Miracle-dz/UniFAR-FTUs huggingface dataset:
Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα

Interaction of glycoprotein Ibα (GPIbα) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIbα and VWF involves the β-switch region, which is a loop in the unliganded GPIbα but switches to a β-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIbα-VWF binding. Gain-of-function mutations (e.g., M239V) in the β-switch reduce the flow requirement for VWF binding, whereas loss-of-function mutations (e.g., A238V) increase the flow requirement. These phenomena cannot be explained by crystal structures or energy calculations. Herein we demonstrate that the β-hairpin is unstable without contacting VWF, in that it switches to a loop in free molecular dynamics simulations. Simulations with a novel flow molecular dynamics algorithm show that the loop conformation is unstable in the presence of flow, as it switches to β-hairpin even without contacting VWF. Compared with the wild-type, it is easier for the M239V mutant but harder for the A238V mutant to switch to β-hairpin in the presence of flow. These results elucidate the structural basis for the two mutants and suggest a regulatory mechanism by which flow activates GPIbα via inducing a loop-to-β-hairpin conformational transition on the β-switch, thereby promoting VWF binding.
Magnetoresistance in an All‐Organic‐Based Spin Valve

Figure 1 . a) Device structure and b) schematic view of the energy levels of V[TCNE] x ( x ≈ 2). Spintronics is the new paradigm of electronics and utilizes the spin degree of freedom of the electron. [ 1 ] In addition to metalbased spintronic devices, which already have wide applications (e.g., read heads of hard disk drives), semiconductor spintronics provides the possibility to combine logic, communication, and storage operation using hybrid devices. [ 2 ] Recently, spintronic devices based on organic materials have attracted much attention because of the potential long spin lifetime due to low spin-orbit coupling and weak hyperfi ne interaction, as well as the ability to fabricate low-cost, light-weight, and mechanically fl exible devices. [ 3–9 ] Organic semiconductors have been used as the spacers in spin valve devices with ferromagnetic metal or transitional metal oxide contacts. One fundamental obstacle for spin injection from a ferromagnetic metal into a semiconductor is the conductivity mismatch. [ 10 ] The development of fully spinpolarized magnetic semiconductors offers a promising route to circumvent this problem. Organic-based magnets such as V[TCNE] x ( x ≈ 2, TCNE: tetracyanoethylene) provide advantages including high magnetic ordering temperature, fully spin-polarized semiconducting electronic structure, chemical tunability, and low-temperature processing. [ 11 ] Here, we show results for spin injection and detection in an all-organic-based spin valve using the organic magnetic semiconductor V[TCNE] x as both the spin injector and analyzer. We observed unusual inverted spin valve effect and propose that the negative magnetoresistance (MR) originates from the spin-dependent tunneling between highly spin-polarized bands split by Coulomb interaction. V[TCNE] x is the fi rst reported room-temperature moleculebased magnet with magnetic ordering temperature T C ≈ 400 K. [ 12 ] The magnetic order originates from the antiferromagnetic coupling between the three unpaired electrons of the V 2 +
Tonic inhibition of chemotaxis in human plasma

We found exaggerated chemotaxis in plasma treated with EDTA and thought that the EDTA might itself be inhibiting a tonic inhibitor(s) of chemotaxis. Our plasma fractionations suggested that evidence should be sought for a lipid moiety carrying this activity, and on spectrometry (LC-MS-MS together with GC-MS analyses), the biologically active but not the inactive fraction contained oleic and arachidonic acids. Because fatty acids are largely protein bound, we flooded plasma preparations with delipidated albumin, reasoning that it would bind enough fatty acids, including inhibitory ones, to counter their tonic inhibition. Indeed, we observed dramatic increases in chemotaxis. Hence, adding delipidated albumin to plasma has a similar effect to that of adding EDTA—amplification of the chemotactic response. Oleic acid in physiologic concentrations diminishes the magnifying effects of both EDTA and of delipidated albumin, and in fact diminishes the chemotactic response even without the presence of the amplifiers of chemotaxis. In contrast, arachidonic acid amplifies further the effect of EDTA but not of delipidated albumin, and this augmentation appears to be caused by an EDTA-dependent enrichment of the chemotactic gradient with leukotriene B4 (LTB4). We conclude that oleic acid, the blood levels of which vary among individuals, is at least one tonic inhibitor of chemotaxis in plasma.
Nanoscale Structure and Mechanism for Enhanced Electromechanical Response of Highly Strained BiFeO3 Thin Films

