Constitutional and acquired genetic variants in ARID5B in pediatric B-cell precursor acute lymphoblastic leukemia.

Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51-67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.

Overcoming passivation through improved mass transport in dense ionic fluids.

Deep Eutectic Solvents (DESs) have recently been shown to be part of a dense ionic fluid continuum between ionic liquids and concentrated aqueous brines. Charge transport was shown to be governed by fluidity, with no discontinuity between molar conductivity and fluidity irrespective of cation, charge density or ionic radius. By adjusting the activity of water and chloride ions, mass transport, speciation and reactivity can be altered. It has been shown that while brines provide a high chloride content at a lower viscosity than DESs, unlike DESs, brines are unable to prevent metal passivation due to their high water content. This results in the possibility to impart a level of selectivity towards metal dissolution (or passivation) when processing mixed metal materials. Forced convection can be used to avoid the issue of slow mass transport in viscous media, and the use of jets or targeted ultrasound are effective methods for overcoming this issue. High-powered ultrasound was applied to copper, cobalt, and aluminium electrodes undergoing anodic dissolution, and linear sweep voltammetry showed a linear current-voltage response at potentials anodic of the oxidation potential under sonication, with total charge passed being 5 to 134 times greater than under silent conditions. Application of ultrasound to silver and nickel electrodes displayed an initial linear current-voltage response, but the increased water content of the brines resulted in passivation. Mass transport throughout the bulk solution is governed by the forced convection imparted by the ultrasound and ionic species must only migrate across the electrical double layer. It is shown that the anodic dissolution of a range of metals classically expected to passivate, e.g. aluminium, can be significantly accelerated under insonation conditions.

Discovering Electrochemistry with an Electrochemistry-Informed Neural Network (ECINN).

Machine learning is increasingly integrated into chemistry research by guiding experimental procedures, correlating structure and function, interpreting large experimental datasets, to distill scientific insights that might be challenging with traditional methods. Such applications, however, largely focus on gaining insights via big data and/or big computation, while neglecting the valuable chemical prior knowledge dwelling in chemists' minds. In this paper, we introduce an Electrochemistry-Informed Neural Network (ECINN) by explicitly embedding electrochemistry priors including the Butler-Volmer (BV), Nernst and diffusion equations on the backbone of neural networks for multi-task discovery of electrochemistry parameters. We applied the ECINN to voltammetry experiments of F e 2 + / F e 3 + ${{\rm F}{{\rm e}}^{2+}/{\rm F}{{\rm e}}^{3+}}$ and R u N H 3 6 2 + / R u N H 3 6 3 + ${{\rm R}{\rm u}{\left({\rm N}{{\rm H}}_{3}\right)}_{6}^{2+{\rm \ }}/{\rm R}{\rm u}{\left({\rm N}{{\rm H}}_{3}\right)}_{6}^{3+{\rm \ }}}$ redox couples to discover electrode kinetics and mass transport parameters. Notably, ECINN seamlessly integrated mass transport with BV to analyze the entire voltammogram to infer transfer coefficients directly, so offering a new approach to Tafel analysis by outdating various mass transport correction methods. In addition, ECINN can help discover the nature of electron transfer and is shown to refute incorrect physics if imposed. This work encourages chemists to embed their domain knowledge into machine learning models to start a new paradigm of chemistry-informed machine learning for better accountability, interpretability, and generalization.

Calcifying Coccolithophore: An Evolutionary Advantage Against Extracellular Oxidative Damage.

The evolutionary advantages afforded by phytoplankton calcification remain enigmatic. In this work, fluoroelectrochemical experiments reveal that the presence of a CaCO3 shell of a naturally calcifying coccolithophore, Coccolithus braarudii, offers protection against extracellular oxidants as measured by the time required for the switch-off in their chlorophyll signal, compared to the deshelled equivalents, suggesting the shift toward calcification offers some advantages for survival in the surface of radical-rich seawater.

Quantifying the Extent of Calcification of a Coccolithophore Using a Coulter Counter.

