bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Age Burial in Wales: Patterns, Practices and Problems
Authors: Davis Oliver 
Published: November 2017

SummaryUntil the latter part of the twentieth century, Iron Age burial in Britain was thought to be largely archaeologically invisible. However, over the last 40 years the recovery of large assemblages of human remains, often from pits and ditches rather than beneath monumental structures, has changed our understanding of Iron Age funerary practices. The problem, though, is that the majority of this material derives from core areas of study, particularly southern England and Yorkshire. Our knowledge of burial in the more peripheral areas of Britain, such as Wales, is much more poorly understood. The perceived paucity of burials from such regions is often still interpreted as resulting from the practice of archaeologically invisible disposal methods such as excarnation or the scattering of cremated remains. This paper presents a comprehensive review and analysis of Iron Age human remains in Wales. Although the resource for study is relatively small, a variety of practices, disposal methods and treatments of bodies can be recognized which challenge our current narratives. The scarcity of burials when compared to other parts of Britain, such as Wessex, is suggested to be a result of both poor preservation and bias in archaeological research strategies, rather than the dominance of an ‘invisible’ burial rite.
Exercises of dynamic stability under unstable conditions increase muscle strength and balance ability in the elderly
Authors: Hamed A. , Bohm S. , Mersmann F. , Arampatzis A. 
Published: November 2017

The purpose of this study was to assess the effectiveness of a specific exercise intervention of mechanisms to control dynamic postural stability under unstable conditions in old adults. Forty‐seven old adults (65‐80 years) were assigned to 2 experimental groups (muscle strength group, n = 15; perturbation‐based group, n = 16) and a control group (n = 16). The strength group performed resistance exercises for leg and trunk muscles, while the perturbation‐based group exercised mechanisms of dynamic stability under unstable conditions. The training duration was 14 weeks, with training sessions twice a week for 1.5 hours. Muscle strength, balance ability, and balance recovery performance were investigated before and after the interventions using maximal isometric plantar flexion and knee extension contractions, the approach of the center of pressure to the anterior limits of stability and simulated forward falls. Both interventions increased balance recovery performance in simulated forward falls (81%, d = 1.50 and 80%, d = 1.08 in the muscle strength and perturbation‐based group, respectively), while the control group did not show any changes. Plantar flexor strength increased 20% (d = 0.72) in the muscle strength and 23% (d = 1.03) in the perturbation‐based group, while muscle strength of the knee extensors increased only in the muscle strength group (8%, d = 0.76). On the other hand, only the perturbation‐based group showed a significant improvement of standing balance ability (38%, d = 1.61). We conclude that a perturbation‐based training program focusing on exercising mechanisms of dynamic stability in unstable conditions has the potential to enhance muscle strength as well as sensory information processing within the motor system during sudden and static balance tasks and, as a consequence, reduce the risk of falls in old adults.
Multiple transmissions of chromosomally integrated human herpesvirus‐6 in one family
Authors: Rashidi Armin , Obeid Karam , Hill Joshua , Warlick Erica D. , Weisdorf Daniel J. 
Published: November 2017

AbstractChromosomally integrated human herpesvirus‐6 (ciHHV‐6) can be transmitted from parent to child or via allogeneic hematopoietic cell transplantation (HCT). We report a case of ciHHV‐6 transmitted via syngeneic HCT, and vertically across 3 generations. ciHHV‐6 was transmitted from a parent to the patient and her identical twin, and from the patient to her son. The patient underwent syngeneic HCT as rescue from chemotherapy‐induced aplasia during which ciHHV‐6 was re‐transmitted to her, this time from her identical twin. This is the first report, to our knowledge, of a patient acquiring ciHHV‐6 once via germline from a parent and again via syngeneic HCT from an identical twin.
Experimental reconstruction of double‐stranded break repair‐mediated plastid DNA insertion into the tobacco nucleus
Authors: Wang Dong , Gu Jinbao , David Rakesh , Wang Zhen , Yang Songtao , Searle Iain R. , Zhu Jian‐Kang , Timmis Jeremy N. 
Published: November 2017