Author(s): Damodaran, Anoop R; Liang, Chen-Wei; He, Qing; Peng, Chun-Yen; Chang, Li; Chu, Ying-Hao; Martin, Lane W | Abstract: The presence of a variety of structural variants in BiFeO3 thin films give rise to exotic electric-field-induced responses and resulting electromechanical responses as large as 5%. Using high-resolution X-ray diffraction and scanning-probe-microscopy-based studies the numerous phases present at the phase boundaries are identified and an intermediate monoclinic phase, in addition to the previously observed rhombohedral- and tetragonal-like phases, is discovered. Copyright © 2011 WILEY-VCH Verlag GmbH a Co. KGaA, Weinheim.
Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer

In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER+) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER−/LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-associated miRNA signature, a stromal miRNA signature, and an overexpressed miRNA cluster located on chromosome 19q23, but these intrinsic miRNA signatures were not associated with tumor aggressiveness. Supervised analysis in the initial subset and subsequent analysis in additional tumors significantly linked four miRNAs (miR-7, miR-128a, miR-210, and miR-516–3p) to ER+/LNN breast cancer aggressiveness (n = 147) and one miRNA (miR-210) to metastatic capability in ER−/LNN breast cancer (n = 114) and in the clinically important triple-negative subgroup (n = 69) (all P < 0.05). Bioinformatic analysis coupled miR-210 to hypoxia/VEGF signaling, miR-7 and miR-516–3p to cell cycle progression and chromosomal instability, and miR-128a to cytokine signaling. In conclusion, our work connects four miRNAs to breast cancer progression and to several distinct biological processes involved therein.
Electron tomography of early melanosomes: Implications for melanogenesis and the generation of fibrillar amyloid sheets

Melanosomes are lysosome-related organelles (LROs) in which melanins are synthesized and stored. Early stage melanosomes are characterized morphologically by intralumenal fibrils upon which melanins are deposited in later stages. The integral membrane protein Pmel17 is a component of the fibrils, can nucleate fibril formation in the absence of other pigment cell-specific proteins, and forms amyloid-like fibrils in vitro. Before fibril formation Pmel17 traffics through multivesicular endosomal compartments, but how these compartments participate in downstream events leading to fibril formation is not fully known. By using high-pressure freezing of MNT-1 melanoma cells and freeze substitution to optimize ultrastructural preservation followed by double tilt 3D electron tomography, we show that the amyloid-like fibrils begin to form in multivesicular compartments, where they radiate from the luminal side of intralumenal membrane vesicles. The fibrils in fully formed stage II premelanosomes organize into sheet-like arrays and exclude the remaining intralumenal vesicles, which are smaller and often in continuity with the limiting membrane. These observations indicate that premelanosome fibrils form in association with intralumenal endosomal membranes. We suggest that similar processes regulate amyloid formation in pathological models.
Direct Fabrication of Functional and Biofunctional Nanostructures Through Reactive Imprinting

One-step reactive imprinting of a protected maleimide polymer provides a nanopatterned maleimide surface via a retro-Diels-Alder reaction. The patterned surfaces are used as scaffolds for the generation of functional and biofunctional structures. The biofunctional surface offers a platform for aligning the cells in the direction of patterns, demonstrating the potential for applications in the field of tissue engineering.
Access to alcohol outlets and harmful alcohol consumption: a multi-level study in Melbourne, Australia.

