Perceiving Nasal Patency through Mucosal Cooling Rather than Air Temperature or Nasal Resistance

Adequate perception of nasal airflow (i.e., nasal patency) is an important consideration for patients with nasal sinus diseases. The perception of a lack of nasal patency becomes the primary symptom that drives these patients to seek medical treatment. However, clinical assessment of nasal patency remains a challenge because we lack objective measurements that correlate well with what patients perceive.The current study examined factors that may influence perceived patency, including air temperature, humidity, mucosal cooling, nasal resistance, and trigeminal sensitivity. Forty-four healthy subjects rated nasal patency while sampling air from three facial exposure boxes that were ventilated with untreated room air, cold air, and dry air, respectively. In all conditions, air temperature and relative humidity inside each box were recorded with sensors connected to a computer. Nasal resistance and minimum airway cross-sectional area (MCA) were measured using rhinomanometry and acoustic rhinometry, respectively. General trigeminal sensitivity was assessed through lateralization thresholds to butanol. No significant correlation was found between perceived patency and nasal resistance or MCA. In contrast, air temperature, humidity, and butanol threshold combined significantly contributed to the ratings of patency, with mucosal cooling (heat loss) being the most heavily weighted predictor. Air humidity significantly influences perceived patency, suggesting that mucosal cooling rather than air temperature alone provides the trigeminal sensation that results in perception of patency. The dynamic cooling between the airstream and the mucosal wall may be quantified experimentally or computationally and could potentially lead to a new clinical evaluation tool

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Foot posture in people with medial compartment knee osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Foot posture has long been considered to contribute to the development of lower limb musculoskeletal conditions as it may alter the mechanical alignment and dynamic function of the lower limb. This study compared foot posture in people with and without medial compartment knee osteoarthritis (OA) using a range of clinical foot measures. The reliability of the foot measures was also assessed.</p> <p>Methods</p> <p>The foot posture of 32 patients with clinically and radiographically-confirmed OA predominantly in the medial compartment of the knee and 28 asymptomatic age-matched healthy controls was investigated using the foot posture index (FPI), vertical navicular height and drop, and the arch index. Independent t tests and effect size (Cohen's d) were used to investigate the differences between the groups in the foot posture measurements.</p> <p>Results</p> <p>Significant differences were found between the control and the knee OA groups in relation to the FPI (1.35 ± 1.43 vs. 2.46 ± 2.18, p = 0.02; <it>d </it>= 0.61, medium effect size), navicular drop (0.02 ± 0.01 vs. 0.03 ± 0.01, p = 0.01; <it>d </it>= 1.02, large effect size) and the arch index (0.22 ± 0.04 vs. 0.26 ± 0.04, p = 0.04; <it>d </it>= 1.02, large effect size). No significant difference was found for vertical navicular height (0.24 ± 0.03 vs. 0.23 ± 0.03, p = 0.54; <it>d </it>= 0.04, negligible effect size).</p> <p>Conclusion</p> <p>People with medial compartment knee OA exhibit a more pronated foot type compared to controls. It is therefore recommended that the assessment of patients with knee OA in clinical practice should include simple foot measures, and that the potential influence of foot structure and function on the efficacy of foot orthoses in the management of medial compartment knee OA be further investigated.</p

The Center for Eukaryotic Structural Genomics

The Center for Eukaryotic Structural Genomics (CESG) is a “specialized” or “technology development” center supported by the Protein Structure Initiative (PSI). CESG’s mission is to develop improved methods for the high-throughput solution of structures from eukaryotic proteins, with a very strong weighting toward human proteins of biomedical relevance. During the first three years of PSI-2, CESG selected targets representing 601 proteins from Homo sapiens, 33 from mouse, 10 from rat, 139 from Galdieria sulphuraria, 35 from Arabidopsis thaliana, 96 from Cyanidioschyzon merolae, 80 from Plasmodium falciparum, 24 from yeast, and about 25 from other eukaryotes. Notably, 30% of all structures of human proteins solved by the PSI Centers were determined at CESG. Whereas eukaryotic proteins generally are considered to be much more challenging targets than prokaryotic proteins, the technology now in place at CESG yields success rates that are comparable to those of the large production centers that work primarily on prokaryotic proteins. We describe here the technological innovations that underlie CESG’s platforms for bioinformatics and laboratory information management, target selection, protein production, and structure determination by X-ray crystallography or NMR spectroscopy

Word Processing differences between dyslexic and control children

BACKGROUND: The aim of this study was to investigate brain responses triggered by different wordclasses in dyslexic and control children. The majority of dyslexic children have difficulties to phonologically assemble a word from sublexical parts following grapheme-to-phoneme correspondences. Therefore, we hypothesised that dyslexic children should mainly differ from controls processing low frequent words that are unfamiliar to the reader. METHODS: We presented different wordclasses (high and low frequent words, pseudowords) in a rapid serial visual word (RSVP) design and performed wavelet analysis on the evoked activity. RESULTS: Dyslexic children had lower evoked power amplitudes and a higher spectral frequency for low frequent words compared to control children. No group differences were found for high frequent words and pseudowords. Control children had higher evoked power amplitudes and a lower spectral frequency for low frequent words compared to high frequent words and pseudowords. This pattern was not present in the dyslexic group. CONCLUSION: Dyslexic children differed from control children only in their brain responses to low frequent words while showing no modulated brain activity in response to the three word types. This might support the hypothesis that dyslexic children are selectively impaired reading words that require sublexical processing. However, the lacking differences between word types raise the question if dyslexic children were able to process the words presented in rapid serial fashion in an adequate way. Therefore the present results should only be interpreted as evidence for a specific sublexical processing deficit with caution

