Molecular modeling on HIF2α-ARNT dimer destabilization caused by HIF2α V192D and/or R171A mutations

The hypoxia-inducible-factors (HIFs) are responsible for cellular adaptations to low oxygen stress by activating transcriptional programs such as erythropoiesis and angiogenesis. Because these programs are related to tumor growth and progression, HIFs have become attractive targets for cancer therapy. To function as oxygen-sensitive regulatory subunits, HIF2α must form a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT). Both HIF and ARNT proteins have a basic-helix-loop-helix (bHLH) domain for DNA reading in their amino-termini, followed by two tandem Per-ARNT-Sim (PAS) domain, namely PAS-A and PAS-B, for HIF-ARNT dimerization, and transactivation domains (TAD) in their carboxyl-termini. According to the recently solved HIF2α-ARNT dimer structure (not covering their TADs), there are six domain-domain interfaces including HIF2α’s bHLH with ARNT’s bHLH, HIF2α’s PAS-A with ARNT’s PAS-A, HIF2α’s PAS-B with ARNT’s PAS-A, HIF2α’s PAS-B with ARNT’s PAS-B, HIF2α’s PAS-A with HIF2α’s PAS-B, and HIF2α’s bHLH with HIF2α’s PAS-B. Structural comparison shows that HIF2α’s bHLH, PAS-A, and PAS-B domains are compactly interconnected; whereas ARNT’s bHLH, PAS-A, and PAS-B domains are linked by long flexible loops to grant structural adaptability to dimerize different bHLH-PAS proteins members. Lately, co-immunoprecipitation experiments have shown that R171A and/or V192D on HIF2α’s PAS-A domain impair HIF2α-ARNT dimerization. Herein we applied molecular dynamics simulations to investigate the structural and dynamic impact brought by these mutations. Our results conclude that these mutated amino residues, located in HIF2α’s PAS-A with HIF2α’s PAS-B interface, change the relative orientation and motion of PAS-A and PAS-B and therefore these two PAS domains are not recognizable by ARNT

Ultrasound cyclo-plasty for moderate glaucoma: Eighteen-month results from a prospective study

PurposeTo evaluate the long-term clinical efficacy of ultrasound cyclo-plasty (UCP) in the treatment of moderate glaucoma and molecular effects in animal experiments.MethodsAn 18-month clinical study was conducted among 32 patients with moderate glaucoma. The primary outcome was surgical success, defined as a reduction in intraocular pressure (IOP) of greater than or equal to 20% from the baseline and an IOP value of greater than 5 mmHg at the last follow-up. The secondary outcomes were related to the quality of life, complications, and mean IOP value at each follow-up. In the animal experiment, 20 New Zealand rabbits were used to establish a high-IOP model and implement UCP. The distribution of aquaporin 4 (AQP4) in the ciliary body and the tissue changes under electron microscopy were observed after surgery.ResultsThe mean patient IOP decreased from 34.9 ± 4.9 mmHg before surgery to 23.5 ± 5.2 mmHg at 18 months after UCP. No vision loss occurred in any patient. Some patients had postoperative complications, but the symptoms were mild and disappeared within 3 months after the surgery. Most patients had good postoperative quality of life. Histology showed that AQP4 remained in the ciliary muscle after UCP, and only the bilayered epithelial cells showed coagulative necrosis. Furthermore, electron microscopic observation revealed the destruction of ciliary process cells covered by ultrasound after UCP.ConclusionUCP is associated with mild postoperative reactions and the mild treatment of ciliary tissue and is a safe and effective method for reducing IOP in moderate glaucoma

Effects of orthographic consistency and homophone density on Chinese spoken word recognition

Studies of alphabetic language have shown that orthographic knowledge influences phonological processing during spoken word recognition. This study utilized the Event-Related Potentials (ERPs) to differentiate two types of phonology-to-orthography (P-to-O) mapping consistencies in Chinese, namely homophone density and orthographic consistency. The ERP data revealed an orthographic consistency effect in the frontal-centrally distributed N400, and a homophone density effect in central-posteriorly distributed late positive component (LPC). Further source analyses using the standardized low-resolution electromagnetic tomography (sLORETA) demonstrated that the orthographic effect was not only localized in the frontal and temporal-parietal regions for phonological processing, but also in the posterior visual cortex for orthographic processing, while the homophone density effect was found in middle temporal gyrus for lexical-semantic selection, and in the temporal-occipital junction for orthographic processing. These results suggest that orthographic information not only shapes the nature of phonological representations, but may also be activated during on-line spoken word recognition

The feedback consistency effect in Chinese character recognition:evidence from a psycholinguistic norm

