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In rodents and humans, the major cellular events at spermatogenesis include self-renewal of spermatogonial stem cells and undifferentiated spermatogonia via mitosis, commitment of spermatogonia to differentiation and transformation to spermatocytes, meiosis, spermiogenesis, and the release of spermatozoa at spermiation. While details of the morphological changes during these cellular events have been delineated, knowledge gap exists between the morphological changes in the seminiferous epithelium and the underlying molecular mechanism(s) that regulate these cellular events. Even though many of the regulatory proteins and biomolecules that modulate spermatogenesis are known based on studies using genetic models, the underlying regulatory mechanism(s), in particular signaling pathways/proteins, remain unexplored since much of the information regarding the signaling regulation is unknown. Studies in the past decade, however, have unequivocally demonstrated that the testis is using several signaling proteins and/or pathways to regulate multiple cellular events to modulate spermatogenesis. These include mTORC1/rpS6/Akt1/2 and p-FAK-Y407. While selective inhibitors and/or agonists and antagonists are available to examine some of these signaling proteins, their use have limitations due to their specificities and also potential systemic cytotoxicity. On the other hand, the use of genetic models has had profound implications for our understanding of the molecular regulation of spermatogenesis, and these knockout (null) models have also revealed the factors that are critical for spermatogenesis. Nonetheless, additional studies using in vitro and in vivo models are necessary to unravel the signaling pathways involved in regulating seminiferous epithelial cycle. Emerging data from studies, such as the use of the adjudin pharmaceutical/toxicant model, have illustrated that this non-hormonal male contraceptive drug is utilizing specific signaling pathways/proteins to induce specific defects in spermatogenesis, yielding mechanistic insights on the regulation of spermatogenesis. We sought to review these recent data in this article, highlighting an interesting approach that can be considered for future studies.

Actin cytoskeleton is crucial to support spermatogenesis in the mammalian testis. However, the molecular mechanism(s) underlying changes of actin cytoskeletal organization in response to cellular events that take place across the seminiferous epithelium (e.g., self-renewal of spermatogonial stem cells, germ cell differentiation, meosis, spermiogenesis, spermiation) at specific stages of the epithelial cycle of spermatogenesis remain largely unexplored. This, at least in part, is due to the lack of suitable study models to identify the crucial regulatory proteins and to investigate how these proteins work in concert to support actin dynamics. Much of the information on the role of actin binding proteins in the literature, namely the actin bundling proteins, actin nucleation proteins and motor proteins, are either findings based on genetic models or morphological analyses. While this information is helpful to delineate the function of these proteins to support spermatogenesis, they are not helpful to identify the regulatory signaling proteins, the signaling pathways and the cascade of events to modulate actin cytoskeleton dynamics. Recent studies based on the use of toxicant models, both in vitro and in vivo, however, have bridged this gap by identifying putative regulatory and signaling proteins of actin cytoskeleton. Herein, we summarize and critically evaluate these findings. We also provide a hypothetical model by which actin cytoskeletal dynamics in Sertoli cells are regulated, which in turn supports spermatid transport across the seminiferous epithelium, and at the blood-testis barrier (BTB) during the epithelial cycle of spermatogenesis.

Objective The bioavailability of the non-hormonal male contraceptive adjudin is low in rats due to the blood-testis barrier (BTB). This study was designed to examine if F5-peptide, an endogenously produced reversible BTB modifier, could enhance the bioavailability of adjudin to affect spermatogenesis and provide a contraceptive effect in rats while reducing systemic toxicity. Study Design We overexpressed F5-peptide in adult male rats (n=10 rats; with 3 or 4 rats for each of the three different experiments noted in the three regimens) by intratesticular injection of a mammalian expression vector pCI-neo (pCI-neo/F5-peptide) vs. empty vector alone (pCI-neo/Ctrl) to be followed by treatment with adjudin by oral gavage at a dose of 10 or 20 mg/kg. The status of spermatogenesis was assessed by histological analysis and dual-labeled immunofluorescence analysis on Day 16. To assess fertility, we allowed treated males (n=3–4 rats) to mate with mature female rats (n=3–4) individually, and assessed the number of pups on Days 23, 36 and 82 to assess fertility and reversibility. Results All 4 treated rats overexpressed with F5-peptide and low-dose adjudin were infertile by Day 36, and half of these rats were fertile by Day 82, illustrating reversibility. However, overexpression of F5-peptide alone (or low-dose adjudin alone) had no effects on fertility in n=3 rats. These findings were consistent with the histology data that illustrated the BTB modifier F5-peptide promoted the action of adjudin to induce germ cell exfoliation, mediated by changes in cytoskeletal organization of F-actin and microtubules across the epithelium, thereby reducing the systemic toxicity of adjudin. Conclusion In this proof-of-concept study, it was shown that overexpression of the F5-peptide prior to administration of adjudin to rats at a low (and ineffective dose by itself) was found to induce reversible male infertility. Implications Overexpression of F5-peptide, an endogenously produced biomolecule in the testis known to induce BTB remodeling, enhanced the contraceptive effect of adjudin in rats, supporting proof of concept studies of BTB disrupters in men.

