Integral membrane protein structure determination using pseudocontact shifts.

Obtaining enough experimental restraints can be a limiting factor in the NMR structure determination of larger proteins. This is particularly the case for large assemblies such as membrane proteins that have been solubilized in a membrane-mimicking environment. Whilst in such cases extensive deuteration strategies are regularly utilised with the aim to improve the spectral quality, these schemes often limit the number of NOEs obtainable, making complementary strategies highly beneficial for successful structure elucidation. Recently, lanthanide-induced pseudocontact shifts (PCSs) have been established as a structural tool for globular proteins. Here, we demonstrate that a PCS-based approach can be successfully applied for the structure determination of integral membrane proteins. Using the 7TM α-helical microbial receptor pSRII, we show that PCS-derived restraints from lanthanide binding tags attached to four different positions of the protein facilitate the backbone structure determination when combined with a limited set of NOEs. In contrast, the same set of NOEs fails to determine the correct 3D fold. The latter situation is frequently encountered in polytopical α-helical membrane proteins and a PCS approach is thus suitable even for this particularly challenging class of membrane proteins. The ease of measuring PCSs makes this an attractive route for structure determination of large membrane proteins in general.This work was supported by the Biotechnology and Biological Sciences Research Council BBSRC [BB/K01983X/1].This paper was originally published in the Journal of Bimolecular NMR (Crick DJ, Wang JX, Graham B, Swarbrick JD, Mott HR, Nietlispach D, Journal of Biomolecular NMR 2015, doi:10.1007/s10858-015-9899-6)

Evidence for Exciton Crystals in a 2D Semiconductor Heterotrilayer

Two-dimensional (2D) transition metal dichalcogenides (TMDC) and their moire interfaces have been demonstrated for correlated electron states, including Mott insulators and electron/hole crystals commensurate with moire superlattices. Here we present spectroscopic evidences for ordered bosons - interlayer exciton crystals in a WSe2/MoSe2/WSe2 trilayer, where the enhanced Coulomb interactions over those in heterobilayers have been predicted to result in exciton ordering. While the dipolar interlayer excitons in the heterobilayer may be ordered by the periodic moire traps, their mutual repulsion results in de-trapping at exciton density larger than 10^11 cm^-2 to form mobile exciton gases and further to electron-hole plasmas, both accompanied by broadening in photoluminescence (PL) peaks and large increases in mobility. In contrast, ordered interlayer excitons in the trilayer are characterized by negligible mobility and by sharper PL peaks persisting to nex larger than 10^12 cm^-2. We find that an optically dark state attributed to the predicted quadrupolar exciton crystal transitions to the bright dipolar excitons either with increasing nex or by an applied electric field. These ordered interlayer excitons may serve as models for the exploration of quantum phase transitions and quantum coherent phenomena.Comment: 16 pages, 4 figures, S

The associations of residential greenness with fetal growth in utero and birth weight: A birth cohort study in Beijing, China

Background: Although studies have examined the association between residential greenness and birth weight, there is no evidence regarding the association between residential greenness and fetal growth in utero. We aimed to investigate the associations of residential greenness with both fetal growth in utero and birth weight. Methods: A birth cohort (2014–2017) with 18,665 singleton pregnancies was established in Tongzhou Maternal and Child hospital of Beijing, China. Residential greenness was matched with maternal residential address and estimated from remote satellite data using normalized difference vegetation index with 200 m and 500 m buffers (NDVI-200 and NDVI-500). Fetal parameters including estimated fetal weight (EFW), abdominal circumference (AC), head circumference (HC) an

Genetic Polymorphisms of the TYMS Gene Are Not Associated with Congenital Cardiac Septal Defects in a Han Chinese Population

Background: Clinical research indicates that periconceptional administration of folic acid can reduce the occurrence of congenital cardiac septal defects (CCSDs). The vital roles of folate exhibits in three ways: the unique methyl donor for DNA expression regulation, the de novo biosynthesis of purine and pyrimidine for DNA construction, and the serum homocysteine removal. Thymidylate synthase (TYMS) is the solo catalysis enzyme for the de novo synthesis of dTMP, which is the essential precursor of DNA biosynthesis and repair process. To examine the role of TYMS in Congenital Cardiac Septal Defects (CCSDs) risk, we investigated whether genetic polymorphisms in the TYMS gene associated with the CCSDs in a Han Chinese population. Method: Polymorphisms in the noncoding region of TYMS were identified via direct sequencing in 32 unrelated individuals composed of half CCSDs and half control subjects. Nine SNPs and two insertion/deletion polymorphisms were genotyped from two independent case-control studies involving a total of 529 CCSDs patients and 876 healthy control participants. The associations were examined by both single polymorphism and haplotype tests using logistic regression. Result: We found that TYMS polymorphisms were not related to the altered CCSDs risk, and even to the changed risk of VSDs subgroup, when tested in both studied groups separately or in combination. In the haplotype analysis, there were no haplotypes significantly associated with risks for CCSDs either. Conclusion: Our results show no association between common genetic polymorphisms of the regulatory region of th

