Miracle-dz/UniFAR-FTUs huggingface dataset:
β-Cyclodextrin-threaded Biocleavable Polyrotaxanes Ameliorate Impaired Autophagic Flux in Niemann-Pick Type C Disease*

Background: Niemann-Pick type C (NPC) disease is associated with the impaired autophagic flux. Results: β-Cyclodextrin (β-CD)-threaded polyrotaxanes reduced autophagosome accumulation, promoted autophagic proteolysis, and facilitated the fusion of autophagosomes and lysosomes in NPC disease, whereas β-CD derivatives further disturbed autophagic flux. Conclusion: β-CD-threaded polyrotaxanes improved impaired autophagic flux in NPC disease. Significance: β-CD-threaded polyrotaxanes may be promising therapeutics for ameliorating impaired autophagy in NPC disease. Niemann-Pick type C (NPC) disease is characterized by the lysosomal accumulation of cholesterols and impaired autophagic flux due to the inhibited fusion of autophagosomes to lysosomes. We have recently developed β-cyclodextrin (β-CD)-threaded biocleavable polyrotaxanes (PRXs), which can release threaded β-CDs in response to intracellular environments as a therapeutic for NPC disease. The biocleavable PRXs exhibited effective cholesterol reduction ability and negligible toxic effect compared with hydroxypropyl-β-CD (HP-β-CD). In this study, we investigated the effect of biocleavable PRX and HP-β-CD on the impaired autophagy in NPC disease. The NPC patient-derived fibroblasts (NPC1 fibroblasts) showed an increase in the number of LC3-positive puncta compared with normal fibroblasts, even in the basal conditions; the HP-β-CD treatment markedly increased the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts, indicating that autophagic flux was further perturbed. In sharp contrast, the biocleavable PRX reduced the number of LC3-positive puncta and the levels of p62 in NPC1 fibroblasts through an mTOR-independent mechanism. The mRFP-GFP-LC3 reporter gene expression experiments revealed that the biocleavable PRX facilitated the formation of autolysosomes to allow for autophagic protein degradation. Therefore, the β-CD-threaded biocleavable PRXs may be promising therapeutics for ameliorating not only cholesterol accumulation but also autophagy impairment in NPC disease.
Mikrozirkulation und Sauerstoffversorgung des Gewebes

Zusammenfassung Die Zahl der Patienten mit peripheren Durchblutungsstörungen steigt aufgrund des zunehmenden Alters und der Lebensweise ständig. Damit einher geht das klinische Interesse, verbesserte Techniken zur Verfügung zu haben, die helfen, periphere Durchblutungsstörungen frühzeitig und mit geringem Aufwand zu diagnostizieren. Eine optische Methode mit dem Namen O2C (oxygen to see), die sowohl die Mikrozirkulation als auch die postkapilläre Sauerstoffsättigung und Blutmenge im Gewebe bestimmt, eröffnet zusätzliche diagnostische Möglichkeiten. Die Methode wird eingehend beschrieben und im Vergleich zu bekannten Untersuchungstechniken, z. B. der tcpO2, erörtert. Die Vorgehensweise zur Untersuchung von Patienten mit pAVK, Wunden und insbesondere mit venösen Abstromproblemen wird dargestellt. Differenziert wird das Vorgehen zur Untersuchung von intakter Haut, von Wunden oder von tiefer liegenden Geweben (z. B. Muskulatur) beschrieben. Besonderes Gewicht wird der Beurteilung des Sauerstoffumsatzes, als funktioneller Parameter, im Gewebe beigemessen. Der Bezug auf Normwerte aus der Literatur rundet die Einführung in die neue Methode ab und zeigt die klinischen Applikationsfelder auf.
A Residue Quartet in the Extracellular Domain of the Prolactin Receptor Selectively Controls Mitogen-activated Protein Kinase Signaling*

