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The contribution describes the legal phenomenon as a playing field characterized by a progressive regression of the law, understood as a sovereign will from top to bottom, both in the vision of formalist legal positivisms in continental Europe and in realist terms, in the United States. Soft law represents the main strategy to subordinate the law to the interests of the economy, elasticizing environmental law, making it favorable to the market, reducing ecology to the simplistic metric of CO2 emissions. The consequence is a retreat of the statist vertical normativity of law which is not replaced by a de facto power granted to those who control the technology, built by design to close spaces for pluralism and democratic action, in the interest of surveillance and concentrated power in private and government oligopolies. The author concludes by advocating the urgency for genuinely innovative categories, particularly in the legal education, such as the commons, capable of including sustainability into a "new ecological jurisprudence committed to inclusion and solidarity rather than exclusion and struggle". [ABSTRACT FROM AUTHOR]

Vanadium dioxide has attracted much interest due to the drastic change of the electrical and optical properties it exhibits during the transition from the semiconductor state to the metallic state, which takes place at a critical temperature of about 68 °C. Much study has been especially devoted to developing advanced fabrication methodologies to improve the performance of VO2 thin films for phase-change applications in optical devices. Films structural and morphological characterisation is normally performed with expensive and time consuming equipment, as x-ray diffractometers, electron microscopes and atomic force microscopes. Here we propose a purely optical approach which combines Polarized Raman Mapping and Phase-Transition by Continuous Wave Optical Excitation (PTCWE) to acquire through two simple measurements structural, morphological and thermal behaviour information on polycrystalline VO2 thin films. The combination of the two techniques allows to reconstruct a complete picture of the properties of the films in a fast and effective manner, and also to unveil an interesting stepped appearance of the hysteresis cycles probably induced by the progressive stabilization of rutile metallic domains embedded in the semiconducting monoclinic matrix. [ABSTRACT FROM AUTHOR]

Chirality, the lack of mirror symmetry, can be mimicked in nanophotonics and plasmonics by breaking the symmetry in light-nanostructure interaction. Here we report on versatile use of nanosphere lithography for the fabrication of low-cost metasurfaces, which exhibit broadband handedness- and angle-dependent extinction in the near-infrared range, thus offering extrinsic chiro-optical behavior. We measure wavelength and angle dependence of the extinction for four samples. Two samples are made of polystyrene nanospheres asymmetrically covered by silver and gold in one case and silver only in the other case, with a nanohole array at the bottom. The other two samples are nanohole arrays, obtained after the nanosphere removal from the first two samples. Rich extrinsic chiral features are governed by different chiro-optical mechanisms in the three-dimensional plasmonic semi-shells and planar nanohole arrays. We also measure Stokes parameters in the same wavelength and incidence angle range and show that the transmitted fields follow the extrinsic chirality features of the extinction dissymmetry. We further study the influences of the nanostructured shapes and in-plane orientations on the intrinsic vs extrinsic chirality. The nanoholes are modelled as oval shapes in metal, showing good agreement with the experiments. We thus confirm that nanosphere lithography can provide different geometries for chiral light manipulation at the nanoscale, with the possibility to extend functionalities with optimized oval shapes and combination of constituent metals. [ABSTRACT FROM AUTHOR]

Feature selection in clustering is a hard task which involves simultaneously the discovery of relevant clusters as well as relevant variables with respect to these clusters. While feature selection algorithms are often model-based through optimised model selection or strong assumptions on the data distribution, we introduce a discriminative clustering model trying to maximise a geometry-aware generalisation of the mutual information called GEMINI with a simple ℓ 1 penalty: the Sparse GEMINI. This algorithm avoids the burden of combinatorial feature subset exploration and is easily scalable to high-dimensional data and large amounts of samples while only designing a discriminative clustering model. We demonstrate the performances of Sparse GEMINI on synthetic datasets and large-scale datasets. Our results show that Sparse GEMINI is a competitive algorithm and has the ability to select relevant subsets of variables with respect to the clustering without using relevance criteria or prior hypotheses. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are a heterogenous group of rare neurodegenerative conditions sharing an autosomal dominant pattern of inheritance. More than 40 SCAs have been genetically determined. However, a systematic review of SCA epidemiology in Europe is still missing. Here we performed a narrative review of the literature on the epidemiology of the most common SCAs in Europe. PubMed, Embase, and MEDLINE were searched from inception until 1 April 2023. All English peer-reviewed articles published were considered and then filtered by abstract examination and subsequently by full text reading. A total of 917 original articles were retrieved. According to the inclusion criteria and after reviewing references for useful papers, a total of 35 articles were included in the review. Overall, SCA3 is the most frequent spinocerebellar ataxia in Europe. Its frequency is strikingly higher in Portugal, followed by Germany, France, and Netherlands. None or few cases were described in Italy, Russia, Poland, Serbia, Finland, and Norway. SCA1 and SCA2 globally displayed similar frequencies, and are more prevalent in Italy, United Kingdom, Poland, Serbia, and France. [ABSTRACT FROM AUTHOR]

Background: Intracranial aneurysm is a pathology related to the biomechanical deterioration of the arterial wall. As yet, there is no method capable of predicting rupture risk based on quantitative, in vivo mechanical data. This study is part of a large-scale project aimed at providing clinicians with a non-invasive, patient-specific decision support tool, based on the in vivo mechanical characterisation of the aneurysm wall. To this end, an original arterial wall deformation device was developed and tested on polymeric phantom arteries. Concurrently, a computational model coupled with the experimental study was developed to improve understanding of the interaction between the arterial wall deformation device and the aneurysm wall. Objective: An original procedure was implemented to validate the numerical model against experimental results. Methods: The deformation induced by the device on the polymeric phantom arteries is quantified by Digital Image Correlation. The Fluid-Structure Interaction between the device and the arterial wall was modelled numerically with the Finite Element method. The validation procedure encompasses the extraction and the interpolation of the numerical results. The computed strains were compared with the data measured experimentally. Results: The numerical results interpolated on the experimental reference image were associated with several deformation device locations. These configurations induced strains and displacements ranges that included the experimental results, which validates the proposed model. Conclusions: The reliability of the procedure was validated with various study cases and artery materials. The procedure could be extended to experimental studies involving more complex phantom arteries in terms of shape and wall heterogeneity. [ABSTRACT FROM AUTHOR]

