Miracle-dz/UniFAR-FTUs huggingface dataset:
Trinity revealed: Stoichiometric complex assembly of a bacterial multidrug efflux pump

The capacity of bacteria to expel from themselves a broad diversity of compounds confers upon them resistance to drugs and other bacteriocidal agents (1). In Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa multidrug efflux is achieved by energy-powered macromolecular machinery that extrudes cytotoxic substances like multiple anti biotics, dyes, bile salts, and detergents from the inner membrane of the cell directly into the medium, bypassing the periplasm and the outer membrane. Known complexes of such multidrug efflux pumps are composed for three types of components: an outer membrane channel, a periplasmic bridge, and an inner membrane energy-transducer. There are a variety of possible inner membrane components, which can include members of the ATP binding cassette transporter superfamily, the major facilitator superfamily, or the resistance nodulation cell division (RND) superfamily. These inner membrane-located units are the major sites for substrate recognition and energy transduction of the entire tripartite system and function in conjunction with the 2 other pump components. The periplasmic bridge component often goes by the name of “membrane fusion protein” (MFP) for historical reasons and is represented by the AcrA protein. Well-characterized representatives of the outer membrane factor (OMF) are channel-like proteins such as TolC. Both the outer membrane and tripartite efflux pumps are considered to be the main barrier for drugs on their way to the inside of the bacterial cell (2). Importantly, only assembly of all 3 components into a trinity results in an active and effective drug efflux phenotype. In this issue of PNAS, Symmons et al. (3) complete the picture of an E. coli 3-component multidrug efflux system with a well-tested and insightful model.
Engineering the Electronic Structure of Graphene

Graphene exhibits many unique electronic properties owing to its linear dispersive electronic band structure around the Dirac point, making it one of the most studied materials in the last 5‐6 years. However, for many applications of graphene, further tuning its electronic band structure is necessary and has been extensively studied ever since graphene was first isolated experimentally. Here we review the major progresses made in electronic structure engineering of graphene, namely by electric and magnetic fields, chemical intercalation and adsorption, stacking geometry, edge‐chirality, defects, as well as strain.
Effect of alendronate on bone density and bone markers in postmenopausal osteoporosis

The aim of this randomized, controlled study was to evalaute effects of 12 months alendronate therapy on bone mineral density (BMD) and markers of bone formation and resorption in women with postmenopausal osteoporosis. Study enrolled women with BMD at least 2 SD below adult, premenopausal BMD mean. Patients to be treated were randomized into two groups. Patients in the control group received 500 mg elemental calcium tablet daily and treatment group received 10 mg/day alendronate and 500 mg elemental calcium tablet for twelve months. Pretreatment characteristics of patients in both groups were similar. A significant increase in BMD of the treatment group patients compared to control group was observed at 12 months ( p< 0.001). Markers of bone formation and resorption in the treatment group reduced significantly at 6 and 12 months of therapy compared to control group ( p< 0.001). In conclusion, we found that 12 months alendronate therapy (10 mg/day) significantly increased BMD in all sites of measurement compared to control group and also significantly reduced markers of bone formation and resorption at all time points (at 6 and 12 months) in postmenopausal women with osteoporosis compared to control group. It is fact that bone density clearly improved by alendronate therapy and the biochemical markers were shown as valid tools for monitoring and prediction of treatment effect of alendronate therapy.
Modulation of long-term memory for object recognition via HDAC inhibition