Cumulating epidemiological studies demonstrated that environmental exposure to endocrine disrupting chemicals (EDCs) during the early stages of fetal development is associated with the increase in disease susceptibility in later life. The fetal developmental plasticity is considered as a protective mechanism against an undesirable prenatal environment. Dioxin is one of the environmental contaminants and is considered a diabetogenic factor. Experimental animal and human epidemiological studies have revealed that dioxin exposure was associated with insulin resistance and altered beta cell function. But the effect of dioxin exposure in early stage of fetal development is still largely unknown. In this report, we used the human embryonic stem cell (hESC) line, VAL-3, as a model, together with Methyl-CpG Binding Domain (MBD) protein-enriched genome sequencing and transcriptome sequencing (RNA-seq), in order to determine the dynamic changes of the epigenetic landscape and transcriptional dysregulation in hESC upon dioxin exposure. The bioinformatics analyses including the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis and Ingenuity Pathway Analysis (IPA) highlighted the predisposed neural, hepatic, cardiac and metabolic toxicological effects of dioxin during the fetal development.

Nowadays, risk factors of triple-negative breast cancer (TNBC) metastasis are not well identified. Our present study reveals that an industrial chemical, bisphenol S (BPS), can promote the migration, but not the proliferation, of TNBC cells in vitro. BPS activates YAP, a key effector of Hippo pathway, by inhibiting its phosphorylation, which promotes YAP nuclear accumulation and up-regulates its downstream genes such as CTGF and ANKRD1. Inhibition of YAP blocks the BPS-triggered cell migration and up-regulation of fibronectin (FN) and vimentin (Vim). BPS rapidly decreases the phosphorylation levels of LATS1 (Ser909) in TNBC cells, which regulates the activation and functions of YAP. Silencing LATS1/2 by siRNA increases BPS-induced dephosphorylation of YAP and extended the half-life of YAP protein. Inhibition of G protein-coupled estrogen receptor 1 (GPER) and its downstream PLCβ/PKC signals attenuate the effects of BPS-induced YAP dephosphorylation and CTGF up-regulation. Targeted inhibition of GPER/YAP inhibits BPS-induced migration of TNBC cells. Collectively, we reveal that GPER/Hippo-YAP signal is involved in BPS-induced migration of TNBC cells.

Considerable human data have shown that the exposure to perfluorooctane sulfonate (PFOS) correlates to the risk of metabolic diseases, however the underlying effects are not clearly elucidated. In this study, we investigated the impacts of PFOS treatment, using in-vivo, ex-vivo and in-vitro approaches, on pancreatic β-cell functions. Mice were oral-gavage with 1 and 5 μg PFOS/g body weight/day for 21 days. The animals showed a significant increase in liver triglycerides, accompanied by a reduction of triglycerides in blood sera and glycogen in livers and muscles. Histological examination of pancreases showed no noticeable changes in the size and number of islets from the control and treatment groups. Immunohistochemistry showed a reduction of staining intensities of insulin and the transcriptional factors (Pdx-1, islet-1) in islets of pancreatic sections from PFOS-treated groups, but no changes in the intensity of Glut2 and glucagon were noted. Transcriptomic study of isolated pancreatic islets treated ex vivo with 1 μM and 10 μM PFOS for 24 h, underlined perturbations of the insulin signaling pathways. Western blot analysis of ex-vivo PFOS-treated islets revealed a significant reduction in the expression levels of the insulin receptor, the IGF1 receptor-β, Pdk1-Akt-mTOR pathways, and Pdx-1. Using the mouse β-cells (Min-6) treated with 1 μM and 10 μM PFOS for 24 h, Western blot analysis consistently showed the PFOS-treatment inhibited Akt-pathway and reduced cellular insulin contents. Moreover, functional studies revealed the inhibitory effects of PFOS on glucose-stimulated insulin-secretion (GSIS) and the rate of ATP production. Our data support the perturbing effects of PFOS on animal metabolism and demonstrate the underlying molecular targets to impair β-cell functions.