Objectives: To assess the incidences of Herpes Simplex-1 and 2 (HSV-1, HSV-2), Cytomegalovirus (CMV), Epstein–Barr Virus (EBV) reactivations in critically ill COVID-19 patients. To determine the association between viral reactivation and in-hospital mortality, Intensive Care Unit Bloodstream infection (ICU–BSI), ventilator-associated pneumonia (VAP). Design: Observational retrospective cohort study. Setting: COVID-19 Intensive Care Unit. Patients: From November 2020 to May 2021, one hundred and twenty patients with COVID-19 severe pneumonia were enrolled and tested for HSV-1, HSV-2, CMV and EBV at the admission in ICU and weekly until discharge or death. The presence of VAP and ICU–BSI was evaluated according to clinical judgement and specific diagnostic criteria. Measurements and main results: One hundred and twenty patients were enrolled. Multiple reactivations occurred in 75/120 (63%) patients, single reactivation in 27/120 patients (23%). The most reactivated Herpesvirus was EBV, found in 78/120 (65%) patients. The multivariate analysis demonstrated that viral reactivation is a strong independent risk factor for in-hospital mortality (OR = 2.46, 95% CI 1.02–5.89), ICU–BSI (OR = 2.37, 95% CI 1.06–5.29) and VAP (OR = 2.64, 95% CI 1.20–5.82). Conclusions: Human Herpesviruses reactivations in critically ill patients with COVID-19 severe Pneumonia are associated with mortality and with a higher risk to develop both VAP and ICU–BSI. Key points: Question: The impact of Human Herpesviruses reactivations on the morbidity and mortality of COVID-19 critically ill patients is controversial. Findings: Critically ill patients with COVID-19 are at high risk for both EBV, HSV and CMV reactivations. Meanings: Further large prospective studies will be necessary to clarify if the presence of active viral replication must be considered causal agent affecting mortality or the indirect manifestation of immune paralysis in the worst patients. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options1. No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years1. Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB2FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB2FGC as a tractable target for antimicrobial drug development.A tethered macrocyclic peptide antibiotic class described here—which shows potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii—blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane through inhibition of the LptB2FGC complex. [ABSTRACT FROM AUTHOR]

Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet1. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics2–6. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens. [ABSTRACT FROM AUTHOR]

Purpose: Although targeted biopsies (TBx) are associated with improved disease assessment, concerns have been raised regarding the risk of prostate cancer (PCa) overgrading due to more accurate biopsy core deployment in the index lesion. Methods: We identified 1672 patients treated with radical prostatectomy (RP) with a positive mpMRI and ISUP ≥ 2 PCa detected via systematic biopsy (SBx) plus TBx. We compared downgrading rates at RP (ISUP 4–5, 3, and 2 at biopsy, to a lower ISUP) for PCa detected via SBx only (group 1), via TBx only (group 2), and eventually for PCa detected with the same ISUP 2–5 at both SBx and TBx (group 3), using multivariable logistic regression models (MVA). Results: Overall, 12 vs 14 vs 6% (n = 176 vs 227 vs 96) downgrading rates were recorded in group 1 vs group 2 vs group 3, respectively (p < 0.001). At MVA, group 2 was more likely to be downgraded (OR 1.26, p = 0.04), as compared to group 1. Conversely, group 3 was less likely to be downgraded at RP (OR 0.42, p < 0.001). Conclusions: Downgrading rates are highest when PCa is present in TBx only and, especially when the highest grade PCa is diagnosed by TBx cores only. Conversely, downgrading rates are lowest when PCa is identified with the same ISUP through both SBx and TBx. The presence of clinically significant disease at SBx + TBx may indicate a more reliable assessment of the disease at the time of biopsy potentially reducing the risk of downgrading at final pathology. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are well known for their beneficial effects, differentiation capacity and regenerative potential. Dental-derived MSCs (DSCs) are more easily accessible and have a non-invasive isolation method rather than MSCs isolated from other sources (umbilical cord, bone marrow, and adipose tissue). In addition, DSCs appear to have a relevant neuro-regenerative potential due to their neural crest origin. However, it is now known that the beneficial effects of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules (neurotrophic factors) released in the conditioned medium (CM) or in the extracellular vesicles (EVs) in particular exosomes (Exos). In this review, we described the similarities and differences between various DSCs. Our focus was on the secretome of DSCs and their applications in cell therapy for neurological disorders. For neuro-regenerative purposes, the secretome of different DSCs has been tested. Among these, the secretome of dental pulp stem cells and stem cells from human exfoliated deciduous teeth have been the most widely studied. Both CM and Exos obtained from DSCs have been shown to promote neurite outgrowth and neuroprotective effects as well as their combination with scaffold materials (to improve their functional integration in the tissue). For these reasons, the secretome obtained from DSCs in combination with scaffold materials may represent a promising tissue engineering approach for neuroprotective and neuro-regenerative treatments. [ABSTRACT FROM AUTHOR]

Long-read sequencing allows analyses of single nucleic-acid molecules and produces sequences in the order of tens to hundreds kilobases. Its application to whole-genome analyses allows identification of complex genomic structural-variants (SVs) with unprecedented resolution. SV identification, however, requires complex computational methods, based on either read-depth or intra- and inter-alignment signatures approaches, which are limited by size or type of SVs. Moreover, most currently available tools only detect germline variants, thus requiring separate computation of sample pairs for comparative analyses. To overcome these limits, we developed a novel tool (Germline And SOmatic structuraL varIants detectioN and gEnotyping; GASOLINE) that groups SV signatures using a sophisticated clustering procedure based on a modified reciprocal overlap criterion, and is designed to identify germline SVs, from single samples, and somatic SVs from paired test and control samples. GASOLINE is a collection of Perl, R and Fortran codes, it analyzes aligned data in BAM format and produces VCF files with statistically significant somatic SVs. Germline or somatic analysis of 30 × sequencing coverage experiments requires 4–5 h with 20 threads. GASOLINE outperformed currently available methods in the detection of both germline and somatic SVs in synthetic and real long-reads datasets. Notably, when applied on a pair of metastatic melanoma and matched-normal sample, GASOLINE identified five genuine somatic SVs that were missed using five different sequencing technologies and state-of-the art SV calling approaches. Thus, GASOLINE identifies germline and somatic SVs with unprecedented accuracy and resolution, outperforming currently available state-of-the-art WGS long-reads computational methods. [ABSTRACT FROM AUTHOR]

