Prenatal treatment with corticosterone via maternal injection induces learning and memory impairments via delaying postsynaptic development in hippocampal CA1 neurons of rats.

Previously, we reported that prenatal exposure to high corticosterone induced attention-deficit hyperactivity disorder (ADHD)-like behaviors with cognitive deficits after weaning. In the present study, cellular mechanisms underlying cortisol-induced cognitive dysfunction were investigated using rat pups (Corti.Pups) born from rat mothers that were repetitively injected with corticosterone during pregnancy. In results, Corti.Pups exhibited the failure of behavioral memory formation in the Morris water maze (MWM) test and the incomplete long-term potentiation (LTP) of hippocampal CA1 neurons. Additionally, glutamatergic excitatory postsynaptic currents (EPSCs) were remarkably suppressed in Corti.Pups compared to normal rat pups. Incomplete LTP and weaker EPSCs in Corti.Pups were attributed to the delayed postsynaptic development of CA1 neurons, showing a higher expression of NR2B subunits and lower expression of PSD-95 and BDNF. These results indicated that the prenatal treatment with corticosterone to elevate cortisol level might potently downregulate the BDNF-mediated signaling critical for the synaptic development of hippocampal CA1 neurons during brain development, and subsequently, induce learning and memory impairment. Our findings suggest a possibility that the prenatal dysregulation of cortisol triggers the epigenetic pathogenesis of neurodevelopmental psychiatric disorders, such as ADHD and autism.

Engineering Escherichia coli for constitutive production of monophosphoryl lipid A vaccine adjuvant.

During the COVID-19 pandemic, expedient vaccine production has been slowed by the shortage of safe and effective raw materials, such as adjuvants, essential components to enhance the efficacy of vaccines. Monophosphoryl lipid A (MPLA) is a potent and safe adjuvant used in human vaccines, including the Shingles vaccine, Shingrix. 3-O-desacyl-4'-monophosphoryl lipid A (MPL), a representative MPLA adjuvant commercialized by GSK, was prepared via chemical conversion of precursors isolated from Salmonella typhimurium R595. However, the high price of these materials limits their use in premium vaccines. To combat the scarcity and high cost of safe raw materials for vaccines, we need to develop a feasible MPLA production method that is easily scaled up to meet industrial requirements. In this study, we engineered peptidoglycan and outer membrane biosynthetic pathways in Escherichia coli and developed a Escherichia coli strain, KHSC0055, that constitutively produces EcML (E. coli-produced monophosphoryl lipid A) without additives such as antibiotics or overexpression inducers. EcML production was optimized on an industrial scale via high-density fed-batch fermentation, and obtained 2.7 g of EcML (about 135,000 doses of vaccine) from a 30-L-scale fermentation. Using KHSC0055, we simplified the production process and decreased the production costs of MPLA. Then, we applied EcML purified from KHSC0055 as an adjuvant for a COVID-19 vaccine candidate (EuCorVac-19) currently in clinical trial stage III in the Philippines. By probing the efficacy and safety of EcML in humans, we established KHSC0055 as an efficient cell factory for MPLA adjuvant production.

Foliar applications of a Malvaceae-derived protein hydrolysate and its fractions differentially modulate yield and functional traits of tomato under optimal and suboptimal nitrogen application.

