Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutation of a kinase allosteric node uncouples dynamics linked to phosphotransfer

Significance Our Girvan–Newman-based community network analysis provides a strategy to explore the effects of protein kinase mutations on the dynamic properties of the kinase core and the allosteric network underlying the catalytic cycle. With this approach, which allows us to identify subtle shifts in dynamics and in particular side-chain rotamer preferences, we can explain the underlying mechanism for loss of function in many different scenarios. Our method is especially relevant for disease-causing mutations that lie far from the active site but show no obvious structural perturbations based on X-ray crystallography. The expertise of protein kinases lies in their dynamic structure, wherein they are able to modulate cellular signaling by their phosphotransferase activity. Only a few hundreds of protein kinases regulate key processes in human cells, and protein kinases play a pivotal role in health and disease. The present study dwells on understanding the working of the protein kinase-molecular switch as an allosteric network of “communities” composed of congruently dynamic residues that make up the protein kinase core. Girvan–Newman algorithm-based community maps of the kinase domain of cAMP-dependent protein kinase A allow for a molecular explanation for the role of protein conformational entropy in its catalytic cycle. The community map of a mutant, Y204A, is analyzed vis-à-vis the wild-type protein to study the perturbations in its dynamic profile such that it interferes with transfer of the γ-phosphate to a protein substrate. Conventional biochemical measurements are used to ascertain the effect of these dynamic perturbations on the kinetic profiles of both proteins. These studies pave the way for understanding how mutations far from the kinase active site can alter its dynamic properties and catalytic function even when major structural perturbations are not obvious from static crystal structures.
Pore space analysis of beech wood: The vessel network

Abstract Water transport in wood is vital for the survival of trees. With synchrotron radiation X-ray tomographic microscopy (SRXTM), it has become possible to characterize and quantify the three-dimensional (3D) network formed by vessels that are responsible for longitudinal transport. In the present study, the spatial size dependence of vessels and the organization inside single growth rings in terms of vessel-induced porosity was studied by SRXTM. Network characteristics, such as connectivity, were deduced by digital image analysis from the processed tomographic data and related to known complex network topologies.
Distributed analysis: the last frontier?

It is widely agreed that the trend toward distributed software development is growing. Although there are difficulties involved, this trend is here to stay, as organizations will continue to search for ways to develop software at lower cost but with same quality. Current research has focused primarily on the later stages of the software development life cycle, especially coding of software requirements. However, as organizations become more virtual, distributed development will become more apparent throughout the entire life cycle. In this study, we investigate distributed analysis in software development. We report on results from a field experiment with two graduate level Information Systems classes, one located in Porto Alegre, Brazil and one in Chicago, U.S. The students in Brazil played the role of users whereas the students in Chicago role-played analysts. The Chicago-based students developed a requirements document for an information system by interviewing the Brazil students using an electronic discussion board. Our findings provide insight into the distributed analysis process and identify sources of potential problems.
Cytosolic pH regulates G Cl through control of phosphorylation states of CFTR.

Our objective in this study was to determine the effect of changes in luminal and cytoplasmic pH on cystic fibrosis transmembrane regulator (CFTR) Cl- conductance ( G Cl). We monitored CFTR G Cl in the apical membranes of sweat ducts as reflected by Cl- diffusion potentials ( V Cl) and transepithelial conductance ( G Cl). We found that luminal pH (5.0-8.5) had little effect on the cAMP/ATP-activated CFTR G Cl, showing that CFTR G Cl is maintained over a broad range of extracellular pH in which it functions physiologically. However, we found that phosphorylation activation of CFTR G Cl is sensitive to intracellular pH. That is, in the presence of cAMP and ATP [adenosine 5'- O-(3-thiotriphosphate)], CFTR could be phosphorylated at physiological pH (6.8) but not at low pH (∼5.5). On the other hand, basic pH prevented endogenous phosphatase(s) from dephosphorylating CFTR.After phosphorylation of CFTR with cAMP and ATP, CFTR G Cl is normally deactivated within 1 min after cAMP is removed, even in the presence of 5 mM ATP. This deactivation was due to an increase in endogenous phosphatase activity relative to kinase activity, since it was reversed by the reapplication of ATP and cAMP. However, increasing cytoplasmic pH significantly delayed the deactivation of CFTR G Cl in a dose-dependent manner, indicating inhibition of dephosphorylation. We conclude that CFTR G Cl may be regulated via shifts in cytoplasmic pH that mediate reciprocal control of endogenous kinase and phosphatase activities. Luminal pH probably has little direct effect on these mechanisms. This regulation of CFTR may be important in shifting electrolyte transport in the duct from conductive to nonconductive modes.
DeepWarp: DNN-based Nonlinear Deformation

