The gravitational waves measured at LIGO are presumed here to come from merging primordial black holes. We ask how these primordial black holes could arise through inflationary models while not ...conflicting with current experiments. Among the approaches that work, we investigate the opportunity for corroboration through experimental probes of gravitational waves at pulsar timing arrays. We provide examples of theories that are already ruled out, theories that will soon be probed, and theories that will not be tested in the foreseeable future. The models that are most strongly constrained are those with a relatively broad primordial power spectrum.
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Many motivated extensions of the Standard Model predict the existence of cosmic strings. Gravitational waves originating from the dynamics of the resulting cosmic string network have the ...ability to probe many otherwise inaccessible properties of the early universe. In this study we show how the spectrum of gravitational waves from a cosmic string network can be used to test the equation of state of the early universe prior to Big Bang Nucleosynthesis (BBN). We also demonstrate that current and planned gravitational wave detectors such as LIGO, LISA, DECIGO/BBO, and ET/CE have the potential to detect signals of a non-standard pre-BBN equation of state and evolution of the early universe (e.g., early non-standard matter domination or kination domination) or new degrees of freedom active in the early universe beyond the sensitivity of terrestrial collider experiments and cosmic microwave background measurements.
Over the last 5 years, physical methods of plasmid delivery have revolutionized the efficiency of nonviral gene transfer, in some cases reaching the efficiencies of viral vectors. In vivo ...electroporation dramatically increases transfection efficiency for a variety of tissues. Other methods with clinical precedent, pressure-perfusion and ultrasound, also improve plasmid gene transfer. Alternatives such as focused laser, magnetic fields and ballistic (gene gun) approaches can also enhance delivery. As plasmid DNA appears to be a safe gene vector system, it seems likely that plasmid with physically enhanced delivery will be used increasingly in clinical trials.
Recent discoveries have revealed that simple repeating DNA sequences, which are known to adopt non-B DNA conformations (such as triplexes, cruciforms, slipped structures, left-handed Z-DNA and ...tetraplexes), are mutagenic. The mutagenesis is due to the non-B DNA conformation rather than to the DNA sequence
per se in the orthodox right-handed Watson-Crick B-form. The human genetic consequences of these non-B structures are ∼20 neurological diseases, ∼50 genomic disorders (caused by gross deletions, inversions, duplications and translocations), and several psychiatric diseases involving polymorphisms in simple repeating sequences. Thus, the convergence of biochemical, genetic and genomic studies has demonstrated a new paradigm implicating the non-B DNA conformations as the mutagenesis specificity determinants, not the sequences as such.
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We analyse a simple extension of the SM with just an additional scalar singlet coupled to the Higgs boson. We discuss the possible probes for electroweak baryogenesis in this model ...including collider searches, gravitational wave and direct dark matter detection signals. We show that a large portion of the model parameter space exists where the observation of gravitational waves would allow detection while the indirect collider searches would not.
What is the incidence, origin and clinical significance of segmental aneuploidy in human oocytes and preimplantation embryos?
Segmental aneuploidy occurs at a considerable frequency in ...preimplantation embryos with a majority being mitotic in origin.
In recent years, accurate techniques for the detection of aneuploidy in single cells have been developed. Research using such methods has confirmed that aneuploidy is a common feature of human oocytes and preimplantation embryos. However, thus far research has mainly focused on loss or gain of whole chromosomes. We utilized sensitive molecular methods to study another important form of cytogenetic abnormality at the earliest stages of human development, namely segmental aneuploidy.
Chromosomal copy number data was obtained from oocytes and embryos of 635 IVF patients, who requested chromosome screening for various reasons, most commonly for advanced maternal age or previously unsuccessful IVF treatments. A total of 3541 samples comprising of 452 human oocytes, 1762 cleavage stage and 1327 blastocyst stage embryos were investigated in the present study.
Whole genome amplification (Sureplex, Illumina) was performed on cells biopsied from oocytes and embryos of IVF patients who requested chromosome screening. The samples were subsequently processed and analyzed for their chromosome complement using microarray comparative genomic hybridization (aCGH), (Illumina, Cambridge, UK).