Triphenyltin (TPT) is widely used as an active ingredient in antifouling paints and fungicides, and continuous release of this highly toxic endocrine disruptor has caused serious pollution to coastal marine ecosystems and organisms worldwide. Using bioassays and transcriptome sequencing, this study comprehensively investigated the molecular toxicity of TPT chloride (TPTCl) to the marine mussel Perna viridis which is a commercially important species and a common biomonitor for marine pollution in Southeast Asia. Our results indicated that TPTCl was highly toxic to adult P. viridis, with a 96-h LC10 and a 96-h EC10 at 18.7 μg/L and 2.7 μg/L, respectively. A 21-day chronic exposure to 2.7 μg/L TPTCl revealed a strong bioaccumulation of TPT in gills (up to 36.48 μg/g dry weight) and hepatopancreas (71.19 μg/g dry weight) of P. viridis. Transcriptome analysis indicated a time course dependent gene expression pattern in both gills and hepatopancreas. Higher numbers of differentially expressed genes were detected at Day 21 (gills: 1686 genes; hepatopancreas: 1450 genes) and at Day 28 (gills: 628 genes; hepatopancreas: 238 genes) when compared with that at Day 7 (gills: 104 genes, hepatopancreas: 112 genes). Exposure to TPT strongly impaired the endocrine system through targeting on nuclear receptors and putative steroid metabolic genes. Moreover, TPT widely disrupted cellular functions, including lipid metabolism, xenobiotic detoxification, immune response and endoplasmic-reticulum-associated degradation expression, which might have caused the bioaccumulation of TPT in the tissues and aggregation of peptides and proteins in cells that further activated the apoptosis process in P. viridis. Overall, this study has advanced our understanding on both ecotoxicity and molecular toxic mechanisms of TPT to marine mussels, and contributed empirical toxicity data for risk assessment and management of TPT contamination.

Sertoli cells isolated from rodents or humans and cultured in vitro are known to establish a functional tight junction (TJ)-permeability barrier that mimics the blood-testis barrier (BTB) in vivo. This model has been widely used by investigators to study the biology of the TJ and the BTB. Studies have shown that environmental toxicants (e.g., perfluorooctanesulfonate (PFOS), bisphenol A (BPA) and cadmium) that exert their disruptive effects to induce Sertoli cell injury using this in vitro model are reproducible in studies in vivo. Thus, this in vitro system provides a convenient approach to probe the molecular mechanism(s) underlying toxicant-induced testis injury but also to provide new insights in understanding spermatogenesis, such as the biology of cell adhesion, spermatid transport, and others. Herein, we provide a brief and critical review based on studies using this in vitro model of Sertoli cell cultures using primary cells isolated from rodent testes versus humans to monitor environmental toxicant-mediated Sertoli cell injury, and this information is relevant to the molecular mechanisms that regulate spermatogenesis. In short, recent findings have shown that environmental toxicants exert their effects on Sertoli cells to induce testis injury through their action on Sertoli cell actin- and/or microtubule-based cytoskeleton. These effects are mediated via their disruptive effects on actin- and/or microtubule-binding proteins. Sertoli cells also utilize differential spatiotemporal expression of these actin binding proteins to confer plasticity to the BTB to regulate germ cell transport across the BTB.

Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D, which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway.

An integrated vehicle control framework is presented, which uses torque vectoring across independently driven wheels for control. The approach is general in nature, but is particularly well suited for electric vehicles due to increased control bandwidth. The novel algorithm optimizes wheel torque outputs in real time, constraining against power management, traction control, chassis configuration, actuator limits, and fault-case limitations. The structure is modular, and designed to adapt for differing vehicles with minimal re-tuning. Simulation and experimental results are provided for a modified electric SUV platform, under a range of dynamic maneuvers in 4WD, FWD, and RWD modes.

