Search

BACKGROUND: Since the colonization of Brazil in 1500, systemic, institutional, and relational racism has produced inequalities for its black and indigenous people. This legacy perpetuates white supremacy and intensifies social inequalities. PURPOSE: This Opinion Piece aims to raise reflexivity on racism in Brazil and its impacts on the occupations of black people within the context of occupational apartheid. KEY ISSUES: We start exploring social justice and occupational justice concepts to map a methodological path for the theoretically informed discussion. Then, we discuss the concept of collective occupations as a possibility for intervention in the face of racial inequalities and introduce some occupational therapy practices to exemplify strategies to tackle the identified challenges. IMPLICATIONS: We conclude by showing that the field of ethnic-racial relations is still only minimally explored in Brazilian occupational therapy. We also point out some possibilities for further studies in the area.

To review the applicability and accessibility of physical activity guidelines for adults living with long-term conditions whilst shielding during the COVID-19. A narrative review with systematic methodology was conducted between 2015 and 2021, with two stages: 1) Search of electronic databases PubMed/Medline, Web of Science, PsycInfo, and Cinahl; 2) search of long-term condition organisations. Sixty-five articles were identified, where nine included specific guidelines during the COVID-19, 28 specific guidelines to individuals living with long-term conditions and 7 identified the utilization of online resources. Twenty-one long-term condition organizations websites were reviewed where all of them included a section regarding physical activity guidelines and seven referred to online and offline accessible resources during COVID-19. Accessibility and applicability were variable across academic databases and long-term conditions organisation websites. Findings could inform long-term condition policy and guidelines development to better and more relevant support people living with long-term conditions to be physically active.

Platelet α-granules regulate hemostasis and myriad other physiological processes, but their biogenesis is unclear. Mutations in only 3 proteins are known to cause α-granule defects and bleeding disorders in humans. Two such proteins, VPS16B and VPS33B, form a complex mediating transport of newly synthesized α-granule proteins through megakaryocyte (MK) endosomal compartments. It is unclear how the VPS16B/VPS33B complex accomplishes this function. Here we report VPS16B/VPS33B associates physically with Syntaxin 12 (Stx12), a SNARE protein that mediates vesicle fusion at endosomes. Importantly, Stx12-deficient MKs display reduced α-granule numbers and overall levels of α-granule proteins, thus revealing Stx12 as a new component of the α-granule biogenesis machinery. VPS16B/VPS33B also binds CCDC22, a component of the CCC complex working at endosome exit sites. CCDC22 competes with Stx12 for binding to VPS16B/VPS33B, suggesting a possible hand-off mechanism. Moreover, the major CCC form expressed in MKs contains COMMD3, one of 10 COMMD proteins. Deficiency of COMMD3/CCDC22 causes reduced α-granule numbers and overall levels of α-granule proteins, establishing the COMMD3/CCC complex as a new factor in α-granule biogenesis. Furthermore, P-selectin traffics through the cell surface in a COMMD3-dependent manner and depletion of COMMD3 results in lysosomal degradation of P-selectin and PF4. Stx12 and COMMD3/CCC deficiency cause less severe phenotypes than VPS16B/VPS33B deficiency, suggesting Stx12 and COMMD3/CCC assist but are less important than VPS16B/VPS33B in α-granule biogenesis. Mechanistically, our results suggest VPS16B/VPS33B coordinates the endosomal entry and exit of α-granule proteins by linking the fusogenic machinery with a ubiquitous endosomal retrieval complex that is repurposed in MKs to make α-granules.

Background Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. Results The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120′. Conclusions A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.

Over the past years, 3D in vitro models have been widely employed in the regenerative medicine field. Among them, organ-on-a-chip technology has the potential to elucidate cellular mechanism exploiting multichannel microfluidic devices to establish 3D co-culture systems that offer control over the cellular, physico-chemical and biochemical microenvironments. To deliver the most relevant cues to cells, it is of paramount importance to select the most appropriate matrix for mimicking the extracellular matrix of the native tissue. Natural polymers-based hydrogels are the elected candidates for reproducing tissue-specific microenvironments in musculoskeletal tissue-on-a-chip models owning to their interesting and peculiar physico-chemical, mechanical and biological properties. Despite these advantages, there is still a gap between the biomaterials complexity in conventional tissue engineering and the application of these biomaterials in 3D in vitro microfluidic models. In this review, the aim is to suggest the adoption of more suitable biomaterials, alternative crosslinking strategies and tissue engineered-inspired approaches in organ-on-a-chip to better mimic the complexity of physiological musculoskeletal tissues. Accordingly, after giving an overview of the musculoskeletal tissue compositions, the properties of the main natural polymers employed in microfluidic systems are investigated, together with the main musculoskeletal tissues-on-a-chip devices.

