P21-activated kinase-1 signaling is required to preserve adipose tissue homeostasis and cardiac function.

While P21-activated kinase-1 (PAK1) has been extensively studied in relation to cardiovascular health and glucose metabolism, its roles within adipose tissue and cardiometabolic diseases are less understood. In this study, we explored the effects of PAK1 deletion on energy balance, adipose tissue homeostasis, and cardiac function utilizing a whole-body PAK1 knockout (PAK1-/-) mouse model. Our findings revealed that body weight differences between PAK1-/- and WT mice emerged at 9 weeks of age, with further increases observed at 12 weeks. Furthermore, PAK1-/- mice displayed increased fat mass and decreased lean mass at 12 weeks, indicating a shift towards adiposity. In conjunction with the increased body weight, PAK1-/- mice had increased food intake and reduced energy expenditure. At a mechanistic level, PAK1 deletion boosted the expression of lipogenic markers while diminishing thermogenic markers expression in adipose tissues, contributing to reduced energy expenditure and the overall obesogenic phenotype. Moreover, our findings highlighted a significant impact on cardiac function following PAK1 deletion, including alterations in calcium kinetics and compromised systolic and lusitropy functions. In summary, our study emphasizes the significant role of PAK1 in weight regulation and cardiac function, enriching our comprehension of heart health and metabolism. These findings could potentially facilitate the identification of novel therapeutic targets in cardiometabolic diseases.

Fertility considerations in targeted biologic therapy with tyrosine kinase inhibitors: a review.

PURPOSE: To review the impact of tyrosine kinase inhibitors (TKIs) on fertility in men and women, embryo development, and early pregnancy, and discuss considerations for fertility preservation in patients taking TKIs. METHODS: A comprehensive literature search using the PubMed database was performed through February 2021 to evaluate the current literature on imatinib, nilotinib, dasatinib, and bosutinib as it relates to fertility and reproduction. Published case series were analyzed for pregnancy outcomes. RESULTS: TKIs adversely affect oocyte and sperm maturation, gonadal function, and overall fertility potential in a self-limited manner. There are insufficient studies regarding long-term consequences on fertility after discontinuation of TKIs. A total of 396 women and 236 men were on a first- or second-generation TKI at the time of conception. Of the women with detailed pregnancy and delivery outcomes (n = 361), 51% (186/361) resulted in a term birth of a normal infant, 4.3% (16/361) of pregnancies had a pregnancy complication, and 5% (20/361) of pregnancies resulted in the live birth of an infant with a congenital anomaly. About 22% of pregnant women (87/396) elected to undergo a termination of pregnancy, while 16% (63/396) of pregnancies ended in a spontaneous abortion. In contrast, of the 236 men, 87% conceived pregnancies which resulted in term deliveries of normal infants. Elective terminations, miscarriage rate, pregnancy complication rate, and incidence of a congenital malformation were all less than those seen in females (4%, 3%, 2%, and 2.5%, respectively). CONCLUSION: Women should be advised to avoid conception while taking a TKI. Women on TKIs who are considering pregnancy should be encouraged to plan the pregnancy to minimize inadvertent first trimester exposure. In women who conceive while taking TKIs, the serious risk of relapse due to discontinuation of TKI should be balanced against the potential risks to the fetus. The risk of teratogenicity to a fathered pregnancy with TKI use is considerably lower. Fertility preservation for a woman taking a TKI can be considered to plan a pregnancy with a minimal TKI-free period. With careful monitoring, providers may consider a TKI washout period followed by controlled ovarian stimulation to cryopreserve oocytes or embryos, with a plan to resume TKIs until ready to conceive or to transfer an embryo to achieve pregnancy quickly. Fertility preservation is also indicated if a patient on TKI is requiring a gonadotoxic therapy or reproductive surgery impacting fertility.

On-Farm Surfaces in Contact with Milk: The Role of Staphylococcus aureus-Containing Biofilms for Udder Health and Milk Quality.

