A Time to Heal: MicroRNA and Circadian Dynamics in Cutaneous Wound Repair

Many biological systems have evolved circadian rhythms based on the daily cycles of daylight and darkness on Earth. Such rhythms are synchronised or entrained to 24-hour cycles, predominantly by light, and disruption of the normal circadian rhythms has been linked to elevation of multiple health risks. The skin serves as a protective barrier to prevent microbial infection and maintain homeostasis of the underlying tissue and the whole organism. However, in chronic non-healing wounds such as diabetic foot ulcers, pressures sores, venous and arterial ulcers, a variety of factors conspire to prevent wound repair. On the other hand, keloids and hypertrophic scars arise from over-active repair mechanisms that fail to cease in a timely fashion, leading to excessive production of extracellular matrix components such as such as collagen. Recent years have seen huge increases in our understanding of the functions of microRNAs (miRNA) in wound repair. Concomitantly, there has been growing recognition of miRNA roles in circadian processes, either as regulators or targets of clock activity or direct responders to external circadian stimuli. In addition, miRNAs are now known to function as intercellular signalling mediators through extracellular vesicles. In this review, we explore the intersection of mechanisms by which circadian and miRNA responses interact with each other in relation to wound repair in the skin, using keratinocytes, macrophages and fibroblasts as exemplars. We highlight areas for further investigation to support the development of translational insights to support circadian medicine in the context of these cells

Identifying stationary series in panels: A Monte Carlo evaluation of sequential panel selection methods

Sequential panel selection methods (spsms — procedures that sequentially use conventional panel unit root tests to identify I(0)I(0) time series in panels) are increasingly used in the empirical literature. We check the reliability of spsms by using Monte Carlo simulations based on generating directly the individual asymptotic pp values to be combined into the panel unit root tests, in this way isolating the classification abilities of the procedures from the small sample properties of the underlying univariate unit root tests. The simulations consider both independent and cross-dependent individual test statistics. Results suggest that spsms may offer advantages over time series tests only under special conditions

An itinerant antiferromagnetic metal without magnetic constituents

Itinerant and local moment magnetism have substantively different origins, and require distinct theoretical treatment. A unified theory of magnetism has long been sought after, and remains elusive, mainly due to the limited number of known itinerant magnetic systems. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn_2 and Sc_3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet (IAFM) with a spin density wave (SDW) ground state, its 3d character has been deemed crucial to it being magnetic. Here we report the discovery of the first IAFM compound with no magnetic constituents, TiAu. Antiferromagnetic order occurs below a Neel temperature T_N ~ 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. This new IAFM challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing long sought-after insights into the effects of spin fluctuations in itinerant electron systems

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The Effects of Cognitive Therapy versus ‘No Intervention’ for Major Depressive Disorder

BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Cognitive therapy may be an effective treatment option for major depressive disorder, but the effects have only had limited assessment in systematic reviews. METHODS/PRINCIPAL FINDINGS: We used The Cochrane systematic review methodology with meta-analyses and trial sequential analyses of randomized trials comparing the effects of cognitive therapy versus 'no intervention' for major depressive disorder. Participants had to be older than 17 years with a primary diagnosis of major depressive disorder to be eligible. Altogether, we included 12 trials randomizing a total of 669 participants. All 12 trials had high risk of bias. Meta-analysis on the Hamilton Rating Scale for Depression showed that cognitive therapy significantly reduced depressive symptoms (four trials; mean difference -3.05 (95% confidence interval (Cl), -5.23 to -0.87; P<0.006)) compared with 'no intervention'. Trial sequential analysis could not confirm this result. Meta-analysis on the Beck Depression Inventory showed that cognitive therapy significantly reduced depressive symptoms (eight trials; mean difference on -4.86 (95% CI -6.44 to -3.28; P = 0.00001)). Trial sequential analysis on these data confirmed the result. Only a few trials reported on 'no remission', suicide inclination, suicide attempts, suicides, and adverse events without significant differences between the compared intervention groups. DISCUSSION: Cognitive therapy might be an effective treatment for depression measured on Hamilton Rating Scale for Depression and Beck Depression Inventory, but these outcomes may be overestimated due to risks of systematic errors (bias) and random errors (play of chance). Furthermore, the effects of cognitive therapy on no remission, suicidality, adverse events, and quality of life are unclear. There is a need for randomized trials with low risk of bias, low risk of random errors, and longer follow-up assessing both benefits and harms with clinically relevant outcome measures

A qualitative evidence synthesis of employees' views of workplace smoking reduction or cessation interventions

