bluuebunny/crossref_metadata_2025_split huggingface dataset:
Creutzfeldt–Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study
Authors: Urwin P. J. M. , Mackenzie J. M. , Llewelyn C. A. , Will R. G. , Hewitt P. E. 
Published: December 2015

Background and ObjectivesThis paper reports the results to 31 May 2015 of an ongoing UK study to look for additional cases of variant Creutzfeldt–Jakob disease (vCJD) transmission by blood transfusion, and to seek evidence whether other subtypes of Creutzfeldt–Jakob disease (CJD) may be transmissible via blood components.Materials and MethodsAll vCJD cases of appropriate age and any sporadic CJD (sCJD) or familial CJD (fCJD) cases with a history of blood donation or transfusion are notified to the UKBS. Donation records are sought and the usage of all donations is determined by look back. Death certificates are obtained for all donors to patients with CJD and recipients of transfused components from patients with CJD who are deceased.ResultsThe study identified 29 sCJD blood donors, of 370 reported, with transfusion to 211 recipients. Five of these recipients were reported to have died with or of dementia, but were not believed to be cases of CJD. The vCJD arm found 18 vCJD blood donors who had donated blood which was issued for clinical usage, of 24 traced donors from 177 UK vCJD cases. To date, 3 cases of vCJD have occurred in 67 recipients identified in this recipient group, and one recipient had post‐mortem confirmation of abnormal prion protein deposition in the spleen (all previously reported).ConclusionThe results of the ongoing TMER study show no new cases of transfusion‐associated vCJD since 2007 and no evidence of transfusion transmission of sCJD.
International Society for Blood Transfusion international survey on blood product wastage in hospitals
Authors: Yazer M. H. , Abraham S. , Beckman N. , Folléa G. 
Published: December 2015

Background and ObjectivesThe ISBT Working Party on Blood Supply Management undertook an international survey of blood component wastage rates.Materials and MethodsUsing a survey website, questions were developed and validated to collect information on component wastage rates and the mechanisms for this wastage at hospital transfusion services around the world. Wastage was calculated as a percentage of the units issued (WAPI), which accounts only for the issued products not the size of the blood bank's inventory.ResultsThere were 85 useable responses over an approximately 6‐month period. The majority of respondents were from Europe (53/85, 62%) and North America (19/85, 22%). The rest were from Oceania, Asia and the Middle East. Most respondents were from major academic teaching hospitals (45/85, 53%) with >1000 beds (32/85, 38%). There was no significant difference in the median regional WAPI wastage rates for RBCs and platelets between Europe (1·6%, 3·3%), North America (1·3%, 2·9%) and the rest of the world (2·4%, 7·2%) (P > 0·05 for all comparisons). Plasma wastage rates were also not different between these 3 regions. Neither RBC shelf life (≤35 days vs. 42 days) nor platelet shelf life (5 days vs 7 days) significantly affected the rate of product expiration in the hospital blood bank.ConclusionThe median wastage rates are low around the world; a more detailed understanding of the specific mechanisms that lead to wastage around the world will help further reduce the rate.
Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development
Authors: Green Judith L. , Moon Robert W. , Whalley David , Bowyer Paul W. , Wallace Claire , Rochani Ankit , Nageshan Rishi K. , Howell Steven A. , Grainger Munira , Jones Hayley M. , Ansell Keith H. , Chapman Timothy M. , Taylor Debra L. , Osborne Simon A. , Baker David A. , Tatu Utpal , Holder Anthony A. 
Published: December 2015

ABSTRACT

Imidazopyridazine compounds are potent, ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1) and of
Plasmodium falciparum
parasite growth
in vitro
. Here, we show that these compounds can be divided into two classes depending on the nature of the aromatic linker between the core and the R2 substituent group. Class 1 compounds have a pyrimidine linker and inhibit parasite growth at late schizogony, whereas class 2 compounds have a nonpyrimidine linker and inhibit growth in the trophozoite stage, indicating different modes of action for the two classes. The compounds also inhibited cyclic GMP (cGMP)-dependent protein kinase (PKG), and their potency against this enzyme was greatly reduced by substitution of the enzyme's gatekeeper residue at the ATP binding site. The effectiveness of the class 1 compounds against a parasite line expressing the modified PKG was also substantially reduced, suggesting that these compounds kill the parasite primarily through inhibition of PKG rather than CDPK1. HSP90 was identified as a binding partner of class 2 compounds, and a representative compound bound to the ATP binding site in the N-terminal domain of HSP90. Reducing the size of the gatekeeper residue of CDPK1 enabled inhibition of the enzyme by bumped kinase inhibitors; however, a parasite line expressing the modified enzyme showed no change in sensitivity to these compounds. Taken together, these findings suggest that CDPK1 may not be a suitable target for further inhibitor development and that the primary mechanism through which the imidazopyridazines kill parasites is by inhibition of PKG or HSP90.
Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages
Authors: Ariffin Juliana K. , das Gupta Kaustav , Kapetanovic Ronan , Iyer Abishek , Reid Robert C. , Fairlie David P. , Sweet Matthew J. 
Published: December 2015

