Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease.

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

Translocations and inversions: major chromosomal rearrangements during Vigna (Leguminosae) evolution.

KEY MESSAGE: Inversions and translocations are the major chromosomal rearrangements involved in Vigna subgenera evolution, being Vigna vexillata the most divergent species. Centromeric repositioning seems to be frequent within the genus. Oligonucleotide-based fluorescence in situ hybridization (Oligo-FISH) provides a powerful chromosome identification system for inferring plant chromosomal evolution. Aiming to understand macrosynteny, chromosomal diversity, and the evolution of bean species from five Vigna subgenera, we constructed cytogenetic maps for eight taxa using oligo-FISH-based chromosome identification. We used oligopainting probes from chromosomes 2 and 3 of Phaseolus vulgaris L. and two barcode probes designed from V. unguiculata (L.) Walp. genome. Additionally, we analyzed genomic blocks among the Ancestral Phaseoleae Karyotype (APK), two V. unguiculata subspecies (V. subg. Vigna), and V. angularis (Willd.) Ohwi & Ohashi (V. subg. Ceratotropis). We observed macrosynteny for chromosomes 2, 3, 4, 6, 7, 8, 9, and 10 in all investigated taxa except for V. vexillata (L.) A. Rich (V. subg. Plectrotropis), in which only chromosomes 4, 7, and 9 were unambiguously identified. Collinearity breaks involved with chromosomes 2 and 3 were revealed. We identified minor differences in the painting pattern among the subgenera, in addition to multiple intra- and interblock inversions and intrachromosomal translocations. Other rearrangements included a pericentric inversion in chromosome 4 (V. subg. Vigna), a reciprocal translocation between chromosomes 1 and 5 (V. subg. Ceratotropis), a potential deletion in chromosome 11 of V. radiata (L.) Wilczek, as well as multiple intrablock inversions and centromere repositioning via genomic blocks. Our study allowed the visualization of karyotypic patterns in each subgenus, revealing important information for understanding intrageneric karyotypic evolution, and suggesting V. vexillata as the most karyotypically divergent species.

Neutrophil virucidal activity against SARS-CoV-2 is mediated by NETs.

BACKGROUND: The inflammation in the lungs and other vital organs in COVID-19 are characterized by the presence of neutrophils and high concentration of neutrophil extracellular traps (NETs), which also seems to mediate host tissue damage. However, it is not known whether NETs could have virucidal activity against SARS-CoV-2. METHODS: We investigated whether NETs could prevent SARS-CoV-2 replication in neutrophils and epithelial cells, and what the consequence of NETs degradation in K18-humanized ACE2 transgenic mice infected with SARS-CoV-2. RESULTS: Here, by immunofluorescence microscopy we observed that viral particles co-localize with NETs in neutrophils isolated from COVID-19 patients or from healthy individuals and infected in vitro. The inhibition of NETs production increased virus replication in neutrophils. In parallel, we observed that NETs inhibited virus abilities to infect and replicate in epithelial cells after 24 h of infection. Degradation of NETs with DNase I prevented their virucidal effect in vitro. Using K18-humanized ACE2 transgenic mice we observed a higher viral load in animals treated with DNase I. On the other hand, the virucidal effect of NETs was not dependent on neutrophil elastase or myeloperoxidase activity. CONCLUSION: Our results provide evidence of the role of NETosis as a mechanism of SARS-CoV-2 viral capture and inhibition.

Tumour necrosis factor plays a deleterious role in the pathogenesis of chikungunya virus infection.