BACKGROUND: Protein hydrolysates (PHs) can enhance plant nitrogen nutrition and improve the quality of vegetables, depending on their bioactive compounds. A tomato greenhouse experiment was conducted under both optimal (14 mM) and suboptimal (2 mM) nitrogen (N-NO3) conditions. Tomatoes were treated with a new Malvaceae-derived PH (MDPH) and its molecular fractions (MDPH1, >10 kDa; MDPH2, 1-10 kDa and MDPH3, <1 kDa). RESULTS: Under optimal N conditions, the plants increased biomass and fruit yield, and showed a higher photosynthetic pigment content in leaves in comparison with suboptimal N, whereas under N-limiting conditions, an increase in dry matter, soluble solid content (SSC) and lycopene, a reduction in firmness, and changes in organic acid and phenolic compounds were observed. With 14 mM N-NO3, MDPH3 stimulated an increase in dry weight and increased yield components and lycopene in the fruit. The MDPH2 fraction also resulted in increased lycopene accumulation in fruit under 14 mM N-NO3. At a low N level, the PH fractions showed distinct effects compared with the whole MDPH and the control, with an increase in biomass for MDPH1 and MDPH2 and a higher pigment content for MDPH3. Regardless of N availability, all the fractions affected fruit quality by increasing SSC, whereas MDPH2 and MDPH3 modified organic acid content and showed a higher concentration of flavonols, lignans, and stilbenes. CONCLUSION: The molecular weight of the peptides modifies the effect of PHs on plant performance, with different behavior depending on the level of N fertilization, confirming the effectiveness of fractioning processes. © 2024 Society of Chemical Industry.

RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter.

BACKGROUND: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. METHODS: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. RESULTS: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. CONCLUSION: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. Video Abstract.

Differential dynamics of cullin deneddylation via COP9 signalosome subunit 5 interaction.

Cullin-RING E3 ubiquitin ligases (CRLs) spatiotemporally regulate the proteasomal degradation of numerous cellular proteins involved in cell cycle control, DNA replication, and maintenance of genome stability. Activation of CRLs is controlled via neddylation by NEDD8-activating, -conjugating, and -attaching enzymes to the C-terminus of scaffold cullins (CULs), whereas the COP9 signalosome (CSN) inactivates CRLs via deneddylation. Here, we show that the deneddylation rate of each CUL is differentially modulated. Dose- or time-dependent treatment with pevonedistat, a small molecule inhibitor of NEDD8-activating enzyme (NAE), rapidly inhibits neddylation in most CULs, including CUL1, CUL3, CUL4A/B, and CUL5, whereas the deneddylation of CUL2 is slowly increased. We revealed that the different deneddylation speeds of each CUL depend on its binding strength with CSN5, the catalytic core of the CSN complex. Immunoprecipitation analysis revealed that CUL2 has a lower binding affinity for CSN5 than other CULs. Consistently, released cells treated with CSN5 inhibitor showed that CUL2 was slowly converted to the deneddylated form compared to the rapid deneddylation of other CULs. These findings provide mechanistic insights into the different dynamics of CULs in neddylation-deneddylation conversion.

The differentially expressed gene signatures of the Cullin 3-RING ubiquitin ligases in neuroendocrine cancer.

Cullin-RING ubiquitin E3 ligase (CRLs) composed of four components including cullin scaffolds, adaptors, substrate receptors, and RING proteins mediates the ubiquitination of approximately 20% of cellular proteins that are involved in numerous biological processes. While CRLs deregulation contributes to the pathogenesis of many diseases, including cancer, how CRLs deregulation occurs is yet to be fully investigated. Here, we demonstrate that components of CRL3 and its transcriptional regulators are possible prognosis marker of neuroendocrine (NE) cancer. Analysis of Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal revealed that expression of CRL3 scaffold Cullin 3 (CUL3) highly correlates with NE signature, and CUL3 silencing inhibited NE cancer proliferation. Moreover, subset of 151 BTB (Bric-a-brac, Tramtrack, Broad complex) domain-containing proteins that have dual roles as substrate receptors and adaptor subunits in CRL3, as well as the expression of transcription factors (TFs) that control the transcription of BTB genes were upregulated in NE cancer. Analysis using published ChIP-sequencing data in small cell lung cancer (SCLC), including NE or non-NE SCLC verified that gene promoter of candidates which show high correlation with NE signature enriched H3K27Ac. These observations suggest that CRL3 is a master regulator of NE cancer and knowledge of specifically regulated CRL3 genes in NE cancer may accelerate new therapeutic approaches.

Association between frailty and dietary quality in community-dwelling elderly: data from the 6th Korea National Health and Nutrition Examination Survey (2014-2015).

