Eosinophilia (EOS) is an important component of airway inflammation and hyperresponsiveness in allergic reactions including those leading to asthma. Although cigarette smoking (CS) is a significant ...contributor to long-term adverse outcomes in these lung disorders, there are also the curious reports of its ability to produce acute suppression of inflammatory responses including EOS through poorly understood mechanisms. One possibility is that proinflammatory processes are suppressed by nicotine in CS acting through nicotinic receptor α7 (α7). Here we addressed the role of α7 in modulating EOS with two mouse models of an allergic response: house dust mites (HDM; Dermatophagoides sp.) and ovalbumin (OVA). The influence of α7 on EOS was experimentally resolved in wild-type mice or in mice in which a point mutation of the α7 receptor (α7
) selectively restricts normal signaling of cellular responses. RNA analysis of alveolar macrophages and the distal lung epithelium indicates that normal α7 function robustly impacts gene expression in the epithelium to HDM and OVA but to different degrees. Notable was allergen-specific α7 modulation of Ccl11 and Ccl24 (eotaxins) expression, which was enhanced in HDM but suppressed in OVA EOS. CS suppressed EOS induced by both OVA and HDM, as well as the inflammatory genes involved, regardless of α7 genotype. These results suggest that EOS in response to HDM or OVA is through signaling pathways that are modulated in a cell-specific manner by α7 and are distinct from CS suppression.
The interferon (IFN) response is the earliest host immune response dedicated to combating viral infection. As such, viruses have evolved strategies to subvert this potent antiviral response. Two ...closely related gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and rhesus macaque rhadinovirus (RRV), are unique in that they express viral homologues to cellular interferon regulatory factors (IRFs), termed viral IRFs (vIRFs). Cellular IRFs are a family of transcription factors that are particularly important for the transcription of type I IFNs. Here, we demonstrate a strategy employed by RRV to ensure rapid inhibition of virus-induced type I IFN induction. We found that RRV vIRF R6, when expressed ectopically, interacts with a transcriptional coactivator, CREB-binding protein (CBP), in the nucleus. As a result, phosphorylated IRF3, an important transcriptional regulator in beta interferon (IFN-β) transcription, fails to effectively bind to the IFN-β promoter, thus inhibiting the activation of IFN-β genes. In addition, we found R6 within RRV virion particles via immunoelectron microscopy and, furthermore, that virion-associated R6 is capable of inhibiting the type I IFN response by preventing efficient binding of IRF3/CBP complexes to the IFN-β promoter in the context of infection. The work shown here is the first example of a vIRF being associated with either the KSHV or RRV virion. The presence of this immunomodulatory protein in the RRV virion provides the virus with an immediate mechanism to evade the host IFN response, thus enabling the virus to effectively establish an infection within the host.
Kaposi's sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are the only viruses known to encode viral homologues to cellular interferon regulatory factors (IRFs), known as vIRFs. In KSHV, these proteins have been shown to play major roles in a variety of cellular processes and are particularly important in the evasion of the host type I interferon (IFN) response. In this study, we delineate the immunomodulatory mechanism of an RRV vIRF and its ability to assist the virus in rapid immune evasion by being prepackaged within the virion, thus providing evidence, for the first time, of a virion-associated vIRF. This work further contributes to our understanding of the mechanisms behind immunomodulation by the RRV vIRFs during infection.
Arginine vasopressin (AVP) made by hypothalamic neurons is released into the circulation to stimulate water resorption by the kidneys and restore water balance after blood loss. Patients who lack ...this antidiuretic hormone suffer from central diabetes insipidus. We observed that many of these patients were anemic and asked whether AVP might play a role in red blood cell (RBC) production. We found that all three AVP receptors are expressed in human and mouse hematopoietic stem and progenitor cells. The AVPR1B appears to play the most important role in regulating erythropoiesis in both human and mouse cells. AVP increases phosphorylation of signal transducer and activator of transcription 5, as erythropoietin (EPO) does. After sublethal irradiation, AVP-deficient Brattleboro rats showed delayed recovery of RBC numbers compared to control rats. In mouse models of anemia (induced by bleeding, irradiation, or increased destruction of circulating RBCs), AVP increased the number of circulating RBCs independently of EPO. In these models, AVP appears to jump-start peripheral blood cell replenishment until EPO can take over. We suggest that specific AVPR1B agonists might be used to induce fast RBC production after bleeding, drug toxicity, or chemotherapy.