Winter weather controls net influx of atmospheric CO2 on the north-west European shelf

Shelf seas play an important role in the global carbon cycle, absorbing atmospheric carbon dioxide (CO2) and exporting carbon (C) to the open ocean and sediments. The magnitude of these processes is poorly constrained, because observations are typically interpolated over multiple years. Here, we used 298500 observations of CO2 fugacity (fCO2) from a single year (2015), to estimate the net influx of atmospheric CO2 as 26.2 ± 4.7 Tg C yr-1 over the open NW European shelf. CO2 influx from the atmosphere was dominated by influx during winter as a consequence of high winds, despite a smaller, thermally-driven, air-sea fCO2 gradient compared to the larger, biologically-driven summer gradient. In order to understand this climate regulation service, we constructed a carbon-budget supplemented by data from the literature, where the NW European shelf is treated as a box with carbon entering and leaving the box. This budget showed that net C-burial was a small sink of 1.3 ± 3.1 Tg C yr-1, while CO2 efflux from estuaries to the atmosphere, removed the majority of river C-inputs. In contrast, the input from the Baltic Sea likely contributes to net export via the continental shelf pump and advection (34.4 ± 6.0 Tg C yr-1)

Key Uncertainties in the Recent Air‐Sea Flux of CO 2

The contemporary air-sea flux of CO2 is investigated by the use of an air-sea flux equation, with particular attention to the uncertainties in global values and their origin with respect to that equation. In particular, uncertainties deriving from the transfer velocity and from sparse upper ocean sampling are investigated. Eight formulations of air-sea gas transfer velocity are used to evaluate the combined standard uncertainty resulting from several sources of error. Depending on expert opinion, a standard uncertainty in transfer velocity of either ~5% or ~10% can be argued and that will contribute a proportional error in air-sea flux. The limited sampling of upper ocean fCO2 is readily apparent in the Surface Ocean CO2 Atlas (SOCAT) databases. The effect of sparse sampling on the calculated fluxes was investigated by a bootstrap method; i.e. treating each ship cruise to an oceanic region as a random episode and creating 10 synthetic datasets by randomly selecting episodes with replacement. Convincing values of global net air-sea flux can only be achieved using upper ocean data collected over several decades, but referenced to a standard year. The global annual referenced values are robust to sparse sampling, but seasonal and regional values exhibit more sampling uncertainty. Additional uncertainties are related to thermal and haline effects and to aspects of air-sea gas exchange not captured by standard models. An estimate of global net CO2 exchange referenced to 2010 of -3.0 ± 0.6 Pg C yr-1 is proposed, where the uncertainty derives primarily from uncertainty in the transfer velocit

Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells

INTRODUCTION: Activation of the type I insulin-like growth factor receptor (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. Transgenic mice expressing a constitutively active IGFIR or IGF-I develop mammary tumors and increased levels of IGFIR have been detected in primary breast cancers. However, the contribution of IGFIR activation in promoting breast cancer progression remains unknown. Mammary epithelial cell lines grown in three-dimensional cultures form acinar structures that mimic the round, polarized, hollow and growth-arrested features of mammary alveoli. We used this system to determine how proliferation and survival signaling by IGFIR activation affects breast epithelial cell biology and contributes to breast cancer progression. METHODS: Pooled, stable MCF-10A breast epithelial cells expressing wild-type IGFIR or kinase-dead IGFIR (K1003A) were generated using retroviral-mediated gene transfer. The effects of over-expression of wild-type or kinase-dead IGFIR on breast epithelial cell biology were analyzed by confocal microscopy of three-dimensional cultures. The contribution of signaling pathways downstream of IGFIR activation to proliferation and apoptosis were determined by pharmacological inhibition of phosphatidylinositol 3' kinase (PI3K) with LY294002, MAP kinase kinase (MEK) with UO126 and mammalian target of rapamycin (mTOR) with rapamycin. RESULTS: We found that MCF-10A cells over-expressing the IGFIR formed large, misshapen acinar structures with filled lumina and disrupted apico-basal polarization. This phenotype was ligand-dependent, occurring with IGF-I or supraphysiological doses of insulin, and did not occur in cells over-expressing the kinase-dead receptor. We observed increased proliferation, decreased apoptosis and increased phosphorylation of Ser(473 )of Akt and Ser(2448 )of mTOR throughout IGFIR structures. Inhibition of PI3K with LY294002 or MEK with UO126 prevented the development of acinar structures from IGFIR-expressing but not control cells. The mTOR inhibitor rapamycin failed to prevent IGFIR-induced hyperproliferation and survival signaling. CONCLUSION: Increased proliferation and survival signaling as well as loss of apico-basal polarity by IGFIR activation in mammary epithelial cells may promote early lesions of breast cancer. Three-dimensional cultures of MCF-10A cells over-expressing the IGFIR are a useful model with which to study the role of IGFIR signaling in breast cancer progression and for characterizing the effects of chemotherapeutics targeted to IGFIR signaling