bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hacking the Cell: Network Intrusion and Exploitation by Adenovirus E1A
Authors: King Cason R. , Zhang Ali , Tessier Tanner M. , Gameiro Steven F. , Mymryk Joe S. 
Published: May 2018

ABSTRACT
As obligate intracellular parasites, viruses are dependent on their infected hosts for survival. Consequently, viruses are under enormous selective pressure to utilize available cellular components and processes to their own advantage. As most, if not all, cellular activities are regulated at some level via protein interactions, host protein interaction networks are particularly vulnerable to viral exploitation. Indeed, viral proteins frequently target highly connected “hub” proteins to “hack” the cellular network, defining the molecular basis for viral control over the host. This widespread and successful strategy of network intrusion and exploitation has evolved convergently among numerous genetically distinct viruses as a result of the endless evolutionary arms race between pathogens and hosts. Here we examine the means by which a particularly well-connected viral hub protein, human adenovirus E1A, compromises and exploits the vulnerabilities of eukaryotic protein interaction networks. Importantly, these interactions identify critical regulatory hubs in the human proteome and help define the molecular basis of their function.
An Attenuated CRISPR-Cas System in Enterococcus faecalis Permits DNA Acquisition
Authors: Hullahalli Karthik , Rodrigues Marinelle , Nguyen Uyen Thy , Palmer Kelli 
Published: May 2018

ABSTRACT

Antibiotic-resistant bacteria are critical public health concerns. Among the prime causative factors for the spread of antibiotic resistance is horizontal gene transfer (HGT). A useful model organism for investigating the relationship between HGT and antibiotic resistance is the opportunistic pathogen
Enterococcus faecalis
, since the species possesses highly conjugative plasmids that readily disseminate antibiotic resistance genes and virulence factors in nature. Unlike many commensal
E. faecalis
strains, the genomes of multidrug-resistant (MDR)
E. faecalis
clinical isolates are enriched for mobile genetic elements (MGEs) and lack
c
lustered
r
egularly
i
nterspaced
s
hort
p
alindromic
r
epeats (CRISPR) and
C
RISPR-
as
sociated protein (Cas) genome defense systems. CRISPR-Cas systems cleave foreign DNA in a programmable, sequence-specific manner and are disadvantageous for MGE-derived genome expansion. An unexplored facet of CRISPR biology in
E. faecalis
is that MGEs that are targeted by native CRISPR-Cas systems can be maintained transiently. Here, we investigate the basis for this “CRISPR tolerance.” We observe that
E. faecalis
can maintain self-targeting constructs that direct Cas9 to cleave the chromosome, but at a fitness cost. Interestingly, DNA repair genes were not upregulated during self-targeting, but integrated prophages were strongly induced. We determined that low
cas9
expression contributes to this transient nonlethality and used this knowledge to develop a robust CRISPR-assisted genome-editing scheme. Our results suggest that
E. faecalis
has maximized the potential for DNA acquisition by attenuating its CRISPR machinery, thereby facilitating the acquisition of potentially beneficial MGEs that may otherwise be restricted by genome defense.

IMPORTANCE
CRISPR-Cas has provided a powerful toolkit to manipulate bacteria, resulting in improved genetic manipulations and novel antimicrobials. These powerful applications rely on the premise that CRISPR-Cas chromosome targeting, which leads to double-stranded DNA breaks, is lethal. In this study, we show that chromosomal CRISPR targeting in
Enterococcus faecalis
is transiently nonlethal. We uncover novel phenotypes associated with this “CRISPR tolerance” and, after determining its genetic basis, develop a genome-editing platform in
E. faecalis
with negligible off-target effects. Our findings reveal a novel strategy exploited by a bacterial pathogen to cope with CRISPR-induced conflicts to more readily accept DNA, and our robust CRISPR editing platform will help simplify genetic modifications in this organism.
Novel Xanthomonas campestris Long-Chain-Specific 3-Oxoacyl-Acyl Carrier Protein Reductase Involved in Diffusible Signal Factor Synthesis
Authors: Hu Zhe , Dong Huijuan , Ma Jin-Cheng , Yu Yonghong , Li Kai-Hui , Guo Qiao-Qiao , Zhang Chao , Zhang Wen-Bin , Cao Xinyun , Cronan John E. , Wang Haihong 
Published: May 2018

