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This study aimed to evaluate whether skeletal development of the Pantanal Caiman (Caiman yacare) is similarly influenced by temperature variation and controlled increases in embryo motility. All eggs were incubated at 90% humidity and 29 °C for the first 45 days. Thereafter, the incubation temperature was either maintained at 29 °C and embryos were treated with 4-aminopyridine (4-AP) on days 46, 47, 48, and 49 (Group I, 29 °C 4-AP, n = 15); maintained at 29 °C (n = 14; Group II); or at 33 °C (n = 14, Group III). Embryonic movement was measured using an Egg Buddy® digital monitor on days 30, 35, 42, 49, 56, and 60, at which point embryos were euthanized and samples were collected for analysis. No differences were observed between groups with varying incubation temperatures. In contrast, embryonic motility was greater in embryos treated with 4-AP (P < 0.001) on day 49, and this was associated with higher proportions of snout-vent and hand lengths. This study demonstrates for the first time that pharmacologically induced increases in embryo motility result in phenotypic changes to the proportion of elements during prenatal ontogeny, thereby effectively altering the adaptation of the species to specific environments. Resumo Este estudo objetivou avaliar os efeitos da temperatura e motilidade embrionária sobre o desenvolvimento esquelético de jacaré-do-pantanal (Caiman yacare). Os ovos foram incubados com 90% de umidade e empregou-se a temperatura de 29°C por 45 dias. Após, para a incubação do Grupo I a temperatura continuou em 29°C, mas associou-se à injeção de 4-aminopiridina (29°C-4AP, n = 15) aplicada nos dias 46, 47, 48 e 49, do Grupo II permaneceu em 29°C (n = 14) e do Grupo III elevou-se para 33°C (n = 14). A movimentação foi mensurada através do monitor digital Egg Buddy® nos dias 30, 35, 42, 49, 56 e 60 dias. Aos 60 dias, os embriões foram eutanasiados e coletadas amostras embrionárias. Na análise estatística não foram observadas diferenças entre os grupos para o fator temperatura sobre a motilidade embrionária no desenvolvimento esquelético. Em contraste, a motilidade evidenciou diferença estatística no dia 49 para o Grupo I (P < 0,001) e apresentou maiores proporções de nariz e mão. Esses dados demonstraram pela primeira vez que o aumento na motilidade, induzidos farmacologicamente resultam em divergências fenotípicas na proporção de segmentos anatômicos durante a ontogenia pré-natal, podendo alterar efetivamente a adaptação dos animais em ambientes específicos.

This work proposes a digital system with cloud neural network with video acquisition to obtain key points of the human pose in patients undergoing physiotherapy rehabilitation of lower limbs in gait mobility, allowing agility in the records, minimizing measurement errors, analysis clinical condition, and the exchange of information between professionals in the field, resulting in a shared knowledge base. A digital camera, 1080p and 60fps, used parallel to the ground, with height adjustment (0.6 to 2.4m), 1.5m from the analysis field (3x3m to 3x10m) is used for measurement, rehabilitation or walking procedures. Values manually entered by the physiotherapist are applied for calibration and definition of limits for comparison with the data obtained by the system. In relation to the current ones, the advantage is given by digitally obtaining anatomical points and body segments while in manuals they allow greater error and too much time in this collection. The system is an auxiliary tool for the physiotherapist to supply the manual limitation and sharing, with agility among professionals, historical data and qualitative analyzes that accurately generate a patient profile and allow the adaptation of the procedures applied with agility, since it provides an immediate graphic analysis.

Os objetivos deste estudo foram desenvolver e validar um dispositivo computadorizado para mensurar a flexibilidade articular; mensurar a flexibilidade em crianças no ensino fundamental de 8 a 10 anos por meio do banco de Wells; comparar os dados alcançados pelo banco de Wells e o dispositivo computadorizado desenvolvido no presente estudo e avaliar a usabilidade do dispositivo. Participaram desta pesquisa 215 voluntários, com idade de 8 a 10 anos, sendo 63,72% (137) do sexo feminino e 36,28% (78) do sexo masculino, devidamente matriculados em uma instituição de ensino na região do Alto Tietê. Para coleta de dados, os voluntários realizaram o teste de flexibilidade utilizando o banco de Wells e o dispositivo computadorizado desenvolvido nessa pesquisa para avaliar a flexibilidade.O dispositivo foi confeccionado numa impressora de tecnologia de impressão 3D. Foi realizada uma avaliação da usabilidade com 15 professores de Educação Física para o produto desenvolvido através da interação de usabilidade baseada no formulário System Sustainability Scale (SUS) que contém 10 questões de múltipla-escolha. Os dados obtidos por medidas objetivas determinadas foram avaliadas quanto à frequência, média e desvio padrão. Foram seguidas como médias aritméticas das três medidas realizadas em cada etapa. Para investigar realizou-se os testes de Mann-Whitney e de Kruskal-Wallis e a tradução de Spearman. Para todas as análises foram consideradas diferenças significativas p

Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathies (CAAs). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that correlated with gold-standard CERAD-like WSI scoring (p=0.07± 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Purpose To evaluate if age, alcohol consumption, and body mass index (BMI) have synergistic effects on seminal quality, and to rank these factors based on their impact on semen. Methods Retrospective study of 9464 patients attending an andrology laboratory. Data on patients' age and daily alcohol intake were provided by the patients. BMI was recorded in the laboratory. Seminal parameters evaluated were volume, sperm concentration and total count, motility, morphology, viability, nuclear maturity, and membrane functional integrity. Results All the seminal parameters evaluated were affected by the synergistic interaction Age x BMI, suggesting that this combination is more potent in affecting semen quality. The variables sperm morphology and nuclear maturity seemed to be especially susceptible since they were affected by the three synergistic interactions. In the logistic regression analysis, age was the most powerful factor since it impacted first on five of the nine parameters, impacting mainly on sperm motility, viability, and morphology, with no effects on sperm count. On the contrary, BMI impacted first in sperm concentration and total sperm count; which was confirmed also by the logistic predictions analysis. Alcohol consumption impacted first on membrane functional integrity and nuclear maturity. A J-shaped association between BMI or alcohol consumption with semen quality was found in the multivariate analysis. Conclusion The factors considered in this study showed a synergistic negative impact on semen quality, being age and unhealthy weight the most important ones. Reducing the exposure to lifestyle risk factors may be promising for improving sperm quality in infertile patients.

The success of the galling insects sharing the same microhabitat depends both on the synchrony of their life cycles with the leaf flushing of the super-host plant and to the asynchrony among their life cycles. The asynchrony of the multivoltine life cycles of Lopesia spp. (Diptera—Cecidomyiidae) is favored by the constant leaf flushing in M. gemmulata, and favors the non-overlapping of gall induction periods. Peculiarly, the univoltine life cycle of the galling Lepidoptera on its stem galls is synchronized to the availability of mature host leaves during the rainy season, which is important for the water potential in host stem branches. The abundance of the Lopesia gall morphotypes follow the phenology of M. gemmulata, which obeys the seasonal pattern of water availability in the neotropical savanna climate.

The impact of Apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells (hiPSCs), post-mortem brain and APOE targeted replacement (APOE-TR) mice. Population and isogenic models demonstrate that APOE4 local haplotype rather than a single risk allele contributes to risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

Women are disproportionately affected by Alzheimer's disease (AD), yet little is known about sex-specific effects on the development of AD in the Down syndrome (DS) population. DS is caused by a full or partial triplication of chromosome 21, which harbors the amyloid precursor protein (APP) gene, among others. The majority of people with DS in their early- to mid-40s will accumulate sufficient amyloid-beta (Aβ) in their brains along with neurofibrillary tangles (NFT) for a neuropathological diagnosis of AD, and the triplication of the APP gene is regarded as the main cause. Studies addressing sex differences with age and impact on dementia in people with DS are inconsistent. However, women with DS experience earlier age of onset of menopause, marked by a drop in estrogen, than women without DS. This review focuses on key sex differences observed with age and AD in people with DS and a discussion of possible underlying mechanisms that could be driving or protecting from AD development in DS. Understanding how biological sex influences the brain will lead to development of dedicated therapeutics and interventions to improve the quality of life for people with DS and AD.

Galling insects manipulate host plant tissues for their own benefit. Because of feeding activity of the gall insects, both structural and metabolic changes occur in the host plant, leading to the formation of an abnormal growth of new organ (the gall). Galls induced by Palaeomystella oligophaga (Lepidoptera) on Macairea radula (Melastomataceae) depend on the constant larval feeding stimulus for establishment and development. The gall consists of two tissue compartments – the storage and nutritive tissues. These two gall tissues were investigated here in terms of the levels of oxidative stress and of a possible differential chemical investment. In addition, we investigated the relationship between gall coloration and the concentration of primary metabolites. Our results supported a differential investment of chemical compounds in the M. radula compartments, with higher concentrations of polysaccharides, malondialdehyde, and phenolic compounds in the storage tissue, and higher total soluble sugar concentrations in the nutritive tissue. Regarding gall colour, conflicting results were observed in the present gall system. Water-soluble polysaccharides were detected at higher concentrations in red galls than in green galls. As a water-soluble polysaccharide, pectin seems to be related to increased anthocyanin stability, a process that might occur in galls, leading to red coloration.

