bluuebunny/crossref_metadata_2025_split huggingface dataset:
Range Expansion and the Origin of USA300 North American Epidemic Methicillin-Resistant
Staphylococcus aureus
Authors: Challagundla Lavanya , Luo Xiao , Tickler Isabella A. , Didelot Xavier , Coleman David C. , Shore Anna C. , Coombs Geoffrey W. , Sordelli Daniel O. , Brown Eric L. , Skov Robert , Larsen Anders Rhod , Reyes Jinnethe , Robledo Iraida E. , Vazquez Guillermo J. , Rivera Raul , Fey Paul D. , Stevenson Kurt , Wang Shu-Hua , Kreiswirth Barry N. , Mediavilla Jose R. , Arias Cesar A. , Planet Paul J. , Nolan Rathel L. , Tenover Fred C. , Goering Richard V. , Robinson D. Ashley 
Published: January 2018

ABSTRACT

The USA300 North American epidemic (USA300-NAE) clone of methicillin-resistant
Staphylococcus aureus
has caused a wave of severe skin and soft tissue infections in the United States since it emerged in the early 2000s, but its geographic origin is obscure. Here we use the population genomic signatures expected from the serial founder effects of a geographic range expansion to infer the origin of USA300-NAE and identify polymorphisms associated with its spread. Genome sequences from 357 isolates from 22 U.S. states and territories and seven other countries are compared. We observe two significant signatures of range expansion, including decreases in genetic diversity and increases in derived allele frequency with geographic distance from the Pennsylvania region. These signatures account for approximately half of the core nucleotide variation of this clone, occur genome wide, and are robust to heterogeneity in temporal sampling of isolates, human population density, and recombination detection methods. The potential for positive selection of a
gyrA
fluoroquinolone resistance allele and several intergenic regions, along with a 2.4 times higher recombination rate in a resistant subclade, is noted. These results are the first to show a pattern of genetic variation that is consistent with a range expansion of an epidemic bacterial clone, and they highlight a rarely considered but potentially common mechanism by which genetic drift may profoundly influence bacterial genetic variation.

IMPORTANCE
The process of geographic spread of an origin population by a series of smaller populations can result in distinctive patterns of genetic variation. We detect these patterns for the first time with an epidemic bacterial clone and use them to uncover the clone’s geographic origin and variants associated with its spread. We study the USA300 clone of methicillin-resistant
Staphylococcus aureus
, which was first noticed in the early 2000s and subsequently became the leading cause of skin and soft tissue infections in the United States. The eastern United States is the most likely origin of epidemic USA300. Relatively few variants, which include an antibiotic resistance mutation, have persisted during this clone’s spread. Our study suggests that an early chapter in the genetic history of this epidemic bacterial clone was greatly influenced by random subsampling of isolates during the clone’s geographic spread.
Role of Heat Shock Proteases in Quorum-Sensing-Mediated Regulation of Biofilm Formation by
Vibrio
Species
Authors: Lee Kyung-Jo , Jung You-Chul , Park Soon-Jung , Lee Kyu-Ho 
Published: January 2018

ABSTRACT

Capsular polysaccharide (CPS) is essential for the dispersal of biofilms formed by the pathogenic bacterium
Vibrio vulnificus
. CPS production is induced by the quorum-sensing (QS) master regulator SmcR when biofilms mature. However,
V. vulnificus
biofilms formed under heat shock conditions did not exhibit the dispersion stage. Transcripts of the CPS gene cluster were at basal levels in the heat-exposed cell owing to reduced cellular levels of SmcR. At least two proteases induced by heat shock, ClpPA and Lon, were responsible for determining the instability of SmcR.
In vitro
and
in vivo
assays demonstrated that SmcR levels were regulated via proteolysis by these proteases, with preferential proteolysis of monomeric SmcR. Thus, CPS production was not induced by QS when bacteria were heat treated. Further studies performed with other
Vibrio
species demonstrated that high temperature deactivated the QS circuits by increased proteolysis of their QS master regulators, thus resulting in alterations to the QS-regulated phenotypes, including biofilm formation.

