range to extract kD. In some excipient conditions studied here, the appropriate protein concentration range needs to be less than 4 mg/mL, remarkably lower than the typical concentration range used in the literature.

Characterization of bean common mosaic virus isolates infecting three leguminous bean crops from South and Southeast Asia.

Bean common mosaic virus (BCMV) is causing economically important diseases in leguminous crops worldwide. In this study, BCMV isolates from country bean (CB, Lablab purpureus), yard-long bean (YLB, Vigna unguiculata) and rajma bean (RB, Phaseolus vulgaris) collected from Bangladesh, Nepal and Cambodia were characterized. Samples tested positive for BCMV in serological assays were subjected to high-throughput sequencing to generate near full-length genome sequences. In pair-wise comparisons of the polyprotein open reading frame, thirteen BCMV isolates from Bangladesh, Cambodia, and Nepal showed sequence identity of 92.1 to 98.8% at the nucleotide and 94.2 to 99% at the amino acid level among themselves and with corresponding sequences of BCMV reported previously. In phylogenetic analyses using the global BCMV sequences, they segregated into five distinct lineages, with RB isolates from Nepal clustering with US1/NL1-clade of common bean isolates from different countries, YLB isolates aligning with blackeye cowpea strain sequences reported from China, and CB isolates from Nepal and Bangladesh clustering with soybean isolates from China. One YLB isolate from Nepal was identified as a putative recombinant. None of the BCMV sequences aligned with isolates representing the RU1 or PStV clades. In grow-out tests, seed samples from local markets showed 14.3 to 38.1% transmission efficiency rate of BCMV with CB seed lots and from 9.5% to 33.3% with YLB seed lots.

Redox-active polyoxovanadates as cofactors in the development of functional protein assemblies.

The interactions of polyoxovanadates (POVs) with proteins have increasingly attracted interest in recent years due to their potential biomedical applications. This is especially the case because of their redox and catalytic properties, which make them interesting for developing artificial metalloenzymes. Organic-inorganic hybrid hexavanadates in particular offer several advantages over all-inorganic POVs. However, they have been scarcely investigated in biological systems even though, as shown in this work, hybrid hexavanadates are highly stable in aqueous solutions up to relatively high pH. Therefore, a novel bis-biotinylated hexavanadate was synthesized and shown to selectively interact with two biotin-binding proteins, avidin and streptavidin. Bridging interactions between multiple proteins led to their self-assembly into supramolecular bio-inorganic hybrid systems that have potential as artificial enzymes with the hexavanadate core as a redox-active cofactor. Moreover, the structure and charge of the hexavanadate core were determined to enhance the binding affinity and slightly alter the secondary structure of the proteins, which affected the size and speed of formation of the assemblies. Hence, tuning the polyoxometalate (POM) core of hybrid POMs (HPOMs) with protein-binding ligands has been demonstrated to be a potential strategy for controlling the self-assembly process while also enabling the formation of novel POM-based biomaterials that could be of interest in biomedicine.

Direct Anterior Total Hip Arthroplasty with VELYS™ Hip Navigation.

We describe the technique of total hip arthroplasty via a direct anterior approach using the Depuy Synthes (Raynham, MA) VELYS™ Hip Navigation system This technique allows one to accurately set the acetabular component position as well as recreate leg length and offset to meet the goals of hip reconstruction in a precise and efficient manner.

Exploring the effects of urban network topologies on entropy trajectories of segregation.

Segregation is a threat to the aspirations of producing a cohesive society and modelling its dynamics can be done in order to help design preventative measures. This work explores the question of whether the network topologies of urban spaces can affect the pace at which populations can become segregated. The simulation dynamics employed augment the canonical Schelling model in such a way that it also captures the affinity for agents to prefer denser regions which also offer sufficient local homogeneity. It is shown that different networks synthetically generated and from real city maps can alter the rate of segregation. The results also show that using the entropy trace on the distribution of agent edge degree across all agents correlates with the segregation reinforcing the relevance of physics inspired modeling of social systems. This investigation shows that it is possible to explore and select network arrangements which can be less conducive towards segregation movements during the stages of urban planning so that the rate is reduced. An additional finding is that the entropic measure is closely associated with the common statistic for such modeling efforts.