bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between litter birthweight and litter size in five goat genotypes
Authors: Mellado Miguel , Meza-Herrera Cesar A. , Arévalo José R. , De Santiago-Miramontes Maria A. , Rodríguez Alvaro , Luna-Orozco Juan R. , Veliz-Deras Francisco G.
Published: January 2011

The aim of the present study was to use a non-linear regression approach to investigate the relationship between litter birthweight and litter size of five breeds of goat under intensive conditions in a hot arid environment. Litter-size and litter-weight data on 20 117 kids from 13 685 litters representing five breeds, namely Saanen, Toggenburg, French Alpine, Anglo-Nubian and Granadina, were compared to evaluate this relationship. Regardless of breed, birthweight for kids born as twins, triplets and quadruplets was, on average, 92%, 87% and 83%, respectively, of that of singleton kids; litter size accounted for 81% of the variation in litter weight. The coefficient of the power regression differed (P < 0.01) among breeds, with similar slopes for French Alpine, Toggenburg and Saanen goats and a smaller litter-weight increase for every additional fetus in Anglo-Nubian and Granadina goats than in other breeds of goat. These results support the hypothesis that, regardless of parity, litter weight in dairy and Granadina goats increases at a reduced rate with increases in litter size, although the rate of change with the increasing number of fetuses was moderate, as indicated by a power regression of the form y = axb between these variables across age categories and breeds of goat.
Nutritional and metabolic modulation of the male effect on the resumption of ovulatory activity in goats
Authors: Rosales-Nieto C. A. , Gamez-Vazquez H. G. , Gudino-Reyes J. , Reyes-Ramirez E. A. , Eaton M. , Stanko R. L. , Meza-Herrera C. A. , Gonzalez-Bulnes A.
Published: January 2011

The present study evaluated possible modulation of the buck effect by nutritional and metabolic cues during the transition to the breeding season in adult goats with divergent bodyweight (BW) and body condition (BCS) at 27°N. In mid-February, goats (Boer × Spanish, n = 32) were assigned to receive one of the following two experimental diets to fulfill different allowances of nutritional requirements: (1) 100% (n = 16; BW = 52.3 ± 1.5 kg, BCS = 1.6 ± 0.1 units; T-100) or (2) 150% (n = 16; BW = 60.9 ± 2.4 kg, BCS = 1.6 ± 0.1 units; T-150) from February to August. Blood samples were collected to analyse thyroxine (T4), triiodothyronine (T3), non-esterified fatty acids (NEFA), triglycerides (Tg) and progesterone (P4). Final BW and BCS favoured (P < 0.001) the T-150 group (74.9 ± 2.8 v. 56.3 ± 1.4 kg, and 4.4 ± 0.2 v. 1.9 ± 0.1 units, respectively). However, mean values for NEFA, Tg, T3 and T4 did not differ (P > 0.05) between the experimental groups. Thereafter, in early August, half of the does in each diet treatment were randomly selected for determining the response to the ‘male effect’ (WM), forming the following two treatment groups: (1) T-100-WM (n = 8), or (2) T-150-WM (n = 8); the remaining does formed two groups without male exposure (WOM), as follows: (3) T-100-WOM (n = 8) and (4) T-150-WOM (n = 8). To evaluate ovarian activity, blood samples were collected from all does on Days 2–4 during the 14-day period after the male exposure. On Day 12, all does exposed to males (16/16), irrespective of the nutritional treatment, depicted ovulatory activity, whereas only 3/16 (18.75%) T-WOM does did, indicating a significant (P < 0.001) difference between these treatment groups. The increased nutritional level of the T-150 group during the anoestrous season did not result in an early onset of ovulatory activity. Does demonstrated similar metabolic hormones and concentrations of blood metabolites between the two nutritional treatments (100 v. 150% of the nutritional requirements), suggesting a high physiological plasticity between the groups, stabilising their metabolism according to the nutritional history female goats faced, and generating similar reproductive outcomes. The male effect seems to be enough to induce oestrus during the late anoestrous season, irrespective of BCS and BW.
Habitat associations of the long-nosed potoroo (Potorous tridactylus) at multiple spatial scales
Authors: Norton Melinda A. , French Kris , Claridge Andrew W.
Published: January 2011

This study examined the coarse- and fine-scale habitat preferences of the long-nosed potoroo (Potorous tridactylus) in the Southern Highlands of New South Wales, in order to inform the management of this threatened species. Live-trapping was conducted in autumn and spring, from 2005 to 2008, at two sites. Macrohabitat preferences were examined by comparing trap success with numerous habitat attributes at each trap site. In spring 2007 and autumn 2008, microhabitat use was also examined, using the spool-and-line technique and forage digging assessments. While potoroos were trapped in a wide range of macrohabitats, they displayed some preference for greater canopy and shrub cover, and ground cover with lower floristic diversity. While most individuals also displayed preferences for various microhabitat attributes, no clear trends were evident across all individuals. Potoroos displayed some foraging preference for microhabitats with higher shrub cover densities and more open ground cover. Despite extensive fox predation risks, individual potoroos did not all preferentially utilise dense ground cover. Future management of known and potential potoroo habitat should aim to provide effective introduced predator control and enhance the diversity of vegetation attributes while avoiding practices that simplify the habitat.
Sexual selection and morphological design: the tale of two territorial butterflies
Authors: Kemp Darrell J.
Published: January 2011

