bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients
Authors: Alhadab Ali A. , Ahmed Mariam A. , Brundage Richard C. 
Published: January 2018

ABSTRACT

We performed pharmacokinetic-pharmacodynamic (PK-PD) and simulation analyses to evaluate a standard amikacin dose of 15 mg/kg once daily in children with cancer and to determine an optimal dosing strategy. A population pharmacokinetic model was developed from clinical data collected in 34 pediatric patients and used in a simulation study to predict the population probability of various dosing regimens to achieve accepted safety (steady-state unbound trough plasma concentration [
fC
min
] of <10 mg/liter)- and efficacy (free, unbound plasma concentration-to-MIC ratio [
fC
max
/MIC] of ≥8)-linked targets. In addition, an adaptive resistance PD (ARPD) model of
Pseudomonas aeruginosa
was built based on literature time-kill curve data and linked to the PK model to perform PK-ARPD simulations and compare results with those of the probability approach. Using the probability approach, an amikacin dose of 60 mg/kg administered once daily is expected to achieve the target
fC
max
/MIC in 80% of pediatric patients weighing 8 to 70 kg with a 97.5% probability, and almost all patients were predicted to have
fC
min
of <10 mg/liter. However, PK-ARPD simulation predicted that 60 mg/kg/day is unlikely to suppress bacterial resistance with repeated dosing. Furthermore, PK-ARPD simulation suggested that amikacin at 90 mg/kg, given in two divided doses (45 mg/kg twice a day), is expected to hit safety and efficacy targets and is associated with a lower rate of bacterial resistance. The disagreement between the two methods is due to the inability of the probability approach to predict development of drug resistance with repeated dosing. This originates from the use of PK-PD indices based on the MIC that neglects measurement errors, ignores the time course dynamic nature of bacterial growth and killing, and incorrectly assumes the MIC to be constant during treatment.
Tn
6450
, a Novel Multidrug Resistance Transposon Characterized in a Proteus mirabilis Isolate from Chicken in China
Authors: Chen Yan-Peng , Lei Chang-Wei , Kong Ling-Han , Zeng Jin-Xin , Zhang Xiu-Zhong , Liu Bi-Hui , Li Yi , Xiang Rong , Wang Yong-Xiang , Chen Dan-Yu , Zhang An-Yun , Wang Hong-Ning 
Published: January 2018

ABSTRACT

A novel 65.8-kb multidrug resistance transposon, designated Tn
6450
, was characterized in a
Proteus mirabilis
isolate from chicken in China. Tn
6450
contains 18 different antimicrobial resistance genes, including cephalosporinase gene
bla
DHA-1
and fluoroquinolone resistance genes
qnrA1
and
aac(6
′
)-Ib-cr
. It carries a class 1/2 hybrid integron composed of
intI2
and a 3′ conserved segment of the class 1 integron. Tn
6450
is derived from Tn
7
via acquisition of new mobile elements and resistance genes.
Trypanosoma cruzi Produces the Specialized Proresolving Mediators Resolvin D1, Resolvin D5, and Resolvin E2
Authors: Colas Romain A. , Ashton Anthony W. , Mukherjee Shankar , Dalli Jesmond , Akide-Ndunge Oscar B. , Huang Huan , Desruisseaux Mahalia S. , Guan Fangxia , Jelicks Linda A. , Matos dos Santos Fabiane , Nagajyothi Jyothi , Zingman Michael A. , Reyes Jinet , Weiss Louis M. , Serhan Charles N. , Tanowitz Herbert B. 
Published: January 2018

