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Abstract In super-resolution, a varying illumination image stack is required. This enriched dataset typically necessitates precise mechanical control and micron-scale optical alignment and repeatability. Here, we introduce a novel methodology for super-resolution microscopy called stochastically structured illumination microscopy (S2IM), which bypasses the need for illumination control exploiting instead the random, uncontrolled movement of the target object. We tested our methodology within the clinically relevant ophthalmoscopic setting, harnessing the inherent saccadic motion of the eye to induce stochastic displacement of the illumination pattern on the retina. We opted to avoid human subjects by utilizing a phantom eye model featuring a retina composed of human induced pluripotent stem cells (iPSC) retinal neurons and replicating the ocular saccadic movements by custom actuators. Our findings demonstrate that S2IM unlocks scan-less super-resolution with a resolution enhancement of 1.91, with promising prospects also beyond ophthalmoscopy applications such as active matter or atmospheric/astronomical observation.

Abstract Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo–IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states and was upregulated in astrocytes in multiple sclerosis lesions. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.

Abstract Chronic kidney disease (CKD) is a major global public health issue and the leading cause of death in Thailand. This study investigated the spatial–temporal association between PM2.5 and its components (organic carbon, black carbon, dust, sulfate, and sea salt) and CKD mortality in Thailand from 2012 to 2021. The Modern-Era Retrospective analysis for Research and Application version 2 (MERRA-2), a NASA atmospheric satellite model, was assessed for the temporal data of PM2.5 concentration and aerosol components. Spatial resources of 77 provinces were integrated using the Geographical Information System (GIS). Multivariate Poisson regression and Bayesian inference analyses were conducted to explore the effects of PM2.5 on CKD mortality across the provinces. Our analysis included 718,686 CKD-related deaths, resulting in a mortality rate of 1107 cases per 100,000 population where was the highest rate in Northeast region. The average age of the deceased was 72.43 ± 13.10 years, with males comprising 50.46% of the cases. Adjusting for age, sex, underlying diseases, co-morbidities, CKD complications, replacement therapy, population density, and income, each 1 µg/m3 increase in PM2.5, black carbon, dust, sulfate, and organic carbon was significantly associated with increased CKD mortality across 77 provinces. Incidence rate ratios were 1.04 (95% CI 1.03–1.04) for PM2.5, 1.11 (95% CI 1.10–1.13) for black carbon, 1.24 (95% CI 1.22–1.25) for dust, 1.16 (95% CI 1.16–1.17) for sulfate, and 1.05 (95% CI 1.04–1.05) for organic carbon. These findings emphasize the significant impact of PM2.5 on CKD mortality and underscore the need for strategies to reduce PM emissions and manage CKD co-morbidities effectively.

Abstract Heterogeneity in the size distribution of cancer cell populations is linked to drug resistance and invasiveness. However, understanding how such heterogeneity arises is still damped by the difficulties of monitoring the proliferation at the typical timescales of mammalian cells. Here, we show how to infer the growth regime and division strategy of leukemia cell populations using live cell fluorescence labeling and flow cytometry in combination with an analytical model where cell growth and division rates depend on powers of the size. We found that the dynamics of the size distribution of Jurkat T-cells is reproduced by (i) a sizer-like division strategy, with (ii) division times following an Erlang distribution and (iii) fluctuations up to ten percent of the inherited fraction of size at division. Overall, our apparatus can be extended to other cell types and environmental conditions allowing for a comprehensive characterization of the growth and division model different cells adopt.

This study reports an experimental investigation of the fatigue and fracture resistance of R350HT, a heat-treated pearlitic rail steel with refined microstructure used in rails. Monotonic tensile, rotating bending, linear elastic plane strain fracture toughness, and fatigue crack growth rate tests are presented. The results are used to outline the basic properties and are corroborated by fractographic investigation. This enables the identification of the dominant type of fracture. Regarding fatigue and fracture resistance, the investigated material shows similar properties as other pearlitic rail steels, such as R260. At room temperature, the dominating fracture is of brittle cleavage type, showing some ductile regions associated with pro-eutectoid.

We consider the functional ℱ(u)≔∫Ωf(x,Du(x))dx,{\mathcal{ {\mathcal F} }}\left(u):= \mathop{\int }\limits_{\Omega }f\left(x,Du\left(x)){\rm{d}}x, where f(x,z)f\left(x,z) satisfies a (p,q)\left(p,q)-growth condition with respect to zz and can be approximated by means of a suitable sequence of functions. We consider BR⋐Ω{B}_{R}\hspace{0.33em}\Subset \hspace{0.33em}\Omega and the spaces X=W1,p(BR,RN)andY=W1,p(BR,RN)∩Wloc1,q(BR,RN).X={W}^{1,p}\left({B}_{R},{{\mathbb{R}}}^{N})\hspace{1.0em}\hspace{0.1em}\text{and}\hspace{0.1em}\hspace{1.0em}Y={W}^{1,p}\left({B}_{R},{{\mathbb{R}}}^{N})\cap {W}_{\hspace{0.1em}\text{loc}\hspace{0.1em}}^{1,q}\left({B}_{R},{{\mathbb{R}}}^{N}). We prove that the lower semicontinuous envelope of ℱ∣Y{\mathcal{ {\mathcal F} }}{| }_{Y} coincides with ℱ{\mathcal{ {\mathcal F} }} or, in other words, that the Lavrentiev term is equal to zero for any admissible function u∈W1,p(BR,RN)u\in {W}^{1,p}\left({B}_{R},{{\mathbb{R}}}^{N}). We perform the approximations by means of functions preserving the values on the boundary of BR{B}_{R}.

