bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Low Keratin Affinity of Efinaconazole Contributes to Its Nail Penetration and Fungicidal Activity in Topical Onychomycosis Treatment
Authors: Sugiura Keita , Sugimoto Noriaki , Hosaka Shinya , Katafuchi-Nagashima Maria , Arakawa Yoshio , Tatsumi Yoshiyuki , Jo Siu William , Pillai Radhakrishnan 
Published: April 2014

ABSTRACT

Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (
P
< 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose
in vitro
studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of
Trichophyton rubrum
under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against
Trichophyton mentagrophytes
comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with
T. mentagrophytes
infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (
P
< 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.
Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms
Authors: Troskie Anscha Mari , Rautenbach Marina , Delattin Nicolas , Vosloo Johan Arnold , Dathe Margitta , Cammue Bruno P. A. , Thevissen Karin 
Published: April 2014

ABSTRACT

Tyrocidines are cationic cyclodecapeptides from
Bacillus aneurinolyticus
that are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonic
Candida albicans
in the low-micromolar range. These tyrocidines also prevented
C. albicans
biofilm formation
in vitro
. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of mature
C. albicans
biofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using a
Caenorhabditis elegans
infection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment.
Characteristics of Escherichia coli Sequence Type 131 Isolates That Produce Extended-Spectrum β-Lactamases: Global Distribution of the
H
30-Rx Sublineage
Authors: Peirano Gisele , van der Bij Akke K. , Freeman Joshua L. , Poirel Laurent , Nordmann Patrice , Costello Michael , Tchesnokova Veronika L. , Pitout Johann D. D. 
Published: April 2014

ABSTRACT

We designed a study to describe the characteristics of sequence type 131 (ST131) lineages, including the
H
30-Rx sublineage, among a global collection of extended-spectrum β-lactamase (ESBL)-producing
Escherichia coli
isolates from 9 countries collected from 2000 to 2011. A total of 240 nonrepeat isolates from Canada, the United States, Brazil, the Netherlands, France, the United Arab Emirates (UAE), India, South Africa, and New Zealand were included. Established PCR, sequencing, and typing methods were used to define ST131 lineages,
H
30 and
H
30-Rx phylogenetic groups,
gyrA
and
parC
mutations, virotypes, and plasmid-mediated quinolone resistance determinants. The majority of the isolates produced CTX-M-15 with
aac(6′)-lb-cr
, belonged to phylogenetic group B2, and were positive for the
H
30 lineage with the
gyrA1AB
and
parC1aAB
mutations. ST131 showed 15 distinct pulsotypes; 43% of the isolates belonged to four pulsotypes, with a global distribution. Seventy-five percent of the ST131 isolates belonged to
H
30-Rx; this sublineage was present in all the countries and was associated with multidrug resistance,
bla
CTX-M-15
,
aac(6′)-lb-cr
, and virotypes A and C. The
H
41 lineage was negative for the ST131
pabB
allele-specific PCR. The multidrug-resistant
H
30-Rx sublineage poses an important public health threat due to its global distribution, association with virotype C, and high prevalence among ST131 isolates that produce CTX-M-15.
Polymorphisms in Pf
mdr1
, Pf
crt
, and Pf
nhe1
Genes Are Associated with Reduced
In Vitro
Activities of Quinine in Plasmodium falciparum Isolates from Western Kenya
Authors: Cheruiyot Jelagat , Ingasia Luicer A. , Omondi Angela A. , Juma Dennis W. , Opot Benjamin H. , Ndegwa Joseph M. , Mativo Joan , Cheruiyot Agnes C. , Yeda Redemptah , Okudo Charles , Muiruri Peninah , Bidii Ngalah S. , Chebon Lorna J. , Angienda Paul O. , Eyase Fredrick L. , Johnson Jacob D. , Bulimo Wallace D. , Andagalu Ben , Akala Hoseah M. , Kamau Edwin 
Published: April 2014