SummaryThe mitochondria and plastids of eukaryotic cells evolved from endosymbiotic prokaryotes. DNA from the endosymbionts has bombarded nuclei since the ancestral prokaryotes were engulfed by a precursor of the nucleated eukaryotic host. An experimental confirmation regarding the molecular mechanisms responsible for organelle DNA incorporation into nuclei has not been performed until the present analysis. Here we introduced double‐stranded DNA breaks into the nuclear genome of tobacco through inducible expression of I‐SceI, and showed experimentally that tobacco chloroplast DNAs insert into nuclear genomes through double‐stranded DNA break repair. Microhomology‐mediated linking of disparate segments of chloroplast DNA occurs frequently during healing of induced nuclear double‐stranded breaks (DSB) but the resulting nuclear integrants are often immediately unstable. Non‐Mendelian inheritance of a selectable marker (neo), used to identify plastid DNA transfer, was observed in the progeny of about 50% of lines emerging from the screen. The instability of these de novo nuclear insertions of plastid DNA (nupts) was shown to be associated with deletion not only of the nupt itself but also of flanking nuclear DNA within one generation of transfer. This deletion of pre‐existing nuclear DNA suggests that the genetic impact of organellar DNA transfer to the nucleus is potentially far greater than previously thought.
Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species
Authors: Chitty Jessica L. , Butler Mark S. , Suboh Azzah , Edwards David J. , Cooper Matthew A. , Fraser James A. , Robertson Avril A. B. 
Published: November 2017

ABSTRACT

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen
Cryptococcus neoformans
is a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 μg/ml. Further testing of octapeptin C4 against 40 clinical isolates of
C. neoformans
var.
grubii
or
neoformans
showed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates of
C. neoformans
var.
gattii
had an MIC of 0.78 to 12.5 μg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of
C. neoformans
influences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents.
Seventy-Five Years of Research on Protein Binding
Authors: Dalhoff Axel 
Published: November 2017

ABSTRACTThis review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifaceted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters, as the free fraction only is antibacterially active and governs pharmacokinetics. Several studies have indicated that independent from protein binding of immunoglobulin G, albumin, α1-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum-antibiotic synergisms. It has been demonstrated that IgG and albumin permeabilized Gram-negative and Gram-positive bacteria and facilitated the uptake of poorly penetrating antibiotics. Alpha-1-acid-glycoprotein and pulmonary surfactant also exerted a permeabilizing activity, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum-antibiotic synergisms do not represent a general phenomenon but are limited to specific drug-bug associations only. Although evidence has been generated to support the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well-controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum-antibiotic synergisms, so these techniques have to be standardized; otherwise, contradictory data or even artifacts will be generated.
Pharmacokinetics and Safety of Omadacycline in Subjects with Impaired Renal Function
Authors: Berg Jolene K. , Tzanis Evan , Garrity-Ryan Lynne , Bai Stephen , Chitra Surya , Manley Amy , Villano Stephen 
Published: November 2017

ABSTRACT

Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (
n
= 8) and in matched healthy subjects (
n
= 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 μg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 μg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 μg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 μg/ml when it was administered after dialysis and 2.33 μg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 μg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.
Characterization of Stress and Innate Immunity Resistance of Wild-Type and Δp66 Borrelia burgdorferi
Authors: Curtis Michael W. , Hahn Beth L. , Zhang Kai , Li Chunhao , Robinson Richard T. , Coburn Jenifer 
Published: November 2017

ABSTRACTBorrelia burgdorferiis a causative agent of Lyme disease, the most common arthropod-borne disease in the United States.B. burgdorferievades host immune defenses to establish a persistent, disseminated infection. Previous work showed that P66-deficientB. burgdorferi(Δp66) is cleared quickly after inoculation in mice. We demonstrate that the Δp66strain is rapidly cleared from the skin inoculation site prior to dissemination. The rapid clearance of Δp66bacteria is not due to inherent defects in multiple properties that might affect infectivity: bacterial outer membrane integrity, motility, chemotactic response, or nutrient acquisition. This led us to the hypothesis that P66 has a role in mouse cathelicidin-related antimicrobial peptide (mCRAMP; a major skin antimicrobial peptide) and/or neutrophil evasion. Neither wild-type (WT) nor Δp66 B. burgdorferiwas susceptible to mCRAMP. To examine the role of neutrophil evasion, we administered neutrophil-depleting antibody anti-Ly6G (1A8) to C3H/HeN mice and subsequently monitored the course ofB. burgdorferiinfection. Δp66mutants were unable to establish infection in neutrophil-depleted mice, suggesting that the important role of P66 during early infection is through another mechanism. Neutrophil depletion did not affect WTB. burgdorferibacterial burdens in the skin (inoculation site), ear, heart, or tibiotarsal joint at early time points postinoculation. This was unexpected given that priorin vitrostudies demonstrated neutrophils phagocytose and killB. burgdorferi. These data, together with our previous work, suggest that despite thein vitroability of host innate defenses to killB. burgdorferi, individual innate immune mechanisms have limited contributions to controlling earlyB. burgdorferiinfection in the laboratory model used.
B Cell Presentation of Chlamydia Antigen Selects Out Protective CD4γ13 T Cells: Implications for Genital Tract Tissue-Resident Memory Lymphocyte Clusters
Authors: Johnson Raymond M. , Yu Hong , Strank Norma Olivares , Karunakaran Karuna , Zhu Ying , Brunham Robert C. 
Published: November 2017

