Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure of MRDI Explains its Dual Function as a Metabolic Enzyme and a Mediator of Cell Invasion

Metastatic melanoma is among the most intractable cancers to treat, where patients show resistance to therapy and limited survival time. A critical step in the development of metastatic melanoma is the acquisition of invasion and transition from thin to thick tumors on the skin, followed by invasion to lymph nodes. Prior studies have shown that metastatic melanoma is associated with dysregulation of RhoA and enhanced expression of a protein named “mediator of RhoA-dependent invasion (MRDI)”. Importantly, MRDI is a “moonlighting” enzyme, with two distinct functions in melanoma cells. First, MRDI acts as a methylthioribose-1-phosphate (MTR-1-P) isomerase, catalyzing a critical step in methionine salvage. Second, MRDI promotes and is necessary for melanoma cell invasion, independent of its catalytic activity. Here, we demonstrate that MtnA, a bacterial MTR-1-P isomerase, rescues the methionine salvage function of MRDI, but is unable to rescue its role in invasion. We then solve the crystal structure of MRDI to a resolution of 2.5 Å, in order to identify structural elements important for its invasion activity. We present this structure and its comparison with other MTR-1-P isomerases, and identify mutations within a region separate from the MTR-1-P binding site which interfere with invasion. Thus, structural elements in MRDI distal from the MTR-1-P catalytic site are responsible for the invasion phenotype.
Pre-existing Periapical Inflammatory Condition Exacerbates Tooth Extraction–induced BRONJ Lesions in Mice

Introduction— Surgical interventions such as tooth extraction increase a chance of developing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BPs) for treatment of bone-related diseases. Tooth extraction is often performed to eliminate pre-existing pathological inflammatory conditions that make the tooth unsalvageable; however, the role of such conditions on bisphosphonate-related ONJ (BRONJ) development following tooth extraction is not clearly defined. Here, we examined the effects of periapical periodontitis on tooth extraction-induced BRONJ development in mice. Methods— Periapical periodontitis was induced by exposing the pulp of the maxillary first molar for 3 weeks in C57/BL6 mice that were intravenously administered with BP. The same tooth was extracted, and after 3 additional weeks, the mice were harvested for histological, histomorphometric, and histochemical staining analyses. Results— Pulp exposure induced periapical radiolucency as demonstrated by increased inflammatory cells, TRAP+ osteoclasts, and bone resorption. When BP was administered, pulp exposure did not induce apical bone resorption despite the presence of inflammatory cells and TRAP+ osteoclasts. While tooth extraction alone induced BRONJ lesions, pulp exposure further increased tooth extraction-induced BRONJ development as demonstrated by the presence of more bone necrosis. Conclusion— Our study demonstrates that pre-existing pathological inflammatory condition such as periapical periodontitis is a predisposing factor that may exacerbate BRONJ development following tooth extraction. Our study further provides a clinical implication whereby periapical periodontitis should be controlled before performing tooth extraction in BP-users in order to reduce the risk of developing BRONJ.
Design of high efficiency centrifugal compressors stages

The modern trend in compressor industry is an extension of the use of multi-shaft centrifugal compressors. Multi-shaft compressors have a number of advantages over single-shaft. The design of such compressors gives opportunity to use an axial inlet for all stages and select the optimum rotational speed for each pair of impellers, which, along with the cooling of the gas after each stage, makes possible to achieve high levels of efficiency. The design of high-efficiency centrifugal compressor stages can be performed on the basis of highly effective stage elements. Such elements are: impellers with spatial blades, vaned and channel diffusers with given velocity distribution. In this paper, impellers with axial-radial blades are considered. The blade profile is determined by the specified pressure distribution along the blade. Such design improves the structure of the gas flow in the interblade channels of the impeller, which leads to an increase in its efficiency. Characteristics of loss coefficients from attack angles for impellers were obtained experimentally. Vaned and channel diffusers, the characteristics of which are given in this article, are designed with the given velocity distribution along the vane. Compared to the classic type of diffuser, such diffusers have lower losses and a wider range of economical operation. For diffusers as well as for impellers, characteristics of loss coefficients from attack angles were obtained. High efficient impellers and diffusers and obtained gas-dynamic characteristics were used in the design of a multi-shaft compressor unit for the production of liquefied natural gas. The initial pressure of the unit is 3bar. The obtained characteristics of loss coefficients from attack angles for the considered impellers and diffusers make it possible to calculate the gas-dynamic characteristics of high-efficient centrifugal compressors stages. The high-efficient centrifugal compressors stages can be designed using high-efficient elements, such as: impeller with spatial blades and vaned diffuser with given velocity distribution.
Mapping chromatin interactions with 5C technology: 5C; a quantitative approach to capturing chromatin conformation over large genomic distances

