The structural and diagenetic evolution of injected sandstones: examples from the Kimmeridgian of NE Scotland

Abstract: Injected sandstones occurring in the Kimmeridgian of NE Scotland along the bounding Great Glen and Helmsdale faults formed when basinal fluids moved upward along the fault zones, fluidizing Oxfordian sands encountered at shallow depth and injecting them into overlying Kimmeridgian strata. The orientation of dykes, in addition to coeval faults and fractures, was controlled by a stress state related to dextral strike-slip along the bounding fault zones. Diagenetic studies of cements allow the reconstruction of the fluid flow history. The origin of deformation bands in sandstone dykes and sills was related to the contraction of the host-rocks against dyke and sill walls following the initial stage of fluidized flow, and these deformation bands are the earliest diagenetic imprint. Early non-ferroan calcite precipitated in injection structures at temperatures between 70 and 100 8C, indicating that it precipitated from relatively hot basinal fluids that drove injection. Coeval calcite-filled fractures show similar temperatures, suggesting that relatively hot fluids were responsible for calcite precipitation in any permeable pathway created by dextral simple shear along the faults. During progressive burial, percolating sea water was responsible for completely cementing the still relatively porous injected sandstones with a second generation of ferroan calcite, which contains fluid inclusions with homogenization temperatures below 50 8C. During this phase, depositional host sandstones were also cemented

Effect of ruxolitinib on the oral mucosa of patients with steroid-refractory chronic Graft-versus-Host disease and oral involvement

BACKGROUND: Chronic Graft-versus-Host Disease (cGVHD) can impact quality of life, especially in patients with oral involvement. Half of the patients with cGVHD do not respond to first-line therapy with corticosteroids and calcineurin inhibitors. Ruxolitinib is effective in steroid-refractory (SR)-cGVHD cases, but the long-term effects of ruxolitinib on the oral mucosa are unknown. OBJECTIVE(S): This study aims to assess the effect of ruxolitinib on the oral mucosa of SR-cGVHD patients with oral involvement. MATERIALS AND METHODS: An observational longitudinal patient study was conducted in 53 patients with SR-cGVHD and oral involvement who were treated with ruxolitinib. The baseline condition of the oral mucosa was compared to its condition at 4 and 12 weeks after starting ruxolitinib. RESULTS: The overall response was 81% (43/53), with a complete response in 53% (28/53) and partial response in 28% (15/53) after 12 weeks (p < 0.001). Men and patients concurrently using immunosuppressive therapy responded better than women (p = 0.005) and patients with ruxolitinib monotherapy (p = 0.02), respectively. At a longer follow-up (median 20 months), oral symptoms were comparable to the 12-week symptoms (p = 0.78), regardless of ruxolitinib use (p = 0.83). CONCLUSION: Ruxolitinib treatment of SR-cGVHD patients with oral involvement was associated with a significant response of the oral manifestations at 12 weeks. CLINICAL RELEVANCE: The oral mucosa of SR-cGVHD patients is likely to improve after 4 and 12 weeks of ruxolitinib treatment. Symptom severity at baseline does not affect the response of the oral mucosa

Long term geological record of a global deep subsurface microbial habitat in sand injection complexes

Peer reviewedPublisher PD

Nuclear receptors in vascular biology

Nuclear receptors sense a wide range of steroids and hormones (estrogens, progesterone, androgens, glucocorticoid, and mineralocorticoid), vitamins (A and D), lipid metabolites, carbohydrates, and xenobiotics. In response to these diverse but critically important mediators, nuclear receptors regulate the homeostatic control of lipids, carbohydrate, cholesterol, and xenobiotic drug metabolism, inflammation, cell differentiation and development, including vascular development. The nuclear receptor family is one of the most important groups of signaling molecules in the body and as such represent some of the most important established and emerging clinical and therapeutic targets. This review will highlight some of the recent trends in nuclear receptor biology related to vascular biology

Perivascular Fat and the Microcirculation: Relevance to Insulin Resistance, Diabetes, and Cardiovascular Disease

