Positive Signature Research Articles

The signature genes of cuproptosis associates with tumor immune microenvironment and predicts prognosis in kidney renal clear cell carcinoma.

Cuproptosis is a new form of cell death, which has great potential to be developed in tumors treatment. Our study aimed to explore the predictive value of cuproptosis-related genes (CRGs) in various cancers, with a focus on kidney renal clear cell carcinoma (KIRC). A total of 9502 pan-cancer patients from TCGA cohort were enrolled. The relationships between CRGs and overall survival (OS) or disease-free survival (DFS) were analyzed. Gene Set Variation Analysis (GSVA) enrichment analysis was performed to explore the expression differences of CRGs. Multivariate Cox regression analysis was used to evaluate the association between GSVA scores and patient survival. KEGG and GO analyses were employed to identify the biological functions and pathways. The expression and prognostic characteristics of FDX1 were examined to evaluate the correlation between FDX1 and KIRC. Cell experiments were conducted to verify whether FDX1 was involved in cuproptosis of Caki-1 cells induced by Elesclomol. Positive cuproptosis signature genes(pos.cu.sig) exhibited the correlation with prognosis in KIRC, and all of these genes showed differential expression between KIRC and normal tissues. The GSVA score of pos.cu.sig was associated with excellent survival (HR=0.61, P<0.05), which can also serve as an independent prognostic factor for KIRC. There was a close correlation between pos.cu.sig and the tumor immune microenvironment in KIRC by KEGG and GO analysis. FDX1 expression was correlated with KIRC grade and positively associated with prognosis in KIRC patients. Compared with the control group, cell proliferation and migration were significantly inhibited, FDX1 expression was up-regulated, and Fe-S cluster protein content was decreased of Caki-1 cells after Elesclomol treatment. This study provides compelling evidence that cuproptosis is closely linked to the prognosis of KIRC. FDX1 holds promise as a viable biomarker and therapeutic target for assessing the effectiveness of tumor immunotherapy in KIRC.

Lorentzian metric spaces and their Gromov–Hausdorff convergence

We present an abstract approach to Lorentzian Gromov–Hausdorff distance and convergence, and an alternative approach to Lorentzian length spaces that does not use auxiliary “positive signature” metrics or other unobserved fields. We begin by defining a notion of (abstract) bounded Lorentzian metric space which is sufficiently general to comprise compact causally convex subsets of globally hyperbolic spacetimes and causets. We define the Gromov–Hausdorff distance and show that two bounded Lorentzian metric spaces at zero GH distance are indeed both isometric and homeomorphic. Then we show how to define from the Lorentzian distance, beside topology, the causal relation and the causal curves for these spaces, obtaining useful limit curve theorems. Next, we define Lorentzian (length) prelength spaces via suitable (maximal) chronal connectedness properties. These definitions are proved to be stable under GH limits. Furthermore, we define bounds on sectional curvature for our Lorentzian length spaces and prove that they are also stable under GH limits. We conclude with a (pre)compactness theorem.

Multiple sulfur isotopes evidence deep intra-slab transport of sulfate-rich fluids