ObjectiveSexual functioning is a multifaceted aspect of human life that can be profoundly affected in patients with glioma. Most frequent symptoms include reduced sexual desire, difficulties in sexual arousal, or low satisfaction. Such symptoms may cause distress or interpersonal difficulties, inevitably resulting in negative outcomes on different domains of patients’ quality of life. Despite this, sexuality is rarely addressed by medical staff and remains understudied. An important question still unanswered is whether sexual dysfunctions in glioma patients correlate with features of the tumor itself, with its treatment, or with the secondary effects of the tumor on the patient’s psychological status. To answer this question, the present study aims to investigate the incidence of sexual life impairments in a very large population of patients with low- and high-grade gliomas, focusing on demographic, clinical, and treatment factors associated with their occurrence and developments.MethodsA total of 148 patients treated for glioma were evaluated for sexual functioning, i.e., sexual dysfunction (SD), relationship status (RS), intercourse frequency (IF), and sexual satisfaction (SS), by using a specific anonymous questionnaire. Descriptive statistics were utilized to investigate participant characteristics and to evaluate the occurrence of sexual problems. Chi-squared tests were performed to detect the association between “SS” or “IF” and different clinical/demographic factors as well as between “SS” or “IF” and the “subjective–personal skills judgment”.ResultsResults showed no difference between male and female patients, a very low frequency (1.4%) of SD, but a consistent percentage (25%) of subjective deterioration in sexual wellbeing. Notably, 24% of patients reported to have interrupted their relationship after the diagnosis. Chi-squared analyses reveal an association between adjuvant treatments (chemotherapy and radiotherapy) and reduction of IF. Interestingly, “SS” or “IF” was not associated with demographic, clinical, or histomolecular factors.ConclusionOur study showed that sexual problems in glioma patients are not uncommon, and they are especially linked to SS, RS, and IF. Specifically, intercourse frequency reduction is associated with the adjuvant treatments. Results highlight the need for improved assessment strategies and interventions tailored to the unique needs of brain tumor patients.

Acute muscle pain is muscle soreness that occurs during or within 24 hours of strenuous activity. Possible causes of acute muscle pain include localized muscle trauma, muscle tear, contusion with acute hemorrhage, or acute compartment syndrome. Isolated ruptures of the rectus femoris muscle are rare clinical conditions that result from excessive muscle strain following an abrupt contraction, incorrect movement, or sudden snap that exceeds the physiological limit of strain that the muscle can withstand. To date, there are few published reports evaluating the results of non-invasive treatment of such injuries. Herein, we report an unusual case of isolated distal rectus femoris tear in a 46-year-old female patient with no risk factors, who initially presented with extensor muscle weakness and pain and was treated conservatively with functional rest, physiotherapy, and cryotherapy.

This paper presents a refined Finite Element (FE) modeling strategy for analyzing the failure behavior of regular masonry structures reinforced with timber-based retrofit solutions. The proposed model schematizes the masonry as brick units, modeled using two-dimensional linear elastic plane stress elements, mutually joined through zero-thickness cohesive interface elements. These interface elements serve to reproduce the nonlinear behavior of masonry because of the occurrence of failure mechanisms of the mortar joints. Reinforced timber frame elements are modeled using truss elements that exhibit elastic brittle fracture behavior. The interaction between the masonry sub-structure and the reinforced timber frame system is accounted for using special constraint conditions that simulate the mechanical behavior of anchorage connections. The reliability of the proposed model in reproducing the failure behavior of masonry is assessed through comparisons with experimental and numerical data available in the literature. Additionally, the efficacy of the retrofit technique based on timber frame structures is investigated in detail through pushover analyses on a two-story masonry wall representative of real-life masonry buildings. The results indicate that the proposed retrofitting strategy is an effective and eco-friendly retrofit solution to enhance the in-plane bearing capacity of masonry structures subjected to horizontal forces.

Correction of the varus deformities in the tibia is necessary because of the excessive pressure exerted on the medial compartment of the knee, which intensifies the degenerative process. Correction strategies encompass a variety of approaches and depend on the patient’s individual characteristics, age, soft tissue condition, and the orthopaedic surgeon’s experience with different surgical materials. Size and location of the deformity, whether gradual or acute, play crucial roles in choosing the most appropriate material and shape. The gradual correction is especially indicated for patients with severe deformities, soft tissue involvement, and a history of bone infections. This study aimed to introduce a gradual correction technique for varus deformities in the tibia using a unilateral external fixator and to describe the postoperative follow-up. This technique offers notable advantages, including accurate correction, better patient acceptance, lighter assembly, less risk of pseudarthrosis, and shorter distraction process owing to the use of a single piece. In addition, the operated limb can support the load on the day after surgery, and dynamic follow-up is performed on an outpatient basis.

This paper presents a refined Finite Element (FE) modeling strategy for analyzing the failure behavior of regular masonry structures reinforced with timber-based retrofit solutions. The proposed model schematizes the masonry as brick units, modeled using two-dimensional linear elastic plane stress elements, mutually joined through zero-thickness cohesive interface elements. These interface elements serve to reproduce the nonlinear behavior of masonry because of the occurrence of failure mechanisms of the mortar joints. Reinforced timber frame elements are modeled using truss elements that exhibit elastic brittle fracture behavior. The interaction between the masonry sub-structure and the reinforced timber frame system is accounted for using special constraint conditions that simulate the mechanical behavior of anchorage connections. The reliability of the proposed model in reproducing the failure behavior of masonry is assessed through comparisons with experimental and numerical data available in the literature. Additionally, the efficacy of the retrofit technique based on timber frame structures is investigated in detail through pushover analyses on a two-story masonry wall representative of real-life masonry buildings. The results indicate that the proposed retrofitting strategy is an effective and eco-friendly retrofit solution to enhance the in-plane bearing capacity of masonry structures subjected to horizontal forces.

