The anatomy of exhumed river-channel belts: Bedform to belt‐scale river kinematics of the Ruby Ranch Member, Cretaceous Cedar Mountain Formation, Utah, USA

Many published interpretations of ancient fluvial systems have relied on observations of extensive outcrops of thick successions. This paper, in contrast, demonstrates that a regional understanding of palaeoriver kinematics, depositional setting and sedimentation rates can be interpreted from local sedimentological measurements of bedform and barform strata. Dune and bar strata, channel planform geometry and bed topography are measured within exhumed fluvial strata exposed as ridges in the Ruby Ranch Member of the Cretaceous Cedar Mountain Formation, Utah, USA. The ridges are composed of lithified stacked channel belts, representing at least five or six re‐occupations of a single‐strand channel. Lateral sections reveal well‐preserved barforms constructed of subaqueous dune cross‐sets. The topography of palaeobarforms is preserved along the top surface of the outcrops. Comparisons of the channel‐belt centreline to local palaeotransport directions indicate that channel planform geometry was preserved through the re‐occupations, rather than being obscured by lateral migration. Rapid avulsions preserved the state of the active channel bed and its individual bars at the time of abandonment. Inferred minimum sedimentation durations for the preserved elements, inferred from cross‐set thickness distributions and assumed bedform migration rates, vary within a belt from one to ten days. Using only these local sedimentological measurements, the depositional setting is interpreted as a fluvial megafan, given the similarity in river kinematics. This paper provides a systematic methodology for the future synthesis of vertical and planview data, including the drone‐equipped 2020 Mars Rover mission, to exhumed fluvial and deltaic strata

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

The Big Five Across Socioeconomic Status: Measurement Invariance, Relationships, and Age Trends

24 pagesAssociations between socioeconomic status (SES) and personality traits have important implications for theory and application. Progress in understanding these associations depends on valid measurement, unbiased estimation, and careful assessment of generalizability. In this registered report, we used data from AIID, a large online study, to address three basic questions about personality and SES. First, we evaluated the measurement invariance of a common measure of personality, the Big Five Inventory, across indicators of educational attainment, income, and occupational prestige. Fit indices showed some instances of detectable noninvariance, but with little practical impact on substantive results. Second, we estimated associations between SES and personality. Results showed that personality and SES were largely independent (most rs < .1), in contrast to predictions derived from several previous studies. Third, we tested whether age trends in personality were moderated by SES. Results did not support predictions from social investment theory, but they did suggest that age trends were largely generalizable across SES. We discuss the implications of these findings for developing and validating personality measures for use in diverse samples. We also discuss the implications for theories that propose that the Big Five are responsive to, or partially responsible for, people’s economic and social conditions

Mamld1 Knockdown Reduces Testosterone Production and Cyp17a1 Expression in Mouse Leydig Tumor Cells

MAMLD1 is known to be a causative gene for hypospadias. Although previous studies have indicated that MAMLD1 mutations result in hypospadias primarily because of compromised testosterone production around the critical period for fetal sex development, the underlying mechanism(s) remains to be clarified. Furthermore, although functional studies have indicated a transactivation function of MAMLD1 for the non-canonical Notch target Hes3, its relevance to testosterone production remains unknown. To examine these matters, we performed Mamld1 knockdown experiments.Mamld1 knockdown was performed with two siRNAs, using mouse Leydig tumor cells (MLTCs). Mamld1 knockdown did not influence the concentrations of pregnenolone and progesterone but significantly reduced those of 17-OH pregnenolone, 17-OH progesterone, dehydroepiandrosterone, androstenedione, and testosterone in the culture media. Furthermore, Mamld1 knockdown significantly decreased Cyp17a1 expression, but did not affect expressions of other genes involved in testosterone biosynthesis as well as in insulin-like 3 production. Hes3 expression was not significantly altered. In addition, while 47 genes were significantly up-regulated (fold change >2.0×) and 38 genes were significantly down-regulated (fold change <0.5×), none of them was known to be involved in testosterone production. Cell proliferation analysis revealed no evidence for compromised proliferation of siRNA-transfected MLTCs.The results, in conjunction with the previous data, imply that Mamld1 enhances Cyp17a1 expression primarily in Leydig cells and permit to produce a sufficient amount of testosterone for male sex development, independently of the Hes3-related non-canonical Notch signaling

Bisphosphonates induce apoptosis in human breast cancer cell lines

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50values of 15, 20 and 3 μM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 μM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells. © 2000 Cancer Research Campaig

Heterogeneous Host Susceptibility Enhances Prevalence of Mixed-Genotype Micro-Parasite Infections