Sub-arc mantle oxidation is often attributed to sulfates from seawater transported in aqueous fluids derived from slab dehydration, but sulfur speciation and origin(s) in high-pressure fluids remain weakly constrained. Here, we use the four sulfur stable isotopes (32S, 33S, 34S, 36S) to decipher processes, e.g. mixing of two end-member reservoirs and open-system reaction occurring during sulfur devolatilization, and deduce the nature and origin of sulfur species in aqueous slab-derived fluids. We analyzed high pressure metamorphic rocks from the Monviso massif Lower Shear Zone (LSZ; Western Alps), recording evidence of an interface-parallel, channelized fluid flow near peak burial metamorphic conditions (∼550 °C and 2.7 GPa). We sampled variably metasomatized Fe-Ti metagabbros, hybrid (talc) schists and serpentinites containing sulfides supposed to preserve the aqueous fluid composition, as well as other alpine metagabbro, metabasalt and serpentinites from greenschist to eclogite-facies devoid of the studied metasomatic overprint.The millimeter to centimeter-sized sulfide crystals found in abundance within LSZ lithologies are mainly pyrites containing inclusions of the peak burial mineral assemblage (e.g. garnet, omphacite, rutile) indicating their crystallization at peak conditions or during incipient exhumation. The sulfides in the non-metasomatic metagabbros and metabasalts cover a narrow range in δ’34S of 0.89 ± 0.63 ‰ and Δ’33S of 0.017 ± 0.01 (n = 6) that could be inherited from hydrothermal sulfides formed on the seafloor. In contrast, the LSZ sulfides from the Fe-Ti metagabbros, serpentinites and hybrid schists (n = 24) are enriched in 34S and 33S (bulk δ’34S from 4.91 to 21.32 ‰ and Δ’33S from 0.02 to 0.06 ‰) compared to the sulfides from the non-metasomatic rocks. Mixing between reduced sulfur species cannot explain all the data without requiring an end-member composition as high as δ34S ∼ 22 ‰ and Δ33S ∼ 0.06 ‰, i.e. values rarely recorded by sulfides in the literature. Instead, we propose that this 33S-34S-enrichment results from open-system sulfate reduction to sulfides in aqueous fluids at 550°C, with an initial δ34S ∼ 12 ± 3 ‰ and Δ33S ∼ 0.025 ± 0.010 ‰. Because this signature is different from seawater sulfate, we suggest that sulfate was produced by hydrothermal sulfide oxidation during antigorite breakdown at 650°C, in agreement with Mg, Ni and Cr enrichments in the metasomatized HP mafic lithologies. This model is consistent with relatively oxidized 34S-enriched arc lavas and can potentially explain recycled sulfur with positive δ34S signature recorded by ocean island basalts.

Chemical manipulation of m1A mediates its detection in human tRNA.

N 1-methyl adenosine (m1A) is a widespread RNA modification present in tRNA, rRNA, and mRNA. m1A modification sites in tRNAs are evolutionarily conserved and its formation on tRNA is catalyzed by methyltransferase TRMT61A and TRMT6 complex. m1A promotes translation initiation and elongation. Due to its positive charge under physiological conditions, m1A can notably modulate RNA structure. It also blocks Watson-Crick-Franklin base-pairing and causes mutation and truncation during reverse transcription. Several misincorporation-based high-throughput sequencing methods have been developed to sequence m1A. In this study, we introduce a reduction-based m1A sequencing (red-m1A-seq). We report that NaBH4 reduction of m1A can improve the mutation and readthrough rates using commercially available RT enzymes to give a better positive signature, while alkaline-catalyzed Dimroth rearrangement can efficiently convert m1A to m6A to provide good controls, allowing the detection of m1A with higher sensitivity and accuracy. We applied red-m1A-seq to sequence human small RNA, and we not only detected all the previously reported tRNA m1A sites, but also new m1A sites in mt-tRNAAsn-GTT and 5.8S rRNA.

Abstract 6430: Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome

Abstract Accumulating evidence has suggested that cancer progression and therapeutic response may depend on not only tumor cells but also their tumor microenvironment (TME). However, their contributory roles are complex and not well understood. Here we report an analysis of 2373 human colorectal cancer (CRC) tumors representing all stages, leading to identification of a 20-gene signature capable of quantifying the cellular contribution of the tumor vs. the TME in determining colorectal cancer prognosis and therapeutic outcome. We classified these tumors into the consensus molecular subtypes (CMS1-4) with distinct, variable TME cellular features defined by CIBERSORT deconvolution analysis of bulk gene expression data. Surprisingly, all the 10 positive signature genes (portending worse survival) were strongly correlated with the TME-rich CMS1 and CMS4 tumors. By contrast, all the 10 negative signature genes (portending better survival) were highly related to the TME-poor CMS2 and CMS3 tumors. A single cell expression analysis from an independent database further revealed that strikingly, all the 10 positive genes were principally expressed by the immune/stromal TME whereas all the 10 negative genes were predominantly expressed in epithelial tumor cells. These data suggest that the TME has an equally important role as do tumor cells in determining CRC prognosis and support targeting the TME to improve survival. Moreover, distinct gene expression from tumor cells versus the TME also showed a differential impact on therapeutic outcome. Retrospective analyses on two independent clinical trial datasets show that the 20-gene signature score significantly predicted progression free survival in metastatic CRC patients treated with cetuximab, an FDA-approved EGFR inhibitor therapy. These data suggest a potential for the 20-gene signature as a predictive biomarker to identify “sensitive” versus “resistant” subpopulations of CRC patients to improve outcome of EGFR-targeted therapy. Citation Format: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden. Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6430.