DeepWarp is an efficient and highly re-usable deep neural network (DNN) based nonlinear deformable simulation framework. Unlike other deep learning applications such as image recognition, where different inputs have a uniform and consistent format (e.g. an array of all the pixels in an image), the input for deformable simulation is quite variable, high-dimensional, and parametrization-unfriendly. Consequently, even though DNN is known for its rich expressivity of nonlinear functions, directly using DNN to reconstruct the force-displacement relation for general deformable simulation is nearly impossible. DeepWarp obviates this difficulty by partially restoring the force-displacement relation via warping the nodal displacement simulated using a simplistic constitutive model -- the linear elasticity. In other words, DeepWarp yields an incremental displacement fix based on a simplified (therefore incorrect) simulation result other than returning the unknown displacement directly. We contrive a compact yet effective feature vector including geodesic, potential and digression to sort training pairs of per-node linear and nonlinear displacement. DeepWarp is robust under different model shapes and tessellations. With the assistance of deformation substructuring, one DNN training is able to handle a wide range of 3D models of various geometries including most examples shown in the paper. Thanks to the linear elasticity and its constant system matrix, the underlying simulator only needs to perform one pre-factorized matrix solve at each time step, and DeepWarp is able to simulate large models in real time.
Non-isothermal Crystallization Kinetics of Glass Oil Palm Fibre Reinforced Phenolformaldehyde Composites

The non-isotherm.1i cryst.lili zat ion kinetics of glass oil pal m rei nforced hyhrid phenol forll1aldehyde compositcs has heen studi ed at di fferent heating rates hy using Dillerential Scanning Calori metry( DSC). Samples of different weight pcn. :entages of fih res have neentested and the results arc annl ysed in thr ligh t of Oznwa's theory. It has heen found that allthe samples studied fo llow the ahove theory very well and . therefore. it has beer ~ mployed to determi ne the Avram i exponent for these composites 1IIIder non-isothermal cond iti ons .
Oncogene‐specific formation of chemoresistant murine hepatic cancer stem cells

At least some cancer stem cells (CSCs) display intrinsic drug resistance that may thwart eradication of a malignancy by chemotherapy. We explored the genesis of such resistance by studying mouse models of liver cancer driven by either MYC or the combination of oncogenic forms of activation of v‐akt murine thymoma viral oncogene homolog (AKT) and NRAS. A common manifestation of chemoresistance in CSCs is efflux of the DNA‐binding dye Hoechst 33342. We found that only the MYC‐driven tumors contained a subset of cells that efflux Hoechst 33342. This “side population” (SP) was enriched for CSCs when compared to non‐SP tumor cells and exhibited markers of hepatic progenitor cells. The SP cells could differentiate into non‐SP tumor cells, with coordinate loss of chemoresistance, progenitor markers, and the enrichment for CSCs. In contrast, non‐SP cells did not give rise to SP cells. Exclusion of Hoechst 33342 is mediated by ATP binding cassette drug transporter proteins that also contribute to chemoresistance in cancer. We found that the multidrug resistance gene 1 (MDR1) transporter was responsible for the efflux of Hoechst from SP cells in our MYC‐driven model. Accordingly, SP cells and their tumor‐initiating subset were more resistant than non‐SP cells to chemotherapeutics that are effluxed by MDR1. Conclusion: The oncogenotype of a tumor can promote a specific mechanism of chemoresistance that can contribute to the survival of hepatic CSCs. Under circumstances that promote differentiation of CSCs into more mature tumor cells, the chemoresistance can be quickly lost. Elucidation of the mechanisms that govern chemoresistance in these mouse models may illuminate the genesis of chemoresistance in human liver cancer. (HEPATOLOGY 2012)
Pocket reflectometry

