The TEX86 proxy, based on the distribution of marine isoprenoidal glycerol dialkyl glycerol tetraether lipids (GDGTs), is increasingly used to reconstruct sea surface temperature (SST) during the ...Eocene epoch (56.0–33.9 Ma). Here we compile published TEX86 records, critically reevaluate them in light of new understandings in TEX86 palaeothermometry, and supplement them with new data in order to evaluate long‐term temperature trends in the Eocene. We investigate the effect of archaea other than marine Thaumarchaeota upon TEX86 values using the branched‐to‐isoprenoid tetraether index (BIT), the abundance of GDGT‐0 relative to crenarchaeol (%GDGT‐0), and the Methane Index (MI). We also introduce a new ratio, %GDGTRS, which may help identify Red Sea‐type GDGT distributions in the geological record. Using the offset between TEX86H and TEX86L (ΔH‐L) and the ratio between GDGT‐2 and GDGT‐3 (2/3), we evaluate different TEX86 calibrations and present the first integrated SST compilation for the Eocene (55 to 34 Ma). Although the available data are still sparse some geographic trends can now be resolved. In the high latitudes (>55°), there was substantial cooling during the Eocene (~6°C). Our compiled record also indicates tropical cooling of ~2.5°C during the same interval. Using an ensemble of climate model simulations that span the Eocene, our results indicate that only a small percentage (~10%) of the reconstructed temperature change can be ascribed to ocean gateway reorganization or paleogeographic change. Collectively, this indicates that atmospheric carbon dioxide (pCO2) was the likely driver of surface water cooling during the descent toward the icehouse.
Key Points
Archaea other than marine Thaumarchaeota exert a minimal impact on most Eocene temperatures
Tropical and high‐latitude cooling during the descent towards the icehouse
Carbon dioxide is the most likely driver of long‐term Eocene cooling
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The human stomach contains two primary domains: the corpus, which contains the fundic epithelium, and the antrum. Each of these domains has distinct cell types and functions, and therefore each ...presents with unique disease pathologies. Here, we detail two protocols to differentiate human pluripotent stem cells (hPSCs) into human gastric organoids (hGOs) that recapitulate both domains. Both protocols begin with the differentiation of hPSCs into definitive endoderm (DE) using activin A, followed by the generation of free-floating 3D posterior foregut spheroids using FGF4, Wnt pathway agonist CHIR99021 (CHIR), BMP pathway antagonist Noggin, and retinoic acid. Embedding spheroids in Matrigel and continuing 3D growth in epidermal growth factor (EGF)-containing medium for 4 weeks results in antral hGOs (hAGOs). To obtain fundic hGOs (hFGOs), spheroids are additionally treated with CHIR and FGF10. Induced differentiation of acid-secreting parietal cells in hFGOs requires temporal treatment of BMP4 and the MEK inhibitor PD0325901 for 48 h on protocol day 30. In total, it takes ~34 d to generate hGOs from hPSCs. To date, this is the only approach that generates functional human differentiated gastric cells de novo from hPSCs.
Plasmon-coupled circular dichroism has emerged as a promising approach for ultrasensitive detection of biomolecular conformations through coupling between molecular chirality and surface plasmons. ...Chiral nanoparticle assemblies without chiral molecules present also have large optical activities. We apply single-particle circular differential scattering spectroscopy coupled with electron imaging and simulations to identify both structural chirality of plasmonic aggregates and plasmon-coupled circular dichroism induced by chiral proteins. We establish that both chiral aggregates and just a few proteins in interparticle gaps of achiral assemblies are responsible for the ensemble signal, but single nanoparticles do not contribute. We furthermore find that the protein plays two roles: It transfers chirality to both chiral and achiral plasmonic substrates, and it is also responsible for the chiral three-dimensional assembly of nanorods. Understanding these underlying factors paves the way toward sensing the chirality of single biomolecules.
Sex differences in the incidence and outcome of human disease are broadly recognized but, in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma ...(GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging-based measure of response, we found that standard therapy is more effective in female compared with male patients with GBM. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical relevance of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together, these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms.
There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about ...the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen‐specific T cell responses and long‐lived antitumor responses capable of combating ...metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first‐generation clinical cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well‐engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technology that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnology for increasing the immunogenicity of the tumor microenvironment (TME), which is critical to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.
