Photo-induced enhanced Raman spectroscopy as a probe for photocatalytic surfaces.

Photo-induced enhanced Raman spectroscopy (PIERS) has emerged as a highly sensitive surface-enhanced Raman spectroscopy (SERS) technique for the detection of ultra-low concentrations of organic molecules. The PIERS mechanism has been largely attributed to UV-induced formation of surface oxygen vacancies (Vo) in semiconductor materials, although alternative interpretations have been suggested. Very recently, PIERS has been proposed as a surface probe for photocatalytic materials, following Vo formation and healing kinetics. This work establishes comparison between PIERS and Vo-induced SERS approaches in defected noble-metal-free titanium dioxide (TiO2-x) films to further confirm the role of Vo in PIERS. Upon application of three post-treatment methods (namely UV-induction, vacuum annealing and argon etching), correlation of Vo kinetics and distribution could be established. A proposed mechanism and further discussion on PIERS as a probe to explore photocatalytic materials are also presented. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 2)'.

The Effect of Photoinduced Surface Oxygen Vacancies on the Charge Carrier Dynamics in TiO2 Films.

Metal-oxide semiconductors (MOS) are widely utilized for catalytic and photocatalytic applications in which the dynamics of charged carriers (e.g., electrons, holes) play important roles. Under operation conditions, photoinduced surface oxygen vacancies (PI-SOV) can greatly impact the dynamics of charge carriers. However, current knowledge regarding the effect of PI-SOV on the dynamics of hole migration in MOS films, such as titanium dioxide, is solely based upon volume-averaged measurements and/or vacuum conditions. This limits the basic understanding of hole-vacancy interactions, as they are not capable of revealing time-resolved variations during operation. Here, we measured the effect of PI-SOV on the dynamics of hole migration using time-resolved atomic force microscopy. Our findings demonstrate that the time constant associated with hole migration is strongly affected by PI-SOV, in a reversible manner. These results will nucleate an insightful understanding of the physics of hole dynamics and thus enable emerging technologies, facilitated by engineering hole-vacancy interactions.

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages.

INTRODUCTION AND AIMS: Oxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. METHODS: THP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. RESULTS: RT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. CONCLUSION: We demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Omics technologies and the study of human ageing.

Normal ageing is associated with diverse physiological changes in all organ systems but the rate and extent of these changes vary markedly among individuals. One aspect of ageing research focuses on the molecular profiling of the changes that occur with increasing age in humans. Such profiling has implications for disease prevention and treatment. New high-throughput 'omics' technologies (such as genomics, metabolomics, metagenomics and transcriptomics) are enabling detailed studies of these molecular changes and are thus revealing information about the biological pathways that change with age.

Rectal Trumpet-Associated Hemorrhage in the Intensive Care Unit: A Quality Improvement Initiative.

The rectal trumpet (RT) is a nasopharyngeal airway device that is inserted into the rectum for management of fecal incontinence. No published data exist on adverse events caused by the use of an RT. The purpose of this quality improvement project was to determine the rate of RT-associated hemorrhage among patients treated with an RT in our transplant intensive care unit (TICU). This quality improvement initiative and retrospective medical record review included all patients (N = 3933) cared for in a single specialty intensive care unit at a tertiary academic medical center between January 1, 2014, and May 31, 2016. We estimate that approximately 400 patients were treated with an RT. We found 3 possible and 9 probable cases of RT-associated hemorrhage, resulting in an estimated incident rate of 3% among RT-treated patients. All of these patients underwent invasive procedures for hemostasis. They received a mean of 4.9 units of packed red blood cell transfusions, and 9 experienced hypotension. Eight out of the 9 probable RT-associated hemorrhage patients experienced hemorrhage only after greater than 7 days of treatment with an RT. Following this initiative, RT use was banned in our TICU. The use of RTs can cause hemorrhage with clinically significant consequences.

Treatment Sequencing in Advanced BRAF-Mutant Melanoma Patients: Current Practice in the United States.

Background: Treatment of advanced BRAF-mutant melanoma has changed dramatically in the past 3 years thanks to the approval of new immunotherapy and targeted therapy agents. Objectives: The goal of our survey was to investigate when immunotherapy and targeted therapy are used in the management of advanced melanoma patients and whether differences exist between the types of setting. Methods: Oncologists from academic centers, community-based centers, and private clinics were invited to participate in an online survey. Survey questions addressed the proportion of BRAF-mutant patients per treatment line, proportion of patients on targeted therapy and immunotherapy available in the United States, and reasons for prescribing each drug class. Results: A total of 101 physicians completed the survey, of which 47 worked in a private clinic, 33 in an academic center, and 21 in a community-based center. Academic center participants tended to see more severe patients (P < .001) and had more patients in second-line treatment than participants from other setting types. In addition, academic center physicians had more patients in clinical trials (P < .001), and they prescribed the ipilimumab and nivolumab combination more frequently. In terms of sequencing, all participants used targeted therapy for severe or rapidly progressing patients and immunotherapy for those who were less severe or slowly progressing. Conclusions: The findings illustrate the differences in treatment approach per type of setting, with patients in academic centers more likely to receive recently approved products or to be enrolled in clinical trials than those in community-based settings.

High nevus counts confer a favorable prognosis in melanoma patients.

A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5- and 10-year melanoma-specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21-0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08-0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up.

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Inhaled nitric oxide in acute pulmonary embolism: a systematic review.

Acute pulmonary embolism (PE) is usually a complication secondary to migration of a deep venous clot or thrombi to lungs, but other significant etiologies include air, amniotic fluid, fat, and bone marrow. Regardless of the underlying etiology, little progress has been made in finding an effective pharmacologic intervention for this serious complication. Among the wide spectrum of PE, massive PE is associated with considerable morbidity and mortality, primarily due to severely elevated pulmonary vascular resistance leading to right ventricular failure, hypoxemia, and cardiogenic shock. We currently have limited therapeutic options at our disposal. Inhaled nitric oxide (iNO) has been proposed as a potential therapeutic agent in cases of acute PE in which hemodynamic compromise secondary to increased pulmonary vascular resistance is present, based on iNO's selective dilation of the pulmonary vasculature and antiplatelet activity. A systematic search of studies using the PubMed database was undertaken in order to assess the available literature. Although there are currently no published randomized controlled trials on the subject, except a recently publish phase I trial involving eight patients, several case reports and case series describe and document the use of iNO in acute PE. The majority of published reports have documented improvements in oxygenation and hemodynamic variables, often within minutes of administration of iNO. These reports, when taken together, raise the possibility that iNO may be a potential therapeutic agent in acute PE. However, based on the current literature, it is not possible to conclude definitively whether iNO is safe and effective. These case reports underscore the need for randomized controlled trials to establish the safety and efficacy of iNO in the treatment of massive acute PE. The purpose of this article is to review the current literature in the use of iNO in the setting of PE given how acute PE causes acute onset of pulmonary hypertension.

A global perspective on assisted reproductive technology fertility treatment: an 8-country fertility specialist survey.

BACKGROUND: Procedures that may optimize success in achieving live births from assisted reproductive technology (ART) continue to be examined. Not yet considered are the perspectives of fertility specialists regarding important developments in the fertility treatment field, current unmet needs, and anticipated future advances. In the current study, an 8-country survey of fertility specialists was conducted to provide a comprehensive, global depiction of fertility treatments across different regions. METHODS: Fertility specialists from France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), China, and Japan were invited to participate in an online survey. Participants were eligible if they personally managed ≥25 patients/month who were experiencing difficulty conceiving, and if they had performed ART fertility treatment with ≥1 patient in the previous month. Quantitative questions addressed the number of patients seen, main infertility causes, number of cycles performed, ART procedure type, and ART outcomes. Qualitative questions covered diagnostic trends, unmet needs, important advances, and expected future developments. RESULTS: The number of fertility specialists who completed the survey included 29 in France, 33 in Germany, 23 in Italy, 38 in Spain, 34 in the UK, 91 in the US, 50 in China, and 65 in Japan. Patient volume increased over the prior 2 years according to 67 % (242/363) of the fertility specialists. As expected, ART outcomes all declined with age in all countries. ART outcomes varied by country, with the highest implantation, pregnancy, and live birth rates reported by fertility specialists in the US and China and the lowest rates reported in France and Italy. The most frequently reported unmet needs in fertility treatment were financial coverage, improved implantation rate, and egg donation. Most frequently named future advancements expected to change the fertility treatment field included improved embryo selection through imaging and/or metabolomics, improved embryo implantation rate, and use of preimplantation genetic diagnosis. CONCLUSIONS: This study, which follows a rigorous survey methodology, elucidates the current state of fertility specialists' practices and perspectives on the global fertility treatment field, which highlights differences and similarities among countries. This research may inform further studies and procedural developments that might better improve and standardize ART.

Extent, causes, and consequences of small RNA expression variation in human adipose tissue.

Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.

Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.

Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻9-1.01×10⁻¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p =  2.61 × 10(-19)), ARPC1A (rs740160; p =  1.56 × 10(-16)), TRIM4 (rs17277546; p =  4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p =  4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

Evaluation of the authenticity of a highly novel environmental sequence from boreal forest soil using ribosomal RNA secondary structure modeling.

The number of sequences from both formally described taxa and uncultured environmental DNA deposited in the International Nucleotide Sequence Databases has increased substantially over the last two decades. Although the majority of these sequences represent authentic gene copies, there is evidence of DNA artifacts in these databases as well. These include lab artifacts, such as PCR chimeras, and biological artifacts such as pseudogenes or other paralogous sequences. Sequences that fall in basal positions in phylogenetic trees and appear distant from known sequences are particularly suspect. Phylogenetic analyses suggest that a novel sequence type (NS1) found in two boreal forest soil clone libraries belongs to the fungal kingdom but does not fall unambiguously within any known phylum. We have evaluated this sequence type using an array of secondary-structure analyses. To our knowledge, such analyses have never been used on environmental ribosomal sequences. Ribosomal secondary structure was modeled for four rRNA loci (ITS1, 5.8S, ITS2, 5' LSU). These models were analyzed for the presence of conserved domains, conserved nucleotide motifs, and compensatory base changes. Minimal free energy (MFE) foldings and GC contents of sequences representing the major fungal clades, as well as NS1, were also compared. NS1 displays secondary rRNA structures consistent with other fungi and many, but not all, conserved nucleotide motifs found across eukaryotes. However, our analyses show that many other authentic sequences from basal fungi lack more of these conserved motifs than does NS1. Together our findings suggest that NS1 represents an authentic gene copy. The methods described here can be used on any rRNA-coding sequence, not just environmental fungal sequences. As new-generation sequencing methods that yield shorter sequences become more widely implemented, methods that evaluate sequence authenticity should also be more widely implemented. For fungi, the adjacent 5.8S and ITS2 loci should be prioritized. This region is not only suited to distinguishing between closely related species, but it is also more informative in terms of expected secondary structure.

A Highly Tunable Silicone-Based Magnetic Elastomer with Nanoscale Homogeneity.

Magnetic elastomers have been widely pursued for sensing and actuation applications. Silicone-based magnetic elastomers have a number of advantages over other materials such as hydrogels, but aggregation of magnetic nanoparticles within silicones is difficult to prevent. Aggregation inherently limits the minimum size of fabricated structures and leads to non-uniform response from structure to structure. We have developed a novel material which is a complex of a silicone polymer (polydimethylsiloxane-co-aminopropylmethylsiloxane) adsorbed onto the surface of magnetite (γ-Fe(2)0(3)) nanoparticles 7-10 nm in diameter. The material is homogenous at very small length scales (< 100 nm) and can be crosslinked to form a flexible, magnetic material which is ideally suited for the fabrication of micro- to nanoscale magnetic actuators. The loading fraction of magnetic nanoparticles in the composite can be varied smoothly from 0 - 50% wt. without loss of homogeneity, providing a simple mechanism for tuning actuator response. We evaluate the material properties of the composite across a range of nanoparticle loading, and demonstrate a magnetic-field-induced increase in compressive modulus as high as 300%. Furthermore, we implement a strategy for predicting the optimal nanoparticle loading for magnetic actuation applications, and show that our predictions correlate well with experimental findings.

Some evolutionary perspectives on Alzheimer's disease pathogenesis and pathology.

There is increasing urgency to develop effective prevention and treatment for Alzheimer's disease (AD) as the aging population swells. Yet, our understanding remains limited for the elemental pathophysiological mechanisms of AD dementia that may be causal, compensatory, or epiphenomenal. To this end, we consider AD and why it exists from the perspectives of natural selection, adaptation, genetic drift, and other evolutionary forces. We discuss the connection between the apolipoprotein E (APOE) allele and AD, with special consideration to APOE ɛ4 as the ancestral allele. The phylogeny of AD-like changes across species is also examined, and pathology and treatment implications of AD are discussed from the perspective of evolutionary medicine. In particular, amyloid-ß (Aß) neuritic plaques and paired helical filament tau (PHFtau) neurofibrillary tangles have been traditionally viewed as injurious pathologies to be targeted, but may be preservative or restorative processes that mitigate harmful neurodegenerative processes or may be epiphenoma of the essential processes that cause neurodegeneration. Thus, we raise fundamental questions about current strategies for AD prevention and therapeutics.