Abstract Objective The present study aimed to perform the Brazilian cultural adaptation of the Parenting and Family Adjustment Scales and to examine its construct validity. Method The sample comprised 315 mothers of 2- to- 5-year-old children. The process of cultural adaptation followed the following steps: translation of the instrument into Portuguese language; synthesis and completion of the first consensus draft of the Portuguese version; back-translation; evaluation by the committee of expert specialist judges; semantic evaluation of the items; calculation of content validity coefficient, and qualitative interview. Finally, a confirmatory factor analysis was conducted. Results The results of confirmatory factor analysis revealed four latent parenting practices in the Brazilian contex, such ast: coercive parenting, encouragement, parental inconsistency, and parent-child relationship. Additionally, the analysis for the family adjustment revealed a two-factor model parental adjustment and family adjustment. Conclusion Parenting and Family Adjustment Scales presents a valid measurement for the Brazilian context, and can be used in future parenting studies.

This paper presents a refined Finite Element (FE) modeling strategy for analyzing the failure behavior of regular masonry structures reinforced with timber-based retrofit solutions. The proposed model schematizes the masonry as brick units, modeled using two-dimensional linear elastic plane stress elements, mutually joined through zero-thickness cohesive interface elements. These interface elements serve to reproduce the nonlinear behavior of masonry because of the occurrence of failure mechanisms of the mortar joints. Reinforced timber frame elements are modeled using truss elements that exhibit elastic brittle fracture behavior. The interaction between the masonry sub-structure and the reinforced timber frame system is accounted for using special constraint conditions that simulate the mechanical behavior of anchorage connections. The reliability of the proposed model in reproducing the failure behavior of masonry is assessed through comparisons with experimental and numerical data available in the literature. Additionally, the efficacy of the retrofit technique based on timber frame structures is investigated in detail through pushover analyses on a two-story masonry wall representative of real-life masonry buildings. The results indicate that the proposed retrofitting strategy is an effective and eco-friendly retrofit solution to enhance the in-plane bearing capacity of masonry structures subjected to horizontal forces.

Introduction: Growing pains are frequent in children, recognizing several causes and sometimes requiring management. Among these conditions, apophysitis and osteochondrosis may interest children who practice sport activities. In this case report, we found an association between a form of osteochondrosis, the Sinding-Larsen-Johansson Disease and a type of apophysitis, the Sever Disease in the same patient. Case Description: A 10-year-old boy presented with a 3-month bilateral non-specific anteroinferior knees and posterior heels pain history with worsening in the last month particularly after athletic activities. Patient presented mild swelling of the bilateral heel face, antalgic gait, bilateral painful palpation over the patella inferior pole and bilateral heel pain. Based on the clinical and instrumental evaluation, bilateral Sinding-Larsen-Johansson Disease and Sever Disease was diagnosed. Temporary abstention from sport and conservative approach led to complete symptoms’ regression after three months and to the gradual return to sport. Discussion and Conclusion: This is a singular case of a combination of Sinding-Larsen-Johansson Disease and the Sever Disease in both lower limbs and with painful symptoms present at the same time. The correct dosage of physical activity and training intensity, education to healthy lifestyle habits, can represent preventive strategies to avoid overuse of childhood diseases.

Abstract Background Type 2 diabetes (T2D) is a risk factor for female breast cancer (FBC). Obesity has also been associated with FBC, also depending on menopausal status. This study aimed to evaluate the impact of obesity and T2D on the development, aggressiveness, and invasiveness of FBC. Methods Demographic, clinical, and histopathological data from 335 women with FBC were collected, and analyzed according to weight category (102 normal weight, 117 overweight, and 116 living with obesity) and the presence/absence of T2D. Results Age at oncologic diagnosis was not statistically significantly different for body weight; women with overweight or obesity were more likely to have an oncologic diagnosis after menopause than normal weight (p 20%). This study highlights the importance of prevention in all women, with early screening, and adequate nutritional programs.

This paper is an investigation of reference production in 84 Italian-Spanish bilingual children aged 8 to 12. The study explores whether such reference production is influenced by either the type of referential expression involved or language dominance by analyzing how these children manage reference. The children’s relative proficiency in the two languages (and thus their language dominance) was assessed through a cloze-test, and their narrative production was evaluated using a retelling task. Results indicated a preference for null pronouns to refer to subjects and full referential expressions for objects, with Italian showing a higher occurrence of full referential expressions. Dominance in either language did not significantly impact reference production. This suggests that bilingual children can distinguish between language-specific patterns, a behavior consistent with adult monolingual groups. These results contribute to our understanding of bilingual reference management and shed light on the role played by language and language dominance.

Abstract Controlling nanoscale tip‐induced material removal is crucial for achieving atomic‐level precision in tomographic sensing with atomic force microscopy (AFM). While advances have enabled volumetric probing of conductive features with nanometer accuracy in solid‐state devices, materials, and photovoltaics, limitations in spatial resolution and volumetric sensitivity persist. This work identifies and addresses in‐plane and vertical tip‐sample junction leakage as sources of parasitic contrast in tomographic AFM, hindering real‐space 3D reconstructions. Novel strategies are proposed to overcome these limitations. First, the contrast mechanisms analyzing nanosized conductive features are explored when confining current collection purely to in‐plane transport, thus allowing reconstruction with a reduction in the overestimation of the lateral dimensions. Furthermore, an adaptive tip‐sample biasing scheme is demonstrated for the mitigation of a class of artefacts induced by the high electric field inside the thin oxide when volumetrically reduced. This significantly enhances vertical sensitivity by approaching the intrinsic limits set by quantum tunneling processes, allowing detailed depth analysis in thin dielectrics. The effectiveness of these methods is showcased in tomographic reconstructions of conductive filaments in valence change memory, highlighting the potential for application in nanoelectronics devices and bulk materials and unlocking new limits for tomographic AFM.

BackgroundFexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit.MethodsThe model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed.ResultsHIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively (p < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced (p < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 (p < 0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22% to 40%.ConclusionA model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during versus only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure.

Abstract The prevalence of longstanding chronic diseases has increased worldwide, along with the average age of the population. As a result, an increasing number of people is affected by two or more chronic conditions simultaneously, and healthcare systems are facing the challenge of treating multimorbid patients effectively. Current therapeutic strategies are suited to manage each chronic condition separately, without considering the whole clinical condition of the patient. This approach may lead to suboptimal clinical outcomes and system inefficiencies (e.g. redundant diagnostic tests and inadequate drug prescriptions). We develop a novel methodology based on the joint implementation of data reduction and clustering algorithms to identify patterns of chronic diseases that are likely to co-occur in multichronic patients. We analyse data from a large adult population of multichronic patients living in Tuscany (Italy) in 2019 which was stratified by sex and age classes. Results demonstrate that (i) cardio-metabolic, endocrine, and neuro-degenerative diseases represent a stable pattern of multimorbidity, and (ii) disease prevalence and clustering vary across ages and between women and men. Identifying the most common multichronic profiles can help tailor medical protocols to patients’ needs and reduce costs. Furthermore, analysing temporal patterns of disease can refine risk predictions for evolutive chronic conditions.

Abstract Disorder is a pervasive characteristic of natural systems, offering a wealth of non-repeating patterns. In this study, we present a novel storage method that harnesses naturally-occurring random structures to store an arbitrary pattern in a memory device. This method, the Stochastic Emergent Storage (SES), builds upon the concept of emergent archetypes, where a training set of imperfect examples (prototypes) is employed to instantiate an archetype in a Hopfield-like network through emergent processes. We demonstrate this non-Hebbian paradigm in the photonic domain by utilizing random transmission matrices, which govern light scattering in a white-paint turbid medium, as prototypes. Through the implementation of programmable hardware, we successfully realize and experimentally validate the capability to store an arbitrary archetype and perform classification at the speed of light. Leveraging the vast number of modes excited by mesoscopic diffusion, our approach enables the simultaneous storage of thousands of memories without requiring any additional fabrication efforts. Similar to a content addressable memory, all stored memories can be collectively assessed against a given pattern to identify the matching element. Furthermore, by organizing memories spatially into distinct classes, they become features within a higher-level categorical (deeper) optical classification layer.

Aim: Severe knee malalignment in children usually needs surgery with different options available in surgical approaches. The aim of this study was to report the results of the surgical correction of severe knee malalignment in children treated with femoral and tibial osteotomy, temporarily fixed with percutaneous Kirschner wires, in a low- and middle-income country (LMIC), with limited medical resources. Materials and methods: Thirty children (age range 4–9 years) with severe knee malalignment were observed and surgically treated in a small children hospital located in the Tanzanian rural outback. A total of 53 deformities were treated. Thirty-two knees presented varus deformity and 21 knees presented valgus deformity. In 9 cases, femoral osteotomy alone was performed, tibial osteotomy alone in 28 cases, combined femoral and tibial osteotomy in 16 cases. Fixation was obtained with crossed percutaneous Kirschner wires, and a post-operative long-leg cast immobilization was applied. Results: Mean pre-operative varus passed from 40°±4 to post-operative 5°±6 valgus. Mean pre-operative valgus passed from 39°±4 to post-operative 8°±5 valgus. Complications included delayed healing of the wounds, skin suffering at the outlet of Kirschner wires, knee stiffness, undercorrection and overcorrection of the deformity. Results were considered excellent in 18 cases, good in 21, fair in 11, poor in 3. Conclusions: This technique allowed us to obtain satisfactory correction of severe knee malalignment with less invasive surgery. Inexpensive hardware such as Kirschner wires, combined with cast immobilization, allowed satisfactory fixation of the osteotomy, and reduction of the overall cost of surgery, as it should be desirable in LMICs.

Introduction: Hip fractures are one of the major disability causes associated with a high morbidity and mortality rate. Early surgery and stable fixation could be associated with better pain control, possibly lower mortality rates, and early recovery of autonomy. Aim: The aim of this study was to analyze a population affected by hip fractures exploring the effects of an early surgery and rehabilitation approach in relation to functional outcomes. Materials and methods: This study included 140 adult patients (mean age 79.35±11.71, range 66-94 years) with hip fractures admitted to the orthopedic unit of the University Hospital of Messina who underwent surgery and a rehabilitation program while hospitalized. Exclusion criteria were patients not surgically treated or discharged with no rehabilitation sessions. Clinical outcomes were evaluated post-surgery and before discharge as follows: pain quantification using the visual analogue scale and functional evaluation using the Barthel Index. A rehabilitation protocol was started within 48 hours after surgery. Results: The study sample resulted in 140 patients. Eighty-seven of them (63.14%) underwent hip replacement surgery, and 53 patients (37.86%) underwent internal fixation surgery. The greater part of the sample (68.42%) had surgery within 48 hours. Patients with more comorbidities had worse clinical outcomes, as shown by the Barthel Index, timing of verticalization and walking, and pain control. Between admission and discharge, the Barthel Index score improved, as did the pain complained of by most patients. Conclusions: A direct connection between orthopedics and the rehabilitation team, even after discharge, should be established and promptly organized to gain the best clinical outcomes. Indeed, we propose the triad early verticalization, pain control, and Barthel Index as a possible tool to define functional quality outcomes in post hip fracture surgery.

