Miracle-dz/UniFAR-FTUs huggingface dataset:
Muscarinic facilitation of GABA release in substantia gelatinosa of the rat spinal dorsal horn

1 Blind patch clamp recordings were made from substantia gelatinosa (SG) neurones in the adult rat spinal cord slice to study the mechanisms of cholinergic modulation of GABAergic inhibition. 2 In the majority of SG neurones tested, carbachol (10 μM) increased the frequency (677 % of control) of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). A portion of these events appeared to result from the generation of spikes by GABAergic interneurones, since large amplitude IPSCs were eliminated by tetrodotoxin (1 μM). 3 The effect of carbachol on spontaneous IPSCs was mimicked by neostigmine, suggesting that GABAergic interneurones are under tonic regulation by cholinergic systems. 4 The frequency of GABAergic miniature IPSCs in the presence of tetrodotoxin (1 μM) was also increased by carbachol without affecting amplitude distribution, indicating that acetylcholine facilitates quantal release of GABA through presynaptic mechanisms. 5 Neither the M1 receptor agonist McN‐A‐343 (10‐300 μM) nor the M2 receptor agonist, arecaidine (10‐100 μM), mimicked the effects of carbachol. All effects of carbachol and neostigmine were antagonized by atropine (1 μM), while pirenzepine (100 nM), methoctramine (1 μM) and hexahydrosiladifenidol hydrochloride, p‐fluoro‐analog (100 nM) had no effect. 6 Focal stimulation of deep dorsal horn, but not dorsolateral funiculus, evoked a similar increase in IPSC frequency to that evoked by carbachol and neostigmine. The stimulation‐induced facilitation of GABAergic transmission lasted for 2‐3 min post stimulation, and the effect was antagonized by atropine (100 nM). 7 Our observations suggest that GABAergic interneurones possess muscarinic receptors on both axon terminals and somatodendritic sites, that the activation of these receptors increases the excitability of inhibitory interneurones and enhances GABA release in SG and that the GABAergic inhibitory system is further controlled by cholinergic neurones located in the deep dorsal horn. Those effects may be responsible for the antinociceptive action produced by the intrathecal administration of muscarinic agonists and acetylcholinesterase inhibitors.
Comparison of six disease severity scores for allergic rhinitis against pollen counts a prospective analysis at population and individual level

Many different symptom (medication) scores are nowadays used as measures of allergic rhinoconjunctivitis severity in individual patients and in clinical trials. Their differences contribute to the heterogeneity of the primary end‐point in meta‐analyses, so that calls for symptom (medication) score harmonization have been launched.
Wind induces variations in spider web geometry and sticky spiral droplet volume

SUMMARY Trap building by animals is rare because it comes at a substantial cost. Using materials with properties that vary across environments maintains trap functionality. The sticky spiral silks of spider orb webs are used to catch flying prey. Web geometry, accompanied by compensatory changes in silk properties, may change across environments to sustain web functionality. We exposed the spider Cyclosa mulmeinensis to wind to test whether wind-induced changes in web geometry are accompanied by changes in aggregate silk droplet morphology, axial thread width or spiral stickiness. We compared: (i) web catching area, (ii) length of total silks, (iii) mesh height, (iv) number of radii, (v) aggregate droplet morphology and (vi) spiral thread stickiness, between webs made by spiders exposed to wind and those made by spiders not exposed to wind. We interpreted co-variation in droplet morphology or spiral stickiness with web capture area, mesh height or spiral length as the silk properties functionally compensating for changes in web geometry to reduce wind drag. Wind-exposed C. mulmeinensis built webs with smaller capture areas, shorter capture spiral lengths and more widely spaced capture spirals, resulting in the expenditure of less silk. Individuals that were exposed to wind also deposited larger droplets of sticky silk but the stickiness of the spiral threads remained unchanged. The larger droplets may be a product of a greater investment in water, or low molecular weight compounds facilitating atmospheric water uptake. Either way, droplet dehydration in wind is likely to be minimized.
Economic burden of cancer survivorship among adults in the United States.

