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In the hepatitis B virus (HBV)-related hepatocellular carcinoma tumor microenvironment (TME), monocytes reportedly impede natural T cell functions PD-L1/PD-1 signaling. However, it remains unclear if T cell receptor-redirected T cells (TCR T cells) are similarly inhibited. Hence, we developed a 3D intrahepatic TME microfluidic model to investigate the immunosuppressive potential of monocytes toward HBV-specific TCR T cells and the role of PD-L1/PD-1 signaling. Interestingly, in our 3D static microfluidic model, we observed that monocytes suppressed only retrovirally transduced (Tdx) TCR T cell cytotoxicity toward cancer cells PD-L1/PD-1, while mRNA electroporated (EP) TCR T cell cytotoxicity was not affected by the presence of monocytes. Importantly, when co-cultured in 2D, both Tdx and EP TCR T cell cytotoxicity toward cancer cells were not suppressed by monocytes, suggesting our 3D model as a superior tool compared to standard 2D assays for predicting TCR T cell efficacy in a preclinical setting, which can thus be used to improve current immunotherapy strategies.

Plain language summaries (PLSs) of scientific publications are intended to distill full-length scientific publications into a short, inclusive, accessible format that can be rapidly comprehended by all potential readers, but often retain cultural and linguistic barriers to accessibility, particularly for audiences in the Asia-Pacific region (APAC). Various publications have attempted to provide guidance on how to prepare PLSs, but there have been limited attempts to standardize structure or content and there is no universal guidance for PLSs. Furthermore, PLSs pertaining to research in patient populations in APAC, or relating to conditions that are prevalent in APAC, should be developed using language and imagery appropriate for the intended audience. This commentary aims to outline key considerations for preparing a PLS for an APAC audience, including language, imagery, and font selection. Developing culturally-sensitive PLSs for potential readers in APAC may increase the audience for the scientific literature and assist effective engagement in the region.

Intratumoral recruitment of immune cells following innate immune activation is critical for anti-tumor immunity and involves cytosolic dsDNA sensing by the cGAS/STING pathway. We have previously shown that KRAS-LKB1 (KL) mutant lung cancer, which is resistant to PD-1 blockade, exhibits silencing of STING, impaired tumor cell production of immune chemoattractants, and T cell exclusion. Since the vasculature is also a critical gatekeeper of immune cell infiltration into tumors, we developed a novel microfluidic model to study KL tumor-vascular interactions. Notably, dsDNA priming of LKB1-reconstituted tumor cells activates the microvasculature, even when tumor cell STING is deleted. cGAS-driven extracellular export of 2'3' cGAMP by cancer cells activates STING signaling in endothelial cells and cooperates with type 1 interferon to increase vascular permeability and expression of E selectin, VCAM-1, and ICAM-1 and T cell adhesion to the endothelium. Thus, tumor cell cGAS-STING signaling not only produces T cell chemoattractants, but also primes tumor vasculature for immune cell escape.

Main conclusionSorghumBase provides a community portal that integrates genetic, genomic, and breeding resources for sorghum germplasm improvement.Public research and development in agriculture rely on proper data and resource sharing within stakeholder communities. For plant breeders, agronomists, molecular biologists, geneticists, and bioinformaticians, centralizing desirable data into a user-friendly hub for crop systems is essential for successful collaborations and breakthroughs in germplasm development. Here, we present the SorghumBase web portal (https://www.sorghumbase.org), a resource for the sorghum research community. SorghumBase hosts a wide range of sorghum genomic information in a modular framework, built with open-source software, to provide a sustainable platform. This initial release of SorghumBase includes: (1) five sorghum reference genome assemblies in a pan-genome browser; (2) genetic variant information for natural diversity panels and ethyl methanesulfonate (EMS)-induced mutant populations; (3) search interface and integrated views of various data types; (4) links supporting interconnectivity with other repositories including genebank, QTL, and gene expression databases; and (5) a content management system to support access to community news and training materials. SorghumBase offers sorghum investigators improved data collation and access that will facilitate the growth of a robust research community to support genomics-assisted breeding.

Modern maize ( Zea mays ssp. mays ) was domesticated from Teosinte parviglumis ( Zea mays ssp. parviglumis ), with subsequent introgressions from Teosinte mexicana ( Zea mays ssp. mexicana ), yielding increased kernel row number, loss of the hard fruit case and dissociation from the cob upon maturity, as well as fewer tillers. Molecular approaches have identified transcription factors controlling these traits, yet revealed that a complex regulatory network is at play. MaizeCODE deploys ENCODE strategies to catalog regulatory regions in the maize genome, generating histone modification and transcription factor ChIP-seq in parallel with transcriptomics datasets in 5 tissues of 3 inbred lines which span the phenotypic diversity of maize, as well as the teosinte inbred TIL11. Transcriptomic analysis reveals that pollen grains share features with endosperm, and express dozens of “proto-miRNAs” potential vestiges of gene drive and hybrid incompatibility. Integrated analysis with chromatin modifications results in the identification of a comprehensive set of regulatory regions in each tissue of each inbred, and notably of distal enhancers expressing non-coding enhancer RNAs bi-directionally, reminiscent of “super enhancers” in animal genomes. Furthermore, the morphological traits selected during domestication are recapitulated, both in gene expression and within regulatory regions containing enhancer RNAs, while highlighting the conflict between enhancer activity and silencing of the neighboring transposable elements. MaizeCODE maps active regulatory regions tied to maize domestication traits in a diverse panel of tissues and inbreds. It reveals bi-directional enhancer RNAs and the molecular conflicts between activity and silencing of non-coding regions.

