bluuebunny/crossref_metadata_2025 huggingface dataset:
High IFN-gamma and TNF production by peripheral NK cells of Colombian patients with different clinical presentation of Plasmodium falciparum
Authors: Agudelo Olga , Bueno Julio , Villa Andres , Maestre Amanda
Published: February 2012

Background

In Colombia, Plasmodium falciparum infection rarely results in severe disease or mortality compared to infections in African populations. During natural infection NK cells exhibit a cytolytic effect and regulate dendritic cells, macrophages, neutrophils as well as affect antigen specific T and B cell responses. To characterize the NK cells in P. falciparum infected patients of a highly endemic region of Colombia, the degree of NK proliferation and production of IFN gamma and TNF production in these cells were explored.

Methods

Seventeen patients with acute and three with severe P. falciparum malaria patients from the Northwest region of the country were recruited in the study. In addition, 20 healthy controls were included: 10 from Medellin (no-transmission area) and 10 from the Uraba region (a malaria endemic area). Immunophenotypic analysis of peripheral mononuclear cells was performed by FACS to detect total number of NK cells, subtypes and intracellular IFNγ and TNF production by NK cells in the different patient groups.

Results

The total mean CD56+/CD3- NK cell proportions in acute and severe malaria subjects were 9.14% (7.15%CD56dim, 2.01%CD56bright) and 19.62% (16.05%CD56dim, 3.58%CD56bright), respectively, in contrast to healthy controls from endemic (total mean CD56+/CD3-1.2%) and non-endemic area (total mean CD56+/CD3- 0.67%). Analysis of basal IFNγ and TNF levels confirmed the CD56bright NK population as the main cytokine producer (p < 0.0001) in the groups affected with malaria, with the CD56dim NK cell exhibiting the highest potential of TNF production after stimulus in the acute malaria group.

Conclusions

The results confirm the important role of not only CD56bright but also of CD56dim NK cell populations as producers of the two cytokines in malaria patients in Colombia.
Effect of H2S on the circadian rhythm of mouse hepatocytes
Authors: Shang Zhanxian , Lu Chao , Chen Sifeng , Hua Luchun , Qian Ruizhe
Published: February 2012

Background

Dysregulation of circadian rhythms can contribute to diseases of lipid metabolism. NAD-dependent deacetylase sirtuin-1(SIRT1) is an important hub which links lipid metabolism with circadian clock by its deacetylation activity depends on intracellular NAD+/NADH content ratio. Hydrogen sulfide (H2S) is an endogenous reductant which can affect the intracellular redox state. Therefore, we hypothesized that exogenous H2S can affect the expression of circadian clock genes mediated by sirt1 thereby affecting body's lipid metabolism. And also because the liver is a typical peripheral circadian clock oscillator that is intimately linked to lipid metabolism. Thus the effect of H2S were observed on 24-hour dynamic expression of 4 central circadian clock genes and sirt1gene in primary cultured hepatocytes.

Results

We established a hepatocyte model that showed a circadian rhythm by serum shock method. And detected that the expression level and the peak of circadian clock genes decreased gradually and H2S could maintain the expression and amplitude of circadian clock genes such as Clock, Per2, Bmal1 and Rev-erbαwithin a certain period time. Accordingly the expression level of sirt1 in H2S group was significantly higher than that in the control group.

Conclusion

Exogenous reductant H2S maintain the circadian rhythm of clock gene in isolated liver cells. We speculated that H2S has changed NAD+/NADH content ratio in hepatocytes and enhanced the activity of SIRT1 protein directly or indirectly, so as to maintain the rhythm of expression of circadian clock genes, they play a role in the prevention and treatment of lipid metabolism-related disease caused by the biological clock disorders.
Effective components screening and anti-myocardial infarction mechanism study of the Chinese medicine NSLF6 based on "system to system" mode
Authors: Liang Qiong-Lin , Liang Xiao-Ping , Wang Yi-Ming , Xie Yuan-Yuan , Zhang Rong-Li , Chen Xi , Gao Rong , Cheng Yi-Jun , Wu Jun , Xu Qing-Bo , Xiao Qing-Zhong , Li Xue , Lv Shu-Feng , Fan Xue-Mei , Zhang Hong-Yang , Zhang Qing-Li , Luo Guo-An
Published: February 2012

Background

Shuanglong formula (SLF), a Chinese medicine composed of panax ginseng and salvia miltiorrhiza exhibited significant effect in the treatment of myocardial infarction (MI) in clinical. Because of the complex nature and lack of stringent quality control, it's difficult to explain the action mechanism of SLF.

