Analysis of the Drosophila and human DPR elements reveals a distinct human variant whose specificity can be enhanced by machine learning.

The RNA polymerase II core promoter is the site of convergence of the signals that lead to the initiation of transcription. Here, we performed a comparative analysis of the downstream core promoter region (DPR) in Drosophila and humans by using machine learning. These studies revealed a distinct human-specific version of the DPR and led to the use of machine learning models for the identification of synthetic extreme DPR motifs with specificity for human transcription factors relative to Drosophila factors and vice versa. More generally, machine learning models could similarly be used to design synthetic DNA elements with customized functional properties.

Identification of the human DPR core promoter element using machine learning.

The RNA polymerase II (Pol II) core promoter is the strategic site of convergence of the signals that lead to the initiation of DNA transcription1-5, but the downstream core promoter in humans has been difficult to understand1-3. Here we analyse the human Pol II core promoter and use machine learning to generate predictive models for the downstream core promoter region (DPR) and the TATA box. We developed a method termed HARPE (high-throughput analysis of randomized promoter elements) to create hundreds of thousands of DPR (or TATA box) variants, each with known transcriptional strength. We then analysed the HARPE data by support vector regression (SVR) to provide comprehensive models for the sequence motifs, and found that the SVR-based approach is more effective than a consensus-based method for predicting transcriptional activity. These results show that the DPR is a functionally important core promoter element that is widely used in human promoters. Notably, there appears to be a duality between the DPR and the TATA box, as many promoters contain one or the other element. More broadly, these findings show that functional DNA motifs can be identified by machine learning analysis of a comprehensive set of sequence variants.

The punctilious RNA polymerase II core promoter.

The signals that direct the initiation of transcription ultimately converge at the core promoter, which is the gateway to transcription. Here we provide an overview of the RNA polymerase II core promoter in bilateria (bilaterally symmetric animals). The core promoter is diverse in terms of its composition and function yet is also punctilious, as it acts with strict rules and precision. We additionally describe an expanded view of the core promoter that comprises the classical DNA sequence motifs, sequence-specific DNA-binding transcription factors, chromatin signals, and DNA structure. This model may eventually lead to a more unified conceptual understanding of the core promoter.

The human initiator is a distinct and abundant element that is precisely positioned in focused core promoters.

DNA sequence signals in the core promoter, such as the initiator (Inr), direct transcription initiation by RNA polymerase II. Here we show that the human Inr has the consensus of BBCA+1BW at focused promoters in which transcription initiates at a single site or a narrow cluster of sites. The analysis of 7678 focused transcription start sites revealed 40% with a perfect match to the Inr and 16% with a single mismatch outside of the CA+1 core. TATA-like sequences are underrepresented in Inr promoters. This consensus is a key component of the DNA sequence rules that specify transcription initiation in humans.

EDIR: exome database of interspersed repeats.

MOTIVATION: Intragenic exonic deletions are known to contribute to genetic diseases and are often flanked by regions of homology. RESULTS: In order to get a more clear view of these interspersed repeats encompassing a coding sequence, we have developed EDIR (Exome Database of Interspersed Repeats) which contains the positions of these structures within the human exome. EDIR has been calculated by an inductive strategy, rather than by a brute force approach and can be queried through an R/Bioconductor package or a web interface allowing the per-gene rapid extraction of homology-flanked sequences throughout the exome. AVAILABILITY AND IMPLEMENTATION: The code used to compile EDIR can be found at https://github.com/lauravongoc/EDIR. The full dataset of EDIR can be queried via an Rshiny application at http://193.70.34.71:3857/edir/. The R package for querying EDIR is called 'EDIRquery' and is available on Bioconductor. The full EDIR dataset can be downloaded from https://osf.io/m3gvx/ or http://193.70.34.71/EDIR.tar.gz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Asymmetric Formal Total Syntheses of (+)- and (-)-Limaspermidine from Chirally Resolved 2-Pyrone Diels-Alder Cycloadducts via Aromatic C-H Amidation and Imino-Diels-Alder Reaction.

A new asymmetric synthetic route to (+)- and (-)-limaspermidine was devised, starting with chirally resolved enantiomerically pure 2-pyrone Diels-Alder cycloadducts. This route utilizes intramolecular Pd-catalyzed aromatic C-H amidation and imino-Diels-Alder reactions to construct the key indoline and indolizidine subunits onto the central cyclohexane core, allowing the straightforward formal total syntheses of both (+)- and (-)-limaspermidine.