Frailty is a progressive age-related disorder associated with odds ratio for subsequent falls, disability, and mortality. This study analyzed the association between frailty odds ratios and diet quality using the Korean Healthy Eating Index in older individuals. Data were obtained for 2,660 community-dwelling individuals aged ≥60 years who participated in the 6th Korea National Health and Nutrition Survey (2014-2015). Frailty was diagnosed following the Fried phenotype index based on five criteria: unintentional weight loss, emotional exhaustion, low physical activity, slow walking speed, and weak grip strength. The participants were categorized as normal, pre-frail, and frail. Diet quality was assessed using Korean Healthy Eating Index scores calculated based on 24-h dietary recall. Compared to the group with the highest Korean Healthy Eating Index score, the group with low Korean Healthy Eating Index showed a 1.71-fold higher pre-frail odds ratio (95% CI 1.31-2.22, p<0.001) and 1.87-fold higher frail odds ratio (95% CI 1.21-2.91, p = 0.009). Also, compared to the group with the highest adequacy score, the group with the lowest score showed a 1.51-fold higher pre-frail odds ratio (95% CI 1.16-1.96, p = 0.010) and a 2.39-fold higher frail odds ratio (95% CI 1.48-3.86, p = 0.002). The findings of this study suggested that a high-quality diet, as assessed by Korean Healthy Eating Index, was negatively associated with the odds ratio of frailty.

Aneurinibacillus sediminis sp. nov., isolated from lagoon sediments.

Two bacterial strains (1-10M-8-7-50T and 1M) were isolated from lagoon sediments. The strains were obligately aerobic, Gram-stain-positive, spore-forming, rod-shaped and motile. Both strains were able to grow at 25-60 ˚C (optimum 40-42 ˚C), at pH 6.0-8.8 (optimum pH 7.0-7.5) and with 0-2.0 % (w/v) (optimum 0-0.8 %) NaCl. The predominant cellular fatty acids were iso-C15 : 0 and iso-C15 : 0 2-OH, and the cell-wall peptidoglycan contained meso-diaminopimelic acid, glutamic acid, glycine and alanine. Phosphatidyl-N-methylethanolamine, phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, two unidentified phosphoglycolipids and three unidentified lipids were present as polar lipids. Genomic DNA G+C content was 41.9 mol%. 16S rRNA gene sequence comparisons of both strains indicated that they belong to the genus Aneurinibacillus within the family Paenibacillaceae of the class Bacilli. Both strains had a sequence similarity of 97.6 % with Aneurinibacillus migulanus B0270T, 97.6 % with Aneurinibacillus aneurinilyticus ATCC 12856T, 97.5 % with 'Aneurinibacillus humi' U33 and <97 % with other members of the genus Aneurinibacillus. The DNA-DNA reassociation value between strain 1-10M-8-7-50T and 1M was >90 %, while strains 1-10M-8-7-50T and 1M were only 35.1±1, 29.8±1 and 24.5±1 % related to A. migulanus KACC 18173T, A. aneurinilyticus KACC 18174T and 'A. humi' U33, respectively. Distinct morphological, physiological and genotypic differences from the previously described taxa support the classification of strain 1-10M-8-7-50T as a representative of a novel species in the genus Aneurinibacillus, for which the name Aneurinibacillus sediminis sp. nov. is proposed. The type strain is 1-10M-8-7-50T (=KEMB 563-460T=JCM 31819T).

De novo transcriptome assembly for rudimentary leaves in Litchi chinesis Sonn. and identification of differentially expressed genes in response to reactive oxygen species.

