cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5126596
title: Supplementary Material for: Longitudinal Effects of Metabolic Syndrome on Alzheimer and Vascular Related Brain Pathology

description: <b><i>Background/Aims:</i></b> This study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)]. <b><i>Methods:</i></b> The study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [<sup>18</sup>F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison. <b><i>Results:</i></b> The vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups. <b><i>Conclusion:</i></b> At the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology.
DOI: 10.6084/m9.figshare.5126599
title: Supplementary Material for: Complement Protein C1q and Adiponectin Stimulate Mer Tyrosine Kinase-Dependent Engulfment of Apoptotic Cells through a Shared Pathway

description: The failure to clear apoptotic cells is linked to defects in development and autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells (efferocytosis), and C1q deficiency leads to the development of lupus. We recently identified a novel molecular mechanism for C1q-dependent efferocytosis in murine macrophages. C1q elicited the expression of Mer tyrosine kinase (Mer), a receptor that regulates efficient efferocytosis and prevention of autoimmunity. To characterize the C1q-dependent signal transduction mechanism, pathway analysis of the transcriptome from C1q-activated macrophages was performed, and it identified the adiponectin signaling pathway as significantly upregulated with C1q. Adiponectin is structurally homologous to C1q and regulates cellular metabolism via downstream activation of 5′adenosine monophosphate-activated protein kinase (AMPK). Macrophage stimulation with C1q resulted in the activation of AMPK, and silencing of AMPK expression using siRNA-inhibited C1q-dependent efferocytosis. Adiponectin signaling also stimulates activation of nuclear receptors, and inhibition of the nuclear receptor retinoid X receptor abrogated C1q-dependent Mer expression and efferocytosis. Furthermore, adiponectin elicited Mer expression and Mer-dependent efferocytosis in macrophages similar to cells stimulated with C1q. Collectively, our results suggest that C1q and adiponectin share a common signal transduction cascade to promote clearance of apoptotic cells, and identify a novel molecular pathway required for efficient efferocytosis.
DOI: 10.6084/m9.figshare.5126605.v1
title: Supplementary Material for: A Common Copy Number Variation Polymorphism in the <b><i>CNTNAP2</i></b> Gene: Sexual Dimorphism in Association with Healthy Aging and Disease

description: <b><i>Background:</i></b> New therapeutic targets are needed to fight aging-related diseases and increase life span. A new female-specific association with diseases and limited survival past 80 years was recently reported for a copy number variation (CNV) in the <i>CNTNAP4 </i>gene from the neurexin superfamily. <b><i>Objective:</i></b> We asked whether there are CNVs that are associated with aging phenotypes within other genes from the neurexin superfamily and whether this association is sex specific. <b><i>Methods:</i></b> Select CNV polymorphisms were genotyped with proprietary TaqMan qPCR assays. <b><i>Results:</i></b> A case/control study, in which a group of 81- to 90-year-old community-dwelling Caucasians with no chronic diseases (case) was compared to a similar control group of 65- to 75-year-olds, revealed a negative association with healthy aging for the ins allele of common esv11910 CNV in the <i>CNTNAP2 </i>gene (n = 388; OR = 0.29, 95% CI: 0.14-0.59, p = 0.0004 for males, and OR = 0.82, 95% CI: 0.42-1.57, p = 0.625 for females). This male-specific association was validated in a study of an independent group of 76- to 80-year-olds. To look for a corresponding positive association of the allele with aging-related diseases, two case subgroups of 81- to 90-year-olds, one composed of individuals with cognitive impairment and the other with various diseases not directly related to the nervous system, such as cardiovascular diseases, etc., were compared to a healthy control subgroup of the same age. A positive male-specific association was found for both cases (OR = 2.75, p = 0.008 for association with cognitive impairment, and OR = 3.18, p = 0.002 for other diseases combined). <b><i>Conclusions:</i></b> A new male-specific association with aging is reported for a CNV in the <i>CNTNAP2 </i>gene. The polymorphism might be useful for diagnosing individual genetic predispositions to healthy aging versus aging complicated by chronic diseases.
DOI: 10.6084/m9.figshare.5126590
title: Supplementary Material for: Virulent <b><i>Francisella tularensis</i></b> Destabilize Host mRNA to Rapidly Suppress Inflammation

description: Highly virulent bacterial pathogens have evolved rapid means to suppress host inflammatory responses by unknown mechanisms. Here, we use virulent <i>Francisella tularensis</i>, the cause of lethal tularemia in humans, as a model to elucidate these mechanisms. We show that following infection of murine macrophages <i>F. tularensis</i> rapidly and selectively destabilizes mRNA containing adenylate-uridylate-rich elements that encode for cytokines and chemokines important in controlling bacterial infection. Degradation of host mRNA encoding interleukin (IL)-1β, IL-6 and CXCL1 did not require viable bacteria or de novo protein synthesis, but did require escape of intracellular organisms from endocytic vesicles into the host cytosol. The specific targeting of host mRNA encoding inflammatory cytokines and chemokines for decay by a bacterial pathogen has not been previously reported. Thus, our findings represent a novel strategy by which a highly virulent pathogen modulates host inflammatory responses critical to the evasion of innate immunity.
DOI: 10.6084/m9.figshare.5126599.v1
title: Supplementary Material for: Complement Protein C1q and Adiponectin Stimulate Mer Tyrosine Kinase-Dependent Engulfment of Apoptotic Cells through a Shared Pathway

description: The failure to clear apoptotic cells is linked to defects in development and autoimmunity. Complement component C1q is required for efficient engulfment of apoptotic cells (efferocytosis), and C1q deficiency leads to the development of lupus. We recently identified a novel molecular mechanism for C1q-dependent efferocytosis in murine macrophages. C1q elicited the expression of Mer tyrosine kinase (Mer), a receptor that regulates efficient efferocytosis and prevention of autoimmunity. To characterize the C1q-dependent signal transduction mechanism, pathway analysis of the transcriptome from C1q-activated macrophages was performed, and it identified the adiponectin signaling pathway as significantly upregulated with C1q. Adiponectin is structurally homologous to C1q and regulates cellular metabolism via downstream activation of 5′adenosine monophosphate-activated protein kinase (AMPK). Macrophage stimulation with C1q resulted in the activation of AMPK, and silencing of AMPK expression using siRNA-inhibited C1q-dependent efferocytosis. Adiponectin signaling also stimulates activation of nuclear receptors, and inhibition of the nuclear receptor retinoid X receptor abrogated C1q-dependent Mer expression and efferocytosis. Furthermore, adiponectin elicited Mer expression and Mer-dependent efferocytosis in macrophages similar to cells stimulated with C1q. Collectively, our results suggest that C1q and adiponectin share a common signal transduction cascade to promote clearance of apoptotic cells, and identify a novel molecular pathway required for efficient efferocytosis.
DOI: 10.6084/m9.figshare.5126590.v1
title: Supplementary Material for: Virulent <b><i>Francisella tularensis</i></b> Destabilize Host mRNA to Rapidly Suppress Inflammation

description: Highly virulent bacterial pathogens have evolved rapid means to suppress host inflammatory responses by unknown mechanisms. Here, we use virulent <i>Francisella tularensis</i>, the cause of lethal tularemia in humans, as a model to elucidate these mechanisms. We show that following infection of murine macrophages <i>F. tularensis</i> rapidly and selectively destabilizes mRNA containing adenylate-uridylate-rich elements that encode for cytokines and chemokines important in controlling bacterial infection. Degradation of host mRNA encoding interleukin (IL)-1β, IL-6 and CXCL1 did not require viable bacteria or de novo protein synthesis, but did require escape of intracellular organisms from endocytic vesicles into the host cytosol. The specific targeting of host mRNA encoding inflammatory cytokines and chemokines for decay by a bacterial pathogen has not been previously reported. Thus, our findings represent a novel strategy by which a highly virulent pathogen modulates host inflammatory responses critical to the evasion of innate immunity.
DOI: 10.6084/m9.figshare.5126593.v1
title: Supplementary Material for: Anterior Temporal Atrophy and Posterior Progression in Patients with Parkinson's Disease

description: <b><i>Background:</i></b> Parkinson's disease (PD) is characterized by specific motor and nonmotor impairments. This suggests that PD is characterized by disease-specific regional cortical atrophy. Given the change of symptoms over time, a concurrent increase in regional atrophy may further be assumed to reflect the dynamic process of disease progression. <b><i>Methods:</i></b> In this study we retrospectively collected T1-weighted MRI scans from previous studies performed in our center, enabling the comparison of gray matter atrophy in 77 PD patients with 87 controls using voxel-based morphometry (VBM). This large VBM analysis provided the opportunity to investigate cortical atrophy in relation with disease progression. <b><i>Results:</i></b> We found significant PD-related reductions of gray matter density bilaterally in the anterior temporal cortex, the left inferior frontal and left extrastriate visual cortex, independent from normal aging. The anterior temporal cortex did not show major progression, whereas particularly the posterior parts of the lateral temporal cortex and adjacent extrastriate visual cortex occurred at a later stage of disease. <b><i>Conclusions:</i></b> Temporal pole atrophy as an early sign of PD is consistent with the PD pathology classification of Braak. The initial anterior temporal atrophy with spread to occipitotemporal and posterior parietal regions may subserve ‘emotion-based' sensorimotor transformations and deficits in the visual domain, respectively, which may be regarded as premotor symptoms.
DOI: 10.6084/m9.figshare.5126581
title: Supplementary Material for: A Previously Unknown Mutation in the Pyruvate Kinase Gene <b><i>(PKLR)</i></b> Identified from a Neonate with Severe Jaundice

description: We report a neonate with early and severe hemolytic jaundice and low erythrocyte pyruvate kinase enzymatic activity (&lt;2 U/g hemoglobin, reference interval 9-22). We found her asymptomatic mother to be heterozygous for a novel <i>PKLR </i>mutation (c.1573delT) with an erythrocyte PK activity of 6.2 U/g hemoglobin. Her asymptomatic father was heterozygous for the common Northern European <i>PKLR</i> mutation (c.1529A) with an erythrocyte PK activity of 3.6 U/g. The neonate was a compound heterozygote with both mutations, but with no other mutations identified by sequencing a panel of 27 genes involved in severe neonatal jaundice.
DOI: 10.6084/m9.figshare.5126584
title: Supplementary Material for: SSEA-4+ CD34- Cells in the Adult Human Heart Show the Molecular Characteristics of a Novel Cardiomyocyte Progenitor Population

description: Stage-specific embryonic antigen (SSEA) expression is used to describe the differentiation state of an embryonic stem cell (ESC). In human ESCs, SSEA-3 and SSEA-4 are highly expressed in undifferentiated cells and downregulated upon differentiation. SSEA-4 has also been described as a marker for adult stem cells in various tissues, including human neonatal cardiac tissue. However, there is currently little data on the expression of SSEAs in human adult cardiac tissue. We obtained right and left atrial biopsies from patients undergoing cardiac surgery. These were dissociated, stained for SSEAs and other cardiac stem cell markers and analyzed by flow cytometry. Directly isolated cells expressed variable levels of SSEA-1, SSEA-3 and SSEA-4. The SSEA-1+ population was established as contaminating hematopoietic cells. The SSEA-4+ population, on the other hand, could be subdivided based on the endothelial progenitor marker CD34. The SSEA-4+ CD34- population in the right atrium had a high gene expression of both early <i>(TBX5, NKX2.5)</i> and late <i>(TNNT2)</i> cardiomyocyte markers. The SSEA-4+ CD34+ population, on the other hand, overlapped with previously described C-kit+ CD45- cardiac stem cells. Primary monolayer-cultured cells retained expression of SSEAs while the cardiomyogenic specification in the SSEA-4+ CD34- population was lost. In tissue sections, SSEA-4+ cells could be identified both within and outside the myocardium. Within the myocardium, some SSEA-4+ cells coexpressed cardiomyogenic markers. In conclusion, the results show that the adult human heart expresses SSEAs and that there is a subpopulation of SSEA-4+ CD34- cells that show features of a cardiomyocyte progenitor population.
DOI: 10.6084/m9.figshare.5126587
title: Supplementary Material for: Cystic Fibrosis Sputum DNA Has NETosis Characteristics and Neutrophil Extracellular Trap Release Is Regulated by Macrophage Migration-Inhibitory Factor

