bluuebunny/crossref_metadata_2025 huggingface dataset:
Mevalonosomes: specific vacuoles containing the mevalonate pathway in Plocamium brasiliense cortical cells (Rhodophyta)
Authors: Paradas Wladimir Costa , Crespo Thalita Mendes , Salgado Leonardo Tavares , de Andrade Leonardo Rodrigues , Soares Angélica Ribeiro , Hellio Claire , Paranhos Ricardo Rogers , Hill Lilian Jorge , de Souza Geysa Marinho , Kelecom Alphonse Germaine Albert Charles , Da Gama Bernardo Antônio Perez , Pereira Renato Crespo , Amado‐Filho Gilberto Menezes
Published: January 2015

This paper has identified, for the first time in a member of the Rhodophyta, a vacuolar organelle containing enzymes that are involved in the mevalonate pathway—an important step in red algal isoprenoid biosynthesis. These organelles were named mevalonosomes (Mev) and were found in the cortical cells (CC) of Plocamium brasiliense, a marine macroalgae that synthesizes several halogenated monoterpenes. P. brasiliense specimens were submitted to a cytochemical analysis of the activity of the 3‐hydroxy‐3‐methylglutaryl‐CoA synthase (HMGS). Using transmission electron microscopy (TEM), we confirmed the presence of HMGS activity within the Mev. Because HMGS is necessary for the biosynthesis of halogenated monoterpenes, we isolated a hexanic fraction (HF) rich in halogenated monoterpenes from P. brasiliense that contained a pentachlorinated monoterpene as a major metabolite. Because terpenes are often related to chemical defense, the antifouling (AF) activity of pentachlorinated monoterpene was tested. We found that the settlement of the mussel Perna perna was reduced by HF treatment (2.25 times less than control; 40% and 90% of fouled surface, respectively; P = 0.001; F9,9 = 1.13). The HF (at 10 μg · mL−1) also inhibited three species of fouling microalgae (Chlorarachnion reptans, Cylindrotheca cloisterium, and Exanthemachrysis gayraliae), while at a higher concentration (50 μg · mL−1), it inhibited the bacteria Halomonas marina, Polaribacter irgensii, Pseudoalteromonas elyakovii, Shewanella putrefaciens, and Vibrio aestuarianus. The AF activity of P. brasiliense halogenated monoterpenes and the localization of HMGS activity inside Mev suggest that this cellular structure found in CC may play a role in thallus protection against biofouling.
Utility of the FIB‐4 Index for hepatocarcinogenesis in hepatitis C virus carriers with normal alanine aminotransferase levels
Authors: Ito T. , Kumada T. , Toyoda H. , Tada T. , Kiriyama S. , Tanikawa M. , Hisanaga Y. , Kanamori A. , Kitabatake S.
Published: January 2015

The FIB‐4 index is a simple formula using age, aspartate aminotransferase, alanine aminotransferase (ALT) and platelet count to evaluate liver fibrosis. We investigated the ability of the FIB‐4 index for hepatocarcinogenesis in hepatitis C virus (HCV) carriers with normal ALT levels. A total of 516 patients with ALT levels persistently at or below 40 IU/L during an observation period of over 3 years were included. Factors associated with the development of HCC were determined. Hepatocellular carcinoma (HCC) developed in 60 of 516 patients (11.6%). The incidence rate of HCC at 5 and 10 years was 2.6% and 17.6%, respectively. When patients were categorized according to the FIB‐4 index as ≤2.0 (n = 226), >2.0 and ≤4.0 (n = 169), and >4.0 (n = 121), the cumulative incidence of HCC at 5 years was 0.5%, 1.3% and 8.0%, respectively, and 2.8%, 25.6% and 37.1% at 10 years, respectively. Patients with FIB‐4 index >4.0 were at the highest risk (P < 0.001). Factors that were significantly associated with HCC in the multivariate analysis were FIB‐4 index >2.0 (hazard ratio (HR), 7.690), FIB‐4 index >4.0 (HR, 8.991), α‐fetoprotein (AFP) >5 ng/mL (HR, 2.742), AFP >10 ng/mL (HR, 4.915) and total bilirubin >1.2 mg/dL (HR, 2.142). A scoring system for hepatocarcinogenesis that combines the FIB‐4 index and AFP predicted patient outcomes with excellent discriminative ability. The FIB‐4 index is strongly associated with the risk of HCC in HCV carriers with normal ALT levels.
Proteins interacting with mitochondrial ATP‐dependent Lon protease (MAP1) in Magnaporthe oryzae are involved in rice blast disease
Authors: Cui Xiao , Wei Yi , Wang Yu‐Han , Li Jian , Wong Fuk‐Ling , Zheng Ya‐Jie , Yan Hai , Liu Shao‐Shuai , Liu Jin‐Liang , Jia Bao‐Lei , Zhang Shi‐Hong
Published: January 2015