Background: Discrimination of cytokine receptor signaling pathways is poorly understood. Results: Manipulation of extracellular prolactin receptor interface residues selectively affected activation of the MAPK pathway but not the STAT5 pathway. Conclusion: MAPK pathway activation correlated with apparent ligand·receptor complex lifetimes suggesting pathway-specific lifetime thresholds for activation. Significance: Discrimination of prolactin receptor signaling is controlled by the extracellular homodimer receptor interface. Cytokine receptors elicit several signaling pathways, but it is poorly understood how they select and discriminate between them. We have scrutinized the prolactin receptor as an archetype model of homodimeric cytokine receptors to address the role of the extracellular membrane proximal domain in signal transfer and pathway selection. Structure-guided manipulation of residues involved in the receptor dimerization interface identified one residue (position 170) that in cell-based assays profoundly altered pathway selectivity and species-specific bio-characteristics. Subsequent in vitro spectroscopic and nuclear magnetic resonance analyses revealed that this residue was part of a residue quartet responsible for specific local structural changes underlying these effects. This included alteration of a novel aromatic T-stack within the membrane proximal domain, which promoted selective signaling affecting primarily the MAPK (ERK1/2) pathway. Importantly, activation of the MAPK pathway correlated with in vitro stabilities of ternary ligand·receptor complexes, suggesting a threshold mean lifetime of the complex necessary to achieve maximal activation. No such dependence was observed for STAT5 signaling. Thus, this study establishes a residue quartet in the extracellular membrane proximal domain of homodimeric cytokine receptors as a key regulator of intracellular signaling discrimination.
Heart failure self-monitoring toolkit

Heart Failure (HF) is one of the most common cardiac syndromes encountered in the primary care setting amongst older adults; it affects more than 6 million people in the United States (Goroll & Mulley, 2009; Papasifakis, n.d.). HF is one of the most common diagnosis of patient readmissions. HF readmissions increase the cost of healthcare and affect the quality of life for individuals. Different strategies such as disease management programs with a focus on patient education have been widely used to reduce the risk of patient readmissions. Evidence-based research has shown that heart failure disease management programs that focus on patient education and telephone follow-up decrease the probability of patient readmissions and increase the individual’s quality of life. In Puerto Rico, there is a dearth of research in heart failure disease management programs and the effectiveness of advanced practice nurses in the management and treatment of patients with heart failure. The purpose of this toolbox is to provide a standardized program for veterans that have had a recent hospital admission (30 days or less) with a diagnosis of decompensated heart failure at the VA Caribbean Healthcare System in San Juan, Puerto Rico.
DIAGNOSTIC VALUE OF ST2 IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Acute Myocardial Infarction (AMI) is a major problem threatening Indonesia and many countries. Each year AMI patients areincreasing. ST2 is a novel cardiac marker for diagnosis and prognosis of acute myocardial infarction. The purpose of this study is toseek the diagnostic value of serum ST2 in patients with AMI. This cross sectional study was conducted in 46 patients with maincomplaint of chest pain at the Emergency Department, Dr. Soetomo Hospital from 20 April to 20 July 2013. Sera were examined forST2, and then the diagnostic value was determined using the clinical criteria of AMI according to the Universal Definition ofMyocardial Infarction (2007) as the gold standard. The results of ST2 serum levels measurement showed a sensitivity of 83% andspecificity of 70% at a cut-off value of ST2 16.64 ng/mL and AUC 0.878, p = 0.000. The concordance examination between usingcTn-T levels and ST2 was 48.1%. A significance correlation was obtained with correlation coefficient r = 0.489, p = 0.001 betweenthe levels of cTn-T and ST2. In result, ST2 serum levels can be used for screening to aid the diagnosis of AMI. There is a weakcorrelation and concordance between cTn-T with ST2. Further research is needed to determine the diagnostic value of ST2 for thedetection of AMI. (FMI 2015;51 106-109)
Co-immunoprecipitation with Tau Isoform-specific Antibodies Reveals Distinct Protein Interactions and Highlights a Putative Role for 2N Tau in Disease*

Alternative splicing generates multiple isoforms of the microtubule-associated protein Tau, but little is known about their specific function. In the adult mouse brain, three Tau isoforms are expressed that contain either 0, 1, or 2 N-terminal inserts (0N, 1N, and 2N). We generated Tau isoform-specific antibodies and performed co-immunoprecipitations followed by tandem mass tag multiplexed quantitative mass spectrometry. We identified novel Tau-interacting proteins of which one-half comprised membrane-bound proteins, localized to the plasma membrane, mitochondria, and other organelles. Tau was also found to interact with proteins involved in presynaptic signal transduction. MetaCore analysis revealed one major Tau interaction cluster that contained 33 Tau pulldown proteins. To explore the pathways in which these proteins are involved, we conducted an ingenuity pathway analysis that revealed two significant overlapping pathways, “cell-to-cell signaling and interaction” and “neurological disease. ” The functional enrichment tool DAVID showed that in particular the 2N Tau-interacting proteins were specifically associated with neurological disease. Finally, for a subset of Tau interactions (apolipoprotein A1 (apoA1), apoE, mitochondrial creatine kinase U-type, β-synuclein, synaptogyrin-3, synaptophysin, syntaxin 1B, synaptotagmin, and synapsin 1), we performed reverse co-immunoprecipitations, confirming the preferential interaction of specific isoforms. For example, apoA1 displayed a 5-fold preference for the interaction with 2N, whereas β-synuclein showed preference for 0N. Remarkably, a reverse immunoprecipitation with apoA1 detected only the 2N isoform. This highlights distinct protein interactions of the different Tau isoforms, suggesting that they execute different functions in brain tissue.
Nursing Practice: Hospital and Home : The Adult

Nursing Practice: An Introduction SECTION I CARE of PATIENTS with COMMON DISORDERS: The Cardiovascular System. The Respiratory System. The Gastrointestinal System, Liver and Biliary Tract. Endocrine and Metabolic Disorders. Genetic Disorders. The Reproductive Systems and the Breast. The Urinary System. The Nervous System. The Musculoskeletal System. Blood Disorders. Skin Disorders. Disorders of the Eye. Disorders of the Ear, Nose, Throat. Disorders of the Mouth. The Immune System and Infectious Disease SECTION II COMMON PATIENT PROBLEMS and RELATED NURSING CARE: Stress. Shock. Pain. Fluid and Electrolyte Balance. Nutrition. Temperature Control. Wound Healing. Continence. Sleep. Communication SECTION III NURSING PATIENTS with SPECIAL NEEDS: The Patient Facing Surgery. The Patient Who Experiences Trauma. The Critically Ill Patient. The Unconscious Patient. The Patient with Burns. The Patient with Cancer. The Chronically Ill Patient. The Terminally Ill Patient. The Patient in Need of Rehabilitation. The Older Person. The Person with Dependency Problems. The Person with HIV/AIDS . Appendices. Index
Apolipoprotein D Internalization Is a Basigin-dependent Mechanism*

Background: ApoD appears to be a protein with multiple functions that could influence inflammatory and oxidative pathways to prevent neurotoxicity. Results: The internalization of apoD is mediated by a specific cell surface receptor. Conclusion: Basigin, a transmembrane glycoprotein, is implicated in the internalization process of apoD. Significance: This is the first evidence that a specific receptor is involved in apoD internalization. Apolipoprotein D (apoD), a member of the lipocalin family, is a 29-kDa secreted glycoprotein that binds and transports small lipophilic molecules. Expressed in several tissues, apoD is up-regulated under different stress stimuli and in a variety of pathologies. Numerous studies have revealed that overexpression of apoD led to neuroprotection in various mouse models of acute stress and neurodegeneration. This multifunctional protein is internalized in several cells types, but the specific internalization mechanism remains unknown. In this study, we demonstrate that the internalization of apoD involves a specific cell surface receptor in 293T cells, identified as the transmembrane glycoprotein basigin (BSG, CD147); more particularly, its low glycosylated form. Our results show that internalized apoD colocalizes with BSG into vesicular compartments. Down-regulation of BSG disrupted the internalization of apoD in cells. In contrast, overexpression of basigin in SH-5YSY cells, which poorly express BSG, restored the uptake of apoD. Cyclophilin A, a known ligand of BSG, competitively reduced apoD internalization, confirming that BSG is a key player in the apoD internalization process. In summary, our results demonstrate that basigin is very likely the apoD receptor and provide additional clues on the mechanisms involved in apoD-mediated functions, including neuroprotection.
Endoplasmic Reticulum (ER) Localization Is Critical for DsbA-L Protein to Suppress ER Stress and Adiponectin Down-regulation in Adipocytes*

Background: DsbA-L has been shown to promote adiponectin multimerization, but the molecular mechanisms remain unknown. Results: The wild type, but not ER localization-defective mutant of DsbA-L, protects against ER stress and adiponectin down-regulation. Conclusion: ER localization is critical for DsbA-L to suppress ER stress and adiponectin down-regulation in adipocytes. Significance: Increasing DsbA-L expression could protect against obesity-induced ER stress and metabolic disorders. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions. We previously reported that adiponectin multimerization and stability are promoted by the disulfide bond A oxidoreductase-like protein (DsbA-L) in cells and in vivo. However, the precise mechanism by which DsbA-L regulates adiponectin biosynthesis remains elusive. Here we show that DsbA-L is co-localized with the endoplasmic reticulum (ER) marker protein disulfide isomerase and the mitochondrial marker MitoTracker. In addition, DsbA-L interacts with the ER chaperone protein Ero1-Lα in 3T3-L1 adipocytes. In silico analysis and truncation mapping studies revealed that DsbA-L contains an ER targeting signal at its N terminus. Deletion of the first 6 residues at the N terminus greatly impaired DsbA-L localization in the ER. Overexpression of the wild type but not the ER localization-defective mutant of DsbA-L protects against thapsigargin-induced ER stress and adiponectin down-regulation in 3T3-L1 adipocytes. In addition, overexpression of the wild type but not the ER localization-defective mutant of DsbA-L promotes adiponectin multimerization. Together, our results reveal that DsbA-L is localized in both the mitochondria and the ER in adipocytes and that its ER localization plays a critical role in suppressing ER stress and promoting adiponectin biosynthesis and secretion.
Trauma Care Manual

Introduction The trauma epidemic Trauma resuscitation: an overview Airway management Thoracic trauma Shock Abdominal trauma Head injuries Opthalmic injuries Spinal injuries Facial injuries Musculoskeletal trauma Injuries due to burns and cold Injuries in children Trauma in women Blast and gunshot injury Anaesthesia and analgesia Psychological reactions for trauma Trauma intensive care Patient transfer Triage Trauma scoring.
Ctr9, a Protein in the Transcription Complex Paf1, Regulates Dopamine Transporter Activity at the Plasma Membrane*

Background: The dopamine transporter controls the concentration of dopamine at the synapse. Results: Ctr9, formerly identified as a nuclei protein, interacts with the dopamine transporter in the cytoplasmic compartment. Conclusion: This interaction facilitates the targeting of the dopamine transporter to the plasma membrane and increases its activity. Significance: Identifying the complete dopamine transporter interactome is essential to understanding how neurotransmission is regulated. Dopamine (DA) is a major regulator of sensorimotor and cognitive functions. The DA transporter (DAT) is the key protein that regulates the spatial and temporal activity of DA release into the synaptic cleft via the rapid reuptake of DA into presynaptic termini. Several lines of evidence have suggested that transporter-interacting proteins may play a role in DAT function and regulation. Here, we identified the tetratricopeptide repeat domain-containing protein Ctr9 as a novel DAT binding partner using a yeast two-hybrid system. We showed that Ctr9 is expressed in dopaminergic neurons and forms a stable complex with DAT in vivo via GST pulldown and co-immunoprecipitation assays. In mammalian cells co-expressing both proteins, Ctr9 partially colocalizes with DAT at the plasma membrane. This interaction between DAT and Ctr9 results in a dramatic enhancement of DAT-mediated DA uptake due to an increased number of DAT transporters at the plasma membrane. We determined that the binding of Ctr9 to DAT requires residues YKF in the first half of the DAT C terminus. In addition, we characterized Ctr9, providing new insight into this protein. Using three-dimensional modeling, we identified three novel tetratricopeptide repeat domains in the Ctr9 sequence, and based on deletion mutation experiments, we demonstrated the role of the SH2 domain of Ctr9 in nuclear localization. Our results demonstrate that Ctr9 localization is not restricted to the nucleus, as previously described for the transcription complex Paf1. Taken together, our data provide evidence that Ctr9 modulates DAT function by regulating its trafficking.
The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein*

Background: HSV-1 inhibits T cell functions, but the underlying mechanism is unclear. Results: The HSV-1 Us3 protein disrupts T cell signal transduction by inhibiting the ubiquitination of LAT. Conclusion: The Us3 protein is a crucial factor to suppress T cell activation in HSV-1 infection. Significance: Inhibition of T cell immunity may promote HSV-1 replication or persistence. Herpes simplex virus 1 (HSV-1) is the most prevalent human virus and causes global morbidity because the virus is able to infect multiple cell types. Remarkably, HSV infection switches between lytic and latent cycles, where T cells play a critical role. However, the precise way of virus-host interactions is incompletely understood. Here we report that HSV-1 productively infected Jurkat T-cells and inhibited antigen-induced T cell receptor activation. We discovered that HSV-1-encoded Us3 protein interrupted TCR signaling and interleukin-2 production by inactivation of the linker for activation of T cells. This study unveils a mechanism by which HSV-1 intrudes into early events of TCR-mediated cell signaling and may provide novel insights into HSV infection, during which the virus escapes from host immune surveillance.
Molecular Basis for the Interaction of the Mammalian Amino Acid Transporters B0AT1 and B0AT3 with Their Ancillary Protein Collectrin*

Background: Collectrin is required for membrane expression of the broad neutral amino acid transporters (B0AT1 and -3). Results: Collectrin activates B0AT1 and B0AT3 in a discrete interaction region of the transporters. Conclusion: A potential conserved ancillary protein binding region in B0AT1/B0AT3 mediates collectrin interactions. Significance: This is the first example of a potential common interaction site for multiple solute carrier 6 family ancillary proteins. Many solute carrier 6 (SLC6) family transporters require ancillary subunits to modify their expression and activity. The main apical membrane neutral amino acid transporters in mouse intestine and kidney, B0AT1 and B0AT3, require the ancillary protein collectrin or ACE2 for plasma membrane expression. Expression and activity of SLC6 neurotransmitter transporters are modulated by interaction with syntaxin 1A. Utilizing monocarboxylate-B0AT1/3 fusion constructs, we discovered that collectrin is also necessary for B0AT1 and B0AT3 catalytic function. Syntaxin 1A and syntaxin 3 inhibit the membrane expression of B0AT1 by competing with collectrin for access. A mutagenesis screening approach identified residues on trans-membrane domains 1α, 5, and 7 on one face of B0AT3 as a key region involved in interaction with collectrin. Mutant analysis established residues that were involved in collectrin-dependent functions as follows: plasma membrane expression of B0AT3, catalytic activation, or both. These results identify a potential binding site for collectrin and other SLC6 ancillary proteins.
Human DNA Polymerase ν Catalyzes Correct and Incorrect DNA Synthesis with High Catalytic Efficiency*

Background: DNA polymerase ν is a low fidelity polymerase with an unknown function. Results: The kinetic mechanism of correct and incorrect base pair formation was determined. Conclusion: Phosphodiester bond formation is rapid for both correct and mispair formation. Significance: The presence of a mispair does not induce the polymerase to adopt a low catalytic conformation. DNA polymerase ν (pol ν) is a low fidelity A-family polymerase with a putative role in interstrand cross-link repair and homologous recombination. We carried out pre-steady-state kinetic analysis to elucidate the kinetic mechanism of this enzyme. We found that the mechanism consists of seven steps, similar that of other A-family polymerases. pol ν binds to DNA with a Kd for DNA of 9.2 nm, with an off-rate constant of 0.013 s−1and an on-rate constant of 14 μm−1 s−1. dNTP binding is rapid with Kd values of 20 and 476 μm for the correct and incorrect dNTP, respectively. Pyrophosphorylation occurs with a Kd value for PPi of 3.7 mm and a maximal rate constant of 11 s−1. Pre-steady-state kinetics, examination of the elemental effect using dNTPαS, and pulse-chase experiments indicate that a rapid phosphodiester bond formation step is flanked by slow conformational changes for both correct and incorrect base pair formation. These experiments in combination with computer simulations indicate that the first conformational change occurs with rate constants of 75 and 20 s−1; rapid phosphodiester bond formation occurs with a Keq of 2.2 and 1.7, and the second conformational change occurs with rate constants of 2.1 and 0.5 s−1, for correct and incorrect base pair formation, respectively. The presence of a mispair does not induce the polymerase to adopt a low catalytic conformation. pol ν catalyzes both correct and mispair formation with high catalytic efficiency.