Method

In this study, we present a "system to system" (S2S) mode. Based on this mode, SLF was simplified successively through bioactivity-guided screening to achieve an optimized minimal phytochemical composition (new formula NSLF6) while maintaining its curative effect for MI.

Results

Pharmacological test combining with the study of systems biology show that NSLF6 has activity for treatment MI through synergistic therapeutic efficacies between total ginsenosides and total salvianolic acids via promoting cardiac cell regeneration and myocardial angiogenesis, antagonistic myocardial cell oxidative damage.

Conclusions

The present S2S mode may be an effective way for the discovery of new composite drugs from traditional medicines.
Low-complexity multiuser MIMO downlink system based on a small-sized CQI quantizer
Authors: Song Jiho , Lee Jong-Ho , Kim Seong-Cheol , Kim Younglok
Published: February 2012

It is known that the conventional semi-orthogonal user selection based on a greedy algorithm cannot provide a globally optimal solution due to its semi-orthogonal property. To find a more optimal user set and prevent the waste of the feedback resource at the base station, we present a multiuser multiple-input multiple-output system using a random beamforming (RBF) scheme, in which one unitary matrix is used. To reduce feedback overhead for channel quality information (CQI), we propose an efficient CQI quantizer based on a closed-form expression of expected SINR for selected users. Numerical results show that the RBF with the proposed CQI quantizer provides better throughput than conventional systems under minor levels of feedback.
Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro
Authors: Schneider Ulf C , Schiffler Jennifer , Hakiy Nahid , Horn Peter , Vajkoczy Peter
Published: February 2012

Background

To functionally characterize pro-inflammatory and vasoconstrictive properties of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage (SAH) in vivo and in vitro.

Methods

The cerebrospinal fluid (CSF) of 10 patients suffering from SAH was applied to the transparent skinfold chamber model in male NMRI mice which allows for in vivo analysis of the microcirculatory response to a superfusat. Microvascular diameter changes were quantified and the numbers of rolling and sticking leukocytes were documented using intravital multifluorescence imaging techniques. Furthermore, the pro-inflammatory properties of CSF were assessed in vitro using a monocyte transendothelial migration assay.

Results

CSF superfusion started to induce significant vasoconstriction on days 4 and 6 after SAH. In parallel, CSF superfusion induced a microvascular leukocyte recruitment, with a significant number of leukocytes rolling (day 6) and sticking (days 2-4) to the endothelium. CSF of patients presenting with cerebral edema induced breakdown of blood vessel integrity in our assay as evidenced by fluorescent marker extravasation. In accordance with leukocyte activation in vivo, significantly higher in vitro monocyte migration rates were found after SAH.

Conclusion

We functionally characterized inflammatory and vasoactive properties of patients' CSF after SAH in vivo and in vitro. This pro-inflammatory milieu in the subarachnoid space might play a pivotal role in the pathophysiology of early and delayed brain injury as well as vasospasm development following SAH.
DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)
Authors: Kaushansky Nathali , Altmann Daniel M , David Chella S , Lassmann Hans , Ben-Nun Avraham
Published: February 2012

Background

Multiple sclerosis (MS) is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP), proteolipidprotein (PLP), myelin oligodendrocyte protein (MOG). MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS.

Methods

The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II-/-), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.

Results

PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.

Conclusions

While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.
Spt6 levels are modulated by PAAF1 and proteasome to regulate the HIV-1 LTR
Authors: Nakamura Mirai , Basavarajaiah Poornima , Rousset Emilie , Beraud Cyprien , Latreille Daniel , Henaoui Imène-Sarah , Lassot Irina , Mari Bernard , Kiernan Rosemary
Published: February 2012

Background

Tat-mediated activation of the HIV-1 promoter depends upon a proteasome-associated factor, PAAF1, which dissociates 26S proteasome to produce 19S RP that is essential for transcriptional elongation. The effect of PAAF1 on proteasome activity could also potentially shield certain factors from proteolysis, which may be implicated in the transcriptional co-activator activity of PAAF1 towards the LTR.