ABSTRACT

In combination with antibiotics, quinine is recommended as the second-line treatment for uncomplicated malaria, an alternative first-line treatment for severe malaria, and for treatment of malaria in the first trimester of pregnancy. Quinine has been shown to have frequent clinical failures, and yet the mechanisms of action and resistance have not been fully elucidated. However, resistance is linked to polymorphisms in multiple genes, including multidrug resistance 1 (Pf
mdr1
), the chloroquine resistance transporter (Pf
crt
), and the sodium/hydrogen exchanger gene (Pf
nhe1
). Here, we investigated the association between
in vitro
quinine susceptibility and genetic polymorphisms in Pf
mdr1
codons 86 and 184, Pf
crt
codon 76, and Pf
nhe1
ms4760 in 88 field isolates from western Kenya.
In vitro
activity was assessed based on the drug concentration that inhibited 50% of parasite growth (the IC
50
), and parasite genetic polymorphisms were determined from DNA sequencing. Data revealed there were significant associations between polymorphism in Pf
mdr1
-86Y, Pf
mdr1
-184F, or Pf
crt
-76T and quinine susceptibility (
P
< 0.0001 for all three associations). Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pf
mdr1
-86Y, Pf
mdr1
-184F, and Pf
crt
-76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pf
mdr1
-N86, Pf
mdr1
-Y184, and Pf
crt
-K76, respectively). In addition, quinine IC
50
values for parasites with Pf
nhe1
ms4760 3 DNNND repeats were significantly higher than for those with 1 or 2 repeats (
P
= 0.033 and
P
= 0.0043, respectively). Clinical efficacy studies are now required to confirm the validity of these markers and the importance of parasite genetic background.
The
mecA
Homolog
mecC
Confers Resistance against β-Lactams in Staphylococcus aureus Irrespective of the Genetic Strain Background
Authors: Ballhausen Britta , Kriegeskorte André , Schleimer Nina , Peters Georg , Becker Karsten 
Published: April 2014

ABSTRACT

In staphylococci, methicillin resistance is mediated by
mecA
-encoded penicillin-binding protein 2a (PBP2a), which has a low affinity for beta-lactams. Recently, a novel PBP2a homolog was described as being encoded by
mecC
, which shares only 70% similarity to
mecA
. To prove that
mecC
is the genetic determinant that confers methicillin resistance in
Staphylococcus aureus
, a
mecC
knockout strain was generated. The
S. aureus
Δ
mecC
strain showed considerably reduced oxacillin and cefoxitin MICs (0.25 and 4 μg/ml, respectively) compared to those of the corresponding wild-type methicillin-resistant
S. aureus
(MRSA) strain (8 and 16 μg/ml, respectively). Complementing the mutant in
trans
with wild-type
mecC
restored the resistance to oxacillin and cefoxitin. By expressing
mecC
and
mecA
in different
S. aureus
clonal lineages, we found that
mecC
mediates resistance irrespective of the genetic strain background, yielding oxacillin and cefoxitin MIC values comparable to those with
mecA
. In addition, we showed that
mecC
expression is inducible by oxacillin, which supports the assumption that a functional beta-lactam-dependent regulatory system is active in MRSA strains possessing staphylococcal cassette chromosome
mec
(SCC
mec
) type XI. In summary, we showed that
mecC
is inducible by oxacillin and mediates beta-lactam resistance in SCC
mec
type XI-carrying strains as well as in different
S. aureus
genetic backgrounds. Furthermore, our results could explain the comparatively low MICs for clinical
mecC
-harboring
S. aureus
isolates.
Chronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression
Authors: Navas Adriana , Vargas Deninson Alejandro , Freudzon Marina , McMahon-Pratt Diane , Saravia Nancy Gore , Gómez María Adelaida 
Published: April 2014

ABSTRACTChronic tegumentary leishmaniasis is characterized by a scarcity of parasites in lesions and a heightened inflammatory response. Deregulated and hyperactive inflammation contributes to tissue damage and parasite persistence. The mechanisms by which immune cells are recruited to the lesion and their relationship to clinical outcomes remain elusive. We examined the expression levels of chemokines and their receptors in relation to clinical outcome in dermal leishmaniasis caused byLeishmania (Viannia) panamensis. Primary macrophages from healthy donors were infected withL. panamensisstrains isolated from self-healing patients (n= 4) and those presenting chronic disease (n= 5). A consistent pattern of upregulation of neutrophil (cxcl1,cxcl2,cxcl5, andcxcl8/il-8) and monocyte (ccl2,ccl7,ccl8,cxcl3, andcxcl10) chemotactic chemokines andccr1andccr5receptor genes, evaluated by reverse transcription-quantitative PCR (qRT-PCR), was observed upon infection with strains from patients with chronic dermal leishmaniasis; induction of CXCL5 and CCL8 was corroborated at the protein level. No apparent upregulation was elicited in macrophages infected with strains from self-healing patients. Expression levels ofccl8,cxcl2,cxcl3, andcxcl5in lesion biopsy specimens from patients with chronic cutaneous leishmaniasis (CL) were compared to those in biopsy specimens from Montenegro skin tests of individuals with asymptomatic infection. Increased expression levels ofcxcl5(P< 0.05),ccl8, andcxcl3were corroborated in chronic CL lesions. Our study revealed a dichotomy in macrophage chemokine gene expression elicited byL. panamensisstrains from patients with self-healing disease and those presenting chronic disease, consistent with parasite-mediated hyperactivation of the inflammatory response driving chronicity. The predominant upregulation of neutrophil and monocyte chemoattractants indicates novel mechanisms of sustained inflammatory activation and may provide new therapeutic targets against chronic dermal leishmaniasis.
Algorithm 939
Authors: Gil Amparo , Segura Javier , Temme Nico M. 
Published: April 2014

