Miracle-dz/UniFAR-FTUs huggingface dataset:
Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins.

We hypothesized that common genomic variation that affected the expression and/or function of the products of the APOC3, APOE, FABP2, and PON1 genes would be associated with variation in biochemical phenotypes in a previously unstudied human sample. We determined genotypes of functional genomic variants of APOC3, APOE, FABP2, and PON1 in 509 adult aboriginal Canadians from an isolated community in Northern Ontario. We tested for genotype associations with plasma lipoprotein traits. We found that (1) common variation at nucleotide -455 of the APOC3 promoter was associated with variation in plasma triglycerides (P = .006) and (2) common variation of APOE determining plasma isoforms of apo E was associated with variation in plasma apo B (P = .009). Analysis of subjects classed by APOC3 markers showed that homozygosity for presence of a C at nucleotide -455 and a T at nucleotide -482 was associated with significantly increased plasma triglycerides in both men and women. Furthermore, this allele was approximately twice as frequent in subjects within the highest quartile of plasma triglycerides as in subjects within the lowest quartile. Since the DNA variation detected by the APOC3 markers affects in vitro expression of the gene product, it is possible that the marker itself caused the associations. However, the associations could also have resulted from linkage disequilibrium with other functional variants in APOC3 or the closely linked APOA1 and/or APOA4 genes.
The Major Neutralizing Antigenic Site on Herpes Simplex Virus Glycoprotein D Overlaps a Receptor-Binding Domain

ABSTRACT Herpes simplex virus (HSV) entry is dependent on the interaction of virion glycoprotein D (gD) with one of several cellular receptors. We previously showed that gD binds specifically to two structurally dissimilar receptors, HveA and HveC. We have continued our studies by using (i) a panel of baculovirus-produced gD molecules with various C-terminal truncations and (ii) a series of gD mutants with nonoverlapping 3-amino-acid deletions between residues 222 and 254. Binding of the potent neutralizing monoclonal antibody (MAb) DL11 (group Ib) was unaffected in forms of gD containing residues 1 to 250 but was greatly diminished in molecules truncated at residue 240 or 234. Both receptor binding and blocking of HSV infection were also affected by these C-terminal truncations. gD-1(234t) bound weakly to both HveA and HveC as determined by enzyme-linked immunosorbent assay (ELISA) and failed to block infection. Interestingly, gD-1(240t) bound well to both receptors but blocked infection poorly, indicating that receptor binding as measured by ELISA is not the only gD function required for blocking. Optical biosensor studies showed that while gD-1(240t) bound HveC with an affinity similar to that of gD-1(306t), the rates of complex formation and dissociation were significantly faster than for gD-1(306t). Complementation analysis showed that any 3-amino-acid deletion between residues 222 and 251 of gD resulted in a nonfunctional protein. Among this set of proteins, three had lost DL11 reactivity (those with deletions between residues 222 and 230). One of these proteins (deletion 222–224) was expressed as a soluble form in the baculovirus system. This protein did not react with DL11, bound to both HveA and HveC poorly as shown by ELISA, and failed to block HSV infection. Since this protein was bound by several other MAbs that recognize discontinuous epitopes, we conclude that residues 222 to 224 are critical for gD function. We propose that the potent virus-neutralizing activity of DL11 (and other group Ib MAbs) likely reflects an overlap between its epitope and a receptor-binding domain of gD.
Combined Deletion of Mouse Dematin-Headpiece and β-Adducin Exerts a Novel Effect on the Spectrin-Actin Junctions Leading to Erythrocyte Fragility and Hemolytic Anemia*