PURPOSE To present nationally representative estimates of the impact of cancer survivorship on medical expenditures and lost productivity among adults in the United States. METHODS Using the 2008 to 2010 Medical Expenditure Panel Survey, we identified 4,960 cancer survivors and 64,431 individuals without a history of cancer age ≥ 18 years. Direct medical costs were measured using annual health care expenditures and examined by source of payment and service type. Indirect morbidity costs were estimated from lost productivity as a result of employment disability, missed work days, and lost household productivity. We evaluated the economic burden of cancer survivorship by estimating excess costs among cancer survivors, stratified by time since diagnosis (recently diagnosed [≤ 1 year] and previously diagnosed [> 1 year]), compared with individuals without a history of cancer using multivariable regression models stratified by age (18 to 64 and ≥ 65 years), controlling for age, sex, race/ethnicity, education, and comorbidities. RESULTS In 2008 to 2010, the annual excess economic burden of cancer survivorship among recently diagnosed cancer survivors was $16,213 per survivor age 18 to 64 years and $16,441 per survivor age ≥ 65 years. Among previously diagnosed cancer survivors, the annual excess burden was $4,427 per survivor age 18 to 64 years and $4,519 per survivor age ≥ 65 years. Excess medical expenditures composed the largest share of the economic burden among cancer survivors, particularly among those recently diagnosed. CONCLUSION The economic impact of cancer survivorship is considerable and is also high years after a cancer diagnosis. Efforts to reduce the economic burden caused by cancer will be increasingly important given the growing population of cancer survivors.
Effects of supplemental protein source and metabolizable energy intake on nutritional status in pregnant ewes.

Two experiments were conducted to evaluate effects of supplemental protein source and ME intake (Exp. 1) on ewe nutritional status during pregnancy. Forty-two mature Targhee ewes were allotted randomly in Exp. 1 to one of six treatments (n = 7) using a 2 x 3 factorial arrangement. Ewes were individually fed chopped barley straw and supplements containing either urea (U), soybean meal (SBM), or blood meal (BM) plus SBM during the 84-d experiment. Straw and supplement intakes were adjusted to meet either 80 or 100% of ME requirements. In Exp. 2, 30 pregnant Targhee ewes that were allotted randomly to one of three groups (n = 10) were individually fed protein supplements similar to those in Exp. 1 and had group access to long-stem barley straw. In Exp. 1, ewes fed BM + SBM gained more (P less than .05) weight, lost less (P less than .05) body condition, and had increased (P less than .05) wool fiber length compared with ewes fed U; SBM ewes were intermediate (P less than .05) in response. Ewes fed BW + SBM had increased (P less than .05) blood urea N and albumin concentrations compared with ewes fed U. Metabolizable energy intake did not affect (P greater than .05) ewe performance or serum metabolite concentrations. Ewes fed BM + SBM in Exp. 2 gained more (P less than .05) weight than ewes fed either SBM or U, and ewes fed SBM lost less weight (P less than .05) than ewes fed U. (ABSTRACT TRUNCATED AT 250 WORDS)
Signaling Pathways for Modulation of Mouse Sperm Motility by Adenosine and Catecholamine Agonists1

Abstract Capacitation of mammalian sperm, including alterations in flagellar motility, is presumably modulated by chemical signals encountered in the female reproductive tract. This work investigates signaling pathways for adenosine and catecholamine agonists that stimulate sperm kinetic activity. We show that 2-chloro-2′-deoxyadenosine and isoproterenol robustly accelerate flagellar beat frequency with EC50s near 10 and 0.05 μM, respectively. The several-fold acceleration is maximal by 60 sec. Although extracellular Ca2+ is required for agonist action on the flagellar beat, agonist treatment does not elevate sperm cytosolic [Ca2+] but does increase cAMP content. Acceleration does not require the conventional transmembrane adenylyl cyclase ADCY3, since it persists in sperm of ADCY3 knockout mice and in wild-type sperm in the presence of the inhibitors of conventional adenylyl cyclases SQ-22536, MDL-12330A, or 2′, 5′-dideoxyadenosine. In contrast, the acceleration by these agents is absent in sperm that lack the predominant atypical adenylyl cyclase, SACY. Responses to these agonists are also absent in sperm from mice lacking the sperm-specific Cα2 catalytic subunit of protein kinase A (PRKACA). Agonist responses also are strongly suppressed in wild-type sperm by the protein kinase inhibitor H-89. These results show that adenosine and catecholamine analogs activate sperm motility by mechanisms that require extracellular Ca2+, the atypical sperm adenylyl cyclase, cAMP, and protein kinase A.
Cerebral autoregulation dynamics in premature newborns.

