68 research outputs found
Asymmetrical Gene Flow in a Hybrid Zone of Hawaiian Schiedea (Caryophyllaceae) Species with Contrasting Mating Systems
Asymmetrical gene flow, which has frequently been documented in naturally occurring hybrid zones, can result from various genetic and demographic factors. Understanding these factors is important for determining the ecological conditions that permitted hybridization and the evolutionary potential inherent in hybrids. Here, we characterized morphological, nuclear, and chloroplast variation in a putative hybrid zone between Schiedea menziesii and S. salicaria, endemic Hawaiian species with contrasting breeding systems. Schiedea menziesii is hermaphroditic with moderate selfing; S. salicaria is gynodioecious and wind-pollinated, with partially selfing hermaphrodites and largely outcrossed females. We tested three hypotheses: 1) putative hybrids were derived from natural crosses between S. menziesii and S. salicaria, 2) gene flow via pollen is unidirectional from S. salicaria to S. menziesii and 3) in the hybrid zone, traits associated with wind pollination would be favored as a result of pollen-swamping by S. salicaria. Schiedea menziesii and S. salicaria have distinct morphologies and chloroplast genomes but are less differentiated at the nuclear loci. Hybrids are most similar to S. menziesii at chloroplast loci, exhibit nuclear allele frequencies in common with both parental species, and resemble S. salicaria in pollen production and pollen size, traits important to wind pollination. Additionally, unlike S. menziesii, the hybrid zone contains many females, suggesting that the nuclear gene responsible for male sterility in S. salicaria has been transferred to hybrid plants. Continued selection of nuclear genes in the hybrid zone may result in a population that resembles S. salicaria, but retains chloroplast lineage(s) of S. menziesii
A Machine Learning Approach for Identifying Novel Cell Type–Specific Transcriptional Regulators of Myogenesis
Transcriptional enhancers integrate the contributions of multiple classes of transcription factors (TFs) to orchestrate the myriad spatio-temporal gene expression programs that occur during development. A molecular understanding of enhancers with similar activities requires the identification of both their unique and their shared sequence features. To address this problem, we combined phylogenetic profiling with a DNA–based enhancer sequence classifier that analyzes the TF binding sites (TFBSs) governing the transcription of a co-expressed gene set. We first assembled a small number of enhancers that are active in Drosophila melanogaster muscle founder cells (FCs) and other mesodermal cell types. Using phylogenetic profiling, we increased the number of enhancers by incorporating orthologous but divergent sequences from other Drosophila species. Functional assays revealed that the diverged enhancer orthologs were active in largely similar patterns as their D. melanogaster counterparts, although there was extensive evolutionary shuffling of known TFBSs. We then built and trained a classifier using this enhancer set and identified additional related enhancers based on the presence or absence of known and putative TFBSs. Predicted FC enhancers were over-represented in proximity to known FC genes; and many of the TFBSs learned by the classifier were found to be critical for enhancer activity, including POU homeodomain, Myb, Ets, Forkhead, and T-box motifs. Empirical testing also revealed that the T-box TF encoded by org-1 is a previously uncharacterized regulator of muscle cell identity. Finally, we found extensive diversity in the composition of TFBSs within known FC enhancers, suggesting that motif combinatorics plays an essential role in the cellular specificity exhibited by such enhancers. In summary, machine learning combined with evolutionary sequence analysis is useful for recognizing novel TFBSs and for facilitating the identification of cognate TFs that coordinate cell type–specific developmental gene expression patterns
Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)
The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and
death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated
organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating
illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without
early treatment can succumb to delayed in-hospital
care and death. Prompt early initiation of sequenced multidrug
therapy (SMDT) is a widely and currently available
solution to stem the tide of hospitalizations and death. A
multipronged therapeutic approach includes 1) adjuvant
nutraceuticals, 2) combination intracellular anti-infective
therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet
agents/anticoagulants, 5) supportive care including supplemental
oxygen, monitoring, and telemedicine. Randomized
trials of individual, novel oral therapies have not
delivered tools for physicians to combat the pandemic in
practice. No single therapeutic option thus far has been
entirely effective and therefore a combination is required
at this time. An urgent immediate pivot from single drug to
SMDT regimens should be employed as a critical strategy
to deal with the large numbers of acute COVID-19 patients
with the aim of reducing the intensity and duration
of symptoms and avoiding hospitalization and death
Detectable clonal mosaicism and its relationship to aging and cancer
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases
Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures
Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo
Evidence for decreased luteinizing hormone-releasing hormone pulse frequency in men with selective elevations of follicle-stimulating hormone
To examine the hypothesis that the frequency of endogenous pulsatile LHRH
stimulation controls the relative secretion of FSH and LH from the
pituitary, we studied men with elevated FSH levels and normal LH levels to
determine whether they have an altered frequency of pulsatile LHRH
secretion compared to normal men. Because peripheral blood measurements of
LHRH do not reflect the pulsatile characteristics of hypothalamic LHRH
secretion, and it is generally accepted that the pulse frequency of LH
secretion is an index of the frequency of endogenous LHRH pulsation, we
used LH pulse frequency as the indicator of LHRH pulse frequency. Frequent
blood sampling was performed to characterize LH pulse patterns in five men
with selective elevations of FSH and seven age-matched normal men.
