Miracle-dz/UniFAR-FTUs huggingface dataset:
Readout design and validation for a 1 mm3 resolution clinical PET system

We designed and built a data acquisition module based on the NOVA RENA-3 ASIC that is suitable for readout of multiple detector types, including APDs, PSAPDs, CZT, CdTe, and Si. The module was designed as a repeatable component for a 1 mm3 resolution breast-dedicated PET system that employs LYSO-PSAPD detectors. The PET system is made of 2 panels, each containing 2304 PSAPDs in a 16 cm × 9 cm × 2 cm volume resulting in 9216 readout channels per panel. The high density of channels drives the requirement for a high density data acquisition module which accurately processes analog signals from the detectors that have traveled up to 63 cm in flexible cables before entering the RENA-3. The readout was tested with one data acquisition module from each panel. Each data acquisition module handles processing of 16 PSAPDs (or 8 dual LSO-PSAPD modules), whose signals are routed over paths 63 cm in length. For the test, two detectors were placed in a face-on configuration. A 22Na point source was placed in between the two modules to generate pair coincidence data. Each data acquisition module was connected to the same computer and list mode single photon data was collected. The coincidence events were energy gated to be in the 511 keV peak and corrected for per crystal time delay and signal amplitude variations in the PSAPD. Data collected from detectors connected to two data acquisition modules over the 63 cm signal path showed the calibrated system will have a paired (coincidence) photon time resolution of 7.23±0.21 ns FWHM (5.11±0.15 ns unpaired) and global energy resolution of 13.6±1.3% FWHM at 511 keV. Coincidence charge injection data to 2 data acquisition modules shows the electronics contribution to coincidence time resolution of the system with multiple modules is 1.33±0.01 ns FWHM. These measurements prove the functionality of the module as well as the feasibility of readout of PSAPD signals over long analog signal paths.
Changes in functional limitation and survival among older Taiwanese, 1993, 1996, and 1999

Using data from the Survey of Health and Living Status of the Elderly in Taiwan, we investigate changes in difficulties in walking and climbing stairs, tasks that represent basic lower-body movements less likely to be influenced by changes in environment and social roles than are activities and instrumental activities of daily living. Results are shown for unadjusted prevalence rates and rates adjusted for changes in population composition. The findings indicate that Taiwan does not appear to be experiencing the improvements in functioning witnessed recently in the United States. Prevalence of functional limitation increased between 1993 and 1996 and between 1996 and 1999. One possible reason is the change in old-age survival, which appears to have benefited those who have functional limitations, especially in a severe form. The Universal Health Insurance programme, established in 1995, may have increased access to care and thus the survival of those in poorest health.
Influence of Coadministration on the Pharmacokinetics of Azimilide Dihydrochloride and Digoxin

The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3‐way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QTc prolongation was characterized by an Emax model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic‐based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CLr (P = .0325), with no change in CLo. Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in Cmax (P = .0176) and a 10% increase in AUCτ (P = .0121). Digoxin coadministration increased the apparent EC50 with no effect on Emax, consistent with competitive inhibition (Ki = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.
Rapid Shortening of Telomere Length in Response to Ceramide Involves the Inhibition of Telomere Binding Activity of Nuclear Glyceraldehyde-3-phosphate Dehydrogenase*

Ceramide has been demonstrated as one of the upstream regulators of telomerase activity. However, the role for ceramide in the control of telomere length remains unknown. It is shown here that treatment of the A549 human lung adenocarcinoma cells with C6-ceramide results in rapid shortening of telomere length. During the examination of ceramide-regulated telomere-binding proteins, nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified to associate with both single- and double-stranded telomeric DNA with high specificity in vitro. The association of nuclear GAPDH with telomeres in interphase nuclei was also demonstrated by co-fluorescence in situ hybridization and chromatin immunoprecipitation analysis. Further data demonstrated that the nuclear localization of GAPDH is regulated by ceramide in a cell cycle-dependent manner parallel with the inhibition of its telomere binding activity in response to ceramide. In addition, the results revealed that nuclear GAPDH is distinct from its cytoplasmic isoform and that telomere binding function of nuclear GAPDH is strikingly higher than the cytoplasmic isoform. More importantly, the functional role for nuclear GAPDH in the maintenance and/or protection of telomeric DNA was identified by partial inhibition of the expression of GAPDH using small interfering RNA, which resulted in rapid shortening of telomeres. In contrast, overexpression of nuclear GAPDH resulted in the protection of telomeric DNA in response to exogenous ceramide as well as in response to anticancer drugs, which have been shown to induce endogenous ceramide levels. Therefore, these results demonstrate a novel function for nuclear GAPDH in the maintenance and/or protection of telomeres and also show that mechanisms of the rapid degradation of telomeres in response to ceramide involve the inhibition of the telomere binding activity of nuclear GAPDH.
Patterning the embryonic kidney: BMP signaling mediates the differentiation of the pronephric tubules and duct in Xenopus laevis