Segmental abnormalities, involving loss or gain of chromosomal fragments in excess of 15 Mb, were found to occur at a high frequency. The incidence of such abnormalities was 10.4% in oocytes, but this increased dramatically during the first 3 days of embryonic development (24.3%), before starting to decline as embryos reached the final (blastocyst) stage of preimplantation development (15.6%). While some segmental errors were clearly of meiotic origin, most appear to arise during the first few mitoses following fertilization. The reduction in frequency at the blastocyst stage suggests that many cells/embryos affected by segmental abnormalities are eliminated (e.g. via arrest of the affected embryos or apoptosis of abnormal cells). Interestingly, sites of chromosome breakage associated with segmental aneuploidy were not entirely random but tended to occur within distinct chromosomal regions. Some of the identified hotspots correspond to known fragile sites while others may be considered novel and may be specific to gametogenesis and/or embryogenesis.
The cytogenetic analysis was performed on biopsies of embryos, which might not be representative of the true incidence of mosaic segmental aneuploidy of the entire embryo.
The findings of this study are valuable for understanding the origin of subchromosomal duplications and deletions, a clinically important class of abnormalities that are a common cause of congenital abnormalities and miscarriage. Furthermore, the results provide additional evidence that control of the cell cycle is more relaxed during the first few mitotic divisions following fertilization, permitting DNA double-strand breaks to occur and persist through cell division. The data are also of great relevance for preimplantation genetic testing, where the detection of segmental aneuploidy is currently considered problematic for embryo diagnosis and patient counseling.
This study was supported by institutional funding (Reprogenetics UK). Additionally, DW is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme. DB was supported by the University of Oxford's Clarendon funding. No conflict of interests to declare.
How do public employees win and lose their collective bargaining rights? And how can public sector labor unions protect those rights? These are the questions answered in From Collective Bargaining to ...Collective Begging. Dominic Wells takes a mixed-methods approach and uses more than five decades of state-level data to analyze the expansion and restriction of rights. Wells identifies the factors that led states to expand collective bargaining rights to public employees, and the conditions under which public employee labor unions can defend against unfavorable state legislation. He presents case studies and coalition strategies from Ohio and Wisconsin to demonstrate how labor unions failed to protect their rights in one state and succeeded in another. From Collective Bargaining to Collective Begging also provides a comprehensive quantitative analysis of the economic, political, and cultural factors that both led states to adopt policies that reduced the obstacles to unionization and also led other states to adopt policies that increased the difficulty to form and maintain a labor union. In his conclusion, Wells suggests the path forward for public sector labor unions and what policies need to be implemented to improve employee labor relations.
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We consider various models realizing baryogenesis during the electroweak phase transition (EWBG). Our focus is their possible detection in future collider experiments and possible ...observation of gravitational waves emitted during the phase transition. We also discuss the possibility of a non-standard cosmological history which can facilitate EWBG. We show how acceptable parameter space can be extended due to such a modification and conclude that next generation precision experiments such as the ILC will be able to confirm or falsify many models realizing EWBG. We also show that, in general, collider searches are a more powerful probe than gravitational wave searches. However, observation of a deviation from the SM without any hints of gravitational waves can point to models with modified cosmological history that generically enable EWBG with weaker phase transition and thus, smaller GW signals.
Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, ...the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.
Precision oncology seeks to integrate multiple layers of data from a patient's cancer to effectively tailor therapy. Conventional chemotherapies are sometimes effective but accompanied by adverse ...events, warranting the identification of a biomarker of chemosensitivity.
Identify an mRNA biomarker that predicts chemosensitivity across solid tumor subtypes.
We performed a pan-solid tumor analysis integrating gene expression and drug sensitivity profiles from 3 cancer cell line datasets to identify transcripts correlated with sensitivity to a panel of chemotherapeutics. We then tested the ability of an mRNA biomarker to predictive clinical outcomes in cohorts of patients with breast, lung, or ovarian cancer.
Expression levels of several mRNA transcripts were significantly correlated with sensitivity or resistance chemotherapeutics in cancer cell line datasets. The only mRNA transcript significantly correlated with sensitization to multiple classes of DNA-damaging chemotherapeutics in all 3 cell line datasets was encoded by Schlafen Family Member 11 (SLFN11). Analyses of multiple breast, lung, and ovarian cancer patient cohorts treated with chemotherapy confirmed SLFN11 mRNA expression as a predictive biomarker of longer overall survival and improved tumor response.
Tumor SLFN11 mRNA expression is a biomarker of sensitivity to an array of DNA-damaging chemotherapeutics across solid tumor subtypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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