Dematin and adducin are actin-binding proteins of the erythrocyte “junctional complex. ” Individually, they exert modest effects on erythrocyte shape and membrane stability, and their homologues are expressed widely in non-erythroid cells. Here we report generation and characterization of double knock-out mice lacking β-adducin and the headpiece domain of dematin. The combined mutations result in altered erythrocyte morphology, increased membrane instability, and severe hemolysis. Peripheral blood analysis shows evidence of severe hemolytic anemia with reduced number of erythrocytes/hematocrit/hemoglobin and an ∼12-fold increase in the number of circulating reticulocytes. The presence of a variety of misshapen and fragmented erythrocytes correlates with increased osmotic fragility and reduced in vivo life span. Despite the apparently normal protein composition of the mutant erythrocyte membrane, the retention of the spectrin-actin complex in the membrane under low ionic strength conditions is significantly reduced by the double mutation. Atomic force microscopy reveals an increase in grain size and a decrease in filament number of the mutant membrane cytoskeleton, although the volume parameter is similar to wild type erythrocytes. Aggregated, disassembled, and irregular features are visualized in the mutant membrane, consistent with the presence of large protein aggregates. Importantly, purified dematin binds to the stripped inside-out vesicles in a saturable manner, and dematin-membrane binding is abolished upon pretreatment of membrane vesicles with trypsin. Together, these results reveal an essential role of dematin and adducin in the maintenance of erythrocyte shape and membrane stability, and they suggest that the dematin-membrane interaction could link the junctional complex to the plasma membrane in erythroid cells.
Interferon-γ-induced Regulation of Peroxisome Proliferator-activated Receptor γ and STATs in Adipocytes*

Interferon-γ (IFN-γ) is known primarily for its roles in immunological responses but also has been shown to affect fat metabolism and adipocyte gene expression. To further investigate the effects of IFN-γ on fat cells, we examined the effects of this cytokine on the expression of adipocyte transcription factors in 3T3-L1 adipocytes. Although IFN-γ regulated the expression of several adipocyte transcription factors, IFN-γ treatment resulted in a rapid reduction of both peroxisome proliferator-activated receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-γ also resulted in a decrease of both CCAAT/enhancer-binding α and sterol regulatory element binding protein (SREBP-1) expression. The short half-life of both the PPARγ mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPARγ in the presence of IFN-γ. Our studies clearly demonstrated that the IFN-γ-induced loss of PPARγ protein is partially inhibited in the presence of two distinct proteasome inhibitors. Moreover, IFN-γ also inhibited the transcription of PPARγ, which was accompanied by a decrease in PPARγ mRNA accumulation. In addition, exposure to IFN-γ resulted in a substantial increase in STAT 1 expression and a small increase in STAT 3 expression. IFN-γ treatment of 3T3-L1 adipocytes (48–96 h) resulted in a substantial inhibition of insulin-sensitive glucose uptake. These data clearly demonstrate that IFN-γ treatment results in the development of insulin resistance, which is accompanied by the regulation of various adipocyte transcription factors, in particular the synthesis and degradation of PPARγ.
Hypoxaemia in hospitalised under-five Nigerian children with pneumonia.

BACKGROUND Hypoxaemia constitutes a possible complication of severe respiratory illness which is often under-reported in developing countries. Therefore, the current study was carried out to determine the prevalence and clinical predictors of hypoxaemia in hospitalized under-five children with pneumonia in Ilorin, Nigeria. METHODS This is a descriptive cross-sectional study of 200 children aged between two months and five years with pneumonia recruited consecutively. Socio-demographic, clinical and laboratory data were obtained. The pulse oximetry measurement was recorded after a stable reading for at least one minute while the child was breathing room air. Hypoxaemia was defined as an arterial oxygen saturation of less than 90%. Data was analyzed using the SPSS 20.0 software. RESULTS The male/female ratio was 1.5:1.The prevalence of hypoxaemia in the children with pneumonia was 41.5%. Using a linear regression analysis, the clinical features that were significantly associated with hypoxaemia were restlessness, lower chest wall indrawing, bronchial breath sounds and tender hepatomegaly (p<0.05 each). Restlessness had a sensitivity of 22.9%, specificity of 91.5%, while chest wall indrawing had a sensitivity of 86.7% and specificity of 53.3%. Bronchial breath sound had a sensitivity of 16.9%, a specificity of 95.7% whereas tender hepatomegaly had a sensitivity of 48.2% and specificity of 82.9%. CONCLUSION There is a high local burden of pneumonia-associated hypoxaemia. Restlessness, chest wall indrawing, bronchial breath sounds and tender hepatomegaly could be useful in detecting pneumonia-related hypoxemia in poorly equipped health facilities.
Preassembled capsids of type D retroviruses contain a signal sufficient for targeting specifically to the plasma membrane

