Regulation of MBK-2/DYRK by CDK-1 and the Pseudophosphatases EGG-4 and EGG-5 during the Oocyte-to-Embryo Transition

SummaryDYRKs are kinases that self-activate in vitro by autophosphorylation of a YTY motif in the kinase domain, but their regulation in vivo is not well understood. In C. elegans zygotes, MBK-2/DYRK phosphorylates oocyte proteins at the end of the meiotic divisions to promote the oocyte-to-embryo transition. Here we demonstrate that MBK-2 is under both positive and negative regulation during the transition. MBK-2 is activated during oocyte maturation by CDK-1-dependent phosphorylation of serine 68, a residue outside of the kinase domain required for full activity in vivo. The pseudotyrosine phosphatases EGG-4 and EGG-5 sequester activated MBK-2 until the meiotic divisions by binding to the YTY motif and inhibiting MBK-2′s kinase activity directly, using a mixed-inhibition mechanism that does not involve tyrosine dephosphorylation. Our findings link cell-cycle progression to MBK-2/DYRK activation and the oocyte-to-embryo transition

Mutation and Lineage Analysis of DNMT3A in BCR-ABL1-negative Chronic Myeloproliferative Neoplasms

SummaryIn addition to the JAK2 V617F mutation, somatic mutation in DNMT3A has been described in BCL-ABL1-negative myeloproliferative neoplasms (MPNs). We have screened for DNMT3A exon 23 mutations in 130 adult Taiwanese patients with chronic phase myeloproliferative neoplasms. Only one somatic DNMT3A R882H mutation was identified in one JAK2 V617F mutation-positive essential thrombocythemia patient (1/91, 1%). Both mutations were detected in the CD34+-, CD19+-, peripheral blood mononuclear cell- and granulocyte-enriched fractions, but were not detected in the CD3+-enriched fraction by lineage analysis. Our findings suggest that DNMT3A mutation is not prevalent in MPNs, and further study is needed to clarify its role in the molecular pathogenesis of myeloproliferative neoplasms

Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.Chemistry and Chemical Biolog

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Regulation of MBK-2/DYRK by CDK-1 and the Pseudophosphatases EGG-4 and EGG-5 during the Oocyte-to-Embryo Transition

SUMMARY DYRKs are kinases that self-activate in vitro by autophosphorylation of a YTY motif in the kinase domain, but their regulation in vivo is not well understood. In C. elegans zygotes, MBK-2/DYRK phosphorylates oocyte proteins at the end of the meiotic divisions to promote the oocyte-to-embryo transition. Here we demonstrate that MBK-2 is under both positive and negative regulation during the transition. MBK-2 is activated during oocyte maturation by CDK-1-dependent phosphorylation of serine 68, a residue outside of the kinase domain required for full activity in vivo. The pseudotyrosine phosphatases EGG-4 and EGG-5 sequester activated MBK-2 until the meiotic divisions by binding to the YTY motif and inhibiting MBK-2 0 s kinase activity directly, using a mixed-inhibition mechanism that does not involve tyrosine dephosphorylation. Our findings link cellcycle progression to MBK-2/DYRK activation and the oocyte-to-embryo transition

Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10−37) and replication groups (p = 6.36 × 10−13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence

Light-induced photoluminescence switching using liquid crystal-dispersed quantum dots

Light-induced photoluminescence (PL) switching using azobenzene-doped liquid crystal (LC)-dispersed quantum dots (QDs) is demonstrated in a format of LC cell and LC-infiltrated tube. Before light irradiation, excitation photons undergo multiple scattering events before emission out of the LC cell, and PL intensity is high. Upon the light irradiation, the trans-to-cis photoisomerization of azobenzene makes the QD-dispersed LCs highly transparent, thus allowing most excitation photons to pass through LCs and decrease PL intensity. This demonstration may allow a new modulating technique for future development of light-switchable, QD-emission-based display or photonic devices

Shock Index Is a Validated Prediction Tool for the Short-Term Survival of Advanced Cancer Patients Presenting to the Emergency Department