Results

Here, we show that Spt6 is targeted by proteasome in the absence of PAAF1. PAAF1 interacts with the N-terminus of Spt6, suggesting that PAAF1 protects Spt6 from proteolysis. Depletion of either PAAF1 or Spt6 reduced histone occupancy at the HIV-1 promoter, and induced the synthesis of aberrant transcripts. Ectopic Spt6 expression or treatment with proteasome inhibitor partially rescued the transcription defect associated with loss of PAAF1. Transcriptional profiling followed by ChIP identified a subset of cellular genes that are regulated in a similar fashion to HIV-1 by Spt6 and/or PAAF1, including many that are involved in cancer, such as BRCA1 and BARD1.

Conclusion

These results show that intracellular levels of Spt6 are fine-tuned by PAAF1 and proteasome, which is required for HIV-1 transcription and extends to cellular genes implicated in cancer.
Cell phone based balance trainer
Authors: Lee Beom-Chan , Kim Jeonghee , Chen Shu , Sienko Kathleen H
Published: February 2012

Background

In their current laboratory-based form, existing vibrotactile sensory augmentation technologies that provide cues of body motion are impractical for home-based rehabilitation use due to their size, weight, complexity, calibration procedures, cost, and fragility.

Methods

We have designed and developed a cell phone based vibrotactile feedback system for potential use in balance rehabilitation training in clinical and home environments. It comprises an iPhone with an embedded tri-axial linear accelerometer, custom software to estimate body tilt, a "tactor bud" accessory that plugs into the headphone jack to provide vibrotactile cues of body tilt, and a battery. Five young healthy subjects (24 ± 2.8 yrs, 3 females and 2 males) and four subjects with vestibular deficits (42.25 ± 13.5 yrs, 2 females and 2 males) participated in a proof-of-concept study to evaluate the effectiveness of the system. Healthy subjects used the system with eyes closed during Romberg, semi-tandem Romberg, and tandem Romberg stances. Subjects with vestibular deficits used the system with both eyes-open and eyes-closed conditions during semi-tandem Romberg stance. Vibrotactile feedback was provided when the subject exceeded either an anterior-posterior (A/P) or a medial-lateral (M/L) body tilt threshold. Subjects were instructed to move away from the vibration.

Results

The system was capable of providing real-time vibrotactile cues that informed corrective postural responses. When feedback was available, both healthy subjects and those with vestibular deficits significantly reduced their A/P or M/L RMS sway (depending on the direction of feedback), had significantly smaller elliptical area fits to their sway trajectory, spent a significantly greater mean percentage time within the no feedback zone, and showed a significantly greater A/P or M/L mean power frequency.

Conclusion

The results suggest that the real-time feedback provided by this system can be used to reduce body sway. Its advantages over more complex laboratory-based and commercial balance training systems in terms of cost, size, weight, functionality, flexibility, and accessibility make it a good candidate for further home-based balance training evaluation.
Bilateral step length estimation using a single inertial measurement unit attached to the pelvis
Authors: Köse Alper , Cereatti Andrea , Della Croce Ugo
Published: February 2012

Background

The estimation of the spatio-temporal gait parameters is of primary importance in both physical activity monitoring and clinical contexts. A method for estimating step length bilaterally, during level walking, using a single inertial measurement unit (IMU) attached to the pelvis is proposed. In contrast to previous studies, based either on a simplified representation of the human gait mechanics or on a general linear regressive model, the proposed method estimates the step length directly from the integration of the acceleration along the direction of progression.

Methods

The IMU was placed at pelvis level fixed to the subject's belt on the right side. The method was validated using measurements from a stereo-photogrammetric system as a gold standard on nine subjects walking ten laps along a closed loop track of about 25 m, varying their speed. For each loop, only the IMU data recorded in a 4 m long portion of the track included in the calibrated volume of the SP system, were used for the analysis. The method takes advantage of the cyclic nature of gait and it requires an accurate determination of the foot contact instances. A combination of a Kalman filter and of an optimally filtered direct and reverse integration applied to the IMU signals formed a single novel method (Kalman and Optimally filtered Step length Estimation - KOSE method). A correction of the IMU displacement due to the pelvic rotation occurring in gait was implemented to estimate the step length and the traversed distance.

Results

The step length was estimated for all subjects with less than 3% error. Traversed distance was assessed with less than 2% error.