Sexual competition promotes sexual selection and may influence the evolution of morphology, physiology and life history. In many flying insects, selection for efficient mate location is thought to have influenced male flight morphology in characteristic ways, with exponents of sit-and-wait tactics selected to possess high acceleration designs (i.e. high flight musculature and relatively small, elongate wings). However, many of these species also engage in elaborate and extended aerial disputes over territory ownership, and the need for contest ability may also select for a particular design. I attempted to tease apart the effects of these two influences by contrasting the flight morphology of two closely related Hypolimnas butterflies: H. bolina and H. alimena. While the males of both species rely predominantly on sit-and-wait tactics, only male H. bolina compete for territories via extended aerial manoeuvres. Males of this species possessed lower body mass per unit wing area (i.e. lower wing loading) and more elongate wings (i.e. higher aspect ratio), but did not differ from male H. alimena in relative flight musculature (thoracic mass). Males of both species varied from conspecific females in having higher relative flight musculature, lower wing loading and lower aspect ratio, which only partly supports expectations based solely upon sexual selection. These data suggest that selection for aerial contest ability may act weakly upon wing parameters, favouring a compromise between power/maneuverability and energetically efficient flight.
Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression
Authors: Boehler Christian , Gauthier Laurent R. , Mortusewicz Oliver , Biard Denis S. , Saliou Jean-Michel , Bresson Anne , Sanglier-Cianferani Sarah , Smith Susan , Schreiber Valérie , Boussin François , Dantzer Françoise
Published: January 2011

The ADP ribosyl transferase [poly(ADP-ribose) polymerase] ARTD3(PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to double-strand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy.
Crystal structures of two active proliferating cell nuclear antigens (PCNAs) encoded by
Thermococcus kodakaraensis
Authors: Ladner Jane E. , Pan Miao , Hurwitz Jerard , Kelman Zvi
Published: January 2011

Proliferating cell nuclear antigen (PCNA) is a ring-shaped protein that encircles duplex DNA and plays an essential role in many DNA metabolic processes in archaea and eukarya. The eukaryotic and euryarchaea genomes contain a single gene encoding for PCNA. Interestingly, the genome of the euryarchaeon
Thermococcus kodakaraensis
contains two PCNA-encoding genes (TK0535 and TK0582), making it unique among the euryarchaea kingdom. It is shown here that the two
T. kodakaraensis
PCNA proteins support processive DNA synthesis by the polymerase. Both proteins form trimeric structures with characteristics similar to those of other archaeal and eukaryal PCNA proteins. One of the notable differences between the TK0535 and TK0582 rings is that the interfaces are different, resulting in different stabilities for the two trimers. The possible implications of these observations for PCNA functions are discussed.
The Berezin transform and 𝑚th-order Bergman metric
Authors: Li Bo
Published: January 2011

We improve upon recent directional derivative estimates for Berezin’s operator calculus, and consider the relation between the

m
m

th-order Bergman metric of Burbea and the classical Bergman metric in the analysis of higher order directional derivative estimates of the Berezin symbols of general bounded operators. A new metric, naturally arising in our analysis, is introduced and certain comparison theorems are established among this metric, the

m
m

th-order Bergman metric and the classical Bergman metric on the unit ball, the polydisk and

C

n

\mathbb C^n

.
On the complexity of the uniform homeomorphism relation between separable Banach spaces
Authors: Gao Su , Jackson Steve , Sarı Bünyamin
Published: January 2011

We investigate the uniform homeomorphism relation between separable Banach spaces and the related relation of local equivalence. We completely characterize the descriptive complexity of local equivalence in the Borel reducibility hierarchy. This also provides a lower bound for the complexity of the uniform homeomorphism.
On certain vanishing identities for Gromov-Witten invariants
Authors: Liu Xiaobo
Published: January 2011

In this paper we study certain vanishing identities for Gromov-Witten invariants conjectured by K. Liu and H. Xu. We will prove their conjectures when the summation range is big compared to the genus. In such cases, we actually obtained vanishing identities which are stronger than their conjectures. We also prove these conjectures in low genus cases.
Einstein and conformally flat critical metrics of the volume functional
Authors: Miao Pengzi , Tam Luen-Fai
Published: January 2011

Let

R
R

be a constant. Let

M

γ
R

\mathcal {M}^R_\gamma

be the space of smooth metrics

g
g

on a given compact manifold

Ω
n

\Omega ^n

(

n
≥
3

n\ge 3

) with smooth boundary

Σ
\Sigma

such that

g
g

has constant scalar curvature

R
R

and

g

|

Σ

g|_{\Sigma }

is a fixed metric

γ
\gamma

on

Σ
\Sigma

. Let

V
(
g
)

