XOL-1 regulates developmental timing by modulating the H3K9 landscape in C. elegans early embryos.

Sex determination in the nematode C. elegans is controlled by the master regulator XOL-1 during embryogenesis. Expression of xol-1 is dependent on the ratio of X chromosomes and autosomes, which differs between XX hermaphrodites and XO males.

The 4.2 ka event is not remarkable in the context of Holocene climate variability.

The "4.2 ka event" is a commonly described abrupt climate excursion that occurred about 4200 years ago. However, the extent to which this event is coherent across regional and larger scales is unclear.

Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human induced pluripotent stem cells (iPSCs) to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity.

Induced pluripotent stem cell-derived engineered T cells, natural killer cells, macrophages, and dendritic cells in immunotherapy.

T cells, natural killer (NK) cells, macrophages (Macs), and dendritic cells (DCs) are among the most common sources for immune-cell-based therapies for cancer. Antitumor activity can be enhanced in induced pluripotent stem cell (iPSC)-derived immune cells by using iPSCs as a platform for stable genetic modifications that impact immuno-activating or -suppressive signaling pathways, such as transducing a chimeric antigen receptor (CAR) or deletion of immunosuppressive checkpoint molecules. This review outlines the utility of four iPSC-derived immune-cell-based therapies, highlight the latest progress and future trends in the genome-editing strategies designed to improve efficacy, safety, and universality, and provides perspectives that compare different contexts in which each of these iPSC-derived immune cell types can be most effectively used.

Revisiting the Holocene global temperature conundrum.

Recent global temperature reconstructions for the current interglacial period (the Holocene, beginning 11,700 years ago) have generated contrasting trends. This Review examines evidence from indicators and drivers of global change, as inferred from proxy records and simulated by climate models, to evaluate whether anthropogenic global warming was preceded by a long-term warming trend or by global cooling. Multimillennial-scale cooling before industrialization requires extra climate forcing and major climate feedbacks that are not well represented in most climate models at present.

CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.

Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model.

iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting.

Treatment of cancer with allogeneic natural killer (NK) cell therapies has seen rapid development, especially use against hematologic malignancies. Clinical trials of NK cell-based adoptive transfer to treat relapsed or refractory malignancies have used peripheral blood, umbilical cord blood and pluripotent stem cell-derived NK cells, with each approach undergoing continued clinical development. Improving the potency of these therapies relies on genetic modifications to improve tumor targeting and to enhance expansion and persistence of the NK cells.

Disease-associated mutations in topoisomerase IIβ result in defective NK cells.

Background: Hoffman syndrome is a syndromic, inborn error of immunity due to autosomal-dominant mutations in TOP2B, an essential gene required to alleviate topological stress during DNA replication and gene transcription. Although mutations identified in patients lead to a block in B-cell development and the absence of circulating B cells, an effect on natural killer (NK) cells was not previously examined.

Objective: We sought to determine whether disease-associated mutations in TOP2B impact NK-cell development and function.

Into the multiverse of gene edited NK cell-based therapeutic strategies.

In this issue of Cell Stem Cell, Woan et al., (2021) investigate the anti-cancer activity of triple gene edited iPSC-derived natural killer (NK) cells and demonstrate that expression of a modified CD16a and interleukin (IL)-15 receptor combined with knockout of CD38 improves NK cell-mediated activity against leukemia and multiple myeloma.

Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis.

With an increasing number of patients with degenerative hepatic diseases, such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol.

Native biodiversity collapse in the eastern Mediterranean.

Global warming causes the poleward shift of the trailing edges of marine ectotherm species distributions. In the semi-enclosed Mediterranean Sea, continental masses and oceanographic barriers do not allow natural connectivity with thermophilic species pools: as trailing edges retreat, a net diversity loss occurs. We quantify this loss on the Israeli shelf, among the warmest areas in the Mediterranean, by comparing current native molluscan richness with the historical one obtained from surficial death assemblages.

Coupled impacts of sea ice variability and North Pacific atmospheric circulation on Holocene hydroclimate in Arctic Alaska.

Arctic Alaska lies at a climatological crossroads between the Arctic and North Pacific Oceans. The modern hydroclimate of the region is responding to rapidly diminishing sea ice, driven in part by changes in heat flux from the North Pacific. Paleoclimate reconstructions have improved our knowledge of Alaska's hydroclimate, but no studies have examined Holocene sea ice, moisture, and ocean-atmosphere circulation in Arctic Alaska, limiting our understanding of the relationship between these phenomena in the past.

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles.

Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56 NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34 hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs).

iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy.