Nowadays, society is oriented toward reducing the production of plastics, which have a significant impact on the environment. In this context, the recycling of existing plastic objects is currently a fundamental step in the mitigation of pollution. Very recently, the outstanding development of artificial intelligence (AI) has concerned and continues to involve a large part of the industrial and informatics sectors. The opportunity to implement big data in the frame of recycling processes is oriented toward the improvement and the optimization of the reproduction of plastic objects, possibly with enhanced properties and durability. Here, a deep cataloguing, characterization and recycling of plastic wastes provided by an industrial sorting plant was performed. The potential improvement of the mechanical properties of the recycled polymers was assessed by the addition of coupling agents. On these bases, a classification system based on the collected results of the recycled materials’ properties was developed, with the aim of laying the groundwork for the improvement of AI databases and helpfully supporting industrial recycling processes.

In this study, we propose a method for assessing the temporal and spatial distribution of Carcharhinus melanopterus in shallow waters using unmanned aerial vehicles (UAVs). Aerial surveys were conducted in Tien Og Bay (Koh Tao, Thailand) thrice daily (morning, afternoon, evening) along a 360 m transect at a 30 m altitude. Environmental factors, including cloudiness, sea conditions, wind, tide, and anthropogenic disturbance, were recorded for each time slot. We developed a Python/AppleScript application to facilitate individual counting, correlating sightings with GPS data and measuring pixel-based length. Abundance varied significantly across time slots (p < 0.001), with a strong morning preference, and was influenced by tide (p = 0.040), favoring low tide. Additionally, abundance related to anthropogenic disturbance (p = 0.048), being higher when anthropogenic activity was absent. Spatial distribution analysis indicated time-related, sector-based abundance differences (p < 0.001). Pixel-based length was converted to Total Length, identifying juveniles. They exhibited a strong sector preference (p < 0.001) irrespective of the time of day. Juvenile abundance remained relatively stable throughout the day, constituting 94.1% of afternoon observations. Between 2020 and 2022, an underwater video survey was conducted to determine the sex ratio of the individuals. Only females and juveniles were sighted in the bay.

The introduction of the term “Metabolic Steatotic Liver Disease” (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver’s increased production of proteins known as “hepatokines” has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.

IntroductionPlant-pathogen interaction is an inexhaustible source of information on how to sustainably control diseases that negatively affect agricultural production. Meloidogyne incognita is a root-knot nematode (RKN), representing a pest for many crops, including tomato (Solanum lycopersicum). RKNs are a global threat to agriculture, especially under climate change, and RNA technologies offer a potential alternative to chemical nematicides. While endogenous microRNAs have been identified in both S. lycopersicum and M. incognita, and their roles have been related to the regulation of developmental changes, no study has investigated the miRNAs cross-kingdom transfer during this interaction.MethodsHere, we propose a bioinformatics pipeline to highlight potential miRNA-dependent cross-kingdom interactions between tomato and M. incognita.ResultsThe obtained data show that nematode miRNAs putatively targeting tomato genes are mostly related to detrimental effects on plant development and defense. Similarly, tomato miRNAs putatively targeting M. incognita biological processes have negative effects on digestion, mobility, and reproduction. To experimentally test this hypothesis, an in vitro feeding assay was carried out using sly-miRNAs selected from the bioinformatics approach. The results show that two tomato miRNAs (sly-miRNA156a, sly-miR169f) soaked by juvenile larvae (J2s) affected their ability to infect plant roots and form galls. This was also coupled with a significant downregulation of predicted target genes (Minc11367, Minc00111), as revealed by a qRT-PCR analysis.DiscussionsTherefore, the current study expands the knowledge related to the cross-kingdom miRNAs involvement in host-parasite interactions and could pave the way for the application of exogenous plant miRNAs as tools to control nematode infection.

Obesity is a heterogeneous condition which results from complex interactions among sex/gender, sociocultural, environmental, and biological factors. Obesity is more prevalent in women in most developed countries, and several clinical and psychological obesity complications show sex-specific patterns. Females differ regarding fat distribution, with males tending to store more visceral fat, which is highly correlated to increased cardiovascular risk. Although women are more likely to be diagnosed with obesity and appear more motivated to lose weight, as confirmed by their greater representation in clinical trials, males show better outcomes in terms of body weight and intra-abdominal fat loss and improvements in the metabolic risk profile. However, only a few relatively recent studies have investigated gender differences in obesity, and sex/gender is rarely considered in the assessment and management of the disease. This review summarizes the evidence of gender differences in obesity prevalence, contributing factors, clinical complications, and psychological challenges. In addition, we explored gender differences in response to obesity treatments in the specific context of new anti-obesity drugs.

This study reports an experimental investigation of the fatigue and fracture resistance of R350HT, a heat-treated pearlitic rail steel with refined microstructure used in rails. Monotonic tensile, rotating bending, linear elastic plane strain fracture toughness, and fatigue crack growth rate tests are presented. The results are used to outline the basic properties and are corroborated by fractographic investigation. This enables the identification of the dominant type of fracture. Regarding fatigue and fracture resistance, the investigated material shows similar properties as other pearlitic rail steels, such as R260. At room temperature, the dominating fracture is of brittle cleavage type, showing some ductile regions associated with pro-eutectoid.