Conclusions

The proposed method provided estimates of step length and traversed distance more accurate than any other method applied to measurements obtained from a single IMU that can be found in the literature. In healthy subjects, it is reasonable to expect that, errors in traversed distance estimation during daily monitoring activity would be of the same order of magnitude of those presented.
Attitudes and knowledge about naloxone and overdose prevention among detained drug users in Ningbo, China
Authors: Liu Yu , Bartlett Nicholas , Li Longhui , Lv Xiuyi , Zhang Yahai , Zhou Wenhua
Published: February 2012

Background

To date there has been limited research on both the prevalence of overdose and drug user knowledge about overdose prevention and response methods in China. In addition, there has been no effort to integrate naloxone information and distribution into pre-release services for drug users detained in isolated compulsory detoxification facilities in China.

Methods

The authors conducted a survey of 279 heroin users in isolated compulsory detoxification centers in Ningbo, China in an attempt to evaluate the possibility of conducting prelease peer naloxone programs in Ningbo isolated compulsory detoxification centers. Respondents' demographic background, history of heroin overdoses, and attitudes/knowledge about overdose prevention and response were collected.

Results

While drug users in Ningbo's compulsory detoxification centers have limited understandings of how to effectively respond to overdoses, they expressed concern about the possibility of overdose, interest in participating in overdose prevention and response programs, and a willingness to help their peers. In general, there was no significant difference in history and attitudes/knowledge of overdose between male and female participants.

Conclusion

Based on the findings of this research, our survey provides preliminary evidence that detained drug users have considerable interest in overdose prevention and response information and willingness to help peers. However, drug users in Ningbo isolated compulsory detoxification centers currently have limited understandings of effective ways of helping to prevent overdose deaths.
Assessment of shoulder position variation and its impact on IMRT and VMAT doses for head and neck cancer
Authors: Neubauer Emily , Dong Lei , Followill David S , Garden Adam S , Court Laurence E , White R Allen , Kry Stephen F
Published: February 2012

Background

For radiotherapy of the head and neck, 5-point mask immobilization is used to stabilize the shoulders. Still, the daily position of the shoulders during treatment may be different from the position in the treatment plan despite correct isocenter setup. The purpose of this study was to determine the interfractional displacement of the shoulders relative to isocenter over the course of treatment and the associated dosimetric effect of this displacement.

Methods

The extent of shoulder displacements relative to isocenter was assessed for 10 patients in 5-point thermoplastic masks using image registration and daily CT-on-rails scans. Dosimetric effects on IMRT and VMAT plans were evaluated in Pinnacle based on simulation CTs modified to represent shoulder shifts between 3 and 15 mm in the superior-inferior, anterior-posterior, and right-left directions. The impact of clinically observed shoulder shifts on the low-neck dose distributions was examined.

Results

Shoulder motion was 2-5 mm in each direction on average but reached 20 mm. Superior shifts resulted in coverage loss, whereas inferior shifts increased the dose to the brachial plexus. These findings were generally consistent for both IMRT and VMAT plans. Over a course of observed shifts, the dose to 99% of the CTV decreased by up to 101 cGy, and the brachial plexus dose increased by up to 72 cGy.

Conclusions

he position of the shoulder affects target coverage and critical structure dose, and may therefore be a concern during the setup of head and neck patients, particularly those with low neck primary disease.
Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity
Authors: Nomoto Masanori , Takeda Yohei , Uchida Shusaku , Mitsuda Koji , Enomoto Hatsune , Saito Kaori , Choi Tesu , Watabe Ayako M , Kobayashi Shizuka , Masushige Shoichi , Manabe Toshiya , Kida Satoshi
Published: February 2012

Background

Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR) could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss.

Results

The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory.

Conclusions

From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain.
Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease
Authors: Ravenstijn Paulien GM , Drenth Henk-Jan , O'Neill Michael J , Danhof Meindert , de Lange Elizabeth CM
Published: February 2012

Background

Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods

In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.

Results

Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.

Conclusions

Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.
Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis
Authors: Sato Mitsuhiko , Uchida Kenzo , Nakajima Hideaki , Miyazaki Tsuyoshi , Guerrero Alexander Rodriguez , Watanabe Shuji , Roberts Sally , Baba Hisatoshi
Published: February 2012

Introduction

Mesenchymal stem cells (MSCs) can differentiate into various connective tissue cells. Several techniques have been used for the clinical application of MSCs in articular cartilage repair; however, there are many issues associated with the selection of the scaffold material, including its ability to support cell viability and differentiation and its retention and degradation in situ. The application of MSCs via a scaffold also requires a technically demanding surgical procedure. The aim of this study was to test the outcome of intra-articular transplantation of mesenchymal stem cells suspended in hyaluronic acid (HA) in the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis (OA).