ABSTRACTSurveillance and defense of the enormous mucosal interface with the nonsterile world are critical to protecting the host from a wide range of pathogens.Chlamydia trachomatisis an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina are poorly suited to surveillance and defense, with limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new lymphoid clusters immediately beneath the epithelium. These memory lymphocyte clusters (MLCs) harboring tissue-resident memory (Trm) T cells are presumed to play an important role in protection from subsequent infections. Histologically, humanChlamydiaMLCs have prominent B cell populations. We investigated the status of genital tract B cells duringC. muridaruminfections and the nature of T cells recovered from immune mice using immune B cells as antigen-presenting cells (APCs). These studies revealed a genital tract plasma B cell population and a novel genital tract CD4 T cell subset producing both gamma interferon (IFN-γ) and interleukin-13 (IL-13). A panel of CD4 T cell clones and microarray analysis showed that the molecular fingerprint of CD4γ13 T cells includes a Trm-like transcriptome. Adoptive transfer of aChlamydia-specific CD4γ13 T cell clone completely prevented oviduct immunopathology without accelerating bacterial clearance. Existence of a CD4γ13 T cell subset provides a plausible explanation for the observation that human peripheral blood mononuclear cell (PBMC)Chlamydia-specific IFN-γ and IL-13 responses predict resistance to reinfection.
The Borrelia burgdorferi Glycosaminoglycan Binding Protein Bgp in the B31 Strain Is Not Essential for Infectivity despite Facilitating Adherence and Tissue Colonization
Authors: Schlachter Samantha , Seshu Janakiram , Lin Tao , Norris Steven , Parveen Nikhat 
Published: November 2017

ABSTRACT

The Lyme disease-causing organism
Borrelia burgdorferi
is transmitted into the mammalian host by an infected-tick bite. Successful infection relies on the ability of this extracellular pathogen to persist and colonize different tissues.
B. burgdorferi
encodes a large number of adhesins that are able to interact with host ligands to facilitate adherence and tissue colonization. Multiple glycosaminoglycan binding proteins present in
B. burgdorferi
offer a degree of redundancy of function during infection, and this highlights the importance of glycosaminoglycans as host cell receptors for spirochete adherence. Of particular interest in this study is
Borrelia
glycosaminoglycan binding protein (Bgp), which binds to heparin-related glycosaminoglycans. The properties of a
bgp
transposon mutant and a
trans
-complemented derivative were compared to those of the wild-type
B. burgdorferi
in the
in vitro
binding assays and in infection studies using a C3H/HeJ mouse infection model. We determined that the loss of Bgp impairs spirochete adherence, infectivity, and tissue colonization, resulting in a reduction of inflammatory manifestations of Lyme disease. Although Bgp is not essential for infectivity, it is an important virulence factor of
B. burgdorferi
that allows adherence and tissue colonization and contributes to disease severity.
Identification and Characterization of Serotype-Specific Variation in Group A Streptococcus Pilus Expression
Authors: Calfee Gregory , Danger Jessica L. , Jain Ira , Miller Eric W. , Sarkar Poulomee , Tjaden Brian , Kreikemeyer Bernd , Sumby Paul 
Published: November 2017

ABSTRACTIsolates of a given bacterial pathogen often display phenotypic variation, and this can negatively impact public health, for example, by reducing the efficacy of preventative measures. Here, we identify that the human pathogen group AStreptococcus(GAS;Streptococcus pyogenes) expresses pili on its cell surface in a serotype-specific manner. Specifically, we show that serotype M3 GAS isolates, which are nonrandomly associated with causing particularly severe and lethal invasive infections, produce negligible amounts of pili relative to serotype M1 and M49 isolates. Performance of an interserotype transcriptome comparison (serotype M1 versus serotype M3) was instrumental in this discovery. We also identified that the transcriptional regulator Nra positively regulates pilus expression in M3 GAS isolates and that the low level of pilus expression of these isolates correlates with a low level ofnratranscription. Finally, we discovered that the phenotypic consequences of low levels of pilus expression by M3 GAS isolates are a reduced ability to adhere to host cells and an increased ability to survive and proliferate in human blood. We propose that an enhanced ability to survive in human blood, in part due to reduced pilus expression, is a contributing factor in the association of serotype M3 isolates with highly invasive infections. In conclusion, our data show that GAS isolates express pili in a serotype-dependent manner and may inform vaccine development, given that pilus proteins are being discussed as possible GAS vaccine antigens.
Polyphosphate Kinase Antagonizes Virulence Gene Expression in Francisella tularensis
Authors: Rohlfing Amy E. , Ramsey Kathryn M. , Dove Simon L. 
Published: November 2017