V(g)

be the volume of

g
∈

M

γ
R

g\in \mathcal {M}^R_\gamma

. In this work, we classify all Einstein or conformally flat metrics which are critical points of

V
(
⋅
)

V( \cdot )

in

M

γ
R

\mathcal {M}^R_\gamma

.
Solution of the truncated moment problem with variety 𝑦=𝑥³
Authors: Fialkow Lawrence
Published: January 2011

We show that positivity, consistency, and the variety condition, which are sufficient to solve the truncated moment problem on planar curves of degree 2, are not sufficient for curves of higher degree. Using new, partly algorithmic, conditions based on positive moment matrix extensions, we present a concrete solution to the truncated moment problem on the curve

y
=

x

3

y=x^{3}

. We also use moment matrix extensions to solve (in a less concrete sense) truncated moment problems on curves of the form

y
=
g
(
x
)

y=g(x)

and

y
g
(
x
)
=
1

yg(x)=1

(

g
∈

R

[
x
]

g\in \mathbb {R}[x]

), leading to degree-bounded weighted sum-of-squares representations for polynomials which are strictly positive on such curves.
Frobenius actions on the de Rham cohomology of Drinfeld modules
Authors: Gekeler Ernst-Ulrich
Published: January 2011

We study the action of endomorphisms of a Drinfeld

A
A

-module

ϕ
\phi

on its de Rham cohomology

H

D
R

(
ϕ
,
L
)

H_{DR}(\phi ,L)

and related modules, in the case where

ϕ
\phi

is defined over a field

L
L

of finite

A
A

-characteristic

p
\frak p

. Among others, we find that the nilspace

H
0

H_0

of the total Frobenius

F

r

D
R

Fr_{DR}

on

H

D
R

(
ϕ
,
L
)

H_{DR}(\phi ,L)

has dimension

h
=

h =

height of

ϕ
\phi

. We define and study a pairing between the

p
\frak p

-torsion

p

ϕ

_{\frak p}\phi

of

ϕ
\phi

and

H

D
R

(
ϕ
,
L
)

H_{DR}(\phi ,L)

, which becomes perfect after dividing out

H
0

H_0

.
Temporal control of a dendritogenesis-linked gene via REST-dependent regulation of nuclear factor I occupancy
Authors: Wang Wei , Shin Yong , Shi Min , Kilpatrick Daniel L.
Published: January 2011

Developing neurons undergo a series of maturational stages, and the timing of these events is critical for formation of synaptic circuitry. Here we addressed temporal regulation of the Gabra6 gene, which is expressed in a delayed manner during dendritogenesis in maturing cerebellar granule neurons (CGNs). Developmental up-regulation of Gabra6 transcription required a binding site for nuclear factor I (NFI) proteins. The amounts and DNA binding activities of NFI proteins were similar in immature and mature CGNs; however, NFI occupancy of the Gabra6 promoter in native chromatin was temporally delayed in parallel with Gabra6 gene expression, both in vivo and in culture. The trans-repressor RE1 silencing transcription factor (REST) occupied the Gabra6 proximal promoter in CGN progenitors and early postmitotic CGNs, and its departure mirrored the initial onset of NFI binding as CGNs differentiated. Furthermore constitutive REST expression blocked both Gabra6 expression and NFI occupancy in mature CGNs, whereas REST knockdown in immature CGNs accelerated the initiation of both events. These studies identify a novel mechanism for controlling the timing of dendritogenesis-associated gene expression in maturing neurons through delayed binding of NFI proteins to chromatin. They also establish a temporal function for REST in preventing premature promoter occupancy by NFI proteins in early-stage postmitotic neurons.
Combination of EuroSCORE and Cardiac Troponin I Improves the Prediction of Adverse Outcome after Cardiac Surgery
Authors: Fellahi Jean-Luc , Le Manach Yannick , Daccache Georges , Riou Bruno , Gérard Jean-Louis , Hanouz Jean-Luc
Published: January 2011

Background

Reclassification tables have never been used to compare concentrations of cardiac troponin I (cTnI) with predictive models of risk in the perioperative setting. The current study aimed to evaluate the prognostic value of pre- and/or postoperative serum cTnI when combined with The European System for Cardiac Operative Risk Evaluation (EuroSCORE) in predicting adverse outcome after cardiac surgery.

Methods

Nine hundred five consecutive patients were included. Standard EuroSCORE as well as preoperative and 24-h postoperative cTnI were measured in all patients. Major adverse cardiac events and in-hospital mortality were chosen as study endpoints. The performance of EuroSCORE with and without pre- and/or postoperative cTnI were assessed by means of receiver operating characteristic curves, net reclassification index, and integrated discrimination improvement analyses. Data are expressed as ±SD.