Although, in principle, the Coulter Counter technique yields an absolute measure of particle volume, in practice, calibration is near-universally employed. For regularly shaped and non-biological samples, the use of latex beads for calibration can provide sufficient accuracy. However, this is not the case with particles encased in biogenically formed calcite. To date, there has been no effective route by which a Coulter Counter can be calibrated to enable the calcification of coccolithophores─single cells encrusted with biogenic calcite─to be quantified. Consequently, herein, we seek to answer the following question: to what extent can a Coulter Counter be used to provide accurate information regarding the calcite content of a single-species coccolithophore population? Through the development of a new calibration methodology, based on the measurement and dynamic tracking of the acid-driven calcite dissolution reaction, a route by which the cellular calcite content can be determined is presented. This new method allows, for the first time, a Coulter Counter to be used to yield an absolute measurement of the amount of calcite per cell.

13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.

Calcium Carbonate Dissolution from the Laboratory to the Ocean: Kinetics and Mechanism.

The ultimate fate, over the course of millennia, of nearly all of the carbon dioxide formed by humankind is for it to react with calcium carbonate in the world's oceans. Although, this reaction is of global relevance, aspects of the calcite dissolution reaction remain poorly described with apparent contradictions present throughout the expansive literature. In this perspective we aim to evidence how a lack of appreciation of the role of mass-transport may have hampered developments in this area. These insights have important implications for both idealised experiments performed under laboratory conditions and for the measurement and modelling of oceanic calcite sediment dissolution.

Sister chromatid cohesion defects are associated with chromosomal copy number heterogeneity in high hyperdiploid childhood acute lymphoblastic leukemia.

High hyperdiploid acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. The main driver event of this disease is a nonrandom aneuploidy consisting of gains of whole chromosomes but without overt evidence of chromosomal instability (CIN). Here, we investigated the frequency and severity of defective sister chromatid cohesion-a phenomenon related to CIN-in primary pediatric ALL. We found that a large proportion (86%) of hyperdiploid cases displayed aberrant cohesion, frequently severe, to compare with 49% of ETV6/RUNX1-positive ALL, which mostly displayed mild defects. In hyperdiploid ALL, cohesion defects were associated with increased chromosomal copy number heterogeneity, which could indicate increased CIN. Furthermore, cohesion defects correlated with RAD21 and NCAPG mRNA expression, suggesting a link to reduced cohesin and condensin levels in hyperdiploid ALL. Knockdown of RAD21 in an ALL cell line led to sister chromatid cohesion defects, aberrant mitoses, and increased heterogeneity in chromosomal copy numbers, similar to what was seen in primary hyperdiploid ALL. In summary, our study shows that aberrant sister chromatid cohesion is frequent but heterogeneous in pediatric high hyperdiploid ALL, ranging from mild to very severe defects, and possibly due to low cohesin or condensin levels. Cases with high levels of aberrant chromosome cohesion displayed increased chromosomal copy number heterogeneity, possibly indicative of increased CIN. These abnormalities may play a role in the clonal evolution of hyperdiploid pediatric ALL.

GAS5 knockdown suppresses inflammation and oxidative stress induced by oxidized low-density lipoprotein in macrophages by sponging miR-135a.

A large number of long non-coding RNAs have been confirmed to play vital roles in regulating various biological processes. Abnormal expression of growth arrest-specific transcript 5 (GAS5) is reported to be involved in the development of atherosclerosis (AS). This work is to explore the detailed mechanism underling how GAS5 regulates AS progression. We found that the abundance of GAS5 was markedly increased, and miR-135a was decreased in AS patient serums and ox-LDL-induced human THP-1 cells dose and time dependently. Interference of GAS5 suppressed inflammation and oxidative stress induced by ox-LDL in THP-1 cells. Mechanistically, GAS5 acted as a molecular sponge of microRNA-135a (miR-135a). Rescue assays indicated that knockdown of miR-135a partially rescued small interference RNA for GAS5-inhibited inflammatory cytokines release and oxidative stress in ox-LDL-triggered THP-1 cells. In conclusion, the absence of GAS5-inhibited inflammatory response and oxidative stress induced by ox-LDL in THP-1 cells via sponging miR-135a, providing a deep insight into the molecular target for AS treatment.

Opto-Electrochemical Dissolution Reveals Coccolith Calcium Carbonate Content.