Advanced cancer patients who are not expected to survive past the short term can benefit from early initiation of palliative care in the emergency department (ED). This discussion, however, requires accurate prognostication of their short-term survival. We previously found in our retrospective study that shock index (SI) is an ideal risk stratification tool in predicting the 60-day mortality risk of advanced cancer patients presenting to the ED. This study is a follow-up prospective validation study conducted from January 2019 to April 2021. A total of 410 advanced cancer patients who presented to the ED of a medical centre and could be followed-up feasibly were recruited. Univariate and multivariable logistic regression analyses were performed with receiver operator calibrating (ROC) curve analysis. Non-survivors had significantly lower body temperatures, higher pulse rates, higher respiratory rates, lower blood pressures, and higher SI. Each 0.1 increment of SI increased the odds of 60-day mortality by 1.591. Area under ROC curve was 0.7819. At optimal cut-off of 0.94, SI had 66.10% accuracy. These results were similar to our previous study, thus validating the use of SI in predicting the 60-day mortality of advanced cancer patients presenting to the ED. Identified patients may be offered palliative care

Association between dietary fiber intake and physical performance in older adults: a nationwide study in Taiwan.

BACKGROUND: Physical performance is a major determinant of health in older adults, and is related to lifestyle factors. Dietary fiber has multiple health benefits. It remains unclear whether fiber intake is independently linked to superior physical performance. We aimed to assess the association between dietary fiber and physical performance in older adults. METHODS: This was a cross-sectional study conducted with community-dwelling adults aged 55 years and older (n=2680) from the ongoing Healthy Aging Longitudinal Study (HALST) in Taiwan 2008-2010. Daily dietary fiber intake was assessed using a validated food frequency questionnaire. Physical performance was determined objectively by measuring gait speed, 6-minute walk distance, timed "up and go" (TUG), summary performance score, hand grip strength. RESULTS: Adjusting for all potential confounders, participants with higher fiber intake had significantly faster gait speed, longer 6-minute walk distance, faster TUG, higher summary performance score, and higher hand grip strength (all P <.05). Comparing with the highest quartile of fiber intake, the lowest quartile of fiber intake was significantly associated with the lowest sex-specific quartile of gait speed (adjusted OR, 2.18 in men [95% CI, 1.33-3.55] and 3.65 in women [95% CI, 2.20-6.05]), 6-minute walk distance (OR, 2.40 in men [95% CI, 1.38-4.17] and 4.32 in women [95% CI, 2.37-7.89]), TUG (OR, 2.42 in men [95% CI, 1.43-4.12] and 3.27 in women [95% CI, 1.94-5.52]), summary performance score (OR, 2.12 in men [95% CI, 1.19-3.78] and 5.47 in women [95% CI, 3.20-9.35]), and hand grip strength (OR, 2.64 in men [95% CI, 1.61-4.32] and 4.43 in women [95% CI, 2.62-7.50]). CONCLUSIONS: Dietary fiber intake was independently associated with better physical performance

Resting-State EEG Signal for Major Depressive Disorder Detection: A Systematic Validation on a Large and Diverse Dataset

Major depressive disorder (MDD) is a global healthcare issue and one of the leading causes of disability. Machine learning combined with non-invasive electroencephalography (EEG) has recently been shown to have the potential to diagnose MDD. However, most of these studies analyzed small samples of participants recruited from a single source, raising serious concerns about the generalizability of these results in clinical practice. Thus, it has become critical to re-evaluate the efficacy of various common EEG features for MDD detection across large and diverse datasets. To address this issue, we collected resting-state EEG data from 400 participants across four medical centers and tested classification performance of four common EEG features: band power (BP), coherence, Higuchi’s fractal dimension, and Katz’s fractal dimension. Then, a sequential backward selection (SBS) method was used to determine the optimal subset. To overcome the large data variability due to an increased data size and multi-site EEG recordings, we introduced the conformal kernel (CK) transformation to further improve the MDD as compared with the healthy control (HC) classification performance of support vector machine (SVM). The results show that (1) coherence features account for 98% of the optimal feature subset; (2) the CK-SVM outperforms other classifiers such as K-nearest neighbors (K-NN), linear discriminant analysis (LDA), and SVM; (3) the combination of the optimal feature subset and CK-SVM achieves a high five-fold cross-validation accuracy of 91.07% on the training set (140 MDD and 140 HC) and 84.16% on the independent test set (60 MDD and 60 HC). The current results suggest that the coherence-based connectivity is a more reliable feature for achieving high and generalizable MDD detection performance in real-life clinical practice