Beginning at 0800-0930 h, blood samples were obtained every 10 min for 24
h through an indwelling iv catheter. Serum LH and FSH levels were measured
by RIA in each sample, and the pattern of LH secretion was determined.
Testosterone (T), estradiol, sex hormone-binding globulin, and free T were
measured in a pooled serum sample from each man. Men with selective
elevations of FSH had fewer LH pulses per 24 h (mean +/- SEM, 10.6 +/-
0.5) than the control group (12.9 +/- 0.6; P less than 0.01). There was no
statistically significant difference in LH pulse amplitude (23 +/- 4 vs.
17 +/- 3 ng/ml). There were no statistically significant differences in T
(4.9 +/- 0.5 vs. 6.1 +/- 0.5 ng/ml), estradiol (23 +/- 7 vs. 31 +/- 5
pg/ml), sex hormone-binding globulin (7.7 +/- 1.4 vs. 7.7 +/- 1.2 ng bound
dihydrotestosterone/ml), or free T (0.16 +/- 0.02 vs. 0.23 +/- 0.04 ng/ml)
in these men vs. normal subjects. We conclude that 1) compared to normal
men, men with selectively elevated FSH levels have decreased LH pulse
frequency, which suggests decreased LHRH pulse frequency; and 2) the
relative secretion rates of LH and FSH by the pituitary may be regulated
by the frequency of pulsatile LHRH secretion from the hypothalamus
Evidence for Decreased Luteinizing Hormone-Releasing Hormone Pulse Frequency in Men with Selective Elevations of Follicle-Stimulating Hormone*
The importance of signal pattern in the transmission of endocrine information: pituitary gonadotropin responses to continuous and pulsatile gonadotropin-releasing hormone
We tested the hypothesis that pulsatile GnRH stimulation of the pituitary
is required for normal gonadotropin secretion in humans. We administered
GnRH in pulsatile and continuous regimens in varying order to each of five
women with hypothalamic amenorrhea and presumed endogenous GnRH
deficiency. Mean serum levels of GnRH were similar during the pulsatile
and continuous regimens. All women ovulated during the pulsatile regimen
(progesterone, greater than 31.8 nmol/L (10 ng/mL); none ovulated during
the continuous regimen. Compared to pretreatment levels, FSH and
estradiol, as measured by RIA, and LH, as measured by bioassay, increased
significantly during the pulsatile GnRH regimen, but not during the
continuous regimen. However, LH and alpha-subunit, as measured by RIA,
increased significantly during both continuous and pulsatile GnRH
administration. We conclude that a pulsatile pattern of GnRH is essential
to normal functioning of the human female reproductive axis. Continuous
administration of GnRH, producing mean serum levels of the peptide
indistinguishable from those found during pulsatile administration,
stimulates some rise in a nonbioactive form of radioimmunoassayable
LH-like material and alpha-subunit, but does not stimulate bioactive LH,
FSH, estradiol, or progesterone and does not lead to ovulation
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