In order to complete a genetic model for the inheritance of chemotype in
Cannabis
, this paper explores the regulation of the propyl-/pentyl cannabinoid ratio. Plants almost pure in compounds with a ...C
5
side chain are by far the most common, and such a chemotype can be considered a wild-type condition. Mutant progenitors with higher levels of the rarer cannabinoid THC-C
3
(tetrahydrocannabivarin) were identified. Their propyl cannabinoid proportion in the total cannabinoid fraction (PC
3
) ranged from 14 to 69 %, which, through selective inbreeding, could be increased to highly specific lineage maxima. Inbred plants with maximised PC
3
derived from the different progenitors, were then crossed with a pure C
5
wild type and the PC
3
distribution patterns of the F
2
s examined. Distinct patterns, compatible with oligogenic and polygenic segregation appeared. It was hypothesised that the PC
3
regulating loci of the six source progenitors would be at least partially different, complementary, and additive in their phenotypical effect. So, high PC
3
offspring from the different lineages were mutually crossed. Inbred lines derived from multi-cross hybrid combinations reached unprecedented PC
3
levels of up to 96 % which supports the hypothesis. For the regulation of C
3
/C
5
ratios, a model of a multiple locus
A
1
–
A
2
–…
A
n
is proposed, with the pentyl- and propyl cannabinoid pathway being enhanced by alleles
A
pe
1−n
and
A
pr
1−n
, respectively.
The ATR kinase phosphorylates both p53 and Chk1 in response to extreme hypoxia (oxygen concentrations of less than 0.02%). In contrast to ATR, loss of ATM does not affect the phosphorylation of these ...or other targets in response to hypoxia. However, hypoxia within tumors is often transient and is inevitably followed by reoxygenation. We hypothesized that ATR activity is induced under hypoxic conditions because of growth arrest and ATM activity increases in response to the oxidative stress of reoxygenation. Using the comet assay to detect DNA damage, we find that reoxygenation induced significant amounts of DNA damage. Two ATR/ATM targets, p53 serine 15 and histone H2AX, were both phosphorylated in response to hypoxia in an ATR-dependent manner. These phosphorylations were then maintained in response to reoxygenation-induced DNA damage in an ATM-dependent manner. The reoxygenation-induced p53 serine 15 phosphorylation was inhibited by the addition of N-acetyl-l-cysteine (NAC), indicating that free radical-induced DNA damage was mediated by reactive oxygen species. Taken together these data implicate both ATR and ATM as critical roles in the response of hypoxia and reperfusion in solid tumors.
For a number of prospective parents, uncertainty during pregnancy starts when an anomaly is found during a routine fetal anomaly scan. This may be followed by numerous tests to determine the etiology ...and nature of the anomaly. In this study, we aimed to understand how prospective parents perceive and manage uncertainty after being confronted with a structural anomaly during their routine ultrasound. Han's taxonomy of uncertainty was used as a framework to identify and understand the different types of uncertainty experienced. Interviews were held in the UK (n = 8 women and n = 1 male partner) and in the Netherlands (n = 7 women) with participants who had experienced uncertainty in their pregnancy after a fetal scan. Data were analyzed using thematic analysis, and the uncertainties experienced by parents were mapped against the dimensions of the Han taxonomy (sources, issues, and locus). Participants' experience of uncertainty was relevant to all dimensions and subcategories of the Han taxonomy, showing its applicability in the prenatal setting. Sources of uncertainty included receiving probabilistic or ambiguous information about the anomaly, or information that was complex and challenging to understand. Issues of uncertainty included were those that were scientific—such as a probable diagnosis with no further information, personal—such as the emotional impact of uncertainty, and practical—such as limited information about medical procedures and practical aspects of care. Additionally, participants described what helped them to manage uncertainty. This included active coping strategies such as searching for information on the Internet, external coping resources such as seeking social support, and internal coping resources such as using positivity and hope. Several recommendations for the healthcare professional to minimize uncertainty and help the patient deal with uncertainty have been proposed based on these findings.
Microbial point-of-care testing (POCT) has potential to revolutionize clinical care. Understanding the prognostic value of microbes identified from the upper respiratory tract (a convenient sampling ...site) is a necessary first step to understand potential for upper respiratory tract POCTs in assisting antimicrobial treatment decisions for respiratory infections (RTIs). The aim was to investigate the relationship between upper respiratory tract microbial detection and disease prognosis, including effects of antimicrobial use.
Data sources were the MEDLINE and Embase databases. Study eligibility criteria consisted of quantitative studies reporting microbiological and prognostic data from patients of all age groups presenting with RTI. Patients presenting to healthcare or research settings with RTI participated. Interventions included upper respiratory tract swab. The methods used were systematic review and meta-analysis.