IMPORTANCE
The term "quorum-sensing mechanism" is used to describe diverse bacterial cell density-dependent activities that are achieved by sensing of the signaling molecules and subsequent signal transduction to the master regulators. These well-known bacterial regulatory systems regulate the expression of diverse virulence factors and the construction of biofilms in pathogenic bacteria. There have been numerous studies designed to control bacterial quorum sensing by using small molecules to antagonize the quorum-sensing regulatory components or to interfere with the signaling molecules. In the present study, we showed that the quorum-sensing regulatory circuits of pathogenic
Vibrio
species were deactivated by heat shock treatment via highly increased proteolysis of the master transcription factors. Our results showed a new mode of quorum deactivation which can be achieved under conditions of high but nonlethal temperature even if the ambient signaling molecules may reach the levels representing high cell density.
Streptococcus pneumoniae
Modulates
Staphylococcus aureus
Biofilm Dispersion and the Transition from Colonization to Invasive Disease
Authors: Reddinger Ryan M. , Luke-Marshall Nicole R. , Sauberan Shauna L. , Hakansson Anders P. , Campagnari Anthony A. 
Published: January 2018

ABSTRACT

Streptococcus pneumoniae
and
Staphylococcus aureus
are ubiquitous upper respiratory opportunistic pathogens. Individually, these Gram-positive microbes are two of the most common causative agents of secondary bacterial pneumonia following influenza A virus infection, and they constitute a significant source of morbidity and mortality. Since the introduction of the pneumococcal conjugate vaccine, rates of cocolonization with both of these bacterial species have increased, despite the traditional view that they are antagonistic and mutually exclusive. The interactions between
S. pneumoniae
and
S. aureus
in the context of colonization and the transition to invasive disease have not been characterized. In this report, we show that
S. pneumoniae
and
S. aureus
form stable dual-species biofilms on epithelial cells
in vitro
. When these biofilms are exposed to physiological changes associated with viral infection,
S. pneumoniae
disperses from the biofilm, whereas
S. aureus
dispersal is inhibited. These findings were supported by results of an
in vivo
study in which we used a novel mouse cocolonization model. In these experiments, mice cocolonized in the nares with both bacterial species were subsequently infected with influenza A virus. The coinfected mice almost exclusively developed pneumococcal pneumonia. These results indicate that despite our previous report that
S. aureus
disseminates into the lungs of mice stably colonized with these bacteria following influenza A virus infection, cocolonization with
S. pneumoniae in vitro
and
in vivo
inhibits
S. aureus
dispersal and transition to disease. This study provides novel insight into both the interactions between
S. pneumoniae
and
S. aureus
during carriage and the transition from colonization to secondary bacterial pneumonia.

IMPORTANCE
In this study, we demonstrate that
Streptococcus pneumoniae
can modulate the pathogenic potential of
Staphylococcus aureus
in a model of secondary bacterial pneumonia. We report that host physiological signals related to viral infection cease to elicit a dispersal response from
S. aureus
while in a dual-species setting with
S. pneumoniae
, in direct contrast to results of previous studies with each species individually. This study underscores the importance of studying polymicrobial communities and their implications in disease states.
Cyclic AMP Regulates Bacterial Persistence through Repression of the Oxidative Stress Response and SOS-Dependent DNA Repair in Uropathogenic
Escherichia coli
Authors: Molina-Quiroz Roberto C. , Silva-Valenzuela Cecilia , Brewster Jennifer , Castro-Nallar Eduardo , Levy Stuart B. , Camilli Andrew 
Published: January 2018

ABSTRACT

Bacterial persistence is a transient, nonheritable physiological state that provides tolerance to bactericidal antibiotics. The stringent response, toxin-antitoxin modules, and stochastic processes, among other mechanisms, play roles in this phenomenon. How persistence is regulated is relatively ill defined. Here we show that cyclic AMP, a global regulator of carbon catabolism and other core processes, is a negative regulator of bacterial persistence in uropathogenic
Escherichia coli
, as measured by survival after exposure to a β-lactam antibiotic. This phenotype is regulated by a set of genes leading to an oxidative stress response and SOS-dependent DNA repair. Thus, persister cells tolerant to cell wall-acting antibiotics must cope with oxidative stress and DNA damage and these processes are regulated by cyclic AMP in uropathogenic
E. coli
.

