Consonance in the carillon.

Previous psychological studies have shown that musical consonance is not only determined by the frequency ratios between tones, but also by the frequency spectra of those tones. However, these prior studies used artificial tones, specifically tones built from a small number of pure tones, which do not match the acoustic complexity of real musical instruments. The present experiment therefore investigates tones recorded from a real musical instrument, the Westerkerk Carillon, conducting a "dense rating" experiment where participants (N = 113) rated musical intervals drawn from the continuous range 0-15 semitones. Results show that the traditional consonances of the major third and the minor sixth become dissonances in the carillon and that small intervals (in particular 0.5-2.5 semitones) also become particularly dissonant. Computational modelling shows that these effects are primarily caused by interference between partials (e.g., beating), but that preference for harmonicity is also necessary to produce an accurate overall account of participants' preferences. The results support musicians' writings about the carillon and contribute to ongoing debates about the psychological mechanisms underpinning consonance perception, in particular disputing the recent claim that interference is largely irrelevant to consonance perception.

Broadband electrical impedance as a novel characterization of oxidative stress in single L6 skeletal muscle cells.

Oxidative stress (OS) is one of the leading causes of cytotoxicity and is linked to many human physio-pathological conditions. In particular, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) induced by OS is debilitating to quality of life, while no clear biological markers have been identified for diagnostic measures. Recently, impedance measurements of peripheral blood cells of ME/CFS patients have been shown as a promising approach to diagnose the disease. Inspired by this study and aiming to interrogate muscle cells directly, we investigated if broadband measurements of single muscle cells could differentiate normal and oxidatively stressed cell populations. We first optimized a protocol through H2O2 treatment to introduce oxidative stress to cultured rat L6 skeletal muscle cells. The treated cells were further characterized through broadband impedance spectroscopy of single cells using a microfluidic lab-on-a-chip system. The resulting dielectric properties of cytoplasm permittivity and conductivity are electrically distinct from normally cultured cells. The reflection and transmission coefficients, ΔS11 and ΔS21, of the normal cells are tightly clustered and closely resemble those of the cell-free solution across the frequency range of 9 kHz to 9 GHz. On the other hand, dielectric properties of the oxidized cells have a wide distribution in the GHz range, deviating both in the positive and negative directions from the normally cultured cells. Simulation results guide our hypothesis that the dielectric differences could be linked to ion alterations, while calcium imaging directly supports the contribution of calcium flux to the observed deviation of S parameters. The unique electrical profile associated with oxidized cells in the GHz frequencies provide a framework for future development of technologies to diagnose oxidative-stress related diseases such as ME/CFS.

E151 (sym15), a pleiotropic mutant of pea (Pisum sativum L.), displays low nodule number, enhanced mycorrhizae, delayed lateral root emergence, and high root cytokinin levels.

In legumes, the formation of rhizobial and mycorrhizal root symbioses is a highly regulated process which requires close communication between plant and microorganism. Plant mutants that have difficulties establishing symbioses are valuable tools for unravelling the mechanisms by which these symbioses are formed and regulated. Here E151, a mutant of Pisum sativum cv. Sparkle, was examined to characterize its root growth and symbiotic defects. The symbioses in terms of colonization intensity, functionality of micro-symbionts, and organ dominance were compared between the mutant and wild type. The endogenous cytokinin (CK) and abscisic acid (ABA) levels and the effect of the exogenous application of these two hormones were determined. E151 was found to be a low and delayed nodulator, exhibiting defects in both the epidermal and cortical programmes though a few mature and functional nodules develop. Mycorrhizal colonization of E151 was intensified, although the fungal functionality was impaired. Furthermore, E151 displayed an altered lateral root (LR) phenotype compared with that of the wild type whereby LR emergence is initially delayed but eventually overcome. No differences in ABA levels were found between the mutant and the wild type, but non-inoculated E151 exhibited significantly high CK levels. It is hypothesized that CK plays an essential role in differentially mediating the entry of the two micro-symbionts into the cortex; whereas it would inhibit the entry of the rhizobia in that tissue, it would promote that of the fungus. E151 is a developmental mutant which may prove to be a useful tool in further understanding the role of hormones in the regulation of beneficial root symbioses.

