Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase ...(D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10–20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.
Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of ...503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β1–42 (Aβ1–42) and tau phosphorylated at threonine 181 (p-tau181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer’s Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ1–42 or p-tau181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes.
•VRF burden potentiates longitudinal plasma NfL increase in preclinical AD.•VRF burden potentiates cognitive decline in preclinical AD, particularly affecting memory.•VRF burden does not influence longitudinal changes in CSF Aβ and tau biomarkers.•Therapies targeting VRFs and AD pathophysiology may enhance trial outcomes.•Plasma NfL is a potential surrogate in trials targeting VRFs and AD pathophysiology.
ABSTRACT We report the detection of orbital modulation, a model solution, and the X-ray properties of a newly discovered contact binary, Two Micron All Sky Survey (2MASS) J11201034−2201340. We ...serendipitously found this X-ray point source outside the error ellipse when searching for possible X-ray counterparts of γ-ray millisecond pulsars among the unidentified objects detected by the Fermi Gamma-ray Space Telescope. The optical counterpart of the X-ray source (unrelated to the γ-ray source) was then identified using archival databases. The long-term Catalina Real-Time Transient Survey detected a precise signal with a period of P = 0.28876208 ( 56 ) days. A follow-up observation made by the Super Light Telescope of Lulin Observatory revealed the binary nature of the object. Utilizing archived photometric data of multi-band surveys, we construct the spectral energy distribution (SED), which is well fit by a K2V spectral template. The fitting result of the orbital profile using the Wilson-Devinney code suggests that 2MASS J11201034-2201340 is a short-period A-type contact binary and the more massive component has a cool spot. The X-ray emission was first noted in observations made by Swift, and then further confirmed and characterized by an XMM-Newton observation. The X-ray spectrum can be described by a power law or thermal Bremsstrahlung. Unfortunately, we could not observe significant X-ray orbital modulation. Finally, according to the SED, this system is estimated to be 690 pc from Earth with a calculated X-ray intensity of ( 0.7 − 1.5 ) × 10 30 erg s−1, which is in the expected range of an X-ray emitting contact binary.
Preliminary results demonstrated that concurrent sunitinib and stereotactic body radiation therapy (SBRT) is an active regimen for metastases limited in number and extent. This analysis was conducted ...to determine the long-term survival and cancer control outcomes for this novel regimen. Forty-six patients with oligometastases, defined as five or fewer clinical detectable metastases from any primary site, were treated on a phase I/II trial from February 2007 to September 2010. The majority of patients were treated with 37.5 mg sunitinib (days 1–28) and SBRT 50 Gy (days 8–12 and 15–19) and maintenance sunitinib was used in 39 % of patients. Median follow up for surviving patients is 3.6 years. The 4-year estimates for local control, distant control, progression-free and overall survival were 75 %, 40 %, 34 % and 29 %, respectively. At last follow-up, 26 % of patients were alive without evidence of disease, 7 % were alive with distant metastases, 48 % died from distant metastases, 2 % died from local progression, 13 % died from comorbid illness, and 4 % died from treatment-related toxicities. Patients with kidney and prostate primary tumors were associated with a significantly improved overall survival (hazard ratio = 0.25,
p
= 0.04). Concurrent sunitinib and SBRT is a promising approach for the treatment of oligometastases and further study of this novel combination is warranted.
The identification of gastric superficial cancerous lesions based on conventional white-light endoscopy (WLE) is challenging, and histological analysis remains the 'gold standard' for the final ...diagnosis. Confocal laser endomicroscopy (CLE) can provide in vivo histological observation without the need for biopsy.
To develop and evaluate CLE imaging criteria for gastric superficial cancerous lesions and to compare the diagnostic value of real-time integrated CLE (iCLE) and WLE alone in distinguishing gastric superficial cancerous lesions.
Prospective study.
Qilu Hospital, Shandong University, Jinan, China.
A total of 182 patients were enrolled into phase I and 1786 patients were enrolled into phase II.