BACKGROUND AND PURPOSE Autoregulation of cerebral blood flow is easily disrupted, and loss of this normal physiological reflex may worsen the neurological outcome for patients undergoing intensive care. We studied the response of cerebral blood flow velocity to changes in mean arterial blood pressure. METHODS Cerebral blood flow velocity was measured with Doppler ultrasonography in one middle cerebral artery for 5-minute periods in 33 babies of gestational age < 33 weeks admitted to a neonatal intensive care unit. Two methods of evaluating autoregulation were developed. The first used linear regression analysis of blood flow velocity on blood pressure. Records were classified as showing loss of autoregulation if the regression slope was greater than a critical value. A minimum change in mean arterial blood pressure of 5 mm Hg and a critical slope of 1.5%/mm Hg were found to be adequate criteria for the classification of records by the regression method. The second method used coherent averaging, a technique similar to that used in recording evoked potentials. Spontaneous transient increases in blood pressure were automatically detected, and the instant corresponding to its maximum rate of rise was used to synchronize averages of the blood pressure and blood velocity transients. The resulting coherent averages were classified into two groups based on the morphology of the cerebral blood flow velocity average. RESULTS Whereas the regression method allowed the classification of only 51 of 106 records, the coherent average method classified 101 of 106 (95.3%) of the records available. For 51 records that were classified by both methods, there was agreement in 42 cases (82.3%). The coherent average of all records classified as having an active autoregulation showed cerebral blood flow velocity returning to baseline much earlier than blood pressure, suggesting that autoregulation was taking place within 1 to 2 seconds. This pattern was absent in records in which autoregulation was classified as absent. CONCLUSIONS Computerized coherent averaging of the cerebral blood flow velocity response to spontaneous blood pressure transients offers a promising new method for noninvasive bedside assessment of autoregulation in patients undergoing intensive care. The time course for autoregulation, when present, is in agreement with that reported in adults.
CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

Angiotensin II (Ang II) is a peptide hormone that, like many cytokines, acts as a proinflammatory agent and growth factor. After injury to the liver, the hormone assists in tissue repair by stimulating hepatocytes and hepatic stellate cells to synthesize extracellular matrix proteins and secrete secondary cytokines and by stimulating myofibroblasts to proliferate. However, under conditions of chronic liver injury, all of these effects conspire to promote pathologic liver fibrosis. Much of this effect of Ang II results from activation of the proinflammatory NF-κB transcription factor in response to stimulation of the type 1 Ang II receptor, a G protein-coupled receptor. Here, we characterize a previously undescribed signaling pathway mediating Ang II-dependent activation of NF-κB, which is composed of three principal proteins, CARMA3, Bcl10, and MALT1. Blocking the function of any of these proteins, through the use of either dominant-negative mutants, RNAi, or gene targeting, effectively abolishes Ang II-dependent NF-κB activation in hepatocytes. In addition, Bcl10−/− mice show defective hepatic cytokine production after Ang II treatment. Evidence also is presented that this pathway activates NF-κB through ubiquitination of IKKγ, the regulatory subunit of the IκB kinase complex. These results elucidate a concrete series of molecular events that link ligand activation of the type 1 Ang II receptor to stimulation of the NF-κB transcription factor. These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system.
Videocapillaroscopic findings in the microcirculation of the psoriatic plaque during etanercept therapy

Vascular endothelial growth factor (VEGF) is a pivotal cytokine in the pathogenesis of psoriasis, and upregulation of VEGF by tumour necrosis factor (TNF)‐α and inflammatory factors causes marked alterations in the cutaneous microcirculation. Etanercept is a fully soluble TNF receptor fusion protein that primarily binds soluble TNF‐α, thus blocking its pro‐angiogenic function.
Serum antibodies to structural proteins of hantavirus arise at different times after infection