ABSTRACT

The alarmone ppGpp is a critical regulator of virulence gene expression in
Francisella tularensis
. In this intracellular pathogen, ppGpp is thought to work in concert with the putative DNA-binding protein PigR and the SspA protein family members MglA and SspA to control a common set of genes. MglA and SspA form a complex that interacts with RNA polymerase (RNAP), and PigR functions by interacting with the RNAP-associated MglA-SspA complex. Prior work suggested that ppGpp indirectly exerts its regulatory effects in
F. tularensis
by promoting the accumulation of polyphosphate in the cell, which in turn was required for formation of the MglA-SspA complex. Here we show that in
Escherichia coli
, neither polyphosphate nor ppGpp is required for formation of the MglA-SspA complex but that ppGpp promotes the interaction between PigR and the MglA-SspA complex. Moreover, we show that polyphosphate kinase, the enzyme responsible for the synthesis of polyphosphate, antagonizes virulence gene expression in
F. tularensis
, a finding that is inconsistent with the notion that polyphosphate accumulation promotes virulence gene expression in this organism. Our findings identify polyphosphate kinase as a novel negative regulator of virulence gene expression in
F. tularensis
and support a model in which ppGpp exerts its positive regulatory effects by promoting the interaction between PigR and the MglA-SspA complex.

IMPORTANCE
In
Francisella tularensis
, MglA and SspA form a complex that associates with RNA polymerase to positively control the expression of key virulence genes. The MglA-SspA complex works together with the putative DNA-binding protein PigR and the alarmone ppGpp. PigR functions by interacting directly with the MglA-SspA complex, but how ppGpp exerts its effects was unclear. Prior work indicated that ppGpp acts by promoting the accumulation of polyphosphate, which is required for MglA and SspA to interact. Here we show that formation of the MglA-SspA complex does not require polyphosphate. Furthermore, we find that polyphosphate antagonizes the expression of virulence genes in
F. tularensis
. Thus, ppGpp does not promote virulence gene expression in this organism through an effect on polyphosphate.
Early-onset group BStreptococcus(EOGBS) infection subsequent to cessation of screening-based intrapartum prophylaxis: findings of an observational study in West London, UK
Authors: Gopal Rao Guduru , Townsend Jane , Stevenson Daniel , Nartey Grace , Hiles Stephen , Bassett Paul , Lamagni Theresa , Nicholl Richard 
Published: November 2017

ObjectivesTo describe the impact on early-onset group BStreptococcus(EOGBS) infection rates following reversion from screening-based to risk-based intrapartum antimicrobial prophylaxis (IAP) for prevention.SettingMaternity services provided by secondary healthcare organisation in North West London.ParticipantsAll women who gave birth in the healthcare organisation between April 2016 and March 2017. There were no exclusions.DesignObservational study comparing EOGBS rates in the postscreening period (2016–2017) with prescreening (2009–2013) and screening periods (2014–2015).MethodsLocal guidelines for risk-based IAP were reintroduced in April 2016. Compliance with guidelines was audited. Gestational age, mode of delivery, maternal demographics and EOGBS rates in three time periods were compared using Poisson regression analysis. EOGBS was defined through GBS being cultured from blood, cerebrospinal fluid or other sterile fluids within 6 days of birth.Primary outcomeEOGBS rates/1000 live births in prescreening, screening and postscreening periodsResultsIncremental changes in maternity population were observed throughout the study period (2009 onwards), in particular the ethnic profile of mothers. Of the 5033 live births in postscreening period, 9 babies developed EOGBS infection. Only one of the mothers of affected babies had a risk factor indicating use of IAP. Comparison of postscreening period with screening period showed a fivefold increase in EOGBS rates after adjustment for ethnicity (1.79 vs 0.33/1000 live births; risk ratio =5.67, p=0.009). There was no significant difference between prescreening and postscreening periods with rates of infection reverting to their prescreening level.ConclusionsThis study provides further evidence of efficacy of screening-based IAP compared with risk-based IAP in prevention of EOGBS in newborns in an area of high incidence.