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Nystagmus induced by applying an intense vibratory stimulus to the skull (SVIN) indicates vestibular functional asymmetry. In unilateral vestibular loss, a 100 Hz bone-conducted vibration given to either mastoid immediately causes a primarily horizontal nystagmus. The test is performed in darkness to avoid visual fixation (VF) but there are no data about how much VF affects the often-intense SVIN. The aim is to analyze the amount of reduction in SVIN when VF is allowed during testing. Thus, all patients seen in a tertiary hospital for vertigo or dizziness with positive SVIN were included. SVIN was recorded for 10 s for each condition: without VF (aSVINwo) and with VF (aSVINw). We obtained an aSVINwo and an aSVINw as average slow-phase velocities (SPV) without and with VF. VF index (FISVIN) was calculated as the ratio of SPV. Among the 124 patients included, spontaneous nystagmus (SN) was found in 25% and the median slow phase velocity (mSPV) (without VF) of SN was 2.6 ± 2.4°/s. Mean FISVIN was 0.27 ± 0.29. FISVIN was 0 in 42 patients, and FISVIN between 0 and 1 was found in 82 (mean FISVIN 0.39 ± 0.02). Fixation suppression was found in all patients with SVIN in cases of peripheral vestibulopathy. FISVIN clearly delineates two populations of patients: with or without a complete visual reduction in nystagmus.

Abstract The telecommunications of the future rely on the concept of a three-dimensional architecture able to integrate terrestrial and non-terrestrial networks with the goal to ensure a reliable and high-speed connectivity to users located anywhere. In this context, free space optical communications constitute a candidate technology for feeder links, thanks to their advantages in terms of bandwidth and achievable data rates. Nonetheless, due to the propagation impediments encountered by an optical beam travelling through atmosphere, flexible and accurate instruments able to support the design of optical feeder links are needed. Therefore, in this paper a link budget numerical tool able to meet these requirements is presented and the link budget analysis for real optical feeder links is performed demonstrating its prediction accuracy by means of the comparison with experimental results for both low Earth orbit and geostationary Earth orbit based configurations. Finally, the limits of the conventional beam wander model are analyzed and overcome.

Peer victimization is critical to study in early and middle childhood as it is associated with adjustment and behavioral problems in adolescence. Because much victimization occurs outside of the purview of adults, self-report measures are important assessments of this construct; however, there is limited evidence for the psychometric properties of the score interpretations of many measures. The goal of the current study was to replicate and extend previous work with the Social Experiences Questionnaire (SEQ; Crick and Grotpeter, Development and Psychopathology 8:367-380, 1996). Specifically, we explored the factor structure of the measure, investigated measurement invariance across gender, age and time, and examined evidence for criterion-related validity of the SEQ score interpretations. Participants were 558 children (49.2% girls; 50.7% boys) within the classrooms of 34 teachers (Kindergarten-5th grade). Children completed the SEQ, and children and teachers completed measures of social and academic functioning in the fall and spring of the school year. Confirmatory factor analysis revealed strong evidence for a two-factor solution (Factor 1: victimization; Factor 2: receipt of prosocial acts), with evidence of invariance across gender, age, and time. There was evidence of criterion-related validity across measures of social and academic functioning. Implications for our understanding of victimization and continued use of the SEQ are discussed.

BackgroundThe electrophysiological mechanism connecting mitral valve prolapse (MVP), premature ventricular complexes and life-threatening ventricular arrhythmia is unknown. A common hypothesis is that stretch activated channels (SACs) play a significant role. SACs can trigger depolarizations or shorten repolarization times in response to myocardial stretch. Through these mechanisms, pathological traction of the papillary muscle (PM), as has been observed in patients with MVP, may induce irregular electrical activity and result in reentrant arrhythmia.MethodsBased on a patient with MVP and mitral annulus disjunction, we modeled the effect of excessive PM traction in a detailed medical image-derived ventricular model by activating SACs in the PM insertion region. By systematically varying the onset of SAC activation following sinus pacing, we identified vulnerability windows for reentry with 1 ms resolution. We explored how reentry was affected by the SAC reversal potential (ESAC) and the size of the region with simulated stretch (SAC region). Finally, the effect of global or focal fibrosis, modeled as reduction in tissue conductivity or mesh splitting (fibrotic microstructure), was investigated.ResultsIn models with healthy tissue or fibrosis modeled solely as CV slowing, we observed two vulnerable periods of reentry: For ESAC of −10 and −30 mV, SAC activated during the T-wave could cause depolarization of the SAC region which lead to reentry. For ESAC of −40 and −70 mV, SAC activated during the QRS complex could result in early repolarization of the SAC region and subsequent reentry. In models with fibrotic microstructure in the SAC region, we observed micro-reentries and a larger variability in which times of SAC activation triggered reentry. In these models, 86% of reentries were triggered during the QRS complex or T-wave. We only observed reentry for sufficiently large SAC regions (>= 8 mm radius in models with healthy tissue).ConclusionStretch of the PM insertion region following sinus activation may initiate ventricular reentry in patients with MVP, with or without fibrosis. Depending on the SAC reversal potential and timing of stretch, reentry may be triggered by ectopy due to SAC-induced depolarizations or by early repolarization within the SAC region.