ABSTRACT

Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with
Salmonella enterica
serovar Typhimurium or
Escherichia coli
results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular
S
. Typhimurium and
E. coli
. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.
Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050
Authors: Maron Maxim I. , Magle Crystal T. , Czesny Beata , Turturice Benjamin A. , Huang Ruili , Zheng Wei , Vaidya Akhil B. , Williamson Kim C. 
Published: December 2015

ABSTRACT

New strategies targeting
Plasmodium falciparum
gametocytes, the sexual-stage parasites that are responsible for malaria transmission, are needed to eradicate this disease. Most commonly used antimalarials are ineffective against
P. falciparum
gametocytes, allowing patients to continue to be infectious for over a week after asexual parasite clearance. A recent screen for gametocytocidal compounds demonstrated that the carboxylic polyether ionophore maduramicin is active at low nanomolar concentrations against
P. falciparum
sexual stages. In this study, we showed that maduramicin has an EC
50
(effective concentration that inhibits the signal by 50%) of 14.8 nM against late-stage gametocytes and significantly blocks
in vivo
transmission in a mouse model of malaria transmission. In contrast to other reported gametocytocidal agents, maduramicin acts rapidly
in vitro
, eliminating gametocytes and asexual schizonts in less than 12 h without affecting uninfected red blood cells (RBCs). Ring stage parasites are cleared by 24 h. Within an hour of drug treatment, 40% of the normally crescent-shaped gametocytes round up and become spherical. The number of round gametocytes increases to >60% by 2 h, even before a change in membrane potential as monitored by MitoProbe DiIC1 (5) is detectable. Maduramicin is not preferentially taken up by gametocyte-infected RBCs compared to uninfected RBCs, suggesting that gametocytes are more sensitive to alterations in cation concentration than RBCs. Moreover, the addition of 15.6 nM maduramicin enhanced the gametocytocidal activity of the pyrazoleamide PA21A050, which is a promising new antimalarial candidate associated with an increase in intracellular Na
+
concentration that is proposed to be due to inhibition of PfATP4, a putative Na
+
pump. These results underscore the importance of cation homeostasis in sexual as well as asexual intraerythrocytic-stage
P. falciparum
parasites and the potential of targeting this pathway for drug development.
Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection
Authors: Lawitz Eric J. , O'Riordan William D. , Asatryan Armen , Freilich Bradley L. , Box Terry D. , Overcash J. Scott , Lovell Sandra , Ng Teresa I. , Liu Wei , Campbell Andrew , Lin Chih-Wei , Yao Betty , Kort Jens 
Published: December 2015

ABSTRACT

ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance
in vitro
. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log
10
IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)
KPC-Like Carbapenemase-Producing Enterobacteriaceae Colonizing Patients in Europe and Israel
Authors: Baraniak A. , Izdebski R. , Fiett J. , Herda M. , Derde L. P. G. , Bonten M. J. M. , Adler A. , Carmeli Y. , Goossens H. , Hryniewicz W. , Brun-Buisson C. , Gniadkowski M. 
Published: December 2015