Although stone tools generally co-occur with early members of the genus
, they are rarely found in direct association with hominins. We report that both Acheulian and Oldowan artifacts and
crania ...were found in close association at 1.26 million years (Ma) ago at Busidima North (BSN12), and ca. 1.6 to 1.5 Ma ago at Dana Aoule North (DAN5) archaeological sites at Gona, Afar, Ethiopia. The BSN12 partial cranium is robust and large, while the DAN5 cranium is smaller and more gracile, suggesting that
was probably a sexually dimorphic species. The evidence from Gona shows behavioral diversity and flexibility with a lengthy and concurrent use of both stone technologies by
, confounding a simple "single species/single technology" view of early
.
Background: The characteristics of atrial fibrillation (AF) episodes in cryptogenic stroke patients have recently been explored in carefully selected patient populations. However, the incidence of AF ...among a large, real-world population of patients with an insertable cardiac monitor (ICM) placed for the detection of AF following a cryptogenic stroke has not been investigated. Methods: Patients in the de-identified Medtronic DiscoveryLink™ database who received an ICM (Reveal LINQ™) for the purpose of AF detection following a cryptogenic stroke were included. AF detection rates (episodes ≥2 min) were quantified using Kaplan-Meier survival estimates at 1 and 6 months and compared to the CRYSTAL AF study at 6 months. The time to AF detection and maximum duration of AF episodes were also analyzed. Results: A total of 1,247 patients (age 65.3 ± 13.0 years) were followed for 182 (IQR 182-182) days. A total of 1,521 AF episodes were detected in 147 patients, resulting in AF detection rates of 4.6 and 12.2% at 30 and 182 days, respectively, and representing a 37% relative increase over that reported in the CRYSTAL AF trial at 6 months. The median time to AF detection was 58 (IQR 11-101) days and the median duration of the longest detected AF episode was 3.4 (IQR 0.4-11.8) h. Conclusions: The real-world incidence of AF among patients being monitored with an ICM after a cryptogenic stroke validates the findings of the CRYSTAL AF trial and suggests that continuous cardiac rhythm monitoring for periods longer than the current guideline recommendation of 30 days may be warranted in the evaluation of patients with cryptogenic stroke.
Two of the major classes of antifungal drugs in clinical use target ergosterol biosynthesis. Despite its importance, our understanding of the transcriptional regulation of ergosterol biosynthesis ...genes in pathogenic fungi is essentially limited to the role of hypoxia and sterol-stress-induced transcription factors such as Upc2 and Upc2A as well as homologs of sterol response element binding (SREB) factors. To identify additional regulators of ergosterol biosynthesis in Candida glabrata, an important human fungal pathogen with reduced susceptibility to ergosterol biosynthesis inhibitors relative to other
spp., we used a serial passaging strategy to isolate suppressors of the fluconazole hypersusceptibility of a
Δ deletion mutant. This led to the identification of loss-of-function mutations in two genes:
, the homolog of a hypoxia gene transcriptional suppressor in Saccharomyces cerevisiae, and
, a transcription factor that is involved in the regulation of carbon dioxide response in C. glabrata. Here, we describe a detailed analysis of the genetic interaction of
and
. In the presence of fluconazole, loss of Rox1 function restores
expression to the
Δ mutant and inhibits the expression of
and
, leading to increased levels of ergosterol and decreased levels of the toxic sterol 14α methyl-ergosta-8,24(28)-dien-3β, 6α-diol, relative to the
Δ mutant. Our observations establish that Rox1 is a negative regulator of
gene biosynthesis and indicate that a least one additional positive transcriptional regulator of
gene biosynthesis must be present in C. glabrata.
