bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinematics of the Lever Arm Swing in Myosin VI
Authors: Mugnai M. L. , Thirumalai D.
Published: October 2016

Myosin VI (MVI) is the only known member of the myosin superfamily that, upon dimerization, walks processively towards the pointed end of the actin filament. The leading head of the dimer directs the trailing head forward with a power stroke, a conformational change of the motor domain exaggerated by the lever arm. Using a new coarse-grained model for the power stroke of a single MVI, we provide the molecular basis for its motility. We show that the power stroke occurs in two major steps: first, the motor domain attains the post-stroke conformation without directing the lever arm forward; second, the lever arm reaches the post-stroke orientation by undergoing a rotational diffusion. From the analysis of the trajectories, we discover that the potential that directs the rotating lever arm towards the post-stroke conformation is almost flat, implying that the lever arm rotation is mostly un-coupled from the motor domain. Because a backward load comparable with the largest inter-head tension in a MVI dimer prevents the rotation of the lever arm, our model suggests that the leading-head lever arm of a MVI dimer is uncoupled, in accord with the inference drawn from polarized Total Internal Reflection Fluorescence (polTIRF) experiments. Our simulations are in quantitative agreement with polTIRF experiments, which validates our structural insights. Finally, we discuss the implications of our model in explaining the broad step-size distribution of MVI stepping pattern, and we make testable predictions.
Quantifying the regulatory effect size of cis-acting genetic variation using allelic fold change
Authors: Mohammadi Pejman , Castel Stephane E , Brown Andrew A , Lappalainen Tuuli
Published: October 2016

Mappingcis-acting expression quantitative trait loci (cis-eQTL) has become a popular approach for characterizing proximal genetic regulatory variants. However, measures used for quantifying the effect size ofcis-eQTLs have been inconsistent and poorly defined. In this paper, we describe log allelic fold change (aFC) as a biologically interpretable and mathematically convenient unit that represents the magnitude of expression change associated with a given genetic variant. This measure is mathematically independent from expression level and allele frequency, applicable to multi-allelic variants, and generalizable to multiple independent variants. We provide tools and guidelines for estimating aFC from eQTL and allelic expression data sets, and apply it to GTEx data. We show that aFC estimates independently derived from eQTL and allelic expression data are highly consistent, and identify technical and biological correlates of eQTL effect size. We generalize aFC to analyze genes with two eQTLs in GTEx, and show that in nearly all cases these eQTLs are independent in their regulatory activity. In summary, aFC is a solid measure ofcis-regulatory effect size that allows quantitative interpretation of cellular regulatory events from population data, and it is a valuable approach for investigating novel aspects of eQTL data sets.
Combining Multiscale Diffusion Kernels for Learning the Structural and Functional Brain Connectivity
Authors: Surampudi Sriniwas G. , Naik Shruti , Sharma Avinash , Bapi Raju Surampudi , Roy Dipanjan
Published: October 2016

The activation of the brain at rest is thought to be at the core of cognitive functions. There have been many attempts at characterizing the functional connectivity at rest from the structure. Recent attempts with diffusion kernel models point to the possibility of a single diffusion kernel that can give a good estimate of the functional connectivity. But our empirical investigations revealed that the hypothesis of a single scale best-fitting kernel across subjects is not tenable. Further, our experiments demonstrate that structure-function relationship across subjects seems to obey a multi-scale diffusion phenomenon. Based on this insight, we propose a multiple diffusion kernel model (MKL) along with a learning framework for estimating the optimal model parameters. We tested our hypothesis on 124 subjects’ data from publicly available NKI_Rockland database. The results establish the viability of the proposed model and also demonstrate several promising features as compared to the single kernel approach. One of the key strengths of the proposed approach is that it does not require hand-tuning of model parameters but actually learns them as part of the optimization process. The learned parameters may be suitable candidates for future investigation of their role in distinguishing health and disease.
Fine mapping ofUr-3, a historically important rust resistance locus in common bean
Authors: Hurtado-Gonzales O.P. , Valentini G. , Gilio T.A.S , Martins A.M. , Song Q. , Pastor-Corrales M.A.
Published: October 2016

Bean rust is a devastating disease of common bean in the Americas and Africa. The historically importantUr-3gene confers resistance to many races of the highly variable bean rust pathogen that overcome all known rust resistance genes. Existing molecular markers taggingUr-3for use in marker assisted selection produce false results. We described here the fine mapping ofUr-3for the development of highly accurate markers linked to this gene. An F2population from Pinto 114 × Aurora was evaluated for its reaction to four different races of the bean rust pathogen. A bulked segregant analysis using the SNP chip BARCBEAN6K_3 positioned the approximate location of theUr-3locus to the lower arm of chromosome Pv11. Specific SSR and SNP markers and haplotype analysis of 18 sequenced bean lines led to position theUr-3locus to a 46.5 Kb genomic region. We discovered a KASP marker, SS68 that was tightly linked to theUr-3locus. Validation of SS68 on a panel of 130 diverse common bean lines and varieties containing all known rust resistance genes revealed that it was highly accurate producing no false results. The SS68 marker will be of great value to pyramidUr-3with other rust resistance genes. It will also reduce significantly time and labor associated with the current phenotypic detection ofUr-3. This is the first utilization of fine mapping to discover markers linked to a rust resistance in common bean.
Protein Microarrays: Flexible Tools for Scientific Innovation
Authors: Neiswinger Johnathan , Uzoma Ijeoma , Cox Eric , Rho HeeSool , Song Guang , Paul Corry , Jeong Jun Seop , Lu Kuan-Yi , Chen Chien-Sheng , Zhu Heng
Published: October 2016