The ATP‐dependent Lon protease is involved in many physiological processes. In bacteria, Lon regulates pathogenesis and, in yeast, Lon protects mitochondia from oxidative damage. However, little is known about Lon in fungal phytopathogens. MAP1, a homologue of Lon in Magnaporthe oryzae, was recently identified to be important for stress resistance and pathogenesis. Here, we focus on a novel pathogenic pathway mediated by MAP1. Based on an interaction system between rice and a tandem affinity purification (TAP)‐tagged MAP1 complementation strain, we identified 23 novel fungal proteins from infected leaves using a TAP approach with mass spectrometry, and confirmed that 14 of these proteins physically interact with MAP1 in vivo. Among these 14 proteins, 11 candidates, presumably localized to the mitochondria, were biochemically determined to be substrates of MAP1 hydrolysis. Deletion mutants were created and functionally analysed to further confirm the involvement of these proteins in pathogenesis. The results indicated that all mutants showed reduced conidiation and sensitivity to hydrogen peroxide. Appressorial formations were not affected, although conidia from certain mutants were morphologically altered. In addition, virulence was reduced in four mutants, enhanced (with lesions forming earlier) in two mutants and remained unchanged in one mutant. Together with the known virulence‐related proteins alternative oxidase and enoyl‐CoA hydratase, we propose that most of the Lon‐interacting proteins are involved in the pathogenic regulation pathway mediated by MAP1 in M. oryzae. Perturbation of this pathway may represent an effective approach for the inhibition of rice blast disease.
Congenital anomalies of the kidney and urinary tract genetics in mice and men
Authors: Caruana Georgina , Bertram John F.
Published: January 2015

The most common cause of paediatric end‐stage kidney disease results from congenital anomalies of the kidney and urinary tract (CAKUT). Genetic manipulation in mice has provided insight into the developmental events that give rise to the broad spectrum of malformations associated with CAKUT. Despite the increase in the number of identified CAKUT‐causing genes, the underlying genetic cause for the majority of patients with CAKUT remains unknown. In this mini‐review, we provide an overview of the genetic causes of CAKUT based on current mouse mutant models, as well as next‐generation sequencing approaches in humans that are helping to bridge the gaps in our understanding.
Bootstrap Co‐integration Rank Testing: The Effect of Bias‐Correcting Parameter Estimates
Authors: Cavaliere Giuseppe , Taylor A. M. Robert , Trenkler Carsten
Published: January 2015

Bootstrap‐based methods for bias‐correcting the first‐stage parameter estimates used in some recently developed bootstrap implementations of co‐integration rank tests are investigated. The procedure constructs estimates of the bias in the original parameter estimates by using the average bias in the corresponding parameter estimates taken across a large number of auxiliary bootstrap replications. A number of possible implementations of this procedure are discussed and concrete recommendations made on the basis of finite sample performance evaluated by Monte Carlo simulation methods. The results show that bootstrap‐based bias‐correction methods can significantly improve the small sample performance of the bootstrap co‐integration rank tests.
Diffuse Capillary Malformation in Association with Fetal Pleural Effusion: Report of Five Patients
Authors: Rork Jillian F. , Alomari Ahmad I. , Mulliken John B. , Fishman Steven J. , Liang Marilyn G.
Published: January 2015

Capillary malformation (CM) can be a “red flag” for several syndromic vascular anomalies. We identified a subset of patients with diffuse CM and fetal pleural effusion and documented the type of CM, the etiology of the pleural effusion, the potential syndromic diagnosis, and outcome. Patients with a history of CM and fetal pleural effusion were identified by searching the database of patients evaluated at the Vascular Anomalies Center at Boston Children's Hospital. Standardized patient interviews and a retrospective review of records, photographs, and imaging studies were conducted. Five patients had diffuse CM and fetal pleural effusion. Two patients had macrocephaly‐CM (M‐CM), one had features of M‐CM and CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis), and one had diffuse CM with overgrowth. The pleural fluid was chylous in four patients. One patient had thoracic lymphatic malformation. Recurrent effusion occurred in one patient coincident with pneumonia at age 11 years. Four patients had a history of reactive airway disease and episodic pulmonary infections. The diagnosis of vascular anomaly–overgrowth syndromes, particularly M‐CM, should be considered in neonates with fetal pleural effusion.
Hyperactive auditory processing in Williams syndrome: Evidence from auditory evoked potentials
Authors: Zarchi Omer , Avni Chen , Attias Josef , Frisch Amos , Carmel Miri , Michaelovsky Elena , Green Tamar , Weizman Abraham , Gothelf Doron
Published: January 2015

The neurophysiologic aberrations underlying the auditory hypersensitivity in Williams syndrome (WS) are not well defined. The P1‐N1‐P2 obligatory complex and mismatch negativity (MMN) response were investigated in 18 participants with WS, and the results were compared with those of 18 age‐ and gender‐matched typically developing (TD) controls. Results revealed significantly higher amplitudes of both the P1‐N1‐P2 obligatory complex and the MMN response in the WS participants than in the TD controls. The P1‐N1‐P2 complex showed an age‐dependent reduction in the TD but not in the WS participants. Moreover, high P1‐N1‐P2 complex was associated with low verbal comprehension scores in WS. This investigation demonstrates that central auditory processing is hyperactive in WS. The increase in auditory brain responses of both the obligatory complex and MMN response suggests aberrant processes of auditory encoding and discrimination in WS. Results also imply that auditory processing may be subjected to a delayed or diverse maturation and may affect the development of high cognitive functioning in WS.
Breed of Boar Influences the Optimal Concentration of Gamma‐oryzanol Needed for Semen Cryopreservation
Authors: Chanapiwat P , Kaeoket K
Published: January 2015