To explore in mice if a 15% food restriction protocol during pregnancy programs the offspring postnatal development, with emphasis on reproductive function, and to assess if ghrelin (Ghrl) administration to mouse dams exerts effects that mimic those obtained under mild caloric restriction. Mice were 15% food-restricted, injected with 4 nmol/animal/day of Ghrl, or injected with the vehicle (control) thorough pregnancy. After birth, the pups did not receive further treatment. Pups born from food-restricted dams (FR pups) were lighter than Ghrl pups at birth, but reached normal weight at adulthood. Ghrl pups were heavier at birth and gained more weight than control pups (C pups). This effect was not associated with plasma IGF-1. FR pups showed a delay in pinna detachment and eye opening, while an advance was observed in Ghrl pups. FR pups showed also impairment in the surface-righting reflex. In both female FR and Ghrl pups, there was an advance in vaginal opening and, in adulthood, FR pups showed a significant decrease in their own litter size and plasma progesterone, and an increase in embryo loss. A delay in testicular descent was evident in male Ghrl pups. Changes in puberty onset were not associated with differences in the expression of Kiss1 in hypothalamic nuclei. Finally, in adulthood, FR pups showed a significant decrease in sperm quality. In conclusion, a mild food restriction thorough gestation exerted programming effects on the offspring, affecting also their reproductive function in adulthood. These effects were not similar to those of intragestational Ghrl administration.

People with Down syndrome (DS) have increased risk of Alzheimer disease (AD), presumably conferred through genetic predispositions arising from trisomy 21. These predispositions necessarily include triplication of the amyloid precursor protein (APP), but also other Ch21 genes that confer risk directly or through interactions with genes on other chromosomes. We discuss evidence that multiple genes on chromosome 21 are associated with metabolic dysfunction in DS. The resulting dysregulated pathways involve the immune system, leading to chronic inflammation; the cerebrovascular system, leading to disruption of the blood brain barrier (BBB); and cellular energy metabolism, promoting increased oxidative stress. In combination, these disruptions may produce a precarious biological milieu that, in the presence of accumulating amyloid, drives the pathophysiological cascade of AD in people with DS. Critically, mechanistic drivers of this dysfunction may be targetable in future clinical trials of pharmaceutical and/or lifestyle interventions.

The terms deodorants and antiperspirants very frequently used interchangeably despite the fact that they employ completely different active substances and mechanisms of action. Antiperspirants are necessarily deodorants due to the lack of substrate to decompose. They nevertheless represent a group of very specific substances that create particular problems due to the presence of aluminium chlorohydrate, or ACH, (Al2(OH)5Cl, 2H2O), aluminium sesquichlorohydrate and aluminium-zirconium complex, which, after hydrolysis, causes intense acidification of the skin, hence the importance of inclusion of emollients and pH regulators in formulations. Moreover, systemic aluminium is thought to be genotoxic and to promote breast cancer, and it is thus at the centre of numerous scientific controversies. Nevertheless, its potential toxicity following topical application is related to its ability to penetrate skin, which is as yet poorly understood but considered very low, a fact that may provide some degree of reassurance regarding its use in cosmetic products. Its role in Alzheimer's disease has not been proven. On the other hand, zirconium salts are considered toxic and are partly regulated in Europe. The problems associated with deodorants are those arising from the presence of antiseptics (triclosan, usnic acid) capable of inducing bacterial resistance, but more particularly, the presence of axillary dermatitis due to the allergenic potential of the fragrances and essential oils used (e.g. isoeugenol, citronellal, lyral, cinnamic aldehyde, etc.).

Although there is a general perception that adolescent social media use is a global phenomenon, there is a scarcity of data on patterns and preferences of social media use among youth in low- and middle-income countries. We here describe self-reported prevalences and perceived effects of social media use in a school-based sample of Brazilian adolescents.We analyzed cross-sectional data on 7,113 adolescents aged 14 to 16 years-old enrolled in 101 public state schools between 2018 and 2019 in Porto Alegre, Brazil.Among the 7,113 with complete data for analyses, 54.9% were female, and 60.6% reported their skin color as white. At least one social media platform was used by 97.7% of adolescents everyday, and 64.7% reported being online "almost constantly". YouTube and WhatsApp were the most popular platforms. Most participants perceived the effect of social media use on their lives as neutral.The pattern of social media use by adolescents in Porto Alegre, Brazil, is similar to that reported for samples from high income countries. Also, we found that those who reported being constantly online were also more likely to report socializing with their friends offline.

