Small Molecules <i>N</i>‑Phenylbenzofuran-2-carboxamide and <i>N</i>‑Phenylbenzo[<i>b</i>]thiophene-2-carboxamide Promote Beta-Amyloid (Aβ42) Aggregation and Mitigate Neurotoxicity

This study reports the unusual ability of small molecules N-phenylbenzofuran-2-carboxamide (7a) and N-phenylbenzo[b]thiophene-2-carboxamide (7b) to promote and accelerate Aβ42 aggregation. In the in vitro aggregation kinetic assays, 7a was able to demonstrate rapid increases in Aβ42 fibrillogenesis ranging from 1.5- to 4.7-fold when tested at 1, 5, 10, and 25 μM compared to Aβ42-alone control. Similarly, compound 7b also exhibited 2.9- to 4.3-fold increases in Aβ42 fibrillogenesis at the concentration range tested. Electron microscopy studies at 1, 5, 10, and 25 μM also demonstrate the ability of compounds 7a and 7b to promote and accelerate Aβ42 aggregation with the formation of long, elongated fibril structures. Both 7a and 7b were not toxic to HT22 hippocampal neuronal cells and strikingly were able to prevent Aβ42-induced cytotoxicity in HT22 hippocampal neuronal cells (cell viability ∼74%) compared to the Aβ42-treated group (cell viability ∼20%). Fluorescence imaging studies using BioTracker 490 green, Hoeschst 33342, and the amyloid binding dye ProteoStat further demonstrate the ability of 7a and 7b to promote Aβ42 fibrillogenesis and prevent Aβ42-induced cytotoxicity to HT22 hippocampal neuronal cells. Computational modeling studies suggest that both 7a and 7b can interact with the Aβ42 oligomer and pentamers and have the potential to modulate the self-assembly pathways. The 8-anilino-1-naphthalenesulfonic acid (ANS) dye binding assay also demonstrates the ability of 7a and 7b to expose the hydrophobic surface of Aβ42 to the solvent surface that promotes self-assembly and rapid fibrillogenesis. These studies demonstrate the unique ability of small molecules 7a and 7b to alter the self-assembly and misfolding pathways of Aβ42 by promoting the formation of nontoxic aggregates. These findings have direct implications in the discovery and development of novel small-molecule-based chemical and pharmacological tools to study the Aβ42 aggregation mechanisms, and in the design of novel antiamyloid therapies to treat Alzheimer’s disease

Formaldehyde Exposure Racial Disparities in Southeast Texas

Formaldehyde (HCHO) exposures during a full year were calculated for different race/ethnicity groups living in Southeast Texas using a chemical transport model tagged to track nine emission categories. Petroleum and industrial emissions were the largest anthropogenic sources of HCHO exposure in Southeast Texas, accounting for 44% of the total HCHO population exposure. Approximately 50% of the HCHO exposures associated with petroleum and industrial sources were directly emitted (primary), while the other 50% formed in the atmosphere (secondary) from precursor emissions of reactive compounds such as ethylene and propylene. Biogenic emissions also formed secondary HCHO that accounted for 11% of the total population-weighted exposure across the study domain. Off-road equipment contributed 3.7% to total population-weighted exposure in Houston, while natural gas combustion contributed 5% in Beaumont. Mobile sources accounted for 3.7% of the total HCHO population exposure, with less than 10% secondary contribution. Exposure disparity patterns changed with the location. Hispanic and Latino residents were exposed to HCHO concentrations +1.75% above average in Houston due to petroleum and industrial sources and natural gas sources. Black and African American residents in Beaumont were exposed to HCHO concentrations +7% above average due to petroleum and industrial sources, off-road equipment, and food cooking. Asian residents in Beaumont were exposed to HCHO concentrations that were +2.5% above average due to HCHO associated with petroleum and industrial sources, off-road vehicles, and food cooking. White residents were exposed to below average HCHO concentrations in all domains because their homes were located further from primary HCHO emission sources. Given the unique features of the exposure disparities in each region, tailored solutions should be developed by local stakeholders. Potential options to consider in the development of those solutions include modifying processes to reduce emissions, installing control equipment to capture emissions, or increasing the distance between industrial sources and residential neighborhoods

Low CBS expression can identify patients who benefit from adjuvant chemotherapy in gastric cancer

Aim: To explore the clinical significance of Cystathionine beta-synthase (CBS) expression in gastric cancer (GC). Research design and methods: CBS expression and clinicopathological/follow-up information of patients with gastric cancer undergoing operation were collected from The Cancer Genome Atlas (TCGA) database. The association of CBS expression with patients’ overall survival (OS) was determined in the entire cohort and different subgroups. Validation was performed in two external cohorts from NCBI Gene Expression Omnibus (GEO) database. The estimated drug response of the tumors with different CBS expressions was characterized. The potential CBS-related cellular pathways in chemoresistance were explored. Results: High CBS was associated with poor OS in patients receiving adjuvant chemotherapy (ACT) but not those without ACT. And ACT was associated with favorable OS in patients with low CBS expression but not those with high CBS expression. The results were verified in two external cohorts. Drug response prediction suggested that patients with low CBS expression showed high sensitivity to 5-Fluorouracil. Gene Set Enrichment Analysis (GSEA) suggested that CBS might contribute to GC chemoresistance via modulating many cellular pathways, including down-regulating apoptosis and P53 pathways while up-regulating DNA repair pathway. Conclusion: Low CBS expression can predict the benefit from ACT in GC.</p

Univariate Predictors of 30 Days and 1 Year Mortality by Cox Regression Analysis.

<p>Age1, cohort age< 65 and age 65–74; Age2, cohort age < 65 and age > = 75; HR, Hazard ratio; CI, confidence interval; other abbreviations seen in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058382#pone-0058382-t001" target="_blank">table 1</a>.</p

Mortality at 30 Days and 1 Year of Different Therapy.

<p>Mortality at 30 Days and 1 Year of Different Therapy.</p

Mortality at 30 Days and 1 Year of Different Therapy in 3 Age Groups.

<p>Mortality at 30 Days and 1 Year of Different Therapy in 3 Age Groups.</p

Predicted cumulative hazard function of 1 year mortality for different age groups of patients.

<p>The curves were constructed according to the age groups with the use of Cox regression analysis.</p

Predicted cumulative hazard function of 1 year mortality for different therapies.

<p>The curves were constructed according to the PCI or conservative therapy with the use of Cox regression analysis.</p

Synthesis, Phase Evolutions, and Stabilities of Boron-Rich Tungsten Borides at High Pressure

Boron-rich tungsten borides such as WB2+x and WB3+x have been highly expected to be superhard with many advantages over conventional superhard materials. However, because the formation of boron-rich tungsten borides is thermodynamically unfavorable at ambient pressure, their crystal structures, compositions, and properties are largely unexplored, which have impeded the rational design of functional materials in the W–B family. In this work, using unique high-pressure reactions, we report a systematic synthesis study of challenging compounds of tungsten borides including WB, WB2+x, and WB3+x. The use of pressure, combined with the controllable temperature, heating duration, and ratios of starting reactants, leads to different compositions and structures of final products with largely tunable crystallite size from nanocrystalline to single-crystal forms. In addition, the optimal conditions for the formation of WB3+x are well investigated by tuning the temperature and starting ratio of reactants, as well as by adding a solvent material. Phase diagrams and stabilities of the involved W–B compounds are also well depicted, which would provide an important guidance for future exploratory synthesis and study of the family of transition-metal borides

Predicted cumulative hazard function of 30 days mortality for different therapies.

<p>The curves were constructed according to the PCI or conservative therapie with the use of Cox regression analysis.</p