Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Simple Mechanism for the Observed Breakdown of the Nernst-Einstein Relation for Ions in Carbon Nanotubes.

In this Letter, we present a simple mechanism that explains the recent experimental observation of the breakdown of the Nernst-Einstein (NE) relation for an ion moving in a carbon nanotube of subnanometer diameter. We argue that the friction acting on the ion is largely independent of the ion velocity, i.e., dry friction, and demonstrate, based on the Langevin equation for a particle subject to both dry and viscous friction, that the NE relation is violated when dry friction dominates. We predict that the ratio of the diffusion constant to the mobility of the ion is a few orders of magnitude smaller than the value predicted by the NE relation, in quantitative agreement with experiment.

Theory of the force of friction acting on water chains flowing through carbon nanotubes.

A simple model for the friction experienced by the one-dimensional water chains that flow through subnanometer diameter carbon nanotubes is studied. The model is based on a lowest order perturbation theory treatment of the friction experienced by the water chains due to the excitation of phonon and electron excitations in both the nanotube and the water chain, as a result of the motion of the chain. On the basis of this model, we are able to demonstrate how the observed flow velocities of water chains through carbon nanotubes of the order of several centimeters per second can be accounted for. If the hydrogen bonds between the water molecules are broken (as would occur if there were an electric field oscillating with a frequency equal to the resonant frequency of the hydrogen bonds present), it is shown that the friction experienced by the water flowing in the tube can be much smaller.

DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.

Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.

Pulling a harmonically bound particle subjected to Coulombic friction: A nonequilibrium analysis.

We address the effects of dry friction, which has emerged only recently to play an important role in some biological systems. In particular, we investigate the nonequilibrium dynamics of a mesoscopic particle, bound to a spring being pulled at a definite speed, moving on a surface with dry friction in a noisy environment. We model the dry friction phenomenologically with a term that is proportional to the sign of the velocity, and by means of numerical simulations of a Langevin equation we show that (a) the frictional force scales with the logarithm of the pulling velocity, (b) the probability distribution function of the spatial displacement away from the potential minimum is non-Gaussian, (c) the fluctuation-dissipation theorem is violated as expected, but (d) the work function obeys the stationary fluctuation theorem, with an effective temperature related to the noise of the system.

Computational modeling predicts ephemeral acidic microdomains in the glutamatergic synaptic cleft.

At chemical synapses, synaptic vesicles release their acidic contents into the cleft, leading to the expectation that the cleft should acidify. However, fluorescent pH probes targeted to the cleft of conventional glutamatergic synapses in both fruit flies and mice reveal cleft alkalinization rather than acidification. Here, using a reaction-diffusion scheme, we modeled pH dynamics at the Drosophila neuromuscular junction as glutamate, ATP, and protons (H+) were released into the cleft. The model incorporates bicarbonate and phosphate buffering systems as well as plasma membrane calcium-ATPase activity and predicts substantial cleft acidification but only for fractions of a millisecond after neurotransmitter release. Thereafter, the cleft rapidly alkalinizes and remains alkaline for over 100 ms because the plasma membrane calcium-ATPase removes H+ from the cleft in exchange for calcium ions from adjacent pre- and postsynaptic compartments, thus recapitulating the empirical data. The extent of synaptic vesicle loading and time course of exocytosis have little influence on the magnitude of acidification. Phosphate but not bicarbonate buffering is effective at suppressing the magnitude and time course of the acid spike, whereas both buffering systems are effective at suppressing cleft alkalinization. The small volume of the cleft levies a powerful influence on the magnitude of alkalinization and its time course. Structural features that open the cleft to adjacent spaces appear to be essential for alleviating the extent of pH transients accompanying neurotransmission.

The molecular mechanisms of probiotic strains in improving ageing bone and muscle of d-galactose-induced ageing rats.

AIM: The aim of this study was to evaluate the molecular mechanisms of Lactobacillus strains in improving ageing of the musculoskeletal system. METHODS AND RESULTS: The anti-ageing mechanism of three probiotics strains Lactobacillus fermentum DR9, Lactobacillus paracasei OFS 0291 and L. helveticus OFS 1515 were evaluated on gastrocnemius muscle and tibia of d-galactose-induced ageing rats. Upon senescence induction, aged rats demonstrated reduced antioxidative genes CAT and SOD expression in both bone and muscle compared to the young rats (P < 0·05). Strain L. fermentum DR9 demonstrated improved expression of SOD in bone and muscle compared to the aged rats (P < 0·05). In the evaluation of myogenesis-related genes, L. paracasei OFS 0291 and L. fermentum DR9 increased the mRNA expression of IGF-1; L. helveticus OFS 1515 and L. fermentum DR9 reduced the expression of MyoD, in contrast to the aged controls (P < 0·05). Protective effects of L. fermentum DR9 on ageing muscle were believed to be contributed by increased AMPK-α2 expression. Among the osteoclastogenesis genes studied, TNF-α expression was highly elevated in tibia of aged rats, while all three probiotics strains ameliorated the expression. Lactobacillus fermentum DR9 also reduced the expression of IL-6 and TRAP in tibia when compared to the aged rats (P < 0·05). All probiotics treatment resulted in declined proinflammatory cytokines IL-1ß in muscle and bone. CONCLUSIONS: Lactobacillus fermentum DR9 appeared to be the strongest strain in modulation of musculoskeletal health during ageing. SIGNIFICANCE AND IMPACT OF THE STUDY: The study demonstrated the protective effects of the bacteria on muscle and bone through antioxidative and anti-inflammatory actions. Therefore, L. fermentum DR9 may serve as a promising targeted anti-ageing therapy.

Enhancement of the ion concentration in a salt solution near a wall due to electrical image potentials and enhancement of surface tension due to the presence of salt.

