High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for ...only a few non-microbial species
. To address this issue, the international Genome 10K (G10K) consortium
has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.
Estrogens are the key hormones regulating the development and function of reproductive organs in all vertebrates. Recent evidence indicates that estrogens play important roles in the immune system, ...cancer development, and other critical biological processes related to human well-being. Obviously, the gonads (ovary and testis) are the primary sites of estrogen synthesis, but estrogens synthesized in extra- gonadal sites play an equally important role in controlling biological activities. Understanding non-gonadal sites of estrogen synthesis and function is crucial and will lead to therapeutic interventions targeting estrogen signaling in disease prevention and treatment. Developing a rationale targeting strategy remains challenging because knowledge of extra-gonadal biosynthesis of estrogens, and the mechanism by which estrogen activity is exerted, is very limited. In this review, we will summarize recent discoveries of extra-gonadal sites of estrogen biosynthesis and their local functions and discuss the significance of the most recent novel discovery of intestinal estrogen biosynthesis. BMB Reports 2016; 49(9): 488-496
Organic electrochemical transistors (OECTs) are highly attractive for applications ranging from circuit elements and neuromorphic devices to transducers for biological sensing, and the archetypal ...channel material is poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS. The operation of OECTs involves the doping and dedoping of a conjugated polymer due to ion intercalation under the application of a gate voltage. However, the challenge is the trade‐off in morphology for mixed conduction since good electronic charge transport requires a high degree of ordering among PEDOT chains, while efficient ion uptake and volumetric doping necessitates open and loose packing of the polymer chains. Ionic‐liquid‐doped PEDOT:PSS that overcomes this limitation is demonstrated. Ionic‐liquid‐doped OECTs show high transconductance, fast transient response, and high device stability over 3600 switching cycles. The OECTs are further capable of having good ion sensitivity and robust toward physical deformation. These findings pave the way for higher performance bioelectronics and flexible/wearable electronics.
Ionic‐liquid doping in poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) allows good electronic and ionic transport. The ionic liquid induces more closely packed order of PEDOT units and forms fibrillar morphology to enhance its carrier mobility and volumetric capacitance simultaneously. Consequently, ionic‐liquid‐doped organic electrochemical transistors (OECTs) show high transconductance, fast transient response, and high device stability over 3600 switching cycles.
Mouse and human stem cells with features similar to those of embryonic stem cells have been derived from testicular cells. Although pluripotent stem cells have been obtained from defined germline ...stem cells (GSCs) of mouse neonatal testis, only multipotent stem cells have been obtained so far from defined cells of mouse adult testis. In this study we describe a robust and reproducible protocol for obtaining germline-derived pluripotent stem (gPS) cells from adult unipotent GSCs. Pluripotency of gPS cells was confirmed by in vitro and in vivo differentiation, including germ cell contribution and transmission. As determined by clonal analyses, gPS cells indeed originate from unipotent GSCs. We propose that the conversion process requires a GSC culture microenvironment that depends on the initial number of plated GSCs and the length of culture time.
Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene
underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the ...robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.
Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic
germline PV carriers, 25 sporadic
methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.
The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic
carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific
variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10
), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.
Assessment of SBS and ID signatures can discriminate CRCs from biallelic
carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product‐inspired synthetic molecules represent an ecologically and economically ...sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX‐1 inhibitors with nanomolar potency. X‐ray structure analysis reveals the binding of the most selective compound to COX‐1. This molecular design approach provides a blueprint for natural product‐inspired hit and lead identification for drug discovery with machine intelligence.
Machine learning models identify cyclooxygenase (COX) activity of the anticancer marine natural product Marinopyrrole A, and automatically construct potent new COX‐1 inhibitors, taking only the natural product as a design template. Crystallographic analysis reveals a unique binding mode of the computer‐generated COX‐1 inhibitor. This approach can provide a template for future drug design in low‐data scenarios.
Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC ...metabolism in vivo using intraoperative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.