Solitary Large Intestinal Diverticulitis in Leatherback Turtles (Dermochelys coriacea).

Leatherback sea turtles are globally distributed and endangered throughout their range. There are limited data available on disease in this species. Initial observations of solitary large intestinal diverticulitis in multiple leatherbacks led to a multi-institutional review of cases. Of 31 subadult and adult turtles for which complete records were available, all had a single exudate-filled diverticulum, as large as 9.0 cm in diameter, arising from the large intestine immediately distal to the ileocecal junction. All lesions were chronic and characterized by ongoing inflammation, numerous intralesional bacteria, marked attenuation of the muscularis, ulceration, and secondary mucosal changes. In three cases, Morganella morganii was isolated from lesions. Diverticulitis was unrelated to the cause of death in all cases, although risk of perforation and other complications are possible.

Environmental determinants of Ixodes ricinus ticks and the incidence of Borrelia burgdorferi sensu lato, the agent of Lyme borreliosis, in Scotland.

Lyme borreliosis (LB) is the most common arthropod-borne disease of humans in the Northern hemisphere. In Europe, the causative agent, Borrelia burgdorferi sensu lato complex, is principally vectored by Ixodes ricinus ticks. The aim of this study was to identify environmental factors influencing questing I. ricinus nymph abundance and B. burgdorferi s.l. infection in questing nymphs using a large-scale survey across Scotland. Ticks, host dung and vegetation were surveyed at 25 woodland sites, and climatic variables from a Geographical Information System (GIS) were extracted for each site. A total of 2397 10 m2 transect surveys were conducted and 13 250 I. ricinus nymphs counted. Questing nymphs were assayed for B. burgdorferi s.l. and the average infection prevalence was 5·6% (range 0·8-13·9%). More questing nymphs and higher incidence of B. burgdorferi s.l. infection were found in areas with higher deer abundance and in mixed/deciduous compared to coniferous forests, as well as weaker correlations with season, altitude, rainfall and ground vegetation. No correlation was found between nymph abundance and infection prevalence within the ranges encountered. An understanding of the environmental conditions associated with tick abundance and pathogen prevalence may be used to reduce risk of exposure and to predict future pathogen prevalence and distributions under environmental changes.

Control of descending vasa recta pericyte membrane potential by angiotensin II.

Using nystatin perforated-patch whole cell recording, we investigated the role of Cl(-) conductance in the modulation of outer medullary descending vasa recta (OMDVR) pericyte membrane potential (Psi m) by ANG II. ANG II (10(-11) to 10(-7) M) consistently depolarized OMDVR and induced Psi m oscillations at lower concentrations. The Cl(-) channel blockers anthracene-9-decarboxylate (1 mM) and niflumic acid (10 microM) hyperpolarized resting pericytes and repolarized ANG II-treated pericytes. In voltage-clamp experiments, ANG II-treated pericytes exhibited slowly activating currents that were nearly eliminated by treatment with niflumic acid (10 microM) or removal of extracellular Ca(2+). Those currents reversed at -31 and -10 mV when extracellular Cl(-) concentration was 152 and 34 mM, respectively. In pericytes held at -70 mV, oscillating inward currents were sometimes observed; the reversal potential also shifted with extracellular Cl(-) concentration. We conclude that ANG II activates a Ca(2+)-dependent Cl(-) conductance in OMDVR pericytes to induce membrane depolarization and Psi m oscillations.

Alternative product of the p16/CKDN2A locus connects the Rb and p53 tumor suppressors.

Two distinct products are specified by the CDKN2A locus, the p16INK4a cyclin dependent kinase inhibitor and a protein termed ARF. ARF has been shown to bind to the Mdm2-p53 complex, resulting in stabilisation of both proteins, and a feedback loop exists through which ARF levels are negatively regulated by p53. Significantly, ARF expression is positively regulated by members of the E2F family of transcription factors. This provides a link between the Rb and p53 pathways and a mechanism whereby inactivation of Rb and release of E2F will lead to the stabilisation and functional activation of p53. The alternative exon encoding the functional amino terminal portion of ARF presumably represents an independent gene that has become co-localized with p16INK4a in order to exploit a common regulatory mechanism or purpose.