Human sensorimotor decision making has a tendency to get ‘stuck in a rut’, being biased towards selecting a previously implemented action structure (hysteresis). Existing explanations propose this is the consequence of an agent efficiently modifying an existing plan, rather than creating a new plan from scratch. Instead, we propose that hysteresis is an emergent property of a system learning from the consequences of its actions. To examine this, 152 participants moved a cursor to a target on a tablet device while avoiding an obstacle. Hysteresis was observed when the obstacle moved sequentially across the screen between trials, whereby the participant continued moving around the same side of the obstacle despite it now requiring a larger movement than the alternative. Two further experiments (n = 20) showed an attenuation when time and resource constraints were eased. We created a simple computational model capturing probabilistic estimate updating that showed the same patterns of results. This provides, to our knowledge, the first computational demonstration of how sensorimotor decision making can get ‘stuck in a rut’ through the updating of the probability estimates associated with actions.

Background: While previous studies have assessed patient reported quality of life (QOL) of various vestibular schwannoma (VS) treatment modalities, few studies have assessed QOL as related to the amount of residual tumor and need for retreatment in a large series of patients. Objective: To assess patient reported QOL outcomes following VS resection with a focus on extent of resection and retreatment. Methods: A retrospective chart review was performed using single-center institutional data of adult patients who underwent VS resection by the senior authors between 1989-2018 at Loyola University Medical Center. The Penn Acoustic Neuroma Quality of Life (PANQOL) survey was sent to all patients via postal mail. Results: Fifty-five percent of 367 total patients were female with a mean age of 61.6 years (SD 12.63). The mean period between surgery and PANQOL response was 11.4 years (IQR: 4.74-7.37). The median tumor size was 2 cm (IQR: 1.5-2.8). The mean total PANQOL score was 70 (SD 19). Patients who required retreatment reported lower overall scores (μdiff = -10.11, 95% CI: -19.48 to -0.74; p = 0.03) and face domain scores (μdiff = -20.34, 95% CI: -29.78 to -10.91; p < .001). There was no association between extent of resection and PANQOL scores in any domain. Conclusion: In an analysis of 367 patients who underwent microsurgical resection of VS, extent of resection did not affect PANQOL scores in contrast to previous reports in the literature, while the need for retreatment and facial function had a significant impact on patient-reported outcomes.

Summary: Background: Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D. Methods: We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function. Findings: We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR 30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m2 (95% C.I. from 1.13 to 2.48; p

Abstract The main limitation to the use of antimicrobial peptides (AMPs) as regular drugs, against antibiotic and antifungal resistance, mainly relates to their rapid degradation by proteolytic enzymes. The introduction of suitable structural changes in the peptide chain can make the peptide less susceptible to the action of proteases, thus overcoming this problem. To improve the plasma stability of calcitermin, a metal-chelating AMP present in the human respiratory tract and investigated in the present study, C- and/or N- terminal modifications have been introduced in the native sequence. Evaluation of peptide stability has been performed to determine the half-life times in human plasma of both native calcitermin and its derivatives. However, the protection of the peptide termini can also affect its metal coordination behaviour. Thus, the characterization of Zn2+ and Cu2+ complexes has been performed by means of several techniques, including potentiometry, high-resolution mass spectrometry, UV–Vis, circular dichroism and EPR. On the basis of the obtained results, it was possible to compare the biological activity of the studied systems, taking into account both the metal-binding ability and the peptide stability to search for a link among them. A significant result of this study is that the N-terminal protection increases the calcitermin half-life over seven times and the formation of metal complexes confers resistance towards degradation almost doubling its half-life.

Abstract Memristive devices that rely on redox-based resistive switching mechanism have attracted great attention for the development of next-generation memory and computing architectures. However, a detailed understanding of the relationship between involved materials, interfaces, and device functionalities still represents a challenge. In this work, we analyse the effect of electrode metals on resistive switching functionalities of NbOx-based memristive cells. For this purpose, the effect of Au, Pt, Ir, TiN, and Nb top electrodes was investigated in devices based on amorphous NbOx grown by anodic oxidation on a Nb substrate exploited also as counter electrode. It is shown that the choice of the metal electrode regulates electronic transport properties of metal–insulator interfaces, strongly influences the electroforming process, and the following resistive switching characteristics. Results show that the electronic blocking character of Schottky interfaces provided by Au and Pt metal electrodes results in better resistive switching performances. It is shown that Pt represents the best choice for the realization of memristive cells when the NbOx thickness is reduced, making possible the realization of memristive cells characterised by low variability in operating voltages, resistance states and with low device-to-device variability. These results can provide new insights towards a rational design of redox-based memristive cells.

Abstract Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells.

Let us consider continuous minimizers $ u : \bar \Omega \subset \mathbb{R}^n \to \mathbb{R}^n $ of $ \mathcal{F}(v) = \int_{\Omega} [|Dv|^p \, + \, |{\rm det}\,Dv|^r] dx, $ with $ p > 1 $ and $ r > 0 $; then it is known that every component $ u^\alpha $ of $ u = (u^1, ..., u^n) $ enjoys maximum principle: the set of interior points $ x $, for which the value $ u^\alpha(x) $ is greater than the supremum on the boundary, has null measure, that is, $ \mathcal{L}^n(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \}) = 0 $. If we change the structure of the functional, it might happen that the maximum principle fails, as in the case $ \mathcal{F}(v) = \int_{\Omega}[\max\{(|Dv|^p - 1); 0 \} \, + \, |{\rm det}\,Dv|^r] dx, $ with $ p > 1 $ and $ r > 0 $. Indeed, for a suitable boundary value, the set of the interior points $ x $, for which the value $ u^\alpha(x) $ is greater than the supremum on the boundary, has a positive measure, that is $ \mathcal{L}^n(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \}) > 0 $. In this paper we show that the measure of the image of these bad points is zero, that is $ \mathcal{L}^n(u(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \})) = 0 $, provided $ p > n $. This is a particular case of a more general theorem.