Alcohol withdrawal is a key component of severe alcohol use disorder. Animal models of alcohol withdrawal tend to focus on traditional anxiety/stress tests. While these have been essential to advancing our understanding of the biology of alcohol withdrawal, abrupt cessation of drinking following heavy alcohol consumption can also trigger withdrawal-related affective states that impact responses to a variety of life events and stressors. To this end, we show that behaviors in a variety of tasks that differ in task demand and intensity are altered during withdrawal in male and female mice after voluntary alcohol access.Male and female miceunderwent six weeks of intermittent two-bottle choice alcohol exposure followed by behavioral tests. The tests included-Home cage: low-stress baseline environment to measure spontaneous natural behaviors; Open field: anxiety-inducing bright novel environment; Looming disc: arena with a protective hut where mice are exposed to a series of discs that mimic an overhead advancing predator, and Robogator-simulated predator task: forced foraging behavioral choice in the presence of an advancing robot predator that "attacks" when mice are near a food pellet in a large open arena.A history of alcohol exposure impacted behaviors in these tasks in a sex-dependent manner. In the home cage, alcohol induced reductions in digging and heightened stress coping through an increase in grooming time. In males, increased rearing yielded greater vigilance/exploration in a familiar environment. The open-field test revealed an anxiety phenotype in both male and female mice exposed to alcohol. Male mice showed no behavioral alterations to the looming disc task, while females exposed to alcohol showed greater escape responses than water controls, indicative of active stress-response behaviors. In males, the Robogator task revealed a hesitant/avoidant phenotype in alcohol-exposed mice under greater task demands.Few drugs show robust evidence of efficacy in clinical trials for alcohol withdrawal. Understanding how withdrawal alters a variety of behaviors in both males and females that are linked to stress coping can increase our understanding of alcohol misuse and aid in developing better medications for treating individuals with AUD.

Binge drinking is a common pattern of excessive alcohol consumption associated with Alcohol Use Disorder (AUD) and unraveling the neurocircuitry that promotes this type of drinking is critical to the development of novel therapeutic interventions. The septal region was once a focal point of alcohol research yet has seen limited study over the last decade in relation to binge drinking. Numerous studies point to involvement of the dorsal septum (dSep) in excessive drinking and withdrawal, but few studies have manipulated this region in the context of binge drinking behavior. The present experiments were primarily designed to determine the effect of chemogenetic manipulation of the dSep on binge-like alcohol drinking in male and female C57BL/6J mice. Mice received bilateral infusion of AAVs harboring hM4Di, hM3Dq, or mCherry into the dSep and subjects were challenged with systemic administration of clozapine-N-oxide (CNO; 3 mg/kg) and vehicle (saline; 0.9%) in the context of binge-like alcohol consumption, locomotor activity, and sucrose drinking. CNO-mediated activation (hM3Dq) of the dSep resulted in a significant increase in binge-like alcohol consumption, locomotor activity, and sucrose intake in male mice. DSep activation promoted sucrose drinking in female mice, but alcohol intake and locomotor activity were unaffected. Conversely, silencing (hM4Di) of the dSep modestly decreased locomotor activity in males and did not influence alcohol or sucrose intake in either sex. Lastly, CNO was without effect in mCherry-expressing control groups. These data support a role for the dSep in promoting excessive, binge-like drinking behavior in a sex-dependent fashion and suggests a broad role for the region in the modulation of locomotor activity as well as general appetitive behavior such as sucrose drinking.

Background Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory bowel diseases (IBD) that affect a significant portion of women in childbearing years. It is known that disease activity in early pregnancy negatively impacts obstetrical and perinatal outcomes, but the impact on infant growth is largely unknown. Aims The objective of this study was to compare the growth of infants born to women with active IBD during pregnancy versus those born to women with IBD in remission during pregnancy. Methods We conducted a prospective cohort study in a Canadian tertiary centre comprised of 98 pregnant women with IBD (63 with UC and 35 with CD) and 13 healthy pregnant women. We collected maternal demographic at trimester 1 and assessed disease activity at each trimester using clinical disease scores and fecal calprotectin. We then collected perinatal outcomes at delivery and followed the infants’ growth and feeding habits up to 12 months of age. Results A total of 103 mother-infant pairs were included in the study, of which 88 infants were born to women with IBD, and 15 born to women with active disease at trimester 1. Active disease at trimester 1 was associated with more adverse obstetrical outcomes, reduced 1-minute and 5-minute APGAR scores and more frequent NICU admissions. Infants born to women with active trimester 1 disease had reduced weight-for-age and length-for-age Z scores up to 6 months of age, in the absence of difference in feeding patterns. In addition, women with active disease at trimester 1 had increased expression of IL-8 and IFN-γ compared to those with trimester 1 remission. Conclusions Active IBD during first trimester is correlated with decreased infant weight and height up to 6 months of age, suggesting that strict disease control during first trimester, or even preconception, is essential for optimizing infant growth and perinatal outcomes. Funding Agencies None