Protein microarrays have emerged as a powerful tool for the scientific community, and their greatest advantage lies in the fact that thousands of reactions can be performed in a parallel and unbiased manner. The first high-density protein microarray, dubbed the “yeast proteome array,” consisted of approximately 5800 full-length yeast proteins and was initially used to identify protein–lipid interactions. Further assays were subsequently developed to allow measurement of protein–DNA, protein–RNA, and protein–protein interactions, as well as four well-known posttranslational modifications: phosphorylation, acetylation, ubiquitylation, and SUMOylation. In this introduction, we describe the advent of high-density protein microarrays, as well as current methods for assessing a wide variety of protein interactions and posttranslational modifications.
Association of Mycobacterium infections in patients with Mendelian susceptibility to mycobacterial disease with venous thromboembolism
Authors: Alinejad Dizaj Maryam , Mahdaviani Seyed Alireza , Tabarsi Payam , Ahari Hamed , Ebrahimi Ahmad , Nadji Seyed Alireza , Emami Habib , Mortaz Esmaeil
Published: October 2016

An association between a hypercoagulable state and Mendelian susceptibility to mycobacterial disease (MSMD) has been established in a few studies; resultant thrombosis is considered rare. In a case‐control study, the prevalence of factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C mutations were investigated in mycobacterium‐infected patients. The study comprised 30 patients with mycobacterial infections (invasive, disseminated and/or recurrent infections with Bacille Calmette–Guerin or non‐tuberculosis mycobacteria and Mycobacterium Tuberculosis with positive results for acid‐fast bacilli and tuberculin skin tests) and 30 normal healthy controls. Forty female (66.7%) and 20 male subjects (33.3%) aged from 3 to 70 years were recruited into this study. Genotyping of targeted genes was performed by RT‐PCR and cytokine TNF‐α concentrations were quantified using a commercially available ELISA kit. Significant associations between mycobacterial infection and TNF‐α production after stimulating peripheral blood mononuclear cells with LPS alone and with IFN‐γ plus LPS were identified. Moreover, genotyping analysis in the studied population revealed a significant association between MTHFR c.677C>T (OR, 3.28; 95% CI, 1.35–7.92; P < 0.05), MTHFR c.1298A>C (OR, 2.33; 95% CI, 1.10–4.93; P < 0.05) and mycobacterial infection in affected patients, indicating susceptibility to venous thromboembolism according to previous studies. Additionally, mycobacterium‐infected patients had a significantly greater prevalence of MTHFR C677T and A1298C mutations than controls.
Communicating Conservation Status: How Different Statistical Assessment Criteria Affect Perceptions of Extinction Risk
Authors: Song Hwanseok , Schuldt Jonathon P.
Published: October 2016

Although alternative forms of statistical and verbal information are routinely used to convey species’ extinction risk to policymakers and the public, little is known about their effects on audience information processing and risk perceptions. To address this gap in literature, we report on an experiment that was designed to explore how perceptions of extinction risk differ as a function of five different assessment benchmarks (Criteria A–E) used by scientists to classify species within IUCN Red List risk levels (e.g., Critically Endangered, Vulnerable), as well as the role of key individual differences in these effects (e.g., rational and experiential thinking styles, environmental concern). Despite their normative equivalence within the IUCN classification system, results revealed divergent effects of specific assessment criteria: on average, describing extinction risk in terms of proportional population decline over time (Criterion A) and number of remaining individuals (Criterion D) evoked the highest level of perceived risk, whereas the single‐event probability of a species becoming extinct (Criterion E) engendered the least perceived risk. Furthermore, participants scoring high in rationality (analytic thinking) were less prone to exhibit these biases compared to those low in rationality. Our findings suggest that despite their equivalence in the eyes of scientific experts, IUCN criteria are indeed capable of engendering different levels of risk perception among lay audiences, effects that carry direct and important implications for those tasked with communicating about conservation status to diverse publics.
Neural correlates of attention and streaming in a perceptually multistable auditory illusion
Authors: Mehta Anahita H. , Yasin Ifat , Oxenham Andrew J. , Shamma Shihab
Published: October 2016

In a complex acoustic environment, acoustic cues and attention interact in the formation of streams within the auditory scene. In this study, a variant of the “octave illusion” [Deutsch (1974). Nature 251, 307–309] was used to investigate the neural correlates of auditory streaming, and to elucidate the effects of attention on the interaction between sequential and concurrent sound segregation in humans. By directing subjects' attention to different frequencies and ears, it was possible to elicit several different illusory percepts with the identical stimulus. The first experiment tested the hypothesis that the illusion depends on the ability of listeners to perceptually stream the target tones from within the alternating sound sequences. In the second experiment, concurrent psychophysical measures and electroencephalography recordings provided neural correlates of the various percepts elicited by the multistable stimulus. The results show that the perception and neural correlates of the auditory illusion can be manipulated robustly by attentional focus and that the illusion is constrained in much the same way as auditory stream segregation, suggesting common underlying mechanisms.
Energy gap evolution across the superconductivity dome in single crystals of (Ba