ABSTRACT

Trypanosoma cruzi
is a protozoan parasite that causes Chagas disease (CD). CD is a persistent, lifelong infection affecting many organs, most notably the heart, where it may result in acute myocarditis and chronic cardiomyopathy. The pathological features include myocardial inflammation and fibrosis. In the Brazil strain-infected CD-1 mouse, which recapitulates many of the features of human infection, we found increased plasma levels of resolvin D1 (RvD1), a specialized proresolving mediator of inflammation, during both the acute and chronic phases of infection (>100 days postinfection) as determined by enzyme-linked immunosorbent assay (ELISA). Additionally, ELISA on lysates of trypomastigotes of both strains Tulahuen and Brazil revealed elevated levels of RvD1 compared with lysates of cultured epimastigotes of
T. cruzi
, tachyzoites of
Toxoplasma gondii
, trypomastigotes of
Trypanosoma brucei
, cultured L
6
E
9
myoblasts, and culture medium containing no cells. Lysates of
T. cruzi
-infected myoblasts also displayed increased levels of RvD1. Lipid mediator metabolomics confirmed that the trypomastigotes of
T. cruzi
produced RvD1, RvD5, and RvE2, which have been demonstrated to modulate the host response to bacterial infections. Plasma RvD1 levels may be both host and parasite derived. Since
T. cruzi
synthesizes specialized proresolving mediators of inflammation, as well as proinflammatory eicosanoids, such as thromboxane A
2
, one may speculate that by using these lipid mediators to modulate its microenvironment, the parasite is able to survive.
Bacteriophages of the Urinary Microbiome
Authors: Miller-Ensminger Taylor , Garretto Andrea , Brenner Jonathon , Thomas-White Krystal , Zambom Adriano , Wolfe Alan J. , Putonti Catherine 
Published: January 2018

ABSTRACT

Bacterial viruses (bacteriophages) play a significant role in microbial community dynamics. Within the human gastrointestinal tract, for instance, associations among bacteriophages (phages), microbiota stability, and human health have been discovered. In contrast to the gastrointestinal tract, the phages associated with the urinary microbiota are largely unknown. Preliminary metagenomic surveys of the urinary virome indicate a rich diversity of novel lytic phage sequences at an abundance far outnumbering that of eukaryotic viruses. These surveys, however, exclude the lysogenic phages residing within the bacteria of the bladder. To characterize this phage population, we examined 181 genomes representative of the phylogenetic diversity of bacterial species within the female urinary microbiota and found 457 phage sequences, 226 of which were predicted with high confidence. Phages were prevalent within the bladder bacteria: 86% of the genomes examined contained at least one phage sequence. Most of these phages are novel, exhibiting no discernible sequence homology to sequences in public data repositories. The presence of phages with substantial sequence similarity within the microbiota of different women supports the existence of a core community of phages within the bladder. Furthermore, the observed variation between the phage populations of women with and without overactive bladder symptoms suggests that phages may contribute to urinary health. To complement our bioinformatic analyses, viable phages were cultivated from the bacterial isolates for characterization; a novel coliphage was isolated, which is obligately lytic in the laboratory strain
Escherichia coli
C. Sequencing of bacterial genomes facilitates a comprehensive cataloguing of the urinary virome and reveals phage-host interactions.

IMPORTANCE
Bacteriophages are abundant within the human body. However, while some niches have been well surveyed, the phage population within the urinary microbiome is largely unknown. Our study is the first survey of the lysogenic phage population within the urinary microbiota. Most notably, the abundance of prophage exceeds that of the bacteria. Furthermore, many of the prophage sequences identified exhibited no recognizable sequence homology to sequences in data repositories. This suggests a rich diversity of uncharacterized phage species present in the bladder. Additionally, we observed a variation in the abundances of phages between bacteria isolated from asymptomatic “healthy” individuals and those with urinary symptoms, thus suggesting that, like phages within the gut, phages within the bladder may contribute to urinary health.
An Autoimmune Disease-Associated Risk Variant in the
TNFAIP3
Gene Plays a Protective Role in Brucellosis That Is Mediated by the NF-κB Signaling Pathway
Authors: Lou Lixin , Bao Wanguo , Liu Xianjun , Song Hongxiao , Wang Yang , Zhang Kaiyu , Gao Wenjing , Li Haijun , Tu Zhengkun , Wang Shaofeng 
Published: January 2018