Intracranial aneurysm is a life-threatening pathology related to the arterial wall alteration. As yet there is no method capable of predicting rupture risk based on quantitative in vivo mechanical data. This work is part of a large-scale project aimed at providing clinicians with a non-invasive patient-specific decision support tool, based on the in vivo mechanical characterisation of the aneurysm wall. First, an original wall deformation device was developed on polymeric phantom arteries. These artery models were obtained by 3D printing and an injection moulding process, each one showing pros and cons of designs of a biofidelic phantom in terms of thickness and local stiffness. A numerical modelling of this experimental study was built as a support for designing phantoms as design process choices and determining the geometrical and mechanical parameters of arteries. A numerical Fluid–Structure Interaction model based on the finite element method was developed. Several wall thicknesses, mechanical properties and deformation device locations were considered. Regarding the 3D printed phantom artery, the numerical model demonstrated that a thin wall thickness should be emphasised instead of a low Young’s modulus to reach a significant and experimentally observable strain. Regarding the injection moulded phantom, the results pointed to a locally reduced aneurysm thickness with a Young’s modulus of 0.7 MPa for the strain analysis. The numerical study provided helpful information regarding the scientific challenges of the experimental study. This work is the keystone of further animal studies and associated patient-specific models.Article highlights: A numerical model of an aneurysm mechanical characterisation device was validated versus Digital Image Correlation results. The local assessment of the polymeric aneurysm wall thickness is not prohibitive for a strain study. Uncertainties related to the locations of an original aneurysm mechanical characterisation device were quantified. [ABSTRACT FROM AUTHOR]

It has been shown that a reciprocal relationship between cancer patients and their family caregivers positively decreases distress in both. In this context we tried to explore the role of relationship reciprocity in the dyad members' symptoms of fatigue and distress (anxiety and depression). Specifically, we aimed to assess the implications of relationship reciprocity testing the link between the various measurements of patient Quality of Life (QoL) and caregiver burden and the other measures of fatigue, distress, and relationship reciprocity. Moreover we aimed to examine the inter-relatedness of patients' and caregivers' relationship reciprocity with their own as well as fatigue and distress of the dyads. A convenience sample of 545 adult cancer patients and their caregivers from 15 cancer centers were examined using a cross-sectional design. Participants were administered dyadic measures (fatigue, distress, relationship reciprocity) and individual measures (patients' QoL and caregivers' burden). Patients' QoL and caregivers' Burden were associated with fatigue, distress and relationship reciprocity. The Actor-Partner Interdependence Model (APIM) revealed that each person's relationship reciprocity was associated with their own distress and fatigue (actor effects); only caregivers' relationship reciprocity was associated with patients' fatigue and distress (partner effects). These findings suggest that the implication of the caregiving relationship for fatigue symptoms in both - patients and caregivers - appears worth of investigation. [ABSTRACT FROM AUTHOR]

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2–4. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1–2 kJ mol−1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control5.Accuracy of free-energy calculations can be improved by constructing an experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate and anhydrate crystal structures on the same energy landscape. [ABSTRACT FROM AUTHOR]

The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the role of intraoperative transvaginal three-dimensional ultrasound (3DUS) during hysteroscopic metroplasty. This is a prospective cohort of consecutive patients with septate uterus undergoing hysteroscopic metroplasty with intraoperative transvaginal 3DUS guidance compared to a historical control group of patients undergoing hysteroscopic metroplasty without 3DUS. We conducted our research in a tertiary care university hospital in Rome, Italy. This study involved nineteen patients undergoing 3DUS-guided hysteroscopic metroplasty for recurrent abortion or infertility compared to 19 age-matched controls undergoing metroplasty without 3DUS guidance. During hysteroscopic metroplasty, 3DUS was performed in the study group when the operator considered the procedure to be completed, according to standards of operative hysteroscopy. If 3DUS diagnosed a residual septum, the procedure was continued until a 3DUS diagnosis of a normal fundus was obtained. The patients were followed with a 3DUS performed 3 months after the procedure. The numbers of complete resections (residual septum absent), suboptimal resections (measurable residual septum of less than 10 mm), and incomplete resections (residual septum > 10 mm) in the intraoperative 3DUS group were compared to the numbers in the control group with no intraoperative 3DUS. At follow-up, measurable residual septa were obtained in 0% of the patients in the 3DUS-guided group versus 26% in the control group (p = 0.04). Residual septa of > 10 mm were obtained in 0% of the 3DUS group versus 10.5% in the control group (p = 0.48). Intraoperative 3DUS reduces the incidence of suboptimal septal resections at hysteroscopic metroplasty. [ABSTRACT FROM AUTHOR]

Background: Given that the pathogenetic process of ALS begins many years prior to its clinical onset, examining patients' residential histories may offer insights on the disease risk factors. Here, we analyzed the spatial distribution of a large ALS cohort in the 50 years preceding the disease onset. Methods: Data from the PARALS register were used. A spatial cluster analysis was performed at the time of disease onset and at 1-year intervals up to 50 years prior to that. Results: A total of 1124 patients were included. The analysis revealed a higher-incidence cluster in a large area (435,000 inhabitants) west of Turin. From 9 to 2 years before their onset, 105 cases were expected and 150 were observed, resulting in a relative risk of 1.49 (P = 0.04). We also found a surprising high number of patients pairs (51) and trios (3) who lived in the same dwelling while not being related. Noticeably, these occurrences were not observed in large dwellings as we would have expected. The probability of this occurring in smaller buildings only by chance was very low (P = 0.01 and P = 0.04 for pairs and trios, respectively). Conclusions: We identified a higher-incidence ALS cluster in the years preceding the disease onset. The cluster area being densely populated, many exposures could have contributed to the high incidence ALS cluster, while we could not find a shared exposure among the dwellings where multiple patients had lived. However, these findings support that exogenous factors are likely involved in the ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Da Vinci three-dimensional (3D) system has been increasingly used in customary surgical settings, gaining fundamental relevance for abdominal, urological, and gynecological laparoscopic surgery. The aim of this research is to evaluate the degree of discomfort and potential changes in the binocular vision and ocular motility of surgical operators, who employ 3D vision systems during Da Vinci robotic surgery. Twenty-four surgeons were enrolled in the study, including twelve who typically use the 3D Da Vinci system and twelve who routinely employ 2D system. Routine general ophthalmological and orthoptic examinations were conducted at baseline (T0), the day before surgery, and 30 min after the 3D or 2D surgery (T1). In addition, surgeons were interviewed using a questionnaire of 18 symptoms, with each item containing three questions regarding the frequency, severity, and bothersomeness of the symptoms, in order to evaluate the degree of discomfort. Mean age at evaluation was 45.28 ± 8.71 years (range 33–63 years). Cover test, uncover test, and fusional amplitude showed no statistically significant difference. After surgery, no statistical difference was observed in the Da Vinci group on the TNO stereotest (p > 0.9999). However, the difference in the 2D group resulted statistically significant (p = 0.0156). Comparing participants (p 0.0001) and time (T0–T1; p = 0.0137), the difference between the two groups was statistically significant. Surgeons using 2D systems reported more discomfort than those using 3D systems. The absence of short-term consequences following surgery with the Da Vinci 3D system is a promising conclusion, considering the numerous advantages of this technology. Nonetheless, multicenter investigations and more studies are required to verify and interpret our findings. [ABSTRACT FROM AUTHOR]