IMPORTANCE
Bacterial persister cells are important in relapsing infections in patients treated with antibiotics and also in the emergence of antibiotic resistance. Our results show that in uropathogenic
E. coli
, the second messenger cyclic AMP negatively regulates persister cell formation, since in its absence much more persister cells form that are tolerant to β-lactams antibiotics. We reveal the mechanism to be decreased levels of reactive oxygen species, specifically hydroxyl radicals, and SOS-dependent DNA repair. Our findings suggest that the oxidative stress response and DNA repair are relevant pathways to target in the design of persister-specific antibiotic compounds.
Visceral hypersensitivity induced by optogenetic activation of the amygdala in conscious rats
Authors: Johnson Anthony C. , Latorre Rocco , Ligon Casey O. , Greenwood-Van Meerveld Beverley 
Published: January 2018

In vivo optogenetics identifies brain circuits controlling behaviors in conscious animals by using light to alter neuronal function and offers a novel tool to study the brain-gut axis. Using adenoviral-mediated expression, we aimed to investigate whether photoactivation with channelrhodopsin (ChR2) or photoinhibition with halorhodopsin (HR3.0) of fibers originating from the central nucleus of the amygdala (CeA) at the bed nucleus of the stria terminalis (BNST) had any effect on colonic sensitivity. We also investigated whether there was any deleterious effect of the adenovirus on the neuronal population or the neuronal phenotype within the CeA-BNST circuitry activated during the optogenetic stimulation. In male rats, the CeA was infected with vectors expressing ChR2 or HR3.0 and fiber optic cannulae were implanted on the BNST. After 8–10 wk, the response to graded, isobaric colonic distension was measured with and without laser stimulation of CeA fibers at the BNST. Immunohistochemistry and histology were used to evaluate vector expression, neuronal integrity, and neurochemical phenotype. Photoactivation of CeA fibers at the BNST with ChR2 induced colonic hypersensitivity, whereas photoinhibition of CeA fibers at the BNST with HR3.0 had no effect on colonic sensitivity. Control groups treated with virus expressing reporter proteins showed no abnormalities in neuronal morphology, neuronal number, or neurochemical phenotype following laser stimulation. Our experimental findings reveal that optogenetic activation of discrete brain nuclei can be used to advance our understanding of complex visceral nociceptive circuitry in a freely moving rat model. NEW & NOTEWORTHY Our findings reveal that optogenetic technology can be employed as a tool to advance understanding of the brain-gut axis. Using adenoviral-mediated expression of opsins, which were activated by laser light and targeted by fiber optic cannulae, we examined central nociceptive circuits mediating visceral pain in a freely moving rat. Photoactivation of amygdala fibers in the stria terminalis with channelrhodopsin induced colonic hypersensitivity, whereas inhibition of the same fibers with halorhodopsin did not alter colonic sensitivity.
Involvement of cAMP/EPAC/Akt signaling in the antiproteolytic effects of pentoxifylline on skeletal muscles of diabetic rats
Authors: Arcaro Carlos Alberto , Assis Renata Pires , Zanon Neusa Maria , Paula-Gomes Silvia , Navegantes Luiz Carlos Carvalho , Kettelhut Isis Carmo , Brunetti Iguatemy Lourenço , Baviera Amanda Martins 
Published: January 2018

Advances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle-wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats. The levels of atrogin-1 and muscle RING finger-1 were decreased, as were the activities of caspase-3 (EDL) and calpains (soleus and EDL), in diabetic rats treated with PTX, which at least partly explains the drop in the ubiquitin conjugate (EDL) levels and in proteasome activity (soleus and EDL). Treatment with PTX decreased PDE activity and increased cAMP content in muscles of diabetic rats; moreover, it also increased both the protein levels of exchange protein directly activated by cAMP (EPAC, a cAMP effector) and the phosphorylation of Akt. The loss of muscle mass was practically prevented in diabetic rats treated with PTX. These findings advance our understanding of the mechanisms underlying the antiproteolytic effects of PTX and suggest the use of PDE inhibitors as a strategy to activate cAMP signaling, which is emerging as a promising target for treating muscle mass loss during atrophic conditions.NEW & NOTEWORTHY cAMP signaling has been explored as a strategy to attenuate skeletal muscle atrophies. Therefore, in addition to β2AR agonists, phosphodiesterase inhibitors such as pentoxifylline (PTX) can be an interesting option. This study advances the understanding of the mechanisms related to the antiproteolytic effects of PTX on skeletal muscles of diabetic rats, which involve the activation of both exchange protein directly activated by cAMP and Akt effectors, inhibiting the expression of atrogenes and calpain/caspase-3-proteolytic machinery.
Modeling sources of interlaboratory variability in electrophysiological properties of mammalian neurons
Authors: Tebaykin Dmitry , Tripathy Shreejoy J. , Binnion Nathalie , Li Brenna , Gerkin Richard C. , Pavlidis Paul 
Published: January 2018

Patch-clamp electrophysiology is widely used to characterize neuronal electrical phenotypes. However, there are no standard experimental conditions for in vitro whole cell patch-clamp electrophysiology, complicating direct comparisons between data sets. In this study, we sought to understand how basic experimental conditions differ among laboratories and how these differences might impact measurements of electrophysiological parameters. We curated the compositions of external bath solutions (artificial cerebrospinal fluid), internal pipette solutions, and other methodological details such as animal strain and age from 509 published neurophysiology articles studying rodent neurons. We found that very few articles used the exact same experimental solutions as any other, and some solution differences stem from recipe inheritance from advisor to advisee as well as changing trends over the years. Next, we used statistical models to understand how the use of different experimental conditions impacts downstream electrophysiological measurements such as resting potential and action potential width. Although these experimental condition features could explain up to 43% of the study-to-study variance in electrophysiological parameters, the majority of the variability was left unexplained. Our results suggest that there are likely additional experimental factors that contribute to cross-laboratory electrophysiological variability, and identifying and addressing these will be important to future efforts to assemble consensus descriptions of neurophysiological phenotypes for mammalian cell types. NEW & NOTEWORTHY This article describes how using different experimental methods during patch-clamp electrophysiology impacts downstream physiological measurements. We characterized how methodologies and experimental solutions differ across articles. We found that differences in methods can explain some, but not all, of the study-to-study variance in electrophysiological measurements. Explicitly accounting for methodological differences using statistical models can help correct downstream electrophysiological measurements for cross-laboratory methodology differences.
Emergent coordination underlying learning to reach to grasp with a brain-machine interface
Authors: Vaidya Mukta , Balasubramanian Karthikeyan , Southerland Joshua , Badreldin Islam , Eleryan Ahmed , Shattuck Kelsey , Gururangan Suchin , Slutzky Marc , Osborne Leslie , Fagg Andrew , Oweiss Karim , Hatsopoulos Nicholas G. 
Published: January 2018