CLE images were blindly evaluated after endoscopy in phase I, and real-time iCLE diagnosis during endoscopy was compared with WLE diagnosis by using histopathology as a gold standard in phase II.
The validity and reliability of the CLE diagnosis for identifying gastric superficial cancerous lesions.
Off-line CLE diagnosis for early gastric cancers had a high sensitivity (88.1%) and specificity (98.6%). When the two-tiered CLE classification of non-cancerous lesions and cancer/high-grade intraepithelial neoplasia (HGIN) lesions was introduced, CLE diagnosis led to a higher sensitivity (90.2%) and specificity (98.5%) (phase I). Real-time iCLE diagnosis had a higher sensitivity (88.9%), specificity (99.3%) and accuracy (98.8%) for gastric superficial cancer/HGIN lesions than WLE diagnosis (sensitivity, 72.2%; specificity, 95.1%; and accuracy, 94.1%) (p < 0.05) (phase II). Limitations This was a single-centre study.
CLE can be used to identify gastric superficial cancer/HGIN lesions with high validity and reliability.
Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent maternal transmission of HBV, owing to its efficacy and safety. However, data are lacking on the long-term safety outcomes in ...children following fetal exposure to TDF.
Children participating in a prospective, multisite trial of maternal TDF treatment during late pregnancy were recruited for follow-up visits once a year. Growth parameters, serum biochemistry, HBV serology, and bone mineral density (BMD) by dual-energy x-ray absorptiometery scan were measured.
One hundred and twenty-eight children, 71 in the TDF and 57 in the control group, completed 255 follow-up visits at the age of 2 to 7 (median, 4.08) years. No differences in z-scores for weight-for-age (0.26 ± 0.90 vs. 0.22 ± 0.99, p = 0.481), z-scores for height-for-age (0.20 ± 1.02 vs. 0.25 ± 0.98, p = 0.812), and estimated glomerular filtration rate (169.12 ± 50.48 vs. 169.06 ± 34.46 ml/min/1.73m2, p = 0.479) were detected. After adjustment for age, sex and HBV status by multiple linear regression, children in the TDF and control group had comparable levels of serum calcium, phosphorus, bone-specific alkaline phosphatase, calcidiol and BMD of lumbar spines (0.55 ± 0.01 vs. 0.57 ± 0.01 g/cm2, p = 0.159) and left hip (0.56 ± 0.01 vs. 0.56 ± 0.01 g/cm2, p = 0.926).
Children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6–7 years after delivery.
NCT01312012 (ClinicalTrials.gov)
Currently there are insufficient long-term safety data in children born to mothers who took antiviral agents during pregnancy to prevent mother-to-infant transmission of hepatitis B virus (HBV). In this study, we found that children of HBV-infected mothers who did or did not receive tenofovir disoproxil fumarate treatment during late pregnancy had comparable long-term growth, renal function, and bone development up to 6-7 years after delivery.
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•Short-term TDF use during pregnancy to prevent maternal HBV transmission is safe.•Children with and without fetal exposure to TDF have comparable long-term growth.•Children's renal function and bone development are unaffected.
form the dominant eukaryotic microbial community on the human skin. The
genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external ...cutaneous environment. The exact role of most
secreted enzymes, including those in interaction with the epithelial surface, is not well characterized. In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of
in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease
in both diseased groups, in lesional and non-lesional skin sites, as compared to healthy subjects. To explore the functional roles of
in skin disease, we generated a knockout mutant of the homologous protease
in the genetically tractable
. We observed the loss of
resulted in dramatic changes in the cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of
colonization, we further demonstrated Mfsap1 contributes to inflammation as observed by reduced edema and inflammatory cell infiltration with the knockout mutant versus wildtype. Taken together, we show that this dominant secretory
aspartyl protease has an important role in enabling a planktonic cellular state that can potentially aid in colonization and additionally as a virulence factor in barrier-compromised skin, further highlighting the importance of considering the contextual relevance when evaluating the functions of secreted microbial enzymes.
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