The capsids of Mason-Pfizer monkey virus (M-PMV), an immunosuppressive type D retrovirus, are preassembled in the infected cell cytoplasm and are then transported to the plasma membrane, where they are enveloped in a virus glycoprotein-containing lipid bilayer. The role of viral glycoprotein in intracellular transport of M-PMV capsids was investigated with a spontaneous mutant (5A) of M-PMV, which we show here to be defective in envelope glycoprotein biosynthesis. DNA sequence analysis of the env gene of mutant 5A reveals a single nucleotide deletion in the middle of the gene, which results in the synthesis of a truncated form of the envelope glycoprotein. Evidence is presented showing that the mutant glycoprotein is not expressed at the cell surface but is retained in the endoplasmic reticulum. Normal levels of gag-pro-pol precursor polyproteins are made and processed in mutant genome-transfected cells, and high levels of noninfectious particles lacking viral glycoprotein are released with normal kinetics into the culture medium. No intracisternal budding of capsids is observed. We conclude that viral glycoprotein is required neither for targeting preassembled capsids of M-PMV to the plasma membrane for final maturation nor for the budding process. Since the presence or absence of M-PMV glycoprotein at the site of budding does not affect the efficiency or kinetics of the targeting process, the preassembled capsid of M-PMV, in contrast to those of intracisternal type A particles, appears to have an intrinsic signal for intracellular transport to the plasma membrane.
Characteristics of triangular fibrocartilage defects in symptomatic and contralateral asymptomatic wrists.

PURPOSE To characterize triangular fibrocartilage (TFC) defects in symptomatic and contralateral asymptomatic wrists. MATERIALS AND METHODS Communicating and noncommunicating defects of the TFC were depicted on bilateral wrist arthrograms in 56 patients with unilateral wrist pain and without associated lesions of the scapholunate or lunotriquetral ligaments. The exact location of each TFC lesion was noted. RESULTS Communicating defects were noted in 36 (64%) of 56 symptomatic and in 26 (46%) of 56 asymptomatic wrists. Twenty-five (69%) of 36 communicating defects were bilateral. Except for one defect in each group of symptomatic and asymptomatic wrists, all communicating defects were noted radially. Noncommunicating defects were noted in 28 (50%) of 56 symptomatic wrists and in 15 (27%) of 56 asymptomatic wrists. Eleven (39%) of 28 noncommunicating defects were bilateral. On the symptomatic side, 28 of 36 noncommunicating defects (including eight multiple defects) were located proximally at the ulnar side. On the asymptomatic side, 11 of 17 noncommunicating defects (including two multiple defects) were at or near the ulna. CONCLUSION Noncommunicating TFC defects, which typically are located on the proximal side of the TFC near its ulnar attachment, have a more reliable association with symptomatic wrists than do communicating defects. Radial-sided communicating defects described in the literature (Palmer type 1A and 1D) as posttraumatic commonly are seen bilaterally and in asymptomatic wrists.
On the bioavailability of oral and subcutaneous 2-chloro-2'-deoxyadenosine in humans: alternative routes of administration.

PURPOSE The antimetabolite 2-chloro-2'-deoxyadenosine (CdA) is a promising alternative to alkylating agents for the treatment of lymphoproliferative disorders. Its use, however, is hampered by the need for intravenous (IV) administration. The aim of the present study was to determine the bioavailability of subcutaneously (SC) and orally administered CdA, and to establish an oral dose of CdA that could supersede IV administration. PATIENTS AND METHODS A previously developed high-performance liquid chromatography method was used for the determination of plasma CdA concentrations in 13 patients. Ten patients were treated on alternate days with 0.14 mg/kg/d CdA as a 2-hour IV infusion or by a SC injection. Three of these patients were also given 0.14 mg/kg CdA orally in enteric-coated capsules. Ten patients were administered CdA orally that was dissolved in phosphate-buffered saline (PBS) after treatment with 20 mg omeprazole 1 and 6 hours before the administration of CdA. RESULTS The bioavailability of SC CdA was 102% +/- 28% (mean +/- SD), and the bioavailability of CdA administered in enteric-coated capsules was 19%, 24%, and 60%. In the three patients who were given 0.14 mg/kg orally dissolved in PBS, the bioavailability was 48% +/- 8%, whereas in the seven patients who received 0.28 mg/kg, the bioavailability was 55% +/- 17%. In the 10 patients who were treated with the CdA solution orally, the coefficients of variation of the areas under the curve (AUCs) after oral and IV administration were similar. Thus, oral administration did not add to the interindividual variability. CONCLUSIONS We conclude that orally administered CdA can supersede IV infusion if the dose is doubled. SC administration gives a high peak concentration of short duration with an AUC identical to that of IV infusion. Thus, SC injection can also be used as an alternative to IV infusion.
Co‐existing basal cell carcinoma and blue nevus in an African‐American woman