Identification and characterization of immunogenic neoantigens in colorectal cancer (CRC).

161 Background: Presentation of neoantigens, short peptides derived from tumor-specific somatic mutations, by HLA molecules triggers the activation of anti-tumor immune response. Recognition of neoantigens by autologous T cells promotes sensitivity to immune checkpoint inhibitors (ICI) in mismatch repair deficient (MMRd)/microsatellite instability high (MSI-H) tumors. Neoantigen-targeted reactivity has also been reported in microsatellite stable (MSS) tumors, and neoantigens are emerging targets for tumor vaccines and adoptive cell therapy. Here, we aimed to comprehensively assess the spectrum of immunogenic neoantigens in CRC to identify new subpopulations for these therapeutic strategies. Methods: 7,053 CRC tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (720-gene panel) and RNA (whole transcriptome) were analyzed. MSI status was determined by immunohistochemistry of MMR proteins and/or NGS. Immune epitope prediction was performed on translated peptide sequences harboring detected mutations using the NetMHCpan v4.0 method in the Immune Epitope Database, with HLA genotyping performed using arcasHLA. Immune/stromal cell abundance in the tumor microenvironment (TME) was estimated from RNA expression profiles using MCP-Counter. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature, TIS). Results: 6,600,005 unique peptide:allele interactions were tested, of which 368,468 (5.6%) were predicted neoantigens with patient-specific HLA alleles, including 16,184 (0.25%) with high affinity. MMRd/MSI-H tumors (6.9%) had higher neoantigen load at all affinity levels compared to MSS, with 10,243 (63.3%) and 5,621 (34.7%) of the predicted high affinity neoantigens exclusively associated with MSS and MMRd/MSI-H, respectively. 32 recurrent high affinity neoantigens were identified in &gt; 10 samples, most frequently derived from APC mutations in MSS tumors (78% of recurrent neoantigens), and from RNF43 (25%), ASXL1 (20%), and KMT2D (15%) in MMRd/MSI-H. TIS scores positively correlated with the abundance of various immune cell populations in the TME, notably cytotoxic lymphocytes (r = 0.46). Among the recurrent high affinity neoantigens, those with the highest mean TIS scores (&gt; 90th percentile) resulted from mutation of MSH3 (K383fs, 5.1%) and KMT2D (multiple variants, 2.8%) in MMRd/MSI-H CRC, while those in MSS CRC derived from SOX9 (multiple variants, 0.2%) and APC (multiple variants, 0.7%) but were not associated with increased mean TIS scores (~55th percentile). Conclusions: This is one of the largest studies to investigate the landscape of immunogenic neoantigens in CRC. We were able to identify candidate recurrent peptides with high HLA binding affinity and an association with a positive TIS signature supporting the role of neoantigens as potential cancer immunotherapy targets.

Presence of sputum IgG against eosinophilic inflammatory proteins in asthma.

