Re-analysis of microarray data reveals insights into altered transcriptional activity of TH17 and TReg signalling in psoriasis

Identifying differential expression of genes in psoriatic and healthy skin by microarray data analysis is a key approach to understand the pathogenesis of psoriasis. Analysis of more than one dataset to identify genes commonly upregulated reduces the likelihood of false positives and narrows down the possible signature genes. Genes controlling the critical balance between T helper 17 and regulatory T cells are of special interest in psoriasis. Our objectives were to identify genes that are consistently upregulated in lesional skin from three published microarray datasets. We carried out a reanalysis of gene expression data extracted from three experiments on samples from psoriatic and nonlesional skin using the same stringency threshold and software and further compared the expression levels of 92 genes related to the T helper 17 and regulatory T cell signaling pathways. We found 73 probe sets representing 57 genes commonly upregulated in lesional skin from all datasets. These included 26 probe sets representing 20 genes that have no previous link to the etiopathogenesis of psoriasis. These genes may represent novel therapeutic targets and surely need more rigorous experimental testing to be validated. Our analysis also identified 12 of 92 genes known to be related to the T helper 17 and regulatory T cell signaling pathways, and these were found to be differentially expressed in the lesional skin samples.

Testing the efficacy of the glacial buzzsaw: insights from the Sredinny Mountains, Kamchatka

Peak altitudes, hypsometry, geology, and former equilibrium-line altitudes (ELAs) are analyzed across the Sredinny Mountains (Kamchatka). Overall, evidence is found to suggest that the glacial buzzsaw has operated to shape the topography of this mountain range, but the strength of this signature is not spatially uniform. In the southern sector of the mountains, we see evidence that an efficient glacial buzzsaw has acted to impose constraints upon topography, limiting peak altitudes, and concentrating land-surface area (hypsometric maxima) close to palaeo-ELAs. By contrast, in the northern sector of the mountains, a number of peaks rise high above the surrounding topography, and land-surface area is concentrated well below palaeo-ELAs. This deviation from a classic ‘buzzsaw signature’, in the northern sector of the mountains, is considered to reflect volcanic construction during the Quaternary, resulting in a series of high altitude peaks, combined with the action of dynamic glaciers, acting to skew basin topography toward low altitudes, well below palaeo-ELAs. These glaciers are considered to have been particularly dynamic because of their off-shore termination, their proximity to moisture-bearing air masses from the North Pacific, and because accumulation was supplemented by snow and ice avalanching from local high altitude peaks. Overall, the data suggest that the buzzsaw remains a valid mechanism to generally explain landscape evolution in mountain regions, but its signature is significantly weakened in mountain basins that experience both volcanic construction and climatic conditions favouring dynamic glaciation.

Rapid formation of robust auditory memories: Insights from noise

Before a natural sound can be recognized, an auditory signature of its source must be learned through experience. Here we used random waveforms to probe the formation of new memories for arbitrary complex sounds. A behavioral measure was designed, based on the detection of repetitions embedded in noises up to 4 s long. Unbeknownst to listeners, some noise samples reoccurred randomly throughout an experimental block. Results showed that repeated exposure induced learning for otherwise totally unpredictable and meaningless sounds. The learning was unsupervised and resilient to interference from other task-relevant noises. When memories were formed, they emerged rapidly, performance became abruptly near-perfect, and multiple noises were remembered for several weeks. The acoustic transformations to which recall was tolerant suggest that the learned features were local in time. We propose that rapid sensory plasticity could explain how the auditory brain creates useful memories from the ever-changing, but sometimes repeating, acoustical world. © 2010 Elsevier Inc.

Microneedle/nanoencapsulation-mediated transdermal delivery:Mechanistic insights

A systematic study was undertaken to gain more insight into the mechanism of transdermal delivery of nanoencapsulated model dyes across microneedle (MN)-treated skin, a complex process not yet explored. Rhodamine B (Rh B) and fluorescein isothiocyanate (FITC) as model hydrophilic and hydrophobic small/medium-size molecules, respectively, were encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and delivered through full thickness porcine skin pretreated with MN array. Permeation through MN-treated skin was affected by physicochemical characteristics of NPs and the encapsulated dyes. Dye flux was enhanced by smaller particle size, hydrophilicity, and negative zeta potential of NPs. Regarding encapsulated dyes, solubility at physiological pH and potential interaction with skin proteins proved to outweigh molecular weight as determinants of skin permeation. Data were verified using confocal laser scanning microscopy imaging. Findings coupled with the literature data are supportive of a mechanism involving influx of NPs, particularly of smaller size, deep into MN-created channels, generating depot dye-rich reservoirs. Molecular diffusion of the released dye across viable skin layers proceeds at a rate determined by its molecular characteristics. Data obtained provide mechanistic information of importance to the development of formulation strategies for more effective intradermal and transdermal MN-mediated delivery of nanoencapsulated therapeutic agents.