A 67‐year‐old African‐American woman presented with an enlarging darkly pigmented plaque on her scalp. Histopathologic examination revealed a basal cell carcinoma juxtaposed to a blue nevus. Interestingly, the most common types of cutaneous collision tumors include melanocytic nevus and basal cell carcinoma. Whether these combinations are simply because of chance or may have a pathophysiologic mechanism is contentious. This is the first documented case of a basal cell carcinoma co‐existing alone with a blue nevus.
The facial skeleton in children affected by rheumatoid arthritis--a roentgen-cephalometric study.

This study is a characterization of the facial frame in profile of children with rheumatoid arthritis. Cephalometric roentgenograms were taken of 18 girls (mean age 15 years 4 months) and 10 boys (mean age 15 years 3 months), who had had destructive changes in the regions of both mandibular condyles for at least 5 years. Similar roentgenograms of presumably healthy children, 20 girls and 20 boys (mean age 15 years 5 months) were available as controls. A number of distances and angles were measured from tracings on acetate films. The facial height of the affected children was on average smaller than that of the controls, the difference being significant posteriorly in both sexes and showing a similar tendency anteriorly in the boys. The maxilla was also smaller vertically in the children with rheumatoid arthritis. The mandible was short and the reduced descent of its posterior part seemed to be only partly compensated for by the exostosis in the gonion region. The lack of any anterior open bite appeared to be related to over-eruption of the lower incisors and a posteriorly elevated occlusal plane associated with subnormally erupted maxillary molars. While the inter-incisal angle and the angle between the mandibular incisors and the nasion-sella line were small, the inclination of the mandibular incisors to the mandibular body seemed virtually normal. The elevation of the mandible at its posterior part evidently results from muscle traction diminishing the gap between the adjoining bones following condylar destruction. The reduced vertical dimension of the maxilla may be an expression of a secondary reaction to the subnormal growth of the mandible.
The cell differentiation protein SpoIIE contains a regulatory site that controls its phosphatase activity in response to asymmetric septation

Summary Starvation induces Bacillus subtilis to initiate a simple, two‐cell developmental process that begins with an asymmetric cell division. Activation of the first compartment‐specific transcription factor, σF, is coupled to this morphological event. SpoIIE, a bifunctional protein, is essential for the compartment‐specific activation of σF and also has a morphogenic activity required for asymmetric cell division. SpoIIE consists of three domains: a hydrophobic N‐terminal domain, which targets the protein to the membrane; a central domain, involved in oligomerization of SpoIIE and interaction with the cell division protein FtsZ; and a C‐terminal domain comprising a PP2C protein phosphatase. Here, we report the isolation of mutations at the very beginning of the central domain of spoIIE, which are capable of activating σF independently of septum formation. Purified mutant proteins showed the same phosphatase activity as the wild‐type protein in vitro. The mutant proteins were fully functional in respect of their localization to sites of asymmetric septation and support of asymmetric division. The data provide strong evidence that the phosphatase domain of SpoIIE is tightly regulated in a way that makes it respond to the formation of the asymmetric septum.
Effect of age on individual retinal layer thickness in normal eyes as measured with spectral-domain optical coherence tomography.