An enzyme‐linked immunosorbent assay (ELISA) was developed for the quantification of serum antibodies against group‐specific epitopes of the glycoproteins (G1, G2) and nucleoprotein (NP) of the genus Hantavirus. This assay was used to study the kinetics of the development of serum antibodies after natural infection with Puumala‐like virus in humans. To this end a panel of 34 serum samples collected from individuals at different times after natural infection was tested by the ELISA. The samples were also tested for specific IgM and IgG levels against Puumala‐like virus, which provided confirmatory data about the presumed timing of infection. It was shown that serum antibodies against the G1 epitope were present in the acute and early convalescent period just before antibodies to the NP epitope could be demonstrated. In contrast, antibodies to two G2 epitopes were present not earlier than in the convalescent and late convalescent period. Since all these categories of antibodies seem to persist for long periods, antibodies against the G1 epitope and the NP epitope may be of specific diagnostic value. Furthermore, levels of G1‐specific antibodies and antibodies to either NP or G2 may allow estimation of the time elapsed following initial infection. © 1992 Wiley‐Liss, Inc.
Comparing ELISA and Surface Plasmon Resonance for Assessing Clinical Immunogenicity of Panitumumab

Evaluation of the immunogenicity of panitumumab, a fully human anti-epidermal growth factor receptor mAb approved for use in colorectal cancer patients, led to the development of two separate immunoassays for the detection of anti-panitumumab Abs. The first immunoassay used a bridging ELISA capable of detecting 10 ng/ml positive control anti-panitumumab Ab. The ELISA incorporated an acid dissociation step to reduce drug interference and tolerated the presence of ∼100-fold molar excess of drug. During eight clinical trials, the ELISA detected developing Ab responses in 2 of 612 (0.3%) subjects. In one of the ELISA positive subjects, neutralizing Abs were detected using an epidermal growth factor receptor phosphorylation bioassay. The second immunoassay used a Biacore biosensor immunoassay format capable of detecting 1 μg/ml positive control Ab while tolerating the presence of equal molar amounts of drug. Although less sensitive and less tolerant to competing drug in the assay, the Biacore assay detected developing Ab responses in 25 of the 604 (4.1%) subjects. Additionally, the Biacore assay identified eight subjects who developed neutralizing Abs. Mouse mAbs with affinities ranging from 1.1 × 10−6 to 8.4 × 10−10 M were used to characterize both assay types. The ELISA was more sensitive for the detection of higher affinity mAbs and detected high-affinity mAbs in the presence of higher molar ratio of drug to mAb. The Biacore assay was more sensitive for detection of lower affinity mAbs and detected low affinity Abs in the presence of higher molar ratios of drug to mAb.
Topographical organization of cortical afferents to extrastriate visual area PO in the macaque: A dual tracer study

We have examined the origin and topography of cortical projections to area PO, an extrastriate visual area located in the parieto‐occipital sulcus of the macaque. Distinguishable retrograde fluorescent tracers were injected into area PO at separate retinotopic loci identified by single‐neuron recording.
In vivo immobilization of enzymatically active polypeptides on the cell surface of Staphylococcus carnosus

Many surface proteins of Gram‐positive bacteria are covalently anchored to the cell wall by a ubiquitous mechanism, involving a specific, C‐terminal sorting signal. To achieve cell‐wall immobilization of a normally secreted enzyme in vivo, we constructed a hybrid protein consisting of Staphylococcus hyicus lipase and the C‐terminal region of Staphylococcus aureus fibronectin binding protein B (FnBPB). This region comprised the authentic cell‐wall‐spanning region and cell‐wall sorting signal of FnBPB. Expression of the hybrid protein in Staphylococcus carnosus resulted in efficient cell‐wall anchoring of enzymatically active lipase. The cell‐wall‐immobilized lipase (approximately 10000 molecules per cell) retained more than 80% of the specific activity, compared to the C‐terminally unmodified S. hyicus lipase secreted by S. carnosus cells. After releasing the hybrid protein from the cell wall by lysostaphin treatment, its specific activity was indistinguishable from that of the unmodified lipase. Thus, the C‐terminal region of FnBPB per se was fully compatible with folding of the lipase to an active conformation. To study the influence of the distance between the cell‐wall sorting signal and the C‐terminus of the lipase on the activity of the immobilized lipase, the length of this spacer region was varied. Reduction of the spacer length gradually reduced the activity of the surface‐immobilized lipase. On the other hand, elongation of this spacer did not stimulate the activity of the immobilized lipase, indicating that the spacer must exceed a critical length of approx. 90 amino acids to allow efficient folding of the enzyme, which probably can only be achieved outside the pep‐tidoglycan web of the cell wall. When the lipase was replaced by another enzyme, the Escherichia coliβ‐lactamase, the resulting hybrid was also efficiently anchored in an active conformation to the cell wall of S, carnosus. These results demonstrate that it is possible to immobilize normally soluble enzymes on the cell wall of S. carnosus ‐ without radically altering their catalytic activity ‐ by fusing them to a cell‐wall‐immobilization unit, consisting of a suitable cellwall‐spanning region and a standard cell‐wall sorting signal.
Regulatory Mechanism for Expression of IL1B Receptors in the Uterine Endometrium and Effects of IL1B on Prostaglandin Synthetic Enzymes During the Implantation Period in Pigs1