Background The need to reduce smoking rates is a recognised public health policy issue in many countries. The workplace offers a potential context for offering smokers’ programmes and interventions to assist smoking cessation or reduction. A qualitative evidence synthesis of employees’ views about such programmes might explain why some interventions appear effective and others not, and can be used to develop evidence-based interventions for this population and setting. Methods A qualitative evidence synthesis of primary research exploring employees’ views about workplace interventions to encourage smoking cessation, including both voluntary programmes and passive interventions, such as restrictions or bans. The method used was theory-based “best fit” framework synthesis. Results Five relevant theories on workplace smoking cessation were identified and used as the basis for an a priori framework. A comprehensive literature search, including interrogation of eight databases, retrieved 747 unique citations for the review. Fifteen primary research studies of qualitative evidence were found to satisfy the inclusion criteria. The synthesis produced an evidence-based conceptual model explaining employees’ experiences of, and preferences regarding, workplace smoking interventions. Conclusion The synthesis suggests that workplace interventions should employ a range of different elements if they are to prove effective in reducing smoking among employees. This is because an employee who feels ready and able to change their behaviour has different needs and preferences from an employee who is not at that stage. Only a multi-faceted intervention can satisfy the requirements of all employees

RUNX3 Regulates Intercellular Adhesion Molecule 3 (ICAM-3) Expression during Macrophage Differentiation and Monocyte Extravasation

The adhesion molecule ICAM-3 belongs to the immunoglobulin gene superfamily and functions as a ligand for the β2 integrins LFA-1, Mac-1 and αdβ2. The expression of ICAM-3 is restricted to cells of the hematopoietic lineage. We present evidences that the ICAM-3 gene promoter exhibits a leukocyte-specific activity, as its activity is significantly higher in ICAM-3+ hematopoietic cell lines. The activity of the ICAM-3 gene promoter is dependent on the occupancy of RUNX cognate sequences both in vitro and in vivo, and whose integrity is required for RUNX responsiveness and for the cooperative actions of RUNX with transcription factors of the Ets and C/EBP families. Protein analysis revealed that ICAM-3 levels diminish upon monocyte-derived macrophage differentiation, monocyte transendothelial migration and dendritic cell maturation, changes that correlate with an increase in RUNX3. Importantly, disruption of RUNX-binding sites led to enhanced promoter activity, and small interfering RNA-mediated reduction of RUNX3 expression resulted in increased ICAM-3 mRNA levels. Altogether these results indicate that the ICAM-3 gene promoter is negatively regulated by RUNX transcription factors, which contribute to the leukocyte-restricted and the regulated expression of ICAM-3 during monocyte-to-macrophage differentiation and monocyte extravasation

The Potential Role of Metalloproteinases in Neurogenesis in the Gerbil Hippocampus Following Global Forebrain Ischemia

BACKGROUND: Matrix metalloproteinases (MMPs) have recently been considered to be involved in the neurogenic response of adult neural stem/progenitor cells. However, there is a lack of information showing direct association between the activation of MMPs and the development of neuronal progenitor cells involving proliferation and/or further differentiation in vulnerable (Cornus Ammoni-CA1) and resistant (dentate gyrus-DG) to ischemic injury areas of the brain hippocampus. PRINCIPAL FINDINGS: We showed that dynamics of MMPs activation in the dentate gyrus correlated closely with the rate of proliferation and differentiation of progenitor cells into mature neurons. In contrast, in the damaged CA1 pyramidal cells layer, despite the fact that some proliferating cells exhibited antigen specific characteristic of newborn neuronal cells, these did not attain maturity. This coincides with the low, near control-level, activity of MMPs. The above results are supported by our in vitro study showing that MMP inhibitors interfered with both the proliferation and differentiation of the human neural stem cell line derived from umbilical cord blood (HUCB-NSCs) toward the neuronal lineage. CONCLUSION: Taken together, the spatial and temporal profiles of MMPs activity suggest that these proteinases could be an important component in neurogenesis-associated processes in post-ischemic brain hippocampus

Ionic Interactions in Biological and Physical Systems: a Variational Treatment

Chemistry is about chemical reactions. Chemistry is about electrons changing their configurations as atoms and molecules react. Chemistry studies reactions as if they occurred in ideal infinitely dilute solutions. But most reactions occur in nonideal solutions. Then everything (charged) interacts with everything else (charged) through the electric field, which is short and long range extending to boundaries of the system. Mathematics has recently been developed to deal with interacting systems of this sort. The variational theory of complex fluids has spawned the theory of liquid crystals. In my view, ionic solutions should be viewed as complex fluids. In both biology and electrochemistry ionic solutions are mixtures highly concentrated (~10M) where they are most important, near electrodes, nucleic acids, enzymes, and ion channels. Calcium is always involved in biological solutions because its concentration in a particular location is the signal that controls many biological functions. Such interacting systems are not simple fluids, and it is no wonder that analysis of interactions, such as the Hofmeister series, rooted in that tradition, has not succeeded as one would hope. We present a variational treatment of hard spheres in a frictional dielectric. The theory automatically extends to spatially nonuniform boundary conditions and the nonequilibrium systems and flows they produce. The theory is unavoidably self-consistent since differential equations are derived (not assumed) from models of (Helmholtz free) energy and dissipation of the electrolyte. The origin of the Hofmeister series is (in my view) an inverse problem that becomes well posed when enough data from disjoint experimental traditions are interpreted with a self-consistent theory.Comment: As prepared for Faraday Discussion, Pavel Jungwirth Organizer, 3 - 5 September 2012, Queens College Oxford, UK on Ion Specific Hofmeister Effects. Version 2 has significant typo corrections in eq. 1 and eq. 4, and has been reformatted to be easier to rea