A content analysis of thinspiration, fitspiration, and bonespiration imagery on social media

Background: On social media, images such as thinspiration, fitspiration, and bonespiration, are shared to inspire certain body ideals. Previous research has demonstrated that exposure to these groups of content is associated with increased body dissatisfaction and decreased self-esteem. It is therefore important that the bodies featured within these groups of content are more fully understood so that effective interventions and preventative measures can be informed, developed, and implemented. Method: A content analysis was conducted on a sample of body-focussed images with the hashtags thinspiration, fitspiration, and bonespiration from three social media platforms. Results: The analyses showed that thinspiration and bonespiration content contained more thin and objectified bodies, compared to fitspiration which featured a greater prevalence of muscles and muscular bodies. In addition, bonespiration content contained more bone protrusions and fewer muscles than thinspiration content. Conclusions: The findings suggest fitspiration may be a less unhealthy type of content; however, a subgroup of imagery was identified which idealised the extremely thin body type and as such this content should also be approached with caution. Future research should utilise qualitative methods to further develop understandings of the body ideals that are constructed within these groups of content and the motivations behind posting this content

UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome

Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles. We aimed to determine why these parallel delivery mechanisms exist and found that UBQLN2 acts with the HSP70-HSP110 disaggregase machinery to clear protein aggregates via the 26S proteasome. UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. We further show that this process is active in the cell nucleus, where another system for aggregate clearance, autophagy, does not act. Finally, we found that mutations in UBQLN2, which lead to neurodegeneration in humans, are defective in chaperone binding, impair aggregate clearance, and cause cognitive deficits in mice

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency

Multiplex protein profiling of bronchial aspirates reveals disease-, mortality- and respiratory sequelae-associated signatures in critically ill patients with ARDS secondary to SARS-CoV-2 infection

IntroductionBronchial aspirates (BAS) obtained during invasive mechanical ventilation (IMV) constitutes a useful tool for molecular phenotyping and decision making.AimTo identify the proteomic determinants associated with disease pathogenesis, all-cause mortality and respiratory sequelae in BAS samples from critically ill patients with SARS-CoV-2-induced ARDSMethodsMulticenter study including 74 critically ill patients with COVID-19 and non-COVID-19 ARDS. BAS were obtained by bronchoaspiration after IMV initiation. Three hundred sixty-four proteins were quantified using proximity extension assay (PEA) technology. Random forest models were used to assess predictor importance.ResultsAfter adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-α were differentially detected in COVID-19 and non-COVID-19 patients. In random forest models for COVID-19, CST5, DPP7, NADK, KYAT1 and TYMP showed the highest variable importance. In COVID-19 patients, reduced levels of ENTPD2 and PTN were observed in nonsurvivors of ICU stay, even after adjustment. AGR2, NQO2, IL-1α, OSM and TRAIL showed the strongest associations with in-ICU mortality and were used to construct a protein-based prediction model. Kaplan-Meier curves revealed a clear separation in mortality risk between subgroups of PTN, ENTPD2 and the prediction model. Cox regression models supported these findings. In survivors, the levels of FCRL1, NTF4 and THOP1 in BAS samples obtained during the ICU stay correlated with lung function (i.e., DLCO levels) 3 months after hospital discharge. Similarly, Flt3L and THOP1 levels were correlated with radiological features (i.e., TSS). These proteins are expressed in immune and nonimmune lung cells. Poor host response to viral infectivity and an inappropriate reparative mechanism seem to be linked with the pathogenesis of the disease and fatal outcomes, respectively.ConclusionBAS proteomics identified novel factors associated with the pathology of SARS-CoV-2-induced ARDS and its adverse outcomes. BAS-based protein testing emerges as a novel tool for risk assessment in the ICU

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondria! numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1(-/-) animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of I immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.Molecular Technology and Informatics for Personalised Medicine and Healt

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

A rare mutation in hypophosphatasia: a case report of adult form and review of the literature

Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism

A rare mutation in hypophosphatasia: a case report of adult form and review of the literature

SUMMARY Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism