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Josephine McCarty had many identities. But in Albany, New York, she was known as \"Dr. Emma Burleigh,\" the abortionist of Howard Street. On January 17, 1872, McCarty boarded a streetcar in Utica, New York, shot her ex-lover in the face, and disembarked, unaware that her bullet had passed through her target's head and into the heart of the innocent man sitting beside him. The unlucky passenger died within minutes. Josephine McCarty was arrested for attempted murder and quickly became the most notorious woman in central New York. The Abortionist of Howard Street was, however, far more than a murderer. In Maryland she was \"Johnny McCarty,\" a blockade runner and spy for Confederate forces. New Yorkers whispered of her as a mistress to corrupt Albany politicians. So who was she? The prosecution in her murder trial claimed she was a calculating and heartless operative both in the bedroom and in her public life. Or was she the victim of ill fortune and the systemic weight of misogyny and male violence? The answer, of course, was not as simple as either narrative. In this absorbing and rich history, R.E. Fulton considers the nuances of Josephine McCarty's life from marriage to divorce, from financial abuse to quarrels with intimate partners and more, trying to decipher the truth behind the stories and myths surrounding McCarty and what ultimately led her to that Utica streetcar with a pistol in her dress pocket. In The Abortionist of Howard Street , Fulton revisites a rich history of women's experience in mid-nineteenth century America, revealing McCarty as a multifaceted, fascinating personification of issues as broad as reproductive health, education, domestic abuse, mental illness, and criminal justice.

The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1) was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS) whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration. These results suggest that pro-inflammatory stimuli can disrupt circadian rhythms in macrophages and that impaired circadian rhythms may contribute to cardiovascular diseases by altering macrophage behavior.

NADPH oxidase5 (Nox5) is a novel Nox isoform which has recently been recognized as having important roles in the pathogenesis of coronary artery disease, acute myocardial infarction, fetal ventricular septal defect and cancer. The activity of Nox5 and production of reactive oxygen species is regulated by intracellular calcium levels and phosphorylation. However, the kinases that phosphorylate Nox5 remain poorly understood. Previous studies have shown that the phosphorylation of Nox5 is PKC dependent, but this contention was based on the use of pharmacological inhibitors and the isoforms of PKC involved remain unknown. Thus, the major goals of this study were to determine whether PKC can directly regulate Nox5 phosphorylation and activity, to identify which isoforms are involved in the process, and to understand the functional significance of this pathway in disease. We found that a relatively specific PKCα inhibitor, Ro-32-0432, dose-dependently inhibited PMA-induced superoxide production from Nox5. PMA-stimulated Nox5 activity was significantly reduced in cells with genetic silencing of PKCα and PKCε, enhanced by loss of PKCδ and the silencing of PKCθ expression was without effect. A constitutively active form of PKCα robustly increased basal and PMA-stimulated Nox5 activity and promoted the phosphorylation of Nox5 on Ser490, Thr494, and Ser498. In contrast, constitutively active PKCε potently inhibited both basal and PMA-dependent Nox5 activity. Co-IP and in vitro kinase assay experiments demonstrated that PKCα directly binds to Nox5 and modifies Nox5 phosphorylation and activity. Exposure of endothelial cells to high glucose significantly increased PKCα activation, and enhanced Nox5 derived superoxide in a manner that was in prevented by a PKCα inhibitor, Go 6976. In summary, our study reveals that PKCα is the primary isoform mediating the activation of Nox5 and this maybe of significance in our understanding of the vascular complications of diabetes and other diseases with increased ROS production.

Michigan has abundant resources for outdoor activity including upland gamebird hunting in the wild and on licensed hunting preserves. Due to the popularity of hunting, Michigan had a thriving gamebird industry before the economic downturn of 2008/2009. After the economic downturn, the number of gamebird preserves decreased. To understand the health issues faced by captive gamebird raisers while the industry was thriving, a 25-year retrospective study of gamebird submissions to the Michigan State University Veterinary Diagnostic Laboratory from 1983 through 2008 was undertaken. Although pheasants, quail, partridges, grouse, and mallard ducks were raised, pheasants greatly outnumbered all other gamebird species, both in numbers and submissions, and quail were the next most predominant species. Causes for submission included parasitic, bacterial, viral, and miscellaneous causes. Parasitic diseases were predominant, with coccidiosis being the leading diagnosis in pheasants and partridges and Capillaria spp. infestation of the crop prevailing in quail. Bacterial diseases were the next most predominant affliction, with clostridial enteritis, both necrotic and ulcerative, in quail, and a variety of bacterial diseases were found in pheasants and partridges. Rotaviral enteritis and adenovirus were the most prevalent viral diseases in pheasants, with adenovirus being the predominant viral disease in quail and paramyxovirus the most prevalent in partridges. From these findings, we conclude that gamebird submissions should be closely screened for parasitic diseases and the diagnosis confirmed at necropsy through scraping and examination of affected tissues.