Histone acetylation is a chromatin modification critically involved in gene regulation during many neural processes. The enzymes that regulate levels of histone acetylation are histone acetyltransferases (HATs), which activate gene expression and histone deacetylases (HDACs), that repress gene expression. Acetylation together with other histone and DNA modifications regulate transcription profiles for specific cellular functions. Our previous research has demonstrated a pivotal role for cyclicAMP response element binding protein (CREB)-binding protein (CBP), a histone acetyltransferase, in long-term memory for novel object recognition (NOR). In fact, every genetically modifiedCbp mutant mouse characterized thus far exhibits impaired long-term memory for NOR. These results suggest that long-term memory for NOR is especially sensitive to alterations in CBP activity. Thus, in the current study, we examined the role of HDACs in memory for NOR. We found that inducing a histone hyperacetylated state via HDAC inhibition transforms a learning event that would not normally result in long-term memory into an event that is now remembered long-term. We have also found that HDAC inhibition generates a type of long-term memory that persists beyond a point at which normal memory for NOR fails. This result is particularly interesting because one alluring aspect of examining the role of chromatin modifications in modulating transcription required for long-term memory processes is that these modifications may provide potentially stable epigenetic markers in the service of activating and/or maintaining transcriptional processes.
Brain sensitivity to print emerges when children learn letter–speech sound correspondences

The acquisition of reading skills is a major landmark process in a human's cognitive development. On the neural level, a new functional network develops during this time, as children typically learn to associate the well-known sounds of their spoken language with unfamiliar characters in alphabetic languages and finally access the meaning of written words, allowing for later reading. A critical component of the mature reading network located in the left occipito-temporal cortex, termed the “visual word-form system” (VWFS), exhibits print-sensitive activation in readers. When and how the sensitivity of the VWFS to print comes about remains an open question. In this study, we demonstrate the initiation of occipito-temporal cortex sensitivity to print using functional MRI (fMRI) (n = 16) and event-related potentials (ERP) (n = 32) in a controlled, longitudinal training study. Print sensitivity of fast (<250 ms) processes in posterior occipito-temporal brain regions accompanied basic associative learning of letter–speech sound correspondences in young (mean age 6.4 ± 0.08 y) nonreading kindergarten children, as shown by concordant ERP and fMRI results. The occipito-temporal print sensitivity thus is established during the earliest phase of reading acquisition in childhood, suggesting that a crucial part of the later reading network first adopts a role in mapping print and sound.
Tailored 3D Mechanical Metamaterials Made by Dip‐in Direct‐Laser‐Writing Optical Lithography

Dip-in direct-laser-writing (DLW) optical lithography allows fabricating complex three-dimensional microstructures without the height restrictions of regular DLW. Bow-tie elements assembled into mechanical metamaterials with positive/zero/negative Poisson's ratio and with sufficient overall size for direct mechanical characterization aim at demonstrating the new possibilities with respect to rationally designed effective materials.
Differential distribution of endoplasmic reticulum controls metabotropic signaling and plasticity at hippocampal synapses

Synaptic plasticity is considered essential for learning and storage of new memories. Whether all synapses on a given neuron have the same ability to express long-term plasticity is not well understood. Synaptic microanatomy could affect the function of local signaling cascades and thus differentially regulate the potential for plasticity at individual synapses. Here, we investigate how the presence of endoplasmic reticulum (ER) in dendritic spines of CA1 pyramidal neurons affects postsynaptic signaling. We show that the ER is targeted selectively to large spines containing strong synapses. In ER-containing spines, we frequently observed synaptically triggered calcium release events of very large amplitudes. Low-frequency stimulation of these spines induced a permanent depression of synaptic potency that was independent of NMDA receptor activation and specific to the stimulated synapses. In contrast, no functional changes were induced in the majority of spines lacking ER. Both calcium release events and long-term depression depended on the activation of metabotropic glutamate receptors and inositol trisphosphate receptors. In summary, spine microanatomy is a reliable indicator for the presence of specific signaling cascades that govern plasticity on a micrometer scale.
Achieving High Field‐Effect Mobility in Amorphous Indium‐Gallium‐Zinc Oxide by Capping a Strong Reduction Layer

An effective approach to reduce defects and increase electron mobility in a-IGZO thin-film transistors (a-IGZO TFTs) is introduced. A strong reduction layer, calcium, is capped onto the back interface of a-IGZO TFT. After calcium capping, the effective electron mobility of a-IGZO TFT increases from 12 cm(2) V(-1) s(-1) to 160 cm(2) V(-1) s(-1). This high mobility is a new record, which implies that the proposed defect reduction effect is key to improve electron transport in oxide semiconductor materials.
Optimized treatment parameters to account for interfractional variability in scanned ion beam therapy of lung cancer