BACKGROUND: Litchi is an evergreen woody tree widely cultivated in subtropical and tropical regions. Defective flowering is a major challenge for litchi production in time of climate change and global warming. Previous studies have shown that high temperature conditions encourage the growth of rudimentary leaves in panicles and suppress litchi flowering, while reactive oxygen species (ROS) generated by methyl viologen dichloride hydrate (MV) promote flowering and abortion of rudimentary leaves. To understand the molecular function of the ROS-induced abortion of rudimentary leaves in litchi, we sequenced and de novo assembled the litchi transcriptome. RESULTS: Our assembly encompassed 82,036 unigenes with a mean size of 710 bp, and over 58% (47,596) of unigenes showed significant similarities to known sequences in GenBank non-redundant (nr) protein database. 5,865 unigenes were found to be differentially expressed between ROS-treated and un-treated rudimentary leaves, and genes encoding signaling components of plant hormones such as ABA and ethylene were significantly enriched. CONCLUSION: Our transcriptome data represents the comprehensive collection of expressed sequence tags (ESTs) of litchi leaves, which is a vital resource for future studies on the genomics of litchi and other closely related species. The identified differentially expressed genes also provided potential candidates for functional analysis of genes involved in litchi flowering underlying the control of rudimentary leaves in the panicles.

Effect of Moxibustion Combined with Other Interventions on Body Weight Reduction in the Treatment of Obesity: A Systematic Review and Meta-Analysis.

Background: Moxibustion has been used in the treatment and prevention of obesity. However, there has been no systematic review or meta-analysis conducted on the use of moxibustion on obesity treatment. This study aimed to evaluate the role of moxibustion in the treatment of obesity. Methods: The Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE/PubMed databases were searched to identify all randomized controlled trials (RCTs) that evaluated the effect of moxibustion on obesity. The primary outcome was body weight. The secondary outcomes were the body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). The risk of bias assessment and meta-analysis were conducted using the Cochrane Collaboration tool. Results: Eleven RCTs involving 761 participants were included in this systematic review and meta-analysis. Other interventions that were included in the analyses were manual acupuncture, electroacupuncture, embedding therapy, herbal medicine, and diet control. Moxibustion combined with other interventions resulted in a significant improvement in body weight reduction (mean difference [MD] -3.32, 95% confidence interval [CI: -4.25 to -2.38]; I2 = 17%), BMI (MD -1.51, 95% CI [-1.88 to -1.14]; I2 = 76%), and WC (MD -2.82, 95% CI [-3.50 to -2.13]; I2 = 75%), but did not improve HC (MD -2.05, 95% CI [-4.21 to 0.11]; I2 = 0%) or WHR (MD -0.01, 95% CI [-0.03 to 0.01]; I2 = 57%). Conclusions: Moxibustion can be used with other interventions to improve body weight, BMI, and WC in people with obesity. However, the conclusions of this review should be cautiously applied to clinical practice because most of the included studies had a high or unclear risk of bias.

Identification of MV-generated ROS responsive EST clones in floral buds of Litchi chinensis Sonn.

KEY MESSAGE: A suppression subtractive hybridization library was constructed using inflorescence primordia of 'Nuomici' litchi to identify EST clones responsive to MV-generated ROS. 93 ESTs could be aligned as unique gene sequences in the inflorescence primordia of litchi. Litchi is an evergreen woody tree widely cultivated in subtropical and tropical regions. However, defective flowering is a pending problem of litchi production. Our previous study indicated that reactive oxygen species (ROS) induced by methyl viologen dichloride hydrate (MV) promotes flowering in litchi. In the present study, a suppression subtractive hybridization (SSH) library was constructed using inflorescence primordia of 'Nuomici' with the aim to find out ROS responsive clones during floral differentiation. 1856 Expressed sequence tag (EST) clones were randomly selected. Clones carrying single exogenous fragments were screened by reverse northern analysis to identify those responsive to MV-generated ROS. A total of 783 differentially expressed EST clones were identified as MV responsive cDNA and were subjected to sequencing. Among them, 26 clones were represented more than three times. 783 clones were aligned to 93 unique gene sequences. The unique genes were classified into 9 categories. 16 % of them were involved in transport facilitation, 11 % in transcription regulation, 4 % in stress response, 9 % in carbohydrate metabolism, 1 % in secondary metabolism, 14 % in intracellular signaling, and 25 % in other metabolism, while 9 % were genes with unknown functions and 11 % were genes with no match in the database.

Bilaterality as a Risk Factor for Recurrence in Papillary Thyroid Carcinoma.