Results

Death occurred in 28 of 905 (3%) patients and major adverse cardiac events in 202/905 (22%) patients. Models including EuroSCORE alone were characterized by a low discriminative power (c-index = 0.60 ± 0.05) in predicting major adverse cardiac events. The c-index increased to 0.61 ± 0.05 (P = 0.46), 0.70 ± 0.04 (P < 0.001), and 0.71 ± 0.04 (P < 0.001) when preoperative, postoperative, and pre/postoperative cTnI were included, respectively. The better predictive ability was confirmed by net reclassification index (0.41 ± 0.08, P < 0.001; 0.67 ± 0.08, P < 0.001; and 0.68 ± 0.08, P < 0.001, respectively) and integrated discrimination improvement (0.003 ± 0.002, P = 0.12; 0.099 ± 0.015, P < 0.001; and 0.094 ± 0.016, P < 0.001, respectively). Similar results were observed for in-hospital mortality.

Conclusions

The combination of EuroSCORE and postoperative cTnI provides the best discriminative power and performance in predicting adverse outcome after cardiac surgery and is suggested as being an effective model that improves early identification of high-risk patients.
Nucleotide requirements at positions +1 to +4 for the initiation of hepatitis C virus positive-strand RNA synthesis
Authors: Nandasoma Udvitha , McCormick Christopher , Griffin Stephen , Harris Mark
Published: January 2011

RNA virus genome replication requires initiation at the precise terminus of the template RNA. To investigate the nucleotide requirements for initiation of hepatitis C virus (HCV) positive-strand RNA replication, a hammerhead ribozyme was inserted at the 5′ end of an HCV subgenomic replicon, allowing the generation of replicons with all four possible nucleotides at position 1. This analysis revealed a preference for a purine nucleotide at this position for initiation of RNA replication. The sequence requirements at positions 2–4 in the context of the J6/JFH-1 virus were also examined by selecting replication-competent virus from a pool containing randomized residues at these positions. There was strong selection for both the wild-type cytosine at position 2, and the wild-type sequence at positions 2–4 (CCU). An adenine residue was well tolerated at positions 3 and 4, which suggests that efficient RNA replication is less dependent on these residues.
Emergence of multiple prion strains from single isolates of ovine scrapie
Authors: Thackray Alana M. , Hopkins Lee , Lockey Richard , Spiropoulos John , Bujdoso Raymond
Published: January 2011

The infectious agent associated with prion diseases such as ovine scrapie shows strain diversity. Ovine prion strains have typically been identified by their transmission properties in wild-type mice. However, strain typing of ovine scrapie isolates in wild-type mice may not reveal properties of the infectious prion agent as they exist in the original host. This could be circumvented if ovine scrapie isolates are passaged in ovine prion protein (PrP)-transgenic mice. This study used incubation time, lesion profile, immunohistochemistry of the disease-associated PrP (PrPSc) and molecular profile to compare the range of ovine prion strains that emerged from sheep scrapie isolates following serial passage in wild-type and ovine PrP transgenic mice. It was found that a diverse range of ovine prion strains emerged from homozygous ARQ and VRQ scrapie isolates passaged in wild-type and ovine PrP transgenic mice. However, strain-specific PrPSc deposition and PrP27–30 molecular profile patterns were identified in ovine PrP transgenic mice that were not detected in wild-type mice. Significantly, it was established that the individual mouse brain selected for transmission during prion strain typing had a significant influence on strain definition. Serial passage of short- and long-incubation-time animals from the same group of scrapie-inoculated mice revealed different prion strain phenotypes. These observations are consistent with the possibility that some scrapie isolates contain more than one prion strain.
Full genomic analyses of two human G2P[4] rotavirus strains detected in 2005: identification of a caprine-like VP3 gene
Authors: Ghosh Souvik , Paul Shyamal Kumar , Hossain Mohammad Akram , Alam Mohammed Mahbub , Ahmed Muzahed Uddin , Kobayashi Nobumichi
Published: January 2011

Although G2P[4] rotaviruses are common causes of infantile diarrhoea, to date only the full genomes of the prototype (strain DS-1) and another old strain, TB-Chen, have been analysed. We report here the full genomic analyses of two Bangladeshi G2P[4] strains, MMC6 and MMC88, detected in 2005. Both the strains exhibited a DS-1-like genotype constellation. Excluding the VP4 and VP7 genes, and except for VP3 of MMC88, the MMC strains were genetically more closely related to the contemporary G2P[4] and several non-G2P[4] human strains than the prototype G2P[4] strain. However, by phylogenetic analyses, the VP2, VP3 (except MMC88), NSP1 and NSP3–5 genes of these strains appeared to share a common origin with those of the prototype strain, whilst their VP1, VP6 and NSP2 genes clustered near a caprine strain. The VP3 gene of MMC88 exhibited maximum relatedness to a local caprine strain, representing the first reported human G2P[4] strain with a gene of animal origin.
Incomplete lineage sorting patterns among human, chimpanzee, and orangutan suggest recent orangutan speciation and widespread selection
Authors: Hobolth Asger , Dutheil Julien Y. , Hawks John , Schierup Mikkel H. , Mailund Thomas
Published: January 2011

