The outbreak of coronavirus disease 2019 (COVID-19), which began in December 2019, is still ongoing in Korea, with >9,000 confirmed cases as of March 25, 2020. COVID-19 is a severe acute respiratory ...syndrome Coronavirus 2 (SARS-CoV-2) infection, and real-time reverse transcription-PCR is currently the most reliable diagnostic method for COVID-19 around the world. Korean Society for Laboratory Medicine and the Korea Centers for Disease Prevention and Control propose guidelines for diagnosing COVID-19 in clinical laboratories in Korea. These guidelines are based on other related domestic and international guidelines, as well as expert opinions and include the selection of test subjects, selection of specimens, diagnostic methods, interpretation of test results, and biosafety.
Replication-Factor-C (RFC) and RFC-like complexes (RLCs) mediate chromatin engagement of the proliferating cell nuclear antigen (PCNA). It remains controversial how RFC and RLCs cooperate to regulate ...PCNA loading and unloading. Here, we show the distinct PCNA loading or unloading activity of each clamp loader. ATAD5-RLC possesses the potent PCNA unloading activity. ATPase motif and collar domain of ATAD5 are crucial for the unloading activity. DNA structures did not affect PCNA unloading activity of ATAD5-RLC. ATAD5-RLC could unload ubiquitinated PCNA. Through single molecule measurements, we reveal that ATAD5-RLC unloaded PCNA through one intermediate state before ATP hydrolysis. RFC loaded PCNA through two intermediate states on DNA, separated by ATP hydrolysis. Replication proteins such as Fen1 could inhibit the PCNA unloading activity of Elg1-RLC, a yeast homolog of ATAD5-RLC in vitro. Our findings provide molecular insights into how PCNA is released from chromatin to finalize DNA replication/repair.
External quality assessment (EQA) is essential for ensuring reliable test results, especially when laboratories are using assays authorized for emergency use for newly emerging pathogens. We ...developed an EQA panel to assess the quality of real-time reverse transcription PCR assays being used in South Korea to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the participation of 23 public health organization laboratories and 95 nongovernmental laboratories involved in SARS-CoV-2 testing, we conducted qualitative and semiquantitative performance assessments by using pooled respiratory samples containing different viral loads of SARS-CoV-2 or human coronavirus OC43. A total of 110 (93.2%) laboratories reported correct results for all qualitative tests; 29 (24.6%) laboratories had >1 outliers according to cycle threshold values. Our EQA panel identified the potential weaknesses of currently available commercial reagent kits. The methodology we used can provide practical experience for those planning to conduct evaluations for testing of SARS-CoV-2 and other emerging pathogens in the future.
There has been a growing interest in the relationship between sedative-hypnotics use and the risk of Alzheimer's dementia (AD) risk. This study aimed to evaluate the risk of AD associated with the ...use of sedative-hypnotics. A retrospective cohort study was conducted with randomly selected 5% samples from ≥50 years old beneficiaries of National Health Insurance Service (NHIS) of Korea from January 2002 to December 2015. The exposure to sedative-hypnotics was defined when prescribed over 30 defined daily dose (DDD) after January 2004 and it was categorized by prescribed dosage, types and half-lives of benzodiazepines. Time-dependent Cox regression model with a lag period of 5-years was used to evaluate the association between use of sedative-hypnotics and the risk of subsequent AD. Sensitivity analysis was performed for restricting sedative-hypnotics only when prescribed with insomnia. A total of 268,170 subjects were identified and subjects exposed to sedative-hypnotics showed a higher risk of AD (HR: 1.79; 95% CI: 1.72-1.86) than those who were not. There was an increased risk of AD among subjects exposed to benzodiazepines or zolpidem (HR: 1.75; 95% CI: 1.67-1.82) and antidepressants or low-dose antipsychotics (HR: 1.63; 95% CI: 1.42-1.87). The risk of AD was increased regardless of dose of sedative-hypnotics and half-life among benzodiazepines, especially in exposure to more than 360 DDD of sedative-hypnotics (HR: 1.78; 95% CI: 1.60-1.99) and the long-acting benzodiazepine (HR:1.77; 95% CI: 1.65-1.89).
The sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. Hypoxia‐inducible factor‐1 ...(HIF‐1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of genes in response to hypoxic stress. This study was designed to investigate the effects of melatonin on tumor growth and angiogenesis, as well as the mechanism underlying the antitumor activities of melatonin. In this study, we show that the administration of melatonin inhibits tumor growth and blocks tumor angiogenesis in mice. Moreover, melatonin diminished the expression of the HIF‐1α protein within the tumor mass during tumorigenesis. Our findings suggest that melatonin is a promising anti‐angiogenic therapeutic agent targeting HIF‐1α in cancer. Considering that HIF‐1α is overexpressed in a majority of human cancers, melatonin could offer a potent therapeutic agent for cancer.
Cinnamic aldehyde (CA), a key flavor compound in cinnamon essential oil, has been identified as an anti-oxidant, anti-angiogenic, and anti-inflammatory material. Recently, the neuroprotective effects ...of CA have been reported in various neurodegenerative disorders, including Parkinson's disease (PD). In neurons, autophagy is tightly regulated, and consequently, the dysregulation of autophagy may induce neurodegenerative disorders. In the present study, we found that the selective dopaminergic neuronal death in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models was prevented by CA. Stimulation of microtubule-associated protein light chain 3 (LC3) puncta mediated by MPTP treatment was decreased by CA. Moreover, down-regulated p62 in the substantia nigra of MPTP mice was increased by administration of CA. Finally, we showed that blockage of autophagy using autophagy inhibitors protected the 1-methyl-4-phenylpyridinium (MPP⁺)-mediated death of BE(2)-M17 cells. Together these results suggest that CA has a neuroprotective effect in a PD model and that inhibition of autophagy might be a promising therapeutic target for PD.
