MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs between 18-22 nucleotides long that regulate gene expression. Expression of miRNAs is altered in tumor compared to normal tissue; there ...is some evidence that these changes may be reflected in the serum of cancer cases compared to healthy individuals. This has yet to be examined in a prospective study where samples are collected before diagnosis.
We used Affymetrix arrays to examine serum miRNA expression profiles in 410 participants in the Sister Study, a prospective cohort study of 50,884 women. All women in the cohort had never been diagnosed with breast cancer at the time of enrollment. We compared global miRNA expression patterns in 205 women who subsequently developed breast cancer and 205 women who remained breast cancer-free. In addition within the case group we examined the association of miRNA expression in serum with different tumor characteristics, including hormone status (ER, PR, and HER-2) and lymph node status.
Overall, 414 of 1,105 of the human miRNAs on the chip were expressed above background levels in 50 or more women. When the average expression among controls was compared to cases using conditional logistic regression, 21 miRNAs were found to be differentially expressed (P≤.05). Using qRT-PCR on a small, independent sample of 5 cases and 5 controls we verified overexpression of the 3 highest expressing miRNAs among cases, miR-18a, miR-181a, and miR-222; the differences were not statistically significant in this small set. The 21 differentially expressed miRNAs are known to target at least 82 genes; using the gene list for pathway analysis we found enrichment of genes involved in cancer-related processes. In a separate case-case analyses restricted to the 21 miRNAs, we found 7 miRNAs with differential expression for women whose breast tumors differed by HER-2 expression, and 10 miRNAs with differential expression by nodal status.
miRNA levels in serum show a number of small differences between women who later develop cancer versus those who remain cancer-free.
The thalamus plays a central and dynamic role in information transmission and processing in the brain. Multiple studies reveal increasing association between schizophrenia and dysfunction of the ...thalamus, in particular the medial dorsal nucleus (MDN), and its projection targets. The medial dorsal thalamic connections to the prefrontal cortex are of particular interest, and explicit in vivo evidence of this connection in healthy humans is sparse. Additionally, recent neuroimaging evidence has demonstrated disconnection among a variety of cortical regions in schizophrenia, though the MDN thalamic prefrontal cortex network has not been extensively probed in schizophrenia. To this end, we have examined thalamo-anterior cingulate cortex connectivity using detection of low-frequency blood oxygen level dependence fluctuations (LFBF) during a resting-state paradigm. Eleven schizophrenic patients and 12 healthy control participants were enrolled in a study of brain thalamocortical connectivity. Resting-state data were collected, and seed-based connectivity analysis was performed to identify the thalamocortical network. First, we have shown there is MDN thalamocortical connectivity in healthy controls, thus demonstrating that LFBF analysis is a manner to probe the thalamocortical network. Additionally, we have found there is statistically significantly reduced thalamocortical connectivity in schizophrenics compared with matched healthy controls. We did not observe any significant difference in motor networks between groups. We have shown that the thalamocortical network is observable using resting-state connectivity in healthy controls and that this network is altered in schizophrenia. These data support a disruption model of the thalamocortical network and are consistent with a disconnection hypothesis of schizophrenia.
Abstract
Host‐associated microbiota can be affected by factors related to environmental change, such as urbanization and invasive species. For example, urban areas often affect food availability for ...animals, which can change their gut microbiota. Invasive parasites can also influence microbiota through competition or indirectly through a change in the host immune response. These interacting factors can have complex effects on host fitness, but few studies have disentangled the relationship between urbanization and parasitism on an organism's gut microbiota. To address this gap in knowledge, we investigated the effects of urbanization and parasitism by the invasive avian vampire fly (
Philornis downsi
) on the gut microbiota of nestling small ground finches (
Geospiza fuliginosa
) on San Cristóbal Island, Galápagos. We conducted a factorial study in which we experimentally manipulated parasite presence in an urban and nonurban area. Faeces were then collected from nestlings to characterize the gut microbiota (i.e. bacterial diversity and community composition). Although we did not find an interactive effect of urbanization and parasitism on the microbiota, we did find main effects of each variable. We found that urban nestlings had lower bacterial diversity and different relative abundances of taxa compared to nonurban nestlings, which could be mediated by introduction of the microbiota of the food items or changes in host physiology. Additionally, parasitized nestlings had lower bacterial richness than nonparasitized nestlings, which could be mediated by a change in the immune system. Overall, this study advances our understanding of the complex effects of anthropogenic stressors on the gut microbiota of birds.
