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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.

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.

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.

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.

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

Highlights • Recent advances in Zika virus drug discovery efforts. • Drug repositioning and computationally guided compounds. • New inhibitors and promising ZIKV molecular targets. • Promising host cell targets for ZIKV drug design. • Lessons learned from ZIKV drug discovery., Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A–Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond., Teaser Zika clinical outcomes might be nefarious impacting newborns for a lifetime. There is still no drug available to cure Zika. We provide guidance to help understand and advance the search for a cure.

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 remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus 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.

COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of SARS-CoV-2-infected individuals with mild respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 25% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Infection of neural stem cell-derived astrocytes changed energy metabolism, altered key proteins and metabolites used to fuel neurons and for biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality1,2. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here we show that SARS-CoV-2 infects human CD4+T helper cells, but not CD8+T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS-CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

Background In the last years, many health apps have been developed to support citizens' and patients' health management. Nevertheless, a thorough evaluation is necessary to support the decision to incorporate them into healthcare systems. Health technology assessment (HTA) could be considered a valid evaluation tool allowing considering different stakeholders' perspectives. This research aimed to look for studies that applied HTA to health apps and to analyze feasibility and limits of HTA in this field. Methods A systematic review was performed considering three databases, namely PubMed, Web of Science (WoS) and University of York-Centre for Reviews and Dissemination database. Being the topic of health app assessment new, articles were considered eligible if they assessed at least two of the domains of the HTA core model suggested by the European network for Health Technology Assessment (EUnetHTA). Furthermore, only articles published in English in the last 5 years were considered. Results A total of 850 articles were found: 383 articles from PubMed, 462 from WoS and 5 from York. After removing duplicates, 708 articles remained and 43 were eventually included after the screening process. Seven articles were focused on apps used by healthcare professionals, while 36 dealt with apps aimed to support patients. None of the papers explicitly mentioned HTA as assessment tool. Indeed, not all the domains of the HTA core model were assessed in any article. Apps' technical description, clinical effectiveness and social aspects were the domains considered more often. On the contrary, costs and economic evaluation was clearly faced by one article only. Conclusions Even though the scientific literature on health apps is growing, the adoption of standardized methods for their evaluation, such as HTA, is still scant. This might be due to peculiarities of health apps and points out the importance of adapting existing methods in order to let a thorough assessment possible.

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer’s disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome. An integrative analysis of single-nucleus assay for transposase-accessible chromatin with sequencing and RNA sequencing in normal and Alzheimer’s disease brain tissue identifies cell-type-specific cis-regulatory elements and candidate target genes at disease-associated loci.

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The present updated systematic review and meta-analysis aims to summarize the evidence from published studies with low risk for any important bias (based on methodological quality assessment) investigating the potential associations of adiposity with sperm quality and reproductive hormones. We conducted a systematic search of the literature published in MEDLINE-PubMed and EMBASE through June 2019. Based on the criteria in our review, 169 eligible publications were used for data abstraction. Finally, 60 articles were included in the qualitative analysis and 28 in the quantitative analysis. Our systematic review results indicated that overweight and/or obesity were associated with low semen quality parameters (i.e., semen volume, sperm count and concentration, sperm vitality and normal morphology) and some specific reproductive hormones (e.g., inhibin B, total testosterone and sex hormone-binding globulin). Overweight and/or obesity were also positively associated with high estradiol concentrations. Meta-analysis indicated that overweight and/or obesity categories were associated with lower sperm quality (i.e., semen volume, sperm count and concentration, sperm vitality, total motility and normal morphology), and underweight category was likewise associated with low sperm normal morphology. In conclusion, our results suggest that maintaining a healthy body weight is important for increasing sperm quality parameters and potentially male fertility.

Funding Acknowledgements Nothing to declare OnBehalf None Background Peri-coronary fat attenuation index (pFAI) has emerged as a clinical marker of coronary inflammation, which is measurable from standard coronary CT angiography (CCTA). It compares well with gold-standard methods for the assessment of coronary inflammation and can predict future cardiovascular events. pFAI could prove invaluable to differentiate an inflammatory from noninflammatory coronary artery status, helping unravel the mechanisms subtending an event classified as myocardial infarction with nonobstructive coronary arteries (MINOCA) or Tako-Tsubo syndrome (TTs). Methods and Results Patients admitted with MINOCA and TTs diagnosis between 2011 and 2018, who had both CCTA and CMR performed during or shortly after the acute phase, were selected and pFAI measured in their index CCTA. pFAI was also measured in a control subjects who had CCTA for atypical chest pain work-up, no obstructive coronary artery disease found in their CCTA and no cardiac events at a minimum 2-year follow-up. In the n = 106 MINOCA/TTs patients selected, mean pFAI averaged for the 3 coronary arteries was -68.37 ± 8.29 vs -78.03 ± 6.20 in the n = 106 controls (p confirmed also when comparing mean pFAI in each single coronary artery between MINOCA/TTs and controls (p particular, were also more frequently found (p controls. Conclusions In MINOCA and TTs patients, CCTA is not only able to detect otherwise angiographically invisible atherosclerotic plaques, but its diagnostic yield can be further expanded using the simple off-line measurement of pFAI for the characterization of peri-coronary fat tissue. In MINOCA/TTs mean pFAI clearly demonstrates higher values in comparison with controls, a finding which has been previously associated with coronary artery inflammation. We speculate that this newly-available diagnostic tool in the future may help select patients for new therapies, for example therapies targeting coronary inflammation. I was able to build a table. Abstract 1176 Figure.

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes/macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor- 1α (HIF - 1α) and consequently promotes glycolysis. HIF- 1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1 ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.

The structural complexity of galls depends on species-specific interaction driven by the galling taxa. However, the host plant and environment stressors can impose limits on gall developmental patterns and impact the establishment of gall morphology. Herein, we employed qualitative and quantitative approaches in order to elucidate how cell divisions, elongation patterns, and tissue organization are determinant for the development of intralaminar gall morphology induced by Pseudophacopteron longicaudatum Malenovský, Burckhardt, Queiroz, Isaias & Oliveira (Hemiptera: Psylloidea: Phacopteronidae) on leaves of Aspidosperma tomentosum Mart. (Apocynaceae). In addition, we aimed to determine which anatomical process can discriminate the stages of gall development, plus, examine the histochemical and cytological profiles of the galls. The differentiated structures, mainly abaxial epidermis and spongy parenchyma, are associated with gall closure, with hyperplastic events concentrated in the young phase of the galls. Thus, epidermis and spongy parenchyma hypertrophy and are responsible for the determination of the nymphal chamber formation and gall shape. The mature galls do not differentiate into a typical nutritive cells and do not develop a histochemical gradient in their tissues. The cytological features of galls such as plastoglobules and multivesicular bodies are related to ROS scavenging mechanisms due the high oxidative stress.