Dose response in micro-parasite infections is usually shallower than predicted by the independent action model, which assumes that each infectious unit has a probability of infection that is independent of the presence of other infectious units. Moreover, the prevalence of mixed-genotype infections was greater than predicted by this model. No probabilistic infection model has been proposed to account for the higher prevalence of mixed-genotype infections. We use model selection within a set of four alternative models to explain high prevalence of mixed-genotype infections in combination with a shallow dose response. These models contrast dependent versus independent action of micro-parasite infectious units, and homogeneous versus heterogeneous host susceptibility. We specifically consider a situation in which genome differences between genotypes are minimal, and highly unlikely to result in genotype-genotype interactions. Data on dose response and mixed-genotype infection prevalence were collected by challenging fifth instar Spodoptera exigua larvae with two genotypes of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), differing only in a 100 bp PCR marker sequence. We show that an independent action model that includes heterogeneity in host susceptibility can explain both the shallow dose response and the high prevalence of mixed-genotype infections. Theoretical results indicate that variation in host susceptibility is inextricably linked to increased prevalence of mixed-genotype infections. We have shown, to our knowledge for the first time, how heterogeneity in host susceptibility affects mixed-genotype infection prevalence. No evidence was found that virions operate dependently. While it has been recognized that heterogeneity in host susceptibility must be included in models of micro-parasite transmission and epidemiology to account for dose response, here we show that heterogeneity in susceptibility is also a fundamental principle explaining patterns of pathogen genetic diversity among hosts in a population. This principle has potentially wide implications for the monitoring, modeling and management of infectious diseases

Multiple Mating and Family Structure of the Western Tent Caterpillar, Malacosoma californicum pluviale: Impact on Disease Resistance

Background Levels of genetic diversity can strongly influence the dynamics and evolutionary changes of natural populations. Survival and disease resistance have been linked to levels of genetic diversity in eusocial insects, yet these relationships remain untested in gregarious insects where disease transmission can be high and selection for resistance is likely to be strong. Methodology/Principal Findings Here we use 8 microsatellite loci to examine genetic variation in 12 families of western tent caterpillars, Malacosoma californicum pluviale from four different island populations to determine the relationship of genetic variability to survival and disease resistance. In addition these genetic markers were used to elucidate the population structure of western tent caterpillars. Multiple paternity was revealed by microsatellite markers, with the number of sires estimated to range from one to three per family (mean ± SE = 1.92±0.23). Observed heterozygosity (HO) of families was not associated to the resistance of families to a nucleopolyhedrovirus (NPV) (r = 0.161, F1,12 = 0.271, P = 0.614), a major cause of mortality in high-density populations, but was positively associated with larval survival (r = 0.635, F1,10 = 5.412, P = 0.048). Genetic differentiation among the families was high (FST = 0.269, P&lt;0.0001), and families from the same island were as differentiated as were families from other islands. Conclusion/Significance We have been able to describe and characterize 8 microsatellite loci, which demonstrate patterns of variation within and between families of western tent caterpillars. We have discovered an association between larval survival and family-level heterozygosity that may be relevant to the population dynamics of this cyclic forest lepidopteran, and this will be the topic of future work

Quantitative Epistasis Analysis and Pathway Inference from Genetic Interaction Data

Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ∼80% of the known relationships without any false positives

PHANGS-JWST First Results: A Global and Moderately Resolved View of Mid-Infrared and CO Line Emission from Galaxies at the Start of the JWST Era

We explore the relationship between mid-infrared (mid-IR) and CO rotational line emission from massive star-forming galaxies, which is one of the tightest scalings in the local universe. We assemble a large set of unresolved and moderately ($\sim 1$ kpc) spatially resolved measurements of CO (1-0) and CO (2-1) intensity, $I_{\rm CO}$, and mid-IR intensity, $I_{\rm MIR}$, at 8, 12, 22, and 24$\mu$m. The $I_{\rm CO}$ vs. $I_{\rm MIR}$ relationship is reasonably described by a power law with slopes $0.7{-}1.2$ and normalization $I_{\rm CO} \sim 1$ K km s$^{-1}$ at $I_{\rm MIR} \sim 1$ MJy sr$^{-1}$. Both the slopes and intercepts vary systematically with choice of line and band. The comparison between the relations measured for CO~(1-0) and CO (2-1) allow us to infer that $R_{21} \propto I_{\rm MIR}^{0.2}$, in good agreement with other work. The $8\mu$m and $12\mu$m bands, with strong PAH features, show steeper CO vs. mid-IR slopes than the $22\mu$m and $24\mu$m, consistent with PAH emission arising not just from CO-bright gas but also from atomic or CO-dark gas. The CO-to-mid-IR ratio correlates with global galaxy stellar mass ($M_\star$) and anti-correlates with SFR/$M_\star$. At $\sim 1$ kpc resolution, the first four PHANGS-JWST targets show CO to mid-IR relationships that are quantitatively similar to our larger literature sample, including showing the steep CO-to-mid-IR slopes for the JWST PAH-tracing bands, although we caution that these initial data have a small sample size and span a limited range of intensities.Comment: 29 pages, 13 figures, key quantitative results in Table 3, Accepted as part of a PHANGS-JWST Focus Issue to appear in Ap