Previous studies suggested that the multifocality of papillary thyroid carcinoma (PTC) would increase the risk of recurrence; however, the impact of its bilaterality remains unclear. Between 2011 and 2018, 1258 patients with PTC underwent total thyroidectomy at Ewha University Medical Center. The 5-year recurrence-free survival rate was 95.7% in patients with bilateral PTC, while those with unilateral multifocal PTC and a unifocal tumor showed a 5-year event-free survival rate of 97.0% and 97.8%, respectively (p = 0.004). A multivariable Cox proportional hazards model indicated that bilaterality (HR 2.550, 95% CI 1.354-4.800), male sex (HR 2.010, 95% CI 1.007-4.013), and tumor size (HR 1.748, 95% CI 1.316-2.323) were associated with recurrence, although unilateral multifocality did not increase the risk of recurrence (HR 1.211, 95% CI 0.348-4.213). In conclusion, bilaterality was associated with aggressive features, including tumor size and microscopic ETE. Moreover, bilaterality was an independent predictor of recurrence in patients with PTC. Patients with bilateral PTC might require careful treatment and follow-up approaches.

Inhibitory effects of Streptococcus salivarius K12 on formation of cariogenic biofilm.

Bacground/purpose: Streptococcus salivarius (S. salivarius) K12 is known to be a probiotic bacterium. The purpose of this study was to investigate anti-cariogenic effects of S. salivarius K12 on cariogenic biofilm. Materials and methods: S. salivarius K12 was cultured in M17 broth. The antimicrobial activity of spent culture medium (SCM) against Streptococcus mutans was investigated. S. salivarius K12 was co-cultivated with S. mutans using a membrane insert. When the biofilm was formed using salivary bacteria and S. mutans, the K12 was inoculated every day. The biomass of biofilm was investigated by a confocal laser scanning microscope. Also, bacterial DNA from the biofilm was extracted, and then bacteria proportion was analyzed by quantitative PCR using specific primers. The expression of gtf genes of S. mutans in the biofilm with or without S. salivarius K12 was analyzed by RT-PCR. Results: The SCM of S. salivarius K12 inhibited the growth of S. mutans. Also, S. salivarius K12 reduced S. mutans growth in co-cultivation. The formation of cariogenic biofilm was reduced by adding S. salivarius K12, and the count of S. mutans in the biofilm was also decreased in the presence of S. salivarius K12. gtfB, gtfC, and gtfD expression of S. mutans in the biofilm was reduced in the presence of S. salivarius K12. Conclusion: S. salivarius K12 may inhibit the formation of cariogenic biofilm by interrupting the growth and glucosyltransferase production of S. mutans.

Gadoxetate disodium-enhanced MRI for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: late portal venous phase may improve identification of enhancing capsule.

PURPOSE: To investigate added value of late portal venous phase (LPVP) for identification of enhancing capsule (EC) on gadoxetate disodium-enhanced MRI (GD-MRI) for diagnosing hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD). METHODS: This retrospective study comprised 116 high-risk patients with 128 pathologically proven HCCs who underwent GD-MRI including arterial phase, conventional portal venous phase (CPVP, 60 s), LPVP (mean, 104.4 ± 6.7 s; range, 90-119 s), and transitional phase (TP, 3 min). Two independent radiologists assessed the presence of major HCC features, including EC on CPVP and/or TP (CPVP/TP) and EC on LPVP. The frequency of EC was compared on GD-MRI between with and without inclusion of LPVP. The radiologists assigned Liver Imaging Reporting and Data System (LI-RADS) v2018 categories before and after identifying EC on LPVP. RESULTS: Of the total 128 HCCs, 74 and 73 revealed EC on CPVP/TP for reviewer 1 and 2, respectively. After inclusion of LPVP, each reviewer identified seven more EC [Reviewer 1, 57.8% (74/128) vs. 63.3% (81/128); Reviewer 2, 57.0% (73/128) vs. 62.5% (80/128); P = 0.016, respectively]. Sensitivities of LR-5 assignment for diagnosing HCCs were not significantly different in GD-MRI with or without LPVP for EC identification [Reviewer 1, 71.9% (92/128) vs. 72.7% (93/128); Reviewer 2, 75.0% (96/128) vs. 75.8% (97/128); P = 1.000, respectively]. CONCLUSION: Including the LPVP in GD-MRI may improve identification of EC of HCC in patients with CLD. However, LI-RADS v2018 using GD-MRI showed comparable sensitivity for diagnosing HCC regardless of applying LPVP for EC.