Down syndrome (DS), the most common genetic cause of intellectual disability, is characterized by the triplication of chromosome 21. The triplication of the amyloid precursor protein gene, amyloid precursor protein (APP), is thought to be the underlying reason why Alzheimer's disease (AD) pathology develops in the DS brain with age. In this chapter, we explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.

The gall structure is built from redifferentiation of host plant tissues, changing the cell wall proprieties and associated functions. Because of the oxidative stress imposed by the galling insect on the plant tissues, some phenotypic traits associated with cell wall metabolism may be suppressed during gall development. Using an immunocytochemical approach we investigated the pectin and glycoprotein composition of the cell walls during non-galled leaf development and galls induced on Aspidosperma tomentosum (Apocynaceae). Embedding in historesin was used for anatomical characterization, as well as for immunocytochemical analyses. The samples were probed with the primary monoclonal antibodies JIM5, JIM7, LM1, LM2, LM5 and LM6. The gall develops especially from cell hypertrophy and hyperplasia of the spongy and palisade parenchyma, which determine its shape. Epitopes of β-D-galactan and α-L-arabinan in the galls were totally suppressed or less expressed. The increased labeling of homogalacturonan epitopes, especially in senescent galls, is a clear indicator that pectin methylesterase activity is maintained despite oxidative stresses imposed by the galling insect. Arabinogalactan proteins were not detected in any non-galled leaf or gall stages. The galling insect deeply changed the structure and deposition pattern of the cell wall, promoting new functionalities in the gall tissue compartments.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is mainly transmitted by airborne droplets generated by infected individuals. Since this and many other pathogens are able to remain viable on inert surfaces for extended periods of time, contaminated surfaces play an important role in SARS-CoV-2 fomite transmission. Cosmetic products are destined to be applied on infection-sensitive sites, such as the lips and eyelids. Therefore, special biosafety precautions should be incorporated into the routine procedures of beauty parlors and shops. Indeed, innovative cosmetics companies are currently searching for disinfection protocols that ensure the customers’ safety in makeup testing. Here, we propose an ultraviolet germicidal irradiation (UVGI) strategy that can be used to reduce the odds of COVID-19 fomite transmission by makeup testers. It is well-known that UVGI effectively inactivates pathogens on flat surfaces and clear fluids. However, ultraviolet-C (UVC) radiation at 254 nm penetrates poorly in turbid and porous materials, such as makeup and lipstick formulations. Thus, we investigated the virucidal effect of UVGI against SARS-CoV-2 deposited on such substrates and compared their performance to that of flat polystyrene surfaces, used as controls. Concentrated infectious SARS-CoV-2 inoculum (106 PFU/mL) deposited on lipstick and makeup powder was completely inactivated (>5log10 reduction) following UVC exposures at 1,260 mJ/cm2, while flat plastic surfaces required 10 times less exposure (126 mJ/cm2) to reach the same microbicidal performance. We conclude that UVGI comprises an effective disinfection strategy to promote biosafety for cosmetics testers. However, appropriate UVC dosimetry must be implemented to overcome inefficiencies caused by the optical properties of turbid materials in lipsticks and makeup powders.

Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.

La nitrurazione è ampiamente utilizzata per migliorare durezza, resistenza a fatica, a usura e a corrosione degli acciai. Il processo di nitrurazione gassosa induce la formazione in superficie della coltre bianca, costituita dai nitruri ε e γ’: il nitruro ε-Fe3N costituisce prevalentemente lo strato esterno più poroso e i nitruri ε-Fe3N e γ’-Fe4N costituiscono il sottostante strato compatto, adeso allo strato di diffusione. Le caratteristiche microstrutturali e, conseguentemente, le proprietà mi- cromeccaniche della coltre bianca influenzano la resistenza a usura dei componenti nitrurati e sempre più frequentemente ai trattamentisti industriali giungono richieste molto differenti in termini di spessore della coltre bianca e strato poroso. Questo lavoro si focalizza sulla caratterizzazione microstrutturale e micromeccanica della coltre bianca prodotta sull’accia- io 42CrMo4 dalla nitrurazione gassosa, mediante microscopia elettronica ad alta risoluzione, diffrazione a RX, scratch test, nanoindentazione e test tribologici ball-on-disk (antagonista: allumina). L’analisi della varianza (ANOVA) è stata utilizzata per valutare l’influenza dello spessore totale della coltre bianca e dello strato poroso sulla resistenza a usura dell’acciaio 42CrMo4 nitrurato. I risultati sperimentali sono stati elaborati mediante Design of Experiments (DoE), con lo scopo di otte- nere un’equazione che descriva il coefficiente di usura come funzione delle proprietà microstrutturali e meccaniche della coltre bianca. I risultati delle prove sperimentali e dell’analisi con il DoE hanno dimostrato che lo spessore dello strato e la porosità influenzano in modo rilevante la resistenza a usura dell’acciaio.

Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01143-1.

Down syndrome (DS) is a form of accelerated aging, and people with DS are highly prone to aging-related conditions that include vascular and neurological disorders. Due to the overexpression of several genes on Chromosome 21, for example genes encoding amyloid precursor protein (APP), superoxide dismutase (SOD), and some of the interferon receptors, those with DS exhibit significant accumulation of amyloid, phospho-tau, oxidative stress, neuronal loss, and neuroinflammation in the brain as they age. In this review, we will summarize the major strides in this research field that have been made in the last few decades, as well as discuss where we are now, and which research areas are considered essential for the field in the future. We examine the scientific history of DS bridging these milestones in research to current efforts in the field. We extrapolate on comorbidities associated with this phenotype and highlight clinical networks in the USA and Europe pursuing clinical research, concluding with funding efforts and recent recommendations to the NIH regarding DS research.

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In the present review, we highlight the physiological role of astrocytes in the CNS, including their communication with other cells in the brain. Furthermore, we discuss exciting findings and novel experimental approaches that elucidate the role of astrocytes in multiple neurological disorders.

Significance As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses, and the chronic inflammation mediated by inflammatory receptors represents a key mechanism by which amyloid-beta (Aβ) drives the development of cognitive decline in Alzheimer’s disease (AD). A crucial aspect of this process is a failure to resolve inflammation, which involves the suppression of inflammatory cell influx and the endocytosis of inflammatory receptors. We found that ablation of the endosomal adaptor target of Myb1 (TOM1) worsens neuroinflammation, impairs microglial phagocytosis, and significantly exacerbates amyloid deposition. Conversely, restoration of TOM1 reverses these effects and reduces Aβ pathology. These results highlight the importance of endosomal adaptors and their interaction with inflammatory receptors in the pathogenesis of AD., Defects in interleukin-1β (IL-1β)–mediated cellular responses contribute to Alzheimer’s disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

Microglia are critical in brain development and Alzheimer's disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.

BackgroundDespite being commonly expressed in the general population, the human leucocyte antigen (HLA)-B27 allele strongly increases the susceptibility to develop spondyloarthritis (SpA). Likewise, the association between the HLA-B51 allele and the development of Behçet’s disease is well documented. In a previous pilot study, we identified similarities and differences in patients with axial or peripheral SpA according to the presence of HLA-B51 only, HLA-B27 only or neither of the two.ObjectivesTo investigate the clinical and imaging findings of SpA patients according to the absence or presence of HLA-B27 or HLA-B51 in an independent validation cohort.MethodsWe retrospectively analyzed patients with axial or peripheral SpA, according to the ASAS criteria, referring to our institution between 2020 and 2021. All patients had been tested for HLA-B alleles. Patients with HLA-B51 haplotype and fulfilling the criteria for Behçet’s disease were excluded.ResultsThe independent validation cohort included 185 patients and was comparable to the original cohort of 236 patients with regard to age, gender, age at diagnosis and symptom duration. In line with the findings in the original cohort we observed that aphtous lesions were more prevalent in patients with HLA-B51 (p< 0.001) while inflammatory bowel disease was more prevalent in the double negative group (p=0.0006). Unlike the original cohort, patients of the validation cohort did not show a different prevalence of inflammatory back pain (IBP) at disease onset or in the disease course based on the HLA status. A sub-analysis by gender demonstrated a comparable prevalence of IBP in males and females within the 3 groups. As novel finding, we observed that enthesitis and psoriasis were significantly more prevalent in the double negative group compared to the B27 and B51 groups (p=0.004) and their prevalence did not differ when comparing B27 and B51 groups. With regard to imaging in patients with axial manifestations, in the original cohort we observed that sacroiliitis, assessed by X-ray or magnetic resonance imaging (MRI), were more prevalent in double negative and HLA-B27 patients, compared to HLA-B51 patients and the latter showed a significant negative association with sacroiliitis on imaging (OR 0.342 CI 0.189-0.619 pConclusionOur findings underscore the clinical and radiological heterogeneity of patients with SpA and HLA-B51 alone or neither HLA-B27 nor HLA-B51 compared to those with HLA-B27 only and underline the need to explore further this area by means of registry data with large real-life cohorts.Disclosure of InterestsNone declared

