Increased Metabolic Rate in X-linked Hypophosphatemic Mice

Hyp mice are a model for human X-linked hypophosphatemia, the most common form of vitamin D-resistant rickets. It has previously been observed that Hyp mice have a greater food consumption per gram body weight than do normal mice. This led to the search for some alteration in metabolism in Hyp mice. We found that oxygen consumption was significantly higher in Hyp mice than in normal C57BL/6J mice and this was accompanied by an increased percentage of cardiac output being delivered to organs of heat production (liver and skeletal muscle), to the skin, and to bone and a decreased percentage to the gastrointestinal tract of Hyp mice. The increased oxygen consumption in Hyp mice was not associated with increased plasma free T4 levels and was not affected by alterations in plasma phosphate produced by a low phosphate diet. The cause of the increased oxygen consumption is not known, and the role that this change and reported changes in distribution of cardiac output may play in the development of X-linked hypophosphatemia is also unknown. Study of the cardiovascular and thermoregulatory systems in Hyp mice should help increase understanding of the underlying mechanisms of this disease

Mapping the UK Webspace: Fifteen Years of British Universities on the Web

This paper maps the national UK web presence on the basis of an analysis of the .uk domain from 1996 to 2010. It reviews previous attempts to use web archives to understand national web domains and describes the dataset. Next, it presents an analysis of the .uk domain, including the overall number of links in the archive and changes in the link density of different second-level domains over time. We then explore changes over time within a particular second-level domain, the academic subdomain .ac.uk, and compare linking practices with variables, including institutional affiliation, league table ranking, and geographic location. We do not detect institutional affiliation affecting linking practices and find only partial evidence of league table ranking affecting network centrality, but find a clear inverse relationship between the density of links and the geographical distance between universities. This echoes prior findings regarding offline academic activity, which allows us to argue that real-world factors like geography continue to shape academic relationships even in the Internet age. We conclude with directions for future uses of web archive resources in this emerging area of research.Comment: To appear in the proceeding of WebSci 201

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma.

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P ¼ 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. ©2017 AACR

Paternal Poly (ADP-ribose) Metabolism Modulates Retention of Inheritable Sperm Histones and Early Embryonic Gene Expression

To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo

Nicotinic Acid Receptor Abnormalities in Human Skin Cancer: Implications for a Role in Epidermal Differentiation

Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein-coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells.Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis

Characterization of BRD4 during mammalian post-meiotic sperm development

During spermiogenesis, the post-meiotic phase of mammalian spermatogenesis, transcription is progressively repressed as nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with protamines. Although BRDT functions in transcription and histone removal in spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of spermatogenic cells revealed BRD4 in a ring around the nuclei of spermatids containing hyper-acetylated histones. The ring lies directly adjacent to the acroplaxome, the cytoskeletal base of the acrosome, previously linked to chromatin reorganization. The BRD4 ring does not form in acrosomal mutant mice. ChIP sequencing in spermatids revealed enrichment of BRD4 and acetylated histones at the promoters of active genes. BRD4 and BRDT show distinct and synergistic binding patterns, with a pronounced enrichment of BRD4 at spermatogenesis-specific genes. Direct association of BRD4 with acetylated H4 decreases in late spermatids as acetylated histones are removed from the condensing nucleus in a wave following the progressing acrosome. These data provide evidence for a prominent transcriptional role of BRD4 and suggest a possible removal mechanism for chromatin components from the genome via the progressing acrosome as transcription is repressed in response to chromatin condensation during spermiogenesis

Creation of maximally entangled photon-number states using optical fiber multiports

We theoretically demonstrate a method for producing the maximally path-entangled state (1/Sqrt[2]) (|N,0> + exp[iN phi] |0,N>) using intensity-symmetric multiport beamsplitters, single photon inputs, and either photon-counting postselection or conditional measurement. The use of postselection enables successful implementation with non-unit efficiency detectors. We also demonstrate how to make the same state more conveniently by replacing one of the single photon inputs by a coherent state.Comment: 4 pages, 1 figure. REVTeX4. Replaced with published versio

Delayed union of femoral fractures in older rats:decreased gene expression

BACKGROUND: Fracture healing slows with age. While 6-week-old rats regain normal bone biomechanics at 4 weeks after fracture, one-year-old rats require more than 26 weeks. The possible role of altered mRNA gene expression in this delayed union was studied. Closed mid-shaft femoral fractures were induced followed by euthanasia at 0 time (unfractured) or at 1, 2, 4 or 6 weeks after fracture in 6-week-old and 12-15-month-old Sprague-Dawley female rats. mRNA levels were measured for osteocalcin, type I collagen α1, type II collagen, bone morphogenetic protein (BMP)-2, BMP-4 and the type IA BMP receptor. RESULTS: For all of the genes studied, the mRNA levels increased in both age groups to a peak at one to two weeks after fracture. All gene expression levels decreased to very low or undetectable levels at four and six weeks after fracture for both age groups. At four weeks after fracture, the younger rats were healed radiographically, but not the older rats. CONCLUSIONS: (1) All genes studied were up-regulated by fracture in both age groups. Thus, the failure of the older rats to heal promptly was not due to the lack of expression of any of the studied genes. (2) The return of the mRNA gene expression to baseline values in the older rats prior to healing may contribute to their delayed union. (3) No genes were overly up-regulated in the older rats. The slower healing response of the older rats did not stimulate a negative-feedback increase in the mRNA expression of stimulatory cytokines

Liberal intervention in the foreign policy thinking of Tony Blair and David Cameron

David Cameron was a critic of Tony Blair’s doctrine of the international community, which was used to justify war in Kosovo and more controversially in Iraq, suggesting caution in projecting military force abroad while in opposition. However, and in spite of making severe cuts to the defence budget, the Cameron-led Coalition government signed Britain up to a military intervention in Libya within a year of coming into office. What does this say about the place liberal interventionism occupies in contemporary British foreign policy? To answer this question, this article studies the nature of what we describe as the ‘bounded liberal’ tradition that has informed British foreign policy thinking since 1945, suggesting that it puts a distinctly UK national twist on conventional conservative thought about international affairs. Its components are: scepticism of grand schemes to remake the world; instinctive Atlanticism; security through collective endeavour; and anti-appeasement. We then compare and contrast the conditions for intervention set out by Tony Blair and David Cameron. We explain the similarities but crucially also the vital differences between the two leaders’ thinking on intervention, with particular reference to Cameron’s perception that Downing Street needed to loosen its control over foreign policy-making after Iraq. Our argument is that policy substance, policy style and party political dilemmas prompted Blair and Cameron to reconnect British foreign policy with its ethical roots, ingraining a bounded liberal posture to British foreign policy after the moral bankruptcy of the John Major years. This return to a patient, pragmatic and ethically informed foreign policy meant that military operations in Kosovo and Libya were undertaken in quite different circumstances, yet came to be justified by similar arguments from the two leaders