Model demonstrates functional purpose of the nasal cycle.

BACKGROUND: Despite the occurrence of the nasal cycle being well documented, the functional purpose of this phenomenon is not well understood. This investigation seeks to better understand the physiological objective of the nasal cycle in terms of airway health through the use of a computational nasal air-conditioning model. METHOD: A new state-variable heat and water mass transfer model is developed to predict airway surface liquid (ASL) hydration status within each nasal airway. Nasal geometry, based on in-vivo magnetic resonance imaging (MRI) data is used to apportion inter-nasal air flow. RESULTS: The results demonstrate that the airway conducting the majority of the airflow also experiences a degree of ASL dehydration, as a consequence of undertaking the bulk of the heat and water mass transfer duties. In contrast, the reduced air conditioning demand within the other airway allows its ASL layer to remain sufficiently hydrated so as to support continuous mucociliary clearance. CONCLUSIONS: It is quantitatively demonstrated in this work how the nasal cycle enables the upper airway to accommodate the contrasting roles of air conditioning and the removal of entrapped contaminants through fluctuation in airflow partitioning between each airway.

A pilot study of an in-vitro bovine trachea model of the effect of continuous positive airway pressure breathing on airway surface liquid.

BACKGROUND: Continuous positive air pressure (CPAP) users frequently report troublesome symptoms of airway dryness and nasal congestion. Clinical investigations have demonstrated that supplementary humidification reduces these symptoms but the reason for their occurrence remains unexplained. Investigations using human computational air-conditioning models are unable to reproduce or quantify the apparent airway drying experienced during CPAP therapy. The purpose of this study was to determine whether augmented air pressures change overall mucosal airway surface liquid (ASL) water supply and, if so, the extent of this effect. METHOD: In an original in vitro experimental set up, maximal ASL supply was determined in whole bovine trachea when exposed to simulated tidal breathing stresses over a range of air pressures. RESULTS: At ambient pressure, the maximal supply of ASL was found to compare well to previously published data (31.2 µl/cm2.hr). CPAP pressures from 5 cm H2O above ambient were found to reduce ASL supply by 22%. Statistical analysis (n = 8) showed a significant difference existed between the ambient and CPAP results (p < 0.0001), and that there was no significant variation between all pressurized results (p = 0.716). CONCLUSIONS: These findings provide preliminary data that ASL supply is reduced by CPAP therapy which may explain the airway drying symptoms associated with this therapy.

A broadly applicable and practical oligomeric (salen) Co catalyst for enantioselective epoxide ring-opening reactions.

The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class.

Pilot Study Investigating Effects of Changing Process Variables on Elastic and Energy-Absorbing Characteristics in Polyurethane/Agglomerated Cork Mix for Use in Micro-Transport Helmet.

This pilot investigation identifies the influence that changing the process variables of curing pressure, curing temperature, and mix ratio of a polyurethane/agglomerated cork matrix has on the mechanical properties of energy absorption, Young's modulus of elasticity, and spring stiffness in safety helmets intended for micro-transport riders. The results are compared to expanded polystyrene, a material commonly used in micro-transport helmets. Mechanical testing of the various samples found that, over the range tested, curing pressure had no effect on any of the mechanical properties, while increasing amounts of resin caused a stiffer structure, and increasing curing temperature led to increased energy absorption. Consistent with the elastic modulus findings, all polyurethane/agglomerated cork test samples demonstrated higher median levels of spring stiffness, ranging from 7.1% to 61.9% greater than those found for expanded polystyrene. The sample mixed at a 1.5:1 binder/cork ratio and cured at 40 °C displayed the closest spring stiffness to EPS. While the mechanical properties of the eco-friendly polyurethane/agglomerated cork matrix did not match those of expanded polystyrene, the difference in performance found in this study is promising. Further investigation into process variables could characterise this more ecologically based matrix with equivalent energy-absorbing and structural characteristics, making it equivalent to currently used expanded polystyrene and suitable for use in micro-transport helmets.

LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling.