The special issue on Advanced Statistical Modeling and Causal Inference with Complex data for Better Decision Making has been inspired by the developments of innovative models and methods to answer challenging substantive questions and support policy choices and decisions. It includes a selection of twelve papers with cutting-edge methodological developments motivated by unique applications with challenging data structures from various fields of science. [ABSTRACT FROM AUTHOR]

Abstract Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF‐1 and SRSF‐5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of LmnaG609G/G609G mice locally reduces SRSF‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS.

Background: Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method: The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results: The patients included (n = 602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock (n = 250, 41.5%), decompensated heart failure (n = 127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment (n = 86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation (n = 82, 13.6%). They received 0.18 ± 0.07 µg/kg/min levosimendan over 26 ± 8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions: We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied. [ABSTRACT FROM AUTHOR]

Understanding the impacts of pasture recovery on soil organic matter accumulation processes is extremely important. For this reason, the quantitative analyses of organic matter are tools capable of evaluating the alteration of the different managements on the processes of formation and maintenance of pastures. The objective of this research was to compare the levels, stocks, and isotopic abundance of carbon and nitrogen in pastures with different years of recovery and secondary forest in eastern Amazon. The following managements were evaluated: secondary forest (SF), perennial pasture (PP), perennial pasture recovered 5 years ago by the intercropping of Corn + Brachiaria brizantha cv. Marandu (ICL5) and recovered 8 years ago by the Corn + Brachiaria brizantha cv. Marandu (ICL8). Contents and stocks of total carbon (C) and nitrogen (T), and abundance of δ13C and δ15N isotopes in different layers were determined. In the ICL8 area, the highest levels of total C and N were observed. The highest levels of total C and N alongside profile were observed in ICL8 treatment. In ICL8 and PP treatments, highest values of C and N were observed when compared to secondary forest. By the natural abundance of δ13C, it was possible to observe the highest enrichment in the PP area, ICL5 and ICL8 intermediate behavior, while in the SF the lowest enrichment. There were no significant differences for δ15N. The longer recovery time of pastures provided increases in the contents and stocks of C and N in the soil and were able to preserve the stable isotopes of 13C derived from C3 plants in the soil. [ABSTRACT FROM AUTHOR]

Tokamaks are the most promising devices to prove the feasibility of energy production using nuclear fusion on Earth which is foreseen as a possible source of energy for the next centuries. In large tokamaks with superconducting poloidal field (PF) coils, the problem of avoiding saturation of the currents is of paramount importance, especially for a reactor such as the European demonstration fusion power plant DEMO. Indeed, reaching the current limits during plasma operation may cause a loss of control of the plasma shape and/or current, leading to a major disruption. Therefore, a current limit avoidance (CLA) system is essential to assure safe operation. Three different algorithms to be implemented within a CLA system are proposed in this paper: two are based on online solutions of constrained optimization problems, while the third one relies on dynamic allocation. The performance assessment for all the proposed solutions is carried out by considering challenging operation scenarios for the DEMO reactor, such as the case where more than one PF current simultaneously saturates during the discharge. An evaluation of the computational burden needed to solve the allocation problem for the various proposed alternatives is also presented, which shows the compliance of the optimization-based approaches with the envisaged deadlines for real-time implementation of the DEMO plasma magnetic control system. [ABSTRACT FROM AUTHOR]

Purpose: Tau/MAPT (microtubule associated protein tau) protein is actively studied for the pathologic consequences of its aberrant proteostasis in central nervous system leading to neurodegenerative diseases. Besides its ability to generate insoluble toxic oligomers, Tau homeostasis has attracted attention for its involvement in the formation of the mitotic spindle. This evidence, in association with the description of Tau expression in extra-neuronal tissues, and mainly in cancer tissues, constitutes the rationale for a more in-depth investigation of Tau role also in neoplastic diseases. Methods: In our study, we investigated the expression of phosphorylated Tau in prostate cancer cell lines with particular focus on the residue Thr231 present in microtubule binding domain. Results: The analysis of prostate cancer cells synchronized with nocodazole demonstrated that the expression of Tau protein phosphorylated at residue Thr231 is restricted to G2/M cell cycle phase. The phosphorylated form was unable to bind tubulin and it does not localize on mitotic spindle. As demonstrated by the use of specific inhibitors, the phosphorylation status of Tau is under the direct control of cdk5 and PP2A, while cdk1 activation was able to exert an indirect control. These mechanisms were also active in cells treated with docetaxel, where counteracting the expression of the dephosphorylated form, by kinase inhibition or protein silencing, determined resistance to drug toxicity. Conclusions: We hypothesize that phosphorylation status of Tau is a key marker for G2/M phase in prostate cancer cells and that the forced modulation of Tau phosphorylation can interfere with the capacity of cell to efficiently progress through G2/M phase. [ABSTRACT FROM AUTHOR]

Purpose: Although enthesitis is a hallmark of several rheumatologic conditions, current imaging methods are still unable to characterize entheses changes because of the corresponding short transverse relaxation times (T2). A growing number of MR studies have used Ultra-High Field (UHF) MRI in order to assess low-T2 tissues e.g., tendon but never in humans. The purpose of the present study was to assess in vivo the enthesis of the quadriceps tendon in healthy subjects using UHF MRI. Methods: Eleven healthy subjects volunteered in an osteoarthritis imaging study. The inclusion criteria were: no knee trauma, Lequesne index = 0, less than 3 h of sport activities per week, and Kellgren and Lawrence grade = 0. 3D MR images were acquired at 7 T using GRE sequences and a T2* mapping. Regions of interest i.e., trabecular bone, subchondral bone, enthesis, and tendon body were identified, and T2* values were quantified and compared. Results: Quadriceps tendon enthesis was visible as a hyper-intense signal. The largest and the lowest T2* values were quantified in the subchondral bone region and the tendon body respectively. T2* value within subchondral bone was significantly higher than T2* value within the enthesis. T2* in subchondral bone region was significantly higher than the whole tendon body T2*. Conclusion: A T2* gradient was observed along the axis from the enthesis toward the tendon body. It illustrates different water biophysical properties. These results provide normative values which could be used in the field of inflammatory rheumatologic diseases and mechanical disorders affecting the tendon. [ABSTRACT FROM AUTHOR]

