bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy
Authors: de Freitas Maria Cristina Foss , Akinci Baris , Neidert Adam , Hench Rita , Oral Elif A 
Published: May 2021

Abstract
Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c&gt;6.5%) and hypertriglyceridemia (&gt;250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.
Protocol Based Standardized Endocrinological Evaluation of Children With Traumatic Brain Injury: A QI Initiative
Authors: Bhat Jayalakshmi Narayan , Gomez Ricardo , Schultz Scott 
Published: May 2021

Abstract
Introduction: Traumatic brain injury (TBI) can disrupt the hypothalamo-pituitary axis, causing central neuroendocrine dysfunction and hormone abnormalities (HPAD). As one-third of children can develop post-traumatic HPAD, a longitudinal and thorough follow up may be required to exclude the transient or late-onset HPAD.
Objective: To implement a protocol for standardized evaluation of children with TBI for the diagnosis of HPAD and to effectively establish a regular inpatient endocrine consultation and outpatient longitudinal follow up. Method: The study was divided into pre-QI (baseline phase) and QI phase (post-intervention phase). During the pre-QI phase, retrospective data were collected on children admitted with TBI at our institution for 1 year. The prevalence of HPAD and the percentage of children longitudinally followed in endocrine clinic were estimated. A consensus-based guidance protocol, detailing clinical and hormonal assay-based evaluation at presentation and during the follow up were formulated and implemented. Prospective data collection will be performed to estimate outcome measures (prevalence of HPAD, rate of initial endocrine consultation and endocrine outpatient follow up) and process measure (protocol adherence rate). Result: During the baseline phase (pre-QI), a total of 27 children, aged ≤19 years were admitted in the year for TBI management. The median (IQR) age at TBI diagnosis was 9 (3, 15) years. Motor vehicle accident was the predominant cause, accounting for 60%. In 85% of patients, the TBI was classified as severe based on GCS. Overall, only 8 children (30%) underwent limited (non-consultation based) endocrine evaluation (7 for central DI and 1 for central hypothyroidism) and 1 patient had complete evaluation (endocrinologist consulted). During the baseline period, the prevalence rate of transient central DI was diagnosed in 1 patient (4%). Implementation of protocol and post-intervention data collection are pending. Conclusion: The lower prevalence rate of HPAD in the current cohort of TBI patients may be due to under evaluation for endocrine dysfunction. QI initiative incorporating standardized evaluation using guiadance protocol will improve identification follow up rates of patients with endocrine dysfunction following TBI.
The Effects of Naphthenic Acids on Tryptophan Metabolism and Peripheral Serotonin Signalling
Authors: Jamshed Laiba , Perono Genevieve A , Jamshed Shanza , Cheung Kim Ann , Thomas Philippe J , Holloway Alison 
Published: May 2021

Abstract
Introduction: Serotonin produced in the periphery has been shown to affect glucose and lipid homeostasis. The availability of the amino acid tryptophan, the precursor of serotonin, affects serotonin availability. In addition, the metabolism of tryptophan via the kynurenine pathway produces physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. There is now evidence demonstrating some environmental xenobiotics, known to affect glucose and lipid homeostasis, can also alter serotonin production and key components of the kynurenine pathway. Recent evidence suggests that exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites can impact endocrine signaling and result in aberrant lipid accumulation and altered glycemic control. However, whether any of these changes can be causally ascribed to altered serotonin synthesis/signaling or tryptophan metabolism remains unknown. The goal of this study was to determine the effects of exposure to naphthenic acid (NA), a key toxicant found in wastewater from bitumen (thick crude oil present in oil sands deposits) extraction on the enzymes involved in tryptophan metabolism and serotonin production.
Methods: McA-RH7777 rat hepatoma cells, were exposed to a technical NA mixture for 48 hours at concentrations within the reported range of NA found in wastewaters from oil extraction. We assessed mRNA expression for key rate-limiting enzymes involved in tryptophan metabolism that lead to either serotonin [Tph1] and/or kynurenine [Ido2 and Tdo2] production, as well as downstream enzymes in the kynurenine pathway [Afmid, Kyat1, Aadat, Kyat3, Kmo, Haao, Acmsd, Qprt]. We also examined the effects of NA on prostaglandin synthesis [Ptgs1, Ptgs2, Ptges] and signalling [Ptger2, Ptger4] as prostaglandins have been shown to be induced by serotonin and are linked to hepatic fat accumulation.
Results: NA treatment significantly increased Tph1 and Ido2 expression; this occurred in association with a significant increase in the expression of the inducible prostaglandin synthase Ptgs2 (COX-2), prostaglandin E synthase Ptges, and prostaglandin receptors Ptger2 and Ptger4. Acmsd was the only downstream enzyme in the kynurenine pathway that was significantly altered by NA treatment.
Conclusion: These results provide proof-of-concept that compounds associated with oil sands extraction have the potential to perturb key components of serotonin synthesis (Tph1) and tryptophan metabolism (Ido2, Acmsd). Furthermore, we found that the increase in Tph1 expression paralleled expression of Ptgs2. As increased prostaglandin production has been reported in association with nonalcoholic steatohepatitis, these data provide a potential mechanism by which exposure to NA and other petroleum-based compounds may increase the risk of metabolic disease.
Inhibition of CXCR2 by Glucocorticoids in Adipose Tissue
Authors: Amatya Shripa , Dhaibar Hemangini , Petrillo Maria Grazia , Cidlowski John A , Topete Diana Cruz 
Published: May 2021