Sputum immunoglobulin G (Sp-IgG) has been discovered to induce cytolytic extracellular trap cell death in eosinophils, suggesting a potential autoimmune mechanism contributing to asthma. This study aimed to explore the potential origin of Sp-IgG and identify clinically relevant subtypes of Sp-IgG that may indicate autoimmune events in asthma. This study included 165 asthmatic patients and 38 healthy volunteers. We measured Sp-IgG and its five subtypes against eosinophil inflammatory proteins (Sp-IgGEPs), including eosinophil peroxidase, eosinophil major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and Charcot-Leyden Crystal protein in varying asthma severity. Clinical and Mendelian randomization (MR) analyses were conducted. A positive Sp-IgGEPs signature (Sp-IgGEPs+) was defined when any of the five Sp-IgGEPs values exceeded the predefined cutoff thresholds, calculated as the mean values of healthy controls plus twice the standard deviation. The levels of Sp-IgG and Sp-IgGEPs were significantly elevated in moderate/severe asthma than those in mild asthma/healthy groups (all p < 0.05). Sp-IgG levels were positively correlated with airway eosinophil and Sp-IgGEPs. MR analysis showed causality between eosinophil and IgG (OR = 1.02, 95%CI = 1.00-1.04, p = 0.020), and elevated IgG was a risk factor for asthma (OR = 2.05, 95%CI = 1.00-4.17, p = 0.049). Subjects with Sp-IgGEPs+ exhibited worse disease severity and served as an independent risk factor contributing to severe asthma (adjusted-OR = 5.818, adjusted-95% CI = 2.193-15.431, adjusted-p < 0.001). Receiver operating characteristic curve analysis demonstrated that the combination of Sp-IgGEPs+ with non-allergic status, an ACT score < 15, and age ≥ 45 years, effectively predicted severe asthma (AUC = 0.84, sensitivity = 86.20%, specificity = 67.80%). This study identifies a significant association between airway eosinophilic inflammation, Sp-IgG, and asthma severity. The Sp-IgGEPs panel potentially serves as the specific biomarker reflecting airway autoimmune events in asthma.

The multiple sulfur isotope architecture of the Kambalda nickel camp, Western Australia

New data on the multiple sulfur isotope signature of Archean sulfides from country rocks and magmatic mineralization at the Moran deposit (Kambalda, Western Australia) were combined with previously published geochemical data to constrain the various stages of the dynamic evolution of this magmatic system, unveiling new insights into the transport mechanisms of sulfide liquids in komatiite magmas. Sulfides in the Archean magmatic and sedimentary host rocks of the komatiites display a unique mass-independent sulfur isotope signature (Δ33S), which records a photochemical reaction of sulfur in an oxygen-poor atmosphere prior to the Great Oxidation Event.Sedimentary rocks that are thought to be assimilated by komatiite show a distinctly positive Δ33S signature (+ 0.9 to + 2.4‰). Early ore sulfides situated above these sedimentary rocks contain relatively few valuable metals and display an overlapping Δ33S range (+ 0.6 to + 1.0‰). Subsequent but still early ore sulfides are situated above basalt, as the sedimentary rocks were thermo-mechanically eroded by the sulfide melt, displaying more mantle-like signatures (+ 0.2 to + 0.3‰) and valuable metal content - indistinguishable from the main ore deposit. This reflects a progressive dilution of the contaminant signature by the magmatic isotope signature of the komatiite liquid. Calculated volumes of the interaction of silicate melt and sulfide melt to explain the metal tenor of the ore and its Δ33S signature indicate a decoupling between chemical and isotopic signatures. This can be explained by upgrading the sulfide melt with valuable metals simultaneously with the dissolution of sulfur in the komatiite melt.

Abelian branched covers of rational surfaces

Abstract We study abelian covers of rational surfaces branched over line arrangements. We use these covers to address the geography problem for closed simply connected nonspin irreducible symplectic 4-manifolds with positive signature.

Development of negative-ion gaseous TPC using micro pattern readout for direction-sensitive dark matter search

NEWAGE is the experiment of direction-sensitive dark matter search using low pressure gaseous TPC with micro pattern strip readout (μ-PIC). It allows to measure the distribution of angles of WIMP-nuclear recoil by track reconstruction, and it allows a positive signature of dark matter. In recent years, large size (∼1 m3) TPC filled with SF6 gas, which is so called “negative-ion gas”, is under development. A TPC with negative ions is a novel technology for the measurement of absolute position of drift direction coordinates in a self-triggering system. The determination of the absolute track position allows to discriminate nuclear recoils in the target gas volume from alpha-rays from the detector surface, which is one of the background sources. Furthermore, diffusion of drifting negative ions is expected to be lower than that of nominal electron drift, which allows to improve angular resolution. This presentation reports the status of the development of negative-ion gaseous TPC with a prototype small chamber. In addition, we started to develop O(100) μm pitch gaseous TPC detector with pixel type readout system to achieve reconstruction of short track nuclear recoils with good angular resolution. It enables to explore lower mass region of direction-sensitive dark matter searches. We also report about the status of the pixel detector development.