In mammals, photoreceptor loss causes permanent blindness, but in zebrafish (
Danio rerio
), photoreceptor loss reprograms Müller glia to function as stem cells, producing progenitors that regenerate ...photoreceptors. MicroRNAs (miRNAs) regulate CNS neurogenesis, but the roles of miRNAs in injury-induced neuronal regeneration are largely unknown. In the embryonic zebrafish retina,
miR-18a
regulates photoreceptor differentiation. The purpose of the current study was to determine, in zebrafish, the function of
miR-18a
during injury-induced photoreceptor regeneration. RT-qPCR, in situ hybridization, and immunohistochemistry showed that
miR-18a
expression increases throughout the retina between 1 and 5 days post-injury (dpi). To test
miR-18a
function during photoreceptor regeneration, we used homozygous
miR-18a
mutants (
miR-18a
mi5012
), and knocked down
miR-18a
with morpholino oligonucleotides. During photoreceptor regeneration,
miR-18a
mi5012
retinas have fewer mature photoreceptors than WT at 7 and 10 dpi, but there is no difference at 14 dpi, indicating that photoreceptor regeneration is delayed. Labeling dividing cells with 5-bromo-2′-deoxyuridine (BrdU) showed that at 7 and 10 dpi, there are excess dividing progenitors in both mutants and morphants, indicating that
miR-18a
negatively regulates injury-induced proliferation. Tracing 5-ethynyl-2′-deoxyuridine (EdU) and BrdU-labeled cells showed that in
miR-18a
mi5012
retinas excess progenitors migrate to other retinal layers in addition to the photoreceptor layer. Inflammation is critical for photoreceptor regeneration, and RT-qPCR showed that in
miR-18a
mi5012
retinas, inflammatory gene expression and microglia activation are prolonged. Suppressing inflammation with dexamethasone rescues the
miR-18a
mi5012
phenotype. Together, these data show that in the injured zebrafish retina, disruption of
miR-18a
alters proliferation, inflammation, the microglia/macrophage response, and the timing of photoreceptor regeneration.
Among one of the older subfields in Buddhist Studies, the study of Theravāda Buddhism is undergoing a revival by contemporary scholars who are revising long-held conventional views of the tradition ...while undertaking new approaches and engaging new subject matter. The term Theravāda has been refined, and research has expanded beyond the analysis of canonical texts to examine contemporary cultural forms, social movements linked with meditation practices, material culture, and vernacular language texts. The Routledge Handbook of Theravāda Buddhism illustrates the growth and new directions of scholarship in the study of Theravāda Buddhism and is structured in four parts:Ideas/IdealsPractices/PersonsTexts/TeachingsImages/ImaginationsOwing largely to the continued vitality of Theravāda Buddhist communities in countries like Sri Lanka, Myanmar, Thailand, Cambodia, and Laos, as well as in diaspora communities across the globe, traditions associated with what is commonly (and fairly recently) called Theravāda attract considerable attention from scholars and practitioners around the world. An in-depth guide to the distinctive features of Theravāda, the Handbook will be an invaluable resource for providing structure and guidance for scholars and students of Asian Religion, Buddhism and, in particular, Theravāda Buddhism.
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•Golden-crowned and white-crowned sparrows have almost identical mitochondrial genomes.•We test incomplete lineage sorting versus mitochondrial introgression.•We find reciprocal ...monophyly of nuclear DNA but shared mitochondrial haplotypes.•Results are consonant with historical hybridization and mitochondrial introgression.•White-crowned sparrows subspecies group into two clades.
The golden-crowned (Zonotrichia atricapilla) and white-crowned (Z. leucophrys) sparrows have been presented as a compelling case for rapid speciation. They display divergence in song and plumage with overlap in their breeding ranges implying reproductive isolation, but have almost identical mitochondrial genomes. Previous research proposed hybridization and subsequent mitochondrial introgression as an alternate explanation, but lacked robust nuclear gene trees to distinguish between introgression and incomplete lineage sorting. We test for signatures of these processes between Z. atricapilla and Z. leucophrys, and investigate the relationships among Z. leucophrys subspecies, using mitochondrial sequencing and a reduced representation nuclear genomic dataset. Contrary to the paraphyly evident in mitochondrial gene trees, we confirmed the reciprocal monophyly of Z. atricapilla and Z. leucophrys using large panels of single nucleotide polymorphisms (SNPs). The pattern of cytonuclear discordance is consistent with limited, historical hybridization and mitochondrial introgression, rather than a recent origin and incomplete lineage sorting between recent sister species. We found evidence of nuclear phylogeographic structure within Z. leucophrys with two distinct clades. Altogether, our results indicate deeper divergences between Z. atricapilla and Z. leucophrys than inferred using mitochondrial markers. Our results demonstrate the limitations of relying solely on mitochondrial DNA for taxonomy, and raise questions about the possibility of selection on the mitochondrial genome during temperature oscillations (e.g. during the Pleistocene). Historical mitochondrial introgression facilitated by past environmental changes could cause erroneous dating of lineage splitting in other taxa when based on mitochondrial DNA alone.
