Direct Measurement of the Positive Acceleration of the Universe and Testing Inhomogeneous Models under Gravitational Wave Cosmology

One possibility for explaining the apparent accelerating expansion of the universe is that we live in the center of a spherically inhomogeneous universe. Although current observations cannot fully distinguish $\Lambda$CDM and these inhomogeneous models, direct measurement of the acceleration of the universe can be a powerful tool in probing them. We have shown that, if $\Lambda$CDM is the correct model, DECIGO/BBO would be able to detect the positive redshift drift (which is the time evolution of the source redshift $z$) in 3--5 year gravitational wave (GW) observations from neutron-star binaries, which enables us to rule out any Lema\^itre-Tolman-Bondi (LTB) void model with monotonically increasing density profile. We may even be able to rule out any LTB model unless we allow unrealistically steep density profile at $z\sim 0$. This test can be performed with GW observations alone, without any reference to electromagnetic observations, and is more powerful than the redshift drift measurement using Lyman $\alpha$ forest.Comment: 5 pages, 2 figure

Pacific origin of the abrupt increase in Indian Ocean heat content during the warming hiatus

Global mean surface warming has stalled since the end of the twentieth century1, 2, but the net radiation imbalance at the top of the atmosphere continues to suggest an increasingly warming planet. This apparent contradiction has been reconciled by an anomalous heat flux into the ocean3, 4, 5, 6, 7, 8, induced by a shift towards a La Niña-like state with cold sea surface temperatures in the eastern tropical Pacific over the past decade or so. A significant portion of the heat missing from the atmosphere is therefore expected to be stored in the Pacific Ocean. However, in situ hydrographic records indicate that Pacific Ocean heat content has been decreasing9. Here, we analyse observations along with simulations from a global ocean–sea ice model to track the pathway of heat. We find that the enhanced heat uptake by the Pacific Ocean has been compensated by an increased heat transport from the Pacific Ocean to the Indian Ocean, carried by the Indonesian throughflow. As a result, Indian Ocean heat content has increased abruptly, which accounts for more than 70% of the global ocean heat gain in the upper 700 m during the past decade. We conclude that the Indian Ocean has become increasingly important in modulating global climate variability

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

DNA repair, genome stability and cancer: a historical perspective

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease.

The miR-17/92 cluster is among the best-studied microRNA clusters. Interest in the cluster and its members has been increasing steadily and the number of publications has grown exponentially since its discovery with more than 1000 articles published in 2012 alone. Originally found to be involved in tumorigenesis, research work in recent years has uncovered unexpected roles for its members in a wide variety of settings that include normal development, immune diseases, cardiovascular diseases, neurodegenerative diseases and aging. In light of its ever-increasing importance and ever-widening regulatory roles, we review here the latest body of knowledge on the cluster\u27s involvement in health and disease as well as provide a novel perspective on the full spectrum of protein-coding and non-coding transcripts that are likely regulated by its members

The molecular and cellular origin of human prostate cancer

Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency. Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background "field" for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression. In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells. Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR-neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs

Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

We have analyzed the sequence heterogeneity of the transcripts of the human HPRT and G6PD single copy genes that are not considered tumor markers. Analyses have been performed on different colon cancers and on the nearby histologically normal tissues of two male patients. Several copies of each cDNA, which were produced by cloning the RT-PCR-amplified fragments of the specific mRNA, have been sequenced. Similar analyses have been performed on blood samples of two ostensibly healthy males as reference controls. The sequence heterogeneity of the HPRT and G6PD genes was also determined on DNA from tumor tissues. The employed analytical approach revealed the presence of low-frequency mutations not detectable by other procedures. The results show that genetic heterogeneity is detectable in HPRT and G6PD transcripts in both tumors and nearby healthy tissues of the two studied colon tumors. Similar frequencies of mutations are observed in patient genomic DNA, indicating that mutations have a somatic origin. HPRT transcripts show genetic heterogeneity also in healthy individuals, in agreement with previous results on human T-cells, while G6PD transcript heterogeneity is a characteristic of the patient tissues. Interestingly, data on TP53 show little, if any, heterogeneity in the same tissues. CONCLUSIONS/SIGNIFICANCE: These findings show that genetic heterogeneity is a peculiarity not only of cancer cells but also of the normal tissue where a tumor arises

Clonal mutations in primary human glial tumors: evidence in support of the mutator hypothesis

<p>Abstract</p> <p>Background</p> <p>A verifiable consequence of the mutator hypothesis is that even low grade neoplasms would accumulate a large number of mutations that do not influence the tumor phenotype (clonal mutations). In this study, we have attempted to quantify the number of clonal mutations in primary human gliomas of astrocytic cell origin. These alterations were identified in tumor tissue, microscopically confirmed to have over 70% neoplastic cells.</p> <p>Methods</p> <p>Random Amplified Polymorphic DNA (RAPD) analysis was performed using a set of fifteen 10-mer primers of arbitrary but definite sequences in 17 WHO grade II astrocytomas (low grade diffuse astrocytoma or DA) and 16 WHO grade IV astrocytomas (Glioblastoma Multiforme or GBM). The RAPD profile of the tumor tissue was compared with that of the leucocyte DNA of the same patient and alteration(s) scored. A quantitative estimate of the overall genomic changes in these tumors was obtained by 2 different modes of calculation.</p> <p>Results</p> <p>The overall change in the tumors was estimated to be 4.24% in DA and 2.29% in GBM by one method and 11.96% and 6.03% in DA and GBM respectively by the other. The difference between high and lower grade tumors was statistically significant by both methods.</p> <p>Conclusion</p> <p>This study demonstrates the presence of extensive clonal mutations in gliomas, more in lower grade. This is consistent with our earlier work demonstrating that technique like RAPD analysis, unbiased for locus, is able to demonstrate more intra-tumor genetic heterogeneity in lower grade gliomas compared to higher grade. The results support the mutator hypothesis proposed by Loeb.</p

Remote Electrical Stimulation by Means of Implanted Rectifiers

Miniaturization of active implantable medical devices is currently compromised by the available means for electrically powering them. Most common energy supply techniques for implants – batteries and inductive couplers – comprise bulky parts which, in most cases, are significantly larger than the circuitry they feed. Here, for overcoming such miniaturization bottleneck in the case of implants for electrical stimulation, it is proposed to make those implants act as rectifiers of high frequency bursts supplied by remote electrodes. In this way, low frequency currents will be generated locally around the implant and these low frequency currents will perform stimulation of excitable tissues whereas the high frequency currents will cause only innocuous heating. The present study numerically demonstrates that low frequency currents capable of stimulation can be produced by a miniature device behaving as a diode when high frequency currents, neither capable of thermal damage nor of stimulation, flow through the tissue where the device is implanted. Moreover, experimental evidence is provided by an in vivo proof of concept model consisting of an anesthetized earthworm in which a commercial diode was implanted. With currently available microelectronic techniques, very thin stimulation capsules (diameter <500 µm) deliverable by injection are easily conceivable