Abstract
Obesity-induced chronic adipose tissue inflammation is a significant risk factor for metabolic and cardiovascular disease (CVD), which affects 30.3 million adults in the United States. Interaction of adipocytes with hormonal, metabolic and immune systems play an integral role in the underlying pathophysiological mechanisms that leads to development of obesity-related complications. Despite this association, the mechanisms that coordinate the inflammatory mediators in causing adipose tissue inflammation are not well understood. Glucocorticoids (GC) are well known for their potent anti-inflammatory actions; however, the mechanism by which GC coordinate the inflammatory response of adipocytes are unknown. From our genome-wide microarray data derived from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice, we found that GR inactivation leads to a significant increase in pro-inflammatory gene in white adipose tissue (WAT). Additionally, WAT isolated from AdipoGRKO mice showed significant increase in immune cell infiltration, which correlates with our gene expression data. Among the top up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (Cxcr2), which is a powerful mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of Cxcr2 in adipocytes and suggested the contribution of Cxcr2 signaling in adipocyte development, its role in integrating adipose tissue inflammatory response is unknown. This led us to hypothesize that GR is critical to repress Cxcr2 gene expression and its pro inflammatory effects in adipocytes. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of Cxcr2 mRNA and protein levels. Furthermore, these effects are mediated by GR acting directly to repress Cxcr2 gene expression. Systemic administration of corticosterone significantly altered Cxcr2 expression in adipose tissue compared to untreated mice further supporting our results. Together our findings suggest that administration of glucocorticoids could inhibit adipose tissue inflammation and alleviate the comorbidities that arise from inflamed adipose tissue.
A Novel Algorithm for Rare Disease Gene Prediction Based on Phenotypic Similarity
Authors: Fan Yibo , Flannick Jason 
Published: May 2021

Abstract
Genetic studies have yielded only a limited number of genes clearly implicated in endocrine disorders, in large part due to two current knowledge gaps. First, genome wide association studies (GWAS) of common diseases have yielded many associations that are hard to translate to causal genes and pathways. Second, whole exome sequencing (WES) studies have transformed diagnosis of rare diseases but often yield many variants of unknown significance that cannot yet be reliably prioritized for disease causality. We hypothesized that phenotypically similar diseases are more likely to share causal genes and pathways. Thus, genes implicated in a (rare or common) disease should be strong candidates to also contribute to a phenotypically similar disease. To test this hypothesis, we aggregated genes (a) for 3,209 rare diseases from OMIM and (b) nearby GWAS signals for 2,316 common diseases from the NHGRI/EBI GWAS catalog. We measured phenotypic similarity based on proximity in the Experimental Factor Ontology (EFO). Across ~2.7M common disease pairs, the number of genes shared increased with phenotypic similarity (Spearman p &lt; 0.1). Similarly, across ~7.4M common and rare disease pairs and ~5.1M rare disease pairs, phenotypic similarity was significantly higher for disease pairs with at least one shared gene compared to those with no shared genes (T-test p &lt; 0.05). We next developed an algorithm to predict genes for a rare disease based on its phenotypic similarity to other diseases and their known genes. Given a rare disease, the algorithm (a) identifies nearby diseases in the EFO; (b) collates their known genes and groups them into gene ontology (GO) terms; and (c) predicts the genes that occur in the most frequently observed GO term as potentially novel disease genes. We evaluated algorithm performance via cross-validation on rare diseases in OMIM. Across 140 rare endocrine diseases, the algorithm predicted on average 4.84 candidate genes with the correct (known but hidden by cross-validation) disease gene within the candidates 23.6% of the time; performance (5.11 candidates, 13.1% success rate) was similar for the other 3,069 rare diseases in OMIM. Examples include Leprechaunism (known gene INSR), for which genes INSR and TWIST2 were predicted based on phenotypic similarity to diseases Barber-Say syndrome, Rabson-Mendenhall syndrome and Gingival fibromatosis-hypertrichosis syndrome. Lubinsky syndrome (no known genes), for which genes ABCD1, LMNA, CNBP were predicted based on phenotypic similarity to diseases Ricker syndrome, X-ALD, DM1, Malouf syndrome, and Noonan syndrome. These data suggest that known phenotypic relationships and disease-gene databases can increase our ability to predict novel genes for less well-studied diseases, potentially speeding the biological translation of GWAS associations for common diseases and increasing the diagnostic yield of WES for rare diseases.
CAPA Neuropeptides Inhibit VA Activity in Malpighian Tubules of the Mosquito, Aedes Aegypti
Authors: Sajadi Farwa , Paluzzi Jean-Paul 
Published: May 2021