In eukaryotes, genome organization can be observed on many levels and at different scales. This organization is important not only to reduce chromosome length but also for the proper execution of various biological processes. High-resolution mapping of spatial chromatin structure was made possible by the development of the chromosome conformation capture (3C) technique. 3C uses chemical cross-linking followed by proximity-based ligation of fragmented DNA to capture frequently interacting chromatin segments in cell populations. Several 3C-related methods capable of higher chromosome conformation mapping throughput were reported afterwards. These techniques include the 3C-carbon copy (5C) approach, which offers the advantage of being highly quantitative and reproducible. We provide here a reference protocol for the production of 5C libraries analyzed by next-generation sequencing or onto microarrays. A procedure used to verify that 3C library templates bear the high quality required to produce superior 5C libraries is also described. We believe that this comprehensive detailed protocol will help guide researchers in probing spatial genome organization and its role in various biological processes.
Smoking, inflammatory patterns and postprandial hypertriglyceridemia 1

Background— Smoking is associated with increased postprandial hypertriglyceridemia (PPT). Inflammation and insulin resistance are potential “drivers” for this phenomenon. We tested whether inflammatory patterns and/or insulin resistance explain the effect of smoking on PPT. Methods and Results— Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n=1036, age 49±16 y) were included. Each participant was asked to suspend use of lipid-lowering drugs for three weeks and was given a high-fat milkshake (83% fat and 700 kcal/m 2 ). Triglyceride concentrations at 0, 3.5 and 6 hr after the fat load were measured. Inflammatory markers were measured at baseline. Principal component analysis was used to derive inflammatory patterns from individual inflammatory markers (hsCRP, IL2 soluble receptor- α , IL6, TNF- α and MCP-1). Insulin resistance (IR) was estimated using the HOMA equation. Repeated measures-ANOVA was used for analyses. Two inflammatory patterns, namely CRP-IL6 pattern and MCP1-TNF- α pattern, were derived. We found significant main (smoking and time) and
Methodology of 1 H NMR Spectroscopy of the Human Brain at Very High Magnetic Fields

An ultrashort-echo-time stimulated echo-acquisition mode (STEAM) pulse sequence with interleaved outer volume suppression and VAPOR (variable power and optimized relaxation delays) water suppression was redesigned and optimized for human applications at 4 and 7 T, taking into account the specific requirements for spectroscopy at high magnetic fields and limitations of currently available hardware. In combination with automatic shimming, automated parameter adjustments and data processing, this method provided a user-friendly tool for routine 1 H nuclear magnetic resonance (NMR) spectroscopy of the human brain at very high magnetic fields. Effects of first- and second-order shimming, single-scan averaging, frequency and phase corrections, and eddy currents were described. LCModel analysis of an in vivo 1 H NMR spectrum measured from the human brain at 7 T allowed reliable quantification of more than fifteen metabolites noninvasively, illustrating the potential of high-field NMR spectroscopy. Examples of spectroscopic studies performed at 4 and 7 T demonstrated the high reproducibility of acquired spectra quality. based on band-selective RF pulses and gradients were developed using “low-field” MR scanners. Pulse sequences designed for single-voxel NMR spectroscopy at high magnetic fields must take into account increased off-resonance effects at high fields that cause chemical shift displacement errors. In addition, high-field NMR spectroscopy of humans has specific requirements for the hardware (performance of the gradient system and RF coils), elimination of B 0 inhomogeneity (shimming), specific absorption rate (SAR), etc.
NAC1, a POZ/BTB protein binds to TDP-43 and has a potential role in Amyotrophic Lateral Sclerosis