The basic function of β-arrestin 2 (Arrb2) is to negatively regulate the G-protein-coupled receptor signaling pathway through facilitating receptor desensitization and internalization. Arrb2 has also ...been reported to play various roles in cancer pathology including the proliferation, migration, invasion, metastasis, and apoptosis of solid tumors. However, the molecular mechanisms underlying the tumorigenic capacities of Arrb2 have not been elucidated. Here, we show a novel function of Arrb2: Arrb2 facilitates the degradation of HIF-1α, which is a master regulator of oxygen homeostasis. We also demonstrate that Arrb2 interacts with HIF-1α and stimulates ubiquitin-mediated 26S proteasomal degradation of HIF-1α by recruiting PHD2 and pVHL. Overexpression of Arrb2 in human glioblastoma cells suppresses HIF-1α signaling, tumor growth, and angiogenesis. Consistent with this antitumorigenic effect of Arrb2, low Arrb2 expression levels correlate with high HIF-1α expression and poor glioblastoma patient survival. These results collectively reveal a novel function of Arrb2 in the oxygen-sensing mechanism that directly regulates HIF-1α stability in human cancers and suggest Arrb2 as a new potential therapeutic target for glioblastoma.
Sub‐nanometric particles (SNPs) of atomic cluster sizes have shown great promise in many fields such as full atom‐to‐atom utilization, but their precise production and stabilization at high mass ...loadings remain a great challenge. As a solution to overcome this challenge, a strategy allowing synthesis and preservation of SNPs at high mass loadings within multishell hollow metal–organic frameworks (MOFs) is demonstrated. First, alternating water‐decomposable and water‐stable MOFs are stacked in succession to build multilayer MOFs. Next, using controlled hydrogen bonding affinity, isolated water molecules are selectively sieved through the hydrophobic nanocages of water‐stable MOFs and transferred one by one to water‐decomposable MOFs. The transmission of water molecules via controlled hydrogen bonding affinity through the water‐stable MOF layers is a key step to realize SNPs from various types of alternating water‐decomposable and water‐stable layers. This process transforms multilayer MOFs into SNP‐embedded multishell hollow MOFs. Additionally, the multishell stabilizes SNPs by π‐backbonding allowing high conductivity to be achieved via the hopping mechanism, and hollow interspaces minimize transport resistance. These features, as demonstrated using SNP‐embedded multishell hollow MOFs with up to five shells, lead to high electrochemical performances including high volumetric capacities and low overpotentials in Li–O2 batteries.
Hydrogen affinity‐controlled water molecule transfers throughout multilayer metal–organic frameworks result in sub‐nanometric particle (SNP)‐embedded multishell hollow metal–organic frameworks (MOFs), where the multishell stabilizes SNPs by π‐backbonding allowing high conductivity and hollow interspaces that minimize transport resistance. Moreover, increasing the mass loading of SNPs within multishell hollow MOFs is demonstrated to enable higher capacities and smaller overpotentials in Li–O2 batteries.
In the recent years, machine learning algorithms have been more widely and increasingly applied in biomedical fields. In particular, their application has been drawing more attention in the field of ...psychiatry, for instance, as diagnostic tests/tools for autism spectrum disorder (ASD). However, given their complexity and potential clinical implications, there is an ongoing need for further research on their accuracy.
This study aimed to perform a systematic review and meta-analysis to summarize the available evidence for the accuracy of machine learning algorithms in diagnosing ASD.
The following databases were searched on November 28, 2018: MEDLINE, EMBASE, CINAHL Complete (with Open Dissertations), PsycINFO, and Institute of Electrical and Electronics Engineers Xplore Digital Library. Studies that used a machine learning algorithm partially or fully for distinguishing individuals with ASD from control subjects and provided accuracy measures were included in our analysis. The bivariate random effects model was applied to the pooled data in a meta-analysis. A subgroup analysis was used to investigate and resolve the source of heterogeneity between studies. True-positive, false-positive, false-negative, and true-negative values from individual studies were used to calculate the pooled sensitivity and specificity values, draw Summary Receiver Operating Characteristics curves, and obtain the area under the curve (AUC) and partial AUC (pAUC).
A total of 43 studies were included for the final analysis, of which a meta-analysis was performed on 40 studies (53 samples with 12,128 participants). A structural magnetic resonance imaging (sMRI) subgroup meta-analysis (12 samples with 1776 participants) showed a sensitivity of 0.83 (95% CI 0.76-0.89), a specificity of 0.84 (95% CI 0.74-0.91), and AUC/pAUC of 0.90/0.83. A functional magnetic resonance imaging/deep neural network subgroup meta-analysis (5 samples with 1345 participants) showed a sensitivity of 0.69 (95% CI 0.62-0.75), specificity of 0.66 (95% CI 0.61-0.70), and AUC/pAUC of 0.71/0.67.
The accuracy of machine learning algorithms for diagnosis of ASD was considered acceptable by few accuracy measures only in cases of sMRI use; however, given the many limitations indicated in our study, further well-designed studies are warranted to extend the potential use of machine learning algorithms to clinical settings.
PROSPERO CRD42018117779; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=117779.
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