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Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Abstract Bacterial death is critical in nutrient recycling. However, the underlying mechanisms that permit macromolecule recycling after bacterial death are largely unknown. We demonstrate that bacteria encode post-mortem protein catabolism via Lon protease released from the dead bacteria. Growth assays reveal that the lysate of Lon protease-null bacteria does not provide a growth benefit to wild type cells. This deficiency is reversed with exogenous recombinant Lon protease, confirming its post-mortem role and is independent of Lon ATPase activity. Biochemistry, growth assays and metabolomics demonstrate that Lon protease facilitates peptide nutrient release, benefitting living cells and acting as a cooperative public good. We also show that the production of Lon protease cannot be explained by a personal benefit to living cells. Although Lon protease can also provide a benefit to living cells under stressful conditions by helping control protein quality, this private benefit does not outweigh the cost under the conditions examined. These results suggest that Lon protease represents a post-mortem adaptation that can potentially be explained by considering the post-mortem indirect benefit to other cells (kin selection). This discovery highlights an unexpected post-mortem biochemistry, reshaping our understanding of nutrient recycling.

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length due to the lack of high-throughput method with nucleotide resolution for individual telomere. Here, we describe a workflow to capture telomeres using newly designed telobaits in human culture cell lines as well as clinical patient samples and measure their length accurately at nucleotide resolution using single-molecule real-time (SMRT) sequencing. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that are dispersed throughout the telomere repeat region. The presence of TVSs disrupts the continuity of the canonical (5'-TTAGGG-3')n telomere repeats, which affects the binding of shelterin complexes at the chromosomal ends and telomere protection. These findings may have profound implications in human aging and diseases.

Abstract Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.

The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.

Cold stimuli and the subsequent activation of β-adrenergic receptor (β-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the β3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the β-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

Vaccination and infection history determine the breadth of neutralizing antibody response to SARS-CoV-2 variants and other sarbecoviruses with breakthrough or natural infection combined with vaccination or booster vaccination with mRNA vaccine providing highest neutralization.

Efficient and broadband visible-light photodetectors will bring great advantages in applications such as biosensing and quantum information. Here the authors develop a photodetector with high quantum efficiency across broad wavelength range suitable for monolithic integration in photonics circuits.

SARS-CoV-2 variants of concern such as the Omicron variant pose a challenge for vaccination and antibody immunotherapy. Here, Zhou et al. isolate a broadly neutralizing antibody (bNAb), named ZCB11, that protects Golden Syrian hamsters against Omicron. Applying CryoEM the authors show that ZCB11 heavy chain predominantly interacts with RBD in up confirmation, which interferes with ACE2 receptor binding.

Bacterial death is critical in nutrient recycling. However, the underlying mechanisms that permit macromolecule recycling after bacterial death are largely unknown. We demonstrate that bacteria encode post-mortem protein catabolism via Lon protease released from the dead bacteria. Growth assays reveal that the lysate of Lon protease-null bacteria does not provide a growth benefit to wild type cells. This deficiency is reversed with exogenous recombinant Lon protease, confirming its post-mortem role and is independent of Lon ATPase activity. Biochemistry, growth assays and metabolomics demonstrate that Lon protease facilitates peptide nutrient release, benefitting living cells and acting as a cooperative public good. We also show that the production of Lon protease cannot be explained by a personal benefit to living cells. Although Lon protease can also provide a benefit to living cells under stressful conditions by helping control protein quality, this private benefit does not outweigh the cost under the conditions examined. These results suggest that Lon protease represents a post-mortem adaptation that can potentially be explained by considering the post-mortem indirect benefit to other cells (kin selection). This discovery highlights an unexpected post-mortem biochemistry, reshaping our understanding of nutrient recycling. Processes that occur after death have not received the same level of attention as the mechanisms of life. In this study, the authors show that bacteria have potentially evolved an altruistic trait to auto-degrade after death, thus permitting population nutrient recycling. [ABSTRACT FROM AUTHOR]

