587 research outputs found
Nonenzymatic Glycosylation of Lepidopteran-Active \u3ci\u3eBacillus thuringiensis\u3c/i\u3e Protein Crystals
We used high-pH anion-exchange chromatography with pulsed amperometric detection to quantify the monosaccharides covalently attached to Bacillus thuringiensis HD-1 (Dipel) crystals. The crystals contained 0.54% sugars, including, in decreasing order of prevalence, glucose, fucose, arabinose/rhamnose, galactose, galactosamine, glucosamine, xylose, and mannose. Three lines of evidence indicated that these sugars arose from nonenzymatic glycosylation: (i) the sugars could not be removed by N- or O-glycanases; (ii) the sugars attached were influenced both by the medium in which the bacteria had been grown and by the time at which the crystals were harvested; and (iii) the chemical identity and stoichiometry of the sugars detected did not fit any known glycoprotein models. Thus, the sugars detected were the product of fermentation conditions rather than bacterial genetics. The implications of these findings are discussed in terms of crystal chemistry, fermentation technology, and the efficacy of B. thuringiensis as a microbial insecticide
Response Assessment of NovoTTF-100A Versus Best Physician\u27s Choice Chemotherapy in Recurrent Glioblastoma
The NovoTTF-100A device emits frequency-tuned alternating electric fields that interfere with tumor cell mitosis. In phase III trial for recurrent glioblastomas, NovoTTF-100A was shown to have equivalent efficacy and less toxicity when compared to Best Physician\u27s Choice (BPC) chemotherapy. We analyzed the characteristics of responders and nonresponders in both cohorts to determine the characteristics of response and potential predictive factors. Tumor response and progression were determined by Macdonald criteria. Time to response, response duration, progression-free survival (PFS) ± Simon-Makuch correction, overall survival (OS), prognostic factors, and relative hazard rates were compared between responders and nonresponders. Median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy, respectively (P = 0.0009). Five of 14 NovoTTF-100A responders but none of seven BPC responders had prior low-grade histology. Mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for nonresponders in the NovoTTF-100A cohort (P \u3c 0.0001). Hazard analysis showed delayed tumor progression in responders compared to nonresponders. Simon-Makuch-adjusted PFS was longer in responders than in nonresponders treated with NovoTTF-100A (P = 0.0007) or BPC chemotherapy (P = 0.0222). Median OS was longer for responders than nonresponders treated with NovoTTF-100A (P \u3c 0.0001) and BPC chemotherapy (P = 0.0235). Pearson analysis showed strong correlation between response and OS in NovoTTF-100A (P = 0.0002) but not in BPC cohort (P = 0.2900). Our results indicate that the response characteristics favor NovoTTF-100A and data on prior low-grade histology and dexamethasone suggest potential genetic and epigenetic determinants of NovoTTF-100A response
Combinations of Griffithsin with Other Carbohydrate-Binding Agents Demonstrate Superior Activity Against HIV Type 1, HIV Type 2, and Selected Carbohydrate-Binding Agent-Resistant HIV Type 1 Strains
Abstract Carbohydrate-binding agents (CBAs) are potential HIV microbicidal agents with a high genetic barrier to resistance. We wanted to evaluate whether two mannose-specific CBAs, recognizing multiple and often distinct glycan structures on the HIV envelope gp120, can interact synergistically against HIV-1, HIV-2, and HIV-1 strains that were selected for resistance against particular CBAs [i.e., 2G12 mAb and microvirin (MVN)]. Paired CBA/CBA combinations mainly showed synergistic activity against both wild-type HIV-1 and HIV-2 but also 2G12 mAb- and MVN-resistant HIV-1 strains as based on the median effect principle with combination indices (CIs) ranging between 0.29 and 0.97. Upon combination, an increase in antiviral potency of griffithsin (GRFT) up to ?12-fold (against HIV-1), ?8-fold (against HIV-2), and ?6-fold (against CBA-resistant HIV-1) was observed. In contrast, HHA/GNA combinations showed additive activity against wild-type HIV-1 and HIV-2 strains, but remarkable synergy with HHA and GNA was observed against 2G12 mAb- and MVN-resistant HIV-1 strains (CI, 0.64 and 0.49, respectively). Overall, combinations of GRFT and other CBAs showed synergistic activity against HIV-1, HIV-2, and even against certain CBA-resistant HIV-1 strains. The CBAs tested appear to have distinct binding patterns on the gp120 envelope and therefore do not necessarily compete with each other's glycan binding sites on gp120. As a result, there might be no steric hindrance between two different CBAs in their competition for glycan binding (except for the HHA/GNA combination). These data are encouraging for the use of paired CBA combinations in topical microbicide applications (e.g., creams, gels, or intravaginal rings) to prevent HIV transmission.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98459/1/aid%2E2012%2E0026.pd
Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis
Malaria is caused by eukaryotic Plasmodium spp. parasites that classically infect red blood cells. These are difficult organisms to investigate genetically because of their AT-rich genomes. Zhang et al. have exploited this peculiarity by using piggyBac transposon insertion sites to achieve saturation-level mutagenesis for identifying and ranking essential genes and drug targets (see the Perspective by White and Rathod). Genes that are current candidates for drug targets were identified as essential, in contrast to many vaccine target genes. Notably, the proteasome degradation pathway was confirmed as a target for developing therapeutic interventions because of the several essential genes involved and the link to the mechanism of action of the current frontline drug, artemisinin
Is type II diabetes mellitus (NIDDM) a surgical disease?