Translational control by the La antigen. Structure requirements for rescue of the double-stranded RNA-mediated inhibition of protein synthesis.

The La antigen is a protein which can bind both single-stranded and double-stranded forms of RNA and has regulatory effects on gene expression at the levels of transcription and translation. It was previously shown to inhibit the activation of the dsRNA-dependent protein kinase PKR by sequestering and/or unwinding double-stranded RNA. Here, we demonstrate that, as predicted by these properties, the La antigen can rescue protein synthesis in the reticulocyte lysate system from inhibition by low concentrations of dsRNA. This effect is reversed by higher concentrations of dsRNA. Using a series of deletion mutants we have investigated the structural features of the La antigen that are required for these effects. The ability to bind dsRNA is influenced by regions within both the previously characterized N-terminal RNP motif and the C-terminal half of the protein. La mutants with either N-terminal or C-terminal deletions retain the ability to inhibit the protein kinase activity of PKR and to rescue protein synthesis from inhibition by dsRNA. It is notable that sequences in the C-terminal half of the La antigen, including a phosphorylation site at Ser366, which are needed for other regulatory effects of the protein on gene expression are dispensable for the effects of La on PKR. We suggest that La regulates PKR activity solely as a result of its ability to act as an RNA-binding protein that can compete with PKR for limiting amounts of dsRNA.

Urinary symptoms and incontinence in women: relationships between occurrence, age, and perceived impact.

BACKGROUND: The prevalence of urinary symptoms that impact on quality-of-life will be important in determining resource allocation in primary care groups. AIM: To determine the prevalence of urinary symptoms and their perceived impact in a community population of women. METHOD: A postal survey using a validated self-completed questionnaire among all women aged over 18 years and registered with one general practice in a major British city. The prevalence rates and perceived impact of a wide range of urinary symptoms and their relationship with age was determined. Data were analysed using the chi-squared test and the chi-squared test for trend. Spearman's rank correlation was used to assess the relationship between symptom severity and perceived impact. RESULTS: The number of completed questionnaires returned was 2075, giving an 80% response rate. Of these, the number of women who reported some degree of incontinence in the previous month was 1414 (69%), although only 578 (30%) indicated that it had social or hygienic impact. Other lower urinary tract symptoms reported included nocturia (19%), poor stream (19%), urgency (61%), and dysuria (23%). The most troublesome symptoms were incontinence for no obvious reason, nocturnal incontinence, and nocturia, with 73%, 69%, and 63% of sufferers, respectively, finding these symptoms troublesome. CONCLUSIONS: Incontinence and other urinary symptoms are more common than previously thought. These symptoms are not always perceived as bothersome or as having a social or hygienic impact, and therefore many women who report urinary leakage do not require treatment. Nocturnal symptoms in women are commoner than might have been supposed and are extremely troublesome to sufferers.

The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2.

The two distinct proteins encoded by the CDKN2A locus are specified by translating the common second exon in alternative reading frames. The product of the alpha transcript, p16(INK4a), is a recognized tumour suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of the retinoblastoma protein by the cyclin-dependent kinases, CDK4 and CDK6. In contrast, the product of the human CDKN2A beta transcript, p14(ARF), activates a p53 response manifest in elevated levels of MDM2 and p21(CIP1) and cell cycle arrest in both G1 and G2/M. As a consequence, p14(ARF)-induced cell cycle arrest is p53 dependent and can be abrogated by the co-expression of human papilloma virus E6 protein. p14(ARF) acts by binding directly to MDM2, resulting in the stabilization of both p53 and MDM2. Conversely, p53 negatively regulates p14(ARF) expression and there is an inverse correlation between p14(ARF) expression and p53 function in human tumour cell lines. However, p14(ARF) expression is not involved in the response to DNA damage. These results place p14(ARF) in an independent pathway upstream of p53 and imply that CDKN2A encodes two proteins that are involved in tumour suppression.

