ARID3C Acts as a Regulator of Monocyte-to-Macrophage Differentiation Interacting with NPM1.

ARID3C is a protein located on human chromosome 9 and expressed at low levels in various organs, yet its biological function has not been elucidated. In this study, we investigated both the cellular localization and function of ARID3C. Employing a combination of LC-MS/MS and deep learning techniques, we identified NPM1 as a binding partner for ARID3C's nuclear shuttling. ARID3C was found to predominantly localize with the nucleus, where it functioned as a transcription factor for genes STAT3, STAT1, and JUNB, thereby facilitating monocyte-to-macrophage differentiation. The precise binding sites between ARID3C and NPM1 were predicted by AlphaFold2. Mutating this binding site prevented ARID3C from interacting with NPM1, resulting in its retention in the cytoplasm instead of translocation to the nucleus. Consequently, ARID3C lost its ability to bind to the promoters of target genes, leading to a loss of monocyte-to-macrophage differentiation. Collectively, our findings indicate that ARID3C forms a complex with NPM1 to translocate to the nucleus, acting as a transcription factor that promotes the expression of the genes involved in monocyte-to-macrophage differentiation.

Identifying Terpenoid Biosynthesis Genes in Euphorbia maculata via Full-Length cDNA Sequencing.

The annual herb Euphorbia maculata L. produces anti-inflammatory and biologically active substances such as triterpenoids, tannins, and polyphenols, and it is used in traditional Chinese medicine. Of these bioactive compounds, terpenoids, also called isoprenoids, are major secondary metabolites in E. maculata. Full-length cDNA sequencing was carried out to characterize the transcripts of terpenoid biosynthesis reference genes and determine the copy numbers of their isoforms using PacBio SMRT sequencing technology. The Illumina short-read sequencing platform was also employed to identify differentially expressed genes (DEGs) in the secondary metabolite pathways from leaves, roots, and stems. PacBio generated 62 million polymerase reads, resulting in 81,433 high-quality reads. From these high-quality reads, we reconstructed a genome of 20,722 genes, in which 20,246 genes (97.8%) did not have paralogs. About 33% of the identified genes had two or more isoforms. DEG analysis revealed that the expression level differed among gene paralogs in the leaf, stem, and root. Whole sets of paralogs and isoforms were identified in the mevalonic acid (MVA), methylerythritol phosphate (MEP), and terpenoid biosynthesis pathways in the E. maculata L. The nucleotide information will be useful for identifying orthologous genes in other terpenoid-producing medicinal plants.

RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes.

RNF20/40 E3 ubiquitin ligase-mediated histone H2B monoubiquitylation plays important roles in many cellular processes, including transcriptional regulation. However, the multiple defects observed in RNF20-depleted cells suggest additional ubiquitylation targets of RNF20/40 beyond histone H2B. Here, using biochemically defined assays employing purified factors and cell-based analyses, we demonstrate that RNF20/40, in conjunction with its cognate E2 ubiquitin-conjugating enzyme RAD6, monoubiquitylates lysine 381 of eEF1BδL, a heat shock transcription factor. Notably, monoubiquitylation of eEF1BδL increases eEF1BδL accumulation and potentiates recruitment of p-TEFb to the promoter regions of heat shock-responsive genes, leading to enhanced transcription of these genes. We further demonstrate that cooperative physical interactions among eEF1BδL, RNF20/40, and HSF1 synergistically promote expression of heat shock-responsive genes. In addition to identifying eEF1BδL as a novel ubiquitylation target of RNF20/40 and elucidating its function, we provide a molecular mechanism for the cooperative function of distinct transcription factors in heat shock-responsive gene transcription.

Factors associated with insufficient response to acute treatment of migraine in Japan: analysis of real-world data from the Adelphi Migraine Disease Specific Programme.