Summary: Eukaryotic DNA replication licensing is a prerequisite for, and plays a role in, regulating genome duplication that occurs exactly once per cell cycle. ORC (origin recognition complex) binds to and marks replication origins throughout the cell cycle and loads other replication-initiation proteins onto replication origins to form pre-replicative complexes (pre-RCs), completing replication licensing. However, how an asymmetric single-heterohexameric ORC structure loads the symmetric MCM (minichromosome maintenance) double hexamers is controversial, and importantly, it remains unknown when and how ORC proteins associate with the newly replicated origins to protect them from invasion by histones. Here, we report an essential and cell-cycle-dependent ORC “dimerization cycle” that plays three fundamental roles in the regulation of DNA replication: providing a symmetric platform to load the symmetric pre-RCs, marking and protecting the nascent sister replication origins for the next licensing, and playing a crucial role to prevent origin re-licensing within the same cell cycle. : Amin et al. provide in vivo evidence for an essential, cell-cycle-dependent, and likely semi-conservative ORC dimerization cycle that regulates eukaryotic chromosomal DNA replication. ORC dimers provide symmetric platforms to load the symmetric pre-RCs at replication origins. ORC de-dimerization produces two single hexamers to bind and protect the two nascent origins. Keywords: DNA replication, replication licensing, pre-RC formation, cell-cycle control, ORC dimerization

In the kidney, disturbance of calcium homeostasis can cause renal hemodynamic changes, leading to glomerulonephritis, tubular damage and renal vascular disease, and thus promotes the development of chronic kidney disease (CKD). Cadmium (Cd) is a toxic heavy metals proved to induce disturbances of calcium homeostasis and nephrotoxicity. Calcium sensing receptor (CaSR) is abundantly expressed in the kidney and plays an important role in maintaining body calcium homeostasis. Our previous study suggested that the activation of CaSR could act as a protective pathway to reduce Cd-induced cytotoxicity in renal proximal tubular cells. However, its application in animal models, its treatment efficacy and underlying mechanisms are still unclear. Therefore, an in vivo animal model (ICR male mouse, n = 5) subjected to Cd-induced nephrotoxicity was used in this study. In the present study, the results indicated that long-term (4 weeks) but not short-term (7 days) Cd exposure induced kidney injury, including induced glomerular atrophy, renal proximal tubule damage, increased malondialdehyde (MDA) level, elevated urine protein quantity, and upregulated kidney injury molecule 1 (KIM-1). It was further observed that chronic Cd exposure induced inhibition of autophagy flux, which triggered kidney apoptosis and injury. However, NPS R-467 restored Cd-inhibited autophagy flux and reduced Cd-induced kidney apoptosis and injury. Finding from this study indicated that activation of CaSR in prevention from nephrotoxicity and kidney injury caused by Cd, which might be helpful for the treatment of clinical CKD.

The segmentation of objects has been an area of interest in numerous fields. The use of texture has been explored to improve convergence in the presence of cluttered backgrounds or objects with distinct textures, where intensity variations are insufficient. Additionally, saliency and feature maps have been applied for contour initialization. However, taking advantage of texture to improve initialization and convergence has not been extensively explored. To address this, we propose a hybrid structural and texture distinctiveness vector field convolution (STVFC) approach, where both the structural characteristics and the concept of texture distinctiveness are incorporated into a multi-functional vector field convolution (VFC) model. In this novel approach, texture distinctiveness is used to enable automatic initialization and is incorporated with intensity variation to improve and accelerate convergence towards the object boundary. Experiments using three datasets, containing natural images and Brodatz textures, demonstrated that STVFC achieved better or comparable segmentation accuracy.

Osmoregulation in fish has been a classical research topic for several decades. Salmon and eels are the widely used model animals because of their wide distribution in different geographical locations and spawning migration between fresh- and salt-water habitats. Numerous fish osmoregulatory hormones and ion transporters were identified for their essential roles in acclimation and adaptation to waters of different salinities. Because of the lack of a genomic database, the scope of most studies, however, is very limited. Recently, our group reported the first high-throughput transcriptomic and proteomic studies to identify hyperosmotic-responsive genes/proteins in gills of Japanese eels. In this study, we aimed to decipher changes in hypo-osmotic-responsive proteins in fish acclimating from seawater (SW) to freshwater (FW) conditions. We collected gill samples from SW-adapted and SW-to-FW-acclimating fish. The respective gill proteins were extracted and labeled using isobaric tags for relative and absolute quantitation (iTRAQ) and analyzed using a high-resolution mass spectrometer. In the short-term transfer from SW to FW, 51 hypo-responsive proteins were detected, and 24 unique hypo-osmotic-responsive proteins were identified (15 up-regulated and nine down-regulated proteins). Our data support the use of an omics approach to facilitate the application of functional genomics in non-model organisms. Biological significance By combining transcriptomic and proteomic approaches, the study has provided the most comprehensive, targeted investigation of eel gill hypo-osmotic responsive proteins that provides molecular insights of osmoregulation mechanisms in a non-model organism, eel. This article is part of a Special Issue entitled: Proteomics of non-model organisms.

