Transferability of Alzheimer disease polygenic risk score across populations and its association with Alzheimer disease-related phenotypes

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. MAIN OUTCOMES AND MEASURES: Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ). RESULTS: A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P \u3c .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aβ deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. CONCLUSIONS AND RELEVANCE: In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD

Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice

Cervical cancer is caused by human papillomavirus (HPV) in collaboration with other non-viral factors. The uterine cervix is hormone responsive and female hormones have been implicated in the pathogenesis of the disease. HPV transgenic mice expressing HPV16 oncogenes E6 ( K14E6 ) and/or E7 ( K14E7 ) have been employed to study a mechanism of estrogen and estrogen receptor ? (ER?) in cervical carcinogenesis. A chronic exposure to physiological levels of exogenous estrogen leads to cervical cancer in the HPV transgenic mice, which depends on ER?. The receptor is composed of multiple functional domains including a DNA-binding domain (DBD), which mediates its binding to estrogen-responsive elements (EREs) on target genes. A transcriptional control of genes by ER? is mediated by either DBD-dependent (classical) or DBD-independent (non-classical) pathway. Although molecular mechanisms of ER? in cancer have been characterized extensively, studies investigating importance of each pathway for carcinogenesis are scarce. In this study, we employ knock-in mice expressing an ER? DBD mutant (E207A/G208A) that is defective specifically for ERE binding. We demonstrate that the ER? DBD mutant fails to support estrogen-induced epithelial cell proliferation and carcinogenesis in the cervix of K14E7 transgenic mice. We also demonstrate that cervical diseases are absent in K14E7 mice when one ER? DBD mutant allele and one wild-type allele are present. We conclude that the ER? classical pathway is required for cervical carcinogenesis in a mouse model

Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation

<p>Abstract</p> <p>Background</p> <p>Minocycline prevents the development of neuropathic and inflammatory pain by inhibiting microglial activation and postsynaptic currents. But, how minocycline obviates acute visceral pain is unclear. The present study investigated whether minocycline had an any antinociceptive effect on acetic acid-induced acute abdominal pain after intraperitoneal (i.p.) administration of saline or minocycline 1 hour before acetic acid injection (1.0%, 250 μl, i.p.).</p> <p>Results</p> <p>Minocycline (4, 10, or 40 mg/kg) significantly decreased acetic acid-induced nociception (0-60 minutes post-injection) and the enhancement in the number of c-Fos positive cells in the T5-L2 spinal cord induced by acetic acid injection. Also, the expression of spinal phosphorylated extracellular signal-regulated kinase (p-ERK) induced by acetic acid was reduced by minocycline pre-administration. Interestingly, intrathecal introduction of PD98059, an ERK upstream kinase inhibitor, markedly blocked the acetic acid-stimulated pain responses.</p> <p>Conclusions</p> <p>These results demonstrate that minocycline effectively inhibits acetic acid-induced acute abdominal nociception via the inhibition of neuronal p-ERK expression in the spinal cord, and that minocycline may have therapeutic potential in suppressing acute abdominal pain.</p

Multilayer fabrication of unobtrusive poly(dimethylsiloxane) nanobrush for tunable cell adhesion

Precise modulation of polymer brush in its thickness and grafting density can cause unexpected cell behaviors and regulated bioactivities. Herein, a nanoscale poly(dimethylsiloxane) (PDMS) brush was employed to use as a controllable material for cell adhesion. Facile fabrication of ultrathin monolayer PDMS nanobrush on an underlying substrate facilitated regaining cell adhesion through long-range cell attractive forces such as the van der Waals forces. We showed that cell adhesion is diminished by increasing the number of nanobrush layers, causing a gradual decrease of the effectiveness of the long-range force. The result demonstrates that ultrathin PDMS nanobrush can either promote or inhibit cell adhesion, which is required for various biomedical fields such as tissue-engineering, anti-fouling coating, and implantable biomaterials and sensors

Optical spectroscopic investigation on the coupling of electronic and magnetic structure in multiferroic hexagonal RMnO3 (R = Gd, Tb, Dy, and Ho) thin films

We investigated the effects of temperature and magnetic field on the electronic structure of hexagonal RMnO3 (R = Gd, Tb, Dy, and Ho) thin films using optical spectroscopy. As the magnetic ordering of the system was disturbed, a systematic change in the electronic structure was commonly identified in this series. The optical absorption peak near 1.7 eV showed an unexpectedly large shift of more than 150 meV from 300 K to 15 K, accompanied by an anomaly of the shift at the Neel temperature. The magnetic field dependent measurement clearly revealed a sizable shift of the corresponding peak when a high magnetic field was applied. Our findings indicated strong coupling between the magnetic ordering and the electronic structure in the multiferroic hexagonal RMnO3 compounds.Comment: 16 pages including 4 figure

High Doses of Bupleurum falcatum Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling

Background and Objective:Bupleurum falcatum (BF) extract, a natural product with anti-inflammatory properties, has been traditionally used to treat menopausal symptoms, but its role in osteoporosis, another serious health concern of menopausal women, remains unknown. Here we investigated whether and how BF prevents estrogen deficiency-induced bone loss using both in vitro and in vivo models.Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and subjected to oral BF treatment daily for 8 weeks. Additionally, pre-osteoclastic RAW 264.7 cells were employed to evaluate the effects of BF and its underlying mechanism on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in vitro.Results: A high dose of BF partially prevented ovariectomy (OVX)-induced bone loss and reduced the levels of tartrate-resistant acid phosphatase (TRAP) in serum and osteoclast numbers in femurs of OVX rats. Furthermore, BF clearly inhibited RANKL-induced osteoclast differentiation and bone resorption activity in RAW 264.7 cells. BF also inhibited the osteoclastogenic transcription factors c-Fos and nuclear factor of activated T cells c1 (NFATc1) and, consequently, downregulated the expression of osteoclast marker genes. Moreover, BF upregulated interferon-β (IFN-β)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) signaling, even though it had no impact on mitogen-activated protein kinases (MAPK) or NF-κB. The inhibition of osteoclast formation by BF was abrogated by iNOS-specific inhibitors. Consistent with cellular studies, BF upregulated iNOS protein expression in femurs from OVX rats.Conclusion: Taken together, our results indicate that BF partially prevented estrogen deficiency-induced bone loss with anti-osteoclastogenic activity potentially due to enhanced iNOS/NO signaling