Contents

The aim of this study was to investigate the influence of boar breed on the optimal concentration of gamma‐oryzanol on the qualities of cryopreserved boar semen. Semen was collected from 20 boars (10 Duroc, 5 Large white and 5 Landrace boars). The semen sample was divided into five groups (A–E) according to the concentration of gamma‐oryzanol in extender II, that is 0, 0.08, 0.16, 0.24 and 0.32 mm, respectively. The semen was cryopreserved by nitrogen vapour and storage in nitrogen tank (−196°C). After storage for a week, samples were thawed at 50°C for 12 s and evaluated for progressive motility, sperm viability and acrosome integrity. The results demonstrated that gamma‐oryzanol significantly improved progressive motility, viability and acrosome integrity of frozen–thawed boar semen. Considering the influence of breeds on the optimal concentration of gamma‐oryzanol, for Duroc boar, gamma‐oryzanol at 0.16 mm (group C) yielded the highest percentage of progressive motility, sperm viability and acrosome integrity. For Large white and Landrace boars, gamma‐oryzanol at 0.24 mm (group D) showed a significantly higher percentage of progressive motility, viability (not significant in Landrace) and acrosome integrity than other concentrations. In conclusion, the optimal concentration of gamma‐oryzanol needed for boar semen cryopreservation in lactose–egg yolk (LEY) freezing extender is not only depended on individual boar but also breed of boar, that is 0.16 mm for Duroc and 0.24 mm for Large white and Landrace.
The Intrauterine Treatment of the Retained Foetal Membrane in Dairy Goats by Ozone: Novel Alternative to Antibiotic Therapy
Authors: Djuricic D , Valpotic H , Samardzija M
Published: January 2015

Contents

One of the major post‐parturient complications in dairy goats is the retention of foetal membrane (RFM), which negatively influences their health, reproductive efficacy and welfare. The aim of this study was to compare the efficiency of intrauterine either ozone (OZ) or antibiotic (AB) treatments to establish the use of OZ as a novel and potential alternative to AB therapy in does with the RFM. The study was performed on 7 herds of dairy goats (n = 563) kept in the farms in Croatia. The conception rate was 563 of 641 total matings or 87.83%. The does from selected farms were observed during early puerperium and were divided into animals without the RFM (n = 522) and with the RFM (n = 41), treated either with foam spray OZ (n = 21) or with foaming AB oxytetracycline tablets (n = 20). The does with the RFM were mated successfully and became pregnant next kidding season, regardless of the treatment applied. Treatment with OZ attained similar results to the standard AB therapy, indicating that it could be novel potential alternative therapy of the RFM in dairy goats.
Vaginal Histological Changes after Using Intravaginal Sponges for Oestrous Synchronization in Anoestrous Ewes
Authors: Manes J , Campero C , Hozbor F , Alberio R , Ungerfeld R
Published: January 2015

Contents

To characterize the histological and cytological vaginal changes generated by the use of intravaginal sponge (IS) applied in oestrous synchronization treatments in ewes during mid‐non‐breeding season. Thirty‐five multiparous ewes were allocated to three experimental groups according to the moment in which the samples were taken: (i) ewes treated with IS containing 60 mg of medroxyprogesterone acetate for 14 days, sampled the day of IS removal (group ISR; n = 10), (ii) or after sponge removal at time of oestrus or 72 h after removal (group AR; n = 14) and (iii) ewes without sponge treatment that were sampled at the day of IS removal of the other groups (group CG; n = 11). Vaginal biopsies and cytological samples were taken from the anterior vaginal fornix area. The vagina of the CG group had a stratified squamous epithelium with a moderate degree of cellular infiltration with lymphocytes and plasma cells in the lamina propia. Treated ewes (ISR and AR) had epithelial hyperplasia and hypertrophy. ISR ewes had haemorrhage and perivascular infiltrate and an increased number of epithelial cells, neutrophils, macrophages and erythrocytes at IS removal. The use of IS generated histological and cytological alterations in the vaginal wall when used for oestrous synchronization in anoestrous ewes.
Nitric oxide selectively suppresses IH currents mediated by HCN1‐containing channels
Authors: Kopp‐Scheinpflug Cornelia , Pigott Beatrice M. , Forsythe Ian D.
Published: January 2015

Key points

The superior olivary complex (SOC) exhibits a spectrum of HCN1 and HCN2 subunit expression, which generate IH currents with fast and slow kinetics, respectively.

Neuronal nitric oxide synthase (nNOS) was broadly distributed across the SOC.

NO hyperpolarizes the half‐activation voltage of HCN1‐mediated currents and caused a slowing of the IH current kinetics in the respective nuclei (medial and lateral superior olives and superior paraolivary nucleus). This signalling was independent of cGMP.

NO also caused a depolarizing shift in the half‐activation voltage of HCN2‐mediated IH currents, increasing activation at resting potentials; this was cGMP‐dependent.

Thus, NO signalling suppressed fast HCN1‐mediated currents and potentiated slow HCN2‐mediated currents, modulating the overall kinetics and magnitude of the endogenous IH.