Coccoliths are plates of biogenic calcium carbonate secreted by calcifying marine phytoplankton; annually these phytoplankton are responsible for exporting >1 billion tonnes (1015  g) of calcite to the deep ocean. Rapid and reliable methods for assessing the degree of calcification are technically challenging because the coccoliths are micron sized and contain picograms (pg) of calcite. Here we pioneer an opto-eletrochemical acid titration of individual coccoliths which allows 3D reconstruction of each individual coccolith via in situ optical imaging enabling direct inference of the coccolith mass. Coccolith mass ranging from 2 to 400 pg are reported herein, evidencing both inter- and intra-species variation over four different species. We foresee this scientific breakthrough, which is independent of knowledge regarding the species and calibration-free, will allow continuous monitoring and reporting of the degree of coccolith calcification in the changing marine environment.

Visualising electrochemical reaction layers: mediated vs. direct oxidation.

Electrochemical treatments are widely used for 'clean up' in which toxic metals and organic compounds are removed using direct or mediated electrolysis. Herein we report novel studies offering proof of concept that spectrofluorometric electrochemistry can provide important mechanistic detail into these processes. A thin layer opto-electrochemical cell, with a carbon fibre (radius 3.5 µm) working electrode, is used to visualise the optical responses of the oxidative destruction of a fluorophore either directly, on an electrode, or via the indirect reaction of the analyte with an electrochemically formed species which 'mediates' the destruction. The optical responses of these two reaction mechanisms are first predicted by numerical simulation followed by experimental validation of each using two fluorescent probes, a redox inactive (in the electrochemical window) 1,3,6,8-pyrenetetrasulfonic acid and the redox-active derivative 8-hydroxypyrene-1,3,6-trisulfonic acid. In the vicinity of a carbon electrode held at different oxidative potentials, the contrast between indirect electro-destruction, chlorination, and direct oxidation is very obvious. Excellent agreement is seen between the numerically predicted fluorescence intensity profiles and experiment.

Fine mapping MHC associations in Graves' disease and its clinical subtypes in Han Chinese.

BACKGROUND: The classical human leucocyte antigen (HLA) genes were the most important genetic determinant for Graves' disease (GD). The aim of the study was to fine map causal variants of the HLA genes. METHODS: We applied imputation with a Pan-Asian HLA reference panel to thoroughly investigate themajor histocompatibility complex (MHC) associations with GD down to the amino acid level of classical HLA genes in 1468 patients with GD and 1490 controls of Han Chinese. RESULTS: The strongest finding across the HLA genes was the association with HLA-DPß1 position 205 (Pomnibus=2.48×10-33). HLA-DPA1*02:02 was the strongest association among the classical HLA alleles, which was in perfect linkage disequilibrium with HLA-DPα1 residue Met11 (OR=1.90, Pbinary=1.76×10-31). Applying stepwise conditional analysis, we identified amino acid position 205 in HLA-DPß1, position 66 and 99 in HLA-B and position 28 in HLA-DRß1 explain majority of the MHC association to GD risk. We further evaluated risk of two clinical subtypes of GD, namely persistent thyroid stimulating hormone receptor antibody -positive (pTRAb+) group and 'non-persistent TRAb positive' (pTRAb-) group after antithyroid drug therapy. We found that HLA-B residues Lys66-Arg69-Val76 could drive pTRAb- GD risk alone, while HLA-DPß1 position 205, HLA-B position 69 and 199 and HLA-DRß1 position 28 drive pTRAb+ GD risk. The risk heterogeneity between pTRAb+ and pTRAb- GD might be driven by HLA-DPα1 Met11. CONCLUSIONS: Four amino acid positions could account for the associations of MHC with GD in Han Chinese. These distinct HLA association patterns indicated the two subtypes have distinct molecular mechanisms of pathogenesis.

The relationship among angiotensinogen genes polymorphisms and hs-CRP and coronary artery disease.