Corepressors play an essential role in nuclear receptor-mediated transcriptional repression. In general, corepressors directly bind to nuclear receptors via CoRNR boxes (L/I-X-X-I/V-I) in the absence of ligand and appear to act as scaffolds to further recruit chromatin remodeling complexes to specific target genes. Here, we describe the identification of the multiple LIM domain protein Ajuba as a unique corepressor for a subset of nuclear hormone receptors. Ajuba contains functional nuclear-receptor interacting motifs and selectively interacts with retinoic acid receptors (RARs) and rexinoid receptor (RXRs) subtypes in a ligand-dependent manner. Simultaneous mutation of these motifs abolishes RAR binding and concomitantly leads to loss of repression on RARE reporter genes. P19 cells depleted of Ajuba are highly sensitized to all-trans retinoic acid (atRA)-induced transcription and differentiation. In the absence of atRA, Ajuba can be readily found at the RARE control elements of RAR endogenous target genes. Stimulation of cells with atRA results in the dissociation of Ajuba from these regions. Moreover, we observed that coexpression of the known Ajuba binding partner Prmt5 (protein arginine methyltransferase-5) inhibited the Ajuba/RAR interaction. The high-affinity Ajuba-RAR/RXR interaction site overlaps the region responsible for Ajuba/Prmt5 binding, and thus binding appears to be mutually exclusive, providing a potential mechanism for these observations. Identification of Ajuba as a unique corepressor for nuclear receptors sheds new light on mechanisms for nuclear receptor-mediated repression and provides a unique target for developing more effective therapeutics to modulate this important pathway.

Pilot study: Post-surgical infections could be related with lack of sharpness in surgical tools.

Despite rigorous sterilization protocols placed in surgical procedures, there is demonstrated evidence that show patients contract infections while hospitalized. This study aims to investigate the presence of biological materials in osteotome surgical tools after sterilization processes, determine the relationship between lack of sharpness and cross-contamination, and evaluate the influence of materials surface coating as a potential contamination preventive. Three commercially available osteotomes with different surface coatings were studied and submitted to a procedure of bone-cutting cycles. After use, each was sterilized and examined under SEM and EDS. Bone contaminants were detected in each osteotome although the PVD coated osteotome demonstrated significantly less contamination than either the as-supplied or electroless nickel coated one. According to the results, there is an association between blade sharpness and post-sterilization bone contamination. These findings suggest either disposable osteotomes should be used in surgical procedures, or an effective sharpen process should both be established and monitored to minimise post-operative infections.

EEG signatures change during unilateral Yogi nasal breathing.

Airflow through the left-and-right nostrils is said to be entrained by an endogenous nasal cycle paced by both poles of the hypothalamus. Yogic practices suggest, and scientific evidence demonstrates, that right-nostril breathing is involved with relatively higher sympathetic activity (arousal states), while left-nostril breathing is associated with a relatively more parasympathetic activity (stress alleviating state). The objective of this study was to further explore this laterality by controlling nasal airflow and observing patterns of cortical activity through encephalographic (EEG) recordings. Thirty subjects participated in this crossover study. The experimental session consisted of a resting phase (baseline), then a period of unilateral nostril breathing (UNB) using the dominant nasal airway, followed by UNB using the non-dominant nasal airway. A 64-channel EEG was recorded throughout the whole session. The effects of nostril-dominance, and nostril-lateralization were assessed using the power spectral density of the neural activity. The differences in power-spectra and source localization were calculated between EEG recorded during UNB and baseline for delta, theta, alpha, beta and gamma bands. Cluster-based permutation tests showed that compared to baseline, EEG spectral power was significantly (1) decreased in all frequency bands for non-dominant nostril UNB, (2) decreased in alpha, beta and gamma bands for dominant nostril UNB, (3) decreased in all bands for left nostril UNB, and (4) decreased in all bands except delta for right nostril UNB. The beta band showed the most widely distributed changes across the scalp. our source localisation results show that breathing with the dominant nostril breathing increases EEG power in the left inferior frontal (alpha band) and left parietal lobule (beta band), whereas non-dominant nostril breathing is related to more diffuse and bilateral effects in posterior areas of the brain.These preliminary findings may stimulate further research in the area, with potential applications to tailored treatment of brain disorders associated with disruption of sympathetic and parasympathetic activity.

Enantioselective decarboxylative alkylation reactions: catalyst development, substrate scope, and mechanistic studies.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic ß-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Inhaled nasopharyngeal nitric oxide concentrations during unilateral nostril breathing - A pilot study.