The Bone morphogenetic proteins (BMPs) mediate a wide range of diverse cellular behaviors throughout development. Previous studies implicated an important role for BMP signaling during the differentiation of the definitive mammalian kidney, the metanephros. In order to examine whether BMP signaling also plays an important role during the patterning of earlier renal systems, we examined the development of the earliest nephric system, the pronephros. Using the amphibian model system Xenopus laevis, in combination with reagents designed to inhibit BMP signaling during specific stages of nephric development, we revealed an evolutionarily conserved role for this signaling pathway during renal morphogenesis. Our results demonstrate that conditional BMP inhibition after specification of the pronephric anlagen is completed, but prior to the onset of morphogenesis and differentiation of renal tissues, results in the severe malformation of both the pronephric duct and tubules. Importantly, the effects of BMP signaling on the developing nephron during this developmental window are specific, only affecting the developing duct and tubules, but not the glomus. These data, combined with previous studies examining metanephric development in mice, provide further support that BMP functions to mediate morphogenesis of the specified renal field during vertebrate embryogenesis. Specifically, BMP signaling is required for the differentiation of two types of nephric structures, the pronephric tubules and duct. Developmental Dynamics 237:132–144, 2008. © 2007 Wiley‐Liss, Inc.
Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice.

Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner.
Bone Morphogenetic Proteins Signal Via SMAD and Mitogen-activated Protein (MAP) Kinase Pathways at Distinct Times during Osteoclastogenesis*

Background: BMPs affect osteoclastogenesis in vitro, but the effects of BMP signaling on osteoclastogenesis in vivo are not well understood. Results: Conditional deletion of BMPRII in osteoclasts results in reduced osteoclastogenesis, resulting in increased bone. Conclusion: BMP signaling is required for proper bone remodeling in vivo. Significance: Identifying factors affecting osteoclast differentiation increase understanding of bone remodeling regulation in vivo. To investigate the role of bone morphogenetic protein (BMP) signaling in osteoclastogenesis in vivo, we eliminated BMPRII in osteoclasts by creating a BMPRIIfl/fl;lysM-Cre mouse strain. Conditional knock-out (cKO) mice are osteopetrotic when compared with WT controls due to a decrease in osteoclast activity. Bone marrow macrophages (BMMs) isolated from cKO mice are severely inhibited in their capacity to differentiate into mature osteoclasts in the presence of M-CSF and receptor activator of NF-κB (RANK) ligand. We also show that BMP noncanonical (MAPK) and canonical (SMAD) pathways are utilized at different stages of osteoclast differentiation. BMP2 induces p38 phosphorylation in pre-fusion osteoclasts and increases SMAD phosphorylation around osteoclast precursor fusion. Phosphorylation of MAPKs was decreased in differentiated BMMs from cKO animals. Treating BMMs with the SMAD inhibitor dorsomorphin confirms the requirement for the canonical pathway around the time of fusion. These results demonstrate the requirement for BMP signaling in osteoclasts for proper bone homeostasis and also explore the complex signaling mechanisms employed by BMP signaling during osteoclast differentiation.
Serologic Detection of Actinobacillus pleuropneumoniae in Swine by Capsular Polysaccharide-Biotin-Streptavidin Enzyme-Linked Immunosorbent Assay

ABSTRACT Serologic detection of Actinobacillus pleuropneumoniaeinfections in swine have been problematic due to antigenic cross-reactivity of Apx toxins, lipopolysaccharide, and outer membrane proteins between A. pleuropneumoniae serotypes and other bacterial species. To maximize serologic specificity and sensitivity, we developed an assay that uses highly purified A. pleuropneumoniae capsular polysaccharide (CP) conjugated to biotin, which is then bound to streptavidin-coated enzyme-linked immunosorbent assay (CP-BS-ELISA) plates. This assay was used to test a panel of 240 serum samples from pigs prior to challenge, after challenge with bacterial species other than A. pleuropneumoniae, or after challenge with A. pleuropneumoniae serotype 1, 5, or 7. Overall assay results for the individual sera tested were reproducible on the same day and on separate days. The sensitivity of the assay was 100% by ELISAs with biotin-CPs of serotypes 1 and 7 and 87.5% by ELISAs with biotin-CP of serotype 5. Specificity was 100% by ELISAs with biotin-CPs of serotypes 1 and 5 and 94.5% by ELISAs with biotin-CP of serotype 7. The biotin-CPs of at least three A. pleuropneumoniae serotypes could be combined for use in a screening assay to detect antibodies to CPs from strains of different serotypes. In conclusion, the CP-BS-ELISA proved to be a serotype-specific and species-specific assay with high sensitivity for the identification of pigs exposed to A. pleuropneumoniae.
Allergy Therapy by Intranasal Administration with Recombinant Lactococcus lactis Producing Bovine β-Lactoglobulin