A web-based telemedicine system for low-resource settings 13 years on: insights from referrers and specialists

Background: One way to tackle health inequalities in resource-poor settings is to establish links between doctors and health professionals there and specialists elsewhere using web-based telemedicine. One such system run by the Swinfen Charitable Trust has been in existence for 13 years which is an unusually long time for such systems.

Objective: We wanted to gain some insights into whether and how this system might be improved.

Methods: We carried out a survey by questionnaire of referrers and specialists over a six months period.

Results: During the study period, a total of 111 cases were referred from 35 different practitioners, of whom 24% were not doctors. Survey replies were received concerning 67 cases, a response rate of 61 per cent. Eighty-seven per cent of the responding referrers found the telemedicine advice useful, and 78% were able to follow the advice provided. As a result of the advice received, the diagnosis was changed in 22% of all cases and confirmed in a further 18 per cent. Patient management was changed in 33 per cent. There was no substantial difference between doctors and non-doctors. During the study period, the 111 cases were responded to by 148 specialists, from whom 108 replies to the questionnaire were received, a response rate of 73 per cent. About half of the specialists (47%) felt that their advice had improved the management of the patients. There were 62 cases where it was possible to match up the opinions of the referrer and the consultants about the value of a specific teleconsultation. In 34 cases (55%) the referrers and specialists agreed about the value. However, in 28 cases (45%) they did not: specialists markedly underestimated the value of a consultation compared to referrers. Both referrers and specialist were extremely positive about the system which appears to be working well. Minor changes such as a clearer referral template and an improved web interface for specialists may improve it.

The Opportunistic Pathogen Propionibacterium acnes: Insights into Typing, Human Disease, Clonal Diversification and CAMP Factor Evolution

We previously described a Multilocus Sequence Typing (MLST) scheme based on eight genes that facilitates population genetic and evolutionary analysis of P. acnes. While MLST is a portable method for unambiguous typing of bacteria, it is expensive and labour intensive. Against this background, we now describe a refined version of this scheme based on two housekeeping (aroE; guaA) and two putative virulence (tly; camp2) genes (MLST) that correctly predicted the phylogroup (IA, IA, IB, IC, II, III), clonal complex (CC) and sequence type (ST) (novel or described) status for 91% isolates (n = 372) via cross-referencing of the four gene allelic profiles to the full eight gene versions available in the MLST database (http://pubmlst.org/pacnes/). Even in the small number of cases where specific STs were not completely resolved, the MLST method still correctly determined phylogroup and CC membership. Examination of nucleotide changes within all the MLST loci provides evidence that point mutations generate new alleles approximately 1.5 times as frequently as recombination; although the latter still plays an important role in the bacterium's evolution. The secreted/cell-associated 'virulence' factors tly and camp2 show no clear evidence of episodic or pervasive positive selection and have diversified at a rate similar to housekeeping loci. The co-evolution of these genes with the core genome might also indicate a role in commensal/normal existence constraining their diversity and preventing their loss from the P. acnes population. The possibility that members of the expanded CAMP factor protein family, including camp2, may have been lost from other propionibacteria, but not P. acnes, would further argue for a possible role in niche/host adaption leading to their retention within the genome. These evolutionary insights may prove important for discussions surrounding camp2 as an immunotherapy target for acne, and the effect such treatments may have on commensal lineages. © 2013 McDowell et al.