Protein degradation is a critical component of cellular maintenance. The intracellular translocation and targeting of the Ubiquitin Proteasome System (UPS) differentially coordinates a protein's half-life and thereby its function. NAC1 (Nucleus Accumbens 1), a member of the POZ/BTB family of proteins, participates in the coordinated proteolysis of synaptic proteins by mediating recruitment of the UPS to dendritic spines. Here we report a novel interaction between NAC1 and TDP-43 (TAR DNA-binding Protein 43), a protein identified as the primary component of ubiquitinated protein aggregates found in patients with Amyotrophic Lateral Sclerosis (ALS). In vitro translated full-length TDP-43 associated with both the POZ/BTB domain and the non-POZ/BTB domain of NAC1 in GST pulldown assays. Other POZ/BTB proteins (including zinc finger POZ/BTB proteins and atypical POZ/BTB proteins) showed weak interactions with TDP-43. In addition, NAC1 and TDP-43 were present in the same immunocomplexes in different regions of mouse brain and spinal cord. In primary spinal cord cultures, TDP-43 expression was mainly nuclear, whereas NAC1 was both nuclear and cytoplasmic. In order to mimic ALS-like toxicity in the spinal cord culture system, we elevated extracellular glutamate levels resulting in the selective loss of motor neurons. Using this model, it was found that glutamate toxicity elicited a dose-dependent translocation of TDP-43 out of the nucleus of cholinergic neurons and increased the colocalization of NAC1 and TDP-43. These findings suggest that NAC1 may function to link TDP-43 to the proteasome; thereby, facilitating the post-translational modifications of TDP-43 that lead to the development of ALS.
Esc4 and the Control of Recombination During Replication

When replication forks stall during DNA synthesis, cells respond by assembling multi-protein complexes to control the various pathways that stabilize the replication machinery, repair the replication fork, and facilitate the reinitiation of processive DNA synthesis. Increasing evidence suggests that cells have evolved scaffolding proteins to orchestrate and control the assembly of these repair complexes, typified in mammalian cells by several BRCT-motif containing proteins, such as Brca1, Xrcc1, and 53BP1. In Saccharomyces cerevisiae , Esc4 contains six such BRCT domains and is required for the most efficient response to a variety of agents that damage DNA. We show that Esc4 interacts with several proteins involved in the repair and processing of stalled or collapsed replication forks, including the recombination protein Rad55. However, the function of Esc4 does not appear to be restricted to a Rad55-dependent process, as we observed an increase in sensitivity to the DNA alkylating agent methane methylsulfonate (MMS) in a esc4 Δ rad55 Δ mutant, as well as in double mutants of esc4 Δ and other recombination genes, compared to the corresponding single mutants. In addition, we show that Esc4 forms multiple nuclear foci in response to treatment with MMS. Similar behavior is also observed in the absence of damage when either of the S-phase checkpoint proteins, Tof1 or Mrc1, is deleted. Thus, we propose that Esc4 associates with ssDNA of stalled forks and acts as a scaffolding protein to recruit and/or modulate the function of other proteins required to reinitiate DNA synthesis. mouse secondary antibody (Upstate), and ECL(+) (AP Biotech).
Structural and Mechanistic Studies of HpxO, a Novel FAD-dependent Urate Oxidase from Klebsiella pneumoniae †,‡

HpxO is a flavin-dependent urate oxidase that catalyzes the hydroxylation of uric acid to 5-hydroxyisourate and functions in a novel pathway for purine catabolism found in Klebsiella pneumoniae. We have determined the structures of HpxO with and without uric acid at 2.0 Å and 2.2 Å, respectively. We have also determined the structure of the R204Q variant at 2.0 Å resolution in the absence of uric acid. The variant structure is very similar to wild type HpxO except for the conformation of Arg103, which interacts with FAD in the variant but not in the wild type structure. Interestingly, the R204Q variant results in the uncoupling of NADH oxidation from uric acid hydroxylation. This suggests that Arg204 facilitates the deprotonation of uric acid activating it for the oxygen transfer. Based on these data, a mechanism for this reaction is proposed consisting of a nucleophilic attack of the urate anion on the flavin hydroperoxide resulting in the formation of 5-hydroxyisourate.
proteins for the first nucleotide in the histone mRNA hairpin loop Specificities of Caenorhabditis elegans and human hairpin binding

The 3 9 ends of animal replication-dependent histone mRNAs are formed by endonucleolytic cleavage of the primary transcripts downstream of a highly conserved RNA hairpin. The hairpin-binding protein (HBP) binds to this RNA element and is involved in histone RNA 3 9 processing. A minimal RNA-binding domain (RBD) of ; 73 amino acids that has no similarity with other known RNA-binding motifs was identified in human HBP [Wang Z-F et al., Genes&Dev, 1996, 10:3028-3040]. The primary sequence identity between human and CaenorhabditiselegansRBDs is 55% compared to 38% for the full-length proteins. We analyzed whether differences between C.elegansand human HBP and hairpins are reflected in the specificity of RNA binding. The C.elegansHBP and its RBD recognize only their cognate RNA hairpins, whereas the human HBP or RBD can bind both the mammalian and the C. elegans hairpins. This selectivity of C.elegansHBP is mostly mediated by the first nucleotide in the loop, which is C in C.elegansand U in all other metazoans. By converting amino acids in the human RBD to the corresponding C.elegansresidues at places where the latter deviates from the consensus, we could identify two amino acid segments that contribute to selectivity for the first nucleotide of the hairpin loop.
Effective algorithm for tomography imaging in threedimensional problems

This article presents a new effective imaging method that can be applied in ultrasonic and radio tomography. The proposed method by changing the shape of the voxels leads to a substantial simplification of the algorithm at the cost of small approximations of the voxels. As proved in the work, these approximations do not have a significant impact on the readability of the image which is several times faster. Streszczenie. W pracy przedstawiono nową efektywną metodę obrazowania, która może mieć zastosowanie w transmisyjnej tomografii ultradźwiękowej lub radiowej. Proponowana metoda zmienia kształt voksela z sześciennego na kulisty dzięki czemu uzyskuje się znaczące uproszczenie algorytmu kosztem niewielkiej aproksymacji wokseli. Jak udowodniono w pracy, przyjęta aproksymacja nie ma znaczącego wpływu na wiarygodność obrazów, a jest kilkukrotnie bardziej efektywna. Efektywny algorytm do konstrukcji trójwymiarowych obrazów tomograficznych
Validation of Velocity-SS-PARSE for Single-shot Flow Measurement

As a variant of SS-PARSE (Single-Shot Parameter Assessment by Retrieval from Signal Encoding), Velocity-SS-PARSE (V-SS-PARSE), a single-shot imaging method has been developed to realize fast and straightforward flow quantification by solving an inverse problem. A robust signal model is described here that includes the local magnetization and its phase evolution during the signal, resulting in a more precise representation of the sampled signal. Magnitude, velocity, relaxation rate and frequency information can be retrieved without any extra reference image acquisitions, as demonstrated by phantom studies. Retrieved magnitude and velocity maps show results comparable to those obtained by phase contrast (PC) methods (correlation of r > 0.99 at p = 0.005) in the presence of stationary background, even with brief single-shot 70 ms acquisition.
A putative functional variant within the ubiquitin-associated domain-containing protein 2 gene ( UBAC2 ) is associated with increased risk of Behçet’s disease