BACKGROUND: Real-world data on sufficient/insufficient response, and predictors of insufficient response, to acute treatments for migraine are limited in Japan. This study aimed to identify factors associated with insufficient response to acute treatment of migraine by exploring significant differences between people with migraine who sufficiently/insufficiently respond to prescribed acute treatment in Japan. METHODS: This was a retrospective analysis of 2014 Adelphi Migraine Disease Specific Programme cross-sectional survey data collected from physicians and their consulting adult patients with migraine in Japan. Insufficient responders to prescribed acute treatment were patients who achieved headache pain freedom within 2 h of acute treatment in no more than three of their last five migraine attacks. Factors associated with insufficient response to prescribed acute migraine treatment were identified using backward logistic regression. RESULTS: Overall, 227/538 (42.2%) patients were classified as insufficient responders to prescribed acute migraine treatment. Significantly more insufficient responders than sufficient responders had consulted a neurologist or a migraine/headache specialist, and had chronic migraine or medication-overuse or tension-type headaches (p < 0.05). More insufficient responders than sufficient responders reported taking acute treatment when/after the pain started (77.0 vs. 68.9%) than at first sign of migraine (p < 0.05). Compared with sufficient responders, insufficient responders reported a significantly higher mean ± standard deviation (SD) Migraine Disability Assessment total score (12.7 ± 23.3 vs. 5.8 ± 10.4, p < 0.001) and lower quality of life (EuroQol-5 Dimensions utility score 0.847 ± 0.19 vs. 0.883 ± 0.16, p = 0.024). Factors significantly associated with insufficient response to acute treatment included seeing a neurologist versus an internist (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.29-2.88; p = 0.002), taking acute medication when/after pain started versus at first sign of migraine (OR 1.65; 95% CI 1.05-2.60; p = 0.030), a higher MIDAS total score (OR 1.04; 95% CI 1.02-1.06; p < 0.001), and presence of comorbid cardiovascular disease (OR 0.53; 95% CI 0.28-0.98; p = 0.044). CONCLUSIONS: Many people with migraine in Japan struggle to adequately treat migraine attacks with prescribed acute medication and exhibit high levels of unmet need for acute treatment. Optimized management strategies utilizing existing therapeutic options as well as additional effective therapeutic options for migraine are required to improve symptoms and quality of life.

A global real-world assessment of the impact on health-related quality of life and work productivity of migraine in patients with insufficient versus good response to triptan medication.

BACKGROUND: Migraine is a chronic, disabling neurological disease characterized by moderate-to-severe headache pain with other symptoms, including nausea, vomiting, and photophobia. Triptans, while generally effective, are insufficiently efficacious in 30-40% of patients and poorly tolerated by or contraindicated in others. We assessed the impact of insufficient response to triptans on health-related quality of life (HRQoL) and work productivity in patients currently receiving any prescribed triptan formulation as their only acute migraine medication. METHODS: Data were from the 2017 Adelphi Migraine Disease Specific Programme, a cross-sectional survey of primary care physicians, neurologists, and headache specialists and their consulting patients with migraine in the USA, France, Germany, Italy, Spain, and UK. Triptan insufficient responders (TIRs) achieved freedom from headache pain within 2 h of acute treatment in ≤3/5 migraine attacks; triptan responders (TRs) achieved pain freedom within 2 h in ≥4/5 attacks. Multivariable general linear model examined differences between TIRs and TRs in HRQoL and work productivity. Logistic regression identified factors associated with insufficient response to triptans. RESULTS: The study included 1413 triptan-treated patients (TIRs: n = 483, 34.2%; TRs: n = 930, 65.8%). TIRs were more likely to be female (76% vs. 70% for TIRs vs TRs, respectively; p = 0.011), older (mean age 42.6 vs. 40.5 years; p = 0.003), and had more headache days/month (7.0 vs. 4.4; p < 0.001). TIRs had significantly more disability, with higher Migraine Disability Scores (MIDAS; 13.2 vs. 7.7; p < 0.001), lower Migraine-specific Quality of Life scores, indicating greater impact (Role Function Restrictive: 62.4 vs. 74.5; Role Function Preventive: 70.0 vs. 82.2; Emotional Function: 67.7 vs. 82.1; all p < 0.001), and lower EQ5D utility scores (0.84 vs. 0.91; p = 0.001). Work productivity and activity were impaired (absenteeism, 8.6% vs. 5.1% for TIRs vs. TRs; presenteeism, 34.3% vs. 21.0%; work impairment, 37.1% vs. 23.3%; overall activity impairment, 39.8% vs. 25.3%; all p < 0.05). CONCLUSION: HRQoL and work productivity were significantly impacted in TIRs versus TRs in this real-world analysis of patients with migraine acutely treated with triptans, highlighting the need for more effective treatments for patients with an insufficient triptan response. Further research is needed to establish causal relationships between insufficient response and these outcomes.

Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and reactive oxygen species generation in A549 and NCI-H1299 non-small cell lung cancer cells.

BACKGROUND: Calotropis gigantea (CG) is a tall and waxy flower that is used as a traditional remedy for fever, indigestion, rheumatism, leprosy, and leukoderma. However, the precise mechanisms of its anticancer effects have not yet been examined in human non-small cell lung cancer (NSCLC) cells. In this study, we investigated whether CG extract exerted an apoptotic effect in A549 and NCI-H1299 NSCLC cells. METHODS: The ethanol extract of CG was prepared, and its apoptotic effects on A549 and NCI-H1299 NSCLC cells were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining, cell cycle analysis, real-time polymerase chain reaction (RT-PCR), western blotting, JC-1 staining, and ROS detection assay. RESULTS: The CG extract induced apoptosis through the stimulation of intrinsic and extrinsic signaling pathways in A549 and NCI-H1299 lung cancer cells. Cell cycle arrest was induced by the CG extract in both cell lines. Reactive oxygen species (ROS), which can induce cell death, were also generated in the CG-treated A549 and NCI-H1299 cells. CONCLUSIONS: These data confirmed that CG caused apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest, and ROS generation in A549 and NCI-H1299 lung cancer cells. Thus, CG can be suggested as a potential agent for lung cancer therapy.

Real-world treatment patterns and patient-reported outcomes in episodic and chronic migraine in Japan: analysis of data from the Adelphi migraine disease specific programme.

BACKGROUND: In Japan, detailed information on the characteristics, disease burden, and treatment patterns of people living with migraine is limited. The aim of this study was to compare clinical characteristics, disease burden, and treatment patterns in people with episodic migraine (EM) or chronic migraine (CM) using real-world data from clinical practice in Japan. METHODS: This was an analysis of data collected in 2014 by the Adelphi Migraine Disease Specific Programme, a cross-sectional survey of physicians and their consulting adult patients in Japan, using physician and patient questionnaires. We report patient demographics, prescribed treatment, work productivity, and quality-of-life data for people with CM (≥15 headache days/month) or EM (not fulfilling CM criteria). In descriptive analyses, continuous and categorical measures were assessed using t-tests and Chi-squared tests, respectively. RESULTS: Physicians provided data for 977 patients (mean age 44.5 years; 77.2% female; 94.5% with EM, 5.5% with CM). A total of 634/977 (64.9%) invited patients (600 with EM; 34 with CM) also provided data. Acute therapy was currently being prescribed in 93.7% and 100% of patients with EM and CM, respectively (p = 0.069); corresponding percentages for current preventive therapy prescriptions were 40.5% and 68.5% (p < 0.001). According to physicians who provided data, preventive therapy was used at least once by significantly fewer patients with EM than with CM (42.3% vs. 68.5%, respectively; p < 0.001). Among patients who provided physicians with information on issues with their current therapy (acute therapy: n = 668 with EM, n = 38 with CM; preventive therapy: n = 295 with EM, n = 21 with CM), lack of efficacy was the most frequently identified problem (acute therapy: EM 35.3%, CM 39.5% [p = 0.833]; preventive therapy: EM 35.3%, CM 52.4% [p = 0.131]). Moderate-to-severe headache-related disability (Migraine Disability Assessment total score ≥ 11) was reported by significantly fewer patients with EM than with CM (21.0% vs. 60.0%, respectively; p < 0.001) among patients who provided data. CONCLUSIONS: Preventive treatment patterns in people with EM versus CM differ in Japan, with both types of migraine posing notable disease burdens. Our findings demonstrate that more effective migraine therapies are required to reduce the burden of the disease.