Sodium sulfide-promoted regiodefined redox condensation of o-nitroanilines with aryl ketones to benzo[a]phenazines and quinoxalines.

Inexpensive sodium sulfide trihydrate was found to promote unprecedented 6e-regio-predefined redox condensation of o-nitroanilines with α-tetralones to benzo[a]phenazines. The method was also successfully extended to acetophenones and higher homologs as reducing partners to provide 2-phenylquinoxalines. Compared to traditional approaches toward benzo[a]phenazine and quinoxaline cores starting with o-phenylenediamines, the present strategy could afford these heterocycles with well-defined regiochemistry based on the structure of starting o-nitroanilines.

The Role of Collagen VIII in the Aging Mouse Kidney.

The gradual loss of kidney function due to increasing age is accompanied by structural changes such as fibrosis of the tissue. The underlying molecular mechanisms are complex, but not yet fully understood. Non-fibrillar collagen type VIII (COL8) could be a potential factor in the fibrosis processes of the aging kidney. A pathophysiological significance of COL8 has already been demonstrated in the context of diabetic kidney disease, with studies showing that it directly influences both the development and progression of renal fibrosis occurring. The aim of this study was to investigate whether COL8 impacts age-related micro-anatomical and functional changes in a mouse model. The kidneys of wild-type (Col8-wt) and COL8-knockout (Col8-ko) mice of different age and sex were characterized with regard to the expression of molecular fibrosis markers, the development of nephrosclerosis and renal function. The age-dependent regulation of COL8 mRNA expression in the wild-type revealed sex-dependent effects that were not observed with collagen IV (COL4). Histochemical staining and protein analysis of profibrotic cytokines TGF-ß1 (transforming growth factor) and CTGF (connective tissue growth factor) in mouse kidneys showed significant age effects as well as interactions of the factors age, sex and Col8 genotype. There were also significant age and Col8 genotype effects in the renal function data analyzed by urinary cystatin C. In summary, the present study shows, for the first time, that COL8 is regulated in an age- and sex-dependent manner in the mouse kidney and that the expression of COL8 influences the severity of age-induced renal fibrosis and function.

Periodontitis and Preeclampsia in Pregnancy: A Systematic Review and Meta-Analysis.

OBJECTIVES: A conflicting body of evidence suggests localized periodontal inflammation spreads systemically during pregnancy inducing adverse pregnancy outcomes. This systematic review and meta-analysis aim to specifically evaluate the relationship between periodontitis and preeclampsia. METHODS: Electronic searches were carried out in Medline, Pubmed, Embase, Lilacs, Cochrane Controlled Clinical Trial Register, CINAHL, ClinicalTrials.gov, and Google Scholar with no restrictions on the year of publication. We identified and selected observational case-control and cohort studies that analyzed the association between periodontal disease and preeclampsia. This meta-analysis was conducted following the PRISMA checklist and MOOSE checklist. Pooled odds ratios, mean difference, and 95% confidence intervals were calculated using the random effect model. Heterogeneity was tested with Cochran's Q statistic. RESULTS: Thirty studies including six cohort- and twenty-four case-control studies were selected. Periodontitis was significantly associated with increased risk for preeclampsia (OR 3.18, 95% CI 2.26 - 4.48, p < 0.00001), especially in a subgroup analysis including cohort studies (OR 4.19, 95% CI 2.23 - 7.87, p < 0.00001). The association was even stronger in a subgroup analysis with lower-middle-income countries (OR 6.70, 95% CI 2.61 - 17.19, p < 0.0001). CONCLUSIONS: Periodontitis appears as a significant risk factor for preeclampsia, which might be even more pronounced in lower-middle-income countries. Future studies to investigate if maternal amelioration of periodontitis prevents preeclampsia might be warranted.

Design, Synthesis and Biological Activities of New Pyrazole Derivatives Possessing Both Coxib and Combretastatins Pharmacophores.

In our efforts to discover novel multi-target agents having better antitumor activities than celecoxib, 21 new aryl-substituted pyrazole derivatives possessing cis-diphenylethylene scaffold were mostly synthesized by a one-pot approach to ethyl 1,4,5-triaryl-1H-pyrazole-3-carboxylates via an improved Claisen condensation - Knorr reaction sequence. The cytotoxic effects of these compounds against three human cancer cell lines HT-29, Hep-G2, MCF-7 as well as their inhibition of NO production were studied. Results showed that incorporation of the important pharmacophoric groups of two original molecules celecoxib and combretastatin A-4 in a single molecule plays an important role in determining a better biological activities of the new coxib-hybrided compounds.