Arthralgia is a hallmark of chikungunya virus (CHIKV) infection and can be very debilitating and associated with a robust local inflammatory response. Many pathophysiological aspects associated with the disease remain to be elucidated. Here, we describe a novel model of CHIKV infection in immunocompetent mice and evaluate the role of tumour necrosis factor in the pathogenesis of the disease. C57BL/6 wild type (WT) or TNF receptor 1 deficient (TNFR1-/- ) mice were inoculated with 1 × 106 PFU of CHIKV in the paw. Alternatively, etanercept was used to inhibit TNF in infected WT mice. Hypernociception, inflammatory and virological analysis were performed. Inoculation of CHIKV into WT mice induced persistent hypernociception. There was significant viral replication in target organs and local production of inflammatory mediators in early time-points after infection. CHIKV infection was associated with specific humoral IgM and IgG responses. In TNFR1-/- mice, there was a decrease in the hypernociception threshold, which was associated with a milder local inflammatory response in the paw but delayed viral clearance. Local or systemic treatment with etanercept reduced CHIKV-induced hypernociception. This is the first study to describe hypernociception, a clinical correlation of arthralgia, in immunocompetent mice infected with CHIKV. It also demonstrates the dual role of TNF in contributing to viral clearance but driving tissue damage and hypernociception. Inhibition of TNF may have therapeutic benefits but its role in viral clearance suggests that viral levels must be monitored in CHIKV-infected patients and that TNF inhibitors should ideally be used in combination with anti-viral drugs.

Mixed circuit training acutely reduces arterial stiffness in patients with chronic stroke: a crossover randomized controlled trial.

PURPOSE: Investigate whether a single bout of mixed circuit training (MCT) can elicit changes in arterial stiffness in patients with chronic stroke. Second, to assess the between-day reproducibility of post-MCT arterial stiffness measurements. METHODS: Seven participants (58 ± 12 years) performed a non-exercise control session (CTL) and two bouts of MCT on separate days in a randomized counterbalanced order. The MCT involved 3 sets of 15 repetition maximum for 10 exercises, with each set separated by 45-s of walking. Brachial-radial pulse wave velocity (br-PWV), radial artery compliance (AC) and reflection index (RI1,2) were assessed 10 min before and 60 min after CTL and MCT. Ambulatory arterial stiffness index (AASI) was calculated from 24-h recovery ambulatory blood pressure monitoring. RESULTS: Compared to CTL, after 60 min of recovery from the 1st and 2nd bouts of MCT, lower values were observed for br-PWV (mean diff = - 3.9 and - 3.7 m/s, respectively, P < 0.01; ICC2,1 = 0.75) and RI1,2 (mean diff = - 16.1 and - 16.0%, respectively, P < 0.05; ICC2,1 = 0.83) concomitant with higher AC (mean diff = 1.2 and 1.0 × 10-6 cm5/dyna, respectively, P < 0.01; ICC2,1 = 0.40). The 24-h AASI was reduced after bouts of MCT vs. CTL (1st and 2nd bouts of MCT vs. CTL: mean diff = - 0.32 and - 0.29 units, respectively, P < 0.001; ICC2,1 = 0.64). CONCLUSION: A single bout of MCT reduces arterial stiffness during laboratory (60 min) and ambulatory (24 h) recovery phases in patients with chronic stroke with moderate-to-high reproducibility. TRIAL REGISTRATION: Ensaiosclinicos.gov.br identifier RBR-5dn5zd.

Spinal cord protection in open and endovascular approaches to thoracoabdominal aortic aneurysms.

Despite advancements in surgical and postoperative management, spinal cord injury has been a persistent complication of both open and endovascular repair of thoracoabdominal and descending thoracic aortic aneurysm. Spinal cord injury can be explained with an ischemia-infarction model which results in local edema of the spinal cord, damaging its structure and leading to reversible or irreversible loss of its function. Perfusion of the spinal cord during aortic procedures can be enhanced by several adjuncts which have been described with a broad variety of evidence in their support. These adjuncts include systemic hypothermia, cerebrospinal fluid drainage, extracorporeal circulation and distal aortic perfusion, segmental arteries reimplantation, left subclavian artery revascularization, and staged aortic repair. The Authors here reviewed and discussed the role of such adjuncts in preventing spinal cord injury from occurring, pinpointing current evidence and outlining future perspectives.

Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline.

Cognitive abilities tend to decline with aging, with variation between individuals, and many studies seek to identify genetic biomarkers that more accurately anticipate risks related to pathological aging. We investigated the influence of BDNF, NTRK2, and FNDC5 single nucleotide polymorphisms (SNPs) on the cognitive performance of young and older adults with contrasting educational backgrounds. We addressed three questions: (1) Is education associated with reduced age-related cognitive decline? (2) Does the presence of SNPs explain the variation in cognitive performance observed late in life? (3) Is education differentially associated with cognition based on the presence of BDNF, NTRK2, or FNDC5 polymorphisms? We measured the cognitive functions of young and older participants, with lower and higher education, using specific and sensitive tests of the Cambridge Automated Neuropsychological Test Assessment Battery. A three-way ANOVA revealed that SNPs were associated with differential performances in executive functions, episodic memory, sustained attention, mental and motor response speed, and visual recognition memory and that higher educational levels improved the affected cognitive functions. The results revealed that distinct SNPs affect cognition late in life differentially, suggesting their utility as potential biomarkers and emphasizing the importance of cognitive stimulation that advanced education early in life provides.

Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology.

BACKGROUND: The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear. OBJECTIVES: We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19. METHODS: We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection. RESULTS: We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage. CONCLUSION: These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.

Effects of Disodium Cromoglycate Treatment in the Early Stage of Diabetic Nephropathy: Focus on Collagen Deposition.

Inflammation is part of the pathophysiology of diabetic nephropathy (DN), and mast cells (MCs) appear to increase in number within the kidney of humans and animals with diabetes. Disodium cromoglycate (CG) not only inhibits the degranulation of MCs but also has several secondary effects that may improve inflammation. However, little is known about the effects of CG treatment on kidney collagen deposition and myofibroblast population in animals with type I diabetes (DM1). Data presented here suggest that the increases in the density and activity of MCs within the kidney in the early stages of DN contribute to tubulointerstitial collagen deposition, even in the absence of alterations in the renal myofibroblast population. Moreover, CG treatment showed renoprotective effects in rats with DM1, which appear to be linked to its mast cell stabilizing property and its ability to avoid some detrimental morphofunctional alterations.

Clinical benefits of music-based interventions on preterm infants' health: A systematic review of randomised trials.

AIM: This systematic review aimed to differentiate and isolate the results of different music-based interventions used with preterm infants in the neonatal intensive care unit and explore their clinical benefits. METHODS: The last search was performed on 5 July 2021 on Web of Science, Scopus, EMBASE, PsycINFO, CINAHL, LILACS and CENTRAL. Only randomised clinical trials that explored the health benefits of music-based interventions were considered. RESULTS: A total of 39 studies were included. All music-based interventions were divided into music medicine and music therapy. The overall results suggested that music medicine interventions were associated with a significant improvement in pain relief; in turn, improvements in cardiac and respiratory function, weight gain, eating behaviour, and quiet alert and sleep states were more consistent in studies that followed a music therapy approach with the presence of a music therapist. CONCLUSION: This review supports the beneficial effects of music-based interventions on the health of preterm infants in a neonatal intensive care unit; however, it also offers suggestions for future studies in order to increase the number of interventions with music therapists, since the results of music therapy approaches were more consistent for physiological and behavioural outcomes.

Literature Review on Ship Localization, Classification, and Detection Methods Based on Optical Sensors and Neural Networks.

Object detection is a common application within the computer vision area. Its tasks include the classic challenges of object localization and classification. As a consequence, object detection is a challenging task. Furthermore, this technique is crucial for maritime applications since situational awareness can bring various benefits to surveillance systems. The literature presents various models to improve automatic target recognition and tracking capabilities that can be applied to and leverage maritime surveillance systems. Therefore, this paper reviews the available models focused on localization, classification, and detection. Moreover, it analyzes several works that apply the discussed models to the maritime surveillance scenario. Finally, it highlights the main opportunities and challenges, encouraging new research in this area.

Leishmania amazonensis hijacks host cell lysosomes involved in plasma membrane repair to induce invasion in fibroblasts.

Intracellular parasites of the genus Leishmania are the causative agents of leishmaniasis. The disease is transmitted by the bite of a sand fly vector, which inoculates the parasite into the skin of mammalian hosts, including humans. During chronic infection the parasite lives and replicates inside phagocytic cells, notably the macrophages. An interesting, but overlooked finding, is that other cell types and even non-phagocytic cells have been found to be infected by Leishmania spp. Nevertheless, the mechanisms by which Leishmania invades such cells had not been previously studied. Here, we show that L. amazonensis can induce their own entry into fibroblasts independently of actin cytoskeleton activity, and, thus, through a mechanism that is distinct from phagocytosis. Invasion involves subversion of host cell functions, such as Ca2+ signaling and recruitment and exocytosis of host cell lysosomes involved in plasma membrane repair.This article has an associated First Person interview with the first author of the paper.