ABSTRACT

The precursors of the diffusible signal factor (DSF) family signals of
Xanthomonas campestris
pv.
campestris
are 3-hydroxyacyl-acyl carrier protein (3-hydroxyacyl-ACP) thioesters having acyl chains of 12 to 13 carbon atoms produced by the fatty acid biosynthetic pathway. We report a novel 3-oxoacyl-ACP reductase encoded by the
X. campestris
pv.
campestris
XCC0416 gene (
fabG2
), which is unable to participate in the initial steps of fatty acyl synthesis. This was shown by the failure of FabG2 expression to allow growth at the nonpermissive temperature of an
Escherichia coli
fabG
temperature-sensitive strain. However, when transformed into the
E. coli
strain together with a plasmid bearing the
Vibrio harveyi
acyl-ACP synthetase gene (
aasS
), growth proceeded, but only when the medium contained octanoic acid.
In vitro
assays showed that FabG2 catalyzes the reduction of long-chain (≥C
8
) 3-oxoacyl-ACPs to 3-hydroxyacyl-ACPs but is only weakly active with shorter-chain (C
4
, C
6
) substrates. FabG1, the housekeeping 3-oxoacyl-ACP reductase encoded within the fatty acid synthesis gene cluster, could be deleted in a strain that overexpressed
fabG2
but only in octanoic acid-supplemented media. Growth of the
X. campestris
pv.
campestris
Δ
fabG1
strain overexpressing
fabG2
required
fabH
for growth with octanoic acid, indicating that octanoyl coenzyme A is elongated by
X. campestris
pv.
campestris
fabH
. Deletion of
fabG2
reduced DSF family signal production, whereas overproduction of either FabG1 or FabG2 in the Δ
fabG2
strain restored DSF family signal levels.

IMPORTANCE
Quorum sensing mediated by DSF signaling molecules regulates pathogenesis in several different phytopathogenic bacteria, including
Xanthomonas campestris
pv.
campestris
. DSF signaling also plays a key role in infection by the human pathogen
Burkholderia cepacia
. The acyl chains of the DSF molecules are diverted and remodeled from a key intermediate of the fatty acid synthesis pathway. We report a
Xanthomonas campestris
pv.
campestris
fatty acid synthesis enzyme, FabG2, of novel specificity that seems tailored to provide DSF signaling molecule precursors.
Quorum Sensing Extracellular Death Peptides Enhance the Endoribonucleolytic Activities of
Mycobacterium tuberculosis
MazF Toxins
Authors: Nigam Akanksha , Kumar Sathish , Engelberg-Kulka Hanna 
Published: May 2018

ABSTRACT

mazEF
is a toxin-antitoxin module located on chromosomes of most bacteria. MazF toxins are endoribonucleases antagonized by MazE antitoxins. Previously, we characterized several quorum sensing peptides called "
e
xtracellular
d
eath
f
actors" (EDFs). When secreted from bacterial cultures, EDFs induce interspecies cell death. EDFs also enhance the endoribonucleolytic activity of
Escherichia coli
MazF.
Mycobacterium tuberculosis
carries several
mazEF
modules. Among them, the endoribonucleolytic activities of MazF proteins mt-1, mt-3, and mt-6 were identified. MazF-mt6 and MazF-mt-3 cleave
M. tuberculosis
rRNAs. Here we report the
in vitro
effects of EDFs on the endoribonucleolytic activities of
M. tuberculosis
MazFs.
Escherichia coli
EDF (
Ec
EDF) and the three
Pseudomonas aeruginosa
EDFs (
Pa
EDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3 and overcome the inhibitory effect of MazE-mt3 or MazE-mt6 on the endoribonucleolytic activities of the respective toxins. We propose that these EDFs can serve as a basis for a novel class of antibiotics against
M. tuberculosis
.