Engineered nanoparticles (NPs) pose a broad spectrum of interesting properties that make them useful for many applications. However, continuous exposure to NPs requires the need to deeply understand the outcomes when these NPs interact with different biological environments. After exposure within (to) these environments, the pristine surfaces of NPs strongly interact with the molecules from the surrounding medium, including metabolites, lipids, glycan, and proteins, forming the so-called protein corona (PC). It is well established that the NP-PC strongly influences the biological fate of various NPs types, including cellular uptake, toxicity, and biodistribution. Thus, for a proper assessment of potential hazards associated with engineered NPs, it is mandatory to study and evaluate the PC that forms around NPs. Herein, we describe protocols in detail for the isolation and characterization of NP-PC complexes and cover the following aspects: 1) isolation protocols for different nanomaterials in a range of exposing media, including magnetic isolation methods for superparamagnetic NPs, 2) NP physico-chemical characterization using advanced and standard techniques available in regular laboratories, and 3) NP- PC characterization of the protein and glycan components.

The new wide-bandgap power semiconductor devices, such as gallium nitride and silicon carbide, have encouraged the development of power electronic converters with better efficiency, higher switching frequency, and smaller packages. However, such fast power converters are characterized by steep pulse width modulation voltage waveforms that cause increased electrical stress on the insulation system of the electric machine windings, eventually leading to premature failure. This poses a serious problem for high-speed applications where high system reliability and safety are required. Therefore, this work aims to show the effects of electrical aging on the high-frequency characteristics of electrical machines and then to assess the damage caused to the windings of a motor by such steep PWM waveforms. Finally, using a high-frequency model of the machine windings, it is possible to identify the parameters that are most affected by electrical stresses and thus assess the aging status of the insulation system.

Objectives: Despite advances in understanding associations among attention-deficit hyperactivity disorder (ADHD), emotion dysregulation (ED), and related outcomes, there is incongruity between ADHD-relevant conceptualizations of ED and available measures of ED. To assess the psychometric properties of a parent-report questionnaire of ED conceptualized as deficits in the ability to modulate the (a) speed/degree of emotion escalation; (b) expression intensity; and (c) speed/degree of de-escalation. Methods: Participants were 209 adolescents with ADHD (78% male; 13.5-17.8 years old [M = 15.2 SD = 0.91]). Questionnaire items were selected from parent-report scales of ED and oppositional defiant disorder and subjected to exploratory factor analysis (EFA) and validity analyses. Results: The EFA revealed two factors, with speed/degree of escalation combined with intensity as factor one, and speed/degree of de-escalation as factor two. Factor one scores were related to ADHD impulsivity symptoms but not to anxiety and depression symptoms and they remained predictors of impulsivity even in the presence of self-report ED, evincing convergent, discriminant, and incremental validity. Factor two scores were related to anxiety and depression but not impulsivity, evincing convergent and discriminant validity. Conclusion: These results inform our understanding of ADHD-relevant ED in adolescence and offer avenues for future research in measurement development, as well as for understanding ED and ADHD-related impairment.

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.

Abstract Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.

Chemically modified small interfering RNAs (siRNAs) are promising therapeutics guiding sequence-specific silencing of disease genes. Identifying chemically modified siRNA sequences that effectively silence target genes remains challenging. Such determinations necessitate computational algorithms. Machine learning is a powerful predictive approach for tackling biological problems but typically requires datasets significantly larger than most available siRNA datasets. Here, we describe a framework applying machine learning to a small dataset (356 modified sequences) for siRNA efficacy prediction. To overcome noise and biological limitations in siRNA datasets, we apply a trichotomous, two-threshold, partitioning approach, producing several combinations of classification threshold pairs. We then test the effects of different thresholds on random forest machine learning model performance using a novel evaluation metric accounting for class imbalances. We identify thresholds yielding a model with high predictive power, outperforming a linear model generated from the same data, that was predictive upon experimental evaluation. Using a novel model feature extraction method, we observe target site base importances and base preferences consistent with our current understanding of the siRNA-mediated silencing mechanism, with the random forest providing higher resolution than the linear model. This framework applies to any classification challenge involving small biological datasets, providing an opportunity to develop high-performing design algorithms for oligonucleotide therapies.