Modelling the response of seismic wavefields to sharp lateral variations in crustal discontinuities is essential for seismic tomography application and path effects correction in earthquake source characterization. This is particularly relevant when wavefields cross back-arc oceanic basins, i.e. mixed continental-oceanic settings. High-frequency (>0.05 Hz) seismic waves resonate and get absorbed across these settings due to a shallow Moho, crustal heterogeneities, and energy leakage. Here, we provide the first high-frequency wave-equation model of full seismograms propagating through realistic 3D back-arc basins. Inversion by parameters trial based on correlation analyses identifies P-, S- and coda-wave as attributes able to estimate jointly 3D Moho variations, sediment thickness, and earthquake source characteristics using data from a single regional earthquake. We use as data waveforms produced by the Accumoli earthquake (Central Italy, 2016), propagating across the Southern Tyrrhenian basin and recorded across Southern Italy. The best model comprises a deep Moho (∼ 18 km) in the middle of the basin and a crustal pinch with the continental crust in Sicily. The deep Moho corresponds to the Issel Bridge, a portion of continental crust trapped between the Vavilov and Marsili volcanic centres. The Accumoli earthquake is optimally described at a depth of 7.3 km using a boxcar with rise time of 6 s. Our results show that the early S-wave coda comprises trapped and reverberating phases sensitive to crustal interfaces. Forward modelling these waves is computationally expensive; however, adding these attributes to tomographic procedures allows modelling both source and structural parameters across oceanic basins. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the microvasculature of the macula and the optic nerve in patients affected by migraine with aura (MA) and without aura (MO) by optical coherence tomography angiography (OCTA), comparing the findings with healthy controls (HC). Methods: We collected data from ocular and orthotic examinations, including eye motility, intraocular pressure measurement, best-corrected visual acuity (BCVA) measurement, objective refraction measurement, fundus examination, macular and optic disk OCTA examination. All subjects were imaged with solix fullrange OCT. The following OCTA parameters were recorded: macular vessel density (VD), inside disc VD, peripapillary VD, disc whole image VD, fovea choriocapillaris VD, fovea VD, parafovea VD, peripapillary thickness, fovea thickness, parafovea thickness, macular full retinal thickness, and foveal avascular zone (FAZ) parameters. Clinical and demographical data about migraine patients were collected by a neurologist. Results: We included 56 eyes from 28 patients with a diagnosis of MO, 32 eyes from 16 patients with a diagnosis of MA, and 32 eyes from 16 HC subjects. The FAZ area was 0.230 ± 0.099 mm2 in the MO group, 0.248 ± 0.091 mm2 in the MA group and 0.184 ± 0.061 mm2 in the control group. The FAZ area was significantly larger in the MA group than in the HC group (p = 0.007). The foveal choriocapillaris VD was significantly lower in MA patients (63.6 ± 2.49%) when compared with MO patients (65.27 ± 3.29%) (p = 0.02). Conclusion: An impairment of retinal microcirculation can be detected in patients with MA, as demonstrated by the enlargement of FAZ. Moreover, the study of choroid circulation may reveal microvascular damage in patients with migraine with aura. OCTA is a useful non-invasive screening tool for the detection of microcirculatory disturbance in patients with migraine. [ABSTRACT FROM AUTHOR]

A multiscale mathematical model describing the metals biosorption on algal–bacterial photogranules within a sequencing batch reactor (SBR) is presented. The model is based on systems of partial differential equations (PDEs) derived from mass conservation principles on a spherical free boundary domain with radial symmetry. Hyperbolic PDEs account for the dynamics of sessile species and their free sorption sites, where metals are adsorbed. Parabolic PDEs govern the diffusion, conversion and adsorption of nutrients and metals. The dual effect of metals on photogranule ecology is also modelled: metal stimulates the production of EPS by sessile species and negatively affects the metabolic activities of microbial species. Accordingly, a stimulation term for EPS production and an inhibition term for metal are included in all microbial kinetics. The formation and evolution of the granule domain are governed by an ordinary differential equation with a vanishing initial value, accounting for microbial growth, attachment and detachment phenomena. The model is completed with systems of impulsive differential equations describing the evolution of dissolved substrates, metals, and planktonic and detached biomasses within the granular-based SBR. The model is integrated numerically to examine the role of the microbial species and EPS in the adsorption process, and the effect of metal concentration and adsorption properties of biofilm components on the metal removal. Numerical results show an accurate description of the photogranules evolution and ecology and confirm the applicability of algal–bacterial photogranule technology for metal-rich wastewater treatment. [ABSTRACT FROM AUTHOR]

Plasmonic nanostructured materials made of nanohole arrays in metal are significant plasmonic devices exhibiting resonances and strong electromagnetic confinement in the visible and near-infrared range. As such, they have been proposed for use in many applications such as biosensing and communications. In this work, we introduce the asymmetry in nanoholes, and investigate its influence on the electromagnetic response by means of broadband experimental characterization and numerical simulations. As a low-cost fabrication process, we use nanosphere lithography, combined with tilted silver evaporation, to obtain a 2D hexagonal array of asymmetric nanoholes in Ag. Our experimental set-up is based on a laser, widely tunable in the near-infrared range, with precise polarization control in the input and in the output. We next resolve the circular polarization degree of the transmitted light when the nanohole array is excited with linear polarization. We attribute the disbalance of left and right transmitted light to the asymmetry of the nanohole, which we support by numerical simulations. We believe that the optimization of such simple plasmonic geometry could lead to multifunctional flat-optic devices. [ABSTRACT FROM AUTHOR]

Background: In-office laryngological procedures became common alternatives to general anesthesia for biopsies, injection laryngoplasties, and laser procedures. The limiting step remains the laryngeal anesthesia whose quality can influence patients' and operators' comfort. Methods: We propose to dye the lidocaine with methylene blue and do an instillation through a catheter introduced in the video-endoscope's operating channel, which permits a progressive anesthesia focused on the larynx, avoiding an unwanted pharyngeal anesthesia and any tracheal irritation. Conclusion: Using blue-dyed lidocaine can help reduce the volume of anesthesia required for an office-based laryngology intervention, improving patients' and surgeon's comfort and reducing anesthesia's side effects. [ABSTRACT FROM AUTHOR]