IMPORTANCE
Mycobacterium tuberculosis
is one of the leading causes of death from infectious disease.
M. tuberculosis
is highly drug resistant, and drug delivery to the infected site is very difficult. In previous studies, we showed that
e
xtracellular
d
eath
f
actors (EDFs) can work as quorum sensing molecules which participate in interspecies bacterial cell death. In this study, we demonstrated the role of different EDFs in the endoribonucleolytic activities of
M. tuberculosis
MazFs.
Escherichia coli
EDF (
Ec
EDF) and the three
Pseudomonas aeruginosa
EDFs (
Pa
EDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3. The current report provides a basis for the use of the EDF peptides
Ec
EDF and
Pa
EDF as novel antibiotics against
M. tuberculosis
.
Regulation of Flagellum Biosynthesis in Response to Cell Envelope Stress in
Salmonella enterica
Serovar Typhimurium
Authors: Spöring Imke , Felgner Sebastian , Preuße Matthias , Eckweiler Denitsa , Rohde Manfred , Häussler Susanne , Weiss Siegfried , Erhardt Marc 
Published: May 2018

ABSTRACT

Flagellum-driven motility of
Salmonella enterica
serovar Typhimurium facilitates host colonization. However, the large extracellular flagellum is also a prime target for the immune system. As consequence, expression of flagella is bistable within a population of
Salmonella
, resulting in flagellated and nonflagellated subpopulations. This allows the bacteria to maximize fitness in hostile environments. The degenerate EAL domain protein RflP (formerly YdiV) is responsible for the bistable expression of flagella by directing the flagellar master regulatory complex FlhD
4
C
2
with respect to proteolytic degradation. Information concerning the environmental cues controlling expression of
rflP
and thus about the bistable flagellar biosynthesis remains ambiguous. Here, we demonstrated that RflP responds to cell envelope stress and alterations of outer membrane integrity. Lipopolysaccharide (LPS) truncation mutants of
Salmonella
Typhimurium exhibited increasing motility defects due to downregulation of flagellar gene expression. Transposon mutagenesis and genetic profiling revealed that σ
24
(RpoE) and Rcs phosphorelay-dependent cell envelope stress response systems sense modifications of the lipopolysaccaride, low pH, and activity of the complement system. This subsequently results in activation of RflP expression and degradation of FlhD
4
C
2
via ClpXP. We speculate that the presence of diverse hostile environments inside the host might result in cell envelope damage and would thus trigger the repression of resource-costly and immunogenic flagellum biosynthesis via activation of the cell envelope stress response.

IMPORTANCE
Pathogenic bacteria such as
Salmonella
Typhimurium sense and adapt to a multitude of changing and stressful environments during host infection. At the initial stage of gastrointestinal colonization,
Salmonella
uses flagellum-mediated motility to reach preferred sites of infection. However, the flagellum also constitutes a prime target for the host’s immune response. Accordingly, the pathogen needs to determine the spatiotemporal stage of infection and control flagellar biosynthesis in a robust manner. We found that
Salmonella
uses signals from cell envelope stress-sensing systems to turn off production of flagella. We speculate that downregulation of flagellum synthesis after cell envelope damage in hostile environments aids survival of
Salmonella
during late stages of infection and provides a means to escape recognition by the immune system.
SUN2 Modulates HIV-1 Infection and Latency through Association with Lamin A/C To Maintain the Repressive Chromatin
Authors: Sun Wei-Wei , Jiao Shi , Sun Li , Zhou Zhaocai , Jin Xia , Wang Jian-Hua 
Published: May 2018