1−
x

K

x

)Fe
2
As
2
Authors: Cho Kyuil , Kończykowski Marcin , Teknowijoyo Serafim , Tanatar Makariy A. , Liu Yong , Lograsso Thomas A. , Straszheim Warren E. , Mishra Vivek , Maiti Saurabh , Hirschfeld Peter J. , Prozorov Ruslan
Published: October 2016

Controlled disorder was used to study the superconducting energy gap in (Ba

1−
x

K

x

)Fe
2
As
2
.
Novel Capsular Polysaccharide Loci and New Diagnostic Tools for High-Throughput Capsular Gene Typing in Streptococcus suis
Authors: Qiu Xiaotong , Bai Xuemei , Lan Ruiting , Zheng Han , Xu Jianguo
Published: October 2016

Streptococcus suis
is an important pathogen of pigs and may cause serious disease in humans. Serotyping is an important tool for detection and epidemiological studies of
S. suis
. Thirty-three reference serotypes and nine novel
cps
loci (NCLs) are recognized in
S. suis
. To gain a better understanding of the prevalence and genetic characteristics of NCLs, we investigated the serotype identity of 486 isolates isolated between 2013 and 2015 in China by capsular gene typing methods. Two hundred seventy-six isolates carried NCLs belonging to 16 groups, 8 of which appear to have not been reported previously. These isolates showed autoagglutination, polyagglutination, or nonagglutination with reference antisera and thus were nonserotypeable. Almost all isolates carrying the unknown NCLs were encapsulated, with various capsular thicknesses, indicating that they are most likely novel serotypes. To simultaneously identify the currently recognized 17 NCLs, an 18-plex detection system using the Luminex xTAG universal array technology was developed. Our data also provide valuable genetic information for monitoring the variations within NCLs by investigating the genetic characteristics of different subtypes within NCLs.

IMPORTANCE
Nonserotypeable
Streptococcus suis
isolates have been reported in many studies, and 9 novel
cps
loci (NCLs) have already been identified in nonserotypeable isolates. Moreover, novel
cps
loci are continually being found. The main purpose of this study was to investigate the prevalence and characteristics of NCLs in
S. suis
isolates recovered between 2013 and 2015 in China. This study provides valuable genetic information for monitoring the variations within NCLs. Meanwhile, a fast and cost-effective 18-plex detection system that can simultaneously identify the currently recognized 17 NCLs was developed in this study. This system will serve as a valuable tool for detecting known and identifying additional novel
cps
loci among nonserotypeable
S. suis
isolates.
Phylogenetic Evidence for Ancient and Persistent Environmental Symbiont Reacquisition in Largidae (Hemiptera: Heteroptera)
Authors: Gordon Eric Robert Lucien , McFrederick Quinn , Weirauch Christiane
Published: October 2016

The insect order Hemiptera, one of the best-studied insect lineages with respect to bacterial symbioses, still contains major branches that lack comprehensive characterization of associated bacterial symbionts. The Pyrrhocoroidea (Largidae [220 species] and Pyrrhocoridae [∼300 species]) is a clade of the hemipteran infraorder Pentatomomorpha. Studies on bacterial symbionts of this group have focused on members of Pyrrhocoridae, but recent examination of species of two genera of Largidae demonstrated divergent symbiotic complexes in these putative sister families. We surveyed the associated bacterial diversity of this group using paired-end Illumina sequencing and targeted Sanger sequencing of bacterial 16S rRNA amplicons of 30 pyrrhocoroid taxa, including 17 species of Largidae, in order to determine bacterial associates and the similarity of associated microbial communities among species. We also used molecular data (4,800 bp in 5 loci, for 57 ingroup and 12 outgroup taxa) to infer a phylogeny of the host superfamily, in order to trace the evolution of symbiotic complexes among Pentatomomorpha species. We undertook multiple lines of investigation (i.e., experimental rearing, fluorescence
in situ
hybridization microscopy, and phylogenetic and coevolutionary analyses) to elucidate potential transmission routes for largid symbionts. We found a prevalent and specific association of Largidae with
Burkholderia
strains of the plant-associated beneficial and environmental clade, housed in midgut tubules. As in other distantly related Heteroptera, symbiotic bacteria seem to be acquired from the environment every generation. We review the current understanding of symbiotic complexes within Pentatomomorpha and discuss means to further investigate the evolution and function of these symbioses.