Candida glabrata is one of the most important human fungal pathogens and has reduced susceptibility to azole-class inhibitors of ergosterol biosynthesis. Although ergosterol is the target of two of the three classes of antifungal drugs, relatively little is known about the regulation of this critical cellular pathway. Sterols are both essential components of the eukaryotic plasma membrane and potential toxins; therefore, sterol homeostasis is critical for cell function. Here, we identified two new negative regulators in C. glabrata of ergosterol (
) biosynthesis gene expression. Our results also indicate that in addition to Upc2A, the only known activator of
genes, additional positive regulators of this pathway must exist.
The high prevalence of fluconazole resistance among clinical isolates of
has greatly hampered the utility of fluconazole for the treatment of invasive candidiasis. Fluconazole resistance in this ...yeast is almost exclusively due to activating mutations in the transcription factor Pdr1, which result in upregulation of the ABC transporter genes
,
, and
and therefore increased fluconazole efflux. However, the regulation of Pdr1 is poorly understood. In order to identify genes that interact with the Pdr1 transcriptional pathway and influence the susceptibility of
to fluconazole, we screened a collection of deletion mutants for those exhibiting increased resistance to fluconazole. Deletion of the gene coding for a protein homologous to the
J protein Jjj1 resulted in decreased fluconazole susceptibility. We used the
flipper method to generate independent deletion mutants for
in an SDD clinical isolate. Expression of both
and
was increased in the absence of
. In the absence of
or
, deletion of
has only a modest effect on fluconazole susceptibility. Transcriptional profiling using transcriptome sequencing (RNA-seq) revealed upregulation of genes of the Pdr1 regulon in the absence of
. Jjj1 appears to be a negative regulator of fluconazole resistance in
and acts primarily through upregulation of the ABC transporter gene
via activation of the Pdr1 transcriptional pathway.
is the second most common species of
recovered from patients with invasive candidiasis. The increasing number of infections due to
, combined with its high rates of resistance to the commonly used, well-tolerated azole class of antifungal agents, has limited the use of this antifungal class. This has led to the preferential use of echinocandins as empirical treatment for serious
infections. The primary mechanism of resistance found in clinical isolates is the presence of an activating mutation in the gene encoding the transcription factor Pdr1 that results in upregulation of one or more of the efflux pumps Cdr1, Pdh1, and Snq2. By developing a better understanding of this mechanism of resistance to the azoles, it will be possible to develop strategies for reclaiming the utility of the azole antifungals against this important fungal pathogen.
Since 2000, significant collections of Latest Miocene hominin fossils have been recovered from Chad, Kenya, and Ethiopia. These fossils have provided a better understanding of earliest hominin ...biology and context. Here, we describe five hominin teeth from two periods (ca. 5.4 Million-years-ago and ca. 6.3 Ma) that were recovered from the Adu-Asa Formation in the Gona Paleoanthropological Research Project area in the Afar, Ethiopia that we assign to either Hominina, gen. et sp. indet. or Ardipithecus kadabba. These specimens are compared with extant African ape and other Latest Miocene and Early Pliocene hominin teeth. The derived morphology of the large, non-sectorial maxillary canine and mandibular third premolar links them with later hominins and they are phenetically distinguishable and thus phyletically distinct from extant apes.
Early life exposures can increase the risk of developing chronic diseases including nonalcoholic fatty liver disease. Maternal high-fat diet increases susceptibility to development of steatosis in ...the offspring. We determined the effect of maternal high-fat diet exposure in utero and
during lactation on offspring liver histopathology, particularly fibrosis. Female C57Bl/6J mice were fed a control or high-fat diet (HFD) for 8 weeks and bred with lean males. Nursing dams were continued on the same diet with offspring sacrificed during the perinatal period or maintained on
either control or high-fat diet for 12 weeks. Increased hepatocyte proliferation and stellate cell activation were observed in the liver of HFD-exposed pups. Offspring exposed to perinatal high-fat diet and high-fat diet postweaning showed extensive hepatosteatosis compared to offspring on
high-fat diet after perinatal control diet. Offspring exposed to perinatal high-fat diet and then placed on control diet for 12 weeks developed steatosis and pericellular fibrosis. Importantly, we found that exposure to perinatal high-fat diet unexpectedly promotes more rapid disease progression
of nonalcoholic fatty liver disease, with a sustained fibrotic phenotype, only in adult offspring fed a postweaning control diet.
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