Staphylococcus aureus is a Gram-positive bacterium that causes intramammary infections and bulk tank milk (BTM) contamination in dairy operations around the world in spite of on-farm application of preventive measures. The study was conducted on a 30-cow dairy farm in the Ñuble Region of Chile. For BTM culture and somatic cell count (SCC) analysis, three consecutive BTM samples were collected. Samples for bacterial culture (n = 16) were collected from macroscopic adherence on previously washed, sanitized, and dry milking equipment surfaces in direct contact with milk during milking or cooling. A total of 48 S. aureus isolates from BTM, milking equipment, and cows' quarters with intramammary infections were analyzed by pulsed-field gel electrophoresis (PFGE). Selected milking equipment pieces were removed for biofilm visualization using scanning electron microscopy (SEM). S. aureus was isolated from all three BTM samples; the average SCC for the three BTM samples was 1,429,333 cells/mL. Fourteen of the 16 samples of milking equipment (87.5%) were culture positive for S. aureus. Biofilms were visualized by SEM in all four removed milking equipment pieces. Microorganisms observed by SEM in those biofilms were mainly coccus-shaped bacteria, and microbiological culture of these biofilms yielded viable S. aureus isolates in all samples. All pulsotypes observed among S. aureus isolates from BTM were indistinguishable from those in milking equipment surfaces. All PFGE pulsotypes observed among S. aureus isolates from biofilms on rubber liners were indistinguishable from isolates from intramammary infections in cows. Our findings suggest that milking equipment films may act as source of S. aureus contamination for BTM and cows during milking, thus compromising the microbiological quality of milk used for manufacturing dairy products.

Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model.

In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid ß protein (Aß). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Aß*56 levels decreased, suggesting a link between tau and Aß oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Aß pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD.

Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles.

Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.

Immuno-spin trapping from biochemistry to medicine: advances, challenges, and pitfalls. Focus on protein-centered radicals.

BACKGROUND: Immuno-spin trapping (IST) is based on the reaction of a spin trap with a free radical to form a stable nitrone adduct, followed by the use of antibodies, rather than traditional electron paramagnetic resonance spectroscopy, to detect the nitrone adduct. IST has been successfully applied to mechanistic in vitro studies, and recently, macromolecule-centered radicals have been detected in models of drug-induced agranulocytosis, hepatotoxicity, cardiotoxicity, and ischemia/reperfusion, as well as in models of neurological, metabolic and immunological diseases. SCOPE OF THE REVIEW: To critically evaluate advances, challenges, and pitfalls as well as the scientific opportunities of IST as applied to the study of protein-centered free radicals generated in stressed organelles, cells, tissues and animal models of disease and exposure. MAJOR CONCLUSIONS: Because the spin trap has to be present at high enough concentrations in the microenvironment where the radical is formed, the possible effects of the spin trap on gene expression, metabolism and cell physiology have to be considered in the use of IST and in the interpretation of results. These factors have not yet been thoroughly dealt with in the literature. GENERAL SIGNIFICANCE: The identification of radicalized proteins during cell/tissue response to stressors will help define their role in the complex cellular response to stressors and pathogenesis; however, the fidelity of spin trapping/immuno-detection and the effects of the spin trap on the biological system should be considered. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.

Amyloid-ß oligomers as a template for secondary amyloidosis in Alzheimer's disease.

Alzheimer's disease is a complex disease characterized by overlapping phenotypes with different neurodegenerative disorders. Oligomers are considered the most toxic species in amyloid pathologies. We examined human AD brain samples using an anti-oligomer antibody generated in our laboratory and detected potential hybrid oligomers composed of amyloid-ß, prion protein, α-synuclein, and TDP-43 phosphorylated at serines 409 and 410. These data and in vitro results suggest that Aß oligomer seeds act as a template for the aggregation of other proteins and generate an overlapping phenotype with other neuronal disorders. Furthermore, these results could explain why anti-amyloid-ß therapy has been unsuccessful.

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

Dual role of p53 amyloid formation in cancer; loss of function and gain of toxicity.