Effects of electrical image potentials on the salt ion concentration near a solid wall are studied using a one-loop approximation treatment of the grand canonical partition function, which is the Debye-Hückel approximation. Electrical image potentials resulting from both metallic and dielectric walls of dielectric constant larger than that of water near the wall are considered. Our treatment of this problem supports the conclusions of an earlier publication by one of the authors which shows that near a solid wall there should be a high concentration of ions, resulting from image potentials. We have also applied our treatment to the increase of the surface tension of a liquid that occurs when salt is dissolved in the liquid. Our treatment gives the -c_{s}log(c_{s}) dependence of the surface tension found by Onsager and Samarasa in the small c_{s} limit, where c_{s} is the salt concentration.

A multi-centre analysis of a decade of endoscopic pharyngeal pouch surgery in Cheshire and Merseyside.

BACKGROUND: There are sparse data on the outcomes of endoscopic stapling of pharyngeal pouches. The Mersey ENT Trainee Collaborative compared regional practice against published benchmarks. METHODS: A 10-year retrospective analysis of endoscopic pharyngeal pouch surgery was conducted and practice was assessed against eight standards. Comparisons were made between results from the tertiary centre and other sites. RESULTS: A total of 225 procedures were performed (range of 1.2-9.2 cases per centre per year). All centres achieved 90 per cent resumption of oral intake within 2 days. All centres achieved less than 2-day hospital stays. Primary success (84 per cent (i.e. abandonment of endoscopic stapling in 16 per cent)), symptom resolution (83 per cent) and recurrence rates (13 per cent) failed to meet the standard across the non-tertiary centres. CONCLUSION: Endoscopic pharyngeal pouch stapling is a procedure with a low mortality and brief in-patient stay. There was significant variance in outcomes across the region. This raises the question of whether this service should become centralised and the preserve of either tertiary centres or sub-specialist practitioners.

Charge regulation of a surface immersed in an electrolyte solution.

In this paper, we investigate theoretically a model of charge regulation of a single charged planar surface immersed in an aqueous electrolyte solution. Assuming that the adsorbed ions are mobile in the charged plane, we formulate a field theory of charge regulation where the numbers of adsorbed ions can be determined consistently by equating the chemical potentials of the adsorbed ions to that of the ions in the bulk. We analyze the mean-field treatment of the model for electrolyte of arbitrary valences, and then beyond, where correlation effects are systematically taken into account in a loop expansion. In particular, we compute exactly various one-loop quantities, including electrostatic potentials, ion distributions, and chemical potentials, not only for symmetric (1, 1) electrolyte but also for asymmetric (2, 1) electrolyte, and make use of these quantities to address charge regulation at the one-loop level. We find that correlation effects give rise to various phase transitions in the adsorption of ions, and present phase diagrams for (1, 1) and (2, 1) electrolytes, whose distinct behaviors suggest that charge regulation, at the one-loop level, is no longer universal but depends crucially on the valency of the ions.

Correction to: Comparison of the clinical effectiveness and safety between the use of denosumab vs bisphosphonates in renal transplant patients.

The original version of this article, published on 03 January 2020 contained a mistake. An author's name was misspelled.

Chemogenetics a robust approach to pharmacology and gene therapy.

Modern developments in organic chemistry, molecular biology, virology, and genetics have opened new, exciting possibilities to better understand physiology and to create innovative, robust therapeutics. One such possibility is the burgeoning field of chemogenetics, a sub-field of chemical genetics that encompasses engineering macromolecules (particularly proteins) to modify how they interact with endogenous and exogenous ligands (particularly small molecules). Early efforts in chemogenetics were focused on parsing the function of a specific enzyme within a closely-related family by creating orthogonal enzyme-ligand pairs (e.g. kinases paired with antagonists). This powerful concept quickly expanded into engineered G-protein-coupled receptors (e.g. DREADDs/RASSL), and more recently into engineered ligand-gated ion channels (eLGIC). The modifications to the receptor focused on eliminating their activation by endogenous ligands, while preserving or enhancing their interaction with pharmacological agents (e.g. small molecule agonist). Creation of such an engineered receptor and delivering it selectively to specific cell types opens new possibilities of accurately and precisely controlling cellular activity. Control of this activity then increases our understanding of the cells function in normal physiology, while also creating the possibility of using it as a therapeutic to address pathophysiology. The DREADDs/RASSL and eLGIC approaches have been particularly impactful in neurosciences but have applications in multiple fields. In this work we introduce the history of the chemogenetic approach, review the seminal work with DREADDs/RASSLs and eLGIC, highlight the breadth of applications, and discuss the strengths and weaknesses associated with this technology, especially in the context of its development into a therapeutic.

Epistaxis and atorvastatin: is there an association and are clinicians aware? A retrospective audit of 100 patients.

OBJECTIVE: Epistaxis is a common ENT presentation. The British National Formulary lists epistaxis as a common side effect of atorvastatin. This study aimed to better understand the relationship between epistaxis and atorvastatin use, and determine whether ENT doctors are aware of its side effect profile. METHODS: A retrospective analysis over 10 months identified 100 individuals who presented to hospital with epistaxis. A questionnaire of 24 ENT registrars was undertaken. RESULTS: Of the 100 patients admitted with epistaxis, 27 were receiving atorvastatin and 21 simvastatin. None of the 24 ENT registrars were aware that epistaxis was a listed common side effect of atorvastatin. CONCLUSION: There was no apparent difference in the proportion of patients admitted with epistaxis taking atorvastatin versus simvastatin. Epistaxis is an unknown side effect of atorvastatin; doctors have an obligation to be aware of the pharmaceutical literature and to consider alternatives, particularly in re-admissions cases.