We search the complete orangutan genome for regions where humans are more closely related to orangutans than to chimpanzees due to incomplete lineage sorting (ILS) in the ancestor of human and chimpanzees. The search uses our recently developed coalescent hidden Markov model (HMM) framework. We find ILS present in ∼1% of the genome, and that the ancestral species of human and chimpanzees never experienced a severe population bottleneck. The existence of ILS is validated with simulations, site pattern analysis, and analysis of rare genomic events. The existence of ILS allows us to disentangle the time of isolation of humans and orangutans (the speciation time) from the genetic divergence time, and we find speciation to be as recent as 9–13 million years ago (Mya; contingent on the calibration point). The analyses provide further support for a recent speciation of human and chimpanzee at ∼4 Mya and a diverse ancestor of human and chimpanzee with an effective population size of about 50,000 individuals. Posterior decoding infers ILS for each nucleotide in the genome, and we use this to deduce patterns of selection in the ancestral species. We demonstrate the effect of background selection in the common ancestor of humans and chimpanzees. In agreement with predictions from population genetics, ILS was found to be reduced in exons and gene-dense regions when we control for confounding factors such as GC content and recombination rate. Finally, we find the broad-scale recombination rate to be conserved through the complete ape phylogeny.
Directed networks reveal genomic barriers and DNA repair bypasses to lateral gene transfer among prokaryotes
Authors: Popa Ovidiu , Hazkani-Covo Einat , Landan Giddy , Martin William , Dagan Tal
Published: January 2011

Lateral gene transfer (LGT) plays a major role in prokaryote evolution with only a few genes that are resistant to it; yet the nature and magnitude of barriers to lateral transfer are still debated. Here, we implement directed networks to investigate donor–recipient events of recent lateral gene transfer among 657 sequenced prokaryote genomes. For 2,129,548 genes investigated, we detected 446,854 recent lateral gene transfer events through nucleotide pattern analysis. Among these, donor–recipient relationships could be specified through phylogenetic reconstruction for 7% of the pairs, yielding 32,028 polarized recent gene acquisition events, which constitute the edges of our directed networks. We find that the frequency of recent LGT is linearly correlated both with genome sequence similarity and with proteome similarity of donor–recipient pairs. Genome sequence similarity accounts for 25% of the variation in gene-transfer frequency, with proteome similarity adding only 1% to the variability explained. The range of donor–recipient GC content similarity within the network is extremely narrow, with 86% of the LGTs occurring between donor–recipient pairs having ≤5% difference in GC content. Hence, genome sequence similarity and GC content similarity are strong barriers to LGT in prokaryotes. But they are not insurmountable, as we detected 1530 recent transfers between distantly related genomes. The directed network revealed that recipient genomes of distant transfers encode proteins of nonhomologous end-joining (NHEJ; a DNA repair mechanism) far more frequently than the recipient lacking that mechanism. This implicates NHEJ in genes spread across distantly related prokaryotes through bypassing the donor–recipient sequence similarity barrier.
Curcumin analog GO‐Y030 is a novel inhibitor of IKKβ that suppresses NF‐κB signaling and induces apoptosis
Authors: Sato Atsuko , Kudo Chieko , Yamakoshi Hiroyuki , Uehara Yoshihiko , Ohori Hisatsugu , Ishioka Chikashi , Iwabuchi Yoshiharu , Shibata Hiroyuki
Published: January 2011

Curcumin is a dietary constituent with tumor‐suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO‐Y030, which has a 30‐fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO‐Y030 on NF‐κB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF‐κB is activated, NF‐κB activation was suppressed to 8–62% of the control value following treatment with 1 μM GO‐Y030, an effect comparable to that of 10 μM curcumin. Direct inhibition of IKKβ kinase activity and suppression of nuclear translocation of the NF‐κB p65 subunit were observed. The 50% growth inhibition concentrations of GO‐Y030 ranged from one‐11th to one‐14th of those of curcumin. GO‐Y030 also induced cell death comparable to that induced by curcumin but at a 10‐fold lower concentration. In pancreatic and thyroid cancer cells, the growth‐inhibitory effect of GO‐Y030 was 4‐ and 15‐fold greater, respectively, than that of curcumin. GO‐Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO‐Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO‐Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy. (Cancer Sci 2011; 102: 1045–1051)
Efficacy of gefitinib for non‐adenocarcinoma non‐small‐cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports
Authors: Shukuya Takehito , Takahashi Toshiaki , Kaira Rieko , Ono Akira , Nakamura Yukiko , Tsuya Asuka , Kenmotsu Hirotsugu , Naito Tateaki , Kaira Kyoichi , Murakami Haruyasu , Endo Masahiro , Takahashi Kazuhisa , Yamamoto Nobuyuki
Published: January 2011