PURPOSE To determine the effect of age on the thickness of individual retinal layers, measured with spectral-domain optical coherence tomography (SD-OCT), in a population of healthy Caucasians. METHODS One hundred and twenty subjects with an age ranging between 18 and 81 years were examined with SD-OCT. Mean layer thickness was calculated for seven retinal layers, in the fovea (region 1 of the 9 Early Treatment Diabetic Retinopathy Study [ETDRS] regions); in the pericentral ring (ETDRS regions 2 to 5); and the peripheral ring (ETDRS regions 6 to 9) following automated segmentation using the Iowa Reference Algorithm. In addition, mean peripapillary retinal nerve fiber layer (RNFL) thickness was measured. The partial correlation test was performed on each layer to determine the effect of age on layer thickness, while correcting for spherical equivalent, sex, and Topcon image quality factor as confounders, followed by Bonferroni corrections to adjust for multiple testing. RESULTS The thickness of the peripapillary RNFL (R = -0.332; P < 0.001); pericentral ganglion cell layer (R = -0.354, P < 0.001); peripheral inner plexiform layer (R = -0.328, P < 0.001); and foveal outer segment layer (R = -0.381, P < 0.001) decreased significantly with increasing age. Foveal RPE thickness (R = 0.467, P < 0.001) increased significantly with increasing age; other layers showed no significant differences with age. CONCLUSIONS Several macular layers and the peripapillary RNFL thickness showed significant changes correlated with age. This should be taken into consideration when analyzing macular layers and the peripapillary RNFL in SD-OCT studies of retinal diseases and glaucoma.
Critical role of aquaporin 3 on growth of human esophageal and oral squamous cell carcinoma

Aquaporins (AQP) play important roles in water and glycerol transport. We examined whether AQP3 is expressed in primary squamous cell carcinoma (SCC) such as esophageal and oral cancer and lymph node metastasis, and whether AQP3 is a potential target for tumor therapy. A high level expression of AQP3 was observed in tumor areas of human primary SCC such as esophageal and lingual cancers, and lymph node metastasis, but was not observed in normal areas. Treatment with pan‐AQP inhibitor caused apoptotic cell death on the SCC cell lines in a concentration‐dependent manner. Small interfering RNA (siRNA) specific for AQP3 also inhibited cell adhesion and growth of SCC, but not those of adenocarcinoma cell lines and fibroblasts. Expression of integrin α5 and β1, counter adhesion molecules for fibronectin, was inhibited by treatment with AQP3‐siRNA. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with AQP3‐siRNA, which then caused decreases in phosphorylation of Erk and MAPK. These results indicate that the decreases in integrins and the inhibition of cell adhesion might cause inhibition of the FAK signaling pathways. Combination of AQP3‐siRNA with cisplatin, a major anti‐cancer drug, strongly inhibited the growth of SCC. Cell death caused by the inhibition of AQP3 was a result of direct interference with cell adhesion involving intracellular FAK‐MAPK signaling pathways. These results imply a potentially important and novel role for the inhibition of AQP3 function via the use of specific siRNA in the treatment of SCC. (Cancer Sci 2011; 102: 1128–1136)
Clonal analysis of adult human olfactory neurosphere forming cells

Olfactory neuroepithelium (ONe) is unique because it contains progenitor cells capable of mitotic division that replace damaged or lost neurons throughout life. We isolated populations of ONe progenitors from adult cadavers and patients undergoing nasal sinus surgery that were heterogeneous and consisted of neuronal and glial progenitors. Progenitor lines have been obtained from these cultures that continue to divide and form nestin positive neurospheres. In the present study, we used clonal and population analyses to probe the self-renewal and multipotency of the neurosphere forming cells (NSFCs). NSFCs plated at the single cell level produced additional neurospheres; dissociation of these spheres resulted in mitotically active cells that continued to divide and produce spheres as long as they were subcultured. The mitotic activity of clonal NSFCs was assessed using bromodeoxyuridine (BrdU) incorporation. Lineage restriction of the clonal cultures was determined using a variety of antibodies that were characteristic of different levels of neuronal commitment: β-tubulin isotype III, neural cell adhesion molecule (NCAM) and microtubule associated protein (MAP2), or glial restriction: astrocytes, glial fibrillary acidic protein (GFAP); and oligodendrocytes, galactocerebroside (GalC). Furthermore, nestin expression, a marker indicative of progenitor nature, decreased in defined medium compared to serum-containing medium. Therefore, adult human ONe-derived neural progenitors retain their capacity for self-renewal, can be clonally expanded, and offer multipotent lineage restriction. Therefore, they are a unique source of progenitors for future cell replacement strategies in the treatment of neurotrauma and neurodegenerative diseases.