Effects of charge and hydrophobicity on the oligomerization of peptides derived from IAPP.

Changes in pH resulting in modifications of charge can dramatically alter the folding and interaction of proteins. This article probes the effects of charge and hydrophobicity on the oligomerization of macrocyclic ß-sheet peptides derived from residues 11-17 of IAPP (RLANFLV). Previous studies have shown that a macrocyclic ß-sheet peptide containing this IAPP sequence (peptide 1Arg) does not form oligomers in aqueous solution at low millimolar concentrations. Replacing arginine with the uncharged isostere citrulline generates a homologue (peptide 1Cit) that forms a tetramer consisting of a sandwich of hydrogen-bonded dimers. The current study probes the role of charge and hydrophobicity by changing residue 11 to glutamic acid (peptide 1Glu) and leucine (peptide 1Leu). Diffusion-ordered spectroscopy (DOSY) studies show that peptides 1Glu and 1Leu form tetramers in solution. NOESY studies confirm that both peptides form the same sandwich-like tetramer as peptide 1Cit. 1H NMR spectroscopy at various concentrations reveals that peptide 1Leu has the highest propensity to form tetramers. The effects of pH and charge on oligomerization are further probed by incorporating histidine at position 11 (peptide 1His). DOSY studies show that peptide 1His forms a tetramer at high pH. At low pH, peptide 1His forms a new species that has not been previously observed by our research group-a dimer. These studies demonstrate the importance of charge and hydrophobicity in the oligomerization of IAPP-derived peptides.

Magnetic NiFe2O4/Exfoliated Graphite as an Efficient Sorbent for Oils and Organic Pollutants.

This study aimed to fabricate, characterize and investigate the applicability of nickel ferrite (NiFe2O4 decorated exfoliated graphite for adsorptive removal of oils and organic compounds. The exfoliated graphite/NiFe2O4 was synthesized via a simple two-step process: (i) exfoliation of the lowcost natural graphite flakes using H2O2 as oxidizing agent and H2SO4 as intercalating agent, (ii) decoration of magnetic NiFe2O4 using the acid citric-based sol-gel process. The synthesized exfoliated graphite/NiFe2O4 hybrid was then applied for the sorption of diesel oil, vegetable oil, gasoline, petroleum ether and tetrahydrofuran. Moreover, the recyclability of the used materials was investigated using either chemical or physical extraction method. Properties of the exfoliated graphite/NiFe2O4 hybrid were analysed using relevant techniques such as Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), X-ray diffraction (XRD), and Vibrating Sample Magnetometry (VSM) and N2 adsorption/desorption measurement.

Long-term outcome in survivors of neonatal tetanus following specialist intensive care in Vietnam.

BACKGROUND: Neonatal tetanus continues to occur in many resource-limited settings but there are few data regarding long-term neurological outcome from the disease, especially in settings with critical care facilities. METHODS: We assessed long-term outcome following neonatal tetanus in infants treated in a pediatric intensive care unit in southern Vietnam. Neurological and neurodevelopmental testing was performed in 17 survivors of neonatal tetanus and 18 control children from the same communities using tools previously validated in Vietnamese children. RESULTS: The median age of children assessed was 36 months. Eight neonatal tetanus survivors and 9 community control cases aged < 42 months were tested using the Bayley III Scales of Infant and Toddler Development (Bayley III-VN) and 8 neonatal tetanus survivors and 9 community controls aged ≥42 months were tested using the Movement Assessment Battery for Children. No significant reductions in growth indices or neurodevelopmental scores were shown in survivors of neonatal tetanus compared to controls although there was a trend towards lower scores in neonatal tetanus survivors. Neurological examination was normal in all children except for two neonatal tetanus survivors with perceptive deafness and one child with mild gross motor abnormality. Neonatal tetanus survivors who had expienced severe disease (Ablett grade ≥ 3) had lower total Bayley III-VN scores than those with mild disease (15 (IQR 14-18) vs 24 (IQR 19-27), p = 0.05) with a significantly lower cognitive domain score (3 (IQR 2-6) severe disease vs 7 (IQR 7-8) mild disease, p = 0.02). CONCLUSIONS: Neonatal tetanus is associated with long-term sequelae in those with severe disease. In view of these findings, prevention of neonatal tetanus should remain a priority.

Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α,ß-unsaturated aromatic side chain.

A new series of vinca-alkaloids derivatives containing various α,ß-unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 µM, thus comparable with vinblastine.

Prognosis value of heart rate variability measured by Camera HRV application in patients after acute myocardial infarction.