The feasibility of carbon mineralization relies on the carbonation efficiency of CO2-reactive minerals, which is largely governed by the water content and state within material mesopores. Yet, the pivotal role of confined water in regulating carbonation efficiency at the nanoscale is not well understood. Here, we show that the maximum CO2 intake occurs at an optimal relative humidity (RHopt) when capillary condensation initiates within the hydrophilic mesopores. At this transition state, the pore becomes filled with metastable low-density water, providing an ideal docking site for CO2 adsorption and forming a mixed metastable state of water/CO2. We prove that RHopt depends on the mesopore size through a Kelvin-like relationship, which yields a robust engineering model to predict RHopt for realistic mineral carbonation. Building upon classical theories of phase transition in hydrophilic mesopores, this study unveils the capacity of the metastable water in CO2 intake and enhances the high-efficiency carbon mineralization with natural ore and industrial wastes in real-world applications. CO2 can be captured in mesoporous alkaline waste materials. Here the authors provide atomistic insight for CO2 adsorption in calcium hydroxide to identify optimal relative humidity conditions for maximum CO2 intake. [ABSTRACT FROM AUTHOR]

The antibody response of children to SARS-CoV-2 is less well studied than in adults. Here Hachim et al. show that children have reduced antibody levels to structural proteins and suggest that the predominance of antibody responses to non-structural proteins can be used to discriminate infection and vaccination.

Although extrapulmonary complications of different organ systems are recognized in patients with severe COVID19 effects are less well studied. Here, Qiao et al. characterize the pathogenesis of SARS-CoV-2 on bone metabolism in Syrian hamster and find that bone loss is associated with virus-mediated cytokine dysregulation.

Association of mRNA translation with the mitotic spindle is thought to be involved in localized production of cell fate determinants. Here, the authors show Vasa facilitates asymmetric translation, which contributes to differential regulation during sea urchin embryogenesis.

The prognosis of high-risk neuroblastoma is poor despite the availability of multimodal treatment. Here the authors show that high-risk neuroblastoma is sensitive to indisulam, a selective degrader of the splicing factor RBM39 through the dual targeting of RNA splicing and metabolism.

Ultrathin transition metal dichalcogenides (TMDs) hold promise for next-generation lightweight photovoltaics. Here, the authors demonstrate the first flexible high power-per-weight TMD solar cells with notably improved power conversion efficiency.

SHP2 promotes RAS-driven MAPK signalling, but it is unclear why cancer cells with distinct KRAS mutations exhibit differential sensitivity to SHP2 inhibition. Here the authors show that KRAS Q61H is decoupled from SHP2- mediated upstream regulation, thus Q61H pancreatic cancer cells maintain MAPK signalling and are refractory to SHP2 inhibitors.

Endogenous ACE2 is a receptor for SARS-CoV-2 and a recombinant soluble ACE2 protein can inhibit SARS-CoV-2 infection acting as a decoy. Here the authors show that B38-CAP, an ACE2-like enzyme but not a decoy for the virus, is protective against SARS-CoV-2-induced lung injury in animal models.

We know that air-water interfaces can generically inactivate viruses, but the mechanisms behind this observation are unclear. Here the authors use simulations to uncover those mechanisms and find that the electrostatic repulsive free energy of an RNA virus increases by several thousands of kBT as it approaches an air-water interface, providing a mechanism for viral destabilization which may induce inactivation.

Why children are generally less susceptible than adults to COVID-19 is unclear and has not extensively been examined longitudinally. Here the authors compare antibodies, cytokines and immune cell responses in adults and children over 6 months post-infection showing, among other things, a reduced CD4+ and CD8+ T cell response in children.

Dietary extracellular vesicles (EVs) could potentially be absorbed by the intestinal tract of the host and exert multiple phenotypic changes. Here, the authors isolate and characterize EVs from raw and commercial bovine milk and show orally administered EVs to have a context specific role in promoting or suppressing primary tumor growth and metastasis in multiple mouse tumor models.

Circulating tumour DNA (ctDNA) represents a non-invasive option to monitor cancer progression. Here, the authors perform deep sequencing of plasma cell-free DNA, and find that nucleosome-dependent cfDNA degradation at 6 specific regulatory regions is predictive of ctDNA burden.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

This study integrates Alzheimer’s disease (AD) GWAS data with myeloid cell genomics, and reports that myeloid active enhancers are most burdened by AD risk alleles. The authors also nominate candidate causal regulatory elements, variants and genes that likely modulate the risk for AD.