Abstract
Haematophagus insects, such as the female Aedes aegypti mosquito, face the challenge of excess ion and water intake after engorgement on a blood meal. To cope with this, adult female A. aegypti have a specialized excretory system that includes the Malpighian tubules (MTs), which are under rigorous control by several neuroendocrine factors to regulate transepithelial movement of ions/water. Produced in the CNS, the mosquito anti-diuretic hormone is a member of the CAPA peptide family, which share homology to the vertebrate neuromedin U peptide. CAPA peptides inhibit fluid secretion of MTs stimulated by select diuretic factors, 5HT and DH31 through the NOS/cGMP/PKG pathway. However, the anti-diuretic signalling mechanism and downstream cellular targets, such as ion channels and transporters, remain unclear. To study whether the V-type H+-ATPase (VA) plays a role in CAPA inhibition, we performed fluid secretion assays in MTs treated with diuretics and bafilomycin, a known VA inhibitor. Bafilomycin significantly inhibited DH31-stimulated fluid secretion 30 min post treatment compared to diuretic controls (p&lt;0.05, n=22). Similar, however, delayed responses were seen in 5HT-stimulated MTs, while no affect was observed in DH44-stimulated secretion. An indirect way to measure whether CAPA inhibits VA activity was to measure the pH of the secreted fluid from diuretic-stimulated MTs treated with CAPA. In DH31-stimulated MTs supplemented with CAPA, there was an immediate significantly higher pH at 40 min, increasing up to 7.73±0.038 compared to control, 7.56±0.038 (p=0.0007, n=20). The pH of 5HT-stimulated MTs treated with CAPA was seen to significantly increase up to 7.75±0.061 (p=0.03, n=10) at the 60 min mark, in agreement with the delayed response previously seen. Unlike the effects observed with DH31 and 5HT, CAPA did not alter the pH of the secreted fluid in DH44-stimulated MTs. Alkalization of the secreted fluid in response to CAPA suggests inhibition of the proton pump, which may lead to constrained cation entry across the apical membrane of the MTs. To understand Na+/K+-ATPase (NKA) and VA activity in response to CAPA, we performed activity assays in diuretic-stimulated MTs. Adult female MTs treated with DH31 resulted in an increase of both NKA and VA activity compared saline controls. As expected, MTs incubated with both DH31 and AedaeCAPA-1 had a lower NKA and VA activity (p&lt;0.05) resulting in activity levels comparable to saline control levels. The results thus far could suggest a novel mechanism for CAPA inhibition, blocking the VA to hinder fluid secretion. Investigating the pathway of CAPA inhibition and its role in countering diuresis will help provide a deeper understanding of the critical process of diuresis and its signaling mechanism.
Effects of Maternal Sucrose Consumption on Inflammation and Steroids in the Placenta and Fetal Brain
Authors: Seib Desiree R , Kachkovski George V , Bodnar Tamara S , Collier Abby C , Soma Kiran K 
Published: May 2021