Nanodiamonds are innovative nanocrystalline carbon particles able to deliver chemically conjugated miRNAs. In oncology, the use of miRNA-based therapies may represent an advantage, based on their ability to simultaneously target multiple intracellular oncogenic targets. Here, nanodiamonds were tested and optimized to deliver miR-34a, a miRNA playing a key role in inhibiting tumor development and progression in many cancers. The physical-chemical properties of nanodiamonds were investigated suggesting electrical stability and uniformity of structure and size. Moreover, we evaluated nanodiamond cytotoxicity on two breast cancer cell models and confirmed their excellent biocompatibility. Subsequently, nanodiamonds were conjugated with miR-34a, using the chemical crosslinker polyethyleneimine; real-time PCR analysis revealed a higher level of miR-34a in cancer cells treated with the different formulations of nanodiamonds than with commercial transfectant. A significant and early nanodiamond-miR-34a uptake was recorded by FACS and fluorescence microscopy analysis in MCF7 and MDA-MB-231 cells. Moreover, nanodiamond-miR-34a significantly inhibited both cell proliferation and migration. Finally, a remarkable anti-tumor effect of miR-34a-conjugated nanodiamonds was observed in both heterotopic and orthotopic murine xenograft models. In conclusion, this study provides a rationale for the development of new therapeutic strategies based on use of miR-34a delivered by nanodiamonds to improve the clinical treatment of neoplasms.

Cartilaginous fish face significant threats due to overfishing and slow reproductive rates, leading to rapid declines in their populations globally. Traditional capture-based surveys, while valuable for gathering ecological information, pose risks to the health and survival of these species. Baited Remote Underwater Video Systems (BRUVS) offer a non-invasive alternative, allowing for standardized surveys across various habitats with minimal disturbance to marine life. This study presents a comprehensive review of BRUVS applications in studying cartilaginous fish, examining 81 peer-reviewed papers spanning from 1990 to 2023. The analysis reveals a significant increase in BRUVS usage over the past three decades, particularly in Australia, South Africa, and Central America. The most common BRUVS configurations include benthic setups, mono-camera systems, and the use of fish from the Clupeidae and Scombridae families as bait. BRUVS have been instrumental in studying 195 chondrichthyan species, providing insights into up to thirteen different aspects of the life histories. Moreover, BRUVS facilitate the monitoring of endangered and data-deficient species, contributing crucial data for conservation efforts. Overall, this study underscores the value of BRUVS as a powerful tool for studying and conserving cartilaginous fish populations worldwide.

We prove the existence of a solution to a quasilinear system of degenerate equations, when the datum is in a Marcinkiewicz space. The main assumption asks the off-diagonal coefficients to have support in the union of a geometric progression of squares.

Abstract Background We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). Methods We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or

Abstract Background In plants, RNase III Dicer-like proteins (DCLs) act as sensors of dsRNAs and process them into short 21- to 24-nucleotide (nt) (s)RNAs. Plant DCL4 is involved in the biogenesis of either functional endogenous or exogenous (i.e. viral) short interfering (si)RNAs, thus playing crucial antiviral roles. Methods In this study we expressed plant DCL4 in Saccharomyces cerevisiae, an RNAi-depleted organism, in which we could highlight the role of dicing as neither Argonautes nor RNA-dependent RNA polymerase is present. We have therefore tested the DCL4 functionality in processing exogenous dsRNA-like substrates, such as a replicase-assisted viral replicon defective-interfering RNA and RNA hairpin substrates, or endogenous antisense transcripts. Results DCL4 was shown to be functional in processing dsRNA-like molecules in vitro and in vivo into 21- and 22-nt sRNAs. Conversely, DCL4 did not efficiently process a replicase-assisted viral replicon in vivo, providing evidence that viral RNAs are not accessible to DCL4 in membranes associated in active replication. Worthy of note, in yeast cells expressing DCL4, 21- and 22-nt sRNAs are associated with endogenous loci. Conclusions We provide new keys to interpret what was studied so far on antiviral DCL4 in the host system. The results all together confirm the role of sense/antisense RNA-based regulation of gene expression, expanding the sense/antisense atlas of S. cerevisiae. The results described herein show that S. cerevisiae can provide insights into the functionality of plant dicers and extend the S. cerevisiae tool to new biotechnological applications.

Abstract Many human neural or neurodegenerative diseases strongly affect the ocular and retinal environment showing peculiar alterations which can be employed as specific disease biomarkers. The noninvasive optical accessibility of the retina makes the ocular investigation a potentially competitive strategy for screening, thus the development of retinal biomarkers is rapidly growing. Nevertheless, a tool to study and image biomarkers or biological samples in a human-like eye environment is still missing. Here we report on a modular and versatile eye model designed to host biological samples, such as retinal cultures differentiated from human induced pluripotent stem cells and ex-vivo retinal tissue, but also suited to host any kind of retinal biomarkers. We characterized the imaging performance of this eye model on standard biomarkers such as Alexa Fluor 532 and Alexa Fluor 594.