Pseudo-Riemann’s quartics in Finsler’s geometry—two-dimensional case

Finsler’s geometry usually describes an extension of Riemmann’s geometry into a direction-dependent geometric structure. Historically, the well-known Riemann’s quartic length element example served as the inspiration for this construction. Surprisingly, the covariant Fresnel equation—a fundamental dispersion relation in solid-state electrodynamics—emerges as the exact same quartic expression. As a result, Riemann’s quartic length expression can be regarded of as a mathematical representation of a well-known physical phenomenon. In this study, we offer numerous Riemann’s quartic examples that show Finsler’s geometry, even in the situation of a positive definite Euclidean signature space, is too restrictive for many applications. The strong axioms of Finsler’s geometry are violated in a substantially greater number of distinctive subsets for the spaces having an indefinite (Minkowski) signature. We suggest a weaker characterization of Finsler’s structure based on explicitly calculated two-dimensional examples. In tangential vector space, this concept permits singular subsets. Only open subsets of a manifold’s tangent bundle are required to satisfy the strong axioms of Finsler’s geometry. We demonstrate the distinctive unique subsets of the Riemann’s quartic in two dimensions and briefly discuss their possible physical origins.

Identifying Genomic Signatures of Positive Selection to Predict Protective Genomic Loci in the Cohort of Lithuanian Clean-Up Workers of the Chornobyl Nuclear Disaster.

Some people resist or recover from health challenges better than others. We studied Lithuanian clean-up workers of the Chornobyl nuclear disaster (LCWC) who worked in the harshest conditions and, despite high ionising radiation doses as well as other factors, continue ageing relatively healthily. Thus, we hypothesised that there might be individual features encoded by the genome which act protectively for better adaptiveness and health that depend on unique positive selection signatures. Whole-genome sequencing was performed for 40 LCWC and a control group composed of 25 men from the general Lithuanian population (LTU). Selective sweep analysis was performed to identify genomic regions which may be under recent positive selection and determine better adaptiveness. Twenty-two autosomal loci with the highest positive selection signature values were identified. Most important, unique loci under positive selection have been identified in the genomes of the LCWC, which may influence the survival and adaptive qualities to extreme conditions, and the disaster itself. Characterising these loci provide a better understanding of the interaction between ongoing microevolutionary processes, multifactorial traits, and diseases. Studying unique groups of disease-resistant individuals could help create new insights for better, more individualised, disease diagnostics and prevention strategies.

Lefschetz fibrations with arbitrary signature

We develop techniques to construct explicit symplectic Lefschetz fibrations over the 2 -sphere with any prescribed signature \sigma and any spin type when \sigma is divisible by 16 . This solves a long-standing conjecture on the existence of such fibrations with positive signature. As applications, we produce symplectic 4 -manifolds that are homeomorphic but not diffeomorphic to connected sums of S^2 \times S^2 , with the smallest topology known to date, as well as larger examples as symplectic Lefschetz fibrations.

Convergent Genomic Signatures of High-Altitude Adaptation among Six Independently Evolved Mammals.

The species living in the Qinghai-Tibet Plateau provide an excellent model system for studying the relationship between molecular convergent evolution and adaptation. Distant species experiencing the same selection pressure (i.e., hypoxia, low temperature and strong ultraviolet radiation) are likely to evolve similar genetic adaptations independently. Here, we performed comparative genomics studies on six independently evolved high-altitude species. The results also showed that the convergent evolution of the six species was mainly reflected at the level of rapidly evolving genes, and the functions of these rapidly evolving genes were mainly related to hypoxia response and DNA damage repair. In addition, we found that high-altitude species had more gene family changes than their low-altitude relatives, except for the order Lagomorpha. The results also show that the convergence of the gene family contraction of high-altitude species is much greater than that of expansion, revealing a possible pattern of species in adapting to high-altitude. Furthermore, we detected a positive selection signature in four genes related to hypoxia response and ultraviolet radiation damage in these six species (FYCO1, ERBIN, SCAMP1 and CXCL10). Our study reveals that hypoxia response might play an important role in the adaptation of independently evolved species to a high-altitude environment, providing a basic perspective for further exploring the high-altitude adaptation mechanism of different related species in the future.