ABSTRACT

Naturally occurring functional variants (rs148314165 and rs200820567, collectively referred to as TT>A) reduce the expression of the tumor necrosis factor alpha-induced protein 3 (
TNFAIP3
) gene, a negative regulator of NF-κB signaling, and predispose individuals to autoimmune disease. In this analysis, we conducted a genetic association study of the TT>A variants in 1,209 controls and 150 patients with brucellosis, an infectious disease, and further assessed the role of the variants in brucellosis. Our data demonstrated that the TT>A variants were correlated with cases of brucellosis (
P
= 0.002; odds ratio [OR] = 0.34) and with individuals who had a positive serum agglutination test (SAT) result (titer of >1/160) (
P
= 4.2 × 10
−6
; OR = 0.23). A functional study demonstrated that brucellosis patients carrying the protective allele (A) showed significantly lower expression levels of the TNFAIP3 gene in their peripheral blood mononuclear cells and showed increased NF-κB signaling. Monocytes from individuals carrying the A allele that were stimulated with
Brucella abortus
had lower mRNA levels of TNFAIP3 and produced more interleukin-10 (IL-10), IL-6, and IL-1β than those from TT allele carriers. These data showed that autoimmune disease-associated risk variants, TT>A, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis. Our findings suggest that a disruption of the normal function of the TNFAIP3 gene might serve as a therapeutic target for the treatment of brucellosis.
Advancing Our Understanding of Protective Maternal Immunity as a Guide for Development of Vaccines To Reduce Congenital Cytomegalovirus Infections
Authors: Permar Sallie R. , Schleiss Mark R. , Plotkin Stanley A. 
Published: January 2018

ABSTRACT
Human cytomegalovirus (HCMV) is the most common congenitally transmitted pathogen worldwide, impacting an estimated 1 million newborns annually. Congenital HCMV (cCMV) infection is a major global contributor to long-term neurologic deficits, including deafness, microcephaly, and neurodevelopmental delay, as well as to fetal loss and occasional infant mortality. Accordingly, design of a maternal vaccine to prevent cCMV continues to be a top public health priority. Nevertheless, we remain without a licensed vaccine. Maternal immunity provides partial protection, as the risk of vertical HCMV transmission from chronically infected mothers is reduced compared to settings in which the mother is newly infected during pregnancy. Therefore, an understanding of the maternal immune correlates of protection against cCMV is critical to informing design of an efficacious maternal vaccine. Although vaccine development is being assiduously pursued by a large number of pharmaceutical manufacturers, biotechnology organizations, and academic researchers, some pessimism has been expressed regarding the issue of whether a vaccine to protect against cCMV is possible. This pessimism is based on observations that natural immunity is not completely protective against maternal reinfection and congenital transmission. However, we assert that optimism regarding vaccine development is indeed justified, on the basis of accruing evidence of immune correlates of protection—readily achievable by vaccination—that are associated with reduced transmission of HCMV to the fetus in seronegative women. In light of the substantial burden on society conferred by cCMV infection, even a modest reduction in the occurrence of this fetal disease is an important public health goal and justifies aggressive clinical evaluation of vaccines currently in the pipeline.
Identification of Poxvirus Genome Uncoating and DNA Replication Factors with Mutually Redundant Roles
Authors: Liu Baoming , Panda Debasis , Mendez-Rios Jorge D. , Ganesan Sundar , Wyatt Linda S. , Moss Bernard 
Published: January 2018

ABSTRACT
Genome uncoating is essential for replication of most viruses. For poxviruses, the process is divided into two stages: removal of the envelope, allowing early gene expression, and breaching of the core wall, allowing DNA release, replication, and late gene expression. Subsequent studies showed that the host proteasome and the viral D5 protein, which has an essential role in DNA replication, are required for vaccinia virus (VACV) genome uncoating. In a search for additional VACV uncoating proteins, we noted a report that described a defect in DNA replication and late expression when the gene encoding a 68-kDa ankyrin repeat/F-box protein (68k-ank), associated with the cellular SCF (Skp1, cullin1, F-box-containing complex) ubiquitin ligase complex, was deleted from the attenuated modified vaccinia virus Ankara (MVA). Here we showed that the 68k-ank deletion mutant exhibited diminished genome uncoating, formation of DNA prereplication sites, and degradation of viral cores as well as an additional, independent defect in DNA synthesis. Deletion of the 68k-ank homolog of VACV strain WR, however, was without effect, suggesting the existence of compensating genes. By inserting VACV genes into an MVA 68k-ank deletion mutant, we discovered that M2, a member of the poxvirus immune evasion (PIE) domain superfamily and a regulator of NF-κB, and C5, a member of the BTB/Kelch superfamily associated with cullin-3-based ligase complexes, independently rescued the 68k-ank deletion phenotype. Thus, poxvirus uncoating and DNA replication are intertwined processes involving at least three viral proteins with mutually redundant functions in addition to D5.