AIMS To assess the association between access to off-premises alcohol outlets and harmful alcohol consumption. DESIGN, SETTING AND PARTICIPANTS Multi-level study of 2334 adults aged 18-75 years from 49 census collector districts (the smallest spatial unit in Australia at the time of survey) in metropolitan Melbourne. MEASUREMENTS Alcohol outlet density was defined as the number of outlets within a 1-km road network of respondents' homes and proximity was the shortest road network distance to the closest outlet from their home. Using multi-level logistic regression we estimated the association between outlet density and proximity and four measures of harmful alcohol consumption: drinking at levels associated with short-term harm at least weekly and monthly; drinking at levels associated with long-term harm and frequency of consumption. FINDINGS Density of alcohol outlets was associated with increased risk of drinking alcohol at levels associated with harm. The strongest association was for short-term harm at least weekly [odds ratio (OR) 1.10, 95% confidence interval (CI) 1.04-1.16]. When density was fitted as a categorical variable, the highest risk of drinking at levels associated with short-term harm was when there were eight or more outlets (short-term harm weekly: OR 2.36, 95% CI 1.22-4.54 and short-term harm monthly: OR 1.80, 95% CI 1.07-3.04). We found no evidence to support an association between proximity and harmful alcohol consumption. CONCLUSIONS The number of off-premises alcohol outlets in a locality is associated with the level of harmful alcohol consumption in that area. Reducing the number of off-premises alcohol outlets could reduce levels of harmful alcohol consumption.
Ion permeation through a Cl−-selective channel designed from a CLC Cl−/H+ exchanger

The CLC family of Cl−-transporting proteins includes both Cl− channels and Cl−/H+ exchange transporters. CLC-ec1, a structurally known bacterial homolog of the transporter subclass, exchanges two Cl− ions per proton with strict, obligatory stoichiometry. Point mutations at two residues, Glu148 and Tyr445, are known to impair H+ movement while preserving Cl− transport. In the x-ray crystal structure of CLC-ec1, these residues form putative “gates” flanking an ion-binding region. In mutants with both of the gate-forming side chains reduced in size, H+ transport is abolished, and unitary Cl− transport rates are greatly increased, well above values expected for transporter mechanisms. Cl− transport rates increase as side-chain volume at these positions is decreased. The crystal structure of a doubly ungated mutant shows a narrow conduit traversing the entire protein transmembrane width. These characteristics suggest that Cl− flux through uncoupled, ungated CLC-ec1 occurs via a channel-like electrodiffusion mechanism rather than an alternating-exposure conformational cycle that has been rendered proton-independent by the gate mutations.
EPs 7630, a Herbal Drug Preparation for Treating Acute Bronchitis in Children and Adults

Herbal medicines play an increasingly important role in the perception of physicians and patients looking for equally effective, albeit safer approaches to conventional management of acute bronchitis. A no antibiotic or delayed antibiotic prescribing strategy to reduce the inappropriate prescribing of antibiotics for respiratory tract infections (RTI) has been advocated since the late 1990’s (Little, 2005). In the light of inappropriate antibiotic use in this indication especially in children and increasing drug resistance rates worldwide, the need for an alternative remedy is crucial (Abbas et al., 2010). There is encouraging evidence derived from high quality randomised clinical trials (RCTs) that EPs 76301, a herbal drug preparation from the roots of Pelargonium sidoides widely used in several countries for the treatment of RTIs in children (≥1 year of age) and adults, is effective in patients with acute bronchitis.
The origin recognition complex is dispensable for endoreplication in Drosophila