Scanned ion beam therapy of lung tumors is severely limited in its clinical applicability by intrafractional organ motion, interference effects between beam and tumor motion (interplay) as well as interfractional anatomic changes. To compensate for dose deterioration by intrafractional motion, motion mitigation techniques, such as gating have been developed. The latter confines the irradiation to a predetermined breathing state, usually the stable end-exhale phase. However, optimization of the treatment parameters is needed to further improve target dose coverage and normal tissue sparing. The aim of the study presented in this dissertation was to determine treatment planning parameters that permit to recover good target coverage and homogeneity during a full course of lung tumor treatments. For 9 lung tumor patients from MD Anderson Cancer Center (MDACC), a total of 70 weekly time-resolved computed tomography (4DCT) datasets were available, which depict the evolution of the patient anatomy over the several fractions of the treatment. Using the GSI in-house treatment planning system (TPS) TRiP4D, 4D simulations were performed on each weekly 4DCT for each patient using gating and optimization of a single treatment plan based on a planning CT acquired prior to treatment. It was found that using a large beam spot size, a short gating window (GW), additional margins and multiple fields permitted to obtain the best results, yielding an average target coverage (V95) of 96.5%. Two motion mitigation techniques, one approximating the rescanning process (multiple irradiations of the target with a fraction of the planned dose) and one combining the latter and gating, were then compared to gating. Both did neither show an improvement in target dose coverage nor in normal tissue sparing. Finally, the total dose delivered to each patient in a simulation of a fractioned treatment was calculated and clinical requirements in terms of target coverage and normal tissue sparing were considered. The results showed that the total V95 obtained for the entire course of the treatment was similar to the one obtained for the planning CT, which shows that interfractional variability was successfully compensated. For 4 patients out of 9, V95 > 95% was thus obtained for both the planning CT and the total dose target coverage. For the rest of the cohort, a slight modification of the contours or dose reduction should permit to obtain a better clinical treatment plan that could be delivered over the course of the treatment. In the presented study, intrafractional motion occuring during the treatment of lung tumors was efficiently mitigated using optimized treatment planning parameters and gating, while interfractional variability showed the largest impact on dose delivery. Nevertheless, this variability was efficiently mitigated, as shown by target dose coverage obtained at the end of the treatment which was very close to the one obtained for the planning CT.
Transcatheter arterial chemoembolization vs. chemoinfusion for unresectable hepatocellular carcinoma in patients with major portal vein thrombosis

Background Transcatheter arterial chemoembolization (TACE) has been limited in palliative treatment of unresectable hepatocellular carcinoma (HCC) with major portal vein (PV) invasion due to the possibility of liver failure following embolization. Transcatheter arterial chemoinfusion (TACI) has been an option in such cases.
Spliceosome discards intermediates via the DEAH box ATPase Prp43p

To promote fidelity in nuclear pre-mRNA splicing, the spliceosome rejects and discards suboptimal substrates that have engaged the spliceosome. Whereas DExD/H box ATPases have been implicated in rejecting suboptimal substrates, the mechanism for discarding suboptimal substrates has remained obscure. Corroborating evidence that suboptimal, mutated lariat intermediates can be exported to the cytoplasm for turnover, we have found that the ribosome can translate mutated lariat intermediates. By glycerol gradient analysis, we have found that the spliceosome can dissociate mutated lariat intermediates in vivo in a manner that requires the DEAH box ATPase Prp43p. Through an in vitro assay, we demonstrate that Prp43p promotes the discard of suboptimal and optimal 5′ exon and lariat intermediates indiscriminately. Finally, we demonstrate a requirement for Prp43p in repressing splicing at a cryptic splice site. We propose a model for the fidelity of exon ligation in which the DEAH box ATPase Prp22p slows the flow of suboptimal intermediates through exon ligation and Prp43p generally promotes discard of intermediates, thereby establishing a pathway for turnover of stalled intermediates. Because Prp43p also promotes spliceosome disassembly after exon ligation, this work establishes a parallel between the discard of suboptimal intermediates and the dissociation of a genuine excised intron product.
Repression of α-synuclein expression and toxicity by microRNA-7

