Measurements of 21 cm Epoch of Reionization (EoR) structure are subject to systematics originating from both the analysis and the observation conditions. Using 2013 data from the Murchison Widefield ...Array (MWA), we show the importance of mitigating both sources of contamination. A direct comparison between results from Beardsley et al. and our updated analysis demonstrates new precision techniques, lowering analysis systematics by a factor of 2.8 in power. We then further lower systematics by excising observations contaminated by ultra-faint RFI, reducing by an additional factor of 3.8 in power for the zenith pointing. With this enhanced analysis precision and newly developed RFI mitigation, we calculate a noise-dominated upper limit on the EoR structure of Δ2 ≤ 3.9 × 103 mK2 at k = 0.20 h Mpc−1 and z = 7 using 21 hr of data, improving previous MWA limits by almost an order of magnitude.
The compact configuration of Phase II of the Murchison Widefield Array (MWA) consists of both a redundant subarray and pseudo-random baselines, offering unique opportunities to perform sky-model and ...redundant interferometric calibration. The highly redundant hexagonal cores give improved power spectrum sensitivity. In this paper, we present the analysis of nearly 40 hr of data targeting one of the MWA's epoch of reionization (EoR) fields observed in 2016. We use both improved analysis techniques presented in Barry et al. and several additional techniques developed for this work, including data quality control methods and interferometric calibration approaches. We show the EoR power spectrum limits at redshift 6.5, 6.8, and 7.1 based on our deep analysis on this 40 hr data set. These limits span a range in k-space of 0.18 h Mpc−1 < k < 1.6 h Mpc−1, with a lowest measurement of Δ2 ≤ 2.39 × 103 mK2 at k = 0.59 h Mpc−1 and z = 6.5.
Age‐related loss of cellular function and increased cell death are characteristic hallmarks of aging. While defects in gene expression and RNA metabolism have been linked with age‐associated human ...neuropathies, it is not clear how the changes that occur in aging neurons contribute to loss of gene expression homeostasis. R‐loops are RNA–DNA hybrids that typically form co‐transcriptionally via annealing of the nascent RNA to the template DNA strand, displacing the non‐template DNA strand. Dysregulation of R‐loop homeostasis has been associated with both transcriptional impairment and genome instability. Importantly, a growing body of evidence links R‐loop accumulation with cellular dysfunction, increased cell death, and chronic disease onset. Here, we characterized the R‐loop landscape in aging Drosophila melanogaster photoreceptor neurons and showed that bulk R‐loop levels increased with age. Further, genome‐wide mapping of R‐loops revealed that transcribed genes accumulated R‐loops over gene bodies during aging, which correlated with decreased expression of long and highly expressed genes. Importantly, while photoreceptor‐specific down‐regulation of Top3β, a DNA/RNA topoisomerase associated with R‐loop resolution, lead to decreased visual function, over‐expression of Top3β or nuclear‐localized RNase H1, which resolves R‐loops, enhanced positive light response during aging. Together, our studies highlight the functional link between dysregulation of R‐loop homeostasis, gene expression, and visual function during aging.
Here, we show that Drosophila photoreceptor neurons accumulated R‐loops during aging specifically across gene bodies of long and highly expressed genes. Moreover, over‐expression of enzymes that modulate R‐loop levels in the eyes enhanced visual response in flies during aging. Our data thus highlight the importance of proper R‐loop levels in the maintenance of gene expression and neuronal function during aging.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Willingness to lay down one's life for a group of non-kin, well documented historically and ethnographically, represents an evolutionary puzzle. Building on research in social psychology, we develop ...a mathematical model showing how conditioning cooperation on previous shared experience can allow individually costly pro-group behavior to evolve. The model generates a series of predictions that we then test empirically in a range of special sample populations (including military veterans, college fraternity/sorority members, football fans, martial arts practitioners, and twins). Our empirical results show that sharing painful experiences produces "identity fusion" - a visceral sense of oneness - which in turn can motivate self-sacrifice, including willingness to fight and die for the group. Practically, our account of how shared dysphoric experiences produce identity fusion helps us better understand such pressing social issues as suicide terrorism, holy wars, sectarian violence, gang-related violence, and other forms of intergroup conflict.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration–approved drug for ...treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells. NOTCH2 and c-MYC gene expression positively correlated with AR expression in samples from patient with hormone refractory disease in which AR expression levels correspond to those typically observed in enzalutamide resistance. Cleaved NOTCH1, HES1 (Hes family BHLH transcription factor 1), and c-MYC protein expression levels are elevated in two enzalutamide-resistant cell lines, MR49F and C4-2R, indicating NOTCH signaling activation. Moreover, inhibition of the overexpressed ADAM metallopeptidase domain 10 (ADAM10) in the resistant cells induces an exclusive reduction in cleaved NOTCH1 expression. Furthermore, exposure of enzalutamide-resistant cells to both PF-03084014 and enzalutamide increased cell death, decreased colony formation ability, and resensitized cells to enzalutamide. Knockdown of NOTCH1 in C4-2R increased enzalutamide sensitivity by decreasing cell proliferation and increasing cleaved PARP expression. In a 22RV1 xenograft model, PF-03084014 and enzalutamide decreased tumor growth through reducing cell proliferation and increasing apoptosis. These results indicate that NOTCH1 signaling may contribute to enzalutamide resistance in prostate cancer, and inhibition of NOTCH signaling can resensitize resistant cells to enzalutamide.