Introduction: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumour of indeterminate malignant potential. The mainstay treatment for DFSP is surgical resection. Given the reported high local recurrence rate, the ideal resection margin for DFSP is unclear. The purpose of this study was to ascertain the local recurrence and metastatic rate of DFSP and DFSP with fibrosarcomatous degeneration (FS-DFSP), with specific attention to margin status in an attempt to address the issue of margin adequacy. Methods: Patients treated for DFSP at a single sarcoma centre were identified from a prospective database. DFSP and FS-DFSP patients with and without prior surgery were included. Patients were followed after surgery to monitor complications, local recurrence and metastasis. Results: The study included 200 patients: 166 patients with DFSP and 34 patients with FS-DFSP. In the DFSP group, nine patients (5.4%) had positive margins, one case (0.6%) developed local recurrence (LR) and no patients developed distant metastases. In the FS-DFSP group, seven patients (20.6%) had positive margins, six patients (17.6%) developed local recurrence (LR) and eight patients (23.5%) developed distant metastases, of which three (37.5%) were in the lungs, one (12.5%) in bone and four (50%) in other soft tissue sites. Discussion and Conclusion: Local recurrence and metastases are extremely rare in patients with DFSP. Achieving a negative as opposed to a wide surgical margin may be sufficient to avoid local recurrence of most DFSP. We suggest that no ongoing surveillance for local or systemic relapse is required for DFSP patients after negative margin resection. For FS-DFSP, we recommend the same surveillance schedule, based on tumour grade, as other soft tissue sarcoma. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation at CpG dinucleotides is a cancer hallmark that is associated with the emergence of resistance to anti cancer treatment, though molecular mechanisms and biological significance remain elusive. Genome scale methylation maps by currently used methods are based on chemical modification of DNA and are best suited for analyses of methylation at CpG rich regions (CpG islands). We report the first high coverage whole-genome map in cancer using the long read nanopore technology, which allows simultaneous DNA-sequence and -methylation analyses on native DNA. We analyzed clonal epigenomic/genomic evolution in Acute Myeloid Leukemias (AMLs) at diagnosis and relapse, after chemotherapy. Long read sequencing coupled to a novel computational method allowed definition of differential methylation at unprecedented resolution, and showed that the relapse methylome is characterized by hypermethylation at both CpG islands and sparse CpGs regions. Most differentially methylated genes, however, were not differentially expressed nor enriched for chemoresistance genes. A small fraction of under-expressed and hyper-methylated genes at sparse CpGs, in the gene body, was significantly enriched in transcription factors (TFs). Remarkably, these few TFs supported large gene-regulatory networks including 50% of all differentially expressed genes in the relapsed AMLs and highly-enriched in chemoresistance genes. Notably, hypermethylated regions at sparse CpGs were poorly conserved in the relapsed AMLs, under-represented at their genomic positions and showed higher methylation entropy, as compared to CpG islands. Analyses of available datasets confirmed TF binding to their target genes and conservation of the same gene-regulatory networks in large patient cohorts. Relapsed AMLs carried few patient specific structural variants and DNA mutations, apparently not involved in drug resistance. Thus, drug resistance in AMLs can be mainly ascribed to the selection of random epigenetic alterations at sparse CpGs of a few transcription factors, which then induce reprogramming of the relapsing phenotype, independently of clonal genomic evolution. DNA methylation patterns from Acute Myeloid Leukemia patients highlight sparse CpG regions as drivers for chemoresistance. [ABSTRACT FROM AUTHOR]

Noninvasive estimation of joint loads is still an open challenge in biomechanics. Although musculoskeletal modeling represents a solid resource, multiple improvements are still necessary to obtain accurate predictions of joint loads and to translate such potential into practical utility. The present study, focused on the hip joint, is aimed at reviewing the state-of-the-art literature on the estimation of hip joint reaction forces through musculoskeletal modeling. Our literature inspection, based on well-defined selection criteria, returned seventeen works, which were compared in terms of methods and results. Deviations between predicted and in vivo measured hip joint loads, taken from the OrthoLoad database, were assessed through quantitative deviation indices. Despite the numerous modeling and computational improvements made over the last two decades, predicted hip joint loads still deviate from their experimental counterparts and typically overestimate them. Several critical aspects have emerged that affect muscle force estimation, hence joint loads. Among them, the physical fidelity of the musculoskeletal model, with its parameters and geometry, plays a crucial role. Also, predicted joint loads are markedly affected by the selected muscle recruitment strategy, which reflects the underlying motor control policy. Practical guidelines for researchers interested in noninvasive estimation of hip joint loads are also provided. [ABSTRACT FROM AUTHOR]

The discovery of nackednaviruses provided new insight into the evolutionary history of the hepatitis B virus (HBV): The common ancestor of HBV and nackednaviruses was non-enveloped and while HBV acquired an envelope during evolution, nackednaviruses remained non-enveloped. We report the capsid structure of the African cichlid nackednavirus (ACNDV), determined by cryo-EM at 3.7 Å resolution. This enables direct comparison with the known capsid structures of HBV and duck HBV, prototypic representatives of the mammalian and avian lineages of the enveloped Hepadnaviridae, respectively. The sequence identity with HBV is 24% and both the ACNDV capsid protein fold and the capsid architecture are very similar to those of the Hepadnaviridae and HBV in particular. Acquisition of the hepadnaviral envelope was thus not accompanied by a major change in capsid structure. Dynamic residues at the spike tip are tentatively assigned by solid-state NMR, while the C-terminal domain is invisible due to dynamics. Solid-state NMR characterization of the capsid structure reveals few conformational differences between the quasi-equivalent subunits of the ACNDV capsid and an overall higher capsid structural disorder compared to HBV. Despite these differences, the capsids of ACNDV and HBV are structurally highly similar despite the 400 million years since their separation. Nackednaviruses and hepatitis B virus (HBV) have a common non-enveloped viral ancestor. While HBV acquired an envelope during evolution, nackednaviruses remained non-enveloped. Here, Pfister et al. apply CryoEM and NMR to characterize the capsid structure of African cichlid nackednavirus (ACNDV) at pH 5.5 and pH 7.5 and show that the capsid structure is very similar to that of HBV. [ABSTRACT FROM AUTHOR]