We present a simple, fast solution for reflectance acquisition using tools that fit into a pocket. Our method captures video of a flat target surface from a fixed video camera lit by a hand-held, moving, linear light source. After processing, we obtain an SVBRDF. We introduce a BRDF chart, analogous to a color "checker" chart, which arranges a set of known-BRDF reference tiles over a small card. A sequence of light responses from the chart tiles as well as from points on the target is captured and matched to reconstruct the target's appearance. We develop a new algorithm for BRDF reconstruction which works directly on these LDR responses, without knowing the light or camera position, or acquiring HDR lighting. It compensates for spatial variation caused by the local (finite distance) camera and light position by warping responses over time to align them to a specular reference. After alignment, we find an optimal linear combination of the Lambertian and purely specular reference responses to match each target point's response. The same weights are then applied to the corresponding (known) reference BRDFs to reconstruct the target point's BRDF. We extend the basic algorithm to also recover varying surface normals by adding two spherical caps for diffuse and specular references to the BRDF chart. We demonstrate convincing results obtained after less than 30 seconds of data capture, using commercial mobile phone cameras in a casual environment.
Behavioral and brain asymmetries in primates: a preliminary evaluation of two evolutionary hypotheses

Contrary to many historical views, recent evidence suggests that species‐level behavioral and brain asymmetries are evident in nonhuman species. Here, we briefly present evidence of behavioral, perceptual, cognitive, functional, and neuroanatomical asymmetries in nonhuman primates. In addition, we describe two historical accounts of the evolutionary origins of hemispheric specialization and present data from nonhuman primates that address these specific theories. Specifically, we first discuss the evidence that genes play specific roles in determining left–right differences in anatomical and functional asymmetries in primates. We next consider and present data on the hypothesis that hemispheric specialization evolved as a by‐product of increasing brain size relative to the surface area of the corpus callosum in different primate species. Last, we discuss some of the challenges in the study of hemispheric specialization in primates and offer some suggestions on how to advance the field.
Translational regulation by bacterial small RNAs via an unusual Hfq-dependent mechanism

In bacteria, the canonical mechanism of translational repression by small RNAs (sRNAs) involves sRNA-mRNA base pairing that occludes the ribosome binding site (RBS), directly preventing translation. In this mechanism, the sRNA is the direct regulator, while the RNA chaperone Hfq plays a supporting role by stabilizing the sRNA. There are a few examples where the sRNA does not directly interfere with ribosome binding, yet translation of the target mRNA is still inhibited. Mechanistically, this non-canonical regulation by sRNAs is poorly understood. Our previous work demonstrated repression of the mannose transporter manX mRNA by the sRNA SgrS, but the regulatory mechanism was unknown. Here, we report that manX translation is controlled by a molecular role-reversal mechanism where Hfq, not the sRNA, is the direct repressor. Hfq binding adjacent to the manX RBS is required for sRNA-mediated translational repression. Translation of manX is also regulated by another sRNA, DicF, via the same non-canonical Hfq-dependent mechanism. Our results suggest that the sRNAs recruit Hfq to its binding site or stabilize the mRNA-Hfq complex. This work adds to the growing number of examples of diverse mechanisms of translational regulation by sRNAs in bacteria.
In vitro Evaluation of Gentamicin Coupled Self-Micro-Emulsifying Drug Delivery Systems ( SMEDDS ) Containing Softisan and Precirol as Lipid Matrix