Type 2 diabetes and its major risk factor, obesity, are a growing burden for public health. The mechanisms that connect obesity and its related disorders, such as insulin resistance, type 2 diabetes, and hypertension, are still undefined. Microvascular dysfunction may be a pathophysiologic link between insulin resistance and hypertension in obesity. Many studies have shown that adipose tissue-derived substances (adipokines) interact with (micro)vascular function and influence insulin sensitivity. In the past, research focused on adipokines from perivascular adipose tissue (PVAT). In this review, we focus on the interactions between adipokines, predominantly from PVAT, and microvascular function in relation to the development of insulin resistance, diabetes, and cardiovascular disease

Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

Smad proteins form multimeric complexes consisting of the ‘common partner’ Smad4 and receptor regulated R-Smads on clustered DNA binding sites. Deciphering how pathway specific Smad complexes multimerize on DNA to regulate gene expression is critical for a better understanding of the cis-regulatory logic of TGF-β and BMP signaling. To this end, we solved the crystal structure of the dimeric Smad4 MH1 domain bound to a palindromic Smad binding element. Surprisingly, the Smad4 MH1 forms a constitutive dimer on the SBE DNA without exhibiting any direct protein–protein interactions suggesting a DNA mediated indirect readout mechanism. However, the R-Smads Smad1, Smad2 and Smad3 homodimerize with substantially decreased efficiency despite pronounced structural similarities to Smad4. Therefore, intricate variations in the DNA structure induced by different Smads and/or variant energetic profiles likely contribute to their propensity to dimerize on DNA. Indeed, competitive binding assays revealed that the Smad4/R-Smad heterodimers predominate under equilibrium conditions while R-Smad homodimers are least favored. Together, we present the structural basis for DNA recognition by Smad4 and demonstrate that Smad4 constitutively homo- and heterodimerizes on DNA in contrast to its R-Smad partner proteins by a mechanism independent of direct protein contacts

Essential Role of Chromatin Remodeling Protein Bptf in Early Mouse Embryos and Embryonic Stem Cells

We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF (Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf−/− embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf−/− embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo

Somatic Mutation Profiles of MSI and MSS Colorectal Cancer Identified by Whole Exome Next Generation Sequencing and Bioinformatics Analysis

BACKGROUND: Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations

A before-after implementation trial of smoking cessation guidelines in hospitalized veterans

Abstract Background Although most hospitalized smokers receive some form of cessation counseling during hospitalization, few receive outpatient cessation counseling and/or pharmacotherapy following discharge, which are key factors associated with long-term cessation. US Department of Veterans Affairs (VA) hospitals are challenged to find resources to implement and maintain the kind of high intensity cessation programs that have been shown to be effective in research studies. Few studies have applied the Chronic Care Model (CCM) to improve inpatient smoking cessation. Specific objectives The primary objective of this protocol is to determine the effect of a nurse-initiated intervention, which couples low-intensity inpatient counseling with sustained proactive telephone counseling, on smoking abstinence in hospitalized patients. Key secondary aims are to determine the impact of the intervention on staff nurses' attitudes toward providing smoking cessation counseling; to identify barriers and facilitators to implementation of smoking cessation guidelines in VA hospitals; and to determine the short-term cost-effectiveness of implementing the intervention. Design Pre-post study design in four VA hospitals Participants Hospitalized patients, aged 18 or older, who smoke at least one cigarette per day. Intervention The intervention will include: nurse training in delivery of bedside cessation counseling, electronic medical record tools (to streamline nursing assessment and documentation, to facilitate prescription of pharmacotherapy), computerized referral of motivated inpatients for proactive telephone counseling, and use of internal nursing facilitators to provide coaching to staff nurses practicing in non-critical care inpatient units. Outcomes The primary endpoint is seven-day point prevalence abstinence at six months following hospital admission and prolonged abstinence after a one-month grace period. To compare abstinence rates during the intervention and baseline periods, we will use random effects logistic regression models, which take the clustered nature of the data within nurses and hospitals into account. We will assess attitudes of staff nurses toward cessation counseling by questionnaire and will identify barriers and facilitators to implementation by using clinician focus groups. To determine the short-term incremental cost per quitter from the perspective of the VA health care system, we will calculate cessation-related costs incurred during the initial hospitalization and six-month follow-up period. Trial number NCT00816036http://deepblue.lib.umich.edu/bitstream/2027.42/112349/1/13012_2009_Article_190.pd