IMPORTANCE
Poxviruses comprise a family of large DNA viruses that infect vertebrates and invertebrates and cause diseases of medical and zoological importance. Poxviruses, unlike most other DNA viruses, replicate in the cytoplasm, and their large genomes usually encode 200 or more proteins with diverse functions. About 90 genes may be essential for chordopoxvirus replication based either on their conservation or individual gene deletion studies. However, this number may underestimate the true number of essential functions because of redundancy. Here we show that any one of three seemingly unrelated and individually nonessential proteins is required for the incompletely understood processes of genome uncoating and DNA replication, an example of synthetic lethality. Thus, poxviruses appear to have a complex genetic interaction network that has not been fully appreciated and which will require multifactor deletion screens to assess.
Tracking brain damage in progressive supranuclear palsy: a longitudinal MRI study
Authors: Agosta Federica , Caso Francesca , Ječmenica-Lukić Milica , Petrović Igor N , Valsasina Paola , Meani Alessandro , Copetti Massimiliano , Kostić Vladimir S , Filippi Massimo 
Published: January 2018

ObjectivesIn this prospective, longitudinal, multiparametric MRI study, we investigated clinical as well as brain grey matter and white matter (WM) regional changes in patients with progressive supranuclear palsy-Richardson’s syndrome (PSP-RS).MethodsTwenty-one patients with PSP-RS were evaluated at baseline relative to 36 healthy controls and after a mean follow-up of 1.4 years with clinical rating scales, neuropsychological tests and MRI scans.ResultsRelative to controls, patients with PSP-RS showed at baseline a typical pattern of brain damage, including midbrain atrophy, frontal cortical thinning and widespread WM involvement of the main infratentorial and supratentorial tracts that exceeded cortical damage. Longitudinal study showed that PSP-RS exhibited no further changes in cortical thinning, which remained relatively focal, while midbrain atrophy and WM damage significantly progressed. Corpus callosum and frontal WM tract changes correlated with the progression of both disease severity and behavioural dysfunction.ConclusionsThis study demonstrated the feasibility of carrying out longitudinal diffusion tensor MRI in patients with PSP-RS and its sensitivity to identifying the progression of pathology. Longitudinal midbrain volume loss and WM changes are associated with PSP disease course.
Impacts of hypoxia on estuarine macroinvertebrate assemblages across a regional nutrient gradient
Authors: Coffin Michael R.S. , Courtenay Simon C. , Knysh Kyle M. , Pater Christina C. , van den Heuvel Michael R. 
Published: January 2018

In this study, we examined the effects of dissolved oxygen, via metrics based on hourly measurements, and other environmental variables on invertebrate assemblages in estuaries spanning a gradient of nutrient loading and geography in the southern Gulf of St. Lawrence, Canada. Upper areas (15–25 practical salinity units (PSU)) of 13 estuaries that were dominated by either seagrass ( Zostera marina Linnaeus, 1753) or macroalgae ( Ulva spp. Linnaeus, 1753) were sampled from June to September 2013. Macroinvertebrate assemblages from Z. marina were found to be distinct from Ulva assemblages for both epifauna and infauna. Small snails dominated each vegetation type, specifically cerithids in Z. marina and hydrobids in Ulva. Although Z. marina had higher species richness, approximately 70% of species were common to both habitats. Faunal communities differed among estuaries with large, within-estuary, temporal variance only observed at Ulva sites impacted by hypoxia and particularly at sites with long water residence time. Indeed, abundances varied by several orders of magnitude in Ulva ranging from zero to thousands of macroinvertebrates. There was a strong negative correlation between hypoxic or anoxic water, 48 h prior to sampling, with relative abundances of amphipods, and a positive correlation with the relative abundances of snails. As one of the first studies to use high-frequency oxygen monitoring, this study revealed probable impacts and the transient nature of hypoxia in eutrophication.
Appearance Modeling via Proxy-to-Image Alignment
Authors: Huang Hui , Xie Ke , Ma Lin , Lischinski Dani , Gong Minglun , Tong Xin , Cohen-Or Daniel 
Published: January 2018