Plant biostimulants as natural alternatives to synthetic auxins in strawberry production: physiological and metabolic insights.

The demand for high-quality strawberries continues to grow, emphasizing the need for innovative agricultural practices to enhance both yield and fruit quality. In this context, the utilization of natural products, such as biostimulants, has emerged as a promising avenue for improving strawberry production while aligning with sustainable and eco-friendly agricultural approaches. This study explores the influence of a bacterial filtrate (BF), a vegetal-derived protein hydrolysate (PH), and a standard synthetic auxin (SA) on strawberry, investigating their effects on yield, fruit quality, mineral composition and metabolomics of leaves and fruits. Agronomic trial revealed that SA and BF significantly enhanced early fruit yield due to their positive influence on flowering and fruit set, while PH treatment favored a gradual and prolonged fruit set, associated with an increased shoot biomass and sustained production. Fruit quality analysis showed that PH-treated fruits exhibited an increase of firmness and soluble solids content, whereas SA-treated fruits displayed lower firmness and soluble solids content. The ionomic analysis of leaves and fruits indicated that all treatments provided sufficient nutrients, with heavy metals within regulatory limits. Metabolomics indicated that PH stimulated primary metabolites, while SA and BF directly affected flavonoid and anthocyanin biosynthesis, and PH increased fruit quality through enhanced production of beneficial metabolites. This research offers valuable insights for optimizing strawberry production and fruit quality by harnessing the potential of natural biostimulants as viable alternative to synthetic compounds.

RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter.

Background Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication origin binding protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. Methods The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. Results RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. Conclusion This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production.

Dopaminergic cell protection and alleviation of neuropsychiatric disease symptoms by VMAT2 expression through the class I HDAC inhibitor TC-H 106.

The importance of vesicular monoamine transporter 2 (VMAT2) in dopamine regulation, which is considered crucial for neuropsychiatric disorders, is currently being studied. Moreover, the development of disease treatments using histone deacetylase (HDAC) inhibitors (HDACi) is actively progressing in various fields. Recently, research on the possibility of regulating neuropsychiatric disorders has been conducted. In this study, we evaluated whether VMAT2 expression increased by an HDACi can fine-tune neuropsychotic behavior, such as attention deficit hyperactivity disorder (ADHD) and protect against the cell toxicity through oxidized dopamine. First, approximately 300 candidate HDACi compounds were added to the SH-SY5Y dopaminergic cell line to identify the possible changes in the VMAT2 expression levels, which were measured using quantitative polymerase chain reaction. The results demonstrated, that treatment with pimelic diphenylamide 106 (TC-H 106), a class I HDACi, increased VMAT2 expression in both the SH-SY5Y cells and mouse brain. The increased VMAT2 expression induced by TC-H 106 alleviated the cytotoxicity attributed to 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+ ) and free dopamine treatment. Moreover, dopamine concentrations, both intracellularly and in the synaptosomes, were significantly elevated by increased VMAT2 expression. These results suggest that dopamine concentration regulation by VMAT2 expression induced by TC-H 106 could alter several related behavioral aspects that was confirmed by attenuation of hyperactivity and impulsivity, which were major characteristics of animal model showing ADHD-like behaviors. These results indicate that HDACi-increased VMAT2 expression offers sufficient protections against dopaminergic cell death induced by oxidative stress. Thus, the epigenetic approach could be considered as therapeutic candidate for neuropsychiatric disease regulation.

Predictors of Recurrence in Patients with Papillary Thyroid Carcinoma: Does Male Sex Matter?