The origin recognition complex (ORC) is an essential component of the prereplication complex (pre-RC) in mitotic cell cycles. The role of ORC as a foundation to assemble the pre-RC is conserved from yeast to human. Furthermore, in metazoans ORC plays a key role in determining the timing of replication initiation and origin usage. In this report we have produced and analyzed a Drosophila orc1 allele to investigate the roles of ORC1 in three different modes of DNA replication during development. As expected, ORC1 is essential for mitotic replication and proliferation in brains and imaginal discs, as well as for gene amplification in ovarian follicle cells. Surprisingly, however, ORC1 is not required for endoreplication. Decreased cell number in orc1 mutant salivary glands is consistent with the idea that undetectable levels of maternal ORC1 during embryogenesis fail to support further proliferation. Nevertheless, these cells begin endoreplicating normally and reach a final ploidy of >1000C in the absence of zygotic synthesis of ORC1. The dispensability of ORC is further supported by an examination of other ORC members, whereas Double-parked protein/Cdt1 and minichromosome maintenance proteins are apparently essential for endoreplication, implying that some aspects of initiation are shared among the three modes of DNA replication. This study provides insight into the physiologic roles of ORC during metazoan development and proposes that DNA replication initiation is governed differently in mitotic and endocycles.
Vertically Aligned and Penetrated Carbon Nanotube/Polymer Composite Film and Promising Electronic Applications

Carbon nanotube (CNT)/polymer composites have been extensively explored for a family of functional materials. [ 1–5 ] CNTs show excellent mechanical, electrical, and thermal properties, while polymers provide high transparency, easy fabrication, and low cost: a combined set of desired properties could not be found from the individual constituents, making these composite materials very useful in various applications such as optoelectronic and sensing devices. [ 6 , 7 ] However, a typical solution fabrication often leads to a random aggregation and dispersion of CNTs in polymer matrix with much lowered properties (see Figure S1), e.g., high electrical resistivity of 10 6 Ω ·cm for a CNT/poly(methyl methacrylate) composite. [ 4 , 8 ] To solve the above bottleneck, a lot of efforts have been paid to improve alignment of CNTs through assistance of electrical fi eld, gas fl owing, and surface-lattice-guided growth or use of CNT sheets. [ 9–16 ] However, it remains diffi cult to effi ciently control their structures, and the mechanical and electrical properties are far removed from the requirements for practical applications. Here, we develop a vertically aligned and penetrated CNT/polymer fi lm in which the CNT density and fi lm thickness can be accurately controlled. These composite fi lms exhibit intriguing optical and mechanical properties, e.g., they can be transparent and fl exible with high strength. Particularly, the composite fi lms exhibit excellent electronic properties due to open CNT ends on the two faces of composite fi lm, which is very promising for various electronic applications. [ 17 , 18 ] A study of the composite fi lms
Top priorities for alcohol regulators in the United States: protecting public health or the alcohol industry?

AIMS This paper describes alcohol industry involvement in the 2010 annual conference proceedings of the National Conference of State Liquor Administrators (NCSLA) in the United States. DESIGN The author attended the conference, observed conference attendees and panelists and identified key themes in the panel sessions. SETTING The NCSLA Annual Meeting took place 20-24 June 2010 in New Orleans, Louisiana. PARTICIPANTS NCSLA meeting attendees and panelists were professionals from state alcohol control systems; federal government agencies; and companies representing the alcohol industry. MEASUREMENTS The total number of conference attendees and participants were counted as well as the number of attendees and participants from regulator, industry and public health sectors. FINDINGS More than two-thirds (72.2%) of the 187 conference attendees were from alcohol producers, importers, wholesalers, retailers or their attorneys. Nearly two-thirds (65.0%) of the 40 panelists were from the alcohol industry. The author of this paper was the only attendee, and the only panelist, representing public health policy. CONCLUSIONS The National Conference of State Liquor Administrators in the United States is dominated by the global companies that produce, import, distribute and sell alcohol, highlighting a lack of public health considerations within the Association's liquor control agenda [corrected].
A Convenient Preparation of Multi‐Spectral Microparticles by Bacteria‐Mediated Assemblies of Conjugated Polymer Nanoparticles for Cell Imaging and Barcoding

A novel technique was developed for preparing encoded multicolour microparticles based on the self-assembly of bacteria and conjugated polymer nanoparticles (CPNs) by a very simple and time-saving manner. These bacteria-CPNs microparticles show multicolor emissions by tuning FRET efficiencies among CPNs under single excitation wavelength and can be successfully applied for cell imaging and optical barcoding.
Cross-regulatory protein–protein interactions between Hox and Pax transcription factors