The yogic pranayama technique of unilateral nostril breathing (UNB) has previously demonstrated improvements in language and anxiety in stroke sufferers, as well as reduced blood pressure and increased heart rate in normal healthy adults. The nose typically passes different amounts of air through each nostril with the greater amount of air passing through the 'patent' side, and a lesser amount through the 'congested' side. Each side of the nose periodically takes turns at carrying the dominant tidal air flow in what is termed the' nasal cycle'. The nasal sinuses are a rich source of inhaled nitric oxide, a colourless and odourless gas that acts as a bronchodilator, vasodilator, and neurotransmitter. Nasal derived nitric oxide (NO) may contribute to the benefits attributed to UNB. This investigation seeks to assess the influence the nasal cycle has on inhaled nasopharyngeal NO concentrations during UNB by comparing unobstructed bilateral nostril breathing to patent-side and congested-side UNB in healthy individuals demonstrating a nasal cycle. After determining the patent and congested nasal sides in healthy adult volunteers, and sampling air at both nostrils, nasopharyngeal inhaled NO concentrations were then assessed during normal nasal at-rest tidal breathing during three different nasal breathing states: first both nostrils, then allocated in randomised order, patent side only, and congested side with only UNB. Nasopharyngeal NO concentrations were found to be consistently higher on both exhalation and inhalation during congested side UNB, when compared with either unilateral patent side UNB or breathing through both nostrils.

Neti pot irrigation volume filling simulation using anatomically accurate in-vivo nasal airway geometry.

Nasal saline irrigation is frequently utilised in rhinosinusitis management, and after nasal and sinus surgery. Nasal saline irrigation improves mucociliary transport and assists inflammatory mediator and post-surgical debris removal. The aim of this study was to assess the influence different head positions, irrigation inflow nostril, and the nasal cycle have on Neti pot nasal saline volume filling within the nasal passages and maxillary sinuses. Computational fluid dynamics modelling using anatomically correct nasal geometry found only minor difference in nasal cavity volume filling with inflow from either side of the nose however both head position and inflow direction were both found to have a major influence on maxillary sinus volume filling. Computational modelling flow velocity results at the nasopharynx were validated using particle image velocimetry. It was also found that directing irrigation inflow into the patent side of the nose while in the head-back position achieved the highest volume filling of both maxillary sinuses.

A general enantioselective route to the chamigrene natural product family.

Described in this report is an enantioselective route toward the chamigrene natural product family. The key disconnections in our synthetic approach include sequential enantioselective decarboxylative allylation and ring-closing olefin metathesis to form the all-carbon quaternary stereocenter and spirocyclic core present in all members of this class of compounds. The generality of this strategy is demonstrated by the first total syntheses of elatol and the proposed structure of laurencenone B, as well as the first enantioselective total syntheses of laurencenone C and α-chamigrene. A brief exploration of the substrate scope of the enantioselective decarboxylative allylation/ring-closing metathesis sequence with fully substituted vinyl chlorides is also presented.

Nasal saline irrigation - A review of current anatomical, clinical and computational modelling approaches.

Nasal saline irrigation is frequently utilised in allergic rhinitis and rhinosinusitis management, and after nasal and sinus surgery. Anatomical modelling, clinical and computational studies guide treatment optimisation. This review offers a comprehensive summary of the modelling methodologies used in previous nasal irrigation studies by undertaking a systematic analysis of anatomical, clinical and computational investigations that assessed nasal saline irrigation using Medline, EMBASE, and Cochrane Review databases. Both procedural and assessment methods were reviewed. It was found that all twenty-four publications reviewed did not discuss the influence of the nasal cycle on internasal geometry and nasal resistance. Cadaver studies misrepresent in vivo nasal geometry. Irrigation pressure and shear forces, which could influence mucociliary transport and postoperative cleaning, were not evaluated. Previous studies focus on irrigation coverage and have not considered the nasal cycle which influences unilateral nasal resistance and thus pressure/ flow relationships and may also increase nasal air-locking. New computational fluid dynamic models could better inform nasal irrigation clinical practice.

Pilot investigation into osteotome hard surface coating and cutting-edge degradation.