ABSTRACT During the implantation period, the porcine conceptus secretes interleukin-1beta (IL1B) that may be involved in the establishment of pregnancy in pigs. However, the regulatory mechanism for IL1B receptor expression and the function of IL1B in the uterine endometrium are not well elucidated. In this study, we determined IL1B receptor expression in the uterine endometrium of pigs during pregnancy. IL1B receptor subtypes, IL1 receptor type I (IL1R1) and IL1 receptor accessory protein (IL1RAP) were expressed in the uterine endometrium with the expression being most abundant on Day 12 of pregnancy primarily in the luminal and glandular epithelial cells. Expression of IL1R1 mRNA increased in response to IL1B in a dose-dependent manner, and expression of IL1RAP mRNA increased in response to both IL1B and estradiol, indicating that expression of endometrial IL1B receptors was regulated cooperatively by IL1B and estrogen of conceptus origin. During the peri-implantation period, the porcine uterine endometrium actively synthesizes and secretes prostaglandins (PGs). IL1B increased expression of PTGS1 and PTGS2 genes that are rate-limiting for PG synthesis in the uterine endometrium. Collectively, the results indicated that IL1B regulates expression of IL1R1 and IL1RAP and stimulates expression of PTGS1 and PTGS2 that are considered to be the most rate-limiting enzymes for endometrial synthesis of PGs during the peri-implantation period of pregnancy in pigs.
Dopamine receptor antagonists impair place conditioning after acute stress in rats

An immediate and robust release of dopamine appears in the brain under an acute stressor, but the functional role of dopamine under stress remains elusive. We recently showed conditioned place preference (CPP) induced by the acute application of a stressor such as being placed on an elevated stand or immobilized in a restraint holder. This study tested whether dopamine is involved in such CPP. The selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively, were injected before stressor manipulation. The doses of SCH23390 (0.025 and 0.05 mg/kg) and raclopride (0.05 and 0.1 mg/kg) used to test for stressor-induced CPP were verified to be ineffective on spontaneous locomotor activity. The results showed that both drugs attenuated the development of stressor-induced CPP. Such a CPP blocking effect by pretreatment of dopamine receptor antagonist was true for either kind of stressor manipulated. These findings indicate that an acute stressor can facilitate a follow-up place conditioning, and that dopamine is involved in the present type of CPP formation.
Serological tumor markers of hepatocellular carcinoma: a meta-analysis

Background The clinical value of serum α-fetoprotein (AFP) to detect hepatocellular carcinoma (HCC) has been questioned due to its low sensitivity and specificity. Other than AFP, several new serum biomarkers including glypican-3 (GPC3), des-γ-carboxy prothrombin (DCP), α-L-fucosidase enzyme (AFU) and vascular endothelial growth factor (VEGF) have been identified as useful HCC markers. Material and methods A systematic search on PubMed, Web of Science and others was performed. Twenty-six case-control studies on HCC-related biomarkers published from 2000 to 2014 were included in this analysis. Data on sensitivity and specificity of tests were extracted and analyzed using the Meta-DiSc 1.4 statistical program. Fixed or random-effects models were used depending on the absence or presence of significant heterogeneity. Summary receiver operating characteristic (sROC) curves were obtained to evaluate the accuracy of the studied markers. Results The areas under the sROC curve of AFP, GPC3, DCP, AFU, VEGF and the combination of each of the last 4 markers with AFP were 0.869, 0.928, 0.832, 0.851, 0.834, 0.964, 0.972, 0.873 and 0.948, respectively. A combination of AFP+GPC3, AFP+DCP or AFP+VEGF was superior to AFP alone in detecting HCC. The area under the sROC curve of GPC3 alone was significantly higher than that of AFP, whereas the areas of DCP, AFU and VEGF were comparable to that of AFP. Conclusions GPC3, DCP, AFU and VEGF are suitable markers for HCC, and their determination with AFP may prove to be useful in the diagnosis and screening of HCC.