bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant cortical excitability reflects the loss of hand dexterity in musician's dystonia
Authors: Furuya Shinichi , Uehara Kazumasa , Sakamoto Takashi , Hanakawa Takashi 
Published: March 2018

Key pointsDystonia is a movement disorder characterized by abnormalities at multifaceted aspects of motor dexterity and neural functions.Evidence bridging between pathophysiology and movement abnormalities is limited.A novel finding was that in focal task‐specific dystonia (FTSD), an aberrantly reduced inhibition at the motor cortex was related to the temporal imprecision of the dexterous finger movements, whereas an elevated facilitation was associated with an abnormally sluggish transition of finger movements from flexion to extension.We newly identified two sets of behavioural–physiological covariations as hallmarks of hand FTSD, which is clinically significant because these findings provide novel evidence connecting distinct types of malfunctions within the motor cortex at rest with distinct aspects of motor dexterity degradation in FTSD patients.AbstractFocal task‐specific dystonia (FTSD) compromises dexterous movements. A proposed pathophysiological mechanism of FTSD involves malfunction of the motor cortex (M1). However, no evidence is yet available regarding whether and how malfunctions of M1 are responsible for the loss of motor dexterity. Here, we addressed this issue by assessing both M1 excitability and detailed movement parameters, as well as their relationships. Transcranial magnetic stimulation was applied over M1 in 20 pianists with FTSD, 20 healthy pianists and 20 non‐musicians. The patients demonstrated both reduced short‐interval intracortical inhibition (SICI) and elevated intracortical facilitation (ICF) compared with the healthy controls. This indicates that the abnormal cortical excitability reflects pathophysiology but not current skills. Hand motor dexterity was evaluated by position sensors during piano playing at two tempi. The patients showed delayed transition from finger flexion to extension at the fastest tempo and greater timing variability of the finger movements. Furthermore, multivariate analyses identified distinct sets of covariation between cortical excitability and dexterity measures. Namely, the SICI measure and ICF measure were associated with the temporal variability of the movements and the quickness of the transition from flexion to extension, respectively. Specifically, the reduced inhibition and elevated facilitation at M1 in pianists was related to the temporal imprecision and impairment of quick transitions in the sequential finger movements. The present study provides novel evidence associating M1 malfunctions with dexterity loss.
Engaging Axiology: Enabling Meaningful Transdisciplinary Collaboration in Adapted Physical Activity
Authors: Peers Danielle 
Published: March 2018

In this article, I explore the concept of axiology in the context of adapted physical activity research and analyze its connection to the more commonly discussed paradigmatic assumptions of epistemology and ontology. Following methodological scholars, I argue for an acknowledgment of the pivotal role that axiology already plays in adapted physical activity research and for the potential interdisciplinary and transdisciplinary opportunities that could be enabled by engaging with axiology in more explicit ways. I discuss a number of potential axiological gaps between the field of adapted physical activity and disability communities, arguing that such differences may undermine attempts at doing meaningful transdisciplinary research with such communities. I offer strategies for bridging these axiological gaps, encouraging us to work together in axiologically reflexive ways in order to increase meaningful opportunities for more people with disabilities to be engaged in the movement-based activities and communities of their choice.
Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam
Authors: Tamma Pranita D. , Fan Yunfan , Bergman Yehudit , Sick-Samuels Anna C. , Hsu Alice J. , Timp Winston , Simner Patricia J. , Prokesch Bonnie C. , Greenberg David E. 
Published: March 2018

ABSTRACT

We report our clinical experience treating a 2-month-old infant with congenital diaphragmatic hernia who experienced prolonged bacteremia with
Burkholderia cepacia
complex (Bcc) despite conventional antibiotic therapy and appropriate source control measures. The infection resolved after initiation of ceftazidime-avibactam. Whole-genome sequencing revealed that the isolate most closely resembled
B. contaminans
and identified the mechanism of resistance that likely contributed to clinical cure with this agent. Ceftazidime-avibactam should be considered salvage therapy for Bcc infections if other treatment options have been exhausted.
Molecular Characterization of OXA-198 Carbapenemase-Producing Pseudomonas aeruginosa Clinical Isolates
Authors: Bonnin Rémy A. , Bogaerts Pierre , Girlich Delphine , Huang Te-Din , Dortet Laurent , Glupczynski Youri , Naas Thierry 
Published: March 2018

ABSTRACT

Carbapenemase-producing
Pseudomonadaceae
have increasingly been reported worldwide, with an ever-increasing heterogeneity of carbapenem resistance mechanisms, depending on the bacterial species and the geographical location. OXA-198 is a plasmid-encoded class D β-lactamase involved in carbapenem resistance in one
Pseudomonas aeruginosa
isolate from Belgium. In the setting of a multicenter survey of carbapenem resistance in
P. aeruginosa
strains in Belgian hospitals in 2013, three additional OXA-198-producing
P. aeruginosa
isolates originating from patients hospitalized in one hospital were detected. To reveal the molecular mechanism underlying the reduced susceptibility to carbapenems, MIC determinations, whole-genome sequencing, and PCR analyses to confirm the genetic organization were performed. The plasmid harboring the
bla
OXA-198
gene was characterized, along with the genetic relatedness of the four
P. aeruginosa
isolates. The
bla
OXA-198
gene was harbored on a class 1 integron carried by an ∼49-kb IncP-type plasmid proposed as IncP-11. The same plasmid was present in all four
P. aeruginosa
isolates. Multilocus sequence typing revealed that the isolates all belonged to sequence type 446, and single-nucleotide polymorphism analysis revealed only a few differences between the isolates. This report describes the structure of a 49-kb plasmid harboring the
bla
OXA-198
gene and presents the first description of OXA-198-producing
P. aeruginosa
isolates associated with a hospital-associated cluster episode.
Variation at Extra-epitopic Amino Acid Residues Influences Suppression of Influenza Virus Replication by M1
58-66
Epitope-Specific CD8
+
T Lymphocytes
Authors: van de Sandt Carolien E. , Pronk Mark R. , van Baalen Carel A. , Fouchier Ron A. M. , Rimmelzwaan Guus F. 
Published: March 2018

ABSTRACT

Influenza virus-specific CD8
+
T lymphocytes (CTLs) contribute to clearance of influenza virus infections and reduce disease severity. Variation at amino acid residues located in or outside CTL epitopes has been shown to affect viral recognition by virus-specific CTLs. In the present study, we investigated the effect of naturally occurring variation at residues outside the conserved immunodominant and HLA*0201-restricted M1
58-66
epitope, located in the influenza virus M1 protein, on the extent of virus replication in the presence of CTLs specific for the epitope. To this end, we used isogenic viruses with an M1 gene segment derived from either an avian or a human influenza virus, HLA-transgenic human epithelial cells, human T cell clones specific for the M1
58-66
epitope or a control epitope, and a novel, purposely developed
in vitro
system to coculture influenza virus-infected cells with T cells. We found that the M gene segment of a human influenza A/H3N2 virus afforded the virus the capacity to replicate better in the presence of M1
58-66
-specific CTLs than the M gene segment of avian viruses. These findings are in concordance with previously observed differential CTL activation, caused by variation at extra-epitopic residues, and may reflect an immune adaptation strategy of human influenza viruses that allows them to cope with potent CTL immunity to the M1
58-66
epitope in HLA-A*0201-positive individuals, resulting in increased virus replication and shedding and possibly increasing disease severity.

IMPORTANCE
Influenza viruses are among the leading causes of acute respiratory tract infections. CD8
+
T lymphocytes display a high degree of cross-reactivity with influenza A viruses of various subtypes and are considered an important correlate of protection. Unraveling viral immune evasion strategies and identifying signs of immune adaptation are important for defining the role of CD8
+
T lymphocytes in affording protection more accurately. Improving our insight into the interaction between influenza viruses and virus-specific CD8
+
T lymphocyte immunity may help to advance our understanding of influenza virus epidemiology, aid in risk assessment of potentially pandemic influenza virus strains, and benefit the design of vaccines that induce more broadly protective immunity.
A Highly Conserved Leucine in Mammarenavirus Matrix Z Protein Is Required for Z Interaction with the Virus L Polymerase and Z Stability in Cells Harboring an Active Viral Ribonucleoprotein
Authors: Iwasaki Masaharu , de la Torre Juan C. 
Published: March 2018

ABSTRACT
Mammarenaviruses cause chronic infections in their natural rodent hosts. Infected rodents shed infectious virus into excreta. Humans are infected through mucosal exposure to aerosols or direct contact of abraded skin with fomites, resulting in a wide range of manifestations from asymptomatic or mild febrile illness to severe life-threatening hemorrhagic fever. The mammarenavirus matrix Z protein has been shown to be a main driving force of virus budding and to act as a negative regulator of viral RNA synthesis. To gain a better understanding of how the Z protein exerts its several different functions, we investigated the interaction between Z and viral polymerase L protein using the prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV). We found that in the presence of an active viral ribonucleoprotein (vRNP), the Z protein translocated from nonionic detergent-resistant, membrane-rich structures to a subcellular compartment with a different membrane composition susceptible to disruption by nonionic detergents. Alanine (A) substitution of a highly conserved leucine (L) at position 72 in LCMV Z protein abrogated Z-L interaction. The L72A mutation did not affect the stability or budding activity of Z when expressed alone, but in the presence of an active vRNP, mutation L72A promoted rapid degradation of Z via a proteasome- and lysosome-independent pathway. Accordingly, L72A mutation in the Z protein resulted in nonviable LCMV. Our findings have uncovered novel aspects of the dynamics of the Z protein for which a highly conserved L residue was strictly required.