Male patients with papillary thyroid carcinoma (PTC) usually have aggressive clinicopathological features, including large tumor size and lymph node metastasis; however, it is unclear whether male sex increases the risk of recurrence. Here, we evaluated the effect of sex on disease-free survival (DFS) of patients with PTC. Between 2009 and 2016, 1252 patients who underwent total thyroidectomy for PTC were enrolled; 157 (12.5%) were male and 1095 (87.5%) were female. With a mean follow-up of 6.6 years, five-year DFS rates were comparable between male and female patients (94.9% vs. 96.9%; p = 0.616) after adjusting for potential confounders. Multivariate Cox regression analysis also demonstrated that male sex was not an independent risk factor for recurrence (HR 1.982, 95% CI 0.831−4.726). Subgroup analyses further indicated that both male and female sex­in terms of their associations with five-year DFS­were comparable with other variables, including age < 55 years (94.5% vs. 97.3%; p = 0.520) and tumor size > 1 cm (91.9% vs. 97.0%; p = 0.243). In conclusion, male sex was not associated with the risk of recurrence in patients with PTC. Male patients do not always require aggressive treatment and follow-up approaches.

The Effect of Cognitive Function Health Care Using Artificial Intelligence Robots for Older Adults: Systematic Review and Meta-analysis.

BACKGROUND: With rapidly aging populations in most parts of the world, it is only natural that the need for caregivers for older adults is going to increase in the near future. Therefore, most technologically proficient countries are in the process of using artificial intelligence (AI) to build socially assistive robots (SAR) to play the role of caregivers in enhancing interaction and social participation among older adults. OBJECTIVE: This study aimed to examine the effect of intervention through AI SAR on the cognitive function of older adults through a systematic literature review. METHODS: We conducted a meta-analysis of the various existing studies on the effect of AI SAR on the cognitive function of older adults to standardize the results and clarify the effect of each method and indicator. Cochrane collaboration and the systematic literature review flow of PRISMA (Preferred Reporting Item Systematic Reviews and Meta-Analyses) were used on original, peer-reviewed studies published from January 2010 to March 2022. The search words were derived by combining keywords including Population, Intervention, and Outcome-according to the Population, Intervention, Comparison, Outcome, Time, Setting, and Study Design principle-for the question "What is the effect of AI SAR on the cognitive function of older adults in comparison with a control group?" (Population: adults aged ≥65 years; Intervention: AI SAR; Comparison: comparison group; Outcome: popular function; and Study Design: prospective study). For any study, if one condition among subjects, intervention, comparison, or study design was different from those indicated, the study was excluded from the literature review. RESULTS: In total, 9 studies were selected (6 randomized controlled trials and 3 quasi-experimental design studies) for the meta-analysis. Publication bias was examined using the contour-enhanced funnel plot method to confirm the reliability and validity of the 9 studies. The meta-analysis revealed that the average effect size of AI SAR was shown to be Hedges g=0.43 (95% CI -0.04 to 0.90), indicating that AI SAR are effective in reducing the Mini Mental State Examination scale, which reflects cognitive function. CONCLUSIONS: The 9 studies that were analyzed used SAR in the form of animals, robots, and humans. Among them, AI SAR in anthropomorphic form were able to improve cognitive function more effectively. The development and expansion of AI SAR programs to various functions including health notification, play therapy, counseling service, conversation, and dementia prevention programs are expected to improve the quality of care for older adults and prevent the overload of caregivers. AI SAR can be considered a representative, digital, and social prescription program and a nonpharmacological intervention program that communicates with older adults 24 hours a day. Despite its effectiveness, ethical issues, the digital literacy needs of older adults, social awareness and reliability, and technological advancement pose challenges in implementing AI SAR. Future research should include bigger sample sizes, pre-post studies, as well as studies using an older adult control group.

Correction: The Effect of Cognitive Function Health Care Using Artificial Intelligence Robots for Older Adults: Systematic Review and Meta-analysis.

[This corrects the article DOI: 10.2196/38896.].