Prevalence of human papillomavirus 6 and 11 variants in recurrent respiratory papillomatosis.

Human papillomavirus (HPV) types 6 and 11 are the etiological agents of recurrent respiratory papillomatosis (RRP). We examined the prevalence and distribution of HPVs 6 and 11 genetic variants in juvenile onset (JORRP) and adult onset (AORRP) laryngeal papillomas. Cases of JORRP and AORRP were collected, retrospectively. HPV detection and genotyping were accessed by polymerase chain reaction-sequencing in 67 RRP samples. Overall, the most prevalent HPV-6 variants were from B1 (55.8%) and B3 (27.9%) sublineages, whereas among HPV-11 positive samples A2 (62.5%) variants were predominant. A higher prevalence of HPV-6 B1 was observed in JORRP (83.3% B1 and 16.7% B3), compared with AORRP cases (58.3% B1 and 41.7% B3). HPV-11 A2 variants were more prevalent both in JORRP (57.2%) and in AORRP cases (70.0%). Nevertheless, with the exception that HPV-6 B1 were significantly less likely to recur, there was a lack of association between any particular HPVs 6 or 11 variant and clinicopathological features. Our data do not support an association between HPVs 6 and 11 variability and RRP.

Oral hairy leukoplakia in a child using a corticosteroid nasal spray.

We report a case of atypical oral hairy leukoplakia (OHL) in a 9-year-old immunocompetent girl treated with fluticasone propionate nasal spray for allergic rhinitis. The OHL in childhood is uncommon and should be included in a differential diagnosis of white lesions in the oral mucosa.

In Vitro Effect of Simulated Tooth Brushing and Children's Mouth Rinses on Physical Properties of Glass Ionomer Cement.

OBJECTIVE: The present study investigated the erosive potential of children's mouthrinses on glass ionomer cement (GIC) samples after simulated toothbrushing. STUDY DESIGN: Forty round-shaped samples of GIC were divided into 3 groups: G1- cetylpyridinium chloride, G2- xylitol and triclosan and G3-Malva sylvestris and xylitol and G4-distilled water as a control group. Prior to the main tests, the samples were submitted to the surface roughness measurement (Ra) and weight analysis (W). Afterward, they were brushed twice day (2× / day) for 15 days and immersed in mouthrinses after the last daily brushing. The final surface roughness (R2) and weight (W2) were determined after completing the tooth brushing-mouth rinsing cycles and the real increase in roughness (ΔRa) and real weight loss (ΔW) were calculated. In addition, stereoscopic images taken at 30× magnification. The data was analyzed by one-way ANOVA and Tukey-test post hoc tests for intergroup comparison and the T-test for dependent samples (α = 0.05). RESULTS: Only group G2 showed increased in roughness ΔRa (1.53 ± 0.94) whereas ΔW values were not significant. However, evident cracks and voids were verified for all tested children's rinses. CONCLUSION: Thus, children's mouthrinse containing xylitol / triclosan increased the GIC roughness, especially when associated with brushing.

IoTDS: A One-Class Classification Approach to Detect Botnets in Internet of Things Devices.

Internet of Things (IoT) devices have become increasingly widespread. Despite their potential of improving multiple application domains, these devices have poor security, which can be explored by attackers to build large-scale botnets. In this work, we propose a host-based approach to detect botnets in IoT devices, named IoTDS (Internet of Things Detection System). It relies on one-class classifiers, which model only the legitimate device behaviour for further detection of deviations, avoiding the manual labelling process. The proposed solution is underpinned by a novel agent-manager architecture based on HTTPS, which prevents the IoT device from being overloaded by the training activities. To analyse the device's behaviour, the approach extracts features from the device's CPU utilisation and temperature, memory consumption, and number of running tasks, meaning that it does not make use of network traffic data. To test our approach, we used an experimental IoT setup containing a device compromised by bot malware. Multiple scenarios were made, including three different IoT device profiles and seven botnets. Four one-class algorithms (Elliptic Envelope, Isolation Forest, Local Outlier Factor, and One-class Support Vector Machine) were evaluated. The results show the proposed system has a good predictive performance for different botnets, achieving a mean F1-score of 94% for the best performing algorithm, the Local Outlier Factor. The system also presented a low impact on the device's energy consumption, and CPU and memory utilisation.