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

Background Heart failure is a leading cause of human morbidity and mortality. Circular RNAs (circRNAs) are a newly discovered class of RNA that have been found to have important physiological and pathological roles. In the current study, we de novo analyzed existing whole transcriptome data from 5 normal and 5 dilated cardiomyopathy (DCM) human heart samples and compared the results with circRNAs that have been previously reported in human, mouse and rat hearts. Results Our analysis identifies a list of cardiac circRNAs that are reliably detected in multiple studies. We have also defined the top 30 most abundant circRNAs in healthy human hearts which include some with previously unrecognized cardiac roles such as circHIPK3_11 and circTULP4_1. We further found that many circRNAs are dysregulated in DCM, particularly transcripts originating from DCM-related gene loci, such as TTN and RYR2 . In addition, we predict the potential of cardiac circRNAs to sponge miRNAs that have reported roles in heart disease. We found that circALMS1_6 has the highest potential to bind miR-133, a microRNA that can regulate cardiac remodeling. Interestingly, we detected a novel class of circRNAs, referred to as read-though (rt)-circRNAs which are produced from exons of two different neighboring genes. Specifically, rt-circRNAs from SCAF8 and TIAM2 were observed to be dysregulated in DCM and these rt-circRNAs have the potential to sponge multiple heart disease-related miRNAs. Conclusions In summary, this study provides a valuable resource for exploring the function of circRNAs in human heart disease and establishes a functional paradigm for identifying novel circRNAs in other tissues.

Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ⩽0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.

Polymicrobial biofilms consisting of fungi and bacteria are frequently formed on endotracheal tubes and may contribute to development of ventilator associated pneumonia (VAP) in critically ill patients. This study aimed to determine the role of early Candida albicans biofilms in supporting dual-species (dual-kingdom) biofilm formation with respiratory pathogens in vitro , and investigated the effect of targeted antifungal treatment on bacterial cells within the biofilms. Dual-species biofilm formation between C . albicans and three respiratory pathogens commonly associated with VAP ( Pseudomonas aeruginosa , Escherichia coli and Staphylococcus aureus ) was studied using quantitative PCR. It was shown that early C . albicans biofilms enhanced the numbers of E . coli and S . aureus (including methicillin resistant S . aureus ; MRSA) but not P . aeruginosa within dual-species biofilms. Transwell assays demonstrated that contact with C . albicans was required for the increased bacterial cell numbers observed. Total Internal Reflection Fluorescence microscopy showed that both wild type and hyphal-deficient C . albicans provided a scaffold for initial bacterial adhesion in dual species biofilms. qPCR results suggested that further maturation of the dual-species biofilm significantly increased bacterial cell numbers, except in the case of E . coli with hyphal-deficient C . albicans ( Ca_gcn5 Δ/Δ). A targeted preventative approach with liposomal amphotericin (AmBisome ® ) resulted in significantly decreased numbers of S . aureus in dual-species biofilms, as determined by propidium monoazide-modified qPCR. Similar results were observed when dual-species biofilms consisting of clinical isolates of C . albicans and MRSA were treated with liposomal amphotericin. However, reductions in E . coli numbers were not observed following liposomal amphotericin treatment. We conclude that early C . albicans biofilms have a key supporting role in dual-species biofilms by enhancing bacterial cell numbers during biofilm maturation. In the setting of increasing antibiotic resistance, an important and unexpected consequence of antifungal treatment of dual-species biofilms, is the additional benefit of decreased growth of multi-drug resistant bacteria such as MRSA, which could represent a novel future preventive strategy.

Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A , was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations ( P =0.005) and more rapid progression to AML ( P =0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.

Obesity remains the most common risk factor for cardiovascular disease in Western nations. While considerable effort has focused on identifying risk factors, which contribute to the increase incidence of complications and disease, an emerging concept is the existence of resilience factors, which mitigate disease. An important resilience factor gaining increased appreciation is the amount of skeletal muscle mass. In this review, we will explore how obesity increases the most-identified vascular component of metabolic vascular disease – endothelial dysfunction—how increases in muscle mass may protect vascular function in the obese population. This review advances the concept the obesity is less a disease of body mass than body composition which is reflected in the degree of negative vascular outcomes and may be of increased relevance in consideration of therapies that promote loss of muscle mass while reducing overall body size.