IMPORTANCE
Several mammarenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever disease in humans and pose important public health concerns in their regions of endemicity. Moreover, mounting evidence indicates that the worldwide-distributed, prototypic mammarenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. The mammarenavirus matrix Z protein plays critical roles in different steps of the viral life cycle by interacting with viral and host cellular components. Here we report that alanine substitution of a highly conserved leucine residue, located at position 72 in LCMV Z protein, abrogated Z-L interaction. The L72A mutation did not affect Z budding activity but promoted its rapid degradation in the presence of an active viral ribonucleoprotein (vRNP). Our findings have uncovered novel aspects of the dynamics of the Z protein for which a highly conserved L residue was strictly required.
Mixed Communities of Mucoid and Nonmucoid
Pseudomonas aeruginosa
Exhibit Enhanced Resistance to Host Antimicrobials
Authors: Malhotra Sankalp , Limoli Dominique H. , English Anthony E. , Parsek Matthew R. , Wozniak Daniel J. 
Published: March 2018

ABSTRACT

Pseudomonas aeruginosa
causes chronic pulmonary infections in patients with cystic fibrosis (CF).
P. aeruginosa
mucoid conversion, defined by overproduction of the exopolysaccharide alginate, correlates with accelerated decline in CF patient lung function. Recalcitrance of the mucoid phenotype to clearance by antibiotics and the immune response is well documented. However, despite advantages conferred by mucoidy, mucoid variants often revert to a nonmucoid phenotype both
in vitro
and
in vivo
. Mixed populations of mucoid isolates and nonmucoid revertants are recovered from CF lungs, suggesting a selective benefit for coexistence of these variants. In this study, cocultures of mucoid and nonmucoid variants exhibited enhanced resistance to two host antimicrobials: LL-37, a cationic antimicrobial peptide, and hydrogen peroxide (H
2
O
2
). Alginate production by mucoid isolates protected nonmucoid variants in consortia from LL-37, as addition of alginate exogenously to nonmucoid variants abrogated LL-37 killing. Conversely, nonmucoid revertants shielded mucoid variants from H
2
O
2
stress via catalase (KatA) production, which was transcriptionally repressed by AlgT and AlgR, central regulators of alginate biosynthesis. Furthermore, extracellular release of KatA by nonmucoid revertants was dependent on
lys
, encoding an endolysin implicated in autolysis and extracellular DNA (eDNA) release. Overall, these data provide a rationale to study interactions of
P. aeruginosa
mucoid and nonmucoid variants as contributors to evasion of innate immunity and persistence within the CF lung.

IMPORTANCE
P. aeruginosa
mucoid conversion within lungs of cystic fibrosis (CF) patients is a hallmark of chronic infection and predictive of poor prognosis. The selective benefit of mixed populations of mucoid and nonmucoid variants, often isolated from chronically infected CF patients, has not been explored. Here, we show that mixed-variant communities of
P. aeruginosa
demonstrate advantages in evasion of innate antimicrobials via production of shared goods: alginate and catalase. These data argue for therapeutically targeting multiple constituents (both mucoid and nonmucoid variants) within diversified
P. aeruginosa
communities
in vivo
, as these variants can differentially shield one another from components of the host response.
HIV-1 Uncoating and Reverse Transcription Require eEF1A Binding to Surface-Exposed Acidic Residues of the Reverse Transcriptase Thumb Domain
Authors: Rawle Daniel J. , Li Dongsheng , Swedberg Joakim E. , Wang Lu , Soares Dinesh C. , Harrich David 
Published: March 2018