Background: In the last years, the use of probiotics such as lactic acid bacteria (LAB) has been proposed as an attractive alternative for the management of allergic diseases. A partial prevention from sensitization to bovine β-lactoglobulin (BLG), one of the major cows’ milk allergens, could be achieved in mice after intranasal administration with a recombinant LAB strain, Lactococcus lactis, producing BLG (LL-BLG). This study aimed to evaluate the effects of the LL-BLG strain in a therapeutic protocol. Methods: Three groups of mice were first orally sensitized to cows’ milk and then intranasally administered with either the LL-BLG strain, BLG protein alone or saline solution. Serum samples were collected to analyze BLG-specific IgE, IgG1 and IgG2a, and mice were further intranasally challenged with BLG to elicit a specific allergic reaction. Results: Treatment with LL-BLG, but not with BLG alone, contributed to diminish IgG1 production in serum and bronchoalveolar lavage fluids. This was associated with decreased IL-4 production and enhanced IFN-γ production by BLG-reactivated splenocytes, suggesting a switch from Th2- to Th1-immune response. Furthermore, we observed that administration of LL-BLG or LL locally reduced the allergic reaction induced after intranasal challenge, as evidenced by decreased release of IL-4 in bronchoalveolar lavage fluids. Conclusion: These preliminary results demonstrate the efficiency of the intranasal administration of LL-BLG for specific therapy against cows’ milk-related allergy.
Mannose Receptor 1 Mediates Cellular Uptake and Endosomal Delivery of CpG-Motif Containing Oligodeoxynucleotides

Recognition of microbial components is critical for activation of TLRs, subsequent innate immune signaling, and directing adaptive immune responses. The DNA sensor TLR9 traffics from the endoplasmic reticulum to endolysosomal compartments where it is cleaved by resident proteases to generate a competent receptor. Activation of TLR9 by CpG-motif containing oligodeoxynucleotides (CpG ODNs) is preceded by agonist endocytosis and delivery into the endolysosomes. The events that dictate this process remain largely unknown; furthermore, it is unclear whether the receptors involved in mediating uptake of exogenous DNA are conserved for both naturally derived pathogenic DNA and synthetic ODNs. In this study, we report that peritoneal macrophages from a wild-derived inbred mouse strain, MOLF/Ei, are hyporesponsive to CpG ODN but are fully responsive to bacterial DNA, thus implying that microbial recognition is not fully recapitulated by a synthetic analog. To identify the gene responsible for the CpG ODN defect, we have performed genome-wide linkage analysis. Using N2 backcross mice, we mapped the trait with high resolution to a single locus containing Mrc1 as the gene conferring the trait. We show that mannose receptor 1 (MRC1; CD206) is involved in CpG ODN uptake and trafficking in wild-derived MOLF/Ei peritoneal macrophages. Furthermore, we show that other strains of wild-derived mice also require MRC1 for CpG-induced cytokine responses. These findings reveal novel functions for MRC1 and demonstrate that wild-derived mice are important and indispensable model for understanding naturally occurring regulators of inflammatory responses in innate immune pathways.
Reversible Acute Kidney Injury following Contrast Exposure and the Risk of Long-Term Mortality

Background: Contrast-induced acute kidney injury (AKI) is a significant cause of morbidity and mortality among hospitalized patients. However, data regarding the long-term prognostic implications of reversible AKI following contrast exposure are limited. Methods: We carried out a prospective 5-year follow-up study of 78 patients with chronic kidney disease who underwent coronary angiography, employing a uniform intravenous hydration protocol supplemented by either acetylcysteine (600 mg orally t.i.d.) or placebo. Results: Contrast-induced AKI (defined as ≥0.5 mg/dl increase in serum creatinine, SCr, or >25% increase above baseline 48 h following contrast exposure) developed in 10 of the 78 patients (13%). All SCr changes were reversible, and were no longer evident 7 days following contrast exposure. At 5 years of follow-up, mortality rates were significantly higher among patients who developed reversible AKI (90%) as compared with those who did not (32%; p < 0.001). Accordingly, multivariable analysis demonstrated that reversible AKI was independently associated with a significant 2.7-fold increase (p = 0.001) in the risk of long-term mortality. Conclusions: Our findings indicate that short-term reductions in renal function following contrast exposure have important long-term prognostic implications in patients with chronic kidney disease. Careful follow-up of SCr levels following contrast exposure is warranted for long-term risk assessment in this population.
Isoflurane Neuroprotection in Rat Hippocampal Slices Decreases with Aging: Changes in Intracellular Ca2+ Regulation and N-methyl-d-aspartate Receptor–mediated Ca2+ Influx