Researchers have demonstrated the importance of phonology in literacy acquisition and in visual word recognition. For example, the spelling-to-sound consistency effect has been observed in visual word recognition tasks, in which the naming responses are faster and more accurate for words with the same letters that also have the same pronunciation (e.g. -ean is always pronounced /in/, as in lean, dean, and bean). In addition, some studies have reported a much less intuitive feedback consistency effect when a rime can be spelled in different ways (e.g. /ip/ in heap and deep) in lexical decision tasks. Such findings suggest that, with activation flowing back and forth between orthographic and phonological units during word processing, any inconsistency in the mappings between orthography and phonology should weaken the stability of the feedback loop, and, thus, should delay recognition. However, several studies have failed to show reliable feedback consistency in printed word recognition. One possible reason for this is that the feedback consistency is naturally confounded with many other variables, such as orthographic neighborhood or bigram frequency, as these variables are difficult to tease apart. Furthermore, there are challenges in designing factorial experiments that perfectly balance lexical stimuli on all factors besides feedback consistency. This study aims to examine the feedback consistency effect in reading Chinese characters by using a normative data of 3,423 Chinese phonograms. We collected the lexical decision time from 180 college students. A linear mixed model analysis was used to examine the feedback consistency effect by taking into account additional properties that may be confounded with feedback consistency, including character frequency, number of strokes, phonetic combinability, semantic combinability, semantic ambiguity, phonetic consistency, noun-to-verb ratios, and morphological boundedness. Some typical effects were observed, such as the more frequent and familiar a character, the faster one can decide it is a real character. More importantly, the linear mixed model analysis revealed a significant feedback consistency effect while controlling for other factors, which indicated that the pronunciation of phonograms might accommodate the organization of Chinese orthographic representation. Our study disentangled the feedback consistency from the many other factors, and supports the view that phonological activation would reverberate to orthographic representation in visual word recognition

Effects of Ca addition on the uptake, translocation, and distribution of Cd in Arabidopsis thaliana

Cadmium (Cd) pollution poses a risk to human health for its accumulation in soil and crops, but this can be alleviated by calcium (Ca) addition. However, its mechanism remains unclear yet. In this study, Arabidopsis thaliana was used to explore the alleviating effects of Ca on Cd toxicity and its specific function during uptake, upward-translocation, and distribution of Cd. Supplementing plants with 5 mM CaCl2 alleviated the intoxication symptoms caused by 50 μM CdCl2, such as smaller leaves, early bolting and root browning. Ca addition decreased uptake of Cd, possibly by reducing the physical adsorption of Cd since the root cell membrane was well maintained and lignin deposition was decreased as well, and by decreasing symplastic Cd transport. Expression of the genes involved (AtZIP2 and AtZIP4) was also decreased. In addition, Ca accumulated in the plant shoot to help facilitating the upward-translocation of Cd, with evidence of higher translocation factor and expression of genes that were involved in Ca transport (AtPCR1) and Cd xylem loading (AtHMA2 and AtHMA4). Dithizone-staining of Cd in leaves showed that in Cd+Ca-treated plants, Ca addition initially protected the leaf stomata by preventing Cd from entering guard cells, but with prolonged Cd treatment facilitated the Cd accumulation around trichomes and maybe its excretion. We conclude that Ca promotes the upward-translocation of Cd and changes its distribution in leaves. The results may have relevance for bioremediation

Coexistence of Reconstructed and Unreconstructed Structures in Structural Transition Regime of Twisted Bilayer Graphene

In twisted bilayer graphene (TBG), a twist-angle-dependent competition between interlayer stacking energy and intralayer elastic energy results in flat rigid layers at large twist angles and lattice reconstruction at small twist angles. Despite enormous scientific interest and effort in the TBG, however, an experimental study of evolution from the rigid lattice to the reconstructed lattice as a function of twist angle is still missing. Here we present a scanning tunneling microscopy and spectroscopy study to reveal the twist-angle-dependent lattice reconstruction in the TBG. Our experiment demonstrates that there is a transition regime between the rigid regime and the relaxed regime and, unexpectedly, the reconstructed and unreconstructed structures coexist in the transition regime. The coexistence of the two distinct structures in this regime may arise from subtle balance between the interlayer stacking energy and intralayer elastic energy in the TBG with intermediate moir\'e sizes.Comment: 4 Figures in main tex

Morphological and multi-gene phylogenetic analyses reveal five new hyphomycetes from freshwater habitats

During the survey on freshwater hyphomycetes in Guangxi, Guizhou and Hainan Provinces, China, five fresh collections were encountered. Based on their morphology, these five isolates were identified as belonging to Hermatomyces, Kirschsteiniothelia, Paramonodictys, Pleopunctum and Sparticola. Multi-gene phylogenetic analyses were performed for each genus, which resulted in the identification of five new species, namely Hermatomyces hainanensis, Kirschsteiniothelia ramus, Paramonodictys globosa, Pleopunctum guizhouense, and Sparticola irregularis. Detailed descriptions and illustrations of the morphological characteristics of these new taxa were provided. This research enriches the biodiversity of freshwater dematiaceous hyphomycetes

A positive feedback loop of IL-17B-IL-17RB activates ERK/β-catenin to promote lung cancer metastasis

Inflammation contributes to the development and progression of cancer. Interleukin-17 (IL-17) is an inflammatory cytokine that functions in inflammation and cancer, as well as several other cellular processes. In this study, we investigated the roles and the prognostic value of IL-17 and the IL-17 receptor (IL-17R) in lung cancer. Gene expression microarray analysis followed by Kaplan-Meier survival curve showed that IL-17B was associated with poor patient survival, and IL-17B receptor (IL-17RB) was up-regulated in lung cancer tissue compared with normal tissue. Expression of IL-17RB was associated with lymph node metastasis and distant metastasis, as well as poor patient survival. IL-17RB overexpression significantly increased cancer cell invasion/migration and metastasis in vitro and in vivo. IL-17RB induced ERK phosphorylation, resulting in GSK3β inactivation and leading to β-catenin up-regulation. IL-17RB also participated in IL-17B synthesis via the ERK pathway. IL-17RB activation is required for IL-17B-mediated ERK phosphorylation. Taken together, IL-17B-IL-17RB signaling and ERK participate in a positive feedback loop that enhances invasion/migration ability in lung cancer cell lines. IL-17RB may therefore serve as an independent prognostic factor and a therapeutic target for lung cancer