OBJECTIVE: To assess the association of gene polymorphisms of angiotensinogen (AGT), the key factor in rennin-angiotensin-aldosterone system (RAAS), with high-sensitivity C-reactive protein (hs-CRP) and coronary artery disease (CAD). METHODS: The current study recruited the patients who were hospitalized and assessed by coronary angiography for suspected CAD. The patients with documented CAD served as CAD group (n = 492) while the patients without documented CAD (n = 87) served as control group. We compared laboratory data and CAD risk factors between the two groups. Furthermore, we analyzed the association of AGT M235T, G217A, G152A, G-6A, A-20C genotypes with coronary artery stenosis and in-stent restenosis. RESULTS: There were significantly differences between two patient groups in sex, smoking history, diabetes mellitus, carotid atherosclerosis, lower limb arteriosclerosis, hs-CRP, blood glucose, and the level of high-density lipoprotein (HDL; P < 0.05). In CAD group, hs-CRP levels increased with increasing number of coronary artery branches (1, 2, or ≥3; P < 0.01), and Gensini integral was positively correlated with hs-CRP levels (r = 0.361, P < 0.01). Frequencies of genotype and allele distribution in individual angiotensinogen loci (M235T, G217A, G152A, G-6A, A-20C) did not differ in two patient groups. Following stratification of patients according to hs-CRP levels (<1 mg/L, 1-3 mg/L, and >3 mg/L), the distribution frequency of allele M235T was statistically different among the groups (P < 0.05). CONCLUSION: In CAD patients, M235T among several AGT gene polymorphisms is associated with elevated hs-CRP levels with AGT C allele as the significant factor for patients with hs-CRP level of more than 1 mg/L.

Sensor histidine kinase is a ß-lactam receptor and induces resistance to ß-lactam antibiotics.

ß-Lactams disrupt bacterial cell wall synthesis, and these agents are the most widely used antibiotics. One of the principle mechanisms by which bacteria resist the action of ß-lactams is by producing ß-lactamases, enzymes that degrade ß-lactams. In Gram-negative bacteria, production of ß-lactamases is often induced in response to the antibiotic-associated damage to the cell wall. Here, we have identified a previously unidentified mechanism that governs ß-lactamase production. In the Gram-negative enteric pathogen Vibrio parahaemolyticus, we found a histidine kinase/response regulator pair (VbrK/VbrR) that controls expression of a ß-lactamase. Mutants lacking either VbrK or VbrR do not produce the ß-lactamase and are no longer resistant to ß-lactam antibiotics. Notably, VbrK autophosphorylation is activated by ß-lactam antibiotics, but not by other lactams. However, single amino acid substitutions in the putative periplasmic binding pocket of VbrK leads its phosphorylation in response to both ß-lactam and other lactams, suggesting that this kinase is a ß-lactam receptor that can directly detect ß-lactam antibiotics instead of detecting the damage to cell wall resulting from ß-lactams. In strong support of this idea, we found that purified periplasmic sensor domain of VbrK binds penicillin, and that such binding is critical for VbrK autophosphorylation and ß-lactamase production. Direct recognition of ß-lactam antibiotics by a histidine kinase receptor may represent an evolutionarily favorable mechanism to defend against ß-lactam antibiotics.

In-situ Electrochemical X-ray Diffraction: A Rigorous Method to Navigate within Phase Diagrams Reveals ß-Fe1+x Se as Superconductor for All x.

We report the precise postsynthetic control of the composition of ß-Fe1+x Se by electrochemistry with simultaneous tracking of the associated structural changes via in situ synchrotron X-ray diffraction. We access the full phase width of 0.01

A σE-Mediated Temperature Gauge Controls a Switch from LuxR-Mediated Virulence Gene Expression to Thermal Stress Adaptation in Vibrio alginolyticus.

In vibrios, the expression of virulence factors is often controlled by LuxR, the master quorum-sensing regulator. Here, we investigate the interplay between LuxR and σE, an alternative sigma factor, during the control of virulence-related gene expression and adaptations to temperature elevations in the zoonotic pathogen Vibrio alginolyticus. An rpoE null V. alginolyticus mutant was unable to adapt to various stresses and was survival-deficient in fish. In wild type V. alginolyticus, the expression of LuxR-regulated virulence factors increased as the temperature was increased from 22°C to 37°C, but mutants lacking σE did not respond to temperature, indicating that σE is critical for the temperature-dependent upregulation of virulence genes. Further analyses revealed that σE binds directly to -10 and -35 elements in the luxR promoter that drive its transcription. ChIP assays showed that σE binds to the promoter regions of luxR, rpoH and rpoE at high temperatures (e.g., 30°C and 37°C). However, at higher temperatures (42°C) that induce thermal stress, σE binding to the luxR promoter decreased, while its binding to the rpoH and rpoE promoters was unchanged. Thus, the temperature-dependent binding of σE to distinct promoters appears to underlie a σE-controlled switch between the expression of virulence genes and adaptation to thermal stress. This study illustrates how a conserved temperature response mechanism integrates into quorum-sensing circuits to regulate both virulence and stress adaptation.