Oligogalacturonide-oxidases (OGOXs) and cellodextrin-oxidase (CELLOX) are plant berberine bridge enzyme-like oligosaccharide-oxidases (OSOXs) that oxidize, respectively, oligogalacturonides (OGs) and cellodextrins (CDs), thereby inactivating their elicitor nature and concomitantly releasing H2O2. Little is known about the physiological role of OSOX activity. By using an ABTS·+-reduction assay, we identified a novel reaction mechanism through which the activity of OSOXs on cell wall oligosaccharides scavenged the radical cation ABTS·+ with an efficiency dependent on the type and length of the oxidized oligosaccharide. In contrast to the oxidation of longer oligomers such as OGs (degree of polymerization from 10 to 15), the activity of OSOXs on short galacturonan- and cellulose-oligomers (degree of polymerization ≤ 4) successfully counteracted the radical cation-generating activity of a fungal laccase, suggesting that OSOXs can generate radical cation scavenging activity in the apoplast with a power proportional to the extent of degradation of the plant cell wall, with possible implications for redox homeostasis and defense against oxidative stress. [ABSTRACT FROM AUTHOR]

Our understanding of protein synthesis has been conceptualised around the structure and function of the bacterial ribosome. This complex macromolecular machine is the target of important antimicrobial drugs, an integral line of defence against infectious diseases. Here, we describe how open access to cryo-electron microscopy facilities combined with bespoke user support enabled structural determination of the translating ribosome from Escherichia coli at 1.55 Å resolution. The obtained structures allow for direct determination of the rRNA sequence to identify ribosome polymorphism sites in the E. coli strain used in this study and enable interpretation of the ribosomal active and peripheral sites at unprecedented resolution. This includes scarcely populated chimeric hybrid states of the ribosome engaged in several tRNA translocation steps resolved at ~2 Å resolution. The current map not only improves our understanding of protein synthesis but also allows for more precise structure-based drug design of antibiotics to tackle rising bacterial resistance. Developments in cryo-EM sample preparation and data collection are pivotal for structure determination. Fromm et al. present a 1.55 Å structure of the translating bacterial ribosome that provides new insights on its function and may allow for more precise structure-based drug design. [ABSTRACT FROM AUTHOR]

Background: MRI studies reported that ALS patients with bulbar and spinal onset showed focal cortical changes in corresponding regions of the motor homunculus. We evaluated the capability of brain 2-[18F]FDG-PET to disclose the metabolic features characterizing patients with pure bulbar or spinal motor impairment. Methods: We classified as pure bulbar (PB) patients with bulbar onset and a normal score in the spinal items of the ALSFRS-R, and as pure spinal (PS) patients with spinal onset and a normal score in the bulbar items at the time of PET. Forty healthy controls (HC) were enrolled. We compared PB and PS, and each patient group with HC. Metabolic clusters showing a statistically significant difference between PB and PS were tested to evaluate their accuracy in discriminating the two groups. We performed a leave-one-out cross-validation (LOOCV) over the entire dataset. Four classifiers were considered: support vector machines (SVM), K-nearest neighbours, linear classifier, and decision tree. Then, we used a separate test set, including 10% of patients, with the remaining 90% composing the training set. Results: We included 63 PB, 271 PS, and 40 HC. PB showed a relative hypometabolism compared to PS in bilateral precentral gyrus in the regions of the motor cortex involved in the control of bulbar function. SVM showed the best performance, resulting in the lowest error rate in both LOOCV (4.19%) and test set (9.09 ± 2.02%). Conclusions: Our data support the concept of the focality of ALS onset and the use of 2-[18F]FDG-PET as a biomarker for precision medicine-oriented clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Various risk factors have been associated with the development of incisional hernia (IH). Some recent papers underlined that visceral fat could be a reliable indicator. Another risk factor which is of increasing clinical interest is sarcopenia. Recent studies have identified it as an independent predictor of poor postoperative outcomes following abdominal surgery. We aimed to investigate the role of visceral fat and skeletal muscle as emerging risk factors for IH after urgent laparotomy. Methods: Patients aged 18 years or older who underwent urgent median laparotomy and with continuous direct suturing of the laparotomy were included. They were categorized into two groups: those with a median IH and those without IH at 12-month follow-up. Demographic data were prospectively collected while CT scans were retrospectively reviewed. The data were compared among two groups. Results: From January 2018 to May 2021, 364 patients underwent urgent surgery in our Department, of whom 222 were aged >18 years old and underwent median laparotomy. Forty-four patients had diagnosis of median IH, while 41 patients without IH were identified as the control group. Statistically significant differences emerged for BMI and for the area of visceral fat. The association with the presence/absence of sarcopenia was not significant. Conclusion: Even when surgery is performed in urgent settings, it could be important to identify patients at risk, especially as CT scans are generally available for all patients with urgent abdominal disease. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder emerging in early life characterized by impairments in social interaction, poor verbal and non-verbal communication, and repetitive patterns of behaviors. Among the best-known genetic risk factors for ASD, there are mutations causing the loss of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) leading to Fragile X syndrome (FXS), a common form of inherited intellectual disability and the leading monogenic cause of ASD. Being a pivotal regulator of motor activity, motivation, attention, and reward processing, dopaminergic neurotransmission has a key role in several neuropsychiatric disorders, including ASD. Fmr1Δexon 8 rats have been validated as a genetic model of ASD based on FMR1 deletion, and they are also a rat model of FXS. Here, we performed behavioral, biochemical and in vivo SPECT neuroimaging experiments to investigate whether Fmr1Δexon 8 rats display ASD-like repetitive behaviors associated with changes in striatal dopamine transporter (DAT) availability assessed through in vivo SPECT neuroimaging. At the behavioral level, Fmr1Δexon 8 rats displayed hyperactivity in the open field test in the absence of repetitive behaviors in the hole board test. However, these behavioral alterations were not associated with changes in striatal DAT availability as assessed by non-invasive in vivo SPECT and Western blot analyses. [ABSTRACT FROM AUTHOR]