Methods and an algorithm for computing the generalized MarcumQ–function (Qμ(x,y)) and the complementary function (Pμ(x,y)) are described. These functions appear in problems of different technical and scientific areas such as, for example, radar detection and communications, statistics, and probability theory, where they are called the noncentral chi-square or the noncentral gamma cumulative distribution functions.The algorithm for computing the Marcum functions combines different methods of evaluation in different regions: series expansions, integral representations, asymptotic expansions, and use of three-term homogeneous recurrence relations. A relative accuracy close to 10−12can be obtained in the parameter region (x,y,μ) ∈ [0,A] ×[0,A] × [1,A],A= 200, while for larger parameters the accuracy decreases (close to 10−11forA= 1000 and close to 5 × 10−11forA= 10000).
Oncolytic Viruses Targeting Tumor Stem Cells
Authors: Chiocca E. Antonio , Blair Donald , Mufson R. Allan 
Published: April 2014

Abstract
A workshop “Targeting Oncolytic Viruses to Tumor Stem Cells,” organized by the Division of Cancer Biology, NCI, NIH, was held on September 6, 2013 in Rockville, MD. Seventeen invited experts presented an overview of their current research in this area and discussed the state of current research on the use of oncolytic viruses targeted to stem cells as a potential cancer therapy. The goal was to evaluate the evidence that this approach might increase the efficacy of oncolytic virus therapy and to identify gaps in knowledge that have retarded progress in this area. Cancer Res; 74(13); 3396–8. ©2014 AACR.
CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis
Authors: Schneiders Famke L. , Prodöhl Jan , Ruben Jurjen M. , O'Toole Tom , Scheper Rik J. , Bonneville Marc , Scotet Emmanuel , Verheul Henk M.W. , de Gruijl Tanja D. , van der Vliet Hans J. 
Published: April 2014

AbstractCD1d-restricted invariant natural killer T cells (iNKT) constitute an important immunoregulatory T-cell subset that can be activated by the synthetic glycolipid α-galactosylceramide (α-GalCer) and play a dominant role in antitumor immunity. Clinical trials with α-GalCer–pulsed monocyte-derived dendritic cells (moDC) have shown anecdotal antitumor activity in advanced cancer. It was reported that phosphoantigen (pAg)-activated Vγ9Vδ2-T cells can acquire characteristics of professional antigen-presenting cells (APC). Considering the clinical immunotherapeutic applications, Vγ9Vδ2-T APC can offer important advantages over moDC, potentially constituting an attractive novel APC platform. Here, we demonstrate that Vγ9Vδ2-T APC can present antigens to iNKT. However, this does not result from de novo synthesis of CD1d by Vγ9Vδ2-T, but critically depends on trogocytosis of CD1d-containing membrane fragments from pAg-expressing cells. CD1d-expressing Vγ9Vδ2-T cells were able to activate iNKT in a CD1d-restricted and α-GalCer–dependent fashion. Although α-GalCer–loaded moDC outperformed Vγ9Vδ2-T APC on a per cell basis, Vγ9Vδ2-T APC possess unique features with respect to clinical immunotherapeutic application that make them an interesting platform for consideration in future clinical trials. Cancer Immunol Res; 2(8); 732–40. ©2014 AACR.
Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells
Authors: Müller Philipp , Martin Kea , Theurich Sebastian , Schreiner Jens , Savic Spasenija , Terszowski Grzegorz , Lardinois Didier , Heinzelmann-Schwarz Viola A. , Schlaak Max , Kvasnicka Hans-Michael , Spagnoli Giulio , Dirnhofer Stephan , Speiser Daniel E. , von Bergwelt-Baildon Michael , Zippelius Alfred 
Published: April 2014

Abstract
Antibody–drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30+ malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen–specific vaccination or blockade of the PD-1–PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies. Cancer Immunol Res; 2(8); 741–55. ©2014 AACR.
Sono e plasticidade neural
Authors: Figuerola Wilfredo Blanco , Ribeiro Sidarta 
Published: April 2014

O sono é um comportamento filogeneticamente antigo que compreende várias fases sequenciais com distintas características neurofisiológicas. Embora a ciência reconheça há várias décadas o papel crucial do sono na consolidação e reestruturação de memórias, os mecanismos subjacentes ainda são objeto de teorias divergentes e intensa atividade de pesquisa. O presente artigo revê as principais evidências do papel mnemônico do sono, discutindo os possíveis mecanismos moleculares e eletrofisiológicos capazes de explicar tal papel tanto em vertebrados quanto em invertebrados.
Memória, individualidade e inconsciente como expressões do funcionamento de redes nervosas: uma breve especulação
Authors: Xavier Gilberto Fernando 
Published: April 2014