A prospective cohort study was conducted to assess the prognostic significance of heart rate variability (HRV) measured by the HRV Camera application in predicting major adverse cardiovascular events (MACE) and all-cause mortality within 3 months after percutaneous coronary intervention (PCI). Of 101 patients, 25 developed MACE and 6 died. Low HRV (SDNN and rMSSD) is associated with increased MACE (p < 0.001 and p = 0.014, respectively) and all-cause mortality rates (p = 0.025 and p = 0.032, respectively). Our study concludes that HRV measured by smartphone applications has significant potential as predictive indicators of MACE and all-cause mortality after PCI, particularly SDNN.

Intrinsically Stretchable Floating Gate Memory Transistors for Data Storage of Electronic Skin Devices.

To propel electronic skin (e-skin) to the next level by integrating artificial intelligence features with advanced sensory capabilities, it is imperative to develop stretchable memory device technology. A stretchable memory device for e-skin must offer, in particular, long-term data storage while ensuring the security of personal information under any type of deformation. However, despite the significance of these needs, technology related to stretchable memory devices remains in its infancy. Here, we report an intrinsically stretchable floating gate (FG) polymer memory transistor. The device features a dual-stimuli (optical and electrical) writing system to prevent easy erasure of recorded data. An FG comprising an intermixture of Ag nanoparticles and elastomer and with proper energy-band alignment between the semiconductor and dielectric facilitated sustainable memory performance, while achieving a high memory on/off ratio (>105) and a long retention time (106 s) with the ability to withstand 50% uniaxial or 30% biaxial strain. In addition, our memory transistor exhibited high mechanical durability over multiple stretching cycles (1000 times), along with excellent environmental stability with respect to factors such as temperature, moisture, air, and delamination. Finally, we fabricated a 7 × 7 active-matrix memory transistor array for personalized storage of e-skin data and successfully demonstrated its functionality.

Autonomous self-healing supramolecular polymer transistors for skin electronics.

Skin-like field-effect transistors are key elements of bio-integrated devices for future user-interactive electronic-skin applications. Despite recent rapid developments in skin-like stretchable transistors, imparting self-healing ability while maintaining necessary electrical performance to these transistors remains a challenge. Herein, we describe a stretchable polymer transistor capable of autonomous self-healing. The active material consists of a blend of an electrically insulating supramolecular polymer with either semiconducting polymers or vapor-deposited metal nanoclusters. A key feature is to employ the same supramolecular self-healing polymer matrix for all active layers, i.e., conductor/semiconductor/dielectric layers, in the skin-like transistor. This provides adhesion and intimate contact between layers, which facilitates effective charge injection and transport under strain after self-healing. Finally, we fabricate skin-like self-healing circuits, including NAND and NOR gates and inverters, both of which are critical components of arithmetic logic units. This work greatly advances practical self-healing skin electronics.

Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities: A multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: Overall IgG seroprevalence was 99.7% (95%CI: 99.2-99.9) for measles and 83.6% (95%CI: 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed postvaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Transformations for the compression of FASTQ quality scores of next-generation sequencing data.

MOTIVATION: The growth of next-generation sequencing means that more effective and efficient archiving methods are needed to store the generated data for public dissemination and in anticipation of more mature analytical methods later. This article examines methods for compressing the quality score component of the data to partly address this problem. RESULTS: We compare several compression policies for quality scores, in terms of both compression effectiveness and overall efficiency. The policies employ lossy and lossless transformations with one of several coding schemes. Experiments show that both lossy and lossless transformations are useful, and that simple coding methods, which consume less computing resources, are highly competitive, especially when random access to reads is needed. AVAILABILITY AND IMPLEMENTATION: Our C++ implementation, released under the Lesser General Public License, is available for download at http://www.cb.k.u-tokyo.ac.jp/asailab/members/rwan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Artificial bee colony algorithm for solving optimal power flow problem.

This paper proposes an artificial bee colony (ABC) algorithm for solving optimal power flow (OPF) problem. The objective of the OPF problem is to minimize total cost of thermal units while satisfying the unit and system constraints such as generator capacity limits, power balance, line flow limits, bus voltages limits, and transformer tap settings limits. The ABC algorithm is an optimization method inspired from the foraging behavior of honey bees. The proposed algorithm has been tested on the IEEE 30-bus, 57-bus, and 118-bus systems. The numerical results have indicated that the proposed algorithm can find high quality solution for the problem in a fast manner via the result comparisons with other methods in the literature. Therefore, the proposed ABC algorithm can be a favorable method for solving the OPF problem.