IMPORTANCE
Obligate symbioses with bacteria are common in insects, particularly Hemiptera, in which various forms of symbiosis occur. However, knowledge regarding symbionts remains incomplete for major hemipteran lineages. Thus, an accurate understanding of how these partnerships evolved and changed over millions of years is not yet achievable. We contribute to our understanding of the evolution of symbiotic complexes in Hemiptera by characterizing bacterial associates of Pyrrhocoroidea, focusing on the family Largidae. Members of Largidae are associated with specific symbiotic
Burkholderia
strains from a different clade than
Burkholderia
symbionts in other
Burkholderia
-associated Hemiptera. Evidence suggests that species of Largidae reacquire specific symbiotic bacteria from the environment every generation, which is a rare strategy for insects, with potentially volatile evolutionary ramifications, but one that must have persisted in Largidae and related lineages since their origin in the Cretaceous Period.
Ferredoxin:NAD
+
Oxidoreductase of Thermoanaerobacterium saccharolyticum and Its Role in Ethanol Formation
Authors: Tian Liang , Lo Jonathan , Shao Xiongjun , Zheng Tianyong , Olson Daniel G. , Lynd Lee R.
Published: October 2016

Ferredoxin:NAD
+
oxidoreductase (NADH-FNOR) catalyzes the transfer of electrons from reduced ferredoxin to NAD
+
. This enzyme has been hypothesized to be the main enzyme responsible for ferredoxin oxidization in the NADH-based ethanol pathway in
Thermoanaerobacterium saccharolyticum
; however, the corresponding gene has not yet been identified. Here, we identified the Tsac_1705 protein as a candidate FNOR based on the homology of its functional domains. We then confirmed its activity
in vitro
with a ferredoxin-based FNOR assay. To determine its role in metabolism, the
tsac_1705
gene was deleted in different strains of
T. saccharolyticum
. In wild-type
T. saccharolyticum
, deletion of
tsac_1705
resulted in a 75% loss of NADH-FNOR activity, which indicated that Tsac_1705 is the main NADH-FNOR in
T.
saccharolyticum
. When both NADH- and NADPH-linked FNOR genes were deleted, the ethanol titer decreased and the ratio of ethanol to acetate approached unity, indicative of the absence of FNOR activity. Finally, we tested the effect of heterologous expression of Tsac_1705 in
Clostridium thermocellum
and found improvements in both the titer and the yield of ethanol.

IMPORTANCE
Redox balance plays a crucial role in many metabolic engineering strategies. Ferredoxins are widely used as electron carriers for anaerobic microorganism and plants. This study identified the gene responsible for electron transfer from ferredoxin to NAD
+
, a key reaction in the ethanol production pathway of this organism and many other metabolic pathways. Identification of this gene is an important step in transferring the ethanol production ability of this organism to other organisms.
Internalization of Heterologous Sugar Transporters by Endogenous α-Arrestins in the Yeast Saccharomyces cerevisiae
Authors: Sen Arpita , Acosta-Sampson Ligia , Alvaro Christopher G. , Ahn Jonathan S. , Cate Jamie H. D. , Thorner Jeremy
Published: October 2016

When expressed in
Saccharomyces cerevisiae
using either of two constitutive yeast promoters (

PGK1
prom

and

CCW12
prom

), the transporters CDT-1 and CDT-2 from the filamentous fungus
Neurospora crassa
are able to catalyze, respectively, active transport and facilitated diffusion of cellobiose (and, for CDT-2, also xylan and its derivatives). In
S. cerevisiae
, endogenous permeases are removed from the plasma membrane by clathrin-mediated endocytosis and are marked for internalization through ubiquitinylation catalyzed by Rsp5, a HECT class ubiquitin:protein ligase (E3). Recruitment of Rsp5 to specific targets is mediated by a 14-member family of endocytic adaptor proteins, termed α-arrestins. Here we demonstrate that CDT-1 and CDT-2 are subject to α-arrestin-mediated endocytosis, that four α-arrestins (Rod1, Rog3, Aly1, and Aly2) are primarily responsible for this internalization, that the presence of the transport substrate promotes transporter endocytosis, and that, at least for CDT-2, residues located in its C-terminal cytosolic domain are necessary for its efficient endocytosis. Both α-arrestin-deficient cells expressing CDT-2 and otherwise wild-type cells expressing CDT-2 mutants unresponsive to α-arrestin-driven internalization exhibit an increased level of plasma membrane-localized transporter compared to that of wild-type cells, and they grow, utilize the transport substrate, and generate ethanol anaerobically better than control cells.

IMPORTANCE
Ethanolic fermentation of the breakdown products of plant biomass by budding yeast
Saccharomyces cerevisiae
remains an attractive biofuel source. To achieve this end, genes for heterologous sugar transporters and the requisite enzyme(s) for subsequent metabolism have been successfully expressed in this yeast. For one of the heterologous transporters examined in this study, we found that the amount of this protein residing in the plasma membrane was the rate-limiting factor for utilization of the cognate carbon source (cellobiose) and its conversion to ethanol.
Genomic Comparisons of Lactobacillus crispatus and Lactobacillus iners Reveal Potential Ecological Drivers of Community Composition in the Vagina
Authors: France Michael T. , Mendes-Soares Helena , Forney Larry J.
Published: October 2016

Lactobacillus crispatus
and
Lactobacillus iners
are common inhabitants of the healthy human vagina. These two species are closely related and are thought to perform similar ecological functions in the vaginal environment. Temporal data on the vaginal microbiome have shown that nontransient instances of cooccurrence are uncommon, while transitions from an
L. iners
-dominated community to one dominated by
L. crispatus
, and vice versa, occur often. This suggests that there is substantial overlap in the fundamental niches of these species. Given this apparent niche overlap, it is unclear how they have been maintained as common inhabitants of the human vagina. In this study, we characterized and compared the genomes of
L. iners
and
L. crispatus
to gain insight into possible mechanisms driving the maintenance of this species diversity. Our results highlight differences in the genomes of these two species that may facilitate the partitioning of their shared niche space. Many of the identified differences may impact the protective benefits provided to the host by these two species.