Improvements in long-read data and scaffolding technologies have enabled rapid generation of reference-quality assemblies for complex genomes. Still, an assessment of critical sequence depth and read length is important for allocating limited resources. To this end, we have generated eight assemblies for the complex genome of the maize inbred line NC358 using PacBio datasets ranging from 20 to 75 × genomic depth and with N50 subread lengths of 11–21 kb. Assemblies with ≤30 × depth and N50 subread length of 11 kb are highly fragmented, with even low-copy genic regions showing degradation at 20 × depth. Distinct sequence-quality thresholds are observed for complete assembly of genes, transposable elements, and highly repetitive genomic features such as telomeres, heterochromatic knobs, and centromeres. In addition, we show high-quality optical maps can dramatically improve contiguity in even our most fragmented base assembly. This study provides a useful resource allocation reference to the community as long-read technologies continue to mature. Sequence depth and read length determine the quality of genome assembly. Here, the authors leverage a set of PacBio reads to develop guidelines for sequencing and assembly of complex plant genomes in order to allocate finite resources using maize as an example.

Background Single-nucleotide polymorphisms (SNPs) are the most widely used form of molecular genetic variation studies. As reference genomes and resequencing data sets expand exponentially, tools must be in place to call SNPs at a similar pace. The genome analysis toolkit (GATK) is one of the most widely used SNP calling software tools publicly available, but unfortunately, high-performance computing versions of this tool have yet to become widely available and affordable. Results Here we report an open-source high-performance computing genome variant calling workflow (HPC-GVCW) for GATK that can run on multiple computing platforms from supercomputers to desktop machines. We benchmarked HPC-GVCW on multiple crop species for performance and accuracy with comparable results with previously published reports (using GATK alone). Finally, we used HPC-GVCW in production mode to call SNPs on a “subpopulation aware” 16-genome rice reference panel with ~ 3000 resequenced rice accessions. The entire process took ~ 16 weeks and resulted in the identification of an average of 27.3 M SNPs/genome and the discovery of ~ 2.3 million novel SNPs that were not present in the flagship reference genome for rice (i.e., IRGSP RefSeq). Conclusions This study developed an open-source pipeline (HPC-GVCW) to run GATK on HPC platforms, which significantly improved the speed at which SNPs can be called. The workflow is widely applicable as demonstrated successfully for four major crop species with genomes ranging in size from 400 Mb to 2.4 Gb. Using HPC-GVCW in production mode to call SNPs on a 25 multi-crop-reference genome data set produced over 1.1 billion SNPs that were publicly released for functional and breeding studies. For rice, many novel SNPs were identified and were found to reside within genes and open chromatin regions that are predicted to have functional consequences. Combined, our results demonstrate the usefulness of combining a high-performance SNP calling architecture solution with a subpopulation-aware reference genome panel for rapid SNP discovery and public deployment.

A major advancement in the field of medicine has been the introduction and usage of direct oral anticoagulants (DOACs) such as dabigatran (Pradaxa), apixaban (Eliquis), and rivaroxaban (Xarelto). DOACs have been increasing in popularity for mainstay anticoagulation pharmacotherapy and are being preferred by physicians over warfarin due to their rapid onset, fewer drug and food interactions, and lack of frequent blood monitoring. DOACs have been indicated in the management of thromboembolic conditions and have been extensively researched in various medical trials and studies before the approval of dabigatran (Pradaxa) in 2010 by the FDA. DOACs, like warfarin, are associated with a risk of bleeding, requiring clearance of the drug from the bloodstream or administration of reversal agents. It is important for physicians to familiarize themselves with the various types of DOACs and their dosages, along with their advantages and disadvantages in comparison to other non-DAOC classes of medications before incorporating them into their patient management plans.

The maintenance of precise cell volume is critical for cell survival. Changes in extracellular osmolarity affect cell volume and may impact various cellular processes such as mitosis, mitochondrial functions, DNA repair as well as cell migration and proliferation. Much of what we know about the mechanisms of cell osmoregulation comes from in vitro two-dimensional (2D) assays that are less physiologically relevant than three-dimensional (3D) in vitro or in vivo settings. Here, we developed a microfluidic model to study the impact of hyper-osmotic stress on the migration, proliferation and ion channel/transporter expression changes of three metastatic cell lines (MDA-MB-231, A549, T24) in 2D versus 3D environments. We observed a global decrease in cell migration and proliferation upon hyper-osmotic stress treatment, with similar responses between 2D and 3D conditions. Specific ion channels/aquaporins are over-expressed in metastatic cells and play a central role during osmo-regulation. Therefore, the effects of hyper-osmotic stress on two transporters, aquaporin 5 (AQP5) and the transient receptor potential cation channel (TRPV4), was investigated. While hyper-osmotic stress had no major impact on the transporters of cells cultured in 2D, cells embedded in collagen gel (3D) decreased their AQP5 expression and exhibited a reduction in intra-cellular translocation of TRPV4. Furthermore, cell dispersion from T24 aggregates embedded in 3D collagen gel decreased with higher levels of hyper-osmotic stress. In conclusion, this study provides evidence on the impact of hyper-osmotic stress on various aspects of metastatic cell progression and highlights the importance of having a 3D cell culture platform in investigating molecular players involved in cancer cell migration.