ABSTRACT

Once HIV-1 enters a cell, the viral core is uncoated by a poorly understood mechanism and the HIV-1 genomic RNA is reverse transcribed into DNA. Host cell factors are essential for these processes, although very few reverse transcription complex binding host cell factors have been convincingly shown to affect uncoating or reverse transcription. We previously reported that cellular eukaryotic translation elongation factor 1A (eEF1A) interacts tightly and directly with HIV-1 reverse transcriptase (RT) for more efficient reverse transcription. Here we report that the surface-exposed acidic residues in the HIV-1 RT thumb domain alpha-J helix and flanking regions are important for interaction with eEF1A. Mutation of surface-exposed acidic thumb domain residues D250, E297, E298, and E300 to arginine resulted in various levels of impairment of the interaction between RT and eEF1A. This indicates that this negatively charged region in the RT thumb domain is important for interaction with the positively charged eEF1A protein. The impairment of RT and eEF1A interaction by the RT mutations correlated with the efficiency of reverse transcription, uncoating, and infectivity. The best example of this is the strictly conserved E300 residue, where mutation significantly impaired the interaction of RT with eEF1A and virus replication in CD4
+
T cells without affecting
in vitro
RT catalytic activity, RT heterodimerization, or RNase H activity. This study demonstrated that the interaction between surface-exposed acidic residues of the RT thumb domain and eEF1A is important for HIV-1 uncoating, reverse transcription, and replication.

IMPORTANCE
HIV-1, like all viruses, requires host cell proteins for its replication. Understanding the mechanisms behind virus-host interactions can lay the foundation for future novel therapeutic developments. Our lab has identified eEF1A as a key HIV-1 RT binding host protein that is important for the reverse transcription of HIV-1 genomic RNA into DNA. Here we identify the first surface-exposed RT residues that underpin interactions with eEF1A. Mutation of one strictly conserved RT residue (E300R) delayed reverse transcription and viral core uncoating and strongly inhibited HIV-1 replication in CD4
+
T cells. This study advances the structural and mechanistic detail of the key RT-eEF1A interaction in HIV-1 infection and indicates its importance in uncoating for the first time. This provides a further basis for the development of an RT-eEF1A interaction-inhibiting anti-HIV-1 drug and suggests that the surface-exposed acidic patch of the RT thumb domain may be an attractive drug target.
Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen
Mucor circinelloides
in Innate Granulomas
In Vivo
Authors: Inglesfield Sarah , Jasiulewicz Aleksandra , Hopwood Matthew , Tyrrell James , Youlden George , Mazon-Moya Maria , Millington Owain R. , Mostowy Serge , Jabbari Sara , Voelz Kerstin 
Published: March 2018

ABSTRACT

Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by
Mucor circinelloides
spores are modeled by a combined
in silico
modeling approach and real-time
in vivo
microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset
in vivo
.
In silico
analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These
in silico
data are supported by an
in vivo
lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas
in vivo
. Disease can be reactivated by immunosuppression. Together, these data represent the first
in vivo
real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients.

IMPORTANCE
Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.
Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
Authors: Herrero-de-Dios Carmen , Day Alison M. , Tillmann Anna T. , Kastora Stavroula L. , Stead David , Salgado Paula S. , Quinn Janet , Brown Alistair J. P. 
Published: March 2018

ABSTRACT

In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulation in the nucleus and the activation of their downstream targets. A specific MAP kinase can regulate different downstream targets depending on the nature of the input signal, thereby raising a key question: what defines the stress-specific outputs of MAP kinases? We find that the Hog1 MAPK contributes to nitrosative-stress resistance in
Candida albicans
even though it displays minimal stress-induced phosphorylation under these conditions. We show that Hog1 becomes oxidized in response to nitrosative stress, accumulates in the nucleus, and regulates the nitrosative stress-induced transcriptome. Mutation of specific cysteine residues revealed that C156 and C161 function together to promote stress resistance, Hog1-mediated nitrosative-stress-induced gene expression, resistance to phagocytic killing, and
C. albicans
virulence. We propose that the oxidation of Hog1, rather than its phosphorylation, contributes to the nitrosative-stress-specific responses of this MAP kinase.

IMPORTANCE
Mitogen-activated protein kinases play key roles in the responses of eukaryotic cells to extracellular signals and are critical for environmental-stress resistance. The widely accepted paradigm is that MAP kinases are activated by phosphorylation, which then triggers their nuclear accumulation and the activation of target proteins and genes that promote cellular adaptation. Our data suggest that alternative forms of posttranslational modification can modulate MAP kinase functionality in
Candida albicans
. We demonstrate that Hog1 is not significantly phosphorylated in response to nitrosative stress, yet it displays nuclear accumulation and contributes to the global transcriptional response to this stress, as well as promoting nitrosative-stress resistance. Instead, nitrosative stress triggers changes in the redox status of Hog1. We also show that specific Hog1 cysteine residues influence its activation of stress genes. Therefore, alternative posttranslational modifications appear to regulate the stress-specific outputs of MAP kinases.