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The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the Cloop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLICdoi:10.1371/journal.pone.0064326 pmid:23667707 pmcid:PMC3648548 fatcat:d5t2gyag7vgevmsxdja4tlbj2u
more »... and thereby shifted the channel activation to a higher agonist concentration. The other site is below the Cloop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the b1-b2 loop or through pre-TM1. The b1-b2 loop occurs in either intra-or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs.
We report an experimental investigation on the Doppler-free saturated absorption spectroscopy of buffer-gas-cooled Barium monofluoride (BaF) molecules in a 4 K cryogenic cell. The obtained spectra with a resolution of 19 MHz, much smaller than previously observed in absorption spectroscopy, clearly resolve the hyperfine transitions. Moreover, we use these high-resolution spectra to fit the hyperfine splittings of excited A(v=0) state and find the hyperfine splitting of thearXiv:2202.02463v1 fatcat:qxbqaivopfcelhyrkpq4axwqwm
more »... A^2Π_1/2(v=0, J=1/2, +) state is about 18 MHz, much higher than the previous theoretically predicted value. This provides important missing information for laser cooling of BaF molecules.
We present a magnetically enhanced laser cooling scheme applicable to multi-level type-II transitions and further diatomic molecules with adiabatic transfer. An angled magnetic field is introduced to not only remix the dark states, but also decompose the multi-level system into several two-level sub-systems in time-ordering, hence allowing multiple photon momentum transfer. For complex multi-level diatomic molecules, although the enhancement gets weakened, our simulations still predict a ∼ 4×arXiv:1902.05212v2 fatcat:sj26vvxlljeytppprjwzdsgy2e
more »... rger value of the maximum achievable cooling force and a wider coolable velocity range compared to the conventional Doppler cooling. A reduced dependence on spontaneous emission of this scheme makes laser cooling a molecule with leakage channels become a feasibility.
The vitamin D receptor (VDR) mediates the immunological function of vitamin D3, which activates macrophages, and vitamin D deficiency has been linked to tuberculosis risk. Single nucleotide polymorphisms (SNPs) in VDR may influence the function of vitamin D and susceptibility to tuberculosis. Methods: This study included 217 patients with pulmonary tuberculosis (PTB) and 383 healthy subjects in a Tibetan Chinese population living in and near Xi'an. Association analyses of SNPs in VDR weredoi:10.1186/s12879-016-1699-4 pmid:27595605 pmcid:PMC5011340 fatcat:miigrxlfbvdebew57xqbvci22u
more »... med with the SPSS 17.0 statistical packages, SNP stats software, Haploview software package (version 4.2), and the SHEsis software platform. Results: Our results revealed a correlation between three SNPs (rs11574143, odds ratio [OR]: 1.47, 95 % confidence interval [CI]: 1.11 -1.94, p = 0.006, p-adjust = 0.030; rs11574079, OR: 0.48, 95 % CI: 0.25 -0.92, p = 0.023, p-adjust = 0. 115; rs11168287, OR: 2.55, 95 % CI: 2.00 -3.25, p = 1.730E-14, p-adjust = 0.865E-13) and PTB based on Chi-square tests. We observed the allele "A" of rs11574143 and rs11168287 increased the PTB risk and the allele "A" of rs11574079 provided a protective effect against PTB. Conclusions: The goal of this study was the identification of putative associations between five SNPs (rs11574143, rs7975232, rs11574079, rs3819545 and rs11168287) in VDR and susceptibility to PTB. Our findings demonstrated associations between VDR polymorphisms and PTB development.
Physical Review A
We proposed a general Zeeman slower scheme applicable to the majority of the laser-coolable molecules. Different from previous schemes, the key idea of our scheme lies in that the compensation of the detuning with the magnetic field is done for the repumping laser instead of the cooling laser. Only atoms or molecules with the right velocity will be repumped and laser slowed. Such scheme is more feasible for molecules with complex energy sturcutres. We apply this scheme for molecules with largedoi:10.1103/physreva.100.053402 fatcat:khomezkdg5hb3okxsqdu732rha
more »... and\'e g-factor of the excited states and polyatomic molecules, and it shows a better slowing efficiency.