The tumor suppressor p53 plays an important role in genome integrity. It is frequently mutated in all types of human cancers, making p53 a key factor in cancer progression. Two phenotypic consequences of these alterations are dominant; a loss of function and a gain of function of p53, which, in several cases, accumulates in intracellular aggregates. Although the nature of such aggregates is still unclear, recent evidence indicates that p53 can undergo conformational transitions leading to amyloid formation. Amyloid diseases, such as, Alzheimer's disease, are characterized by the accumulation of insoluble aggregates displaying the fibrillar conformation. We decided to investigate the propensity of wild type p53 to aggregate and its consequent assembly into different amyloid species, such as oligomers and fibrils; and to determine if these changes in conformation lead to a loss of function of p53. Furthermore, we analyzed cases of Basal Cell Carcinoma (BCC), for the presence of p53 amyloids. Here, we show that p53 forms amyloid oligomers and fibrils, which coincide with p53 inability of binding to DNA consensus sequences. Both p53 amyloid oligomers and fibrils were detected in BCC cancer samples. Additionally, we demonstrate that p53 oligomers are the most cytotoxic to human cell cultures. Our study reveals p53 amyloid formation and demonstrates its dual role in the pathogenesis of cancer by producing a loss of protein function and a gain of toxic function, extensively described in several amyloidogenic diseases. Our results suggest that under certain circumstances, cancer could be considered a protein-conformation disease.

Activation of brown adipose tissue by a low-protein diet ameliorates hyperglycemia in a diabetic lipodystrophy mouse model.

Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IR FKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IR FKO mice have profound insulin resistance, hyperglycemia, and whitenng of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IR FKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IR FKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.

Activation of brown adipose tissue by a low-protein diet ameliorates hyperglycemia in a diabetic lipodystrophy mouse model.

Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IRFKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IRFKO mice have profound insulin resistance, hyperglycemia, and whitening of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IRFKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IRFKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.

Preference of acromegaly patients for treatment attributes in Spain.

OBJECTIVE: Acromegaly is a rare disease caused by increased growth hormone secretion and a subsequent increase in insulin-like growth factor I (IGF-I) levels. Patients display multiple comorbidities that affect their quality of life (QoL). Treatment aims to maintain good biochemical control, tumour control and reduce the risk of comorbidities; however, their impact on QoL has been overlooked until recently. We interviewed patients to explore their preferences with regard to treatment attributes. DESIGN: A cross-sectional study based on interviews and a discrete choice experiment (DCE) in a Spanish cohort. METHODS: Adult patients diagnosed with acromegaly ≥1 year before the start of the study and under treatment were included. Treatment attributes were collected from patient testimony during face-to-face interviews. Then, a DCE was performed to elicit patient preferences for certain treatment attributes. RESULTS: Sixty-seven patients completed the study. QoL improvement was the most important treatment attribute (37%), followed by IGF-I control (20%), blood sugar control (17%) and tumour control (13%). Secondary attributes were pain associated with the route of administration (7%), diarrhoea (2%), administration method (2%) and storage conditions (2%). We then calculated the theoretical share of preference for existing treatments, based on the individual preference utility for each attribute and level. Pegvisomant obtained the highest share of preference overall, and the highest preference as a second-line treatment (53 and 95%, respectively). CONCLUSIONS: QoL greatly influences patient treatment preference. Since acromegaly patients are informed and aware of their disease, treatment choices should always be shared with patients.

Short-term complications and post-acute sequelae in hospitalized paediatric patients with COVID-19 and obesity: A multicenter cohort study.

BACKGROUND: Obesity increases the severity of coronavirus disease 2019 illness in adults. The role of obesity in short-term complications and post-acute sequelae in children is not well defined. OBJECTIVE: To evaluate the relationship between obesity and short-term complications and post-acute sequelae of SARS-CoV-2 infection in hospitalized paediatric patients. METHODS: An observational study was conducted in three tertiary hospitals, including paediatric hospitalized patients with a confirmatory SARS-CoV-2 RT-PCR from March 2020 to December 2021. Obesity was defined according to WHO 2006 (0-2 years) and CDC 2000 (2-20 years) growth references. Short-term outcomes were intensive care unit admission, ventilatory support, superinfections, acute kidney injury, and mortality. Neurological, respiratory, and cardiological symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms were considered as post-acute sequalae. Adjusted linear, logistic regression and generalized estimating equations models were performed. RESULTS: A total of 216 individuals were included, and 67 (31.02%) of them had obesity. Obesity was associated with intensive care unit admission (aOR = 5.63, CI95% 2.90-10.94), oxygen requirement (aOR = 2.77, CI95% 1.36-5.63), non-invasive ventilatory support (aOR = 6.81, CI95% 2.11-22.04), overall superinfections (aOR = 3.02 CI95% 1.45-6.31), and suspected bacterial pneumonia (aOR = 3.00 CI95% 1.44-6.23). For post-acute sequalae, obesity was associated with dyspnea (aOR = 9.91 CI95% 1.92-51.10) and muscle weakness (aOR = 20.04 CI95% 2.50-160.65). CONCLUSIONS: In paediatric hospitalized patients with COVID-19, severe short-term outcomes and post-acute sequelae are associated with obesity. Recognizing obesity as a key comorbidity is essential to develop targeted strategies for prevention of COVID-19 complications in children.