Quiescin Sulfhydryl Oxidase 1 (QSOX1) Secreted by Lung Cancer Cells Promotes Cancer Metastasis.

As lung cancer shows the highest mortality in cancer-related death, serum biomarkers are demanded for lung cancer diagnosis and its treatment. To discover lung cancer protein biomarkers, secreted proteins from primary cultured lung cancer and adjacent normal tissues from patients were subjected to LC/MS⁻MS proteomic analysis. Quiescin sulfhydryl oxidase (QSOX1) was selected as a biomarker candidate from the enriched proteins in the secretion of lung cancer cells. QSOX1 levels were higher in 82% (51 of 62 tissues) of lung cancer tissues compared to adjacent normal tissues. Importantly, QSOX1 serum levels were significantly higher in cancer patients (p < 0.05, Area Under curve (AUC) = 0.89) when measured by multiple reaction monitoring (MRM). Higher levels of QSOX1 were also uniquely detected in lung cancer tissues, among several other solid cancers, by immunohistochemistry. QSOX1-knock-downed Lewis lung cancer (LLC) cells were less viable from oxidative stress and reduced migration and invasion. In addition, LLC mouse models with QSOX1 knock-down also proved that QSOX1 functions in promoting cancer metastasis. In conclusion, QSOX1 might be a lung cancer tissue-derived biomarker and be involved in the promotion of lung cancers, and thus can be a therapeutic target for lung cancers.

Hochu-ekki-to Treatment Improves Reproductive and Immune Modulation in the Stress-Induced Rat Model of Polycystic Ovarian Syndrome.

The traditional herbal medicine, Hochu-ekki-to, has been shown to have preventive effects on viral infection and stress. This study aimed to evaluate the clinical effects of Hochu-ekki-to on two stress-related rat models of polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into control and treatment groups, the latter of which were subjected to stress induced by exposure to adrenocorticotropic hormone (ACTH) or cold temperatures. After these stress inductions, rats were orally treated with dissolved Hochu-ekki-to once per day for 7 days. Rats subjected to the two different stressors exhibited upregulation of steroid hormone receptors (in ovaries) and reproductive hormones (in blood), and consequent stimulation of abnormal follicle development accompanied by elevation of Hsp 90 expression (in ovaries). Treatment with Hochu-ekki-to for 7 days after stress induction increased immune functions, reduced the stress-induced activation of Hsp 90, and normalized the levels of the tested steroid hormone receptors and reproductive hormones. Our findings suggest that stress stimulations may promote the activation of Hsp 90 via the dysregulation of steroid hormone receptors and reproductive hormones, but that post-stress treatment with Hochu-ekki-to improves reproductive and immune functions in the ovaries of stressed rats.

Characterization of Site-Specific N-Glycopeptide Isoforms of α-1-Acid Glycoprotein from an Interlaboratory Study Using LC-MS/MS.