Methods

Commercially available human MSCs were cultured, labeled with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE), suspended in either PBS or HA, and injected into the knee joints of 7-month-old animals. The control animals were injected with either PBS or HA alone. The animals were sacrificed at 1, 3, and 5 weeks post transplantation, the knee joints harvested, and fluorescent microscopic analysis was performed. Histological and immunohistochemical analysis were performed at 5 weeks post transplantation.

Results

At 5 weeks post transplantation, partial cartilage repair was noted in the HA-MSC group but not in the other groups. Examination of CFDA-SE-labeled cells demonstrated migration, differentiation, and proliferation of MSC in the HA-MSC group. There was strong immunostaining for type II collagen around both residual chondrocytes and transplanted MSCs in the OA cartilage.

Conclusion

This scaffold-free and technically undemanding technique appears to result in the regeneration of articular cartilage in the spontaneous OA animal model. Although further examination of the long-term effects of transplantation is necessary, the findings suggest that intra-articular injection of HA-MSC mixture is potentially beneficial for OA.
Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis
Authors: Carter Natalie A , Rosser Elizabeth C , Mauri Claudia
Published: February 2012

Introduction

Interleukin-10 (IL-10) producing B cells, also known as regulatory B (Breg) cells, play a key role in controlling autoimmunity. Our laboratory and others have demonstrated a pivotal role for Bregs in rheumatological disorders, including experimental models of arthritis and lupus. The aim of this study was to identify the role of endogenous IL-10 secreting B cells in vivo in controlling the induction and disease progression of collagen-induced arthritis (CIA).

Methods

We generated chimeric mice that had IL-10 knocked-out specifically in the B cell population. These mice were compared with wild-type (WT) B cell chimeric mice for their susceptibility to CIA.

Results

Here we report that chimeric mice specifically lacking IL-10 producing B cells (IL-10-/- B cell) developed an exacerbated CIA compared to chimeric wild type B cell (WT B cell) mice. A marked increase in inflammatory Th1 and Th17 cells were detected in IL-10-/-B cell mice compared to WT B cell mice. Furthermore, there was a reduction in IL-10 secreting CD4+ Tr1 cells in these animals.

Conclusions

IL-10 producing B cells restrain inflammation by promoting differentiation of immuno-regulatory over pro-inflammatory T cells and, hence, act to maintain tolerance.
Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma
Authors: Serrero Ginette , Hawkins Douglas M , Yue Binbin , Ioffe Olga , Bejarano Pablo , Phillips Jeffrey T , Head Jonathan F , Elliott Robert L , Tkaczuk Katherine R , Godwin Andrew K , Weaver JoEllen , Kim Wes E
Published: February 2012

Introduction

GP88 (progranulin) has been implicated in tumorigenesis and resistance to anti-estrogen therapies for estrogen receptor positive (ER+) breast cancer. Previous pathological studies showed that GP88 is expressed in invasive ductal carcinoma (IDC), but not in normal mammary epithelial tissue, benign lesions or lobular carcinoma. Based on these results, the present study examines GP88 prognostic significance in association with recurrence and death risks for ER+ IDC patients.

Methods

Two retrospective multi-site clinical studies examined GP88 expression by immunohistochemistry (IHC) analysis of paraffin-embedded breast tumor tissue sections from ER+ IDC patients (lymph node positive and negative, stage 1 to 3) in correlation with patients' survival outcomes. The training study established a GP88 cut-off value associated with decreased disease-free (DFS) and overall (OS) survivals. The validation study verified the GP88 cut-off value and compared GP88 prognostic information with other prognostic factors, particularly tumor size, grade, disease stage and lymph node status in multivariate analysis.

Results

GP88 expression is associated with a statistically significant increase in recurrence risk for ER+ IDC patients. The training study established that GP88 3+ score was associated with decreased DFS (P = 0.0004) and OS (P = 0.0036). The independent validation study verified that GP88 3+ score was associated with a 5.9-fold higher hazard of disease recurrence and a 2.5-fold higher mortality hazard compared to patients with tumor GP88 < 3+. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression and treatments.