ABSTRACT

In a 2008-2011 survey, 17,945 patients in 18 hospital units in Europe and Israel were screened for carriage of
Klebsiella pneumoniae
carbapenemase (KPC)-producing
Enterobacteriaceae
, resulting in identification of 124 positive patients. The isolates were dominated by
Klebsiella pneumoniae
sequence type 258 (ST258) KPC-2 and ST512 KPC-3, mainly from Greece and Italy, respectively, whereas Israeli isolates were of diverse species, clones, and KPC variants. Various
bla
KPC
platforms were observed, among which IncFII
K
-FIB
K
plasmids with
bla
KPC-2/-3
genes in the Tn
4401
a transposon prevailed.
Dissection of Francisella-Host Cell Interactions in Dictyostelium discoideum
Authors: Lampe Elisabeth O. , Brenz Yannick , Herrmann Lydia , Repnik Urska , Griffiths Gareth , Zingmark Carl , Sjöstedt Anders , Winther-Larsen Hanne C. , Hagedorn Monica 
Published: December 2015

ABSTRACT

Francisella
bacteria cause severe disease in both vertebrates and invertebrates and include one of the most infectious human pathogens. Mammalian cell lines have mainly been used to study the mechanisms by which
Francisella
manipulates its host to replicate within a large variety of hosts and cell types, including macrophages. Here, we describe the establishment of a genetically and biochemically tractable infection model: the amoeba
Dictyostelium discoideum
combined with the fish pathogen
Francisella noatunensis
subsp.
noatunensis
. Phagocytosed
F. noatunensis
subsp.
noatunensis
interacts with the endosomal pathway and escapes further phagosomal maturation by translocating into the host cell cytosol.
F. noatunensis
subsp.
noatunensis
lacking IglC, a known virulence determinant required for
Francisella
intracellular replication, follows the normal phagosomal maturation and does not grow in
Dictyostelium
. The attenuation of the
F. noatunensis
subsp.
noatunensis
Δ
iglC
mutant was confirmed in a zebrafish embryo model, where growth of
F. noatunensis
subsp.
noatunensis
Δ
iglC
was restricted. In
Dictyostelium
,
F. noatunensis
subsp.
noatunensis
interacts with the autophagic machinery. The intracellular bacteria colocalize with autophagic markers, and when autophagy is impaired (
Dictyostelium
Δ
atg1
),
F. noatunensis
subsp.
noatunensis
accumulates within
Dictyostelium
cells. Altogether, the
Dictyostelium-F. noatunensis
subsp.
noatunensis
infection model recapitulates the course of infection described in other host systems. The genetic and biochemical tractability of the system allows new approaches to elucidate the dynamic interactions between pathogenic
Francisella
and its host organism.
High Genetic Diversity of Newcastle Disease Virus in Wild and Domestic Birds in Northeastern China from 2013 to 2015 Reveals Potential Epidemic Trends
Authors: Zhang Pingze , Xie Guangyao , Liu Xinxin , Ai Lili , Chen Yanyu , Meng Xin , Bi Yuhai , Chen Jianjun , Sun Yuzhang , Stoeger Tobias , Ding Zhuang , Yin Renfu 
Published: December 2015

ABSTRACT
Newcastle disease (ND), caused by the virulent Newcastle disease virus (NDV), is one of the most important viral diseases of birds globally, but little is currently known regarding enzootic trends of NDV in northeastern China, especially for class I viruses. Thus, we performed a surveillance study for NDV in northeastern China from 2013 to 2015. A total 755 samples from wild and domestic birds in wetlands and live bird markets (LBMs) were collected, and 10 isolates of NDV were identified. Genetic and phylogenetic analyses showed that five isolates from LBMs belong to class I subgenotype 1b, two (one from wild birds and one from LBMs) belong to the vaccine-like class II genotype II, and three (all from wild birds) belong to class II subgenotype Ib. Interestingly, the five class I isolates had epidemiological connections with viruses from southern, eastern, and southeastern China. Our findings, together with recent prevalence trends of class I and virulent class II NDV in China, suggest possible virus transmission between wild and domestic birds and the potential for an NDV epidemic in the future.
Endophytic Bacterium-Triggered Reactive Oxygen Species Directly Increase Oxygenous Sesquiterpenoid Content and Diversity in Atractylodes lancea
Authors: Zhou Jia-Yu , Yuan Jie , Li Xia , Ning Yi-Fan , Dai Chuan-Chao 
Published: December 2015

