This paper reviews and refines the technique of dating martian surfaces by using impact-crater isochrons (defined as size distributions of impact craters on undisturbed martian surfaces of specified ...ages). In the 1970s, this system identified not only abundant ancient martian volcanic surfaces, but also extensive lava plains with ages of a few 10
8 y-old; this dating was initially controversial but confirmed in the 1980s and 90s by martian meteorites. The present update utilizes updated estimates of the Mars/Moon cratering ratio (the most important calibration factor), improves treatment of gravity and impact velocity scaling effects, combines aspects of the crater size distribution data from earlier work by both Neukum and Hartmann, and for the first time applies a correction for loss of small meteoroids in the martian atmosphere from Popova et al. (2003, Meteorit. Planet. Sci. 38, 905–925). The updated isochrons are not radically different from the previous “2002 iteration” but fit observed data better and give somewhat older model ages for features dated from small craters (diameter
D
<
100
m
). Crater counts from young lava flows in various areas give good fits to the new isochrons over as much as 3 orders of magnitude in
D, confirming the general isochron shape and giving crater retention ages in the range of some 10
6 to some 10
8 y, interpreted as lava flow ages. More complex, older units are also discussed. Uncertainties are greatest if only small craters (
D
≲
100
m
) are used. Suggestions by other workers of gross uncertainties, due to local secondary craters and deposition/exhumation, are discussed; they do not refute our conclusions of significant volcanic, fluvial, and other geologic activity in the last few percent of martian geologic time or the importance of cratering as a tool for studying processes such as exhumation. Indeed, crater count data suggest certain very recent episodes of deposition, exhumation, and ice flow, possibly associated with obliquity cycles of
∼
10
7
y
timescale. Evidence from ancient surfaces suggests higher rates of volcanism, fluvial activity, glaciation, and other processes in Noachian/Hesperian time than in Amazonian time.
Current global patterns of biodiversity result from processes that operate over both space and time and thus require an integrated macroecological and macroevolutionary perspective. Molecular time ...trees have advanced our understanding of the tempo and mode of diversification and have identified remarkable adaptive radiations across the tree of life. However, incomplete joint phylogenetic and geographic sampling has limited broad-scale inference. Thus, the relative prevalence of rapid radiations and the importance of their geographic settings in shaping global biodiversity patterns remain unclear. Here we present, analyse and map the first complete dated phylogeny of all 9,993 extant species of birds, a widely studied group showing many unique adaptations. We find that birds have undergone a strong increase in diversification rate from about 50 million years ago to the near present. This acceleration is due to a number of significant rate increases, both within songbirds and within other young and mostly temperate radiations including the waterfowl, gulls and woodpeckers. Importantly, species characterized with very high past diversification rates are interspersed throughout the avian tree and across geographic space. Geographically, the major differences in diversification rates are hemispheric rather than latitudinal, with bird assemblages in Asia, North America and southern South America containing a disproportionate number of species from recent rapid radiations. The contribution of rapidly radiating lineages to both temporal diversification dynamics and spatial distributions of species diversity illustrates the benefits of an inclusive geographical and taxonomical perspective. Overall, whereas constituent clades may exhibit slowdowns, the adaptive zone into which modern birds have diversified since the Cretaceous may still offer opportunities for diversification.
Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability
. In an effort to identify ...alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials
. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8
T cells, decreasing the prevalence of exhausted CD8
T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1
precursor CD8
T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.
Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have been shown to significantly reduce hospitalization for heart failure (HHF) and cardiovascular (CV) mortality in various CV outcome trials in ...patients with and without type 2 diabetes mellitus (T2D). SGLT2 inhibition further increased haemoglobin and haematocrit levels by an as yet unknown mechanism, and this increase has been shown to be an independent predictor of the CV benefit of these agents, for example, in the EMPA‐REG OUTCOME trial. The present analysis of the EMPA haemodynamic study examined the early and delayed effects of empagliflozin treatment on haemoglobin and haematocrit levels, in addition to measures of erythropoiesis and iron metabolism, to better understand the underlying mechanisms. In this prospective, placebo‐controlled, double‐blind, randomized, two‐arm parallel, interventional and exploratory study, 44 patients with T2D were randomized into two groups and received empagliflozin 10 mg or placebo for a period of 3 months in addition to their concomitant medication. Blood and urine was collected at baseline, on Day 1, on Day 3 and after 3 months of treatment to investigate effects on haematological variables, erythropoietin concentrations and indices of iron stores. Baseline characteristics were comparable in the empagliflozin (n = 20) and placebo (n = 22) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; Day 1: 48.4 ± 34.7 g/24 h; P < 0.001) as well as urinary volume (baseline: 1740 ± 601 mL/24 h; Day 1: 2112 ± 837 mL/24 h; P = 0.011) already after 1 day and throughout the 3‐month study period, while haematocrit and haemoglobin were only increased after 3 months of treatment (haematocrit: baseline: 40.6% ± 4.6%; Month 3: 42.2% ± 4.8%, P < 0.001; haemoglobin: baseline: 136 ± 19 g/L; Month 3: 142 ± 25 g/L; P = 0.008). In addition, after 3 months, empagliflozin further increased red blood cell count (P < 0.001) and transferrin concentrations (P = 0.063) and there was a trend toward increased erythropoietin levels (P = 0.117), while ferritin (P = 0.017), total iron (P = 0.053) and transferrin saturation levels (P = 0.030) decreased. Interestingly, the increase in urinary glucose excretion significantly correlated with the induction of erythropoietin in empagliflozin‐treated patients at the 3‐month timepoint (Spearman rho 0.64; P = 0.008). Empagliflozin increased haemoglobin concentrations and haematocrit with a delayed time kinetic, which was most likely attributable to increased erythropoiesis with augmented iron utilization and not haemoconcentration. This might be attributable to reduced tubular glucose reabsorption in response to SGLT2 inhibition, possibly resulting in diminished cellular stress as a mechanism for increased renal erythropoietin secretion.
Abstract A regime of coexistence of asynchronous and clustered dynamics is analysed for globally coupled homogeneous and heterogeneous inhibitory networks of quadratic integrate-and-fire (QIF) ...neurons subject to Gaussian noise. The analysis is based on accurate extensive simulations and complemented by a mean-field description in terms of low-dimensional next generation neural mass models for heterogeneously distributed synaptic couplings. The asynchronous regime is observable at low noise and becomes unstable via a sub-critical Hopf bifurcation at sufficiently large noise. This gives rise to a coexistence region between the asynchronous and the clustered regime. The clustered phase is characterised by population bursts in the γ -range (30–120 Hz), where neurons are split in two equally populated clusters firing in alternation. This clustering behaviour is quite peculiar: despite the global activity being essentially periodic, single neurons display switching between the two clusters due to heterogeneity and/or noise.
One of the first specialized collections of nucleic acid sequences in life sciences was the 'compilation of tRNA sequences and sequences of tRNA genes' (http://www.trna.uni-bayreuth.de). Here, an ...updated and completely restructured version of this compilation is presented (http://trnadb.bioinf.uni-leipzig.de). The new database, tRNAdb, is hosted and maintained in cooperation between the universities of Leipzig, Marburg, and Strasbourg. Reimplemented as a relational database, tRNAdb will be updated periodically and is searchable in a highly flexible and user-friendly way. Currently, it contains more than 12 000 tRNA genes, classified into families according to amino acid specificity. Furthermore, the implementation of the NCBI taxonomy tree facilitates phylogeny-related queries. The database provides various services including graphical representations of tRNA secondary structures, a customizable output of aligned or un-aligned sequences with a variety of individual and combinable search criteria, as well as the construction of consensus sequences for any selected set of tRNAs.