Abstract
Consumption of sucrose (table sugar) is high in much of the world. The effects of a maternal diet high in sucrose on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level has effects on the mother’s physiology and steroids, as well as long-lasting and sex-specific effects on the adult offspring’s brain and behavior. In the mothers, there are metabolic effects of sucrose intake, such as impaired glucose tolerance, increased liver lipids, and increased adipose inflammation. In rat dams, sucrose intake also decreases corticosterone levels in the blood but not in the brain. In the adult male offspring, preference for a high-sucrose diet and a high-fat diet increases due to maternal sucrose intake. In addition, maternal sucrose intake increases motivation for sugar rewards in a progressive ratio schedule of reinforcement in adult male offspring. In adult female offspring, corticosterone levels increase in the blood and brain as a result of maternal sucrose intake. In this study, we investigated the underlying mechanisms of the observed behavioral and endocrine effects in the adult offspring. Here, we examined cytokines and anti-inflammatory steroids in the placenta, amniotic fluid, and fetal blood and brain. In our model, we feed rat dams either a high-sucrose diet (26% of kCal) or an isocaloric, matched, control diet (1% sucrose) 10 weeks prior to and during gestation. At embryonic day 19 (E19), we collected maternal blood, placenta, amniotic fluid, fetal blood, and fetal brain. We use Palkovits punch to microdissect the placenta and fetal brain. Next, we use a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, which is highly precise and specific, to measure multiple steroids (e.g. corticosterone, progesterone, estradiol, allopregnanolone). The method is highly sensitive, and we can measure neurosteroids in multiple regions of the fetal brain (e.g. prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus). Moreover, we will examine steroidogenic enzymes and cytokines in the fetal brain and placenta. Preliminary data show distinct steroid patterns in amniotic fluid and fetal blood, as well as in different parts of the placenta.
Effects of Pre and Post-Natal Androgen Exposure on Psychosexual Aspects and Gender Change in Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency
Authors: Batista Rafael Loch , Inacio Marlene , de Miranda Mirela Costa , Madureira Guiomar , Gomes Larissa Garcia , Rodrigues Andresa De Santi , Bachega Tania A , Mendonca Berenice Bilharinho 
Published: May 2021

Abstract
Introduction: Congenital Adrenal Hyperplasia (CAH) is defined as a group of autosomal recessive disorders characterized by a deficiency of the enzyme required to synthesize cortisol by the adrenal cortex. Defects in the 21-hydroxylase enzyme make up 90% of CAH. These defects impaired cortisol synthesis leading to an ACTH increase resulting in androgen excess in both salt-wasting (SW) or simple virilizing (SV) forms. As androgens play a role in the human psychosexual development favoring male psychosexuality, this study was designed to evaluate the impact of androgen exposure on the psychosexuality of individuals with CAH due 21-hydroxylase deficiency. Methods: This retrospective cohort includes 46,XX individuals (115 female-assigned; 8 male-assigned) with a molecular diagnosis of CAH due to CYP21A2 pathogenic variants in homozygous or compounds heterozygous state. External genitalia virilization was scored using Prader scale. Phenotype, time at diagnosis, sex assignment, and gender change were assessed. The gender role at childhood was assessed through the playmates and toys profile at childhood. Gender identity was assessed by a projective psychological test (HTP). Sexual orientation was assessed by self-report sexual identity. Compliance of glucocorticoid replacement was assessed by adequate testosterone and androstenedione serum levels for age. Results: CAH was diagnosed at the neonatal time in 73% (n=78). Fifth-nine (51%) had the SW form and 49% (n=56) had the SV form. While all cases of SW were diagnosed at the neonatal time (0.12 ± 0.14 months), the mean age at diagnosis among SV was 6.03 ± 8.45 years (p=&lt;.001). The median of Prader score was 3 in both forms. Male sex assignment was associated with more virilized external genitalia (p=.002). Gender change occurred in 6 cases (female to male), all with SV form. The prader score was higher among those who changed gender (p=.01). All of those who changed their gender had poor treatment compliance. A total of 13% (n=15) of all groups defined themselves as homosexual. There was a strong association between male toys and preference for male playmates in childhood with homosexuality and male gender identity in adulthood with both gender change from female to male and homosexuality. Conclusion: Prenatal androgen exposure favors male psychosexuality in 46,XX CAH individuals as observed by the association between highest Prader scores and all assessed psychosexual outcomes. This influence is also substantiated by post-natal androgen exposure as observed by compliance issues and late diagnosis among those who changed from female to male gender.