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (INaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of INaT and a decrease of potassium currents, especially slowly inactivating potassium currents (IAS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of INaT and total potassium current as well as IAS currents induced by STZ were normalized by GAS. This study provides a clear cellular basis for the peripheral analgesic action of gastrodin for the treatment of chronic pain, including PDN

Polymer ultrapermeability from the inefficient packing of 2D chains

The promise of ultrapermeable polymers, such as poly(trimethylsilylpropyne) (PTMSP), for reducing the size and increasing the efficiency of membranes for gas separations remains unfulfilled due to their poor selectivity. We report an ultrapermeable polymer of intrinsic microporosity (PIM-TMN-Trip) that is substantially more selective than PTMSP. From molecular simulations and experimental measurement we find that the inefficient packing of the two-dimensional (2D) chains of PIM-TMN-Trip generates a high concentration of both small (<0.7 nm) and large (0.7–1.0 nm) micropores, the former enhancing selectivity and the latter permeability. Gas permeability data for PIM-TMN-Trip surpass the 2008 Robeson upper bounds for O2/N2, H2/N2, CO2/N2, H2/CH4 and CO2/CH4, with the potential for biogas purification and carbon capture demonstrated for relevant gas mixtures. Comparisons between PIM-TMN-Trip and structurally similar polymers with three-dimensional (3D) contorted chains confirm that its additional intrinsic microporosity is generated from the awkward packing of its 2D polymer chains in a 3D amorphous solid. This strategy of shape-directed packing of chains of microporous polymers may be applied to other rigid polymers for gas separations

Simultaneous Impact of the Presence of Foreign MNEs on Indigenous Firms’ Exports and Domestic Sales

YesIncorporating the global production network approach and competitor analysis, this paper establishes an analytical framework with two hypotheses for the role of foreign multinational enterprises (FMNEs) in indigenous firms’ exports and domestic sales. First, the presence of FMNEs as a whole is likely to have a negative impact on indigenous firms’ domestic sales but a simultaneous positive impact on their exports in an emerging economy like China. Second, the presence of MNEs from Hong Kong, Macau and Taiwan (HMT MNEs) is more likely to generate this pattern of impact than MNEs from other countries (Other FMNEs). The FDI-led export strategy contributed to the dominance of the scenario described by the first hypothesis in China, while a higher degree of market commonality and resource similarity of HMT MNEs with that of indigenous Chinese firms than Other FMNEs leads to the second hypothesis. These novel hypotheses are tested and supported by a very large and recent firm-level panel dataset from Chinese manufacturing

Population genomics of marine zooplankton

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here for personal use, not for redistribution. The definitive version was published in Bucklin, Ann et al. "Population Genomics of Marine Zooplankton." Population Genomics: Marine Organisms. Ed. Om P. Rajora and Marjorie Oleksiak. Springer, 2018. doi:10.1007/13836_2017_9.The exceptionally large population size and cosmopolitan biogeographic distribution that distinguish many – but not all – marine zooplankton species generate similarly exceptional patterns of population genetic and genomic diversity and structure. The phylogenetic diversity of zooplankton has slowed the application of population genomic approaches, due to lack of genomic resources for closelyrelated species and diversity of genomic architecture, including highly-replicated genomes of many crustaceans. Use of numerous genomic markers, especially single nucleotide polymorphisms (SNPs), is transforming our ability to analyze population genetics and connectivity of marine zooplankton, and providing new understanding and different answers than earlier analyses, which typically used mitochondrial DNA and microsatellite markers. Population genomic approaches have confirmed that, despite high dispersal potential, many zooplankton species exhibit genetic structuring among geographic populations, especially at large ocean-basin scales, and have revealed patterns and pathways of population connectivity that do not always track ocean circulation. Genomic and transcriptomic resources are critically needed to allow further examination of micro-evolution and local adaptation, including identification of genes that show evidence of selection. These new tools will also enable further examination of the significance of small-scale genetic heterogeneity of marine zooplankton, to discriminate genetic “noise” in large and patchy populations from local adaptation to environmental conditions and change.Support was provided by the US National Science Foundation to AB and RJO (PLR-1044982) and to RJO (MCB-1613856); support to IS and MC was provided by Nord University (Norway)