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ater) were stronger, stiffer and required greater stress to produce a fracture than the respective hosts' eggs. These features were affected by eggshell microstructure and ultrastructure, related to the increase in the intercrystalline boundary network acting in cooperation with the increase in palisade layer thickness. Both structural features generate more options and greater lengths of intercrystalline paths, increasing the energy consumed in crack or fissure propagation. The reported patterns of all these diverse eggshell features support a new set of interpretations, confirming several hypotheses regarding the impact of the two reproductive strategies (parasitic versus parental) and parasitic egg destruction behaviors (more versus less frequently puncturing).Androgen receptor (AR) splice variants are proposed to be a potential driver of lethal castration-resistant prostate cancer. AR splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation anti-androgens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work, we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining fluorescence resonance energy transfer and fluorescence recovery after photobleaching, we demonstrate that these heterodimers undergo conformational changes following DNA binding, indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics, suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homodimer or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.

Core Outcome Sets (COSs) are necessary to standardize reporting in research studies. This is urgently required in the field of chronic subdural hematoma (CSDH), one of the most common disease entities managed in neurosurgery and the topic of several recent trials. To complement the development of a COS, a standardized definition and baseline Data Elements (DEs) to be collected in CSDH patients, would further improve study quality and comparability in this heterogeneous population.

To, first, define a standardized COS for reporting in all future CSDH studies; and, second, to identify a unified CSDH Definition and set of DEs for reporting in future CSDH studies.

The overall study design includes a Delphi survey process among 150 respondents from 2 main stakeholder groups healthcare professionals or researchers (HCPRs) and Patients or carers. HCPR, patients and carers will all be invited to complete the survey on the COS, only the HCPR survey will include questions on definition and DE.

It is expected that the COS, definition, and DE will be developed through this Delphi survey and that these can be applied in future CSDH studies. This is necessary to help align future research studies on CSDH and to understand the effects of different treatments on patient function and recovery.

This Delphi survey should result in consensus on a COS and a standardized CSDH Definition and DEs to be used in future CSDH studies.

This Delphi survey should result in consensus on a COS and a standardized CSDH Definition and DEs to be used in future CSDH studies.

Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

We identified a novel homozygous intronic GHR variant (g.542700940T>G, c.618+836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional trg common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.Diabetes mellitus (DM) in children is most often caused by impaired insulin secretion (type 1 DM). In some children, the underlying mechanism for DM is increased insulin resistance, which can have different underlying causes. While the majority of these children require insulin dosages less than 2.0 U/kg/day to achieve normoglycemia, higher insulin requirements indicate severe insulin resistance. Considering the therapeutic challenges in patients with severe insulin resistance, early diagnosis of the underlying cause is essential in order to consider targeted therapies and to prevent diabetic complications. Although rare, several disorders can attribute to severe insulin resistance in pediatric patients. Most of these disorders are diagnosed through advanced diagnostic tests, which are not commonly available in low- or middle-income countries. Entinostat in vitro Based on a case of DM with severe insulin resistance in a Surinamese adolescent who was later confirmed to have autosomal recessive congenital generalized lipodystrophy, type 1 (Berardinelli-Seip syndrome), we provide a systematic approach to the differential diagnosis and work-up. We show that a thorough review of medical history and physical examination generally provide sufficient information to diagnose a child with insulin-resistant DM correctly, and therefore, our approach is especially applicable to low- or middle-income countries.

Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with Multiple Endocrine Neoplasia Type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor promoting roles in several cancer types. We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.

Through an international collaboration between MD Anderson Cancer Center (MDACC), the National Institutes of Health (NIH), and the University Medical Center Utrecht (UMCU), plasma polyamine levels were assessed using mass spectrometry in a total of 84 patients with MEN1 (20 with distant metastatic dpNETs (cases) and 64 with either indolent dpNETs or no dpNETs (controls)). A mouse model of MEN1-pNET, Men1 fl/flPdx1-Cre Tg, was used to test time-dependent changes in plasma polyamines associated with disease progression.

A 3-marker plasma polyamine signature (3MP n-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the three participating centers. The fixed 3MP yielded an AUC of 0.84 (95% CI 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing cases from controls in an independent test set from MDACC. In Men1 fl/flPdx1-Cre Tg mice, the 3MP was elevated early and remained high during disease progression.

Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.

Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16al fibrosis.Thyrotropin, traditionally seen as a pituitary hormone that regulates thyroid glands, has additional roles in physiology including skeletal remodeling. Population-based observations in subjects with euthyroidism or subclinical hyperthyroidism indicated a negative association between bone mass and low-normalTSH. The findings of correlative studies were supported by small intervention trials using recombinant human TSH (rhTSH) injection, and genetic and case-based evidence. Genetically-modified mouse models, which disrupt the reciprocal relationship between TSH and thyroid hormone, have allowed us to examine an independent role of TSH. Since the first description of osteoporotic phenotype in haploinsufficient Tshr +/- mice with normal thyroid hormone levels, the anti-osteoclastic effect of TSH has been documented in in vitro and in vivo studies. Further studies showed that increased osteoclastogenesis in Tshr-deficient mice was mediated by TNFα. Low TSH not only increased osteoclastogenesis, but also decreased osteoblastogenesis in bone marrow-derived primary osteoblast cultures. However, later in vivo studies using small and intermittent dose of rhTSH showed pro-anabolic effect, which suggests that its action might be dose- and frequency-dependent. TSHR was shown to interact with IGF1R, and VEGF and Wnt pathway might play a role in TSH effect on osteoblasts. The expression and direct skeletal effect of a biologically active splice variant of TSHβ subunit (TSHβv) in bone-marrow-derived macrophage and other immune cells suggest local skeletal effect of TSHR. Further studies of how locally secreted TSHβv and systemic TSHβ interact in skeletal remodeling through the endocrine, immune and skeletal system will help us better understand the hyperthyroidism-induced bone disease.

Person-centeredness is a foundation of high-quality health systems but is poorly measured in low and middle-income countries. We piloted an online survey of four low and middle-income countries (LMICs) to identify the prevalence and correlates of excellent patient-reported quality of care.

We administered a cross-sectional online survey using Random Domain Intercept Technology to collect a sample of random internet users across India, Kenya, Mexico, and Nigeria in November 2016. The primary outcome was patient-reported quality of care. Covariates included age, gender, level of education, urban/rural residence, person for whom care was sought, type of provider seen, public or private sector status of the health facility, and type of facility. The exposure was an index of health system responsiveness based on a framework from the World Health Organization. We used descriptive statistics to determine the prevalence of excellent patient-reported quality of care and multivariable Poisson regression to calculate adjusted prevalence ratios (aPR) for predictors of excellent patient-reported quality.