A Study of the myc Gene in Feline Leukaemias

I isolated and characterised a clone of the normal feline c-myc gene. Sequence analysis showed the gene to be highly related in other mammals but less well related in the chicken. The feline c-myc gene possessed an apparently non-coding first exon with a dual promoter structure, similar to that found in the human and mouse c-myc genes. The sequences of three independent FeLV v-myc genes were compared to that of the c-myc gene to identify possible structural alterations involved in myc oncogenic activation. The c-myc clone also provided probes to map c-myc rearrangements in feline thymic lymphosarcomas. Some rearrangements were due to FeLV integration within or upstream of c-myc, but one case involved a complex 3' alteration which was apparently not directly virus-induced. S1 nuclease mapping of RNA from normal cells using c-myc probes located 5' discontinuities to each of the two promoter-like sequences (P1 and P2), and a major 3' discontinuity mapping to the most 3' of two possible polyadenylation signals. Tumours carrying c-myc rearrangements did not display readily obvious abnormalities in the structure or levels of c-myc RNA, except for case T24 which appeared to contain RNA lacking exon 1 sequences. However, the ratio of P1 to P2 RNAs detected in tumours varied considerably and was high in tumours with a rearrangement adjacent to c-myc, although it was equally high in some tumours with an ostensibly normal c-myc gene structure. There was a consistent lack of detectable RNA from normal c-myc alleles in tumours containing different myc-transducing FeLVs. Also, in tumour T24 which expressed a rearranged c-myc gene, RNA from the normal c-myc allele could not be detected. The phenotype of thymic tumours was characterised with respect to expression of RNA of the a and beta-chains of the T-cell antigen receptor (TCR). Several tumours, including all those induced by two myc-transducing FeLVs and others carrying a rearranged c-myc gene, contained TCR a and beta-chain transcripts. This study provided preliminary evidence that one tumour contained independently transduced myc and beta-chain TCR genes present in separate FeLV proviruses, suggesting a direct role for TCR genes in oncogenesis

TheEffects of Decision Aid Recommendations on Users’ Cognitive Processes, Memories, and Judgments

This study extends the existing decision aid literature by examining the influence of decision aid recommendations on users’ memories, decision processes, and judgments. Existing research suggests that decision aids can be beneficial in a variety of settings. Judgments or decisions, the outputs of the decision- making process, are the focus of most of the decision aid research. This study offers a more comprehensive investigation of the impact of decision aids by examining both the outputs of the decision-making process and the inputs and processes that lead to judgment and decision-making. An experiment is conducted that examines the influence of decision aid recommendations on memory patterns, search, cue usage, and judgments. Specifically, the study focuses on how positive and negative decision aid recommendations and the timing of receipt of the decision aid recommendation differentially affect these components of the decision process. The key findings of the research are: (1) decision aid recommendations create strong affective responses that are encoded in memory and cause users to reconstruct memories of financial data to be consistent with the affective response, (2) receiving a decision aid recommendation at the start of a task creates a strong initial response that acts as an initial hypothesis wherein users’ subsequent information search patterns exhibit a confirming bias, (3) receiving a decision aid recommendation later in the task creates a strong response that initiates professional skepticism and causes users’ subsequent information search patterns to exhibit a disconfirming bias, (4) decision aid recommendations influence the choice of information cues users believe to be important, (5) decision aid recommendations exert influence on users’ judgments, with the amount of influence diminishing as additional information is received, and (6) working memory capacity is a determinant in the ability to recall financial information but does not determine the extent of influence decision aid recommendations have on users. These findings, when considered together, validate the need for a more complete examination of how decision aids impact the entire decision-making process to identify potential negative consequences in addition to proposed benefits. This research demonstrates that task structure can be manipulated to mitigate certain undesirable consequences of decision aid use

1A. Thyroid hormone receptors in GtoPdb v.2023.1

Thyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [12, 2]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [42]

1A. Thyroid hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Thyroid hormone receptors (TRs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [10]) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (T4) and thyroid hormone (triiodothyronine). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. NH-3 has been described as an antagonist at TRs with modest selectivity for TRβ [38]

Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors

The deafness caused by early onset hypothyroidism indicates that thyroid hormone is essential for the development of hearing. We investigated the underlying roles of the TRa1 and TRß thyroid hormone receptors in the auditory system using receptor-deficient mice. TRa1 and TRß, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRß is required for hearing because TRß-deficient (Thrb tm1/tm1) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I K,f) in the cochlear inner hair cells. Here, we show that although TRa1 is individually dispensable, TRa1 and TRß synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb tm1/tm1 mice, the deletion of all TRs inThra tm1/tm1 Thrb tm1/tm1mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction ofI K,f in inner hair cells was not markedly more retarded than in Thrb tm1/tm1mice, suggesting that this feature of hair cell maturation is primarily TRß-dependent. These results indicate that distinct pathways mediated by TRß alone or by TRß and TRa1 together facilitate control over an extended range of functions during the maturation of the cochlea

Are "part-time" general practitioners workforce idlers or committed professionals?