Unraveling the Heterogeneity of Multiple Myeloma Cells By Single-Cell RNA Sequencing Analysis

Multiple myeloma (MM) is a malignancy of clonal plasma cells with identical variable-diversity-joining (VDJ) region recombination of immunoglobulin loci (called repertoire) and extensive genome or transcriptome heterogeneity. Even though many new treatment modalities have been developed and the prognosis of patients has improved significantly, most cases of MM remain incurable. Recent evidence suggests that non-genetic cell plasticity and changes in cell state underlie the therapy resistance and tumor relapse, but the mechanisms remain largely unknown. Here, we have attempted to understand comprehensive architecture of the entire tumor cell populations using repertoire clonality as fingerprint. First, we subdivided bone marrow samples of primary MM at different stages (n=8) into 11 fractions based on the known surface antigens of MM and performed bulk RNA sequencing (bulk RNA-seq). Analysis of the repertoire revealed that tumor cells were also present in some minor fractions other than the main fraction (Lin-/CD19-/CD38++/CD138+) as the stage progressed. Importantly, cells with clonal repertoire were detected in CD138 negative fraction (Lin-/CD19-/CD38++/CD138-) in most samples (Monoclonal gammopathy of undetermined significance (MGUS) / Smoldering multiple myeloma (SMM) = 4.15±2.28%, Primary MM = 6.78±3.59%, Relapse MM = 7.8±5.82% [mean±95%Cl], n=24). The CD138 positive and negative cells were also morphologically different, suggesting that they were composed by cells of distinct characteristics. Indeed, comparison of the transcriptome data revealed 296 differentially expressed genes (DEGs) between these fractions (250 up-regulated and 46 down-regulated in CD138 negative fractions). Of interest, several pathways related to H3K4 methylation were positively enriched in CD138 negative fraction (p <0.001), which included KMT2A, KMT2B, KMT2C, KMT2D, and ASH1L, suggesting that differential methylation of histone H4 accounts for the heterogeneity of MM. In order to achieve a high-resolution and comprehensive evaluation of the entire tumor cell populations, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ targeted sequencing (scVDJ-seq) concurrently on Lin-/CD38++ sorted cells of 8 bone marrow samples from 7 patients including pre- and post-treatment status samples. This method allowed us to define normal cells and MM cells at the single-cell level by clonal repertoire sequence independent of transcriptome characteristics. We divided 18,031 MM cells into 23 clusters after integration. We first defined CD138 positive and negative MM gene signature using bulk RNA-seq data and then evaluated the scRNA-seq data. Notably, the CD138 axis appeared to clearly subdivide main MM populations into those with CD138 positive and negative MM gene signature. We also found that a part of clusters, which showed CD138 negative MM gene signature, tended to remain at high proportions after treatment. These populations were characterized by low expression levels of MHC class-I components and TNFRSF17/BCMA as well as high expression of MCL1, MALAT1 and NEAT1, which have been previously implicated in treatment resistance, and were present in all samples. H3K4 methylation related genes were also up-regulated in these populations. Furthermore, we found several clusters with unique and interesting characteristics independent of the CD138 axis. Trajectory and velocity analysis suggested that all cell populations transit to each other. Taken together, our results establish the heterogeneity of MM cells by the CD138 axis, which may be characterized by epigenetic plasticity. They also highlight CD138 negative population as a potential cause of treatment resistance and relapse. By using information of repertoire, we have achieved a comprehensive and accurate single-cell analysis of MM cell diversity that was not limited by cell surface antigens or transcriptome characteristics. We are currently analyzing near minimal residual disease (MRD) level samples using the same scRNA-seq methods and the functional and epigenetic properties of CD138 positive and negative MM cells.