A New Composite Electrode Applied for Studying the Electrochemistry of Insoluble Particles: α-HgS.

The redox chemistry of solid α-HgS particles is revealed using a carbon/PVDF composite containing α-HgS, carbon black, polyvinylidene fluoride (PVDF). The electrochemical behaviour of the carbon/PVDF composite is first characterised with three water insoluble organic solids. Then the reduction of solid α-HgS particles is investigated and found to occur at a high negative potential, -1.82 V versus saturated mercury sulphate reference electrode, to form metallic mercury and sulphide ions. The subsequent oxidation of metallic mercury and sulphide occurs at +0.24 and -0.49 V versus MSE respectively.

Reaction Layer Imaging Using Fluorescence Electrochemical Microscopy.

The chemical confinement of a pH sensitive fluorophore to a thin-reaction layer adjacent to an electrode surface is explored as a potentially innovative route to improving the spatial resolution of fluorescence electrochemical microscopy. A thin layer opto-electrochemical cell is designed, facilitating the visualization of a carbon fiber (diameter 7.0 µm) electrochemical interface. Proton consumption is driven at the interface by the reduction of benzoquinone to hydroquinone and the resulting interfacial pH change is revealed using the fluorophore 8-hydoxypyrene-1,3,6-trisulfonic acid. It is demonstrated that the proton depletion zone may be constrained and controlled by the addition of a finite acid concentration to the system. Simulation of the resulting fluorescence intensity profiles is achieved on the basis of a finite difference model, with excellent agreement between the theoretical and experimental results.

Genome analysis and in vivo virulence of porcine extraintestinal pathogenic Escherichia coli strain PCN033.

BACKGROUND: Strains of extraintestinal pathogenic Escherichia coli (ExPEC) can invade and colonize extraintestinal sites and cause a wide range of infections. Genomic analysis of ExPEC has mainly focused on isolates of human and avian origins, with porcine ExPEC isolates yet to be sequenced. To better understand the genomic attributes underlying the pathogenicity of porcine ExPEC, we isolated two E. coli strains PCN033 and PCN061 from pigs, assessed their in vivo virulence, and completed and compared their genomes. RESULTS: Animal experiments demonstrated that strain PCN033, but not PCN061, was pathogenic in a pig model. The chromosome of PCN033 was 384 kb larger than that of PCN061. Among the PCN033-specific sequences, genes encoding adhesins, unique lipopolysaccharide, unique capsular polysaccharide, iron acquisition and transport systems, and metabolism were identified. Additionally, a large plasmid PCN033p3 harboring many typical ExPEC virulence factors was identified in PCN033. Based on the genetic variation between PCN033 and PCN061, corresponding phenotypic differences in flagellum-dependent swarming motility and metabolism were verified. Furthermore, the comparative genomic analyses showed that the PCN033 genome shared many similarities with genomic sequences of human ExPEC strains. Additionally, comparison of PCN033 genome with other nine characteristic E. coli genomes revealed 425 PCN033-special coding sequences. Genes of this subset included those encoding type I restriction-modification (R-M) system, type VI secretion system (T6SS) and membrane-associated proteins. CONCLUSIONS: The genetic and phenotypic differences between PCN033 and PCN061 could partially explain their differences in virulence, and also provide insight towards the molecular mechanisms of porcine ExPEC infections. Additionally, the similarities between the genomes of PCN033 and human ExPEC strains suggest that some connections between porcine and human ExPEC strains exist. The first completed genomic sequence for porcine ExPEC and the genomic differences identified by comparative analyses provide a baseline understanding of porcine ExPEC genetics and lay the foundation for their further study.