Objectives— Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet’s disease. Herein, we establish the genetic effect within the UBAC2 gene, replicate this genetic association, and identify a functional variant within this locus. Methods— A total of 676 Behçet’s disease patients and 1,096 controls were studied. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls, and 144 patients and 560 controls, from Turkey and Italy, respectively. Genotyping of 14 SNPs within and around UBAC2 was performed using TaqMan SNP genotyping assays. Results— The genetic association between Behçet’s disease and UBAC2 was established, replicated and confirmed (Meta-analysis OR= 1.84, meta-analysis P= 1.69X10 − 7 ). Haplotype analysis identified both a disease risk and a protective haplotype (P= 0.00014 and 0.0075, respectively). Using conditional haplotype analysis we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrate that rs7999348 tags a functional variant associated with increased mRNA expression of a UBAC2 transcript variant in PBMCs of individuals homozygous for the Behçet’s disease-associated “G” allele. Further, our data suggest the possibility of multiple genetic effects that increase susceptibility to Behçet’s disease in the UBAC2 locus. We
VALUES AND LIMITATIONS OF STATISTICAL MODELS

Methodological consequences of population heterogeneity for the sequential logit model in studies of education transitions are now well understood. There are two main mechanisms by which heterogeneity may cause biases to parameter estimates in sequential logit models: outcome incommensurability and population incommensurability. These methodological problems are intrinsic to the substantive research question and thus are not easily remediable with better statistical models. All statistical solutions require extra information in the form of additional data or additional assumptions. In some settings, the researcher may explicitly introduce a form of heterogeneity into the sequential logit model and then evaluate the model. In other settings, the researcher may wish to stay with the conventional sequential logit model and interpret the results descriptively.
Electrostatic stabilization in four-helix bundle proteins

Charge substitutions generated by site-directed mutagenesis at the termini of adjacent anti-parallel a-helices in a four-helix bundle protein were used to determine a precise value for the contribution of indirect charge-charge interactions to overall protein stability, and to simulate the electrostatic effects of a-helix macrodipoles. Thermodynamic double mutant cycles were constructed to measure the interaction energy between such charges on adjacent anti-parallel helices in the four-helix bundle cytochrome b562 from Escherichia coli. Previously, theoretical calculations of helix macrodipole interactions using modeled four-helix bundle proteins have predicted values ranging over an order of magnitude from 0.2 to 2.5 kcal/mol. Our system represents the first experimental evidence for electrostatic interactions such as those between partial charges due to helix macrodipole charges. At the positions mutated, we have measured a favorable interaction energy of 0.6 kcal/mol between opposite charges simulating an anti-parallel helix pair. Pairs of negative or positive charges simulating a parallel orientation of helices produce an unfavorable interaction of similar magnitude. The interaction energies show a strong dependence upon ionic strength, consistent with an electrostatic effect. Indirect electrostatic contacts do appear to confer a limited stabilization upon the association of anti-parallel packing of helices, favoring this orientation by as much as 1 kcal/mol at 20 mM K phosphate.
Poor Pre-Pregnancy and Antepartum Mental Health Predicts Postpartum Mental Health Problems among US Women: A Nationally Representative Population-Based Study

Purpose— Mental health problems disproportionately affect women, particularly during childbearing years. However, there is a paucity of research on the determinants of postpartum mental health problems using representative US populations. Taking a life course perspective, we determined the potential risk factors for postpartum mental health problems, with a particular focus on the role of mental health before and during pregnancy. Methods— We examined data on 1,863 mothers from eleven panels of the 1996-2006 Medical Expenditure Panel Survey (MEPS). Poor postpartum mental health was defined using self-reports of mental health conditions, symptoms of mental health conditions, or global mental health ratings of “fair” or “poor. ” Results— 9.5% of women reported experiencing postpartum mental health problems, with over half of these women reporting a history of poor mental health. Poor pre-pregnancy mental health and poor antepartum mental health both independently increased the odds of having postpartum mental health problems. Staged multivariate analyses revealed that poor antepartum mental health attenuated the relationship between pre-pregnancy and postpartum mental health problems. Additionally, significant disparities exist in women's report of postpartum mental health status. Conclusions— While poor antepartum mental health is the strongest predictor of postpartum mental health problems, pre-pregnancy mental health is also important. Accordingly, health care providers should identify, treat, and follow women with a history of poor mental health, as they are particularly susceptible to postpartum mental health problems. This will ensure that women and their children are in the best possible health and mental health during the postpartum period and beyond.