Hyperpolarization‐activated non‐specific cation‐permeable channels (HCN) mediate IH currents, which are modulated by cGMP and cAMP and by nitric oxide (NO) signalling. Channel properties depend upon subunit composition (HCN1–4 and accessory subunits) as demonstrated in expression systems, but physiological relevance requires investigation in native neurons with intact intracellular signalling. Here we use the superior olivary complex (SOC), which exhibits a distinctive pattern of HCN1 and HCN2 expression, to investigate NO modulation of the respective IH currents, and compare properties in wild‐type and HCN1 knockout mice. The medial nucleus of the trapezoid body (MNTB) expresses HCN2 subunits exclusively, and sends inhibitory projections to the medial and lateral superior olives (MSO, LSO) and the superior paraolivary nucleus (SPN). In contrast to the MNTB, these target nuclei possess an IH with fast kinetics, and they express HCN1 subunits. NO is generated in the SOC following synaptic activity and here we show that NO selectively suppresses HCN1, while enhancing IH mediated by HCN2 subunits. NO hyperpolarizes the half‐activation of HCN1‐mediated currents and slows the kinetics of native IH currents in the MSO, LSO and SPN. This modulation was independent of cGMP and absent in transgenic mice lacking HCN1. Independently, NO signalling depolarizes the half‐activation of HCN2‐mediated IH currents in a cGMP‐dependent manner. Thus, NO selectively suppresses fast HCN1‐mediated IH and facilitates a slow HCN2‐mediated IH, so generating a spectrum of modulation, dependent on the local expression of HCN1 and/or HCN2.
Molecular underpinnings of ventral surface chemoreceptor function: focus on KCNQ channels
Authors: Mulkey Daniel K. , Hawkins Virginia E. , Hawryluk Joanna M. , Takakura Ana C. , Moreira Thiago S. , Tzingounis Anastasios V.
Published: January 2015

Central chemoreception is the mechanism by which CO2/H+‐sensitive neurons (i.e. chemoreceptors) regulate breathing in response to changes in tissue CO2/H+. Neurons in the retrotrapezoid nucleus (RTN) directly regulate breathing in response to changes in tissue CO2/H+ and function as a key locus of respiratory control by integrating information from several respiratory centres, including the medullary raphe. Therefore, chemosensitive RTN neurons appear to be critically important for maintaining breathing, thus understanding molecular mechanisms that regulate RTN chemoreceptor function may identify therapeutic targets for the treatment of respiratory control disorders. We have recently shown that KCNQ (Kv7) channels in the RTN are essential determinants of spontaneous activity ex vivo, and downstream effectors for serotonergic modulation of breathing. Considering that loss of function mutations in KCNQ channels can cause certain types of epilepsy including those associated with sudden unexplained death in epilepsy (SUDEP), we propose that dysfunctions of KCNQ channels may be one cause for epilepsy and respiratory problems associated with SUDEP. In this review, we will summarize the role of KCNQ channels in the regulation of RTN chemoreceptor function, and suggest that these channels represent useful therapeutic targets for the treatment of respiratory control disorders.
KCNQ1 channel modulation by KCNE proteins via the voltage‐sensing domain
Authors: Nakajo Koichi , Kubo Yoshihiro
Published: January 2015

The gating of the KCNQ1 potassium channel is drastically regulated by auxiliary subunit KCNE proteins. KCNE1, for example, slows the activation kinetics of KCNQ1 by two orders of magnitude. Like other voltage‐gated ion channels, the opening of KCNQ1 is regulated by the voltage‐sensing domain (VSD; S1–S4 segments). Although it has been known that KCNE proteins interact with KCNQ1 via the pore domain, some recent reports suggest that the VSD movement may be altered by KCNE. The altered VSD movement of KCNQ1 by KCNE proteins has been examined by site‐directed mutagenesis, the scanning cysteine accessibility method (SCAM), voltage clamp fluorometry (VCF) and gating charge measurements. These accumulated data support the idea that KCNE proteins interact with the VSDs of KCNQ1 and modulate the gating of the KCNQ1 channel. In this review, we will summarize recent findings and current views of the KCNQ1 modulation by KCNE via the VSD. In this context, we discuss our recent findings that KCNE1 may alter physical interactions between the S4 segment (VSD) and the S5 segment (pore domain) of KCNQ1. Based on these findings from ourselves and others, we propose a hypothetical mechanism for how KCNE1 binding alters the VSD movement and the gating of the channel.
Dynamics of a Levitron under a periodic magnetic forcing
Authors: Pérez Alberto T. , García-Sánchez Pablo
Published: January 2015

The Levitron is a toy that consists of a spinning top that levitates over a magnetic base for a few minutes, until air drag decreases the spin rate below a certain limit. Stable levitation, lasting hours or even days, has been achieved for Levitrons that were externally driven by either an air jet or an alternating magnetic field. We report measurements of stable levitation for the latter case. We show that the top precession couples with the frequency of the alternating field, so that the precession period equals the period of the field. In addition, the top rotates around itself with the same period. We present numerical simulations that reproduce the essential features of this dynamics. It is also shown that the magnetic torque that drives the top is due to a misalignment between the magnetic dipole moment and the mechanical axis of the top.
Gibbs, Boltzmann, and negative temperatures
Authors: Frenkel Daan , Warren Patrick B.
Published: January 2015

