Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal ...carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63
TCF7
myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63
TCF7
myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
To determine whether an intervention to reduce eveningness chronotype improves sleep, circadian, and health (emotional, cognitive, behavioral, social, physical) outcomes.
Youth aged 10 to 18 years ...with an evening chronotype and who were "at risk" in 1 of 5 health domains were randomized to: (a) Transdiagnostic Sleep and Circadian Intervention for Youth (TranS-C; n = 89) or (b) Psychoeducation (PE; n = 87) at a university-based clinic. Treatments were 6 individual, weekly 50-minute sessions during the school year. TranS-C addresses sleep and circadian problems experienced by youth by integrating evidence-based treatments derived from basic research. PE provides education on the interrelationship between sleep, stress, diet, and health.
Relative to PE, TranS-C was not associated with greater pre-post change for total sleep time (TST) or bed time (BT) on weeknights but was associated with greater reduction in evening circadian preference (pre-post increase of 3.89 points, 95% CI = 2.94-4.85, for TranS-C, and 2.01 points, 95% CI = 1.05-2.97 for PE, p = 0.006), earlier endogenous circadian phase, less weeknight-weekend discrepancy in TST and wakeup time, less daytime sleepiness, and better self-reported sleep via youth and parent report. In terms of functioning in the five health domains, relative to PE, TranS-C was not associated with greater pre-post change on the primary outcome. However, there were significant interactions favoring TranS-C on the Parent-Reported Composite Risk Scores for cognitive health.
For at-risk youth, the evidence supports the use of TranS-C over PE for improving sleep and circadian functioning, and improving health on selected outcomes.
Triple Vulnerability? Circadian Tendency, Sleep Deprivation and Adolescence. https://clinicaltrials.gov; NCT01828320.
Placozoans are a phylum of nonbilaterian marine animals currently represented by a single described species, Trichoplax adhaerens, Schulze 1883. Placozoans arguably show the simplest animal ...morphology, which is identical among isolates collected worldwide, despite an apparently sizeable genetic diversity within the phylum. Here, we use a comparative genomics approach for a deeper appreciation of the structure and causes of the deeply diverging lineages in the Placozoa. We generated a high-quality draft genome of the genetic lineage H13 isolated from Hong Kong and compared it to the distantly related T. adhaerens. We uncovered substantial structural differences between the two genomes that point to a deep genomic separation and provide support that adaptation by gene duplication is likely a crucial mechanism in placozoan speciation. We further provide genetic evidence for reproductively isolated species and suggest a genus-level difference of H13 to T. adhaerens, justifying the designation of H13 as a new species, Hoilungia hongkongensis nov. gen., nov. spec., now the second described placozoan species and the first in a new genus. Our multilevel comparative genomics approach is, therefore, likely to prove valuable for species distinctions in other cryptic microscopic animal groups that lack diagnostic morphological characters, such as some nematodes, copepods, rotifers, or mites.
Legumain is a lysosomal cysteine protease whose biological function remains poorly defined. Legumain activity is up-regulated in most human cancers and inflammatory diseases most likely as the result ...of high expression in populations of activated macrophages. Within the tumor microenvironment, legumain activity is thought to promote tumorigenesis. To obtain a greater understanding of the role of legumain activity during cancer progression and inflammation, we developed an activity-based probe that becomes fluorescent only upon binding active legumain. This probe is highly selective for legumain, even in the context of whole cells and tissues, and is also a more effective label of legumain than previously reported probes. Here we present the synthesis and application of our probe to the analysis of legumain activity in primary macrophages and in two mouse models of cancer. We find that legumain activity is highly correlated with macrophage activation and furthermore that it is an ideal marker for primary tumor inflammation and early stage metastatic lesions.
Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic ...marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS-ratios in patients with CAP.
We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.
There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = -0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR:2.8, 95% CI: 1.48-5.28) and DHEA (OR: 2.62,95% CI: 1.28-5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.
Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
Abstract
The human microbiome is comprised of a complex and diverse community of organisms that is subject to dynamic changes over time. As such, cross-sectional studies of the microbiome provide a ...multitude of information for a specific body site at a particular time, but they fail to account for temporal changes in microbial constituents resulting from various factors. To address this shortcoming, longitudinal research studies of the human microbiome investigate the influence of various factors on the microbiome of individuals within a group or community setting. These studies are vital to address the effects of host and/or environmental factors on microbiome composition as well as the potential contribution of microbiome members during the course of an infection. The relationship between microbial constituents and disease development has been previously explored for skin and soft tissue infections (SSTIs) within congregate military trainees. Accordingly, approximately 25% of the population carries
Staphylococcus aureus
within their nasal cavity, and these colonized individuals are known to be at increased risk for SSTIs. To examine the evolution of the nasal microbiota of U.S. Army Infantry trainees, individuals were sampled longitudinally from their arrival at Fort Benning, Georgia, until completion of their training 90 days later. These samples were then processed to determine
S. aureus
colonization status and to profile the nasal microbiota using 16S rRNA gene-based methods. Microbiota stability differed dramatically among the individual trainees; some subjects exhibited great stability, some subjects showed gradual temporal changes and some subjects displayed a dramatic shift in nasal microbiota composition. Further analysis utilizing the available trainee metadata suggests that the major drivers of nasal microbiota stability may be
S. aureus
colonization status and geographic origin of the trainees. Nasal microbiota evolution within the congregate setting imposed by military training is a complex process that appears to be affected by numerous factors. This finding may indicate that future campaigns to prevent
S. aureu
s colonization and future SSTIs among high-risk military trainees may require a ‘personalized’ approach.