description: Neutrophils are the main proinflammatory cell type in chronically infected lungs of cystic fibrosis (CF) patients; however, they fail to effectively clear the colonizing pathogens. Here, we investigated the molecular composition of non-mucoid and mucoid <i>Pseudomonas aeruginosa</i>-induced neutrophil extracellular traps (NETs) in vitro and compared them to the DNA-protein complexes present in the CF sputum. The protein composition of<i> P. aeruginosa</i>-induced NET fragments revealed that irrespective of the inducing stimuli, NET fragments were decorated with a conserved set of proteins. The DNA-protein complexes derived from CF sputum were consistent with NETosis and shared a similar protein signature, suggesting that the majority of the extracellular DNA was NET derived. The ability of polymorphonuclear leukocytes to produce NETs in response to <i>P. aeruginosa </i>was driven by macrophage migration-inhibitory factor (MIF) by promoting mitogen-activated protein kinase. Analysis of 132 CF patient samples revealed that elevated MIF protein levels correlated with poorer lung function. We suggest that targeting MIF by small molecular inhibitors might reduce the presence of extracellular DNA and serve as an adjunct to the use of antimicrobial drugs that could ultimately reduce bacterial fitness in the lungs during the later stages of CF disease.
DOI: 10.6084/m9.figshare.5126575
title: Supplementary Material for: What Is Sensitive Skin? A Systematic Literature Review of Objective Measurements

description: Despite sensitive skin being highly prevalent, no consensus on the definition and pathomechanism of sensitive skin exists. Here we report the results of a systematic literature review of diagnostic methods for sensitive skin at clinical, histological and biophysical levels. A systematic search revealed 27 out of 1,701 articles which we appraised in detail. Impaired skin barrier function and increased vascular reactivity are most often associated with sensitive skin. We identified key reasons causing an ambiguity around the sensitive skin phenomenon. We propose using standardized selection methods of subjects by a multifactorial questionnaire spanning a range of provocations, including those of chemical, mechanical and environmental origin, followed by clinical, histological and top-notch biophysical measurements. This could lead to a breakthrough in the understanding of the sensitive skin phenomenon, fueling advances of biomedical and dermatological science. © 2014 S. Karger AG, Basel
DOI: 10.6084/m9.figshare.5126578
title: Supplementary Material for: PTEN Loss-Mediated Akt Activation Increases the Properties of Cancer Stem-Like Cell Populations in Prostate Cancer

description: <b><i>Objective:</i></b> To demonstrate that the PTEN/PI3K/Akt/NF-κB pathway plays an important role in regulating the prostate cancer stem-like cell population by upregulating ABCG2. <b><i>Methods:</i></b> Targeted PTEN knockdown in human prostate DU145 and 22Rv1 cells using a small interfering RNA were confirmed by immunoblot analysis using antibodies of PTEN, phospho-Akt, Akt, and a-tubulin. Knockdown PTEN DU145 and 22Rv1 cells were augmented, and the stem cell-like properties were examined by cell viability and tumor sphere formation and treated by Akt IV inhibitor to provide the signal transduction pathway. Luciferase activity assays were performed. <b><i>Results:</i></b> The knockdown of PTEN in prostate cancer cell lines increased the stem-like properties of the cells, including their sphere-forming ability, stem cell population number, epithelial-mesenchymal transition-related gene expression, and ABCG2 expression. Additionally, PTEN expression was highly associated with elevated expression of phospho-Akt. Treatment with an Akt inhibitor suppressed the PTEN-mediated effects on the properties of these stem-like cells as well as drug resistance, ABCG2 expression, and the NF-κB pathway. <b><i>Conclusion:</i></b> The loss of PTEN in prostate cancer cells resulted in an increased PI3K/Akt pathway. Due to the Akt activation, PTEN loss may play an important role in prostate cancer by promoting cancer stemness through a mechanism that involves enhanced NF-κB signaling.
DOI: 10.6084/m9.figshare.5126569
title: Supplementary Material for: Cytoarchitecture of the Telencephalon in the Coral Reef Multiband Butterflyfish (<b><i>Chaetodon multicinctus</i></b>: Perciformes)