Distributions of Platinum Group Elements and Re-Os Isotope Systematics in Chromite from the Coobina Chromitite Deposit in Western Australia: Implications for Chromite as a Sulfide Mineralization Indicator

ABSTRACTThe abundance of Ru in chromite has been suggested as an indicator of sulfide liquid saturation in komatiites. The komatiite magma-derived Archean Coobina intrusion is known to be barren in terms of sulfide mineralization. Therefore, the Coobina intrusion can serve as a useful case study to test the applicability of Ru abundance in chromite as a potential indicator for sulfide mineralization, as well as for better understanding the PGE-chromite association in general.The Coobina intrusion is a highly deformed layered intrusion interpreted to be a flared dike. It contains multiple massive chromitite seams that have been recently mined for metallurgical-grade chromite. In this study, 18 samples from chromitite seams throughout this intrusion are investigated for their whole-rock platinum group element (PGE) contents, which are compared to their chromite mineral chemistry (including PGE content), the platinum group mineral (PGM) mineralogy, and Re-Os isotope systematics. Each sample has a similar chromite major and minor element chemistry, but a unique trace element signature, even within the same seam. In general, there are higher concentrations of Ru (&amp;gt;300 ppb) within chromite in the southeast (toward the feeder dike) and lower concentrations (&amp;lt;50 ppb Ru) in the northwest. At a sample scale, Ru in the whole rock and Ru in solid solution in the chromite are inversely correlated, while Ir shows a positive correlation between the whole rock and chromite mineral chemistry, indicating differing partitioning behaviors within the iridium-group PGE (IPGE = Os, Ir, Ru). The inverse correlation between Ru in solid solution within chromite and Ru in whole-rock chromitite suggests that, for seams with high Ru in whole rock, Ru is occurring within separate PGM phases. This is supported by the observation that the samples with high whole-rock Ru also have a high number of visible metal alloy and/or PGM inclusions. Although these inclusions are not necessarily Ru-rich phases, their presence suggests that there is a preference for these samples to form nuggets, which may restrict Ru partitioning into the chromite crystal structure. We suggest that the low Ru values in the Coobina chromite are a result of transient sulfide saturation. The Re-Os isotopic composition of the Coobina chromitite is chondritic [γ187Os(3.189 Ga) = −0.63 ± 0.21] and is consistent with derivation of the Coobina parental magma from the convecting upper mantle source, providing evidence for the mantle origin of the Coobina PGE inventory.If using chromite as a detrital indicator mineral for magmatic sulfide exploration, it must be kept in mind that transient sulfide saturation within chromitite seams may give a false positive signature.

Population genetic analyses inferred a limited genetic diversity across the pvama-1 DI domain among Plasmodium vivax isolates from Khyber Pakhtunkhwa regions of Pakistan

BackgroundPlasmodium vivax apical membrane antigen-1 (pvama-1) is an important vaccine candidate against Malaria. The genetic composition assessment of pvama-1 from wide-range geography is vital to plan the antigen based vaccine designing against Malaria.MethodsThe blood samples were collected from 84 P. vivax positive malaria patients from different districts of Khyber Pakhtunkhwa (KP) province of Pakistan. The highly polymorphic and immunogenic domain-I (DI) region of pvama-1 was PCR amplified and DNA sequenced. The QC based sequences raw data filtration was done using DNASTAR package. The downstream population genetic analyses were performed using MEGA4, DnaSP, Arlequin v3.5 and Network.5 resources.ResultsThe analyses unveiled total 57 haplotypes of pvama-1 (DI) in KP samples with majorly prevalent H-14 and H-5 haplotypes. Pairwise comparative population genetics analyses identified limited to moderate genetic distinctions among the samples collected from different districts of KP, Pakistan. In context of worldwide available data, the KP samples depicted major genetic differentiation against the Korean samples with Fst = 0.40915 (P-value = 0.0001), while least distinction was observed against Indian and Iranian samples. The statistically significant negative values of Fu and Li’s D* and F* tests indicate the evidence of population expansion and directional positive selection signature. The slow LD decay across the nucleotide distance in KP isolates indicates low nucleotide diversity. In context of reference pvama-1 sequence, the KP samples were identified to have 09 novel non-synonymous single nucleotide polymorphisms (nsSNPs), including several trimorphic and tetramorphic substitutions. Few of these nsSNPs are mapped within the B-cell predicted epitopic motifs of the pvama-1, and possibly modulate the immune response mechanism.ConclusionLow genetic differentiation was observed across the pvama-1 DI among the P. vivax isolates acquired from widespread regions of KP province of Pakistan. The information may implicate in future vaccine designing strategies based on antigenic features of pvama-1.