The efficacy of gefitinib for patients with non‐adenocarcinoma non‐small‐cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non‐adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non‐adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty‐seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large‐cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty‐one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression‐free survival (mPFS) was 27%, 67–70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non‐adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67–70%vs 92–93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non‐adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. (Cancer Sci 2011; 102: 1032–1037)
c‐Jun N‐terminal kinase activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of retinoic acid receptor α protein in hepatic cells
Authors: Hoshikawa Yoshiko , Kanki Keita , Ashla An Afida , Arakaki Yuta , Azumi Junya , Yasui Toshihiro , Tezuka Yuta , Matsumi Yoshiaki , Tsuchiya Hiroyuki , Kurimasa Akihiro , Hisatome Ichiro , Hirano Tadamichi , Fujimoto Jiro , Kagechika Hiroyuki , Shomori Kohei , Ito Hisao , Shiota Goshi
Published: January 2011

We previously reported that impaired retinoid signaling causes hepatocellular carcinoma (HCC) through oxidative stress. However, the interaction between oxidative stress and retinoid signaling has not been fully understood. To address this issue, the effects of hydrogen peroxide on the transcriptional activity of RAR/RXR heterodimers, RARα and RXRα proteins and intracellular signaling pathways were examined. The transcriptional activity of RAR/RXR examined by the DR5‐tk‐Luc reporter assay was significantly suppressed. The RARα protein level began to decrease at 6 h after treatment and declined thereafter. However, RARα mRNA were not changed. Activation of extracellular regulated kinases (ERK), p38, c‐Jun N‐terminal kinase (JNK) and Akt was observed after treatment of hydrogen peroxide. SP600125, an inhibitor of JNK, reversed the RARα protein level reduced by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARα protein. Transfection of wild‐type JNK‐constitutive actively expressing plasmid, but not kinase‐negative JNK‐expressing plasmid caused reduction of RARα protein. Proteasomal degradation of RARα was observed after anisomycin treatment; however, the mutant RARα, of which phosphorylation sites are replaced with alanines, was not degradated. In hepatitis C virus (HCV)‐related human liver tissues, phospho‐JNK and RARα reciprocally expressed with the progression of liver disease. Finally, the staining of 8‐OHdG and thioredoxin was increased with the disease progression. These data indicate that JNK activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of RARα, suggesting that a vicious cycle between aberrant retinoid signaling and oxidative stress accelerates hepatocarcinogenesis. (Cancer Sci 2011; 102: 934–941)
Lopinavir/ritonavir population pharmacokinetics in neonates and infants
Authors: Urien Saik , Firtion Ghislaine , Anderson Suzanne T. , Hirt Deborah , Solas Caroline , Peytavin Gilles , Faye Albert , Thuret Isabelle , Leprevost Marthe , Giraud Carole , Lyall Hermione , Khoo Saye , Blanche Stéphane , Tréluyer Jean‐Marc
Published: January 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Lopinavir/ritonavir pharmacokinetics have been fully investigated in adults and children.

WHAT THIS STUDY ADDS

• Lopinavir/ritonavir population pharmacokinetics in 96 neonates and infants from birth to less than 2 years (1.16 to 10.4 kg) showed that CL/F and V/F were dependent on body weight on an allometric basis and post‐menstrual age.

AIMS Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS A one‐compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h−1 70 kg−1 and 91.7 l 70 kg−1. The relative bioavailabilty, F, increased with post‐menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h−1, 80 mg 12 h−1 and 120 mg 12 h−1 in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.
Chytrid infections and diatom spring blooms: paradoxical effects of climate warming on fungal epidemics in lakes
Authors: IBELINGS BAS W. , GSELL ALENA S. , MOOIJ WOLF M. , Van DONK ELLEN , Van Den WYNGAERT SILKE , De SENERPONT DOMIS LISETTE N.
Published: January 2011

1. We describe the dynamics of host–parasite interactions over a period of more than 30 years between the freshwater diatom Asterionella formosa and two highly virulent chytrid parasites (Rhizophydium planktonicum and Zygorhizidium planktonicum) in Lake Maarsseveen, The Netherlands. This period is characterised by a significant warming trend which is strongest in spring.

2. The key spring event in lakes, the diatom bloom, was in many years dominated by Asterionella. We examine whether and how climate warming has affected the prevalence of infection in Asterionella by chytrids.

3. In years with cold winters/early springs, a dense Asterionella bloom is followed by epidemic development of disease as high Asterionella densities greatly facilitate transmission of chytrid zoospores. This sequence of events is absent in milder winters.

4. Earlier experimental studies have shown that the parasite is almost non‐infective at water temperatures below 3 °C, offering a disease‐free window of opportunity for growth of Asterionella. Climate warming has reduced periods in which water temperature remains <3 °C, narrowing the window of opportunity for uninfected growth. Consequently, Asterionella continuously suffers from infection, albeit at low levels.

5. Population reduction as a result of low level infection allows other diatoms to take over as dominant species, possibly through priority effects.

6. In mild winters, chytrid infections no longer reach epidemic levels, but remain at low prevalence since transmission is impaired at low host densities. Climate warming thus affects both host and parasite in intricate ways, with the host denied a bloom and consequently the parasite denied an epidemic.

7. A shift from Asterionella to a mixed diatom community in years with mild winters may benefit the food web, because of the poor edibility of Asterionella, unless the numerous chytrid zoospores produced during epidemics significantly contribute to zooplankton nutrition.