Glycoprotein conformations are complex and heterogeneous. Currently, site-specific characterization of glycopeptides is a challenge. We sought to establish an efficient method of N-glycoprotein characterization using mass spectrometry (MS). Using alpha-1-acid glycoprotein (AGP) as a model N-glycoprotein, we identified its tryptic N-glycopeptides and examined the data reproducibility in seven laboratories running different LC-MS/MS platforms. We used three test samples and one blind sample to evaluate instrument performance with entire sample preparation workflow. 165 site-specific N-glycopeptides representative of all N-glycosylation sites were identified from AGP 1 and AGP 2 isoforms. The glycopeptide fragmentations by collision-induced dissociation or higher-energy collisional dissociation (HCD) varied based on the MS analyzer. Orbitrap Elite identified the greatest number of AGP N-glycopeptides, followed by Triple TOF and Q-Exactive Plus. Reproducible generation of oxonium ions, glycan-cleaved glycopeptide fragment ions, and peptide backbone fragment ions was essential for successful identification. Laboratory proficiency affected the number of identified N-glycopeptides. The relative quantities of the 10 major N-glycopeptide isoforms of AGP detected in four laboratories were compared to assess reproducibility. Quantitative analysis showed that the coefficient of variation was <25% for all test samples. Our analytical protocol yielded identification and quantification of site-specific N-glycopeptide isoforms of AGP from control and disease plasma sample.

Stanniocalcin-2 (STC2): A potential lung cancer biomarker promotes lung cancer metastasis and progression.

The homodimeric glycoprotein, stanniocalcin 2 (STC2) is previously known to be involved in the regulation of calcium and phosphate transport in the kidney and also reported to play multiple roles in several cancers. However, its function and clinical significance in lung cancer have never been reported and still remain uncertain. Here, we investigated the possibility of STC2 as a lung cancer biomarker and identified its potential role in lung cancer cell growth, metastasis and progression. Proteomic analysis of secretome of primary cultured lung cancer cells revealed higher expression of STC2 in cancers compared to that of adjacent normal cells. RT-PCR and Western blot analyses showed higher mRNA and protein expressions of STC2 in lung cancer tissues compared to the adjacent normal tissues. Knockdown of STC2 in H460 lung cancer cells slowed down cell growth progression and colony formation. Further analysis revealed suppression of migration, invasion and delayed G0/G1 cell cycle progression in the STC2 knockdown cells. STC2 knockdown also attenuated the H202-induced oxidative stress on H460 cell viability with a subsequent increase in intracellular ROS levels, which suggest a protective role of STC2 in redox regulatory system of lung cancer. These findings suggest that STC2 can be a potential lung cancer biomarker and plays a positive role in lung cancer metastasis and progression. This article is part of a Special Issue entitled: Medical Proteomics.

Proteogenomic Study beyond Chromosome 9: New Insight into Expressed Variant Proteome and Transcriptome in Human Lung Adenocarcinoma Tissues.

This is a report of a human proteome project (HPP) related to chromosome 9 (Chr 9). To reveal missing proteins and undiscovered features in proteogenomes, both LC-MS/MS analysis and next-generation RNA sequencing (RNA-seq)-based identification and characterization were conducted on five pairs of lung adenocarcinoma tumors and adjacent nontumor tissues. Before our previous Chromosome-Centric Human Proteome Project (C-HPP) special issue, there were 170 remaining missing proteins on Chr 9 (neXtProt 2013.09.26 rel.); 133 remain at present (neXtProt 2015.04.28 rel.). In the proteomics study, we found two missing protein candidates that require follow-up work and one unrevealed protein across all chromosomes. RNA-seq analysis detected RNA expression for four nonsynonymous (NS) single nucleotide polymorphisms (SNPs) (in CDH17, HIST1H1T, SAPCD2, and ZNF695) and three synonymous SNPs (in CDH17, CST1, and HNF1A) in all five tumor tissues but not in any of the adjacent normal tissues. By constructing a cancer patient sample-specific protein database based on individual RNA-seq data and by searching the proteomics data from the same sample, we identified four missense mutations in four genes (LTF, HDLBP, TF, and HBD). Two of these mutations were found in tumor samples but not in paired normal tissues. In summary, our proteogenomic study of human primary lung tumor tissues detected additional and revealed novel missense mutations and synonymous SNP signatures, some of which are specific to lung cancers. Data from mass spectrometry have been deposited in the ProteomeXchange with the identifier PXD002523.