SIGLEC-1 in Systemic Sclerosis: A Useful Biomarker for Differential Diagnosis.

Systemic Sclerosis (SSc) is a clinically heterogeneous disease that includes an upregulation of type I interferons (IFNs). The aim of this observational study was to investigate the IFN-regulated protein Sialic Acid–Binding Ig-like Lectin 1 (SIGLEC-1) as a biomarker for disease phenotype, therapeutic response, and differential diagnosis in SSc. Levels of SIGLEC-1 expression on monocytes of 203 SSc patients were determined in a cross-sectional and longitudinal analysis using multicolor flow cytometry, then compared to 119 patients with other rheumatic diseases and 13 healthy controls. SSc patients higher SIGLEC-1 expression on monocytes (2097.94 ± 2134.39) than HCs (1167.45 ± 380.93; p = 0.49), but significantly lower levels than SLE (8761.66 ± 8325.74; p < 0.001) and MCTD (6414.50 ± 1846.55; p < 0.001) patients. A positive SIGELC-1 signature was associated with reduced forced expiratory volume (p = 0.007); however, we were unable to find an association with fibrotic or vascular disease manifestations. SIGLEC-1 remained stable over time and was independent of changes in immunosuppressive therapy. However, SIGLEC-1 is suitable for differentiating SSc from other connective tissue diseases. SIGLEC-1 expression on monocytes can be useful in the differential diagnosis of connective tissue disease but not as a biomarker for SSc disease manifestations or activity.

Evolutionary origin of pathogenic GJB2 alleles in China.

The frequency of the pathogenic allele of the autosomal recessive deafness gene GJB2 varies among different populations in the world, and accumulates to a sufficiently high frequency in certain population. The purpose of this study is to investigate the origin and evolution of GJB2 pathogenic alleles in Chinese deaf patients. Children with non-syndromic hearing loss, and their parents, from 295 families were recruited. Customized capture probes targeted at 943 single nucleotide polymorphisms (SNPs) related to GJB2 gene were designed for sequencing of genomic DNA in blood samples. Haplotypes carrying pathogenic allele were analyzed through linkage disequilibrium block building, ancestry tracing, and extended haplotype heterozygosity calculation. Two pathogenic GJB2 alleles, c.235delC (18.41%) and c.109G > A (15.57%), were observed in 867 donors. For c.235delC allele, three different core haplotypes with one major haplotype (97.32%) were found, and their core SNPs were 100% conserved. For c.109G > A allele, six different haplotypes with one major haplotype (93.28%) were found and the major c.109G > A allele evolved from a specific ancestral haplotype. Geographical origins of donors carrying GJB2 c.109G > A and c.235delC core haplotypes centered between Qinghai and Neimenggu. GJB2 c.235delC has long-range linkage disequilibrium. No positive selection signature was found for GJB2 c.235delC or c.109G > A in the studied population. In conclusion, we discovered a single origin of GJB2 c.235delC allele and multiple independent origins of GJB2 c.109G > A allele. Alternative to positive selection or multiple independent recurrent mutation event, population bottleneck effect might account for the observed high population frequency of these pathogenic alleles.

A Two-Stage Siamese Network Model for Offline Handwritten Signature Verification

Offline handwritten signature verification is one of the most prevalent and prominent biometric methods in many application fields. Siamese neural network, which can extract and compare the writers’ style features, proves to be efficient in verifying the offline signature. However, the traditional Siamese neural network fails to represent the writers’ writing style fully and suffers from low performance when the distribution of positive and negative handwritten signature samples is unbalanced. To address this issue, this study proposes a two-stage Siamese neural network model for accurate offline handwritten signature verification with two main ideas: (a) adopting a two-stage Siamese neural network to verify original and enhanced handwritten signatures simultaneously, and (b) utilizing the Focal Loss to deal with the extreme imbalance between positive and negative offline signatures. Experimental results on four challenging handwritten signature datasets with different languages demonstrate that compared with state-of-the-art models, our proposed model achieves better performance. Furthermore, this study tries to extend the proposed model to the Chinese signature dataset in the real environment, which is a significant attempt in the field of Chinese signature identification.