Since February 1, 1980, 515 morbidly obese patients have undergone
the Greenville gastric bypass (GGB) operation. Of these,
212 (41.2%) were euglycemic, 288 (55.9%) were either diabetic
or had glucose intolerance, and 15 (2.9%) were unable to complete
the evaluation. After the operation, only 30 (5.8%) patients remained
diabetic (and 20 of these improved), 457 (88.7%) became
and have remained euglycemic, and inadequate data prevented
classification of the other 28 (5.4%). The patients who failed to
return to normal glucose values were older and their diabetes
was of longer duration than those who did. The effect of the
GGB was not only limited to the correction of abnormal glucose
levels. The GGB also corrected the abnormal levels of fasting
insulin and glycosylated hemoglobin in a cohort of 52 consecutive
severely obese patients with non-insulin-dependent diabetes. The
GGB effectively controls weight. If morbid obesity is defined as
100 pounds over ideal body weight, 89% of the patients are no
longer "morbidly" obese within 2 years. In most patients, the
control of the weight has been well maintained during the 11
years of follow-up; most of the upward creep in weight of 20.8%
between 24 and 132 months was from the 49 (9.5%) patients
who had staple line breakdowns between the large and small
gastric pouches. Non-insulin-dependent diabetes, previously
considered a chronic unrelenting disease, can be controlled in
the severely obese by the gastric bypass. Whether the correction
of glucose metabolism affects the complications of diabetes is
unknown. Whether the gastric bypass should be considered for
patients with advanced non-insulin-dependent diabetes but who
are not severely obese deserves consideration. The GGB has an
unacceptably high rate of staple line failure. Accordingly, the
authors have recently changed their procedure to one that divides
the stomach rather than partitions it with staples. Originally published Annals of Surgery, Vol. 215, No. 6, June 199
Case report 427
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46783/1/256_2004_Article_BF00361481.pd
Gender Differences in Russian Colour Naming
In the present study we explored Russian colour naming in a web-based psycholinguistic experiment
(http://www.colournaming.com). Colour singletons representing the Munsell Color Solid (N=600 in total) were presented on a computer monitor and named using an unconstrained colour-naming method. Respondents were
Russian speakers (N=713). For gender-split equal-size samples (NF=333, NM=333) we estimated and compared (i)
location of centroids of 12 Russian basic colour terms (BCTs); (ii) the number of words in colour descriptors; (iii) occurrences of BCTs most frequent non-BCTs. We found a close correspondence between females’ and males’
BCT centroids. Among individual BCTs, the highest inter-gender agreement was for seryj ‘grey’ and goluboj
‘light blue’, while the lowest was for sinij ‘dark blue’ and krasnyj ‘red’. Females revealed a significantly richer repertory of distinct colour descriptors, with great variety of monolexemic non-BCTs and “fancy” colour names; in comparison, males offered relatively more BCTs or their compounds. Along with these measures, we gauged
denotata of most frequent CTs, reflected by linguistic segmentation of colour space, by employing a synthetic
observer trained by gender-specific responses. This psycholinguistic representation revealed females’ more
refined linguistic segmentation, compared to males, with higher linguistic density predominantly along the redgreen axis of colour space
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images
of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL
maps are derived through computational staining using a convolutional neural network trained to
classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and
correlation with overall survival. TIL map structural patterns were grouped using standard
histopathological parameters. These patterns are enriched in particular T cell subpopulations
derived from molecular measures. TIL densities and spatial structure were differentially enriched
among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial
infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic
patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for
the TCGA image archives with insights into the tumor-immune microenvironment
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