ABSTRACT
The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5′-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host’s modulation of HIV-1 transcription and latency. Here we revealed that “Sad1 and UNC84 domain containing 2” (SUN2), an inner nuclear membrane protein, maintained the repressive chromatin and inhibited HIV LTR-driven transcription of proviral DNA through an association with lamin A/C. Specifically, lamin A/C tethered SUN2 to the nucleosomes 1 and 2 of the HIV-1 5′-LTR to block the initiation and elongation of HIV-1 transcription. SUN2 knockdown converted chromatin to an active form and thus enhanced the phosphorylation of RNA polymerase II and its recruitment to the 5′-LTR HIV-1 proviral DNA, leading to reactivation of HIV-1 from latency. Conversely, the exogenous factors such as tumor necrosis factor alpha (TNF-α) induced reactivation, and the replication of HIV-1 led to the disassociation between SUN2 and lamin A/C, suggesting that disruption of the association between SUN2 and lamin A/C to convert the repressive chromatin to the active form might be a prerequisite for the initiation of HIV-1 transcription and replication. Together, our findings indicate that SUN2 is a novel chromatin reassembly factor that helps to maintain chromatin in a repressive state and consequently inhibits HIV-1 transcription.

IMPORTANCE
Despite the successful use of scores of antiretroviral drugs, HIV latency poses a major impediment to virus eradication. Elucidation of the mechanism of latency facilitates the discovery of new therapeutic strategies. It has been known that the formation of repressive chromatin at the 5′-LTR of HIV-1 proviral DNA impedes viral transcription and maintains viral latency, but how the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. In this study, we performed in-depth virological and cell biological studies and discovered that an inner nuclear membrane protein, SUN2, is a novel chromatin reassembly factor that maintains repressive chromatin and thus modulates HIV-1 transcription and latency: therefore, targeting SUN2 may lead to new strategies for HIV cure.
Invasive Methicillin-Resistant Staphylococcus aureus USA500 Strains from the U.S. Emerging Infections Program Constitute Three Geographically Distinct Lineages
Authors: Frisch M. B. , Castillo-Ramírez S. , Petit R. A. , Farley M. M. , Ray S. M. , Albrecht V. S. , Limbago B. M. , Hernandez J. , See I. , Satola S. W. , Read T. D. 
Published: May 2018

In this work, we have removed some of the confusion surrounding the use of the name “USA500,” placed USA500 strains in the context of the CC8 group, and developed a strategy for assignment to subclades based on genome sequence. Our new phylogeny of USA300/USA500 will be a reference point for understanding the genetic adaptations that have allowed multiple highly virulent clonal strains to emerge from within CC8 over the past 50 years.
T-piece resuscitators: how do they compare?
Authors: Hinder Murray , McEwan Alistair , Drevhammer Thomas , Donaldson Snorri , Tracy Mark Brian 
Published: May 2018

BackgroundThe T-piece resuscitator (TPR) has seen increased use as a primary resuscitation device with newborns. Traditional TPR design uses a high resistance expiratory valve to produce positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) at resuscitation. A new TPR device that uses a dual flow ratio valve (fluidic flip) to produce PEEP/CPAP is now available (rPAP). We aimed to compare the measured ventilation performance of different TPR devices in a controlled bench test study.Design/methodsSingle operator provided positive pressure ventilation to an incremental testlung compliance (Crs) model (0.5–5 mL/cmH2O) with five different brands of TPR device (Atom, Neopuff, rPAP, GE Panda warmer and Draeger Resuscitaire). At recommended peak inflation pressure (PIP) 20 cmH2O, PEEP of 5 cmH2O and rate of 60 inflations per minute.Results1864 inflations were analysed. Four of the five devices tested demonstrated inadvertent elevations in mean PEEP (5.5–10.3 cmH2O, p<0.001) from set value as Crs was increased, while one device (rPAP) remained at the set value. Measured PIP exceeded the set value in two infant warmer devices (GE and Draeger) with inbuilt TPR at Crs of 0.5 (24.5 and 23.5 cmH2O, p<0.001). Significant differences were seen in tidal volumes across devices particularly at higher Crs (p<0.001).ConclusionsResults show important variation in delivered ventilation from set values due to inherent TPR device design characteristics with a range of lung compliances expected at birth. Device-generated inadvertent PEEP and overdelivery of PIP may be clinically deleterious for term and preterm newborns or infants with larger Crs during resuscitation.
Shedding Light on Hexaquarks
Authors: Bashkanov M. , Skorodko T. , Clement H. , Watts D. P. 
Published: May 2018