BACKGROUND: The traditional view of general practice holds that only general practitioners (GPs) in full-time clinical practice can provide quality patient care. Nevertheless, increasing numbers of GPs are choosing to work sessionally, that is, ostensibly “part-time”. There are concerns about the health workforce’s ability to meet demand and also fears that patient care may be compromised. We sought answers to a) what activities do GPs undertake when not consulting patients, b) why do they choose to work sessionally, and c) does sessional general practice reflect a lack of commitment to patients and the profession? METHODS: Semi-structured interviews were conducted with GPs who worked sessionally, (i.e. six or fewer sessions a week in clinical general practice, where a session comprises four consecutive hours of patient care). These data were analysed qualitatively and saturation was reached. RESULTS: The majority of participants were in full-time paid employment, while part-time in clinical general practice. They reported that consultations increasingly required the management of patients with complex, chronic conditions who also required psychological management. Coupled with unrealistic patient expectations, these factors led GPs to be concerned about maintaining the quality patient care they considered professionally desirable. Many diversified their work activities to ensure that they retained their professional standards. CONCLUSIONS: “Part-time” general practice is a misnomer that masks the contribution these GPs make as part of the health workforce. Sessional practice more accurately describes the nature of our participants’ clinical work. Their choice of sessional work is a professional response to the increasing demands within the consultation. It enables GPs to maintain their commitment to quality patient care and their profession, while attenuating the challenges of demanding consultations. Sessional general practitioners demonstrate strong commitment to their patients and the profession

An intronic SNP in the thyroid hormone receptor β gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor β2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone

<p>Abstract</p> <p>Background</p> <p>The syndrome of resistance to thyroid hormone (RTH) is caused by mutations in the thyroid hormone receptor β gene (<it>THRB</it>). The syndrome varies from asymptomatic to diffuse hypothyroidism, to pituitary-selective resistance with predominance of hyperthyroid signs and symptoms. The wide spectrum of clinical presentation is not completely attributable to specific <it>THRB </it>mutations. The <it>THRB </it>gene encodes two main isoforms, TR β1 which is widely distributed, and TR β2, whose expression is limited to the cochlea, retina, hypothalamus, and pituitary. Recent data demonstrated that in mice an intron enhancer region plays a critical role in the pituitary expression of the β2 isoform of the receptor. We thus hypothesized that polymorphisms in the human homologous region could modulate the pituitary expression of the mutated gene contributing to the clinical presentation of RTH.</p> <p>Methods</p> <p>Screening and <it>in vitro </it>characterization of polymorphisms of the intron enhancer region of the <it>THRB </it>gene in the index case of pituitary-selective RTH.</p> <p>Results</p> <p>The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in <it>cis </it>with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the <it>THRB </it>gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR β2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele.</p> <p>Conclusions</p> <p>The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases.</p

Effects of a nanoscopic filler on the structure and dynamics of a simulated polymer melt and the relationship to ultra-thin films

We perform molecular dynamics simulations of an idealized polymer melt surrounding a nanoscopic filler particle to probe the effects of a filler on the local melt structure and dynamics. We show that the glass transition temperature $T_g$ of the melt can be shifted to either higher or lower temperatures by appropriately tuning the interactions between polymer and filler. A gradual change of the polymer dynamics approaching the filler surface causes the change in the glass transition. We also find that while the bulk structure of the polymers changes little, the polymers close to the surface tend to be elongated and flattened, independent of the type of interaction we study. Consequently, the dynamics appear strongly influenced by the interactions, while the melt structure is only altered by the geometric constraints imposed by the presence of the filler. Our findings show a strong similarity to those obtained for ultra-thin polymer films (thickness $\lesssim 100$ nm) suggesting that both ultra-thin films and filled-polymer systems might be understood in the same context

The Kepler Science Operations Center Pipeline Framework Extensions

The Kepler Science Operations Center (SOC) is responsible for several aspects of the Kepler Mission, including managing targets, generating on-board data compression tables, monitoring photometer health and status, processing the science data, and exporting the pipeline products to the mission archive. We describe how the generic pipeline framework software developed for Kepler is extended to achieve these goals, including pipeline configurations for processing science data and other support roles, and custom unit of work generators that control how the Kepler data are partitioned and distributed across the computing cluster. We describe the interface between the Java software that manages the retrieval and storage of the data for a given unit of work and the MATLAB algorithms that process these data. The data for each unit of work are packaged into a single file that contains everything needed by the science algorithms, allowing these files to be used to debug and evolve the algorithms offline

Detection of Potential Transit Signals in the First Three Quarters of Kepler Mission Data

We present the results of a search for potential transit signals in the first three quarters of photometry data acquired by the Kepler Mission. The targets of the search include 151,722 stars which were observed over the full interval and an additional 19,132 stars which were observed for only 1 or 2 quarters. From this set of targets we find a total of 5,392 detections which meet the Kepler detection criteria: those criteria are periodicity of the signal, an acceptable signal-to-noise ratio, and a composition test which rejects spurious detections which contain non-physical combinations of events. The detected signals are dominated by events with relatively low signal-to-noise ratio and by events with relatively short periods. The distribution of estimated transit depths appears to peak in the range between 40 and 100 parts per million, with a few detections down to fewer than 10 parts per million. The detected signals are compared to a set of known transit events in the Kepler field of view which were derived by a different method using a longer data interval; the comparison shows that the current search correctly identified 88.1% of the known events. A tabulation of the detected transit signals, examples which illustrate the analysis and detection process, a discussion of future plans and open, potentially fruitful, areas of further research are included