Conclusions

The survival factor GP88 is a novel prognostic biomarker, predictive of recurrence risk and increased mortality for non-metastatic ER+ IDC patients. Of importance, our data show that GP88 continues to be a prognostic factor even after five years. These results also provide evidence that GP88 provides prognostic information independent of tumor and clinical characteristics and would support prospective study to examine whether GP88 expression could help stratify patients with ER+ tumors for adjuvant therapy.
Interferometric application of static corrections
Authors: Henley David C.
Published: February 2012

Correcting reflection seismic data for the effects of near-surface irregularities is a persistent problem usually addressed at least partly by static corrections applied to traces. However, there are areas where static corrections are ineffective because basic assumptions are violated. The assumptions which fail most often are surface consistency and stationarity, which are central to the concept of static corrections. To address this failure, I mapped raw seismic traces into the radial trace domain and gathered the radial traces by common surface angle. Then I imposed a more general constraint, raypath consistency, which simultaneously introduces nonstationarity. Conventional static correction also assumes implicitly that reflection events consist of single discrete arrivals. This is not true, however, in regions where near-surface multipathing and scattering complicate reflection event waveforms. Borrowing from recent work in seismic inferometry, I removed the single-arrival assumption by using trace crosscorrelations to estimate and deconvolve surface functions from traces, rather than applying time shifts. The entire crosscorrelation function is used in every case, so both timing and waveform variations are removed by the deconvolution. The operation is applied in the common-angle domain, so it is raypath consistent and nonstationary. The method, dubbed “raypath interferometry,” was applied successfully to a set of 2D Arctic field data with serious surface consistency and multipath problems, and to a set of 3C 2D land data with very large S-wave receiver statics. Although intended primarily for use on seismic data for which conventional statics corrections fail, raypath interferometry can be used on any seismic data; its assumptions include single-arrival events and surface consistency as special cases.
Developmental Increase in Kisspeptin-54 Release in Vivo Is Independent of the Pubertal Increase in Estradiol in Female Rhesus Monkeys (Macaca mulatta)
Authors: Guerriero Kathryn A. , Keen Kim L. , Terasawa Ei
Published: February 2012

Kisspeptin (KP) signaling has been proposed as an important regulator in the mechanism of puberty. In this study, to determine the role of KP in puberty, we assessed the in vivo release pattern of KP-54 from the basal hypothalamus/stalk-median eminence in prepubertal and pubertal ovarian-intact female rhesus monkeys. We found that there was a developmental increase in mean KP-54 release, pulse frequency, and pulse amplitude, which is parallel to the developmental changes in GnRH release that we previously reported. Moreover, a nocturnal increase in KP-54 release becomes prominent after the onset of puberty. Because the pubertal increase in GnRH release occurs independent of the pubertal increase in circulating gonadal steroids, we further examined whether ovariectomy (OVX) modifies the release pattern of KP-54. Results show that OVX in pubertal monkeys enhanced mean KP-54 release and pulse amplitude but not pulse frequency, whereas OVX did not alter the release pattern of KP-54 in prepubertal monkeys. Estradiol replacement in OVX pubertal monkeys suppressed mean KP-54 release and pulse amplitude but not pulse frequency. Estradiol replacement in OVX prepubertal monkeys did not alter the KP-54 release pattern. Collectively these results suggest that the pubertal increase in KP release occurs independent of the pubertal increase in circulating estradiol. Nevertheless, the pubertal increase in KP release is not likely responsible for the initiation of the pubertal increase in GnRH release. Rather, after puberty onset, the increase in KP release contributes to further increase GnRH release during the progression of puberty.
The Loss of Hoxa5 Function Causes Estrous Acyclicity and Ovarian Epithelial Inclusion Cysts
Authors: Gendronneau Gaëlle , Boucherat Olivier , Aubin Josée , Lemieux Margot , Jeannotte Lucie
Published: February 2012