Several new findings in the four, five and six quark systems reheat the interest in the field of multiquark states (beyond the trivial [Formula: see text] and [Formula: see text]). A lot of progress has recently been made in the 6q sector, on both the theoretical and experimental side. A resonance like structure observed in double-pionic fusion to the deuteron, at M = 2.38 GeV with [Formula: see text] = 70 MeV and [Formula: see text] has been consistently observed in a wealth of reaction channels, supporting the existence of a resonant dibaryon state - the [Formula: see text]. These studies include measurement of all the principle strong decay channels in pn collisions in the quasifree mode by the WASA-at-COSY and HADES collaborations. The internal structure of the [Formula: see text] is largely unknown. It can contain various ”hidden color” 6q configurations, [Formula: see text] molecular states with angular momentum L = 0,2,4,6 as well as meson-assisted dressed dibaryon structures. The large set of experimental data obtained to date gives some constraints on the internal structure of the [Formula: see text] dibaryon, but does not settle the issue. The [Formula: see text] is the only multiquark state which can be produced copiously at current facilities, offering unique access to information beyond its basic quantum numbers, particularly its physical size and internal structure.
Activated NO pathway in uterine arteries during pregnancy in an IUGR rat model
Authors: Bigonnesse Emilie , Sicotte Benoit , Brochu Michèle 
Published: May 2018

Insufficient development of the uteroplacental circulation may contribute to the development of intrauterine growth restriction (IUGR). We developed a rat model of IUGR by administering a low-Na+ diet. This diet reduces maternal blood volume expansion and uteroplacental perfusion. We hypothesized that an impaired endothelial function in radial arteries decreases vasorelaxation and lowers placental perfusion in this IUGR model. The objective was to assess radial uterine artery responses to vasoactive agents in the IUGR model versus controls. The vasoactive agents included phenylephrine and carbachol, use of a pressurized artery myograph, in the absence or presence of inhibitors of nitric oxide (NO) synthase [ N-nitro-l-arginine methyl ester (l-NAME)], cyclooxygenase (Ibuprofen), and endothelium-dependent hyperpolarization {apamin/1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole}, allowing better characterization of the mechanism implicated in endothelium-dependent relaxation. The results show that 1) the diameter of uterine radial arteries was significantly decreased in the IUGR group; 2) sensitivity to phenylephrine was reduced in IUGR arteries, which could be returned to control group values by inhibition of NO production; 3) the relaxation response to carbachol was increased in IUGR rats, principally mediated by endothelium-dependent hyperpolarization in both groups; 4) NO synthase inhibition by l-NAME decreased the maximum relaxation to carbachol only in the IUGR group; and 5) relaxation response to NO donors is increased in IUGR compared with control radial arteries. Contrary to the hypothesis, results in the IUGR model indicate that the NO pathway is activated in radial uterine arteries, most likely in compensation for the reduction in blood uteroplacental perfusion. NEW & NOTEWORTHY In contrast to genetic or surgical models of intrauterine growth restriction, the diet-induced model of reduced maternal volume expansion shows the nitric oxide pathway to be activated in the uterine artery, possibly from increased shear stress and/or placental factors.
PSMD5 Inactivation Promotes 26S Proteasome Assembly during Colorectal Tumor Progression
Authors: Levin Avi , Minis Adi , Lalazar Gadi , Rodriguez Jose , Steller Hermann 
Published: May 2018

Abstract
Protein degradation by the ubiquitin–proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism, and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Reexpression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of polyubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.
Significance: Enhanced cancer-associated proteasome assembly is a major stress response that allows tumors to adapt to and to withstand protein overload.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3458/F1.large.jpg. Cancer Res; 78(13); 3458–68. ©2018 AACR.