Searches identified 5156 articles, of which 754 were duplicates and 4258 excluded on title or abstract. A total of 144 full texts were screened; 21 articles were retained. Studies reported data for 15 microbes and 26 prognostic measures (390 potential associations). One hundred and seven (27%) associations were investigated statistically, of which 38 (36%) were significant. Most studies reported only prognostic value of test positive results. Meta-analyses suggested hospitalization duration was longer for patients with respiratory syncytial virus than adenovirus and influenza, but significant heterogeneity was observed between studies.
A quarter of potential prognostic associations have been investigated. Of these, a third were significant, suggesting considerable potential for POCT. Future research should investigate prognostic value of positive and negative tests, and interactions between test results, use of antimicrobials and microbial resistance.
This paper outlines the design features, data collection methods and analytic strategies of the International Tobacco Control (ITC) Four Country Survey, a prospective study of more than 2000 ...longitudinal respondents per country with yearly replenishments. This survey possesses unique features that sets it apart among surveys on tobacco use and cessation. One of these features is the use of theory-driven conceptual models. In this paper, however, the focus is on the two key statistical features of the survey: longitudinal and “quasi-experimental” designs. Although it is often possible to address the same scientific questions with a cross-sectional or a longitudinal study, the latter has the major advantage of being able to distinguish changes over time within individuals from differences among people at baseline (that is, differences between age and cohort effects). Furthermore, quasi-experiments, where countries not implementing a given new tobacco control policy act as the control group to which the country implementing such a policy will be compared, provide much stronger evidence than observational studies on the effects of national-level tobacco control policies. In summary, application of rigorous research methods enables this survey to be a rich data resource, not only to evaluate policies, but also to gain new insights into the natural history of smoking cessation, through longitudinal analyses of smoker behaviour.
Understanding the molecular mechanisms that regulate cellular proliferation and differentiation is a central theme of developmental biology. MicroRNAs (miRNAs) are a class of regulatory RNAs of ∼22 ...nucleotides that post-transcriptionally regulate gene expression. Increasing evidence points to the potential role of miRNAs in various biological processes. Here we show that miRNA-1 (miR-1) and miRNA-133 (miR-133), which are clustered on the same chromosomal loci, are transcribed together in a tissue-specific manner during development. miR-1 and miR-133 have distinct roles in modulating skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in Xenopus laevis embryos in vivo. miR-1 promotes myogenesis by targeting histone deacetylase 4 (HDAC4), a transcriptional repressor of muscle gene expression. By contrast, miR-133 enhances myoblast proliferation by repressing serum response factor (SRF). Our results show that two mature miRNAs, derived from the same miRNA polycistron and transcribed together, can carry out distinct biological functions. Together, our studies suggest a molecular mechanism in which miRNAs participate in transcriptional circuits that control skeletal muscle gene expression and embryonic development.
Subcostal hernias are categorized as L1 based on the European Hernia Society (EHS) classification and frequently involve M1, M2, and L2 sites. These are common after hepatopancreatic and biliary ...surgeries. The literature on subcostal hernias mostly comprises of retrospective reviews of small heterogenous cohorts, unsurprisingly leading to no consensus or guidelines. Given the limited literature and lack of consensus or guidelines for dealing with these hernias, we planned for a Delphi consensus to aid in decision making to repair subcostal hernias.
We adopted a modified Delphi technique to establish consensus regarding the definition, characteristics, and surgical aspects of managing subcostal hernias (SCH). It was a four-phase Delphi study reflecting the widely accepted model, consisting of: 1. Creating a query. 2. Building an expert panel. 3. Executing the Delphi rounds. 4. Analysing, presenting, and reporting the Delphi results. More than 70% of agreement was defined as a consensus statement.
The 22 experts who agreed to participate in this Delphi process for Subcostal Hernias (SCH) comprised 7 UK surgeons, 6 mainland European surgeons, 4 Indians, 3 from the USA, and 2 from Southeast Asia. This Delphi study on subcostal hernias achieved consensus on the following areas-use of mesh in elective cases; the retromuscular position with strong discouragement for onlay mesh; use of macroporous medium-weight polypropylene mesh; use of the subcostal incision over midline incision if there is no previous midline incision; TAR over ACST; defect closure where MAS is used; transverse suturing over vertical suturing for closure of circular defects; and use of peritoneal flap when necessary.
This Delphi consensus defines subcostal hernias and gives insight into the consensus for incision, dissection plane, mesh placement, mesh type, and mesh fixation for these hernias.
Objectives This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. Background Recent studies ...demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. Methods Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. Results Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. Conclusions The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart.
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