BACKGROUND: Osteotomes are bone cutting tools commonly reused in orthopedic surgical procedures. Despite undergoing rigorous cleaning, visual inspection, and sterilization procedures between every use, the condition of the cutting blade edge is commonly not qualitatively assessed. Subjective feedback from surgeons suggests a large variation in osteotome cutting-edge sharpness is found during use. This study seeks to investigate the retention of osteotome cutting-edge sharpness by comparing the wear resistance of as-supplied, electroless nickel, and titanium nitride coated osteotomes following a series of bone cutting tests. METHODS: Changes in edge sharpness were assessed using visual inspection, depth penetration testing that quantified change in the blade sharpness index, and scanning electron microscopy visual analysis. Visual inspection of each osteotome blade edge was then compared to qualitative blade sharpness index measurement. RESULTS: After use, no cutting-edge damage or change in blade sharpness was detected by visual examination of all three osteotomes; however, the as-supplied osteotome demonstrated 50% loss of blade sharpness index compared to 30% and 15% reduction for the electroless nickel and titanium nitride coated osteotomes, respectively. This finding was supported by scanning electron microscopy evaluation that found greater mechanical damage had occurred along the cutting edge of the as-supplied osteotome compared to the two coated with wear resistant materials. CONCLUSIONS: The rapid loss of blade sharpness found in the as-supplied osteotome supports the degradation in cutting performance frequently reported by surgeons. The findings from this study demonstrate blade sharpness index better detects cutting-edge wear compared to visual inspection. Results from this pilot study also suggest the coating of osteotomes in hard-wearing biocompatible materials assists in retaining cutting-edge sharpness over multiple uses. Further study using a larger sample size is required to validate these findings.

The catalytic asymmetric total synthesis of elatol.

Described in this report is the first total synthesis of elatol, a halogenated sesquiterpene in the chamigrene natural product family. The key disconnections in our synthetic approach include an enantioselective decarboxylative allylation to form the all-carbon quaternary stereocenter and a ring-closing olefin metathesis to concomitantly form the spirocyclic core as well as the fully substituted chlorinated olefin. This strategy represents a general platform for accessing the chamigrene natural product family, as demonstrated by the synthesis of (+)-laurencenone B as an intermediate in our route.

Mouse double minute 2 associates with chromatin in the presence of p53 and is released to facilitate activation of transcription.

The tumor suppressor p53 is a potent transcription factor of which the ability to mediate transcription is inhibited through an interaction with the oncoprotein mouse double minute 2 (Mdm2). The present study has tested the hypothesis that Mdm2 inhibits the p53 response in normally growing cells by binding to chromatin-associated p53. Using chromatin immunoprecipitation, we show that Mdm2 localizes with p53 at its responsive elements on the waf1 and mdm2 genes in human cell lines expressing p53, but not in cell lines lacking p53 expression, indicating that Mdm2 is recruited to regions of DNA in a p53-dependent manner. Interestingly, our results show a decrease of Mdm2 protein associated with p53-responsive elements on the waf1 and mdm2 genes when p53-induced transcription is activated either by DNA damage or through controlled overexpression of p53. Rapid activation of p53 transcriptional activity before increasing p53 protein levels was observed with addition of either small-molecule inhibitors to disrupt the p53-Mdm2 interaction or small interfering RNA to mdm2. These findings indicate Mdm2 transiently localizes with p53 at responsive elements and suggest that latent p53 results from the recruitment of Mdm2 to chromatin.

KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions.

The DNA damage response requires a coordinated nucleo-cytoplasmic cascade of events, which ultimately converge on damaged DNA packaged in chromatin. Few connections between the proteins that remodel chromatin and the proteins that mediate this damage response have been shown. We have investigated the DNA damage-induced phosphorylation of the KRAB-ZFP-associated protein 1 (KAP1), the dedicated corepressor for Krüppel-associated box (KRAB) zinc finger protein (ZFP) proteins. We show that KAP1 is rapidly phosphorylated following DNA damage by members of the phosphatidylinositol-3 kinase-like family of kinases. This phosphorylation occurs at a single amino acid residue that is conserved from mice to humans and is located adjacent to the bromodomain, suggesting that it may regulate chromatin recognition by that module. Phosphorylated KAP1 rapidly localizes to sites of DNA strand breaks in the nucleus in response to ionizing radiation. This discovery provides a novel link between chromatin-mediated transcriptional repression and the recognition/repair of DNA, which must be accomplished by the cellular DNA damage response.

Model identifies causes of nasal drying during pressurised breathing.