Do Nonagenarians siblings provide mutual support? Insights from the EU GeHA project

Introduction.– Sibling relationships have been described as intimate,
congenial, loyal, apathetic or hostile but little is known about
sibling relationships in very old age.Weasked nonagenarian brothers
and sisters from the EU-funded Genetics of Healthy Ageing
(GeHA) project whether they had felt supported by having a living
sibling to have better coping abilities.
Methods and results.– Nonagenarian siblings were a convenience
sample from four countries from the GeHA study–Italy, Poland,
N Ireland, Finland. All were consented willing participants. Most
male/female dyads demonstrated healthy respect for each other’s
opinion and their sibling relationship fits the “loyal” type, though
with a clear sense of independence.Noneof the eight female/female
nor the one male/male dyad seemed to fit the “intimate” description;
two might be described as “apathetic”, while the other two
seemed to show aspects of family “loyalty”, alongside other traits
perhaps best described as “congenial”. There were apparent different
cultural influences across Europe with siblings in Italy and
Poland more likely to report supportive siblinghood, compared to
sibling pairs/trios in Finland or N Ireland where self-resilience and
independence seemed more common. Polish and Italian nonagenarians
often felt supported by their religious faith and church.
Conclusions.– In general, nonagenarian siblings most often demonstrated
loyal family relationships, which may have helped each
other’s coping and survival mechanisms. However, there was
widespread evidence of tolerance for individual decision-making.
Perhaps rather, these 90-year-olds survive because they are
resilient and independent and don’t need to depend on each other!

New insights into dihydrogenphosphate recognition with dirhenium(I) tricarbonyl complexes bridged by a thiourea moiety

Three thiourea bridged 2,2’-bipyridine ligands bearing either a single thiourea group (L1), or two units separated by either a para (L2) or meta-substituted (L3) aromatic spacer, along with the corresponding bis(fac-tricarbonylrhenium(I)) complexes are reported. The three ligands all show the anticipated binding to acetate. However 1H NMR titrations reveal an unusual cooperative binding to, and selectivity for, two dihydrogenphosphate ions. The rhenium(I) complexes similarly demonstrate unusual sigmoidal titration curves, and in the case of {Re(CO)3Br}2(-L1) a surprisingly strong interaction to two anions. These were further exemplified in the emissive behaviour leading to the conclusion that there is an unusual interaction with dihydrogenphosphate, giving an initial increase in the emission, followed by a decrease and a blue shift in wavelength possibly as a result of partial deprotonation. It appears that dihydrogenphosphate binds cooperatively, with the addition of a second anion enhancing the interaction of the first, probably by proton transfer; this could explain the remarkable selectivity for phosphate seen with many reported anion receptors.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Integrating petrography, mineralogy and hydrochemistry to constrain the influence and distribution of groundwater contributions to baseflow in poorly productive aquifers: Insights from Gortinlieve catchment, Co. Donegal, NW Ireland

Identifying groundwater contributions to baseflowforms an essential part of surfacewater body characterisation. The Gortinlieve catchment (5 km2) comprises a headwater stream network of the Carrigans River, itself a tributary of the River Foyle, NW Ireland. The bedrock comprises poorly productive metasediments that are characterised by fracture porosity. We present the findings of a multi-disciplinary study that integrates new hydrochemical and mineralogical investigations with existing hydraulic, geophysical and structural data to identify the scales of groundwater flow and the nature of groundwater/bedrock interaction (chemical denudation). At the catchment scale, the development of deep weathering profiles is controlled by NE-SW regional scale fracture zones associated with mountain building during the Grampian orogeny. In-situ chemical denudation of mineral phases is controlled by micro- to meso-scale fractures related to Alpine compression during Palaeocene to Oligocene times. The alteration of primary muscovite, chlorite (clinochlore) and albite along the surfaces of these small-scale fractures has resulted in the precipitation of illite, montmorillonite and illite/montmorillonite clay admixtures. The interconnected but discontinuous nature of these small-scale structures highlights the role of larger scale faults and fissures in the supply and transportation of weathering solutions to/from the sites of mineral weathering. The dissolution of primarily mineral phases releases the major ions Mg, Ca and HCO3 that are shown to subsequently formthe chemical makeup of groundwaters. Borehole groundwater and stream baseflow hydrochemical data are used to constrain the depths of groundwater flow pathways influencing the chemistry of surface waters throughout the stream profile. The results show that it is predominantly the lower part of the catchment, which receives inputs from catchment/regional scale groundwater flow, that is found to contribute to the maintenance of annual baseflow levels. This study identifies the importance
of deep groundwater in maintaining annual baseflow levels in poorly productive bedrock systems.