Activation of 2'-5' oligoadenylate synthetase by single-stranded and double-stranded RNA aptamers.

A number of small RNA molecules that are high affinity ligands for the 46-kDa form of human 2'-5' oligoadenylate synthetase have been identified by the SELEX method. Surface plasmon resonance analysis indicates that these RNAs bind to the enzyme with dissociation constants in the nanomolar range. Competition experiments indicate that the binding site for the small RNAs on the 2'-5' oligoadenylate synthetase molecule at least partially overlaps that for the synthetic double-stranded RNA, poly(I).poly(C). Several of the RNAs function as potent activators of 2'-5' oligoadenylate synthetase in vitro, although there is no correlation between binding affinity and ability to activate. The RNA aptamers having the strongest activation potential appear to have few base-paired regions. This suggests that 2'-5' oligoadenylate synthetase, which has previously been believed to be activated only by double-stranded RNA, can also be activated by RNA ligands with little secondary structure. Since 2'-5' oligoadenylate synthetase possesses no homology to other known RNA-binding proteins, the development of small specific ligands by SELEX should facilitate studies of RNA-protein interactions and may reveal novel features of the structure-function relationships involving this enzyme.

The La antigen inhibits the activation of the interferon-inducible protein kinase PKR by sequestering and unwinding double-stranded RNA.

The La (SS-B) autoimmune antigen is an RNA-binding protein that is present in both nucleus and cytoplasm of eukaryotic cells. The spectrum of RNAs that interact with the La antigen includes species which also bind to the interferon-inducible protein kinase PKR. We have investigated whether the La antigen can regulate the activity of PKR and have observed that both the autophosphorylation of the protein kinase that accompanies its activation by dsRNA and the dsRNA-dependent phosphorylation of the alpha subunit of polypeptide chain initiation factor eIF-2 by PKR are inhibited in the presence of recombinant La antigen. This inhibition is partially relieved at higher concentrations of dsRNA. Once activated by dsRNA the protein kinase activity of PKR is insensitive to the La antigen. We have demonstrated by a filter binding assay that La is a dsRNA binding protein. Furthermore, when recombinant La is incubated with a 900 bp synthetic dsRNA or with naturally occurring reovirus dsRNA it converts these substrates to single-stranded forms. We conclude that the La antigen inhibits the dsRNA-dependent activation of PKR by binding and unwinding dsRNA and that it may therefore play a role in the regulation of this protein kinase in interferon-treated or virus-infected cells.

Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs.

This review describes the structure and function of the double-stranded RNA-dependent protein kinase (PKR) and its interaction with RNA activators and inhibitors. The abilities of small virally-encoded RNAs such as VAI RNA of adenovirus, the Epstein-Barr virus encoded (EBER) RNAs and the Tat-responsive region RNA of HIV-1 to bind to and regulate PKR are reviewed, and the physiological implications of such regulation for the control of viral replication and cell growth are discussed. The potential effects on the activity of PKR of other proteins that bind double-stranded RNA and/or small viral and cellular RNAs are also considered.

Physical therapy for patients after bone marrow transplantation.

The purpose of this article is to provide an overview of bone marrow transplantation (BMT) as it relates to the practice of physical therapy based on experiences at a cancer research center. This overview includes information on the diseases treated with BMT, patient treatment regimens during hospitalization, and complications commonly encountered. Physical therapy guidelines are suggested for the evaluation of and therapeutic intervention for patients after BMT.

Trisomy of 1q in preleukaemia with progression to acute leukaemia.

Marrow cells from an untreated man with preleukaemia were found to have trisomy for the long arm of chromosome 1 which was translocated to the end of the long arm of number 11, i.e., 46,XY, -11,+t (1:11) (q11 or q12; q25). The same abnormality was found in metaphases from 8 individual granulocytic colonies. With development of acute myelomonocytic leukaemia, in addition to the basic chromosome abnormality, trisomy of chromosome 8 and an extra chromosome number 19 with partial deletion were found. Fibroblasts grown from marrow biopsy material showed a normal diploid complement, 46,XY.