Abstract Understanding the mechanisms driving bio-molecules binding and determining the resulting complexes’ stability is fundamental for the prediction of binding regions, which is the starting point for drug-ability and design. Characteristics like the preferentially hydrophobic composition of the binding interfaces, the role of van der Waals interactions, and the consequent shape complementarity between the interacting molecular surfaces are well established. However, no consensus has yet been reached on the role of electrostatic. Here, we perform extensive analyses on a large dataset of protein complexes for which both experimental binding affinity and pH data were available. Probing the amino acid composition, the disposition of the charges, and the electrostatic potential they generated on the protein molecular surfaces, we found that (i) although different classes of dimers do not present marked differences in the amino acid composition and charges disposition in the binding region, (ii) homodimers with identical binding region show higher electrostatic compatibility with respect to both homodimers with non-identical binding region and heterodimers. Interestingly, (iii) shape and electrostatic complementarity, for patches defined on short-range interactions, behave oppositely when one stratifies the complexes by their binding affinity: complexes with higher binding affinity present high values of shape complementarity (the role of the Lennard-Jones potential predominates) while electrostatic tends to be randomly distributed. Conversely, complexes with low values of binding affinity exploit Coulombic complementarity to acquire specificity, suggesting that electrostatic complementarity may play a greater role in transient (or less stable) complexes. In light of these results, (iv) we provide a novel, fast, and efficient method, based on the 2D Zernike polynomial formalism, to measure electrostatic complementarity without the need of knowing the complex structure. Expanding the electrostatic potential on a basis of 2D orthogonal polynomials, we can discriminate between transient and permanent protein complexes with an AUC of the ROC of $$\sim$$ ∼ 0.8. Ultimately, our work helps shedding light on the non-trivial relationship between the hydrophobic and electrostatic contributions in the binding interfaces, thus favoring the development of new predictive methods for binding affinity characterization.

Recent advances in gene editing are enabling the engineering of cells with an unprecedented level of scale. To capitalize on this opportunity, new methods are needed to accelerate the different steps required to manufacture and handle engineered cells. Here, we describe the development of an integrated software and hardware platform to automate Fluorescence-Activated Cell Sorting (FACS), a central step for the selection of cells displaying desired molecular attributes. Sorting large numbers of samples is laborious, and, to date, no automated system exists to sequentially manage FACS samples, likely owing to the need to tailor sorting conditions ("gating") to each individual sample. Our platform is built around a commercial instrument and integrates the handling and transfer of samples to and from the instrument, autonomous control of the instrument's software, and the algorithmic generation of sorting gates, resulting in walkaway functionality. Automation eliminates operator errors, standardizes gating conditions by eliminating operator-to-operator variations, and reduces hands-on labor by 93%. Moreover, our strategy for automating the operation of a commercial instrument control software in the absence of an Application Program Interface (API) exemplifies a universal solution for other instruments that lack an API. Our software and hardware designs are fully open-source and include step-by-step build documentation to contribute to a growing open ecosystem of tools for high-throughput cell biology.

Core-shell configurations are ubiquitous in nature such as in the form of bacterial and cells. Inspired by this, microcapsules are designed with actives as the cores surrounded by thin shells. They not only play an increasing role as artificial models for understanding dynamic behaviors of biological cells in flows, but are also becoming a fundamental class of artificial vehicles at the heart of drug delivery and release in applications. The mechanical properties of the shells are of great importance in this context. Here, we review recent experimental and theoretical characterizations of microcapsules, focusing on the soft and deformable particles with liquid cores. We begin by exploring the concept and fabrication of artificial microcapsules, followed by a discussion of different methods on the mechanical characterization of the shell.

Background: There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. Objective: This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. Methods: An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. Results: Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. Conclusions: Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.

People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium–hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.

El objetivo de estas páginas es explorar las consecuencias de incluir mecanismos de competición como parte de la explicación de algunos fenómenos linguísticos. La pregunta de base que anima estas reflexiones es, en último extremo, la del lugar de las relaciones paradigmáticas en la organización del sistema lingüístico: su estatuto, su papel en la interpretación y en la gramática, y sus potencialidades explicativas. El repaso de diferentes fenómenos interpretativos muestra las ventajas de los enfoques inferenciales (basados en la existencia de alternativas) sobre los modelos basados en el código. Adoptando una perspectiva más amplia, se examina luego la noción de competición en otros dominios gramaticales. Quedan, así, de manifiesto los retos a los que las explicaciones en términos de competición deben afrontar, y también las nuevas rutas abiertas por la investigación reciente.

Abstract Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

Abstract Background Hotspots of intraspecific genetic diversity represent invaluable resources for species to cope with environmental changes, and their identification is increasingly recognized as a major goal of conservation ecology research. However, even for iconic and endangered species, conservation strategies are often planned without thorough information on the geographic patterns of genetic variation. Here, we investigated the spatial patterns of genetic variation of the endangered Hermann’s tortoise Testudo hermanni in the Italian Peninsula by genotyping 174 individuals at 7 microsatellite loci, with the aim to contribute to planning effective conservation strategies. Results Ordination-based and Bayesian clustering analyses consistently identified three main genetic clusters, one spread in the central and northern part of the peninsula, and two restricted to southern Italy and Sicily, respectively. The highest levels of genetic diversity were found in populations of the southern cluster and, in particular, at the northern edges of its distribution (He > 0.6, Ar > 2.8 ), that correspond to areas of putative secondary contact and admixture between distinct lineages. Our results clearly identify a hotspot of genetic diversity for the Hermann’s tortoise in southern Italy. Conclusion We inferred the evolutionary history and the spatial patterns of genetic variation of the Hermann’s tortoise in the Italian Peninsula. We identified three main genetic clusters along the peninsula and a hotspot of intraspecific diversity in southern Italy. Our results underline the urgent need for conservation actions to warrant the long-term persistence of viable tortoise populations in this area. Furthrmore, these data add further evidence to the role of southern Italy as a biodiversity hotspot for temperate fauna, claiming for higher consideration of this area in large scale conservation programs.