8. Our study demonstrates the potential complexity of climate change impacts on disease. A reduction in the likelihood of epidemic development of a virulent parasite would seem to be of great benefit to the host, but this was not the case. Unexpected, sometimes paradoxical consequences of climate change can be expected and suggest that the view of a ‘warmer hence sicker world’ may not always apply.
An integrative literature review of student retention in programmes of nursing and midwifery education: why do students stay?
Authors: Cameron Joan , Roxburgh Michelle , Taylor Julie , Lauder William
Published: January 2011

Aims and objectives.  The purpose of the review was to identify student characteristics and strategies in research studies investigating retention (why students stay) as opposed to attrition (why students leave) nursing and midwifery preregistration programmes.

Background.  Retention in nursing and midwifery programmes is a serious international problem. Many governments are committed to diversifying both the student population and the health care workforce. This has led to higher education institutes in some countries offering places on nursing and midwifery programmes to students with non‐traditional entry qualifications. There are suggestions that the policy of widening access has contributed to the challenges of retention in nursing and midwifery programmes.

Design.  Integrative literature review.

Method.  Undertaken using electronic databases and specific search terms, 15 articles were identified and reviewed. The critical appraisal tools produced by CASP (2009) were used to evaluate the quality of the data. Findings from the identified research literature were analysed using qualitative content analysis.

Results.  Two broad themes emerged from the analysis: Programme and Personal. Subthemes were identified in these that give clues as to why students stay: profession, support, student characteristics and family.

Conclusions.  Personal commitment and good support seem to be essential for students to remain on undergraduate programmes of nursing and midwifery. The term ‘support’ is rarely explicit and requires to be more clearly defined. Furthermore, studies reviewed fail to indicate clearly how to identify when students are most vulnerable and which interventions are most appropriate in different situations in supporting retaining students on programmes.

Relevance to clinical practice.  Nursing and midwifery student retention is a political and professional problem. Collaboration between clinical placement providers, academic institutions, students and their families is required to address the issue. Illumination of factors that help students stay may help us devise interventions that prevent future students leaving.
Molecular and proteomic analyses highlight the importance of ubiquitination for the stress resistance, metabolic adaptation, morphogenetic regulation and virulence of Candida albicans
Authors: Leach Michelle D. , Stead David A. , Argo Evelyn , MacCallum Donna M. , Brown Alistair J. P.
Published: January 2011

Post‐translational modifications of proteins play key roles in eukaryotic growth, differentiation and environmental adaptation. In model systems the ubiquitination of specific proteins contributes to the control of cell cycle progression, stress adaptation and metabolic reprogramming. We have combined molecular, cellular and proteomic approaches to examine the roles of ubiquitination in Candida albicans, because little is known about ubiquitination in this major fungal pathogen of humans. Independent null (ubi4/ubi4) and conditional (MET3p‐UBI4/ubi4) mutations were constructed at the C. albicans polyubiquitin‐encoding locus. These mutants displayed morphological and cell cycle defects, as well as sensitivity to thermal, oxidative and cell wall stresses. Furthermore, ubi4/ubi4 cells rapidly lost viability under starvation conditions. Consistent with these phenotypes, proteins with roles in stress responses (Gnd1, Pst2, Ssb1), metabolism (Acs2, Eno1, Fba1, Gpd2, Pdx3, Pgk1, Tkl1) and ubiquitination (Ubi4, Ubi3, Pre1, Pre3, Rpt5) were among the ubiquitination targets we identified, further indicating that ubiquitination plays key roles in growth, stress responses and metabolic adaptation in C. albicans. Clearly ubiquitination plays key roles in the regulation of fundamental cellular processes that underpin the pathogenicity of this medically important fungus. This was confirmed by the observation that the virulence of C. albicans ubi4/ubi4 cells is significantly attenuated.
A Common Promoter Variant of TBX21 is Associated with Allele Specific Binding to Yin‐Yang 1 and Reduced Gene Expression
Authors: Li J.‐R. , Li J.‐G. , Deng G.‐H. , Zhao W.‐L. , Dan Y.‐J. , Wang Y.‐M. , Chen S.
Published: January 2011

T‐bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon‐γ, and its expression level is linked to autoimmune, infectious, and allergic diseases. A T to C base substitution has been identified at position ‐1993 in the TBX21 (encoding T‐bet) promoter and has been associated with asthma and systemic lupus erythematosus. This study aimed to investigate the molecular mechanisms responsible for the influence of the T‐1993C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T‐bet, IFN‐γ and IL‐4 expression in activated CD4+ T cells. The presence of a ‐1993T allele obviously increases promoter activity compared with that of a promoter with a ‐1993C allele. TBX21 promoter carrying ‐1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying ‐1993T allele. YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor. The C to T base exchange relieves the repression mediated by YY1. The individuals carrying ‐1993C allele were determined to have significantly diminished expression of TBX21 and IFN‐γ and increased IL‐4 production in cells compared with the individuals carrying ‐1993T allele (P < 0.05). These findings demonstrate that the TBX21 T‐1993C polymorphism represses TBX21 expression and Th1 cytokine production through control of YY1, which might result in the imbalance between Th1 and Th2 immune responses in autoimmune or allergic diseases.
Deltamethrin Increases Candida albicans Infection Susceptibility in Mice
Authors: Rehman H. , Mohan A. , Tabassum H. , Ahmad F. , Rahman S. , Parvez S. , Raisuddin S.
Published: January 2011