Endowing 3D objects with realistic surface appearance is a challenging and time-demanding task, as real-world surfaces typically exhibit a plethora of spatially variant geometric and photometric detail. Not surprisingly, computer artists commonly use images of real-world objects as an inspiration and a reference for their digital creations. However, despite two decades of research on image-based modeling, there are still no tools available for automatically extracting the detailed appearance (microgeometry and texture) of a 3D surface from a single image. In this article, we present a novel user-assisted approach for quickly and easily extracting a nonparametric appearance model from a single photograph of a reference object.
The extraction process requires a user-provided proxy, whose geometry roughly approximates that of the object in the image. Since the proxy is just a rough approximation, it is necessary to align and deform it so as to match the reference object. The main contribution of this work is a novel technique to perform such an alignment, which enables accurate joint recovery of geometric detail and reflectance. The correlations between the recovered geometry at various scales and the spatially varying reflectance constitute a nonparametric appearance model. Once extracted, the appearance model may then be applied to various 3D shapes, whose large-scale geometry may differ considerably from that of the original reference object. Thus, our approach makes it possible to construct an appearance library, allowing users to easily enrich detail-less 3D shapes with realistic geometric detail and surface texture.
Deletion of estrogen receptor α in skeletal muscle results in impaired contractility in female mice
Authors: Collins Brittany C. , Mader Tara L. , Cabelka Christine A. , Iñigo Melissa R. , Spangenburg Espen E. , Lowe Dawn A. 
Published: January 2018

Estradiol deficiency in females can result in skeletal muscle strength loss, and treatment with estradiol mitigates the loss. There are three primary estrogen receptors (ERs), and estradiol elicits effects through these receptors in various tissues. Ubiquitous ERα-knockout mice exhibit numerous biological disorders, but little is known regarding the specific role of ERα in skeletal muscle contractile function. The purpose of this study was to determine the impact of skeletal muscle-specific ERα deletion on contractile function, hypothesizing that ERα is a main receptor through which estradiol affects muscle strength in females. Deletion of ERα specifically in skeletal muscle (skmERαKO) did not affect body mass compared with wild-type littermates (skmERαWT) until 26 wk of age, at which time body mass of skmERαKO mice began to increase disproportionally. Overall, skmERαKO mice had low strength demonstrated in multiple muscles and by several contractile parameters. Isolated extensor digitorum longus muscles from skmERαKO mice produced 16% less eccentric and 16–26% less submaximal and maximal isometric force, and isolated soleus muscles were more fatigable, with impaired force recovery relative to skmERαWT mice. In vivo maximal torque productions by plantarflexors and dorsiflexors were 16% and 12% lower in skmERαKO than skmERαWT mice, and skmERαKO muscles had low phosphorylation of myosin regulatory light chain. Plantarflexors also generated 21–32% less power, submaximal isometric and peak concentric torques. Data support the hypothesis that ablation of ERα in skeletal muscle results in muscle weakness, suggesting that the beneficial effects of estradiol on muscle strength are receptor mediated through ERα.NEW & NOTEWORTHY We comprehensively measured in vitro and in vivo skeletal muscle contractility in female estrogen receptor α (ERα) skeletal muscle-specific knockout mice and report that force generation is impaired across multiple parameters. These results support the hypothesis that a primary mechanism through which estradiol elicits its effects on strength is mediated by ERα. Evidence is presented that estradiol signaling through ERα appears to modulate force at the molecular level via posttranslational modifications of myosin regulatory light chain.
ОРГАНІЗАЦІЯ МЕДИЧНОЇ ОСВІТИ НА ЗАХІДНОУКРАЇНСЬКИХ ЗЕМЛЯХ У ДРУГІЙ ПОЛОВИНІ XVIII – XIX СТ.
Authors: Savaryn T. V. 
Published: January 2018

Мета роботи – проаналізувати історію виникнення та організації навчальних закладів для підготовки медичних працівників на західноукраїнських землях у другій половині XVIII – XIX ст.Основна частина. У статті використаний бібліографічний метод вивчення бібліотечних каталогів; класифікація та систематизація джерел з історії медицини, педагогіки; хронологічний метод, що дозволив проаналізувати особливості становлення і розвитку медичної освіти у різні історичні періоди.У статті відтворено структуру системи медичної освіти на західноукраїнських землях у другій половині XVIII – XIX ст.; уточнено відомості про професійну та наукову діяльність видатних українських лікарів цього періоду.Висновок. Визначальними критеріями процесу розвитку медичної освіти можна назвати: поступове зростання мережі закладів медичної освіти, збільшення числа кафедр, збільшення кількості студентів і викладачів у них, розширення змісту навчання, зміна рівня професійної підготовки медиків.