In a recent paper, Dunkel and Hilbert [Nat. Phys. 10, 67–72 (2014)] use an entropy definition due to Gibbs to provide a “consistent thermostatistics” that forbids negative absolute temperatures. Here, we argue that the Gibbs entropy fails to satisfy a basic requirement of thermodynamics, namely, that when two bodies are in thermal equilibrium, they should be at the same temperature. The entropy definition due to Boltzmann does meet this test, and moreover, in the thermodynamic limit can be shown to satisfy Dunkel and Hilbert's consistency criterion. Thus, far from being forbidden, negative temperatures are inevitable, in systems with bounded energy spectra.
Casimir effect from a scattering approach
Authors: Ingold Gert-Ludwig , Lambrecht Astrid
Published: January 2015

The Casimir force is a spectacular consequence of the existence of vacuum fluctuations and thus deserves a place in courses on quantum theory. We argue that the scattering approach within a one-dimensional field theory is well suited to a discussion of the Casimir effect. It avoids in a transparent way divergences appearing in the evaluation of the vacuum energy. Furthermore, the scattering approach connects in a natural manner to the standard discussion of one-dimensional scattering problems in a quantum theory course. Finally, it allows for the introduction to students of the methods employed in the current research literature to determine the Casimir force in real-world systems.
The van der Waals interaction in one, two, and three dimensions
Authors: Ipsen A. C. , Splittorff K.
Published: January 2015

The van der Waals interaction between two polarizable atoms is considered. In three dimensions, the standard form with an attractive 1/R6 potential is obtained from second-order quantum perturbation theory. When the electron motion is restricted to lower dimensions (but the 1/R Coulomb potential is retained), new terms in the expansion appear and alter both the sign and the R-dependence of the interaction.
The Effectiveness of Foot Orthotics in Improving Postural Control in Individuals With Chronic Ankle Instability: A Critically Appraised Topic
Authors: Gabriner Michael L. , Braun Brittany A. , Houston Megan N. , Hoch Matthew C.
Published: January 2015

Clinical Scenario:

Chronic ankle instability (CAI) is a condition commonly experienced by physically active individuals. It has been suggested that foot orthotics may increase a CAI patient’s postural control.

Clinical Question:

For patients with CAI, is there evidence to suggest that an orthotic intervention will help improve postural control?

Summary of Key Findings:

The literature was searched for studies of level 2 evidence or higher that investigated the effects of foot orthotics on postural control in patients with CAI. The search of the literature produced 5 possible studies for inclusion; 2 studies met the inclusion criteria and were included. One randomized controlled trial and 1 outcomes study were included. Foot orthotics appear to be effective at improving postural control in patients with CAI.

Clinical Bottom Line:

There is moderate evidence to support the use of foot orthotics in the treatment of CAI to help improve postural control.

Strength of Recommendation:

There is grade B evidence that foot orthotics help improve postural control in people with CAI. The Centre of Evidence Based Medicine recommends a grade of B for level 2 evidence with consistent findings.
Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model
Authors: Lood Rolf , Winer Benjamin Y. , Pelzek Adam J. , Diez-Martinez Roberto , Thandar Mya , Euler Chad W. , Schuch Raymond , Fischetti Vincent A.
Published: January 2015

Acinetobacter baumannii
, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13
A. baumannii
strains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killing
A. baumannii
. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all tested
A. baumannii
clinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilm
A. baumannii
both
in vitro
and
in vivo
. Finally, PlyF307 rescued mice from lethal
A. baumannii
bacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found in
Acinetobacter
phage.
Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague
Authors: Tiner Bethany L. , Sha Jian , Kirtley Michelle L. , Erova Tatiana E. , Popov Vsevolod L. , Baze Wallace B. , van Lier Christina J. , Ponnusamy Duraisamy , Andersson Jourdan A. , Motin Vladimir L. , Chauhan Sadhana , Chopra Ashok K.
Published: January 2015

Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated
Yersinia pestis
CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the
ail
gene (encoding the
a
ttachment-
i
nvasion
l
ocus) from wild-type (WT) strain CO92 or its
lpp
single and Δ
lpp
Δ
msbB
double mutants. While the Δ
ail
single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the Δ
lpp
Δ
ail
double mutant and the Δ
lpp
Δ
msbB
Δ
ail
triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD
50
) equivalent to 6,800 LD
50
s of WT CO92. The mutant-infected animals developed balanced T
H
1- and T
H
2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD
50
s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by
in vivo
imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the
ail
gene from the Δ
lpp
Δ
msbB
double mutant severely attenuated
Y. pestis
CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection.
Competitive Science: Is Competition Ruining Science?
Authors: Fang Ferric C. , Casadevall Arturo
Published: January 2015

Science has always been a competitive undertaking. Despite recognition of the benefits of cooperation and team science, reduced availability of funding and jobs has made science more competitive than ever. Here we consider the benefits of competition in providing incentives to scientists and the adverse effects of competition on resource sharing, research integrity, and creativity. The history of science shows that transformative discoveries often occur in the absence of competition, which only emerges once fields are established and goals are defined. Measures to encourage collaboration and ameliorate competition in the scientific enterprise are discussed.
Burkholderia pseudomallei Type III Secretion System Cluster 3 ATPase BsaS, a Chemotherapeutic Target for Small-Molecule ATPase Inhibitors
Authors: Gong Lan , Lai Shu-Chin , Treerat Puthayalai , Prescott Mark , Adler Ben , Boyce John D. , Devenish Rodney J.
Published: January 2015