IMPORTANCE
The microbial communities that inhabit the human vagina play a critical role in the maintenance of vaginal health through the production of lactic acid and lowering the environmental pH. This precludes the growth of nonindigenous organisms and protects against infectious disease. The two most common types of vaginal communities are dominated by either
Lactobacillus iners
or
Lactobacillus crispatus
, while some communities alternate between the two over time. We combined ecological theory with state-of-the-art genome analyses to characterize how these two species might partition their shared niche space in the vagina. We show that the genomes of
L. iners
and
L. crispatus
differ in many respects, several of which may drive differences in their competitive abilities in the vagina. Our results provide insight into factors that drive the complicated temporal dynamics of the vaginal microbiome and demonstrate how closely related microbial species partition shared fundamental niche space.
Microbial Glucuronoyl Esterases: 10 Years after Discovery
Authors: Biely Peter
Published: October 2016

A carbohydrate esterase called glucuronoyl esterase (GE) was discovered 10 years ago in a cellulolytic system of the wood-rotting fungus
Schizophyllum commune
. Genes coding for GEs were subsequently found in a number of microbial genomes, and a new family of carbohydrate esterases (CE15) has been established. The multidomain structures of GEs, together with their catalytic properties on artificial substrates and positive effect on enzymatic saccharification of plant biomass, led to the view that the esterases evolved for hydrolysis of the ester linkages between 4-
O
-methyl-
d
-glucuronic acid of plant glucuronoxylans and lignin alcohols, one of the crosslinks in the plant cell walls. This idea of the function of GEs is further supported by the effects of cloning of fungal GEs in plants and by very recently reported evidence for changes in the size of isolated lignin-carbohydrate complexes due to uronic acid de-esterification. These facts make GEs interesting candidates for biotechnological applications in plant biomass processing and genetic modification of plants. This article is a brief summary of current knowledge of these relatively recent and unexplored esterases.
Freshwater Bacteria Release Methane as a By-Product of Phosphorus Acquisition
Authors: Yao Mengyin , Henny Cynthia , Maresca Julia A.
Published: October 2016

Freshwater lakes emit large amounts of methane, some of which is produced in oxic surface waters. Two potential pathways for aerobic methane production exist: methanogenesis in oxygenated water, which has been observed in some lakes, and demethylation of small organic molecules. Although methane is produced via demethylation in oxic marine environments, this mechanism of methane release has not yet been demonstrated in freshwater systems. Genes related to the C-P lyase pathway, which cleaves C-P bonds in phosphonate compounds, were found in a metagenomic survey of the surface water of Lake Matano, which is chronically P starved and methane rich. We demonstrate that four bacterial isolates from Lake Matano obtain P from methylphosphonate and release methane and that this activity is repressed by phosphate. We further demonstrate that expression of
phnJ
, which encodes the enzyme that releases methane, is higher in the presence of methylphosphonate and lower when both methylphosphonate and phosphate are added. This gene is also found in most of the metagenomic data sets from freshwater environments. These experiments link methylphosphonate degradation and methane production with gene expression and phosphate availability in freshwater organisms and suggest that some of the excess methane in the Lake Matano surface water, and in other methane-rich lakes, may be produced by P-starved bacteria.

IMPORTANCE
Methane is an important greenhouse gas and contributes substantially to global warming. Although freshwater environments are known to release methane into the atmosphere, estimates of the amount of methane emitted by freshwater lakes vary from 8 to 73 Tg per year. Methane emissions are difficult to predict in part because the source of the methane can vary: it is the end product of the energy-conserving pathway in methanogenic archaea, which live predominantly in anoxic sediments or waters but have also been identified in some oxic freshwater environments. More recently, methane release from small organic molecules has been observed in oxic marine environments. Here we show that demethylation of methylphosphonate may also contribute to methane release from lakes and that phosphate can repress this activity. Since lakes are typically phosphorus limited, some methane release in these environments may be a by-product of phosphorus metabolism rather than carbon or energy metabolism. Methane emissions from lakes are currently predicted using primary production, eutrophication status, extent of anoxia, and the shape and size of the lake; to improve prediction of methane emissions, phosphorus availability and sources may also need to be included in these models.
Phosphinothricin Acetyltransferases Identified Using
In Vivo
,
In Vitro
, and Bioinformatic Analyses
Authors: VanDrisse Chelsey M. , Hentchel Kristy L. , Escalante-Semerena Jorge C.
Published: October 2016

Acetylation of small molecules is widespread in nature, and in some cases, cells use this process to detoxify harmful chemicals.
Streptomyces
species utilize a
G
cn5

