Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF ...are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)+ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2+ monocytes in murine CF lungs drive pathogenic transforming growth factor β (TGF-β) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-β signaling and prevents lung tissue damage. This study identifies CCR2+ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.
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•Chronic neutrophilic inflammation causes lung damage in patients with cystic fibrosis (CF)•CCR2+ monocytes (cMons) accumulate in inflamed human and murine CF lungs•cMons drive lung damage via neutrophil recruitment and TGF-β signaling in CF•Targeting cMon recruitment by CCR2 inhibition prevents lung damage in CF
Lung damage starts early in life in people with cystic fibrosis (CF) and continuously progresses, ultimately leading to respiratory failure. Öz et al. show that recruited classical monocytes are the key drivers of signaling pathways that drive lung damage in CF and are thus a potential therapeutic target.
The authors report on an in-depth statistical and parametrical investigation on the microwave performance of graphene FETs on sapphire substrate. The devices differ for the gate-drain/source distance ...and for the gate length, having kept instead the gate width constant. Microwave S-parameters have been measured for the different devices. Their results demonstrate that the cut-off frequency does not monotonically increase with the scaling of the device geometry and that it exists an optimal region in the gate-drain/source and gate-length space which maximises the microwave performance.
Studies using the Mouse Grimace Scale have shown that for many NSAID, including meloxicam, minimal doses of at least 20 mg/kg may be necessary to achieve adequate peri- and post-operative analgesia ...in mice. However, more data are needed to determine whether such NSAID doses exceed the
threshold for gastrointestinal ulceration or induce other relevant pathology. We administered equal volumes of saline or injectable meloxicam (1 or 5 mg/mL) at a dose of 20 mg/kg SC to 20 young adult male and female C57BL/6N mice daily for 6 d and performed necropsies on all mice on the seventh
day. Mice given 5 mg/mL meloxicam subcutaneously developed significantly more severe pathology at the injection site than saline controls. Pathology was characterized by full-thickness epidermal necrosis; cavitary lesions within subcutis, muscle, or fat; steatitis; and myositis. Mice that
received 1 mg/mL meloxicam subcutaneously developed lesions that were qualitatively similar but far less severe than those after 5 mg/mL. However, no pathologic lesions typically associated with NSAID toxicity, such as gastric ulceration and liver and kidney lesions, were seen. These results
demonstrate that although meloxicam injected subcutaneously causes concentration-dependent skin pathology at the injection site, a dose of 20 mg/kg can be safely administered subcutaneously at a concentration of 1 mg/mL for as long as 6 d.
While the amygdala receives early tau deposition in Alzheimer’s disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric ...symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms.
We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In the tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores.
Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex, but medial amygdala to retrosplenial cortex was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau.
Our findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may relate to early mood symptoms in AD.
The presence of a CA repeat within the 3′‐untranslated region (UTR) of the dystrophin gene has been reported previously in several species. Because microsatellites showing high cross‐species homology ...can be conveniently used as markers in those species for which detailed linkage maps have not yet been developed, we evaluated whether the CA repeat could be amplified from a wide variety of mammalian species. Using a single pair of canine‐specific oligonucleotide primers, we successfully amplified the 3′‐UTR from 18 different carnivore and six additional species (human, chimpanzee, goat, cow, rabbit and mouse) and show conservation of the CA repeat in the dystrophin gene from a wide range of evolutionarily diverse mammalian species.
Objective
To assess how changes in curriculum, accreditation standards, and certification and licensure competencies impacted how medical students and physician residents value interprofessional team ...and patient‐centered care.
Primary Data Source
The Department of Veterans Affairs Learners’ Perceptions Survey (2003–2013). The nationally administered survey asked a representative sample of 56,569 U.S. medical students and physician residents, with a comparison group of 78,038 nonphysician trainees, to rate satisfaction with 28 elements, in two overall domains, describing their clinical learning experiences at VA medical centers.
Study Design
Value preferences were scored as independent adjusted associations between an element (interprofessional team, patient‐centered preceptor) and the respective overall domain (clinical learning environment, faculty, and preceptors) relative to a referent element (quality of clinical care, quality of preceptor).