Hox genes encode transcription factors that play essential roles during embryo morphogenesis and organogenesis. Expression of several Hox members persists at the adult age, indicating a wide spectrum of action from embryonic to postnatal life. In the present study, we reported that in adult mice, the Hoxa5 gene shows a dynamic expression profile in the ovary that depends on the estrous cycle, the gestational status, and the age of the female, suggesting that Hoxa5 may have distinct physiological functions in the ovary. Consistent with a role for Hoxa5 in ovarian function, Hoxa5−/− nulliparous females exhibit precocious puberty and an early onset of estrous acyclicity. They show a prolonged estrous cycle with increased metestrus-diestrus length, a phenotype that worsens with age. Older mutant females also develop ovarian epithelial inclusion cysts reminiscent of human endosalpingiosis. Immunolabeling studies suggest that these cysts originate from the ovarian surface epithelium, a source of epithelial ovarian carcinomas. Staining of the Hoxa5−/− ovarian cysts by the ovarian cancer markers paired box gene 8 (PAX8) and Wilms' tumor 1 (WT1) further strengthens the notion that these cysts may constitute preneoplastic lesions. Moreover, the deregulation of the estrous cycle and the presence of ovarian epithelial cysts in Hoxa5−/− older females correlate with a reduced expression of specific epidermal growth factor receptor signaling components, namely Egfr, Areg, and Btc. Altogether, our data unveil that Hoxa5, a stroma-specific gene, plays a significant role in ovarian biology and may be involved in ovarian cancer predisposition.
Body Weight Impact on Puberty: Effects of High-Calorie Diet on Puberty Onset in Female Rhesus Monkeys
Authors: Terasawa Ei , Kurian Joseph R. , Keen Kim L. , Shiel Nicholas A. , Colman Ricki J. , Capuano Saverio V.
Published: February 2012

Secular trends toward a declining age at puberty onset with correlated changes in body weight have been reported in economically advanced countries. This has been attributed to excess calorie intake along with reduced physical activity in children. However, because the timing of puberty in humans is also influenced by other factors, such as genetic traits, living conditions, geographical location, and environmental chemicals, it is difficult to distinguish the effect of diet and body size from other factors in a human population. Here we report that feeding juvenile female rhesus monkeys born and raised at the Wisconsin National Primate Research Center with a high-calorie diet results in acceleration of body growth and precocious menarche. The monkeys fed a high-calorie diet also had an elevated body mass index. The most significant treatment effects on circulating hormones were increased leptin and IGF-I levels throughout the experiment. The findings of this study suggest the importance of close monitoring of juvenile feeding behaviors as an important intervention to reduce the prevalence of precocious development and metabolic diseases in adulthood.
Sexual Dimorphism of Growth Hormone in the Hypothalamus: Regulation by Estradiol
Authors: Addison Melisande L. , Rissman Emilie F.
Published: February 2012

GH is best known as an anterior pituitary hormone fundamental in regulating growth, differentiation, and metabolism. GH peptide and mRNA are also present in brain, in which their functions are less well known. Here we describe the distribution of GH neurons and fibers and sex differences in Gh mRNA in adult mouse brain. Cell bodies exhibiting GH immunoreactivity are distributed in many brain regions, particularly in the hypothalamus in which retrograde labeling suggests that some of these cells project to the median eminence. To determine whether Gh mRNA is sexual dimorphic, we carried out quantitative RT-PCR on microdissected brain nuclei. Ovary-intact mice had elevated Gh mRNA in the arcuate nucleus and medial preoptic area (MPOA) compared with gonad-intact males. In males, castration increased Gh mRNA in the MPOA, whereas ovariectomy decreased Gh mRNA in both regions. When gonadectomized adults of both sexes were treated with estradiol Gh mRNA increased in females but had no effect in castrated males. Tamoxifen was able to blunt the rise in Gh mRNA in response to estradiol in females. In addition, we found that estrogen receptor-α is coexpressed in GH neurons in the MPOA and arcuate nucleus. In summary, the findings reveal sexual dimorphisms in Gh gene expression in areas of the brain associated with reproduction and behavior. Interestingly, estradiol enhances Gh mRNA in females only, suggesting that multiple factors orchestrate this sexual dimorphism.
Emerging Role of Mast Cells and Macrophages in Cardiovascular and Metabolic Diseases
Authors: Xu Jia-Ming , Shi Guo-Ping
Published: February 2012

Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data from animal studies suggest that mast cells act similarly to macrophages and other inflammatory cells and contribute to human diseases through cell–cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bring new hope to human patients suffering from these conditions.
Scaling of wingbeat frequency with body mass in bats and limits to maximum bat size
Authors: Norberg Ulla M. Lindhe , Norberg R. Åke
Published: February 2012