Homeotic Hox selector genes encode highly conserved transcriptional regulators involved in the differentiation of multicellular organisms. Ectopic expression of the Antennapedia (ANTP) homeodomain protein in Drosophila imaginal discs induces distinct phenotypes, including an antenna-to-leg transformation and eye reduction. We have proposed that the eye loss phenotype is a consequence of a negative posttranslational control mechanism because of direct protein–protein interactions between ANTP and Eyeless (EY). In the present work, we analyzed the effect of various ANTP homeodomain mutations for their interaction with EY and for head development. Contrasting with the eye loss phenotype, we provide evidence that the antenna-to-leg transformation involves ANTP DNA-binding activity. In a complementary genetic screen performed in yeast, we isolated mutations located in the N terminus of the ANTP homeodomain that inhibit direct interactions with EY without abolishing DNA binding in vitro and in vivo. In a bimolecular fluorescence complementation assay, we detected the ANTP–EY interaction in vivo, these interactions occurring through the paired domain and/or the homeodomain of EY. These results demonstrate that the homeodomain supports multiple molecular regulatory functions in addition to protein–DNA and protein–RNA interactions; it is also involved in protein–protein interactions.
Multi-level analysis of alcohol-related injury and drinking pattern: emergency department data from 19 countries.

Aim While drinking in the event is an important factor in injury occurrence, the pattern of usual drinking may also be important in risk of injury. Explored here is the relationship of an alcohol-related injury with an individual usual drinking pattern. Design Alcohol-related injury is examined using hierarchical linear models, taking into account individual usual volume of consumption over the past 12 months, as well as aggregate-level detrimental drinking pattern (DDP) and alcohol policy measures. Setting Data analyzed are from emergency departments (EDs) in 19 countries, comprising three collaborative studies on alcohol and injury, all of which used a similar methodology. Participants The sample comprised 14 132 injured drinkers across 46 emergency room (ER) studies. Measurements Alcohol-related injury was measured, separately, by any self-reported drinking prior to injury, a blood alcohol concentration (BAC) ≥ 0.08 and self-reported causal attribution of injury to drinking. Findings While individual usual volume strongly predicted an alcohol-related injury for all three measures, usual drinking pattern also predicted an alcohol-related injury (controlling for volume), with episodic heavy and frequent heavy drinking both more predictive of alcohol-related injury than other drinking patterns. When individual usual volume and drinking pattern were controlled, DDP was no longer a significant predictor of alcohol-related injury. Alcohol policy measures were predictive of both BAC and causal attribution (the stronger the policy the lower the rates of alcohol-related injury). Conclusions Volume of alcohol typically consumed and occurrence of heavy drinking episodes are associated independently with incidence of alcohol-related injury. The stronger the anti-alcohol policies in a country, the lower the rates of alcohol-related injury.
Simultaneous Bayesian gene tree reconstruction and reconciliation analysis

We present GSR, a probabilistic model integrating gene duplication, sequence evolution, and a relaxed molecular clock for substitution rates, that enables genomewide analysis of gene families. The gene duplication and loss process is a major cause for incongruence between gene and species tree, and deterministic methods have been developed to explain such differences through tree reconciliations. Although probabilistic methods for phylogenetic inference have been around for decades, probabilistic reconciliation methods are far less established. Based on our model, we have implemented a Bayesian analysis tool, PrIME-GSR, for gene tree inference that takes a known species tree into account. Our implementation is sound and we demonstrate its utility for genomewide gene-family analysis by applying it to recently presented yeast data. We validate PrIME-GSR by comparing with previous analyses of these data that take advantage of gene order information. In a case study we apply our method to the ADH gene family and are able to draw biologically relevant conclusions concerning gene duplications creating key yeast phenotypes. On a higher level this shows the biological relevance of our method. The obtained results demonstrate the value of a relaxed molecular clock. Our good performance will extend to species where gene order conservation is insufficient.