Gentamicin (GM), a broad-spectrum aminoglycoside antibiotic has insignificant small intestinal absorption and this makes its oral administration impracticable. Its orally administrable product in addition to parenteral delivery formula is necessary. In this study in vitro evaluation of the stability of a self-micro-emulsifying drug delivery systems (SMEDDS) prepared with varying ratios of softisan ® 154 (S-154) and precirol ® ATO 5 (P-5) and loaded with GM was carried out. Batches of SMEDDS were prepared as: A1, S-154/P-5(1:1), A2, S-154/P-5(1:1), A3, S-154/P-5(1:1), A4, S-154/P-5(1:1) loaded with 50, 100, 200 and 0 mg of GM respectively. Similarly batches B1,S-154/P5(1:2), B2,S-154/P-5(1:2), B3,S-154/P-5(1:2), B4,S-154/P-5(1:2) and C1,S-154/P-5(2:1), C2,S-154/P-5(2:1), C3,S-154/P-5(2:1), C4,S-154/P-5(2:1) were prepared. The microparticles yield, time dependent particle size, pH, thermal analysis, encapsulation efficiency and in vitro antimicrobial efficacy of the SMEDDS were investigated. Batch B3, S-154/P-5(1:2) gave the highest yield of micro-particles while those of B1, S-154/P5(1:2) and C2, S-154/P-5(2:1) respectively were the most stable. Between 7 and 60 days, B1, S-154/P-5 (1:2), B2, S-154/P-5 (1:2), B3, S-154/P-5 (1:2), C1, S-154/P-5 (2:1) and C2, S-154/P-5 (2:1) were stable in their pH. Batch B3, S-154/P-5 (1:2) presented with higher encapsulation efficiency as well as thermostability. The highest inhibition zone diameter (IZD) of 14 mm was obtained with C3, S-154/P-5(2:1). This compared to A3, S-154/P-5(1:1) and B3, S-154/P-5(1:2) with IZDs of 9 and 12 mm respectively. The formulations containing softisan and precirol in the ratio of 1:2 and 2:1 respectively were most stable in pH, particle size and thermostability and may likely be useful for oral administration.
Detecting the Geographical Pattern of Speciation from Species‐Level Phylogenies

We introduce a general approach for investigating the role of geography in speciation, based on analyzing the geography of sister clades across all nodes in a species‐level phylogeny. We examine the predictions of allopatric, sympatric, and peripatric models of speciation in several animal groups, using patterns of range overlap and range size symmetry between sister clades. A simple model of cladogenesis incorporating random movements of species' ranges is used to illustrate the effects of range changes on expected patterns. We find evidence for a predominantly allopatric mode of speciation in our study groups, with sympatry arising through postspeciational range changes. In addition, we find that relatively recent speciation events are characterized by greater asymmetry in range size between sister clades than expected under our null models, providing potential support for the peripatric model of speciation. We discuss the possible confounding effects of postspeciational range changes on our conclusions.
Drug Susceptibility Profiling and Genetic Determinants of Drug Resistance in Mycobacterium kansasii

ABSTRACT Very few studies have examined drug susceptibility of Mycobacterium kansasii, and they involve a limited number of strains. The purpose of this study was to determine drug susceptibility profiles of M. kansasii isolates representing a spectrum of species genotypes (subtypes) with two different methodologies, i.e., broth microdilution and Etest assays. To confirm drug resistance, drug target genes were sequenced. A collection of 85 M. kansasii isolates, including representatives of eight different subtypes (I to VI, I/II, and IIB) from eight countries, was used. Drug susceptibility against 13 and 8 antimycobacterial agents was tested by using broth microdilution and Etest, respectively. For drug-resistant or high-MIC isolates, eight structural genes (rrl, katG, inhA, embB, rrs, rpsL, gyrA, and gyrB) and one regulatory region (embCA) were PCR amplified and sequenced in the search for resistance-associated mutations. All isolates tested were susceptible to rifampin (RIF), amikacin (AMK), co-trimoxazole (SXT), rifabutin (RFB), moxifloxacin (MXF), and linezolid (LZD) according to the microdilution method. Resistance to ethambutol (EMB), ciprofloxacin (CIP), and clarithromycin (CLR) was found in 83 (97.7%), 17 (20%), and 1 (1.2%) isolate, respectively. The calculated concordance between the Etest and dilution method was 22.6% for AMK, 4.8% for streptomycin (STR), 3.2% for CLR, and 1.6% for RIF. For EMB, INH, and SXT, not even a single MIC value determined by one method equaled that by the second method. The only mutations disclosed were A2266C transversion at the rrl gene (CLR-resistant strain) and A128G transition at the rpsL gene (strain with STR MIC of >64 mg/liter). In conclusion, eight drugs, including RIF, CLR, AMK, SXT, RFB, MXF, LZD, and ethionamide (ETO), showed high in vitro activity against M. kansasii isolates. Discrepancies of the results between the reference microdilution method and Etest preclude the use of the latter for drug susceptibility determination in M. kansasii. Drug resistance in M. kansasii may have different genetic determinants than resistance to the same drugs in M. tuberculosis.
Accuracy, Precision, Ease-Of-Use, and Cost of Methods to Test Ebola-Relevant Chlorine Solutions