Objectives. Ménière disease (MD) is an idiopathic disorder that affects hearing and inner ear balance. Intratympanic gentamicin (ITG) is recognized as an effective treatment for uncontrolled MD characterized by persistent vertigo attacks despite therapy. The video head impulse test (vHIT) and skull vibration-induced nystagmus (SVIN) are validated methods for evaluating vestibular function. A progressive linear relationship has been identified between the slow-phase velocity (SPV) of SVIN determined using a 100-Hz skull vibrator and the gain difference (healthy ear/affected ear) measured by vHIT. The aim of this study was to ascertain whether the SPV of SVIN was associated with the recovery of vestibular function following ITG treatment. Consequently, we sought to determine whether SVIN could predict the onset of new vertigo attacks in patients with MD who were treated with ITG. Methods. A prospective longitudinal case-control study was conducted. Several variables were recorded post-ITG and throughout the follow-up period, followed by statistical analyses. Two groups were compared: patients who experienced vertigo attacks 6 months after ITG and those who did not. Results. The sample comprised 88 patients diagnosed with MD who underwent ITG treatment. Of the 18 patients who experienced recurring vertigo attacks, 15 demonstrated gain recovery in the affected ear. However, all 18 patients exhibited a decrease in the SPV of SVIN. Conclusion. The SPV of SVIN may be more sensitive than vHIT in identifying the recovery of vestibular function following ITG administration. To our knowledge, this is the first study to illustrate the link between a reduction in SPV and the likelihood of vertigo episodes in patients with MD who have been treated with ITG.

Research has identified at least three patterns of direct involvement in bullying and victimization: bullying, bullying-victimized, and predominantly victimized. However, little is known about risk and protective factors for these patterns. As such, the goals of the present study were to establish these patterns and examine risk and protective factors. Participants were 775 middle school students in grades 5-8. Latent profile analysis revealed three groups: a bullying-victimized group (5.2%), a predominantly victimized group (8.9%), and an uninvolved group (85.9%). Emotion dysregulation and beliefs in support of aggression conferred risk for membership in the bullying-victimized group, whereas internalizing problems conferred risk for membership in the predominantly victimized group. One aspect of school culture -- willingness to seek help -- buffered risk for membership only in the bullying-victimized group. Given these differential patterns, researchers and practitioners may wish to further consider the utility of targeted interventions and treatments.

Cyclic tetrapyrrole derivatives such as porphyrins, chlorins, corrins (compounds with a corrin core), and phthalocyanines are a family of molecules containing four pyrrole rings usually coordinating a metal ion (Mg, Cu, Fe, Zn, etc.). Here, we report the characterization of some representative cyclic tetrapyrrole derivatives by MALDI-ToF/ToF MS analyses, including heme b and c, phthalocyanines, and protoporphyrins after proper matrix selection. Both neutral and acidic matrices were evaluated to assess potential demetallation, adduct formation, and fragmentation. While chlorophylls exhibited magnesium demetallation in acidic matrices, cyclic tetrapyrroles with Fe, Zn, Co, Cu, or Ni remained steadfast against demetallation across all conditions. Phthalocyanines and protoporphyrins were also detectable without a matrix using laser desorption ionization (LDI); however, the incorporation of matrices achieved the highest ionization yield, enhanced sensitivity, and negligible fragmentation. Three standard proteins, i.e., myoglobin, hemoglobin, and cytochrome c, were analyzed either intact or enzymatically digested, yielding heme b and heme c ions along with accompanying peptides. Furthermore, we successfully detected and characterized heme b in real samples, including blood, bovine and cod liver, and mussel. As a result, MALDI MS/MS emerged as a powerful tool for straightforward cyclic tetrapyrrole identification, even in highly complex samples. Our work paves the way for a more comprehensive understanding of cyclic tetrapyrroles in biological and industrial settings, including the geochemical field, as these compounds are a source of significant geological and geochemical information in sediments and crude oils.