BackgroundLocal and systemic reactions have been observed after all vaccines for SARS-CoV-2 but in the majority of cases, symptoms are mild and self-limiting. However, evidence on more severe clinical scenarios, requiring admission to hospital or referral to outpatient clinics after the administration of SARS-CoV-2 vaccines has accrued. This also includes newly diagnosed diseases, such as cardiovascular and immune-mediated inflammatory diseases (IMID).ObjectivesWe aimed at quantifying the burden of post-vaccine hospital admissions/referrals and of newly diagnosed IMID.MethodsClinical records of patients referred to our Internal Medicine institution (both inpatients and outpatients) between February and June 2021 were retrospectively assessed. Subjects having received one or more doses of any of the EMA-approved SARS-CoV-2 vaccines within the previous 30 days were included. Subjects with a previous diagnosis of IMID were excluded.ResultsOur cohort included 99 patients, 45 females and 54 males, with a mean age of 64 years and a median of 3 comorbities (range 0-7). Eighty-eight patients (89%) required admission to the Internal Medicine ward while 11 were referred to the outpatient clinic. 68 (69%) of patients received the vaccine BNT162b2, 16 (16%) the ChAdOx1 nCoV-19, 9 (9%) the mRNA-1273 and 6 (6%) the Ad26.COV2.S. Twenty-seven (27%) subjects developed symptoms after the first vaccine dose with a mean latency of 2 days (median=0 indicating symptom onset on the day of the vaccine administration). Twenty-four (24%) subjects developed symptoms after the second dose with a mean latency of 4 days (median 1 day). All the other subjects did not develop symptoms within the week after the vaccine and were admitted for reasons apparently unrelated to vaccine administration. The number of presenting complaints ranged between 1 and 4 with 87% of subjects presenting with 1 or two coexisting complaints. Gastrointestinal manifestations were the most frequent being the presenting complaint in 31 (31%) of patients followed by severe fatigue/appetite loss in 19 (19%) of subjects, fever in 18 (18.2%) and neurological manifestation in 16 (16%) of subjects. A temporal and causal association with the SARS-CoV-2 vaccine was identified since all other known causes for these manifestations were ruled out. No in-hospital deaths were observed and 19 (19%) patients were diagnosed with a new onset IMID (Table 1). The clinical picture of these subjects was not significantly different from that of patients without a confirmed IMID and neither were demographic features. No association with the type of vaccine was observed.Table 1.Immune-mediated inflammatory diseases diagnosed after SARS-CoV2 vaccination (N=19)DiseaseNumber of patientsRheumatoid arthritis5Psoriatic arthritis2IgA vasculitis2Spondyloarthritis1Giant cell arteritis1Polymyalgia rheumatica1Gout1Primary biliary cholangitis1Antiphospholipid syndrome1Graves’ disease1Ulcerative colitis1Autoimmune thrombocytopenia1Leukocytoclastic vasculitis1ConclusionOur data show that post-vaccine newly diagnosed IMID may represent a challenge in clinical practice and it seems that no demographic or clinical feature is able to predict their onset. A multidisciplinary cooperation and registry data are needed in order to reliably estimate and define the impact of SARS-CoV-2 vaccinations on new onset IMID.Disclosure of InterestsNone declared

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are relevant to fetal and infant growth and development. Objective: to assess whether long-term exposure to dietary ω-3 PUFA imbalance alters pre- and/or postnatal pups' development and reproductive function later in life. Mice dams were fed with ω-3 PUFA Control (soybean oil, 7%), Deficient (sunflower oil, 7%) or Excess (blend oil; 4.2% cod-liver+2.8% soybean) diet before conception and throughout gestation-lactation and later on, their pups received the same diet from weaning to adulthood. Offspring somatic, neurobiological and reproductive parameters were evaluated. Excess pups were lighter during the preweaning period and shorter in length from postnatal day (PND) 7 to 49, compared to Control pups (P