The role of friction on wear evolution is manifold since it interplays with lubrication regime, nominal contact point, and contact pressure distribution. Nevertheless, in the literature many wear models simulate wear assuming frictionless contact conditions to simplify the analyses. That assumption, physically not realistic, often appears as a contradiction, permitted in numerical simulations where friction and wear can be considered independent phenomena. This study aims to validate the frictionless assumption in wear models with steady nominal contact point, such as in many common configurations, e.g. pin on plate/pin on disc. Wear was simulated according to the Archard wear law for both non-conformal and conformal pin-on-plate contact pairs in reciprocating motion, assuming frictionless and frictional contact conditions, varying the coefficient of friction f in the range 0–0.4. Finite Element wear models were developed in Ansys® both with implicit and explicit kinematics. Results demonstrate that the effect of friction on contact pressure distribution and worn profiles and on their evolution is negligible (differences lower than 0.05%). Thus, wear can be predicted using models in frictionless conditions which allow to extremely reduce the computational costs that represent a limit of FE wear simulations. Additionally, a procedure with implicit kinematics was compared to the explicit one resulting valid and computationally convenient, especially in case of non-conformal contact. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association between adverse experiences during Hurricane María and mental and emotional distress in Puerto Rico. Methods: This cross-sectional study used baseline data from adult (30–75 years) participants of the Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic Disease Trends (PROSPECT). Enrolled individuals prior to COVID-19 who completed a 33-item questionnaire on Hurricane María-related experiences (sub-categorized as personal, service, or property losses), depression symptomatology, post-traumatic stress disorder (PTSD), and anxiety were included for analysis (n = 456). Results: Most participants experienced fear for their family's safety, damage to their home and personal items, communication outages, and water shortages. Each additional stressor was significantly associated with higher odds of depression symptoms, PTSD, and anxiety. Personal losses were significantly associated with higher likelihood of all outcomes, while services losses were associated with depression symptoms and anxiety; property loss was not significantly associated with any outcome. Conclusions: Adverse experiences during a major natural disaster are associated with mental and emotional distress. Strategies to minimize hardships during natural disasters, especially personal and service losses, are essential to preserve mental health. Post-disaster psychological support to individuals is crucial. [ABSTRACT FROM AUTHOR]

Objective: We examined links among dietary patterns (DPs), insulin resistance (IR), and diabetes risk by heritage in the Hispanic Community Health Study/Study of Latinos. Methods: Hispanics/Latinos of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American heritage aged 18–74 years and diabetes-free completed two 24 h dietary recalls at baseline (2008–2011) and provided 6-year follow-up data (2014–2017; n = 7774). We classified 6-year IR status [improved, unchanged (referent), worsened] using a 1-SD change in fasting insulin between visits and defined incident diabetes based on American Diabetes Association criteria. We derived heritage-specific DPs via principal factor analysis and estimated their associations with 6-year IR status (multinomial) and incident diabetes (binary) using complex survey-based logistic regression. Results: Five overarching DPs based on high-loading foods were shared by two or more heritage groups: "Burger, Fries, & Soft Drinks"; "White Rice, Beans, & Red Meats"; "Fish & Whole Grains"; "Cheese & Sweets"; and "Stew & Corn". Comparing highest-to-lowest DP quintiles, the Dominican "Burger, Fries, & Soft Drinks" and Cuban "White Rice, Beans, & Red Meats" DPs were associated with worsened 6-year IR status (log-odds: 2.35, 95% CI: 1.02, 3.68, Ptrend = 0.037 and log-odds: 1.27, 95% CI: 0.49, 2.06, Ptrend = 0.009, respectively). The Puerto Rican "Burger, Fries, & Soft Drinks" and the Central American "White Rice, Beans, & Red Meats" DPs were associated with greater diabetes incidence (OR: 3.00, 95% CI:1.50, 5.99 and OR: 2.41, 95% CI: 1.05, 5.50, respectively). Conclusions: A diet characterized by higher intakes of burgers, fries, and soft drinks and another characterized by higher intakes of white rice, beans, and red meats may be adversely associated with IR and diabetes risk in some Hispanic/Latino heritage groups. Future work is needed to offer more heritage-specific dietary guidance for diabetes prevention in this population. [ABSTRACT FROM AUTHOR]

Understanding temperature production and regulation in endotherm organisms becomes a crucial challenge facing the increased frequency and intensity of heat strokes related to global warming. Mitochondria, located at the crossroad of metabolism, respiration, Ca2+ homeostasis, and apoptosis, were recently proposed to further act as cellular radiators, with an estimated inner temperature reaching 50 °C in common cell lines. This inner thermogenesis might be further exacerbated in organs devoted to produce consistent efforts as muscles, or heat as brown adipose tissue, in response to acute solicitations. Consequently, pathways promoting respiratory chain uncoupling and mitochondrial activity, such as Ca2+ fluxes, uncoupling proteins, futile cycling, and substrate supplies, provide the main processes controlling heat production and cell temperature. The mitochondrial thermogenesis might be further amplified by cytoplasmic mechanisms promoting the over-consumption of ATP pools. Considering these new thermic paradigms, we discuss here all conventional wisdoms linking mitochondrial functions to cellular thermogenesis in different physiological conditions. [ABSTRACT FROM AUTHOR]

We introduce Flexible Representative Democracy (FRD), a novel hybrid of Representative Democracy and Direct Democracy in which voters can alter the issue-dependent weights of a set of elected representatives. In line with the literature on Interactive Democracy, our model allows the voters to actively determine the degree to which the system is direct versus representative. However, unlike Liquid Democracy, Flexible Representative Democracy uses strictly non-transitive delegations, making delegation cycles impossible, and maintains a fixed set of accountable, elected representatives. We present Flexible Representative Democracy and analyze it using a computational approach with issues that are binary and symmetric. We compare the outcomes of various voting systems using Direct Democracy with majority voting as an ideal baseline. First, we demonstrate the shortcomings of Representative Democracy in our model. We provide NP-Hardness results for electing an ideal set of representatives, discuss pathologies, and demonstrate empirically that common multi-winner election rules for selecting representatives do not perform well in expectation. To analyze the effects of adding delegation to representative voting systems, we begin by providing theoretical results on how issue-specific delegations determine outcomes. Finally, we provide empirical results comparing the outcomes of various voting systems: Representative Democracy, Proxy Voting, and FRD with issue-specific delegations. Our results show that variants of Proxy Voting yield no discernible benefit over unweighted representatives and reveal the potential for Flexible Representative Democracy to improve outcomes as voter participation increases. [ABSTRACT FROM AUTHOR]

Office-based laryngology procedures evolved in the recent years with all the technology advances and have gained popularity among laryngologists. The indications enlarged, making it a valid surgical option for almost all voice disorders. This emerging technique raise the question of the place left for traditional phonosurgeries in the operating room under general anesthesia. We reviewed our surgical activity in our laryngology referral center from 2018 to 2023. Since we started the in-office procedures in 2018, the number of these interventions significantly increased, accompanying a significant increase in our total surgical activity. We noted no significant decrease in the number of interventions done in the operating room, which made us consider the office-based procedures as a complimentary and not a competitive option for traditional surgeries, helping us increase our total number of interventions, and thus offer patients more opportunities for a quicker medical care. Our register review showed also a change of treatment trends for unilateral vocal fold paralysis, with office-based interventions becoming the first-line treatment. [ABSTRACT FROM AUTHOR]