To prevent transmission in Ebola Virus Disease (EVD) outbreaks, it is recommended to disinfect living things (hands and people) with 0.05% chlorine solution and non-living things (surfaces, personal protective equipment, dead bodies) with 0.5% chlorine solution. In the current West African EVD outbreak, these solutions (manufactured from calcium hypochlorite (HTH), sodium dichloroisocyanurate (NaDCC), and sodium hypochlorite (NaOCl)) have been widely used in both Ebola Treatment Unit and community settings. To ensure solution quality, testing is necessary, however test method appropriateness for these Ebola-relevant concentrations has not previously been evaluated. We identified fourteen commercially-available methods to test Ebola-relevant chlorine solution concentrations, including two titration methods, four DPD dilution methods, and six test strips. We assessed these methods by: 1) determining accuracy and precision by measuring in quintuplicate five different 0.05% and 0.5% chlorine solutions manufactured from NaDCC, HTH, and NaOCl; 2) conducting volunteer testing to assess ease-of-use; and, 3) determining costs. Accuracy was greatest in titration methods (reference-12.4% error compared to reference method), then DPD dilution methods (2.4–19% error), then test strips (5.2–48% error); precision followed this same trend. Two methods had an accuracy of <10% error across all five chlorine solutions with good precision: Hach digital titration for 0.05% and 0.5% solutions (recommended for contexts with trained personnel and financial resources), and Serim test strips for 0.05% solutions (recommended for contexts where rapid, inexpensive, and low-training burden testing is needed). Measurement error from test methods not including pH adjustment varied significantly across the five chlorine solutions, which had pH values 5–11. Volunteers found test strip easiest and titration hardest; costs per 100 tests were $14–37 for test strips and $33–609 for titration. Given the ease-of-use and cost benefits of test strips, we recommend further development of test strips robust to pH variation and appropriate for Ebola-relevant chlorine solution concentrations.
Occurrence and seasonal dynamics of RNA viral genotypes in three contrasting temperate lakes

Decades of research have demonstrated the crucial importance of viruses in freshwater ecosystems. However, few studies have focused on the seasonal dynamics and potential hosts of RNA viruses. We surveyed microbial-sized (i.e. 5–0.2 μm) mixed community plankton transcriptomes for RNA viral genomes and investigated their distribution between microbial and macrobial plankton over a seasonal cycle across three temperate lakes by quantitative reverse transcriptase PCR (qRT-PCR). A total of 30 contigs bearing similarity to RNA viral genomes were recovered from a global assembly of 30 plankton RNA libraries. Of these, only 13 were found in >2 libraries and recruited >100 reads (of 9.13 x 107 total reads), representing several picornaviruses, two tobamoviruses and a reovirus. We quantified the abundance of four picornaviruses and the reovirus monthly from August 2014 to May 2015. Patterns of viral abundance in the >5 μm size fraction and representation in microbial-sized community RNA libraries over time suggest that one picornavirus genotype (TS24835) and the reovirus (TS148892) may infect small (<5 μm) eukaryotic microorganisms, while two other picornaviruses (TS24641 and TS4340) may infect larger (>5 μm) eukaryotic microorganisms or metazoa. Our data also suggest that picornavirus TS152062 may originate from an allochthonous host. All five viral genotypes were present in at least one size fraction across all 3 lakes during the year, suggesting that RNA viruses may easily disperse between adjacent aquatic habitats. Our data therefore demonstrate that RNA viruses are widespread in temperate lacustrine ecosystems, and may provide evidence of viral infection in larger eukaryotes (including metazoa) inhabiting the lakes.