Melioidosis is an infectious disease of high mortality for humans and other animal species; it is prevalent in tropical regions worldwide. The pathogenesis of melioidosis depends on the ability of its causative agent, the Gram-negative bacterium
Burkholderia pseudomallei
, to enter and survive in host cells.
B. pseudomallei
can escape from the phagosome into the cytosol of phagocytic cells where it replicates and acquires actin-mediated motility, avoiding killing by the autophagy-dependent process, LC3 (microtubule-associated protein light chain 3)-associated phagocytosis (LAP). The type III secretion system cluster 3 (TTSS3) facilitates bacterial escape from phagosomes, although the mechanism has not been fully elucidated. Given the recent identification of small-molecule inhibitors of the TTSS ATPase, we sought to determine the potential of the predicted TTSS3 ATPase, encoded by
bsaS
, as a target for chemotherapeutic treatment of infection. A
B. pseudomallei
bsaS
deletion mutant was generated and used as a control against which to assess the effect of inhibitor treatment. Infection of RAW 264.7 cells with wild-type bacteria and subsequent treatment with the ATPase inhibitor compound 939 resulted in reduced intracellular bacterial survival, reduced escape from phagosomes, and increased colocalization with both LC3 and the lysosomal marker LAMP1 (lysosome-associated membrane protein 1). These changes were similar to those observed for infection of RAW 264.7 cells with the
bsaS
deletion mutant. We propose that treatment with the ATPase inhibitor compound 939 decreased intracellular bacterial survival through a reduced ability of bacteria to escape from phagosomes and increased killing via LAP. Therefore, small-molecule inhibitors of the TTSS3 ATPase have potential as therapeutic treatments against melioidosis.
Engineering the Genome of Thermus thermophilus Using a Counterselectable Marker
Authors: Carr Jennifer F. , Danziger Michael E. , Huang Athena L. , Dahlberg Albert E. , Gregory Steven T.
Published: January 2015

Thermus thermophilus
is an extremely thermophilic bacterium that is widely used as a model thermophile, in large part due to its amenability to genetic manipulation. Here we describe a system for the introduction of genomic point mutations or deletions using a counterselectable marker consisting of a conditionally lethal mutant allele of
pheS
encoding the phenylalanyl-tRNA synthetase α-subunit. Mutant PheS with an A294G amino acid substitution renders cells sensitive to the phenylalanine analog
p
-chlorophenylalanine. Insertion of the mutant
pheS
allele via a linked kanamycin resistance gene into a chromosomal locus provides a gene replacement intermediate that can be removed by homologous recombination using
p
-chlorophenylalanine as a counterselective agent. This selection is suitable for the sequential introduction of multiple mutations to produce a final strain unmarked by an antibiotic resistance gene. We demonstrated the utility of this method by constructing strains bearing either a point mutation in or a precise deletion of the
rrsB
gene encoding 16S rRNA. We also used this selection to identify spontaneous, large-scale deletions in the pTT27 megaplasmid, apparently mediated by either of the
T. thermophilus
insertion elements IS
Tth7
and IS
Tth8
. One such deletion removed 121 kb, including 118 genes, or over half of pTT27, including multiple sugar hydrolase genes, and facilitated the development of a plasmid-encoded reporter system based on β-galactosidase. The ability to introduce mutations ranging from single base substitutions to large-scale deletions provides a potentially powerful tool for engineering the genome of
T. thermophilus
and possibly other thermophiles as well.

IMPORTANCE
Thermus thermophilus
is an extreme thermophile that has played an important part in the development of both biotechnology and basic biological research. Its suitability as a genetic model system is established by its natural competence for transformation, but the scarcity of genetic tools limits the kinds of manipulations that can currently be performed. We have developed a counterselectable marker that allows the introduction of unmarked deletions and point mutations into the
T. thermophilus
genome. We find that this marker can also be used to select large chromosomal deletions apparently resulting from aberrant transposition of endogenous insertion sequences. This system has the potential to advance the genetic manipulation of this important model organism.
Evaluation of the Potential Impact of Ebola Virus Genomic Drift on the Efficacy of Sequence-Based Candidate Therapeutics
Authors: Kugelman Jeffrey R. , Sanchez-Lockhart Mariano , Andersen Kristian G. , Gire Stephen , Park Daniel J. , Sealfon Rachel , Lin Aaron E. , Wohl Shirlee , Sabeti Pardis C. , Kuhn Jens H. , Palacios Gustavo F.
Published: January 2015