N

-
a
cetyl
t
ransferase (GNAT), known as Bar, to acetylate and detoxify a self-produced toxin,
p
hos
p
hino
t
hricin (PPT), a glutamate analogue. Bar homologues, such as MddA from
Salmonella enterica
, acetylate methionine analogues such as methionine sulfoximine (MSX) and methionine sulfone (MSO), but not PPT, even though Bar homologues are annotated as PPT acetyltransferases.
S. enterica
was used as a heterologous host to determine whether or not putative PPT acetyltransferases from various sources could acetylate PPT, MSX, and MSO.
In vitro
and
in vivo
analyses identified substrates acetylated by putative PPT acetyltransferases from
Deinococcus radiodurans
(DR_1057 and DR_1182) and
Geobacillus kaustophilus
(GK0593 and GK2920).
In vivo
, synthesis of DR_1182, GK0593, and GK2920 blocked the inhibitory effects of PPT, MSX, and MSO. In contrast, DR_1057 did not detoxify any of the above substrates. Results of
in vitro
studies were consistent with the
in vivo
results. In addition, phylogenetic analyses were used to predict the functionality of annotated PPT acetyltransferases in
Burkholderia xenovorans
,
Bacillus subtilis
,
Staphylococcus aureus
,
Acinetobacter baylyi
, and
Escherichia coli
.

IMPORTANCE
The work reported here provides an example of the use of a heterologous system for the identification of enzyme function. Many members of this superfamily of proteins do not have a known function, or it has been annotated solely on the basis of sequence homology to previously characterized enzymes. The critical role of
G
cn5

N

-
a
cetyl
t
ransferases (GNATs) in the modulation of central metabolic processes, and in controlling metabolic stress, necessitates approaches that can reveal their physiological role. The combination of
in vivo
,
in vitro
, and bioinformatics approaches reported here identified GNATs that can acetylate and detoxify phosphinothricin.
Correlation of global risk assessment with cardiovascular complications in patients with diabetes mellitus living in Puerto Rico
Authors: Rodríguez-Vigil Efraín , Rodríguez-Chacón Migdalia , Ruiz Valcarcel José J
Published: October 2016

Objective

The objective of this study was to assess the current relationship between certain demographics and chemical factors, and the risk of cardiovascular complications, within a Puerto Rican population with diabetes mellitus.

Research design and methods

A total of 2075 patients with diabetes mellitus were retrospectively evaluated to determine the influence of certain demographics and chemical variables on the appearance of cardiovascular complications. A group of demographic and laboratory variables were analyzed. Our sample was obtained, based on convenience, from an endocrinologist's office in an area of about 250 000 people. All the patients met the American Diabetes Association (ADA) definitions for diabetes mellitus. The study covered a time period of 8 years. The patients signed an informed consent document at their first office visit. Data were obtained by the endocrinologist in charge.

Results

We considered the demographic variables of sex, age, time with diabetes, lipid profile, metabolic control (measured with glycated hemoglobin levels), and microalbumin renal excretion. Cardiovascular complications were more prevalent in patients with poor metabolic control, those with prolonged disease duration, men, and patients who were more than 50 years of age. We found no relationship between cardiovascular disease, systolic blood pressure over 130 mm Hg, body mass index and low-density lipoprotein cholesterol levels over 100 mg/dL.

Conclusions

In Puerto Rican patients with diabetes mellitus, there is a statistically significant relationship between patient's gender, age, disease duration, glycemic control and increased kidney microalbumin excretion with cardiovascular complications.
Management of hepatitis C genotype 4 in the directly acting antivirals era
Authors: Hathorn Emma , Elsharkawy Ahmed M
Published: October 2016

Genotype 4 chronic hepatitis C (G4 HCV) accounts for 13% of worldwide HCV infections; with 10 million people infected with the virus across the world. Up to the end of 2013, the only treatment option for G4 HCV was treatment with pegylated interferon and ribavirin for 24–48 weeks. Since late 2013, treatment of G4 HCV has been transformed by the licensing of many directly acting antiviral agents (DAA). It is an exciting time to be involved in the management of HCV generally and G4 particularly. Interferon-free DAA regimens are now a reality for G4 HCV. This review will highlight these developments and discuss the data behind the use of these drugs. It will also highlight future regimens that are likely to be available over the coming years.
Association of neck circumference with general and abdominal obesity in children and adolescents: the weight disorders survey of the CASPIAN-IV study
Authors: Kelishadi Roya , Djalalinia Shirin , Motlagh Mohammad Esmaiel , Rahimi Ali , Bahreynian Maryam , Arefirad Tahereh , Ardalan Gelayol , Safiri Saeid , Hasani Motahare , Asayesh Hamid , Mansourian Morteza , Qorbani Mostafa
Published: October 2016

Objectives

This study aimed to evaluate the association of neck circumference (NC) with obesity to determine the sex-specific and age-specific optimal cut-off points of this measure in association with obesity in a national sample of the Iranian paediatric population.

Methods

This survey on weight disorders was conducted among a national sample of Iranian children and adolescents, aged 6–18 years. Using the area under the curve (AUC) of the receiver operator characteristic curves, we evaluated the association of NC with general and abdominal obesity.