Differential activation of the ER stress factor XBP1 by oligomeric assemblies.

Several neurodegenerative disorders are characterized by protein misfolding, a phenomenon that results in perturbation of cellular homeostasis. We recently identified the protective activity of the ER stress response factor XBP1 (X-box binding protein 1) against Amyloid-ß1-42 (Aß42) neurotoxicity in cellular and Drosophila models of Alzheimer's disease. Additionally, subtoxic concentrations of Aß42 soluble aggregates (oligomers) induced accumulation of spliced (active) XBP1 transcripts, supporting the involvement of the ER stress response in Aß42 neurotoxicity. Here, we tested the ability of three additional disease-related amyloidogenic proteins to induce ER stress by analyzing XBP1 activation at the RNA level. Treatment of human SY5Y neuroblastoma cells with homogeneous preparations of α-Synuclein (α-Syn), Prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34) confirmed the high toxicity of oligomers compared to monomers and fibers. Additionally, α-Syn oligomers, but not monomers or fibers, demonstrated potent induction of XBP1 splicing. On the other hand, PrP106-126 and ABri1-34 did not activate XBP1. These results illustrate the biological complexity of these structurally related assemblies and argue that oligomer toxicity depends on the activation of amyloid-specific cellular responses.

Ultrasonographic technique to differentiate enhanced myometrial vascularity/arteriovenous malformation from retained products of conception.

PURPOSE: To objective of this study is to discuss the ultrasonographic technique to diagnose uterine enhanced myometrial vascularity/arteriovenous malformation (EMV/AVM) and differentiate it from retained products of conception. The study also reviews the management and outcome of EMV/AVM. METHODS: We present a series of three women who developed EMV after early pregnancy loss and a control case of incomplete abortion, where colour Doppler ultrasound was used to distinguish retained products of conception from features of EMV. Clinical status and imaging findings, including peak systolic velocity (PSV), were used for the initial risk stratification of the patients. All cases with EMV/AVM were managed expectantly with serial ultrasound imaging and trending human chorionic gonadotropin levels. The patient with retained products of conception was managed by hysteroscopy and curettage. RESULTS: In all cases, presentation was suggestive of incomplete abortion with retained products of conception. However, colour Doppler ultrasound demonstrated hypoechoic areas within the endometrium extending into the myometrium with a high maximum PSV. In the control case, colour Doppler ultrasound noted a heterogeneous area in the left uterine cavity; however, vascular flow in this area was distinct from the endometrium, suggesting retained products of conception. All three women with EMV were managed expectantly with close monitoring and good outcomes. CONCLUSION: In patients with early pregnancy loss and bleeding or persistently elevated human chorionic gonadotropin levels, clinical status and appropriate use of ultrasound imaging with colour Doppler, including PSV measurement, can assist in recognition of EMV/AVM. Expectant management with serial ultrasound evaluation is a safe treatment option for EMV/AVM with low PSV and can minimise complications such as need for blood transfusion, uterine artery embolization, and hysterectomy.

Biofilms in hoses utilized to divert colostrum and milk on dairy farms: A report exploring their potential role in herd health, milk quality, and public health.

Biofilms in milking equipment on dairy farms have been associated with failures in cleaning and sanitizing protocols. These biofilms on milking equipment can be a source of contamination for bulk tank milk and a concern for animal and public health, as biofilms can become on-farm reservoirs for pathogenic bacteria that cause disease in cows and humans. This report describes a cross-sectional study on 3 dairy farms, where hoses used to divert waste milk, transition milk, and colostrum were analyzed by culture methods and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to assess the presence of pathogenic bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella spp. In addition, the presence of biofilms was analyzed using scanning electron microscopy and confocal spectral microscopy. Biofilms composed of multispecies microbial communities were observed on the surfaces of all milk hoses. In two dairy farms, S. aureus, P. aeruginosa, Klebsiella pneumoniae, and Klebsiella oxytoca were isolated from the milk hose samples collected. Cleaning and sanitation protocols of all surfaces in contact with milk or colostrum are crucial. Hoses used to collect waste milk, colostrum, and transition milk can be a source of biofilms and hence pathogenic bacteria. Waste milk used to feed calves can constitute a biosecurity issue and a source of pathogens, therefore an increased exposure and threat for the whole herd health and, potentially, for human health.