O presente estudo parte de uma breve explanação sobre como a estrutura e o funcionamento do sistema nervoso facultam a formação de memórias ao longo da história de interação do organismo com o ambiente, e sobre como as alterações na conectividade nervosa em função dessas experiências levam à construção de uma complexa rede associativa cuja estrutura é inteiramente dependente da história individual. Discute-se ainda como a atividade dessa rede nervosa representa experiências vividas, como se gera a imaginação do ponto de vista nervoso, e especula-se sobre como a atividade da rede geraria o inconsciente psicanalítico. Por fim, especula-se brevemente sobre como o funcionamento da rede nervosa permite explicar alguns conceitos centrais da teoria psicanalítica, além de seu principal método de abordagem.
Pensamento como margem, lacuna e falta: memória, trauma, luto e esquecimento
Authors: Endo Paulo 
Published: April 2014

Este artigo examina alguns conceitos fundamentais nos estudos sobre a memória social; destaca a importância de contextualizar o desenvolvimento desses conceitos tanto na produção intelectual sobre o tema quanto em seus usos no interior das chamadas “lutas pela memória”. O artigo privilegia a discussão das experiências-conceito de luto, trauma e esquecimento e propõe aos estudos sobre a memória que levem em conta a abundante produção de conceitos e tensões continuamente produzidos nesse campo.
Memória coletiva, trauma e cultura: um debate
Authors: Santos Myrian Sepúlveda dos 
Published: April 2014

Os estudos sobre memória se multiplicaram a partir da década de 80, abrindo uma agenda interdisciplinar e questionamentos teóricos. Na última década, considera-se uma diferenciação entre a memória cotidiana ou comunicativa, diretamente formada por grupos sociais, conforme estabelecido pelo sociólogo francês Maurice Halbwachs, e a memória cultural, que seria a relação entre a memória individual e do grupo com um ponto fixo. Nesse último caso, autores como o historiador alemão Aby Warburg têm sido considerados. Além disso, há estudos sobre a transmissão de experiências traumáticas. A norte-americana Marianne Hirsch, especializada em literatura comparada, criou o termo “pós-memória” para caracterizar a experiência daqueles que crescem dominados por narrativas e silêncios daqueles que viveram eventos traumáticos. O objetivo deste artigo é analisar a pertinência teórica de conceitos como memória cultural e pós-memória.
O Brasil na arquibancada: notas sobre a sociabilidade torcedora
Authors: Campos Flavio de , Toledo Luiz Henrique de 
Published: April 2014

Este artigo oferece uma amostragem da pesquisa intitulada “O Brasil na Arquibancada”, visando identificar elementos da sociabilidade torcedora dos seguidores das equipes que disputaram as séries B e C do Campeonato Brasileiro de 2012, até mesmo como contraponto aos comportamentos dos torcedores e condições gerais do espetáculo associados à organização da Copa do Mundo de 2014.
Deuteronomy 12 and the Law of the Central Sanctuary noch einmal
Authors: Arnold Bill T. 
Published: April 2014

Abstract
Critiques the recent attempt by Frederick E. Greenspahn to call into question the interpretation of Deut 12 as instituting cult centralization. The paper first considers Greenspahn’s argument that the definite article in the phrase “the place” at Deut 12:5 (and 12:14) is a generic article. The paper also critiques Greenspahn’s assumption that the theory of cult centralization is narrowly based upon a misreading of the definite article at Deut 12:5 (and 12:14). On the contrary, it is argued here that the theory is more broadly dependent on internal data of the chapter and external connections with other portions of the Pentateuch.
The Frame of Sacrificing in Judges
Authors: Sutskover Talia 
Published: April 2014

Abstract
Elements of the semantic frame of Sacrificing recurrently appear at key positions throughout the narratives of Judges. Humans in Judges are violently treated as animals, and many times treated as victims brought to sacrifice. This is the case of Ehud Ben Gera killing Eglon, the cutting of Adoni-Bezekʼs fingers by the tribe of Judah, and the Philistines slaughtered by Shamgar’s oxgoad, thus suggesting images of cattle violently handled by the Israelite judges. In addition, Jephthahʼs daughter is sacrificed, and an Israelite concubine is slaughtered by a Levite. Other elements present in the narratives also evoke the semantic frame of Sacrificing; Abimelech kills his brothers on a single stone, which may represent an altar. He scatters salt over the city of Shechem, a procedure connected to the preparation of sacrifices in the Bible, and Ehud Ben Gerahʼs right thigh symbolizes the thigh of the altar (Lev 1:11). These actual and symbolic acts of violence and sacrificing point at a deterioration of moral standards in the period of the Judges, and perhaps implicitly criticize the priestly way of life, in which sacrificing is a significant procedure.