Modulation of ligand-heme reactivity by binding pocket residues demonstrated in cytochrome c' over the femtosecond-second temporal range

The ability of hemoproteins to discriminate between diatomic molecules, and the subsequent affinity for their chosen ligand, is fundamental to the existence of life. These processes are often controlled by precise structural arrangements in proteins, with heme pocket residues driving reactivity and specificity. One such protein is cytochrome c', which has the ability to bind nitric oxide (NO) and carbon monoxide (CO) on opposite faces of the heme, a property that is shared with soluble guanylate cycle. Like soluble guanylate cyclase, cytochrome c' also excludes O completely from the binding pocket. Previous studies have shown that the NO binding mechanism is regulated by a proximal arginine residue (R124) and a distal leucine residue (L16). Here, we have investigated the roles of these residues in maintaining the affinity for NO in the heme binding environment by using various time-resolved spectroscopy techniques that span the entire femtosecond-second temporal range in the UV-vis spectrum, and the femtosecond-nanosecond range by IR spectroscopy. Our findings indicate that the tightly regulated NO rebinding events following excitation in wild-type cytochrome c' are affected in the R124A variant. In the R124A variant, vibrational and electronic changes extend continuously across all time scales (from fs-s), in contrast to wild-type cytochrome c' and the L16A variant. Based on these findings, we propose a NO (re)binding mechanism for the R124A variant of cytochrome c' that is distinct from that in wild-type cytochrome c'. In the wider context, these findings emphasize the importance of heme pocket architecture in maintaining the reactivity of hemoproteins towards their chosen ligand, and demonstrate the power of spectroscopic probes spanning a wide temporal range. © 2013 FEBS.

The physiology of singing and implications for 'Singing for Lung Health' as a therapy for individuals with chronic obstructive pulmonary disease

Singing is an increasingly popular activity for people with chronic obstructive pulmonary disease (COPD). Research to date suggests that ‘Singing for Lung Health’ may improve various health measures, including health-related quality-of-life. Singing and breathing are closely linked processes affecting one another. In this narrative review, we explore the physiological rationale for ‘Singing for Lung Health’ as an intervention, focusing on the abnormalities of pulmonary mechanics seen in COPD and how these might be impacted by singing. The potential beneficial physiological mechanisms outlined here require further in-depth evaluation

Heat and fluid flow in a scraped-surface heat exchanger containing a fluid with temperature-dependent viscosity

Scraped-surface heat exchangers (SSHEs) are extensively used in a wide variety of industrial settings where the continuous processing of fluids and fluid-like materials is involved. The steady non-isothermal flow of a Newtonian fluid with temperature-dependent viscosity in a narrow-gap SSHE when a constant temperature difference is imposed across the gap between the rotor and the stator is investigated. The mathematical model is formulated and the exact analytical solutions for the heat and fluid flow of a fluid with a general dependence of viscosity on temperature for a general blade shape are obtained. These solutions are then presented for the specific case of an exponential dependence of viscosity on temperature. Asymptotic methods are employed to investigate the behaviour of the solutions in several special limiting geometries and in the limits of weak and strong thermoviscosity. In particular, in the limit of strong thermoviscosity (i.e., strong heating or cooling and/or strong dependence of viscosity on temperature) the transverse and axial velocities become uniform in the bulk of the flow with boundary layers forming either just below the blade and just below the stationary upper wall or just above the blade and just above the moving lower wall. Results are presented for the most realistic case of a linear blade which illustrate the effect of varying the thermoviscosity of the fluid and the geometry of the SSHE on the flow

The physiology of singing and implications for 'Singing for Lung Health' as a therapy for individuals with Chronic Obstructive Pulmonary Disease

Singing is an increasingly popular activity for people with chronic obstructive pulmonary disease (COPD). Research to date suggests that ‘Singing for Lung Health’ may improve various health measures, including health-related quality-of-life. Singing and breathing are closely linked processes affecting one another. In this narrative review, we explore the physiological rationale for ‘Singing for Lung Health’ as an intervention, focusing on the abnormalities of pulmonary mechanics seen in COPD and how these might be impacted by singing. The potential beneficial physiological mechanisms outlined here require further in-depth evaluation

Comparing performance of primary care clinicians in the interpretation of SPIROmetry with or without Artificial Intelligence Decision support software (SPIRO-AID): a protocol for a randomised controlled trial.

INTRODUCTION: Spirometry is a point-of-care lung function test that helps support the diagnosis and monitoring of chronic lung disease. The quality and interpretation accuracy of spirometry is variable in primary care. This study aims to evaluate whether artificial intelligence (AI) decision support software improves the performance of primary care clinicians in the interpretation of spirometry, against reference standard (expert interpretation). METHODS AND ANALYSIS: A parallel, two-group, statistician-blinded, randomised controlled trial of primary care clinicians in the UK, who refer for, or interpret, spirometry. People with specialist training in respiratory medicine to consultant level were excluded. A minimum target of 228 primary care clinician participants will be randomised with a 1:1 allocation to assess fifty de-identified, real-world patient spirometry sessions through an online platform either with (intervention group) or without (control group) AI decision support software report. Outcomes will cover primary care clinicians' spirometry interpretation performance including measures of technical quality assessment, spirometry pattern recognition and diagnostic prediction, compared with reference standard. Clinicians' self-rated confidence in spirometry interpretation will also be evaluated. The primary outcome is the proportion of the 50 spirometry sessions where the participant's preferred diagnosis matches the reference diagnosis. Unpaired t-tests and analysis of covariance will be used to estimate the difference in primary outcome between intervention and control groups. ETHICS AND DISSEMINATION: This study has been reviewed and given favourable opinion by Health Research Authority Wales (reference: 22/HRA/5023). Results will be submitted for publication in peer-reviewed journals, presented at relevant national and international conferences, disseminated through social media, patient and public routes and directly shared with stakeholders. TRIAL REGISTRATION NUMBER: NCT05933694