Background:Most in vitro neuroprotection studies with isoflurane have involved cells obtained during the embryonic or early postnatal period. However, in mature rodents, isoflurane neuroprotection does not persist. The authors determined whether neuroprotection of hippocampal slices with isoflurane decreases with aging and is due to decreased intracellular Ca2+ regulation and survival protein phosphorylation. Methods:Hippocampal slices from 5-day-old, 1-month-old, and 19- to 23-month-old rats were deprived of oxygen and glucose for 5–30 min in media bubbled with 1% isoflurane. Cell death was assessed in the CA1, CA3, and dentate regions, and intracellular Ca2+ concentration was measured in CA1 neurons. N-methyl-d-aspartate receptor (NMDAR)–dependent Ca2+ influx was measured and the phosphorylation of NMDARs, and the survival proteins Akt and mitogen-activated protein kinase p42/44 were quantified. Results:Twenty minutes of oxygen and glucose deprivation killed approximately 40–60% of neurons in CA3 and dentate in all age groups. Isoflurane, 1%, reduced death of CA1, CA3, and dentate neurons in slices from 5-day-old rats but not those from 23-month-old rats. In 5-day slices, isoflurane attenuated NMDAR-mediated Ca2+ influx, whereas in aging slices, Ca2+ influx was increased protein kinase C. In aging slices, isoflurane did not increase the phosphorylation of Akt and p42/44. Conclusions:Isoflurane neuroprotection of hippocampal slices during oxygen and glucose deprivation decreases with age. Isoflurane does not prevent large increases in intracellular Ca2+ concentration during oxygen and glucose deprivation and does not induce the phosphorylation of the prosurvival proteins in aging slices. A protein kinase C–mediated increase in NMDAR activity may result in increased excitotoxicity and decreased neuroprotection by volatile anesthetics in the aging brain.
Age-Stratified Seroprevalence of Neutralizing Antibodies to Astrovirus Types 1 to 7 in Humans in The Netherlands

ABSTRACT Astroviruses are a new family of positive-stranded RNA viruses that cause gastroenteritis in a wide range of animals and in humans. Seven types of astrovirus, tentatively considered serotypes, have been distinguished by enzyme-linked immunosorbent assays (ELISA) or immunoelectron microscopy, but it is unclear whether the serotype designation is used properly. To test human sera for the presence of neutralizing antibodies and to type field strains, neutralization tests (NT) using CaCo2 tissue-culture-adapted astrovirus strains 1 to 7 and the corresponding rabbit reference sera were developed. In rabbits, neutralizing antibodies were predominantly serotype specific, with the exception of low-level cross-reactivity in astrovirus serotype 4 reference serum with astrovirus serotype 1 virus. Similarly, in humans, no evidence of cross-reactivity was found for the serotype combinations tested (all except the combination 1 and 7 and the combination 6 and 7). Typing by NT was concordant with typing by ELISA and genotyping, with one exception. The seroprevalence rates of neutralizing antibodies in an age-stratified sample of the population in Utrecht Province (n = 242) were 91% for astrovirus serotype 1, 69% for astrovirus serotype 3, 56% for astrovirus serotype 4, 36% for astrovirus serotype 5, 31% for astrovirus serotype 2, 16% for astrovirus serotype 6, and 10% for astrovirus serotype 7. Acquisition of antibodies was slower among persons seropositive for astrovirus serotype 5 than among those seropositive for astrovirus serotypes 1 to 4, suggesting that the epidemiology of serotype 5 astrovirus is different from that of astrovirus serotypes 1 to 4.
Dynamic phasor estimates through maximally flat differentiators

Estimates of the dynamic phasor and its derivatives are obtained using the weighted least-squares solution of a Taylor approximation with classical windows as weighting factors. It is demonstrated that the least-squares solution simultaneously approximates the time function and its spectrum, and this twofold solution in turn is equivalent to the simultaneous approximation of the ideal frequency responses of the differentiators at once on the bandpass centered at the desired central frequency. Therefore the differentiators are maximally flat in the interval centered at the desired frequency. The filters designed with the rectangular and Hamming windows are shown as examples of baseband differentiators.