The development of coordinated reach-to-grasp movement has been well studied in infants and children. However, the role of motor cortex during this development is unclear because it is difficult to study in humans. We took the approach of using a brain-machine interface (BMI) paradigm in rhesus macaques with prior therapeutic amputations to examine the emergence of novel, coordinated reach to grasp. Previous research has shown that after amputation, the cortical area previously involved in the control of the lost limb undergoes reorganization, but prior BMI work has largely relied on finding neurons that already encode specific movement-related information. In this study, we taught macaques to cortically control a robotic arm and hand through operant conditioning, using neurons that were not explicitly reach or grasp related. Over the course of training, stereotypical patterns emerged and stabilized in the cross-covariance between the reaching and grasping velocity profiles, between pairs of neurons involved in controlling reach and grasp, and to a comparable, but lesser, extent between other stable neurons in the network. In fact, we found evidence of this structured coordination between pairs composed of all combinations of neurons decoding reach or grasp and other stable neurons in the network. The degree of and participation in coordination was highly correlated across all pair types. Our approach provides a unique model for studying the development of novel, coordinated reach-to-grasp movement at the behavioral and cortical levels. NEW & NOTEWORTHY Given that motor cortex undergoes reorganization after amputation, our work focuses on training nonhuman primates with chronic amputations to use neurons that are not reach or grasp related to control a robotic arm to reach to grasp through the use of operant conditioning, mimicking early development. We studied the development of a novel, coordinated behavior at the behavioral and cortical level, and the neural plasticity in M1 associated with learning to use a brain-machine interface.
Genomic Analyses and Precision Oncology in Gastroesophageal Cancer: Forwards or Backwards?
Authors: Sundar Raghav , Tan Patrick 
Published: January 2018

Abstract
Summary: Gastroesophageal adenocarcinoma (GEA) comprises a myriad of distinct subtypes with significant interpatient, intrapatient, and intratumor heterogeneity. Strategies for tackling molecular heterogeneity will be essential for the success of GEA precision oncology—in this regard, blood-based “liquid biopsies” may provide broader views of the real-time genomic landscape of this disease, identifying actionable biomarkers and monitoring therapy resistance. Cancer Discov; 8(1); 14–6. ©2018 AACR.
See related article by Pectasides et al., p. 37.
See related article by Janjigian et al., p. 49.
STARTING-SICH Nomogram to Predict Symptomatic Intracerebral Hemorrhage After Intravenous Thrombolysis for Stroke
Authors: Cappellari Manuel , Turcato Gianni , Forlivesi Stefano , Zivelonghi Cecilia , Bovi Paolo , Bonetti Bruno , Toni Danilo 
Published: January 2018

Background and Purpose—
Symptomatic intracerebral hemorrhage (sICH) is a rare but the most feared complication of intravenous thrombolysis for ischemic stroke. We aimed to develop and validate a nomogram for individualized prediction of sICH in intravenous thrombolysis–treated stroke patients included in the multicenter SITS-ISTR (Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register).

Methods—
All patients registered in the SITS-ISTR by 179 Italian centers between May 2001 and March 2016 were originally included. The main outcome measure was sICH per the European Cooperative Acute Stroke Study II definition (any type of intracerebral hemorrhage with increase of ≥4 National Institutes of Health Stroke Scale score points from baseline or death <7 days). On the basis of multivariate logistic model, the nomogram was generated. We assessed the discriminative performance by using the area under the receiver-operating characteristic curve and calibration of risk prediction model by using the Hosmer–Lemeshow test.

Results—

A total of 15 949 patients with complete data for generating the nomogram was randomly dichotomized into training (3/4; n=12 030) and test (1/4; n=3919) sets. After multivariate logistic regression, 10 variables remained independent predictors of sICH to compose the STARTING-SICH (systolic blood pressure, age, onset-to-treatment time for thrombolysis, National Institutes of Health Stroke Scale score, glucose, aspirin alone, aspirin plus clopidogrel, anticoagulant with INR ≤1.7, current infarction sign, hyperdense artery sign) nomogram. The area under the receiver-operating characteristic curve of STARTING-SICH was 0.739. Calibration was good (
P
=0.327 for the Hosmer–Lemeshow test).

Conclusions—
The STARTING-SICH is the first nomogram developed and validated in a large SITS-ISTR cohort for individualized prediction of sICH in intravenous thrombolysis–treated stroke patients.