Principal Findings
Physician trainees valued interprofessional (14 percent vs. 37 percent, p < .001) and patient‐centered learning (21 percent vs. 36 percent, p < .001) less than their nonphysician counterparts. Physician preferences for interprofessional learning showed modest increases over time (2.5 percent/year, p < .001), driven mostly by internal medicine and surgery residents. Preferences did not increase with trainees’ academic progress.
Conclusions
Despite changes in medical education, physician trainees continue to lag behind their nonphysician counterparts in valuing experience with interprofessional team and patient‐centered care.
Introduction
Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1‐42 (Aβ1‐42) or phosphorylated tau, but additional strategies are needed to reduce ...neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post‐synaptic, on spines, where they regulate cAMP‐calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally‐occurring tau pathology.
Methods
Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)),
Aged rhesus macaques were treated daily with the GCPII inhibitor, 2‐MPPA (2‐3‐mercaptopropyl‐penanedioic acid (2‐MPPA)),
Results
Aged macaques that received 2‐MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2‐MPPA‐ and vehicle‐treated monkeys showed cognitive improvement; 2‐MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2‐MPPA administration, confirmed in dlPFC samples.
Discussion
These data provide proof‐of‐concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism.
Highlights
Inflammation is a key driver of sporadic Alzheimer's disease.
GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.
Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.
GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.
Abstract
Informatics methodologies exploit computer-assisted techniques to help biomedical researchers manage large amounts of information. In this paper, we focus on the biomedical research ...literature (MEDLINE). We first provide an overview of some text mining techniques that offer assistance in research by identifying biomedical entities (e.g., genes, substances, and diseases) and relations between them in text.
We then discuss Semantic MEDLINE, an application that integrates PubMed document retrieval, concept and relation identification, and visualization, thus enabling a user to explore concepts and relations from within a set of retrieved citations. Semantic MEDLINE provides a roadmap through content and helps users discern patterns in large numbers of retrieved citations. We illustrate its use with an informatics method we call “discovery browsing,” which provides a principled way of navigating through selected aspects of some biomedical research area. The method supports an iterative process that accommodates learning and hypothesis formation in which a user is provided with high level connections before delving into details.
As a use case, we examine current developments in basic research on mechanisms of Alzheimer’s disease. Out of the nearly 90 000 citations returned by the PubMed query “Alzheimer’s disease,” discovery browsing led us to 73 citations on sortilin and that disorder. We provide a synopsis of the basic research reported in 15 of these. There is wide-spread consensus among researchers working with a range of animal models and human cells that increased sortilin expression and decreased receptor expression are associated with amyloid beta and/or amyloid precursor protein.
The homeobox gene Hhex has recently been shown to be essential for normal liver, thyroid and forebrain development. Hhex(-/-) mice die by mid-gestation (E14.5) and the cause of their early demise ...remains unclear. Because Hhex is expressed in the developing blood islands at E7.0 in the endothelium of the developing vasculature and heart at E9.0-9.5, and in the ventral foregut endoderm at E8.5-9.0, it has been postulated to play a critical role in heart and vascular development. We show here, for the first time, that a null mutation of Hhex results in striking abnormalities of cardiac and vascular development which include: (1) defective vasculogenesis, (2) hypoplasia of the right ventricle, (3) overabundant endocardial cushions accompanied by ventricular septal defects, outflow tract abnormalities and atrio-ventricular (AV) valve dysplasia and (4) aberrant development of the compact myocardium. The dramatic enlargement of the endocardial cushions in the absence of Hhex is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Interestingly, vascular endothelial growth factor A (Vegfa) levels in the hearts of Hhex(-/-) mice were elevated as much as three-fold between E9.5 and E11.5, and treatment of cultured Hhex(-/-) AV explants with truncated soluble Vegfa receptor 1, sFlt-1, an inhibitor of Vegf signaling, completely abolished the excessive epithelial-mesenchymal transformation seen in the absence of Hhex. Therefore, Hhex expression in the ventral foregut endoderm and/or the endothelium is necessary for normal cardiovascular development in vivo, and one function of Hhex is to repress Vegfa levels during development.
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