Results

This national survey was conducted among 23 043 school students (50.8% boys) with a mean age (SD) of 12.55 (3.31) years. A significant association was documented between NC and other anthropometric measures in both sexes and in the whole population. In all age groups and genders, NC performed relatively well in classifying participants to overweight (AUC: 0.67 to 0.75, p<0.001), general obesity (AUC: 0.81 to 0.85, p<0.001) and abdominal obesity (AUC: 0.73 to 0.78, p<0.001).

Conclusions

NC can be considered as a simple time-saving clinical tool for obesity detection in large population-based studies in children and adolescents. It is significantly correlated with indices of adiposity and can reliably identify children with general and abdominal obesity in the Iranian paediatric population.
Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort
Authors: Talman Paul , Duong Thi , Vucic Steve , Mathers Susan , Venkatesh Svetha , Henderson Robert , Rowe Dominic , Schultz David , Edis Robert , Needham Merrilee , Macdonnell Richard , McCombe Pamela , Birks Carol , Kiernan Matthew
Published: October 2016

Objective

To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia.

Methods

Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death.

Design

Prospective observational cohort study.

Participants

1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015.

Results

5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12 months for the ALS phenotypes, 18 months for the flail limb phenotypes and 19 months for PLS. Riluzole treatment was started in 78–85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12 months in the ALS phenotypes and 15–18 months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8–36% of ALS phenotypes and 2–9% of the flail phenotypes. Non-invasive ventilation was started in 16–22% of ALS phenotypes and 21–29% of flail phenotypes.

Conclusions

The establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries.
Effects of a nutrition plus exercise programme on physical function in sarcopenic obese elderly people: study protocol for a randomised controlled trial
Authors: Shen Shan-Shan , Chu Jiao-Jiao , Cheng Lei , Zeng Xing-Kun , He Ting , Xu Li-Yu , Li Jiang-Ru , Chen Xu-Jiao
Published: October 2016

Introduction

With a rapidly ageing population, sarcopenic obesity, defined as decreased muscle mass and function combined with increased body fat, is a complex health problem. Although sarcopenic obesity contributes to a decline in physical function and exacerbates frailty in older adults, evidence from clinical trials about the effect of exercise and nutrition on this complex syndrome in Chinese older adults is lacking.

Methods and analysis

We devised a study protocol for a single-blind randomised controlled trial. Sarcopenia is described as age-related decline in muscle mass plus low muscle strength and/or low physical performance. Obesity is defined as a percentage of body fat above the 60th centile. Ninety-two eligible participants will be randomly assigned to a control group, nutrition group, exercise group and nutrition plus exercise group to receive an 8-week intervention and 12-week follow-up. The primary outcomes will be the change in short physical performance battery scores, grip strength and 6 m usual gait speed. The secondary outcomes will include basic activities of daily living scores, instrumental activity daily living scores, body composition and body anthropometric indexes. For all main analyses, the principle of intention-to-treat will be used.

Ethics and dissemination

This study was approved by the medical ethics committee of Zhejiang Hospital on 25 November 2015. The study will present data targeting the clinical effects of nutrition and exercise on physical function and body composition in a Chinese older population with sarcopenic obesity. The results will help to provide important clinical evidence of the role of complex non-pharmaceutical interventions for sarcopenic obese older people. The findings of this study will be submitted to peer-reviewed medical journals for publication and presented at relevant academic conferences.

Trial registration number

ChiCTR-IOR-15007501; Pre-results.
Effect of cricoid pressure on laryngeal view during prehospital tracheal intubation: a propensity-based analysis
Authors: Caruana Emmanuel , Chevret Sylvie , Pirracchio Romain
Published: October 2016

Background

The benefit of cricoid pressure during tracheal intubation is still debated and, due to its potential negative impact on laryngeal views, its routine use is questioned. The goal of this study was to estimate its impact on laryngeal view.

Methods

All patients intubated in the prehospital setting were included. Three different propensity score (PS) models were used and compared in terms of the balance achieved between those patients who received cricoid pressure and those who did not. The PS model that optimised the balance was retained in order to estimate the relationship between cricoid pressure and the following outcomes: difficult laryngoscopy, intubation-related complications and difficult intubation.

Results

Among the 1195 patients included, 499 (41.7%) received cricoid pressure. The optimal PS included seven variables (cardiac arrest, altered neurological status, shock, respiratory distress, gender, obesity, patient's position). After PS matching, no significant risk difference (RD) in the rate of difficult laryngoscopy was found between the patients who received cricoid pressure and those who did not (RD=0.001, 95% CI −0.07 to 0.08, p=0.50). No significant difference was found in terms of difficult intubation (RD=0.06, 95% CI −0.13 to 0.25, p=0.28) and in terms of prevalence of complications, except for airway trauma that were more frequent in cricoid pressure group (RD=0.03, 95% CI 0.002 to 0.05, p=0.01).