Platelet α-granules play important roles in platelet function. They contain hundreds of proteins that are synthesized by the megakaryocyte or taken up by endocytosis. The trafficking pathways that mediate platelet α-granule biogenesis are incompletely understood, especially with regard to cargo synthesized by the megakaryocyte. Vacuolar-protein sorting 33B (VPS33B) and VPS16B are essential proteins for α-granule biogenesis, but they are largely uncharacterized. Here, we adapted a powerful method to directly map the pathway followed by newly synthesized cargo proteins to reach α-granules. Using this method, we revealed the recycling endosome as a key intermediate compartment in α-granule biogenesis. We then used CRISPR/Cas9 gene editing to knock out VPS33B in pluripotent stem cell–derived immortalized megakaryocyte cells (imMKCLs). Consistent with the observations in platelets from patients with VPS33B mutation, VPS33B-knockout (KO) imMKCLs have drastically reduced levels of α-granule proteins platelet factor 4, von Willebrand factor, and P-selectin. VPS33B and VPS16B form a distinct and small complex in imMKCLs with the same hydrodynamic radius as the recombinant VPS33B-VPS16B heterodimer purified from bacteria. Mechanistically, the VPS33B-VPS16B complex ensures the correct trafficking of α-granule proteins. VPS33B deficiency results in α-granule cargo degradation in lysosomes. VPS16B steady-state levels are significantly lower in VPS33B-KO imMKCLs, suggesting that VPS16B is destabilized in the absence of its partner. Exogenous expression of green fluorescent protein–VPS33B in VPS33B-KO imMKCLs reconstitutes the complex, which localizes to the recycling endosome, further defining this compartment as a key intermediate in α-granule biogenesis. These results advance our understanding of platelet α-granule biogenesis and open new avenues for the study of these organelles.

The bilateral cooperation between the Institute for Polymer, Composite and Biomaterials IPCB-CNR and the Accademia Aeronautica di Pozzuoli was founded in 2021 with ambitious expectations and development relating to the innovating projects of the new "Training Units Drones Academy Research Team" (DART) and "Academy Space Team for Research and Aerospace studies" (ASTRA). The DART Training Unit is working on the projects Black Ops and Italo: the former projects aims to develop a quadcopter drone to constitute a situational awareness increaser for the tactical operations of the Airforce Raiders, while the second one focuses on the development of the opportunity to develop a fixed-wing drone which is able to autonomously circumnavigate the globe at tropospheric height by 2025.

INTRODUCTION Over the past few years, several studies have been highlighting the great potential of ?-glucans as a multifunctional modulators of wound healing alone and/or incorporated in a polymeric matrix [1]. ?-glucans represent the major components of cell walls of bacteria, fungi, yeast and cereals, mainly oat and barley, and their structural and biological properties strictly depend on the source. Among them, barley ?-glucans are extensively studied as they have shown interesting antimicrobial and wound healing properties [2]. In this study, ?-glucan based mixtures (containing proteins, fats and other polysaccharides, such as starch) were extracted from barley at different pH, through a very simple and low cost extraction process. The obtained mixtures were then employed for film preparation and the cell biocompatibility was studied. To this aim, different cell lines involved in wound healing, human dermal fibroblasts (HDF) and human umbilical vein endothelial cells (HUVEC), were used through direct and indirect in vitro assays (following ISO 10993-5 guidelines). The viability and migration of fibroblast and endothelial cells were analysed by using the in vitro scratch wound healing assay. In addition, cell adhesion was investigated by confocal microscopy. Furthermore, the effect on inflammation response modulation, was carried out on a murine macrophage J774 cell line in order to assess the effects of ?-glucan on inflammatory and anti-inflammatory cytokines production (IL-6, IL-10, IL-1?). The results suggested that ?-glucan films supported cell proliferation and migration. Moreover, these films are able to modulate the inflammation process in terms of inflammatory and anti-inflammatory cytokines levels.

Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.

Biofabrication is enriching the tissue engineering field with new ways of producing structurally organized complex tissues. Among the numerous bioinks under investigation, hyaluronic acid (HA) and its derivatives stand out for their biological relevance, cytocompatibility, shear-thinning properties, and potential to fine-tune the desired properties with chemical modification. In this paper, we review the recent advances on bioinks containing HA. The available literature is presented based on subjects including the rheological properties in connection with printability, the chemical strategies for endowing HA with the desired properties, the clinical application, the most advanced preclinical studies, the advantages and limitations in comparison with similar biopolymer-based bioinks, and future perspectives.