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Arsenic is a carcinogenic contaminant of water and food and a growing threat to human health in many regions of the world. This study focuses on the fern Pteris vittata (Pteridaceae), which ...is extraordinary in its ability to tolerate and hyperaccumulate very high levels of arsenic that would kill any other plant or animal outside the Pteridaceae. Here, we use RNA-seq to identify three genes (GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE (PvGAPC1), ORGANIC CATION TRANSPORTER 4 (PvOCT4), and GLUTATHIONE S-TRANSFERASE (PvGSTF1) that are highly upregulated by arsenic and are necessary for arsenic tolerance, as demonstrated by RNAi. The proteins encoded by these genes have unexpected properties: PvGAPC1 has an unusual active site and a much greater affinity for arsenate than phosphate; PvGSTF1 has arsenate reductase activity; and PvOCT4 localizes as puncta in the cytoplasm. Surprisingly, PvGAPC1, PvGSTF1, and arsenate localize in a similar pattern. These results are consistent with a model that describes the fate of arsenate once it enters the cell. It involves the conversion of arsenate into 1-arseno-3-phosphoglycerate by PvGAPC1. This “chemically trapped” arsenate is pumped into specific arsenic metabolizing vesicles by the PvOCT4 protein. Once inside these vesicles, 1-arseno-3-phosphoglycerate hydrolyses to release arsenate, which is then reduced by PvGSTF1 to arsenite, the form of arsenic stored in the vacuoles of this fern. This mechanism is strikingly similar to one recently described Pseudomonas aeruginosa, whose tolerance to arsenic also involves the biosynthesis and transport of 1-arseno-3-phosphoglycerate, indicating that P. vittata has evolved a simple, bacterial-like mechanism for arsenic tolerance.
•Genes involved in arsenic tolerance in Pteris vittata were identified by RNA-seq•PvGAPC1, PvOCT4, and PvGSTF1 are essential for tolerance to arsenic•PvGAPC1 has high affinity for arsenate, and PvGSTF1 has arsenate reductase activity•A new bacterial-like mechanism for arsenic tolerance in this fern is proposed
How does the fern Pteris vittata tolerate and accumulate exceptionally high levels of arsenic? Cai et al. identify three genes in this fern that are crucial for this extraordinary trait. Characterizing the functions of these genes reveals that this fern has evolved a bacterial-like mechanism that allows it to sequester this deadly toxin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Previous research has found that behavioural synchrony between people leads to greater prosocial tendencies towards co‐performers. In this study, we investigated the scope of this prosocial effect: ...does it extend beyond the performance group to an extended ingroup (extended parochial prosociality) or even to other people in general (generalized prosociality)? Participants performed a simple rhythmic movement either in time (synchrony condition) or out of time (asynchrony condition) with each other. Before and during the rhythmic movement, participants were exposed to a prime that made salient an extended ingroup identity. After the task, half of the participants had the opportunity to help an extended ingroup member; the other half had the opportunity to help an outgroup member. We found a main effect of our synchrony manipulation across both help targets suggesting that the prosocial effects of synchrony extend to non‐performers. Furthermore, there was a significantly higher proportion of participants willing to help an outgroup member after moving collectively in synchrony. This study shows that under certain intergroup contexts synchrony can lead to generalized prosociality with performers displaying greater prosociality even towards outgroup members.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated ...and characterized C57Bl/6-derived KPC (
) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of
or
in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1
) failed to generate sizable tumors, a phenotype completely rescued by restoration of
expression. Expression profiling of KPC and KPC-Par-1
cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1
cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised
mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1
tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.
Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell ...immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine. Such "decoy" receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.
Background
Carcinoma–associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the ...mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub‐populations of human prostate CAF can be identified and functionally characterized.
Methods
Single‐cell RNA‐seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non‐tumorigenic, initiated prostate epithelial BPH‐1 cells. Resultant grafts were assessed for inflammatory cell recruitment.
Results
Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub‐renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine‐related genes of individual clusters. Migration of THP‐1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF‐derived chemokine CCL2 may be responsible for CAF‐stimulated migration of THP‐1 cells, since neutralization of this chemokine abrogates migration capacity.
Conclusions
CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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