Until recently, Ebola virus (EBOV) was a rarely encountered human pathogen that caused disease among small populations with extraordinarily high lethality. At the end of 2013, EBOV initiated an unprecedented disease outbreak in West Africa that is still ongoing and has already caused thousands of deaths. Recent studies revealed the genomic changes this particular EBOV variant undergoes over time during human-to-human transmission. Here we highlight the genomic changes that might negatively impact the efficacy of currently available EBOV sequence-based candidate therapeutics, such as small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and antibodies. Ten of the observed mutations modify the sequence of the binding sites of monoclonal antibody (MAb) 13F6, MAb 1H3, MAb 6D8, MAb 13C6, and siRNA EK-1, VP24, and VP35 targets and might influence the binding efficacy of the sequence-based therapeutics, suggesting that their efficacy should be reevaluated against the currently circulating strain.
Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus
Authors: Utset Tammy O , Baskaran Amrutha , Segal Barbara M , Trupin Laura , Ogale Sarika , Herberich Ellen , Kalunian Kenneth
Published: January 2015

Objective

To assess prevalence and correlates of work presenteeism, absenteeism and work disability (WD) in patients with systemic lupus erythematous (SLE) and matched controls.

Methods

Patients with SLE from six medical centres were recruited to complete a questionnaire consisting of several prevalidated survey instruments. The subject's rheumatologist completed medical history. Subjects recruited two non-SLE ‘best friend’ controls with matching demographics to complete a control survey. Analyses employed Student's t tests, χ2tests and logistic regression models.

Results

344 subjects with SLE and 322 controls submitted completed questionnaires. Mean pain, fatigue, Brief Cognitive Symptoms Index (BCSI) scores and depressive symptoms were worse in patients with SLE with WD (all p<0.01). WD was associated with African–American race, older age (51–65 years) and less than 4-year college education (all p<0.01). High presenteeism was associated with low pain and fatigue levels, higher BCSI scores and negatively correlated with depressive symptoms (all p<0.05). Increased pain and fatigue were associated with elevated absenteeism (p<0.05). Subjects with physically and cognitively demanding work reported worse presenteeism compared with controls with similar jobs (77% vs 85%, p<0.05 and 75% vs 85%, p<0.001), respectively. Patients with most cognitively demanding jobs reported greater weekly absenteeism (mean, 5.9 h) compared with controls (mean, 6.9 overtime hours, p<0.05).

Conclusions

The questionnaire demonstrated increased WD in SLE. Highly physical and highly cognitive jobs are challenging to patients with SLE and had increased absenteeism compared with controls. Depressive symptoms were correlated with better presenteeism without major socio-demographic determinants. Employability may be enhanced by improving treatment of depressive symptoms in patients with SLE.
Detecting density dependence from spatial patterns in a heterogeneous subtropical forest of central China
Authors: Guo Yili , Lu Zhijun , Wang Qinggang , Lu Junmeng , Xu Yaozhan , Meng Hongjie , Liu Haibo , Zhang Jiaxin , Bao Dachuan , Qiao Xiujuan , Huang Handong , Jiang Mingxi
Published: January 2015

Accumulating evidence suggests that density dependence, whether at early or late life stages, is an important mechanism regulating plant population structure. However, the opposing effects of habitat heterogeneity and species-level variation might have confounded the prevalence of density dependence in natural forests. These compatible ideas were rarely considered simultaneously. In this study, we applied a spatial statistical technique to examine (i) the prevalence of density dependence at late life stages after controlling for habitat heterogeneity and (ii) the relationships between species traits and the strength of density dependence in a newly established, 25 ha subtropical mountain forest plot in central China. Of the 88 (75%) tree species analyzed, 66 were found to exhibit density dependence predominantly at very close distances among neighbors in the species-rich subtropical forest. In addition, the strength of density dependence was associated with species traits. Our findings identified strong density dependence among trees that had greater stature and were rarer. We concluded that density dependence was a prevalent mechanism for regulating the population structure of most tree species and both habitat heterogeneity and species-level variation played crucial roles in shaping the strength of density dependence in natural forests.
Weighted interpolation from certain singular affine hypersurfaces
Authors: Pingali Vamsi P.
Published: January 2015

We prove that square integrable (with respect to a plurisubharmonic weight) holomorphic functions can be extended in a square integrable manner from certain singular hypersurfaces (which include uniformly flat, normal crossing divisors) to entire functions in affine space. This gives evidence to a conjecture regarding the positivity of the curvature of the weight under consideration.
Emergent gravity paradigm: Recent progress
Authors: Padmanabhan T.
Published: January 2015

Research during the last one decade or so suggests that the gravitational field equations in a large class of theories (including, but not limited to, general relativity) have the same status as the equations of, say, gas dynamics or elasticity. This paradigm provides a refreshingly different way of interpreting spacetime dynamics and highlights the fact that several features of classical gravitational theories have direct thermodynamic interpretation. I review the recent progress in this approach, achieved during the last few years.
Quarks and a unified theory of Nature fundamental forces
Authors: Antoniadis I.
Published: January 2015

Quarks were introduced 50 years ago opening the road towards our understanding of the elementary constituents of matter and their fundamental interactions. Since then, a spectacular progress has been made with important discoveries that led to the establishment of the Standard Theory that describes accurately the basic constituents of the observable matter, namely quarks and leptons, interacting with the exchange of three fundamental forces, the weak, electromagnetic and strong force. Particle physics is now entering a new era driven by the quest of understanding of the composition of our Universe such as the unobservable (dark) matter, the hierarchy of masses and forces, the unification of all fundamental interactions with gravity in a consistent quantum framework, and several other important questions. A candidate theory providing answers to many of these questions is string theory that replaces the notion of point particles by extended objects, such as closed and open strings. In this short note, I will give a brief overview of string unification, describe in particular how quarks and leptons can emerge and discuss what are possible predictions for particle physics and cosmology that could test these ideas.
Continuous piecewise affine transformation for image registration
Authors: Lee Yun-Shan , Hwang Wen-Liang , Tian Xiaolin
Published: January 2015