The Effect of Oral Citicoline and Docosahexaenoic Acid on the Visual Field of Patients with Glaucoma: A Randomized Trial.

The role of nutraceuticals in the treatment of glaucoma remains controversial. The aim of this study was to evaluate the effect of citicoline, vitamin C, and docosahexaenoic acid (DHA) in patients with glaucoma. METHODS: This was a prospective, randomized study. Patients with glaucoma were randomized to one of four groups and treated for 3 months with vitamin C, DHA, citicoline, or a combination of DHA and citicoline. We conducted a complete ophthalmic examination and visual fields each month and calculated the slopes of field indices. Changes in visual field indices (VFIs) and their slopes were assessed in each group and compared. RESULTS: Seventy-three persons were included in the study. Mean defect (MD) significantly improved (p = 0.001) from -9.52 ± 4.36 to -7.85 ± 4.36 dB during the study period in persons taking DHA + citicoline. Similarly, the mean VFI significantly improved (p = 0.001) in this group. The only treatment group showing a statistically significant improvement (p = 0.006) in the MD (from -0.1041 ± 0.2471 to 0.1383 ± 0.2544 dB/month) and VFI slope was the group treated with DHA+citicoline. CONCLUSIONS: The combination of oral treatment with DHA + citicoline significantly improved VF indices and their slopes in patients with glaucoma after 3 months of treatment.

The prion-like transmission of tau oligomers via exosomes.

The conversion and transmission of misfolded proteins established the basis for the prion concept. Neurodegenerative diseases are considered "prion-like" disorders that lack infectivity. Among them, tauopathies are characterized by the conversion of native tau protein into an abnormally folded aggregate. During the progression of the disease, misfolded tau polymerizes into oligomers and intracellular neurofibrillary tangles (NFTs). While the toxicity of NFTs is an ongoing debate, the contribution of tau oligomers to early onset neurodegenerative pathogenesis is accepted. Tau oligomers are readily transferred from neuron to neuron propagating through the brain inducing neurodegeneration. Recently, transmission of tau oligomers via exosomes is now proposed. There is still too much to uncover about tau misfolding and propagation. Here we summarize novel findings of tau oligomers transmission and propagation via exosomes.

Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.

Acromegaly disease activity according to ACRODAT®, a cross-sectional study in Spain: ACROVAL study.

OBJECTIVES: To evaluate disease activity status using the Acromegaly Disease Activity Tool (ACRODAT®) in a cohort of Spanish acromegaly patients, to assess the relationship between the level of disease activity according to both ACRODAT® and the physicians' clinical evaluation, and to study the potential discrepancies in the perception of symptoms between physicians and patients. DESIGN: Multicenter, observational, descriptive and cross-sectional study. METHODS: Disease activity was assessed in adult patients with acromegaly under pharmacological treatment during at least 6 months using ACRODAT®. RESULTS: According to ACRODAT®, 48.2%, 31.8% and 20.0% of a total of 111 patients were classified as having a stable disease (S), mild disease activity (M-DA) and significant disease activity (S-DA) respectively. ACRODAT® classification of disease activity significantly correlated with physicians' opinion, with a moderate inter-rater agreement and a specificity of 92.45% (PPV = 86.21%). No correlation was found between IGF-I levels and severity of symptoms or quality of life (QoL). A decision to take clinical action was significantly more frequent in S-DA and M-DA patients than S patients but no action was taken on 5 (22.7%) and 27 (77.1%) S-DA and M-DA patients, respectively CONCLUSIONS: ACRODAT® detected disease activity in 51.8% of patients. Interestingly, although M-DA and S-DA patients were likely to be in the process of being controlled, action was not always taken on these patients. ACRODAT® is a validated and highly specific tool that may be useful to routinely monitor acromegaly and to identify patients with non-obvious disease activity by incorporating "patient-centred" parameters like symptoms and QoL to the clinical evaluation of acromegaly.