Graphical
Describes how rationally engineered materials are opening up new opportunities for enhancing the immunogenicity and therapeutic efficacy of cancer vaccines.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Despite the global prevalence of gastric disease, there are few adequate models in which to study the fundus epithelium of the human stomach. We differentiated human pluripotent stem cells (hPSCs) ...into gastric organoids containing fundic epithelium by first identifying and then recapitulating key events in embryonic fundus development. We found that disruption of Wnt/β-catenin signalling in mouse embryos led to conversion of fundic to antral epithelium, and that β-catenin activation in hPSC-derived foregut progenitors promoted the development of human fundic-type gastric organoids (hFGOs). We then used hFGOs to identify temporally distinct roles for multiple signalling pathways in epithelial morphogenesis and differentiation of fundic cell types, including chief cells and functional parietal cells. hFGOs are a powerful model for studying the development of the human fundus and the molecular bases of human gastric physiology and pathophysiology, and also represent a new platform for drug discovery.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Approaches towards habitat conservation and restoration often include supplementing or enhancing existing, degraded, or lost natural habitats. In aquatic environments, a popular approach towards ...habitat enhancement is the introduction of underwater human-made structures or artificial reefs. Despite the nearly global prevalence of artificial reefs deployed to enhance habitat, it remains debated whether these structures function similarly to comparable natural reefs. To help resolve this question, we conducted a literature review and accompanying meta-analysis of fish community metrics on artificial reefs within the coastal ocean and made comparisons with naturally-occurring reference reefs (rocky reefs and coral reefs). Our findings from a synthesis of 39 relevant studies revealed that, across reef ecosystems, artificial reefs support comparable levels of fish density, biomass, species richness, and diversity to natural reefs. Additional analyses demonstrated that nuances in these patterns were associated with the geographic setting (ocean basin, latitude zone) and artificial reef material. These findings suggest that, while artificial reefs can mimic natural reefs in terms of the fish assemblages they support, artificial reefs are not one-size-fits-all tools for habitat enhancement. Instead, artificial reefs should be considered strategically based on location-specific scientific assessments and resource needs to maximize benefits of habitat enhancement.
Tomato Atypical Receptor Kinase 1 (TARK1) is a pseudokinase required for postinvasion immunity. TARK1 was originally identified as a target of the
effector protein
outer protein N (XopN), a ...suppressor of early defense signaling. How TARK1 participates in immune signal transduction is not well understood. To gain insight into TARK1's role in tomato (
) immunity, we used a proteomics approach to isolate and identify TARK1-associated immune complexes formed during infection. We found that TARK1 interacts with proteins predicted to be associated with stomatal movement. TARK1 CRISPR mutants and overexpression (OE) lines did not display differences in light-induced stomatal opening or abscisic acid-induced stomatal closure; however, they did show altered stomatal movement responses to bacteria and biotic elicitors. Notably, we found that TARK1 CRISPR plants were resistant to
pathovar tomato strain DC3000-induced stomatal reopening, and TARK1 OE plants were insensitive to
pathovar tomato strain DC3118 (coronatine deficit)-induced stomatal closure. We also found that TARK1 OE in leaves resulted in increased susceptibility to bacterial invasion. Collectively, our results indicate that TARK1 functions in stomatal movement only in response to biotic elicitors and support a model in which TARK1 regulates stomatal opening postelicitation.
In this paper, we review the TEX86 palaeothermometer for sea surface temperature (SST) and evaluate its application to the Palaeogene, with a focus on the principal ecological, physical or chemical ...processes that can bias glycerol dialkyl glycerol tetraether (GDGT) distributions. Recent investigations of Palaeogene sediments have revealed temperature offsets between two different GDGT-based approaches, TEX86L and TEX86H, with the former agreeing with SST estimates derived from inorganic proxies (Hollis et al., 2012). These are surprising observations because the two GDGT approaches, although based on two distinct groups of compounds, apparently agree at SSTs>15°C in modern oceans. Here we reassess the relationship between raw GDGT distributions and the ratios used to construct TEX86H and TEX86 in both the modern core-top dataset and a new compilation of Palaeogene data. We show that the offset between TEX86H and TEX86L (ΔH–L) is a function of the GDGT-2/GDGT-3 ratio (2/3 ratio), and that this can be used to separate low- and high-latitude GDGT distributions in the modern core-top dataset: a range of 2/3 ratios and ΔH–L values occur in polar regions, whereas 2/3 ratios are high and ΔH–L values are small at temperatures >15°C. However, in the Palaeogene dataset, we observe a wide range of 2/3 ratios, even for SST estimates above 15°C. Crucially, we find that water depth is a better discriminator of ΔH–L values and 2/3 ratios than SST in the combined modern and Palaeogene dataset: ΔH–L values are low (<3.0°C) and 2/3 ratios are high (>5.0) where water depth is >1000m.
Modern water column studies show that the 2/3 ratios in suspended particulate matter (SPM) increase with depth, suggesting that high 2/3 ratios reflect a contribution from Archaea living in the deeper water column. This suggests that export dynamics influence GDGT-derived SST estimates. We argue for new approaches to SST reconstruction: 1) continued use of core-top calibrations, in which export dynamics have been implicitly incorporated into the current core-top calibration datasets, but with the influence of water depth taken into account; and 2) use of SPM or mesocosm-based calibrations, with water depth and palaeo-export dynamics independently assessed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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