Patients nasally breathing pressurised air frequently experience symptoms suggestive of upper airway drying. While supplementary humidification is often used for symptom relief, the cause(s) of nasal drying symptoms remains speculative. Recent investigations have found augmented air pressure affects airway surface liquid (ASL) supply and inter-nasal airflow apportionment. However the influence these two factors have on ASL hydration is unknown. The purpose of this study is to determine how ASL supply and airflow apportionment affect ASL hydration status for both ambient and pressurised air breathing conditions. This is done by modifying and adapting a nasal air-conditioning and ASL supply model. Model predictions of change in inter-nasal airflow apportionment closely follow in-vivo results and demonstrate for the first time abnormal ASL dehydration occurring during augmented pressure breathing. This work quantitatively establishes why patients nasal breathing pressurised air frequently report adverse airway drying symptoms. The findings from this investigation demonstrate that both nasal airways simultaneously experience severe ASL dehydration during pressurised breathing.

Nasal airway responses to nasal continuous positive airway pressure breathing: An in-vivo pilot study.

The nasal cycle, through variation in nasal airflow partitioning, allows the upper airway to accommodate the contrasting demands of air conditioning and removal of entrapped air contaminants. The purpose of this study was to investigate the influence of nasal continuous positive airway pressure (nCPAP) breathing has on both nasal airflow partitioning and nasal geometry. Using a custom-made nasal mask, twenty healthy participants had the airflow in each naris measured during normal nasal breathing followed by nCPAP breathing. Eight participants also underwent magnetic resonance imaging (MRI) of the nasal region during spontaneous nasal breathing, and then nCPAP breathing over a range of air pressures. During nCPAP breathing, a simultaneous reduction in airflow through the patent airway together with a corresponding increase in airway flow within the congested nasal airway were observed in sixteen of the twenty participants. Nasal airflow resistance is inversely proportional to airway cross-sectional area. MRI data analysis during nCPAP breathing confirmed airway cross-sectional area reduced along the patent airway while the congested airway experienced an increase in this parameter. During awake breathing, nCPAP disturbs the normal inter-nasal airflow partitioning. This could partially explain the adverse nasal drying symptoms frequently reported by many users of this therapy.

Desulfurization of phosphorothioate oligonucleotides via the sulfur-by-oxygen replacement induced by the hydroxyl radical during negative electrospray ionization mass spectrometry.

While the occurrence of desulfurization of phosphorothioate oligonucleotides in solution is well established, this study represents the first attempt to investigate the basis of the unexpected desulfurization via the net sulfur-by-oxygen (S-O) replacement during negative electrospray ionization (ESI). The current work, facilitated by quantitative mass deconvolution, demonstrates that considerable desulfurization can take place even under common negative ESI operating conditions. The extent of desulfurization is dependent on the molar phosphorothioate oligonucleotide-to-hydroxyl radical ratio, which is consistent with the corona discharge-induced origin of the hydroxyl radical leading to the S-O replacement. This hypothesis is supported by the fact that an increase of the high-performance liquid chromatography (HPLC) flow rate and the on-column concentration of a phosphorothioate oligonucleotide, as well as a decrease of the electrospray voltage reduce the degree of desulfurization. Comparative LC-tandem mass spectrometry (MS/MS) sequencing of a phosphorothioate oligonucleotide and its corresponding desulfurization product revealed evidence that the S-O replacement occurs at multiple phosphorothioate internucleotide linkage sites. In practice, the most convenient and effective strategy for minimizing this P = O artifact is to increase the LC flow rate and the on-column concentration of phosphorothioate oligonucleotides. Another approach to mitigate possible detrimental effects of the undesired desulfurization is to operate the ESI source at a very low electrospray voltage to diminish the corona discharge; however this will significantly compromise sensitivity when analyzing the low-level P = O impurities in phosphorothioate oligonucleotides.

Correlation of nasal morphology to air-conditioning and clearance function.

Nasal morphology plays an important functional role in the maintenance of upper airway health. Identification of functional regions, based on morphological attributes, assists in correlating location to primary purpose. The effects of morphological variation on heat and water mass transport in congested and patent nasal airways were investigated by examining nasal cross-sectional MRI images from 8 healthy subjects. This research confirms the previous identification of functional air-conditioning regions within the nose. The first is the anterior region where the morphology prevents over-stressing of tissue heat and fluid supply near the nares. The second is the mid region where low flow velocity favours olfaction and particle deposition. The third is the posterior region which demonstrates an increase in heat and water mass flux coefficients to compensate for rising air humidity and temperature. Factors identified within the congested airway that favour enhanced mucocillary clearance were also identified.