Gln-362 of angiopoietin-2 mediates migration of tumor and endothelial cells through association with α5ß1 integrin.

Angiopoietin-2 (Ang-2) not only regulates angiogenesis by binding to its well known receptor Tie2 on endothelial cells but also controls sprouting of Tie2-negative angiogenic endothelial cells and invasion of Tie2-negative non-endothelial cells by binding to integrins. However, the molecular mechanism of the Ang-2/integrin association has been unclear. In this study, we found that the Gln-362 residue of Ang-2 was essential for binding to α5ß1 integrin. A Q362E Ang-2 mutant, which still bound to Tie2, failed to associate with α5ß1 integrin and was unable to activate the integrin downstream signaling of focal adhesion kinase. In addition, unlike wild-type Ang-2, the Q362E Ang-2 mutant was defective in mediating invasion of Tie2-negative glioma or Tie2-positive endothelial cells. Furthermore, the tailpiece domain of the α5 subunit in α5ß1 integrin was critical for binding to Ang-2. Taken together, these results provide a novel insight into the mechanism of integrin regulation by Ang-2, which contributes to tumor invasion and endothelial cell migration in a Tie2-independent manner.

Proteogenomic analysis of human chromosome 9-encoded genes from human samples and lung cancer tissues.

The Chromosome-centric Human Proteome Project (C-HPP) was recently initiated as an international collaborative effort. Our team adopted chromosome 9 (Chr 9) and performed a bioinformatics and proteogenomic analysis to catalog Chr 9-encoded proteins from normal tissues, lung cancer cell lines, and lung cancer tissues. Approximately 74.7% of the Chr 9 genes of the human genome were identified, which included approximately 28% of missing proteins (46 of 162) on Chr 9 compared with the list of missing proteins from the neXtProt Master Table (2013-09). In addition, we performed a comparative proteomics analysis between normal lung and lung cancer tissues. On the basis of the data analysis, 15 proteins from Chr 9 were detected only in lung cancer tissues. Finally, we conducted a proteogenomic analysis to discover Chr 9-residing single nucleotide polymorphisms (SNP) and mutations described in the COSMIC cancer mutation database. We identified 21 SNPs and four mutations containing peptides on Chr 9 from normal human cells/tissues and lung cancer cell lines, respectively. In summary, this study provides valuable information of the human proteome for the scientific community as part of C-HPP. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000603.

Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. Medicare beneficiaries.

OBJECTIVE: Neurologic diseases such as stroke are risk factors for new-onset epilepsy in older adults. Recent evidence suggests that psychiatric disorders independently predict epilepsy in older male veterans. Our aim was to examine the relationship between these disorders in a population-based study of older adults that also included women and minorities. METHODS: We used a national 5% random sample of 2005 Medicare beneficiaries including all 50 US states and Washington, DC. Beneficiaries were 65 years of age or older, with continuous Medicare Part A and Part B coverage and not in managed care plans. Epilepsy cases were identified from claims for physician visits, hospitalizations, and outpatient procedures. We used logistic regressions for the overall sample and stratified by gender to determine whether risk of new-onset epilepsy was associated with prior history of psychiatric (i.e., depression, psychosis, bipolar disorder, schizophrenia, posttraumatic stress disorder (PTSD), adjustment disorder, and substance abuse/dependence) and neurologic conditions (i.e., cerebrovascular disease, dementia, traumatic brain injury, brain tumor, metastatic cancer). RESULTS: Preexisting psychiatric disorders were significantly associated with new-onset epilepsy in the study population as were the neurologic conditions evaluated. Five of the seven psychiatric disorders examined were independently associated with new-onset epilepsy; substance abuse, psychosis, bipolar disorder, schizophrenia, and depression. Gender interaction effects were found for substance abuse/dependence and brain tumors. SIGNIFICANCE: Both neurologic and psychiatric factors significantly predicted new-onset epilepsy in a population-based sample of male and female older adults. These results support earlier findings and extend the understanding of risk models for new-onset epilepsy in broader older adult populations.

Disease progression and costs at the 3-year follow-up of the GERAS-US study.

Introduction: GERAS-US prospectively characterized clinical and economic outcomes of early symptomatic Alzheimer's disease (AD). Societal cost changes were examined in amyloid-positive patients with mild cognitive impairment due to AD (MCI) and mild dementia due to AD (MILD). Methods: Cognition, function, and caregiver burden were assessed using Mini-Mental State Examination (MMSE), Cognitive Function Index (CFI), and Zarit Burden Interview, respectively. Costs are presented as least square mean for the overall population and for MCI versus MILD using mixed model repeated measures. Results: MMSE score and CFI worsened. Total societal costs (dollars/month) for MCI and MILD, respectively, were higher at baseline ($2430 and $4063) but steady from 6 ($1977 and $3032) to 36 months ($2007 and $3392). Direct non-medical costs rose significantly for MILD. Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months. Discussion: Function and cognition declined in MILD. Non-medical costs reflect the increasing impact of AD even in its early stages. HIGHLIGHTS: In the GERAS-US study, total societal costs for patients with mild cognitive impairment due to Alzheimer's disease (MCI) and mild dementia due to Alzheimer's disease (MILD) were higher at baseline but steady from 6 to 36 months.Mini-Mental State Examination (MMSE) and Cognitive Function Index (CFI) worsened; the rate of decline was significant for patients with MILD but not for those with MCI.There was a rise in direct non-medical costs at 36 months for patients with MILD.Caregiver burden was higher for MILD versus MCI at 12, 18, and 24 months.Slowing the rate of disease progression in this early symptomatic population may allow patients to maintain their ability to carry out everyday activities longer.

Outcomes and Factors Associated with Insufficient Effectiveness of Acute Treatments of Migraine in Japan: Results of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) Study.

BACKGROUND: Knowledge of patient outcomes and treatment effectiveness associated with acute migraine treatments in Japan is lacking. OBJECTIVE: To describe patient-reported outcomes (PROs) and treatment effectiveness in three acute treatment groups from OVERCOME (Japan): over-the-counter (OTC) only, prescription nonsteroidal anti-inflammatory drugs/acetaminophen (Rx-NSAIDs/ACE) only, and triptans. METHODS: OVERCOME (Japan) was an observational, cross-sectional, population-based web survey of people with migraine (July-September 2020). PROs, including the Migraine-Specific Quality of Life Questionnaire (MSQ), Migraine Interictal Burden Scale (MIBS-4), Migraine Disability Assessment (MIDAS), and Work Productivity and Activity Impairment Questionnaire: Migraine (WPAI-M), were compared pairwise between treatment groups. Logistic regression was used to examine treatment effectiveness. RESULTS: The analysis included 9075 survey respondents (OTC only: n = 5791; Rx-NSAIDs/ACE only: n = 751; triptans: n = 2533). Triptan users reported the lowest MSQ scores, most severe disability (MIDAS: 20.7% versus 6.3% and 11.6%) and severe interictal burden (MIBS-4: 50.1% versus 21.2% and 19.8%), and greatest work impairment (WPAI-M: 50.4% versus 32.2% and 30.8%) compared with the OTC and Rx-NSAIDs/ACE groups, respectively. Treatment effectiveness was very poor-to-poor for 60.9%, 43.1%, and 47.6% of the triptan, OTC, and Rx-NSAIDs/ACE groups, respectively. Severe interictal burden was significantly associated with insufficient treatment effectiveness (odds ratios, severe versus no burden: 0.47 [95% confidence interval: 0.40-0.54], 0.56 [0.35-0.89], and 0.41 [0.32-0.52], for the OTC, Rx-NSAIDs/ACE, and triptan groups, respectively). CONCLUSION: People with high migraine burden used triptans for acute treatment, but many reported poor treatment effectiveness. Education may be required to promote better treatments, including earlier introduction of migraine-specific acute and preventive medications.