The image registration problem involves determining a geometric transformation to properly align images of interest. This paper proposes a transformation approach called Continuous Piecewise Affine Transformation (CPAT) to model the geometric distortion in images. The associated design methodology for the 2D registration problem is also discussed. Registration on CPAT has two advantages: (1) The optimal transformation has a closed form analytical solution; and (2) the transformation is invertible and transitive. Because of these advantages, CPAT could be used for real-time registration and progressive registration, where the registration speed and transitivity property are important for the successful completion of the tasks. The results of experiments demonstrate the efficacy of CPAT in resolving the image registration problem.
Prevalence and Molecular Epidemiological Data on Dirofilaria immitis in Dogs from Northeastern States of India
Authors: Borthakur Sonjoy Kumar , Deka Dilip Kumar , Islam Saidul , Sarma Dilip Kumar , Sarmah Prabhat Chandra
Published: January 2015

The aim of the present study was to determine the prevalence of Dirofilaria immitis in stray, pet, and working dogs (n = 413, 266, and 103, resp.) from Guwahati (Assam) and Aizawl (Mizoram), areas located in two Northeastern States of India. Diagnostic methods applied were microscopy (wet film and Knott’s concentration technique), immunological test (Ag ELISA by SNAP 4Dx ELISA kit), and molecular tools (polymerase chain reaction and sequencing), which evidenced 11.38, 18.03, and 13.93% of positive animals, respectively. No significant differences were observed by area (18.23% versus 17.68%) nor by sex (18.1% versus 17.9%), whereas stray dogs proved more infected than other groups (P < 0.05). ELISA test evidenced an overall 22.69% of occult infections, mainly in working dogs (60%), and molecular techniques detected Dirofilaria (Nochtiella) repens in 4 stray dogs from Guwahati. Characterization of D. immitis isolates for ITS‐2 region showed close identity with South Asian isolates.
Soil As Levels and Bioaccumulation inSuaeda salsaandPhragmites australisWetlands of the Yellow River Estuary, China
Authors: Wang Junjing , Bai Junhong , Gao Zhaoqin , Lu Qiongqiong , Zhao Qingqing
Published: January 2015

Little information is available on As contamination dynamics in the soil-plant systems of wetlands. Total arsenic (As) in soil and plant samples fromSuaeda salsaandPhragmites australiswetlands was measured in the Yellow River Estuary (YRE) in summer and autumn of 2007 to investigate the seasonal changes in As concentrations in different wetlands. The results showed that soil As levels greatly exceeded the global and regional background values. As levels in soil and the roots and stems of both types of plants were much higher in summer than in autumn, whereas leaf As showed higher level in autumn. Soil sulfur was the main factor influencing As levels inSuaeda salsawetlands, whereas soil porosity was the most important factor forPhragmites australiswetlands. The contamination factor (CF) showed moderately to considerably polluted levels of As in both wetland soils. Plant roots and leaves ofSuaeda salsahad higher As concentrations and biological concentration factors (BCFs) than stems, while the leaves and stems ofPhragmites australisshowed higher As levels and BCFs than roots. Compared toPhragmites australis,Suaeda salsagenerally showed higher translocation factor (TF), while TF values for both plant species were higher in summer than in autumn.
All Pass Network Based MSO Using OTRA
Authors: Pandey Rajeshwari , Pandey Neeta , Mullick Romita , Yadav Sarjana , Anurag Rashika
Published: January 2015

This paper presents multiphase sinusoidal oscillators (MSOs) using operational transresistance amplifier (OTRA) based all pass networks. Both even and odd phase oscillations of equal amplitudes which are equally spaced in phase can be produced using single all pass section per phase. The proposed MSOs provide voltage output and can readily be used for driving voltage input circuits without increasing component count. The effect of nonideality of OTRA on the circuit performance is also analysed. The functionality of the proposed circuit is verified through PSPICE simulations.
Five-Aminosalicylic Acid: An Update for the Reappraisal of an Old Drug
Authors: Perrotta Cristiana , Pellegrino Paolo , Moroni Eliana , De Palma Clara , Cervia Davide , Danelli Piergiorgio , Clementi Emilio
Published: January 2015

Inflammatory bowel disease (IBD) comprises several conditions with chronic or recurring immune response and inflammation of the gastrointestinal apparatus, of which ulcerative colitis and Crohn’s disease are the commonest forms. This disease has a significant prevalence and it is of an unknown aethiology. Five-aminosalicylic acid (5-ASA) and its derivatives are among the oldest drugs approved for the treatment of the IBD. In this review we reapprise aspects of 5-ASA mechanism of action, safety, and efficacy that in our opinion make it a valuable drug that can be fruitfully tailored in personalised treatments as a therapeutic option alongside other immune-modifying agents.