With anecdotal observations of atypical recurrences following minimally invasive surgery and alongside new concerns following cervical cancer surgery, there is a need to evaluate cancer specific ...outcomes for minimally invasive kidney cancer surgery using national data. We evaluated cancer specific outcomes following minimally invasive surgery vs open surgery for early stage kidney cancer.
We performed a retrospective population based cohort study using data from the SEER (Surveillance, Epidemiology, and End Results) program linked with Medicare claims that included beneficiaries at least 66 years old diagnosed between 2004 and 2013 with early stage, nonurothelial kidney cancer who underwent surgical resection within a year of diagnosis. We compared overall survival, disease specific survival, rate of second kidney cancer surgery and rate of postoperative systemic cancer therapy based on whether surgery was minimally invasive surgery or an open resection. Multivariable regression was used to account for confounders.
A total of 5,150 patients were included in analysis and 3,062 (59.5%) underwent minimally invasive surgery. On multivariable analysis minimally invasive surgery was not associated with differences in overall survival (HR 0.94, 95% CI 0.84-1.06) or disease specific survival (HR 0.96, 95% CI 0.83-1.11). Patients treated with minimally invasive surgery were more likely to receive systemic cancer therapy (HR 1.31, 95% CI 1.09-1.59). No difference in the rate of second surgery associated with surgical approach was observed.
Use of minimally invasive surgery for early stage kidney cancer was not associated with differences in overall or disease specific survival, or the rate of second kidney cancer surgery. Patients treated with minimally invasive surgery received more postoperative systemic therapy, which could represent a disparate cancer specific outcome associated with minimally invasive surgery.
Infections of fungi by mycoviruses are often symptomless but sometimes also fatal, as they perturb sporulation, growth, and, if applicable, virulence of the fungal host. Hypovirulence-inducing ...mycoviruses, therefore, represent a powerful means to defeat fungal epidemics on crop plants. Infection with Fusarium graminearum virus China 9 (FgV-ch9), a double-stranded RNA (dsRNA) chrysovirus-like mycovirus, debilitates
, the causal agent of fusarium head blight. In search for potential symptom alleviation or aggravation factors in
, we consecutively infected a custom-made
mutant collection with FgV-ch9 and found a mutant with constantly elevated expression of a gene coding for a putative mRNA-binding protein that did not show any disease symptoms despite harboring large amounts of virus. Deletion of this gene, named virus response 1 (
), resulted in phenotypes identical to those observed in the virus-infected wild type with respect to growth, reproduction, and virulence. Similarly, the viral structural protein coded on segment 3 (P3) caused virus infection-like symptoms when expressed in the wild type but not in the
overexpression mutant. Gene expression analysis revealed a drastic downregulation of
in the presence of virus and in mutants expressing P3. We conclude that symptom development and severity correlate with gene expression levels of
This was confirmed by comparative transcriptome analysis, showing a large transcriptional overlap between the virus-infected wild type, the
deletion mutant, and the P3-expressing mutant. Hence,
represents a fundamental host factor for the expression of virus-related symptoms and helps us understand the underlying mechanism of hypovirulence.
Virus infections of phytopathogenic fungi occasionally impair growth, reproduction, and virulence, a phenomenon referred to as hypovirulence. Hypovirulence-inducing mycoviruses, therefore, represent a powerful means to defeat fungal epidemics on crop plants. However, the poor understanding of the molecular basis of hypovirulence induction limits their application. Using the devastating fungal pathogen on cereal crops,
, we identified an mRNA binding protein (named virus response 1,
) which is involved in symptom expression. Downregulation of
in the virus-infected fungus and
deletion evoke virus infection-like symptoms, while constitutive expression overrules the cytopathic effects of the virus infection. Intriguingly, the presence of a specific viral structural protein is sufficient to trigger the fungal response, i.e.,
downregulation, and symptom development similar to virus infection. The advancements in understanding fungal infection and response may aid biological pest control approaches using mycoviruses or viral proteins to prevent future
epidemics.
A facile synthesis approach for the synthesis of ternary intermetallic nanocrystals was demonstrated exemplarily with the Heusler compound Co2FeGa. The method, involving prefabricated multiwalled ...carbon nanotubes which act as a template and protective shell, results in the formation of mainly spherical, chemically stable, and crystalline nanoparticles with a well-defined diameter distribution. As an example, for novel functionalities arising from downscaling a bulk material, we observe an enhancement of the coercive field of the Co2FeGa nanocrystals by a factor of ≈30. Our work can facilitate the exploration and eventually the tuning of physical properties of ternary and other intermetallic compounds at the nanoscale.
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