description: Detailed neuroanatomical studies of model species are necessary to facilitate comparative experiments which test hypotheses relevant to brain evolution and function. Butterflyfishes (Chaetodontidae) boast numerous sympatric species that differ in social behavior, aggression and feeding ecology. However, the ability to test hypotheses relevant to brain function in this family is hindered by the lack of detailed neural descriptions. The cytoarchitecture of the telencephalon in the monogamous and territorial multiband butterflyfish, <i>Chaetodon multicinctus,</i> was determined with Nissl-stained serial sections and an immunohistochemical analysis of arginine vasotocin (AVT), serotonin, substance P and tyrosine hydroxylase. The ventral telencephalon was similar to that of other perciform fishes studied, with one major difference. A previously undescribed postcommissural region, the cuneate nucleus, was identified and putatively assigned to the ventral telencephalon. While the function of this nucleus is unknown, preliminary studies indicate that it may be part of a behaviorally relevant subpallial neural circuit that is modulated by AVT. The dorsal telencephalon consisted of 15 subdivisions among central, medial, lateral, dorsal and posterior zones. Several regions of the dorsal telencephalon of <i>C. multicinctus</i> differed from many other perciform fishes examined thus far. The nucleus taenia was in a more caudal position, and the central and lateral zones were enlarged. Within the lateral zone, an unusual third, ventral subdivision and a large-celled division were present. One hypothesis is that the enlarged ventral subdivision of the lateral zone (potential hippocampus homolog) relates to an enhancement of spatial learning or olfactory memory, which are important for this coral reef fish. This study provides the neuroanatomical basis for future comparative and evolutionary studies of brain organization and neuropeptide distributions, physiological studies of neural processing and insight into the complex social behavior of butterflyfishes.
DOI: 10.6084/m9.figshare.5126572
title: Supplementary Material for: Effect of an Isoenergetic Traditional Mediterranean Diet on the High-Density Lipoprotein Proteome in Men with the Metabolic Syndrome

description: <b><i>Background/Aims:</i></b> The objective of this preliminary study was to examine the impact of the Mediterranean diet (MedDiet) on the high-density lipoprotein (HDL) proteome in men with the metabolic syndrome (MetS). <b><i>Methods:</i></b> Twenty-six men with the MetS first consumed a standardized baseline North American isoenergetic control diet (5 weeks) and then consumed an isoenergetic MedDiet (5 weeks), both in full feeding condition. The HDL fraction was isolated by ultracentrifugation at the end of each diet and the HDL proteome assessed by isobaric tags for relative and absolute quantitation and mass spectrometry. <b><i>Results:</i></b> Of all proteins identified within HDL, only 3 showed significant changes in relative abundance after the MedDiet versus the control diet, including a reduction in inflammation-related inter-α-trypsin inhibitor heavy chain H4 (fold change: 0.62) and hemoglobin subunits α (fold change: 0.40) and β (fold change: 0.46). Other HDL-bound proteins associated with functions related to lipid metabolism/cholesterol homeostasis, oxidation, coagulation, complement activation and immunity were unchanged after consumption of the MedDiet for 5 weeks. <b><i>Conclusions:</i></b> Changes in the HDL proteome may explain, at least partly, the well-known anti-inflammatory effect ascribed to the MedDiet. Otherwise, short-term consumption of the MedDiet seems to have little impact on other features of the HDL proteome in men with the MetS.