The aim of this study was to objectively evaluate lameness in dogs affected by a unilateral cranial cruciate ligament rupture (CrCLR) treated with porous tibial tuberosity advancement before surgery and at three different timepoints after surgery, using the GAITRite® system (version 4.9Wr), a pressure-sensitive walkway system that is able to calculate several spatiotemporal gait parameters simultaneously for each limb. The dogs walked on the pressure-sensitive walkway before (T0) and 30 (T1), 90 (T2), and 120 (T3) days after surgery. Pressure measurements (gait lameness score and total pressure index %) were collected for S (treated with porous TTA) and C (healthy contralateral limb) at T0, T1, T2, and T3 and statistically evaluated. An ANOVA test was performed to compare the data, and a value of p < 0.05 was considered significant. Twenty dogs (n = 20) of various common breeds and ages with CrCLR were enrolled in the study. The results showed that there was a statistically significant difference in the GAIT4Dog® lameness score (GLS) and TPI% between S and C for each timepoint. Statistically significant differences in the GLS and TPI% between S at T0 and S at T2 and between S at T0 and S at T3 (p < 0.001) were found. The results showed that there was a statistically significant difference in the GAIT4Dog® lameness score (GLS) and TPI% between S and C for each timepoint. Statistically significant differences in the GLS and TPI% between S at T0 and S at T2 and between S at T0 and S at T3 were found. The GLS and TPI% increased statistically significantly from 90 days after surgery compared to the preoperative measurements. Moreover, comparing the GLS and TPI% between the treated limb and the control limb showed that a statistically significant difference remained at each timepoint.

Abstract Background The widespread use of nano-biomaterials (NBMs) has increased the chance of human exposure. Although ingestion is one of the major routes of exposure to NBMs, it is not thoroughly studied to date. NBMs are expected to be dramatically modified following the transit into the oral-gastric-intestinal (OGI) tract. How these transformations affect their interaction with intestinal cells is still poorly understood. NBMs of different chemical nature—lipid-surfactant nanoparticles (LSNPs), carbon nanoparticles (CNPs), surface modified Fe3O4 nanoparticles (FNPs) and hydroxyapatite nanoparticles (HNPs)—were treated in a simulated human digestive system (SHDS) and then characterised. The biological effects of SHDS-treated and untreated NBMs were evaluated on primary (HCoEpiC) and immortalised (Caco-2, HCT116) epithelial intestinal cells and on an intestinal barrier model. Results The application of the in vitro SDHS modified the biocompatibility of NBMs on gastrointestinal cells. The differences between SHDS-treated and untreated NBMs could be attributed to the irreversible modification of the NBMs in the SHDS. Aggregation was detected for all NBMs regardless of their chemical nature, while pH- or enzyme-mediated partial degradation was detected for hydroxyapatite or polymer-coated iron oxide nanoparticles and lipid nanoparticles, respectively. The formation of a bio-corona, which contains proteases, was also demonstrated on all the analysed NBMs. In viability assays, undifferentiated primary cells were more sensitive than immortalised cells to digested NBMs, but neither pristine nor treated NBMs affected the intestinal barrier viability and permeability. SHDS-treated NBMs up-regulated the tight junction genes (claudin 3 and 5, occludin, zonula occludens 1) in intestinal barrier, with different patterns between each NBM, and increase the expression of both pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-22, IL-10). Notably, none of these NBMs showed any significant genotoxic effect. Conclusions Overall, the results add a piece of evidence on the importance of applying validated in vitro SHDS models for the assessment of NBM intestinal toxicity/biocompatibility. We propose the association of chemical and microscopic characterization, SHDS and in vitro tests on both immortalised and primary cells as a robust screening pipeline useful to monitor the changes in the physico-chemical properties of ingested NBMs and their effects on intestinal cells.

Nanomaterials have a range of potential applications, however, toxicity remains a concern, limiting application and requiring extensive testing. Here, the authors report on a predictive framework made using a range of tests linking materials properties with toxicity, allowing the prediction of toxicity from physiochemical and biological properties.

Abstract Photoreduction of CO2 with sunlight to produce solar fuels, also named artificial photosynthesis, is considered one of the most attractive strategies to face the challenge of reducing greenhouse gases and achieving climate neutrality. Following an approach in line with the principles of the circular economy, the low-cost catalytic system (1) based on an industrial by-product such as steel slag was assessed, which was properly modified with nanostructured palladium on its surface in order to make it capable of promoting the conversion of CO2 into methanol and hydrogen through a two-stage process of photoreduction and thermal conversion having formic acid as the intermediate. Notably, for the first time in the literature steel slag is used as photoreduction catalyst.