Approximate Bayesian computation and ecological niche models elucidate the demographic history and current fragmented population distribution of a Korean endemic shrub.

Climatic fluctuations and geological events since the LGM are believed to have significantly impacted the population size, distribution, and mobility of many species that we observe today. In this paper, we determined the processes driving the phylogeographic structure of the Korean endemic white forsythia by combining the use of genome-wide SNPs and predicting paleoclimatic habitats during the LGM (21 kya), Early Holocene (10 kya), Mid-Holocene (6 kya), and Late Holocene (3 kya). Using a maximum of 1897 SNPs retrieved from 124 samples across nine wild populations, five environmental predictors, and the species' natural occurrence records, we aimed to infer the species' demographic history and reconstruct its possible paleodistributions with the use of approximate Bayesian computation and ecological niche models, respectively. Under this integrated framework, we found strong evidence for patterns of range shift and expansion, and population divergence events from the onset of the Holocene, resulting in the formation of its five distinct genetic units. The most highly supported model inferred that after the split of an ancestral population into the southern group and a larger central metapopulation lineage, the latter gave rise to the eastern and northern clusters, before finally dividing into two sub-central groups. While the use of molecular data allowed us to identify and refine the (phylo)genetic relationships of the species' lineages and populations, the use of ecological data helped us infer a past LGM refugium and the directions of post-glacial range dynamics. The time frames of these demographic events were shown to be congruent with climatic and geological events that affected the central Korean Peninsula during these periods. These findings gave us a better understanding of the consequences of past spatiotemporal factors that may have resulted in the current fragmented population distribution of this endangered plant.

Numerical study on the hydrodynamic performance and internal flow of an axial-flow pump with various inlet flow angles.

In this study, numerical simulation was employed to predict the performance and internal flow characteristics of the inlet of an axial-flow pump by assigning an absolute flow angle to the inlet guide vane (IGV) trailing-edge flow. Further, the finite volume method based on the three-dimensional Reynolds-averaged Navier-Stokes equations was employed to discretize the governing equations. The shear stress transport model was used as the turbulence model, and an appropriate number of nodes were selected for the hexahedral grid system through a grid-dependency test. The performance curve and changes in the internal flow field were investigated based on the variation in the flow angle at the inlet of the axial-flow pump. These results can be used to establish an efficient operational plan by adjusting the IGV angle of IGV when installing a variable IGV for an axial-flow pump.

Isolation and Characterization of the Genes Involved in the Berberine Synthesis Pathway in Asian Blue Cohosh, Caulophyllum robustum.

Caulophyllum robustum, commonly named Asian blue cohosh, is a perennial herb in the family Berberidaceae. It has traditionally been used for folk medicine in China. We isolated berberine from the leaves, stem, roots, and fruits of C. robustum, and this is the first report on berberine in this species. Transcriptome analysis was conducted for the characterization of berberine biosynthesis genes in C. robustum, in which, all the genes for berberine biosynthesis were identified. From 40,094 transcripts, using gene ontology (GO) analysis, 26,750 transcripts were assigned their functions in the categories of biological process, molecular function, and cellular component. In the analysis of genes expressed in different tissues, the numbers of genes in the categories of intrinsic component of membrane and transferase activity were up-regulated in leaves versus stem. The berberine synthesis genes in C. robustum were characterized by phylogenetic analysis with corresponding genes from other berberine-producing species. The co-existence of genes from different plant families in the deepest branch subclade implies that the differentiation of berberine synthesis genes occurred early in the evolution of berberine-producing plants. Furthermore, the copy number increment of the berberine synthesis genes was detected at the species level.