α-Synuclein is a key protein in Parkinson's disease (PD) because it accumulates as fibrillar aggregates in pathologic hallmark features in affected brain regions, most notably in nigral dopaminergic neurons. Intraneuronal levels of this protein appear critical in mediating its toxicity, because multiplication of its gene locus leads to autosomal dominant PD, and transgenic animal models overexpressing human α-synuclein manifest impaired function or decreased survival of dopaminergic neurons. Here, we show that microRNA-7 (miR-7), which is expressed mainly in neurons, represses α-synuclein protein levels through the 3′-untranslated region (UTR) of α-synuclein mRNA. Importantly, miR-7-induced down-regulation of α-synuclein protects cells against oxidative stress. Further, in the MPTP-induced neurotoxin model of PD in cultured cells and in mice, miR-7 expression decreases, possibly contributing to increased α-synuclein expression. These findings provide a mechanism by which α-synuclein levels are regulated in neurons, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for PD and other α-synucleinopathies.
COFACTOR: improved protein function prediction by combining structure, sequence and protein–protein interaction information

Abstract The COFACTOR web server is a unified platform for structure-based multiple-level protein function predictions. By structurally threading low-resolution structural models through the BioLiP library, the COFACTOR server infers three categories of protein functions including gene ontology, enzyme commission and ligand-binding sites from various analogous and homologous function templates. Here, we report recent improvements of the COFACTOR server in the development of new pipelines to infer functional insights from sequence profile alignments and protein–protein interaction networks. Large-scale benchmark tests show that the new hybrid COFACTOR approach significantly improves the function annotation accuracy of the former structure-based pipeline and other state-of-the-art functional annotation methods, particularly for targets that have no close homology templates. The updated COFACTOR server and the template libraries are available at http://zhanglab.ccmb. med.umich. edu/COFACTOR/.
Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role

The immune receptor signaling pathway is used by nonimmune cells, but the molecular adaptations that underlie its functional diversification are not known. Circulating platelets use the immune receptor homologue glycoprotein VI (GPVI) to respond to collagen exposed at sites of vessel injury. In contrast to immune cell responses, platelet activation must take place within seconds to successfully form thrombi in flowing blood. Here, we show that the GPVI receptor utilizes a unique intracellular proline-rich domain (PRD) to accelerate platelet activation, a requirement for efficient platelet adhesion to collagen under flow. The GPVI PRD specifically binds the Src-family kinase Lyn and directly activates it, presumably through SH3 displacement. In resting platelets, Lyn is constitutively bound to GPVI in an activated state and platelets lacking Lyn exhibit defective collagen adhesion like that of platelets with GPVI receptors lacking the PRD. These findings define a molecular priming mechanism that enables an immune-type receptor to adopt a hemostatic function. These studies also demonstrate that active kinases can constitutively associate with immune-type receptors without initiating signal transduction before receptor ligation, consistent with a recent molecular model of immune receptor signaling in which receptor ligation is required to bring active kinases to their receptor substrates.
Superhydrophobic Surfaces with Photocatalytic Self‐Cleaning Properties by Nanocomposite Coating of TiO2 and Polytetrafluoroethylene

Superhydrophobic surfaces with photocatalytic self-cleaning properties are designed through coating a nanocomposite TiO(2) photocatalyst and hydrophobic polytetrafluoroethylene onto a structured substrate by applying a co-deposition technique. This coating realizes adequate photocatalytic activity for self-cleaning and inducing unique surface wettability changes. The nanocomposite can contain multiple functions, enabling energy-saving and maintenance-free characteristics.
Calcium influx is sufficient to induce muscular dystrophy through a TRPC-dependent mechanism