Macroalgal responses to ocean acidification depend on nutrient and light levels

Ocean acidification may benefit algae that are able to capitalize on increased carbon availability for photosynthesis, but it is expected to have adverse effects on calcified algae through dissolution. Shifts in dominance between primary producers will have knock-on effects on marine ecosystems and will likely vary regionally, depending on factors such as irradiance (light vs. shade) and nutrient levels (oligotrophic vs. eutrophic). Thus experiments are needed to evaluate interactive effects of combined stressors in the field. In this study, we investigated the physiological responses of macroalgae near a CO2 seep in oligotrophic waters off Vulcano (Italy). The algae were incubated in situ at 0.2 m depth using a combination of three mean CO2 levels (500, 700-800 and 1200 μatm CO2), two light levels (100 and 70% of surface irradiance) and two nutrient levels of N, P, and K (enriched vs. non-enriched treatments) in the non-calcified macroalga Cystoseira compressa (Phaeophyceae, Fucales) and calcified Padina pavonica (Phaeophyceae, Dictyotales). A suite of biochemical assays and in vivo chlorophyll a fluorescence parameters showed that elevated CO2 levels benefitted both of these algae, although their responses varied depending on light and nutrient availability. In C. compressa, elevated CO2 treatments resulted in higher carbon content and antioxidant activity in shaded conditions both with and without nutrient enrichment-they had more Chla, phenols and fucoxanthin with nutrient enrichment and higher quantum yield (Fv/Fm) and photosynthetic efficiency (αETR) without nutrient enrichment. In P. pavonica, elevated CO2 treatments had higher carbon content, Fv/Fm, αETR, and Chla regardless of nutrient levels-they had higher concentrations of phenolic compounds in nutrient enriched, fully-lit conditions and more antioxidants in shaded, nutrient enriched conditions. Nitrogen content increased significantly in fertilized treatments, confirming that these algae were nutrient limited in this oligotrophic part of the Mediterranean. Our findings strengthen evidence that brown algae can be expected to proliferate as the oceans acidify where physicochemical conditions, such as nutrient levels and light, permit

Hormone replacement therapy and risk of epithelial ovarian cancer

It has been suggested that oestrogen replacement therapy is associated with risk of epithelial ovarian cancer of the endometrioid type. Using data from an Australian population-based case–control study, the relation between unopposed oestrogen replacement therapy and epithelial ovarian cancer, both overall and according to histological type, was examined. A total of 793 eligible incident cases of epithelial ovarian cancer diagnosed from 1990 to 1993 among women living in Queensland, New South Wales and Victoria were identified. These were compared with 855 eligible female controls selected at random from the electoral roll, stratified by age and geographic region. Trained interviewers administered standard questionnaires to obtain detailed reproductive and contraceptive histories, as well as details about hormone replacement therapy and pelvic operations. No clear associations were observed between use of hormone replacement therapy overall and risk of ovarian cancer. Unopposed oestrogen replacement therapy was, however, associated with a significant increase in risk of endometrioid or clear cell epithelial ovarian tumours (odds ratio (OR) 2.56; 95% confidence interval (CI) 1.32–4.94). In addition, the risk associated with oestrogen replacement therapy was much larger in women with an intact genital tract (OR 3.00; 95% Cl 1.54–5.85) than in those with a history of either hysterectomy or tubal ligation. Post-menopausal oestrogen replacement therapy may, therefore, be a risk factor associated with endometrioid and clear cell tumours in particular. Additionally, the risk may be increased predominantly in women with an intact genital tract. These associations could reflect a possible role of endometriosis in the development of endometrioid or clear cell ovarian tumours. © 1999 Cancer Research Campaig

Morphological and Geochemical Evidence of Eumelanin Preservation in the Feathers of the Early Cretaceous Bird, Gansus yumenensis

Recent studies have shown evidence for the preservation of colour in fossilized soft tissues by imaging melanosomes, melanin pigment containing organelles. This study combines geochemical analyses with morphological observations to investigate the preservation of melanosomes and melanin within feathers of the Early Cretaceous bird, Gansus yumenensis. Scanning electron microscopy reveals structures concordant with those previously identified as eumelanosomes within visually dark areas of the feathers but not in lighter areas or sedimentary matrices. Fourier transform infrared analyses show different spectra for the feathers and their matrices; melanic functional groups appear in the feather including carboxylic acid and ketone groups that are not seen in the matrix. When mapped, the carboxylic acid group absorption faithfully replicates the visually dark areas of the feathers. Electron Paramagnetic Resonance spectroscopy of one specimen demonstrates the presence of organic signals but proved too insensitive to resolve melanin. Pyrolysis gas chromatography mass spectrometry shows a similar distribution of aliphatic material within both feathers that are different from those of their respective matrices. In combination, these techniques strongly suggest that not only do the feathers contain endogenous organic material, but that both geochemical and morphological evidence supports the preservation of original eumelanic pigment residue