The ability to fly opens up ecological opportunities but flight mechanics and muscle energetics impose constraints, one of which is that the maximum body size must be kept below a rather low limit. The muscle power available for flight increases in proportion to flight muscle mass and wingbeat frequency. The maximum wingbeat frequency attainable among increasingly large animals decreases faster than the minimum frequency required, so eventually they coincide, thereby defining the maximum body mass at which the available power just matches up to the power required for sustained aerobic flight. Here, we report new wingbeat frequency data for 27 morphologically diverse bat species representing nine families, and additional data from the literature for another 38 species, together spanning a range from 2.0 to 870 g. For these species, wingbeat frequency decreases with increasing body mass as Mb–0.26. We filmed 25 of our 27 species in free flight outdoors, and for these the wingbeat frequency varies as Mb–0.30. These exponents are strikingly similar to the body mass dependency Mb–0.27 among birds, but the wingbeat frequency is higher in birds than in bats for any given body mass. The downstroke muscle mass is also a larger proportion of the body mass in birds. We applied these empirically based scaling functions for wingbeat frequency in bats to biomechanical theories about how the power required for flight and the power available converge as animal size increases. To this end we estimated the muscle mass-specific power required for the largest flying extant bird (12–16 kg) and assumed that the largest potential bat would exert similar muscle mass-specific power. Given the observed scaling of wingbeat frequency and the proportion of the body mass that is made up by flight muscles in birds and bats, we estimated the maximum potential body mass for bats to be 1.1–2.3 kg. The largest bats, extinct or extant, weigh 1.6 kg. This is within the range expected if it is the bat characteristic flight muscle mass and wingbeat frequency that limit the maximum body mass in bats. It is only a tenth the mass of the largest flying extant bird.
Papiliochrome II pigment reduces the angle dependency of structural wing colouration innireusgroup papilionids
Authors: Wilts Bodo D. , Trzeciak Tomasz M. , Vukusic Peter , Stavenga Doekele G.
Published: February 2012

The wings of four papilionid butterfly species of the nireus group, Papilio bromius, P. epiphorbas, P. nireus and P. oribazus, are marked by blue-green coloured bands surrounded by black margins. The cover scales in the coloured bands contain a violet-absorbing, blue-fluorescing pigment. The fluorescence and absorbance spectra of the nireus group wings are very similar to those of the wings of the Japanese yellow swallowtail, Papilio xuthus, and thus the pigment is presumably papiliochrome II. The scale structures of P.xuthus are arranged irregularly, and both the fluorescence and light reflection are diffuse. In the nireus papilionids, the spatial fluorescence distribution of the scales is also diffuse, but the reflection is specular. The scales have a multilayered structure, consisting of two main laminae. We show that the papiliochrome II pigment in the upper lamina of the scales functions as a violet-blocking long-pass filter in front of the lower lamina, thus limiting the reflectance spectrum to the blue-green wavelength range. Optical modelling showed that the papiliochrome II filter effectively removes the angle dependency of the reflectance spectra – that is, it reduces the wing iridescence. The contribution of the fluorescence signal to the visual appearance is minor.
Copper and zinc detoxification in Gammarus pulex (L.)
Authors: Khan Farhan R. , Bury Nicolas R. , Hogstrand Christer
Published: February 2012

To negate the toxicity of labile intracellular metals, some aquatic organisms partition metals into specific subcellular locations for detoxification, namely the soluble heat-stable cytosol and insoluble metal-rich granules. The aim of the present study was to characterise these subcellular storage sites in the freshwater crustacean Gammarus pulex (Linnaeus) following in situ exposures upstream (Drym, low metal) and downstream (Relubbus, elevated metal) of copper- and zinc-rich inflows into the River Hayle (Cornwall, UK). In the cytosol of gammarids exposed at Relubbus, copper and zinc associated to a 7.5-kDa metallothionein-like protein (MTLP) that was largely absent from gammarids prior to exposure. Exposure at Relubbus caused MTLP concentrations to increase 4- to 5-fold between days 2 and 4, indicating an induction response to increased labile intracellular metal. On day 16, spherical calcium-rich granules (0.5–2.5 μmol l–1) were visualised and analysed in the posterior caeca of gammarids exposed at both sites. Following exposure at Relubbus, granules contained trace amounts of copper, but zinc was absent. Granules in gammarids exposed at Drym contained no detectable copper or zinc. Granule formation appeared to be independent of exposure. Within the posterior caeca, granules have been associated with calcium storage during the crustacean molt, rather than in detoxification of trace metals. However, the granular copper burden appeared to follow environmental Cu availabilities. Thus, we describe Cu sequestration within molt-cycle calcium storage granules. As both MTLP concentrations and granule formation in crustaceans are affected upon by molting, we hypothesise that detoxification might impact upon this existing process.