Disentangling Magnetic Hardening and Molecular Spin Chain Contributions to Exchange Bias in Ferromagnet/Molecule Bilayers.

We performed ferromagnetic resonance and magnetometry experiments to clarify the relationship between two reported magnetic exchange effects arising from interfacial spin-polarized charge transfer in ferromagnetic metal (FM)/molecule bilayers: the magnetic hardening effect and spinterface-stabilized molecular spin chains. To disentangle these effects, we tuned the metal phthalocyanine molecule central site's magnetic moment to enhance or suppress the formation of spin chains in the molecular film. We find that both effects are distinct, and additive. In the process, we extend the list of FM/molecule candidate pairs that are known to generate magnetic exchange effects, experimentally confirm the predicted increase in anisotropy upon molecular adsorption, and show that spin chains within the molecular film can enhance magnetic exchange. Our results confirm, as an echo to progress regarding inorganic spintronic tunnelling, that spintronic tunnelling across structurally ordered organic barriers has been reached through previous magnetotransport experiments.

Chronic Hematoma of the Neck.

Chronic hematomas are defined as hematomas with slow, progressive growth over many weeks. They are an extremely rare cause of acute neck swelling in the pediatric population. They consist of an organized central mass of blood with granulation tissue and fibrotic changes peripherally. The presence of a capsule prevents resorption but allows for intracapsular bleeding with subsequent expansion. We describe a case of a 6-year-old girl who presented to the emergency department with a spontaneously occurring left neck mass in the supraclavicular region. A possible neoplasm was suggested on imaging. The patient was referred to a head and neck surgeon, she underwent a thorough workup, and the mass was ultimately surgically excised. Histologically, the mass was confirmed to be a chronic hematoma. The patient recovered uneventfully, and there has been no recurrence.

A mixed form of intravascular papillary endothelial hyperplasia in an uncommon location: case and literature review.

Intravascular papillary endothelial hyperplasia (IPEH) is an unusual benign, non-neoplastic vascular lesion that usually occurs in skin, but is uncommon in the oral cavity. Herein, we review the pertinent literature of oraiiPEH and report a new mixed form. A 61-year- old man presented with an ulcerated nodule in the lingual portion of the gingiva related to the left mandibular canine. An excisional biopsy was performed presuming the clinical diagnosis of pyogenic granuloma. Histopathological analysis showed areas of granulation tissue consistent with pyogenic  granuloma. But in  addition, there  were thin-wall dilated vessels with papillary projections of endothelial cells producing vascular channels, associated with  an area of  organizing  thrombus. These microscopic findings led to the diagnosis of pyogenic  granuloma  associated with  IPEH. The immunohistochemical  reactions revealed a diffuse positivity of the vascular cells for CD-34 and smooth muscle actin antibodies.In addition,there was partial positivity for podoplanin and negativity for CD-1OS in the IPEH areas. No signs of recurrence were observed after 6 months of follow-up. The most prevalent site of IPEH in the oral region is the lower lip. IPEH is slightly more common in women and exhibits peaks of prevalence between the fourth and sixth decades of life.

Exchange bias and room-temperature magnetic order in molecular layers.

Molecular semiconductors may exhibit antiferromagnetic correlations well below room temperature. Although inorganic antiferromagnetic layers may exchange bias single-molecule magnets, the reciprocal effect of an antiferromagnetic molecular layer magnetically pinning an inorganic ferromagnetic layer through exchange bias has so far not been observed. We report on the magnetic interplay, extending beyond the interface, between a cobalt ferromagnetic layer and a paramagnetic organic manganese phthalocyanine (MnPc) layer. These ferromagnetic/organic interfaces are called spinterfaces because spin polarization arises on them. The robust magnetism of the Co/MnPc spinterface stabilizes antiferromagnetic ordering at room temperature within subsequent MnPc monolayers away from the interface. The inferred magnetic coupling strength is much larger than that found in similar bulk, thin or ultrathin systems. In addition, at lower temperature, the antiferromagnetic MnPc layer induces an exchange bias on the Co film, which is magnetically pinned. These findings create new routes towards designing organic spintronic devices.