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•Human NSCLC tumors have enhanced glucose oxidation relative to adjacent benign lung•NSCLC tumors oxidize multiple types of nutrients in vivo•Glucose metabolism is heterogeneous within and between human tumors
Preoperative multimodality imaging combined with intraoperative 13C-glucose infusions reveals significant heterogeneity in tumor metabolism between patients and within individual tumors.
Ovulation is preceded by intraovarian inflammatory reactions that occur in response to the preovulatory gonadotropin surge. As a main inflammatory event, leukocytes infiltrate the ovary and release ...proteolytic enzymes that degrade the extracellular matrix weakening the follicular wall, a required step for follicle rupture. This study aimed to quantitatively measure the infiltrating leukocytes, determine their cell types, and localize infiltration sites in the periovulatory rat ovary. Cycling adult and gonadotropin-stimulated immature rats were used as animal models. Ovaries were collected at five different stages of estrous cycle in the adult rats (diestrus, 1700 h; proestrus, 1500 h; proestrus, 2400 h; estrus, 0600 h; and metestrus, 1700 h) and at five different time points after superovulation induction in the immature rats (pregnant mare’s serum gonadotrophin, 0 h; pregnant mare’s serum gonadotrophin, 48 h; human chorionic gonadotropin, 6 h; human chorionic gonadotropin, 12 h; and human chorionic gonadotropin, 24 h). The ovaries were either dissociated into a single cell suspension for flow cytometric analysis or fixed for immunohistochemical localization of the leukocytes. Similar numbers of leukocytes were seen throughout the estrous cycle (∼500,000/ovary), except proestrus 2400 when 2-fold higher numbers of leukocytes were found (∼1.1 million/ovary). A similar trend of periovulatory rise of leukocyte numbers was seen in the superovulation-induced immature rat model, recapitulating a dramatic increase in leukocyte numbers upon gonadotropin stimulation. Both macrophage/granulocytes and lymphocytes were among the infiltrating leukocytes and were localized in the theca and interstitial tissues, where platelet-endothelial cell adhesion molecule-1 and intercellular adhesion molecule-1 may play roles in the transmigration of leukocytes, because their expressions correlates spatiotemporally with the infiltrating leukocytes. In addition, a strong inverse relationship between leukocyte numbers in the ovary and spleen, as well as significant reduction of leukocyte infiltration in the splenectomized rats, were seen, indicating that the spleen may serve as an immediate supplier of leukocytes to the periovulatory ovary.
A comprehensive quantitative measurement of leukocyte infiltration in the ovaries of adult and superovulation-induced immature rats is presented.
ABSTRACT
Volatile elements play a crucial role in the formation of planetary systems. Their abundance and distribution in protoplanetary discs provide vital insights into the connection between ...formation processes and the atmospheric composition of individual planets. Sulfur, being one of the most abundant elements in planet-forming environments, is of great significance, and now observable in exoplanets with JWST. However, planetary formation models currently lack vital knowledge regarding sulfur chemistry in protoplanetary discs. Developing a deeper understanding of the major volatile sulfur carriers in discs is essential to building models that can meaningfully predict planetary atmospheric composition, and reconstruct planetary formation pathways. In this work, we combine archival observations with new data from the Atacama Large sub-Millimeter Array (ALMA) and the Atacama Pathfinder EXperiment (APEX), covering a range of sulfur-bearing species/isotopologs. We interpret this data using the dali thermo-chemical code, for which our model is highly refined and disc-specific. We find that volatile sulfur is heavily depleted from the cosmic value by a factor of ∼1000, with a disc-averaged abundance of S/H ∼ 10−8. We show that the gas-phase sulfur abundance varies radially by ≳3 orders of magnitude, with the highest abundances inside the inner dust ring and coincident with the outer dust ring at r ∼ 150–230 au. Extracting chemical abundances from our models, we find OCS, H2CS, and CS to be the dominant molecular carriers in the gas phase. We also infer the presence of a substantial OCS ice reservoir. We relate our results to the potential atmospheric composition of planets in HD 100546, and the wider exoplanet population.
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