ABSTRACT

Oxygenous terpenoids are active components of many medicinal plants. However, current studies that have focused on enzymatic oxidation reactions cannot comprehensively clarify the mechanisms of oxygenous terpenoid synthesis and diversity. This study shows that an endophytic bacterium can trigger the generation of reactive oxygen species (ROS) that directly increase oxygenous sesquiterpenoid content and diversity in
Atractylodes lancea
.
A. lancea
is a famous but endangered Chinese medicinal plant that contains abundant oxygenous sesquiterpenoids. Geo-authentic
A. lancea
produces a wider range and a greater abundance of oxygenous sesquiterpenoids than the cultivated herb. Our previous studies have shown the mechanisms behind endophytic promotion of the production of sesquiterpenoid hydrocarbon scaffolds; however, how endophytes promote the formation of oxygenous sesquiterpenoids and their diversity is unclear. After colonization by
Pseudomonas fluorescens
ALEB7B, oxidative burst and oxygenous sesquiterpenoid accumulation in
A. lancea
occur synchronously. Treatment with exogenous hydrogen peroxide (H
2
O
2
) or singlet oxygen induces oxidative burst and promotes oxygenous sesquiterpenoid accumulation
in planta
. Conversely, pretreatment of plantlets with the ROS scavenger ascorbic acid significantly inhibits the oxidative burst and oxygenous sesquiterpenoid accumulation induced by
P. fluorescens
ALEB7B. Further
in vitro
oxidation experiments show that several oxygenous sesquiterpenoids can be obtained from direct oxidation caused by H
2
O
2
or singlet oxygen. In summary, this study demonstrates that endophytic bacterium-triggered ROS can directly oxidize oxygen-free sesquiterpenoids and increase the oxygenous sesquiterpenoid content and diversity in
A. lancea
, providing a novel explanation of the mechanisms of oxygenous terpenoid synthesis
in planta
and an essential complementarity to enzymatic oxidation reactions.
Visualizing Bdellovibrio bacteriovorus by Using the tdTomato Fluorescent Protein
Authors: Mukherjee Somdatta , Brothers Kimberly M. , Shanks Robert M. Q. , Kadouri Daniel E. 
Published: December 2015

ABSTRACT

Bdellovibrio bacteriovorus
is a Gram-negative bacterium that belongs to the delta subgroup of proteobacteria and is characterized by a predatory life cycle. In recent years, work has highlighted the potential use of this predator to control bacteria and biofilms. Traditionally, the reduction in prey cells was used to monitor predation dynamics. In this study, we introduced pMQ414, a plasmid that expresses the tdTomato fluorescent reporter protein, into a host-independent strain and a host-dependent strain of
B. bacteriovorus
109J. The new construct was used to conveniently monitor predator proliferation in real time, in different growth conditions, in the presence of lytic enzymes, and on several prey bacteria, replicating previous studies that used plaque analysis to quantify
B. bacteriovorus
. The new fluorescent plasmid also enabled us to visualize the predator in liquid cultures, in the context of a biofilm, and in association with human epithelial cells.
AraC-Type Regulator Rsp Adapts Staphylococcus aureus Gene Expression to Acute Infection
Authors: Li Tianming , He Lei , Song Yan , Villaruz Amer E. , Joo Hwang-Soo , Liu Qian , Zhu Yuanjun , Wang Yanan , Qin Juanxiu , Otto Michael , Li Min 
Published: December 2015

ABSTRACT

Staphylococcus aureus
is an important human pathogen that can cause two categories of severe infections. Acute infections are characterized by pronounced toxin production, while chronic infections often involve biofilm formation. However, it is poorly understood how
S. aureus
controls the expression of genes associated with acute versus biofilm-associated virulence. We here identified an AraC-type transcriptional regulator, Rsp, that promotes the production of key toxins while repressing major biofilm-associated genes and biofilm formation. Genome-wide transcriptional analysis and modeling of regulatory networks indicated that upregulation of the accessory gene regulator (Agr) and downregulation of the
ica
operon coding for the biofilm exopolysaccharide polysaccharide intercellular adhesin (PIA) were central to the regulatory impact of Rsp on virulence. Notably, the Rsp protein directly bound to the
agrP2
and
icaADBC
promoters, resulting in strongly increased levels of the Agr-controlled toxins phenol-soluble modulins (PSMs) and alpha-toxin and reduced production of PIA. Accordingly, Rsp was essential for the development of bacteremia and skin infection, representing major types of acute
S. aureus
infection. Our findings give important insight into how
S. aureus
adapts the expression of its broad arsenal of virulence genes to promote different types of disease manifestations and identify the Rsp regulator as a potential target for strategies to control acute
S. aureus
infection.