Abstract Objective Utilization, outcomes and, particularly, cost between transfemoral (TF), transapical (TA) and transaortic (TAO) transcatheter aortic valve replacement (TAVR) patients have yet to ...be comprehensively evaluated. Methods All Medicare fee-for-service patients undergoing TF (n=4065), TA (n=691), or TAO (n=274) TAVR between January 1, 2011 and November 30, 2012 were identified using Health Care Procedure Classification Codes present on Medicare claims. Hospital charges from Medicare claims were converted to costs using hospital-specific Medicare cost-to-charge ratios. Results TA and TAO patients were similar in age, race, and common comorbidities. Compared to TF patients, TA and TAO patients were more likely to be female and to have peripheral vascular disease, chronic lung disease, and renal failure. Thirty-day mortality rates were higher among TA and TAO patients than among TF patients (TA=9.6%, TAO=8.0%, TF=5.0%, p <0.001). Adjusted mortality beyond 1 year did not differ by access. TA patients were more likely to require cardiopulmonary bypass (CPB). Increased adjusted mortality was associated with CPB (HR 2.13, p<0.01) and increased 30 day cost ($62,000 IQR $45,100 - $86,400 v $48,800 IQR $38,100 - $62,900, p < 0.01). Cost at 30 days was lowest for TF ($48,600) compared to TA ($49,800, p < 0.01) and TAO ($53,200, p = 0.03). Conclusion For patients ineligible to receive TF TAVR, TAO and TA approaches offer similar clinical outcomes at similar cost with acceptable operative- and one-year survival, except higher rates of cardiopulmonary bypass use in TA patients. CPB was associated with worse survival and increased costs.
is a Rho-guanine nucleotide exchange factor that was previously implicated in kidney injury in the Dahl salt-sensitive (SS) rat, a model of hypertension-related chronic kidney disease. Reduced
...expression in an SS-
-minimal congenic strain (spontaneously hypertensive rat allele substituted for S allele) significantly decreased proteinuria, fibrosis, and improved renal hemodynamics, without impacting blood pressure compared with the control SS (SS-wild type). Here, SS-
and SS-wild type rats were placed on either low or elevated salt (0.3% or 2% NaCl) from 4 to 12 weeks of age. On low salt, starting at week 6 and through week 12, SS-
animals demonstrated a 3-fold decrease in proteinuria compared with SS-wild type. On high salt, beginning at week 6, SS-
animals demonstrated >2-fold lower proteinuria from weeks 8 to 12 and 30 mm Hg lower BP compared with SS-wild type. To better understand the molecular mechanisms of the renal protection from loss of
, both RNA sequencing and discovery proteomics were performed on kidneys from week 4 (before onset of renal injury/proteinuria between groups) and at week 12 (low salt). The omics data sets revealed loss of
(SS-
) initiates early transcriptome/protein changes in the cytoskeleton starting as early as week 4 that impact a number of cellular functions, including actin cytoskeletal regulation, mitochondrial metabolism, and solute carrier transporters. In summary, in vivo phenotyping coupled with a multi-omics approach provides strong evidence that increased
expression in the Dahl SS rat leads to actin cytoskeleton-mediated changes in cell morphology and cell function that promote kidney injury, hypertension, and decline in kidney function.
Naturally-occurring surface topographies abound in nature and endow diverse properties,
i.e.
, superhydrophobicity, adhesion, anti-fouling, self-cleaning, anti-glare, anti-bacterial, and many others. ...Researchers have attempted to replicate such topographies to create human-made surfaces with desired functionalities. For example, combining the surface topography with judicial chemical composition could provide an effective, non-toxic solution to combat non-specific biofouling. A systematic look at the effect of geometry, modulus, and chemistry on adhesion is warranted. In this work, we use a model system that comprises silica (SiO
x
) beads interacting with a substrate made of a commercial polydimethylsiloxane kit (PDMS, Sylgard 184) featuring a sinusoidal topography. To examine the impact of interactions on particle settlement, we functionalize the surfaces of both the PDMS substrate and the SiO
x
beads with polyacrylic acid (PAA) and polyethyleneimine (PEI), respectively. We also use the PDMS commercial kit coated with liquid glass (LG) to study the effect of the substrate modulus on particle settlement. Substrates with a higher aspect ratio (
i.e.
, amplitude/periodicity) encourage adsorption of particles along the sides of the channel compared with substrates with lower aspect ratio. We employ colloidal probe microscopy to demonstrate the effect of interaction between the substrate and the particle. The interplay among the surface modulus, geometry, and interactions between the surface and the particle governs particle settlement on sinusoidally-corrugated substrates.
The interplay among the surface modulus, geometry, and interactions between the surface and the particle governs particle settlement on sinusoidally-corrugated substrates.
The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SS
mutant) strain is associated with elevations in glomerular ...filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SS
) and SS
mutant rats. However, by 18 wk of age, the SS
mutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SS
rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SS
mutant than SS
rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SS
mutant compared with SS
rats. Kidneys from the SS
mutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SS
rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (
; cholesterol efflux regulatory protein 2), in SS
mutant compared with SS
rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.
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