Abstract
RNase P is the endonuclease responsible for the 5′ processing of precursor tRNAs (pre-tRNAs). Unlike the single-subunit protein-only RNase P (PRORP) found in plants or protists, human ...mitochondrial RNase P is a multi-enzyme assembly that in addition to the homologous PRORP subunit comprises a methyltransferase (TRMT10C) and a dehydrogenase (SDR5C1) subunit; these proteins, but not their enzymatic activities, are required for efficient pre-tRNA cleavage. Here we report a kinetic analysis of the cleavage reaction by human PRORP and its interplay with TRMT10C-SDR5C1 including 12 different mitochondrial pre-tRNAs. Surprisingly, we found that PRORP alone binds pre-tRNAs with nanomolar affinity and can even cleave some of them at reduced efficiency without the other subunits. Thus, the ancient binding mode, involving the tRNA elbow and PRORP’s PPR domain, appears basically retained by human PRORP, and its metallonuclease domain is in principle correctly folded and functional. Our findings support a model according to which the main function of TRMT10C-SDR5C1 is to direct PRORP’s nuclease domain to the cleavage site, thereby increasing the rate and accuracy of cleavage. This functional dependence of human PRORP on an extra tRNA-binding protein complex likely reflects an evolutionary adaptation to the erosion of canonical structural features in mitochondrial tRNAs.
Graphical Abstract
Graphical Abstract
MicroRNAs (miRNA) aberrantly expressed in tumors may offer novel therapeutic approaches to treatment. miR-145 is downregulated in various cancers including colon carcinoma in which in vitro studies ...have established proapoptotic and antiproliferative roles. miR-33a was connected recently to cancer through its capacity to downregulate the oncogenic kinase Pim-1. To date, miRNA replacement therapy has been hampered by the lack of robust nonviral delivery methods for in vivo administration. Here we report a method of miRNA delivery by using polyethylenimine (PEI)-mediated delivery of unmodified miRNAs, using miR-145 and miR-33a to preclinically validate the method in a mouse model of colon carcinoma. After systemic or local application of low molecular weight PEI/miRNA complexes, intact miRNA molecules were delivered into mouse xenograft tumors, where they caused profound antitumor effects. miR-145 delivery reduced tumor proliferation and increased apoptosis, with concomitant repression of c-Myc and ERK5 as novel regulatory target of miR-145. Similarly, systemic injection of PEI-complexed miR-33a was validated as a novel therapeutic targeting method for Pim-1, with antitumor effects comparable with PEI/siRNA-mediated direct in vivo knockdown of Pim-1 in the model. Our findings show that chemically unmodified miRNAs complexed with PEI can be used in an efficient and biocompatible strategy of miRNA replacement therapy, as illustrated by efficacious delivery of PEI/miR-145 and PEI/miR-33a complexes in colon carcinoma.
This study examines the history of the paradigm concerning a lunar (or solar-system-wide) terminal cataclysm (also called “Late Heavy Bombardment” or LHB), a putative, brief spike in impacts at ~3.9 ...Ga ago, preceded by low impact rates. We examine origin of the ideas, why they were accepted, and why the ideas are currently being seriously revised, if not abandoned. The paper is divided into the following sections: Overview of paradigm. Pre-Apollo views (1949–1969). Initial suggestions of cataclysm (ca. 1974). Ironies. Alternative suggestions, megaregolith evolution (1970s). Impact melt rocks “establish” cataclysm (1990). Imbrium redux (ca. 1998). Impact melt clasts (early 2000s). Dating of front-side lunar basins? Dynamical models “explain” the cataclysm (c. 2000s). Asteroids as a test case. Impact melts predating 4.0 Ga ago (ca. 2008–present.). Biological issues. Growing doubts (ca. 1994–2014). Evolving Dynamical Models (ca. 2001–present). Connections to lunar origin. Dismantling the paradigm (2015–2018). “Megaregolith Evolution Model” for explaining the data. Conclusions and new directions for future work.
Abstract
We numerically investigate the dynamics of an SIR model with infection level-based lockdowns on Small-World networks. Using a large-deviation approach, namely the Wang–Landau algorithm, we ...study the distribution of the cumulative fraction of infected individuals. We are able to resolve the density of states for values as low as 10
−85
. Hence, we measure the distribution on its full support giving a complete characterization of this quantity. The lockdowns are implemented by severing a certain fraction of the edges in the Small-World network, and are initiated and released at different levels of infection, which are varied within this study. We observe points of non-analytical behaviour for the pdf and discontinuous transitions for correlations with other quantities such as the maximum fraction of infected and the duration of outbreaks. Further, empirical rate functions were calculated for different system sizes, for which a convergence is clearly visible indicating that the large-deviation principle is valid for the system with lockdowns.
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