Authors' Contributions Xue Luo, Chen Liang, and Ning Li contributed equally to this work. ...doi:10.1155/2020/9480537 fatcat:fngb6octvrcajgg2geu4z4tvtm
Quinoa (Chenopodium quinoa Willd.) is a balanced nutritional crop, but its breeding improvement has been limited by the lack of information on its genetics and genomics. Therefore, it is necessary to obtain knowledge on genomic variation, population structure, and genetic diversity and to develop novel Insertion/ Deletion (InDel) markers for quinoa by whole-genome re-sequencing. Results: We re-sequenced 11 quinoa accessions and obtained a coverage depth between approximately 7× to 23× thedoi:10.1186/s12864-017-4093-8 pmid:28870149 pmcid:PMC5584319 fatcat:ibls33suwjdtfo3tnoxovscnqe
more »... genome. Based on the 1453-megabase (Mb) assembly from the reference accession Riobamba, 8,441,022 filtered bi-allelic single nucleotide polymorphisms (SNPs) and 842,783 filtered InDels were identified, with an estimated SNP and InDel density of 5.81 and 0.58 per kilobase (kb). From the genomic InDel variations, 85 dimorphic InDel markers were newly developed and validated. Together with the 62 simple sequence repeat (SSR) markers reported, a total of 147 markers were used for genotyping the 129 quinoa accessions. Molecular grouping analysis showed classification into two major groups, the Andean highland (composed of the northern and southern highland subgroups) and Chilean coastal, based on combined STRUCTURE, phylogenetic tree and PCA (Principle Component Analysis) analyses. Further analysis of the genetic diversity exhibited a decreasing tendency from the Chilean coast group to the Andean highland group, and the gene flow between subgroups was more frequent than that between the two subgroups and the Chilean coastal group. The majority of the variations (approximately 70%) were found through an analysis of molecular variation (AMOVA) due to the diversity between the groups. This was congruent with the observation of a highly significant F ST value (0.705) between the groups, demonstrating significant genetic differentiation between the Andean highland type of quinoa and the Chilean coastal type. Moreover, a core set of 16 quinoa germplasms that capture all 362 alleles was selected using a simulated annealing method. Conclusions: The large number of SNPs and InDels identified in this study demonstrated that the quinoa genome is enriched with genomic variations. Genetic population structure, genetic core germplasms and dimorphic InDel markers are useful resources for genetic analysis and quinoa breeding.
Peter Liang: study concept and design, data analysis and interpretation of data; critical revision of manuscript. ... Yuhe Xia: data analysis, biostatistics. John Inadomi: critical revision of manuscript. Simona Kwon: critical revision of manuscript. Chau Trinh-Shevrin: critical revision of manuscript. ...doi:10.1002/cam4.2084 pmid:30843666 pmcid:PMC6536964 fatcat:twcv4twbrnbcppkshjrfb7na5q
et al. 2018. "The functional and structural alterations of the striatum in chronic spontaneous urticaria." Scientific Reports 8 (1): 1725. The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSUdoi:10.1038/s41598-018-19962-2 pmid:29379058 pmcid:PMC5789061 fatcat:d2dn7q5bu5hndfprl6xer4w3ay
more »... atients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient's clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch. Chronic spontaneous urticaria (CSU) is a common disorder characterized by the spontaneous eruption of short-lived (<24 h) itchy wheals, with or without angioedema, for a period longer than 6 weeks 1 . CSU affects 0.5-1.0% of the population at any given time and severely diminishes the quality of life of patients 2,3 . Despite its prevalence, there is a lack of understanding of the pathology of CSU and consequently, limited treatment options. Standard therapy with regular doses of non-sedating second-generation H1 antihistamines (H1AH) are ineffective for more than 50% of patients with CSU 2 . Accumulating evidence suggests that the skin and brain are functionally connected 4,5 . For instance, the brain shares numerous mediators with skin through the hypothalamic-pituitary-adrenal axis (HPA axis) 4 . Studies have shown that the HPA axis may be altered in stress-related skin diseases, resulting in the activation of mast cells 6,7 , which are the primary effector cells in CSU 8 . The most common clinical manifestation of CSU is repeated itching and scratching. Studies suggest that the brain plays a key role in the itch-scratch cycle 9 . Functional brain imaging studies have identified brain regions associated with the itch-scratch cycle, such as the primary somatosensory cortex (SI), secondary somatosensory cortex (SII), primary motor cortex (MI), premotor cortex (PM), supplementary motor area (SMA), cerebellum, the prefrontal cortex (PFC), the striatum, and thalamus 10-14 . In recent years, resting-state functional magnetic resonance imaging (rs-fMRI) has been applied to investigate the intrinsic functional organization of the brain 15-17 . There are many resting-state fMRI data analysis methods, some of which focus on local connectivity and examine the properties of spontaneous local brain activity, such as the amplitude of low-frequency fluctuations (ALFF), and others which focus on long-range connectivity among different brain regions, such as seed-based resting state functional connectivity 18 . As a reliable and reproducible