Deltamethrin, an alpha‐cyano type II synthetic pyrethroid insecticide, is used to control a wide range of insects on a variety of crops and vectors of diseases. Deltamethrin has been previously reported for its immunotoxic effects and therefore its exposure may affect the host resistance to infection and tumour challenge. Effect of exposure of deltamethrin on host resistance to Candida albicans infection was examined in Swiss albino mice. The objective of this study was to investigate the modulatory action of deltamethrin in C. albicans infected mice. The dose of deltamethrin was initially tested and selected from our previous study (18 mg/kg). Percentage of infection in deltamethrin treated animals increased faster when compared to that of the controls. Deltamethrin exposure along with C. albicans infection caused alteration of humoral immune response. The number of colony forming unit in liver and spleen were also found to be significantly increased in the treated group. The results from our present study suggest that deltamethrin exhibits an immunosuppressive effect and has a negative impact on host resistance to C. albicans infection.
Participation of Inkt Cells in the Early and Late Components of Tc1‐Mediated DNFB Contact Sensitivity: Cooperative Role of γδ‐T Cells
Authors: Askenase P. W. , Majewska‐Szczepanik M. , Kerfoot S. , Szczepanik M.
Published: January 2011

Prior studies of classical 24 h responses in TNP‐Cl (picryl chloride) allergic contact sensitivity (CS), showed mediation by Th1 cells in CBA mice, and established that 24 h elicitation of responses requires an early 2 h CS‐initiating component dependent on iNKT cells, IL‐4 and B‐1 B cells. Here, we studied the other form of cytotoxic T cell (Tc1) CS in DNFB sensitized BALB/c mice and determined that similar CS‐initiation also is required. We systematically tested each step of the initiation pathway in this model. Thus, DNFB Tc1 CS was significantly impaired in iNKT cell deficient CD1d−/− and Jα18−/− mice, IL4Rα−/− and STAT‐6−/− mice, and also in pan B‐cell deficient JH−/− mice. Further, the Tc1 DNFB CS‐initiating component, like Th1 response to TNP‐Cl, was elicited by only 1‐day after immunization, due to B‐1 cells. In summary, we show that CS‐Initiation also is required in Tc1 CS. Further, we have newly determined regulatory support of both the early and late components of DNFB induced Tc1 CS by iNKT cells and γδ‐T cells. In summary, both iNKT cells and assisting γδ‐T cells are involved in initiating and effector phases of DNFB induced CS.
An immunohistochemical study of the serotonin 1A receptor in the hippocampus of subjects with Alzheimer's disease
Authors: Mizukami Katsuyoshi , Ishikawa Masanori , Akatsu Hiroyasu , Abrahamson Eric E. , Ikonomovic Milos D. , Asada Takashi
Published: January 2011

Alzheimer's disease (AD) is associated with neuronal degeneration, synaptic loss and deficits in multiple neurotransmitter systems. Alterations in the serotonin 1A (5‐HT1A) receptor can contribute to impaired cognitive function in AD, and both in vitro binding and Positron emission tomography (PET) imaging studies have demonstrated that 5‐HT1A receptors in the hippocampus/medial temporal cortex are affected early in AD. This neuropathological study examined the localization and immunoreaction intensity of 5‐HT1A receptor protein in AD hippocampus with the goal to determine whether neuronal receptor levels are influenced by the severity of NFT severity defined by Braaks' pathological staging and to provide immunohistochemical confirmation of the binding assays and PET imaging studies. Subjects included AD patients and non‐AD controls (NC) stratified into three Braaks' stages (Braak 0–II, NC; Braak III/IV and V/VI, AD). In the Braak 0–II group, 5‐HT1A‐immunoreactivity (ir) was prominent in the neuropil of the CA1 and subiculum, moderate in the dentate gyrus molecular layer (DGml), and low in the CA3 and CA4. No changes in 5‐HT1A‐ir were observed in the hippocampus of AD subjects in the Braak III/IV group. Hippocampal 5‐HT1A‐ir intensity was markedly decreased in the CA1 region in 6/11 (54.5%) subjects in the Braak V/VI group. Across all three groups combined, there was a statistically significant association between reduced 5HT1A‐ir and neuronal loss in the CA1, but not in the CA3. The present data demonstrate that hippocampal 5‐HT1A receptors are mainly preserved until the end‐stage of NFT progression in AD. Thus, the utility of PET imaging using a 5‐HT1A‐specific radiolabeled probe as a marker of hippocampal neuronal loss may be limited to the CA1 field in advanced stage AD cases.