Conclusions

No significant relationship was found between the use of cricoid pressure for prehospital intubation and difficult laryngoscopy. Cricoid pressure was found to be associated with more airway trauma. This finding could question its routine use.
Reduction in erythrocyte-bound complement activation products and titres of anti-C1q antibodies associate with clinical improvement in systemic lupus erythematosus
Authors: Buyon Jill , Furie Richard , Putterman Chaim , Ramsey-Goldman Rosalind , Kalunian Kenneth , Barken Derren , Conklin John , Dervieux Thierry
Published: October 2016

Background

The relationship between cell-bound complement activation products (CB-CAPs: EC4d, EC3d), anti-C1q, soluble complement C3/C4 and disease activity in systemic lupus erythematosus (SLE) was evaluated.

Methods

Per protocol, at baseline all SLE subjects enrolled in this longitudinal study presented with active disease and elevated CB-CAPs. At each monthly visit, the non-serological (ns) Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA-SLEDAI) and the British Isles Lupus Assessment Group (BILAG)-2004 index scores were determined as was a random urinary protein to creatinine ratio (uPCR). Short-form 36 (SF-36) questionnaires were also collected. All soluble markers were determined using immunoassays, while EC4d and EC3d were determined using flow cytometry. Statistical analysis consisted of linear mixed models with random intercept and fixed slopes.

Results

A total of 36 SLE subjects (mean age 34 years; 94% female) were enrolled and evaluated monthly for an average 11 visits per subject. Clinical improvements were observed during the study, with significant decreases in ns-SELENA-SLEDAI scores, BILAG-2004 index scores and uPCR, and increases in all domains of SF-36 (p<0.01). The longitudinal decrease in ns-SELENA-SLEDAI and BILAG-2004 index scores was significantly associated with reduced EC4d and EC3d levels, reduced anti-C1q titres and increased serum complement C3/C4 (p<0.05). The changes in uPCR significantly correlated with C3, C4, anti-C1q and EC4d, with EC4d outperforming C3/C4 by a multivariate analysis. The reduced EC4d or EC3d was associated with improvements in at least six out of the eight domains of SF-36 and outperformed C3/C4. Anti-dsDNA titres did not correlate with changes in disease activity.

Conclusions

These data indicate that CB-CAPs and anti-C1q are helpful in monitoring patients with SLE.
High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer
Authors: Min Kyueng-Whan , Kim Dong-Hoon , Do Sung-Im , Pyo Jung-Soo , Chae Seoung Wan , Sohn Jin Hee , Kim Kyungeun , Lee Hyun Joo , Kim Dong Hyun , Oh Sukjoong , Choi Seon Hyeong , Park Yong Lai , Park Chan Heun , Kwon Mi Jung , Moon Kyoung Min
Published: October 2016

Aims

Breast cancers are heterogeneous, making it essential to recognise several biomarkers for cancer outcome predictions. Ki67 proliferation index and B cell lymphoma 2 (BCL2) proteins are widely used as prognostic indicators in many types of malignancies. While Ki67 is a marker of normal or tumour cell proliferation, BCL2 plays a central role in antiproliferative activities. A combination of these two biomarkers with contrary purposes can provide enhanced prognostic accuracy than an analysis using a single biomarker.

Methods

We evaluated Ki67 and BCL2 expression with 203 cases of breast cancer. The relative expression of each biomarker named as Ki67/BCL2 index was divided into two groups (low vs high) with the use of area under receiver operating characteristic curves.

Results

There were significant correlations between Ki67/BCL2 index and clinicopathological findings such as age, tumour stage, size and necrosis, histological grade, extensive intraductal component, lymphatic and vascular invasion, oestrogen receptor, progesterone receptor, human epithelial growth factor receptor 2 and p53 expression (all p<0.05). In univariate and multivariate analyses, high Ki67/BCL2 index correlated with shorter disease-free survival and overall survival in patients with early stage invasive ductal carcinoma (all p<0.05).

Conclusions

The Ki67/BCL2 index should be considered as a prognostic predictor in patients with early stage invasive ductal carcinoma.
Estimate of energy constituents of the universe in ΛCDM
Authors: Huang Jung-Jeng , Wang Meng-Jong
Published: October 2016

We propose that the Hubble law can be viewed as the de Broglie relation on a cosmic scale. We show how the entropy of the Universe can be estimated in the ΛCDM model and its extended version, and how the quest for the maximal entropy leads to the energy constituents of the current Universe.
Design of Configurable gm−C Biquadratic Filter
Authors: Bhanja Mousumi , Ray Baidyanath
Published: October 2016

Design methodology of a voltage-mode programmable biquadratic filter using minimum components is proposed in this paper. Multifunction second-order filter has been implemented using two first-order filter sections. The proposed biquadratic filter has been realized with operational transconductance amplifier (OTA). Cut-off frequency and [Formula: see text]-factor of the biquadratic are controlled by the transconductance of the OTAs. The proposed design technique keeps all the sensitivities to lower values. The biquadratic filter operates at high frequency. The proposed structure is transformed into a third-order multifunction filter by adding minimum component, a single capacitor. Design of higher order filter using the proposed second-order function also has been investigated. The proposed synthesis is validated with SPICE simulation in 0.13[Formula: see text][Formula: see text]m technology. Total harmonic distortion, output noise, corner simulations, Monte Carlo analysis due to the circuit parameter and process parameter variation have been studied.