Muscular dystrophy is a general term encompassing muscle disorders that cause weakness and wasting, typically leading to premature death. Membrane instability, as a result of a genetic disruption within the dystrophin-glycoprotein complex (DGC), is thought to induce myofiber degeneration, although the downstream mechanism whereby membrane fragility leads to disease remains controversial. One potential mechanism that has yet to be definitively proven in vivo is that unregulated calcium influx initiates disease in dystrophic myofibers. Here we demonstrate that calcium itself is sufficient to cause a dystrophic phenotype in skeletal muscle independent of membrane fragility. For example, overexpression of transient receptor potential canonical 3 (TRPC3) and the associated increase in calcium influx resulted in a phenotype of muscular dystrophy nearly identical to that observed in DGC-lacking dystrophic disease models, including a highly similar molecular signature of gene expression changes. Furthermore, transgene-mediated inhibition of TRPC channels in mice dramatically reduced calcium influx and dystrophic disease manifestations associated with the mdx mutation (dystrophin gene) and deletion of the δ-sarcoglycan (Scgd) gene. These results demonstrate that calcium itself is sufficient to induce muscular dystrophy in vivo, and that TRPC channels are key disease initiators downstream of the unstable membrane that characterizes many types of muscular dystrophy.
IS ACROMEGALY A HYPERCOAGULABLE CONDITION? CASE REPORTS AND REVIEW OF THE LITERATURE

Introduction: Cardiovascular complications are a major cause of morbidity and mortality in patients with uncontrolled acromegaly. However, there are no published reports of an increased risk of venous thromboembolism (VTE) in such patients. We report three patients with uncontrolled acromegaly who presented with VTE. Clinical Cases: A 52-year-old male with uncontrolled acromegaly despite transsphenoidal (TSP) surgery and medical therapy presented in 2012 with acute chest pain and shortness of breath that was later con rmed as secondary to pulmonary embolism. A 44-year-old male immigrant, previously treated for acromegaly with radiation therapy alone, in 1992, in his native country, was referred to our centre in 2006 for acromegaly which remained uncontrolled despite medical therapy until 2009 when he achieved remission through TSP surgery. He had several episodes of VTE between 2008 and 2010. A 69-year-old male with uncontrolled acromegaly for 28 years despite two surgical resections and radiation therapy in 1986 and 1992, as well as continuous medical therapy, presented with VTE of the right axillary vein and bilateral pulmonary emboli in 2011. A thrombophilia screen in case 1 showed mild protein S de ciency, case 2 was homozygous for factor V Leiden (FVL) mutation and case 3 was heterozygous for FVL. Extensive investigations revealed no evidence of malignancy and echocardiography showed preserved ejection fraction in all three patients. Conclusion: Patients with uncontrolled acromegaly may be at increased risk of VTE. However, larger studies are required to further assess this association and determine the underlying cause. Key words: Acromegaly, pituitary tumours, thromboembolism
Ribosomal DNA contributes to global chromatin regulation

The 35S ribosomal RNA genes (rDNA) are organized as repeated arrays in many organisms. Epigenetic regulation of transcription of the rRNA results in only a subset of copies being transcribed, making rDNA an important model for understanding epigenetic chromatin modification. We have created an allelic series of deletions within the rDNA array of the Drosophila Y chromosome that affect nucleolus size and morphology, but do not limit steady-state rRNA concentrations. These rDNA deletions result in reduced heterochromatin-induced gene silencing elsewhere in the genome, and the extent of the rDNA deletion correlates with the loss of silencing. Consistent with this, chromosomes isolated from strains mutated in genes required for proper heterochromatin formation have very small rDNA arrays, reinforcing the connection between heterochromatin and the rDNA. In wild-type cells, which undergo spontaneous natural rDNA loss, we observed the same correlation between loss of rDNA and loss of heterochromatin-induced silencing, showing that the volatility of rDNA arrays may epigenetically influence gene expression through normal development and differentiation. We propose that the rDNA contributes to a balance between heterochromatin and euchromatin in the nucleus, and alterations in rDNA—induced or natural—affect this balance.