The development of immunotherapeutic monoclonal antibodies targeting checkpoint inhibitory receptors, such as programmed cell death 1 (PD-1), or their ligands, such as PD-L1, has transformed the oncology landscape. However, durable tumor regression is limited to a minority of patients. Therefore, combining immunotherapies with those targeting checkpoint inhibitory receptors is a promising strategy to bolster antitumor responses and improve response rates.

Review of radiographic findings in COVID-19.

The purpose of this study is to review the published literature for the range of radiographic findings present in patients suffering from coronavirus disease 2019 infection. This novel corona virus is currently the cause of a worldwide pandemic. Pulmonary symptoms and signs dominate the clinical picture and radiologists are called upon to evaluate chest radiographs (CXR) and computed tomography (CT) images to assess for infiltrates and to define their extent, distribution and progression.

Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity.

Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer (NK) cells. Here, we develop human CISH-knockout (CISH) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH iPSC-NK cells demonstrate increased IL-15-mediated JAK-STAT signaling activity.

Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals the FGF1-RUNX2 association in neural crest-derived osteoprogenitors.

Human pluripotent stem cells (hPSCs) can provide a platform to model bone organogenesis and disease. To reflect the developmental process of the human skeleton, hPSC differentiation methods should include osteogenic progenitors (OPs) arising from three distinct embryonic lineages: the paraxial mesoderm, lateral plate mesoderm, and neural crest. Although OP differentiation protocols have been developed, the lineage from which they are derived, as well as characterization of their genetic and molecular differences, has not been well reported.

Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity.

Antibody-dependent cellular cytotoxicity (ADCC) is a key effector mechanism of natural killer (NK) cells that is mediated by therapeutic monoclonal antibodies (mAbs). This process is facilitated by the Fc receptor CD16a on human NK cells. CD16a appears to be the only activating receptor on NK cells that is cleaved by the metalloprotease a disintegrin and metalloproteinase-17 upon stimulation.

Outcomes and Cost-Effectiveness of Autologous Hematopoietic Cell Transplant for Multiple Sclerosis.

Purpose Of Review: This review presents a critical appraisal of the use of autologous hematopoietic cell transplant (AHCT) for the treatment of multiple sclerosis. We present the reader with a brief review on the AHCT procedure, its immunomodulatory mechanism of action in MS, the most recent evidence in support of its use in patients with relapsing-remitting multiple sclerosis (RRMS), as well as its cost considerations.

Recent Findings: The first meta-analysis of clinical trials of AHCT for patients with MS demonstrated durable 5-year progression-free survival rates and low treatment-related mortality.

Engineered human pluripotent stem cell-derived natural killer cells: the next frontier for cancer immunotherapy.

Adoptive immunotherapy using immune effector cells has revolutionized cancer treatments with approval of two autologous chimeric antigen receptor (CAR) T cell therapies by the US FDA. Clinical trials using natural killer (NK) cell-based adoptive immunotherapy have been shown to be safe and effective for treatment of multiple malignancies, especially acute myelogenous leukemia. However, most of these trails use primary NK cells isolated from peripheral or cord blood which can have donor-dependent variability and can be challenging to genetic engineer to improve antitumor functions, limiting the widespread use of this promising new therapy.

An Improved Method to Produce Clinical-Scale Natural Killer Cells from Human Pluripotent Stem Cells.

Human natural killer (NK) cell-based adoptive anticancer immunotherapy has gained intense interest with many clinical trials actively recruiting patients to treat a variety of both hematological malignancies and solid tumors. Most of these trials use primary NK cells isolated either from peripheral blood (PB-NK cells) or umbilical cord blood (UCB-NK cells), though these sources require NK cell collection for each patient leading to donor variability and heterogeneity in the NK cell populations. In contrast, NK cells derived human embryonic stem cells (hESC-NK cells) or induced pluripotent stem cells (hiPSC-NK cells) provide more homogeneous cell populations that can be grown at clinical scale, and genetically engineered if needed.

A decline in molluscan carbonate production driven by the loss of vegetated habitats encoded in the Holocene sedimentary record of the Gulf of Trieste.

Carbonate sediments in non-vegetated habitats on the north-east Adriatic shelf are dominated by shells of molluscs. However, the rate of carbonate molluscan production prior to the 20th century eutrophication and overfishing on this and other shelves remains unknown because: (i) monitoring of ecosystems prior to the 20th century was scarce; and (ii) ecosystem history inferred from cores is masked by condensation and mixing. Here, based on geochronological dating of four bivalve species, carbonate production during the Holocene is assessed in the Gulf of Trieste, where algal and seagrass habitats underwent a major decline during the 20th century.