Chemotherapy is one of the few effective choices for patients with advanced or recurrent gastric cancer (GC). However, the development of mutidrug resistance (MDR) to cancer chemotherapy is a major obstacle to the effective treatment of advanced GC. Additionally, the mechanism of MDR remains to be determined. In the present study, we tested IC 50 of cisplating (DDP), vincristine (VCR) and 5-fluorouracil (5-FU) in SGC7901, SGC7901/DDP and SGC7901/VCR gastric cancer cells using an MTT assay. Thedoi:10.3892/or.2015.3757 pmid:25633261 fatcat:dm2rv2wvnfh3nd25hf6sakml7e
more »... xpression of let-7b and c-Myc in these cells was detected by qPCR and western blot analysis. The relationship between let-7b and c-Myc was explored using a luciferase reporter assay. Transfection of let-7b mimic or inhibitor was used to confirm the effect of let-7b on drug sensitivity in chemotherapy via the regulation of c-Myc expression. We found that the expression of let-7b was lower in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells than that in chemotherapysensitive SGC7901 cells. By contrast, the expression of c-Myc was higher in SGC7901/DDP and SGC7901/VCR cells than that in SGC7901 cells. Furthermore, we confirmed that let-7b suppresses c-Myc gene expression at the mRNA and protein levels in a sequence-specific manner, while transfection of let-7b mimic increases drug sensitivity in chemotherapyresistant SGC7901/DDP and SGC7901/VCR cells by targeting downregulation of c-Myc. In SGC7901 drug-sensitive cells, however, the sensitivity of chemotherapy was significantly decreased following let-7b inhibitor transfection. The present study results demonstrated that let-7b increases drug sensitivity in chemotherapy-resistant SGC7901/DDP and SGC7901/VCR gastric cancer cells by targeting the downregulation of c-Myc and that, let-7b mimic reverses MDR by promoting cancer stem cell differentiation controlled by double-negative autoregulatory loops (Lin28/let-7 and Myc/let-7) and a double-positive autoregulatory loop (Lin28/Lin28B/Myc) existing in GC cells, which remains to be confirmed.
Liang et al revealed that miR-506 targets LHX2 to repress EMT and lymph node metastasis in nasopharyngeal carcinoma. ...doi:10.3892/or.2020.7703 pmid:32700744 pmcid:PMC7448411 fatcat:exk7d3rtwnfvpcx7a67bz6smii
The adrenal gland protein AD-004 was identi®ed in the human adrenal gland. Full-length AD-004 contains 172 amino acids, with a predicted molecular weight of about 20 kDa. In attempts to crystallize human AD-004, the gene was subcloned into a modi®ed pET vector, pET21-DEST, with an N-terminal His 5 tag using the Gateway cloning system, followed by protein expression in Escherichia coli strain BL21(DE3). The protein was puri®ed in two steps to near-homogeneity and was crystallized. The crystalsdoi:10.1107/s0907444904010467 pmid:15213396 fatcat:hysdedmgqrg57gopg6f2ulygee
more »... long to space group P6 1 or P6 5 , with unit-cell parameters a = b = 99.56, c = 57.19 A Ê . A complete 2.0 A Ê data set has been collected at a rotating-anode X-ray source and structure determination is under way.
Yuhe Zhu performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the paper, and approved the final draft. ... Chen Liang performed the experiments, prepared figures and/or tables, and approved the final draft. Nanjue Cao analyzed the data, prepared figures and/or tables, and approved the final draft. ...doi:10.7717/peerj.9292 pmid:32742764 pmcid:PMC7365136 fatcat:z4gnicmsvbaazhfsaphyscrehq
Background Metabolic reprogramming is a hallmark of cancer. However, the roles of long noncoding RNAs (lncRNAs) in cancer metabolism, especially glucose metabolism remain largely unknown. Results In this study, we identified and functionally characterized a novel metabolism-related lncRNA, LINC00930, which was upregulated and associated with tumorigenesis, lymphatic invasion, metastasis, and poor prognosis in nasopharyngeal carcinoma (NPC). Functionally, LINC00930 was required for increaseddoi:10.1186/s13046-022-02282-9 pmid:35209949 pmcid:PMC8867671 fatcat:sj6xqqtqvfhy3l554yakrdlzoq
more »... olysis activity and cell proliferation in multiple NPC models in vitro and in vivo. Mechanistically, LINC00930 served as a scaffold to recruit the RBBP5 and GCN5 complex to the PFKFB3 promoter and increased H3K4 trimethylation and H3K9 acetylation levels in the PFKFB3 promoter region, which epigenetically transactivating PFKFB3, and thus promoting glycolytic flux and cell cycle progression. Clinically, targeting LINC00930 and PFKFB3 in combination with radiotherapy induced tumor regression. Conclusions Collectively, LINC00930 is mechanistically, functionally and clinically oncogenic in NPC. Targeting LINC00930 and its pathway may be meaningful for treating patients with NPC.
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