Exposure of animals to perfluorooctanoic acid (PFOA), a surfactant used in emulsion polymerization processes causes early pregnancy loss, delayed growth and development of fetuses. The mechanisms of action are largely unknown. We studied the effect of PFOA on implantation using an in vitro spheroid-endometrial cell co-culture model. PFOA (10–100 μM) significantly reduced Jeg-3 spheroid attachment on RL95-2 endometrial cells. PFOA also suppressed β-catenin expression in Jeg-3 cells. The Wnt agonist Wnt3a stimulated β-catenin expression in Jeg-3 cells and reversed the PFOA suppression of the spheroid attachment. The putative PFOA receptors (PPARα, β, γ) present in both cell lines were not affected by PFOA (0.01–100 μM). The PPARα antagonist MK886 restored the β-catenin and E-cadherin expression levels in Jeg-3 cells and reversed the suppression of the spheroid attachment caused by PFOA. Taken together, PFOA suppresses spheroid attachment through PPARα and Wnt signaling pathways via down-regulation of β-catenin and E-cadherin expression.

Background Osmotic stress transcription factor 1/transforming growth factor-β-stimulated clone 22 domain 3 (Ostf1/Tsc22d3) is a transcription factor that plays an osmoregulatory role in euryhaline fishes. Its mRNA and protein levels are up-regulated under hyperosmotic stress. However, its osmoregulatory and developmental functions have not been studied in any stenohaline freshwater fishes. Zebrafish is an excellent model to perform such study to unfold the functional role of Tsc22d3. Methods We identified the zebrafish Tsc22d3 and performed knockdown studies using morpholino antisense oligonucleotide (MO). Results Zebrafish Tsc22d3 did not response to hypertonic stress and ts22d3 knockdown or overexpression by injecting MO or capped RNA did not change the transcriptional levels of any of the known ionocyte markers. To reveal the unknown function of zebrafish Tsc22d3, we performed several in situ molecular marker studies on tsc22d3 morphants and found that Tsc22d3 plays multi-functional roles in dorsoventral (DV) patterning, segmentation, and brain development. We then aimed to identify the mechanism of Tsc22d3 in the earliest stages of DV patterning. Our results demonstrated that tsc22d3 is a ventralizing gene that can stimulate the transcription of bone morphogenetic protein 4 ( bmp4 ) and, thus, has a positive effect on the Bmp signaling pathway. Furthermore, we showed that Tsc22d3 interacts with deubiquitylating enzymes, ubiquitin-specific protease 15 (Usp15) and ovarian tumor domain containing protein 4 (Otud4). In addition, the interruption of Bmp4 signaling by double knockdown of usp15 and otud4 reduced the ventralized effects in tsc22d3 -overexpressing embryos. Conclusions This is the first study to identify new developmental functions of Tsc22d3 in zebrafish. General significance Zebrafish tsc22d3 is a ventralizing gene and plays a role in early embryogenesis.

Osmoregulation is an essential mechanism for euryhaline fish. Gill cells undergo rapid mechanism to maintain the cellular homeostasis during osmotic stress. Reports have suggested that gill cells may be able to migrate between primary filament and secondary lamella during seawater acclimination. However, the factor that can trigger such process is not well-known. Previously, we identified the osmotic stress transcription factor 1b (Ostf1b) in medaka and found that it is an early hypertonic responsive gene and can activate the c-Jun N-terminal kinase (JNK) pathway. In this report, we aim to know if Ostf1b plays the role in the migration. Ostf1b was ectopic expressed in the human embryonic kidney cell line (HEK293) to understand the Ostf1b function. Results clearly demonstrated that Ostf1b could constitutively activate the Rho kinase 1 (ROCK1) and myosin light chain 2 (MLC2) signalling pathway that promotes cell migration, epithelial mesenchymal transition (EMT) and cytoskeletal dynamics through stress fibre formation. The study supports the notion of cell migration and cytoskeleton rearrangement theories in osmoregulation.

The members of stanniocalcins (STCs: STC-1 and STC-2) family are known to be involved in tumor progression and metastasis. Although current evidences suggest the involvement of STCs in vascular biology, the functional roles of STCs in angiogenesis have not yet been elucidated. The objective of this study was to decipher the roles of STCs in angiogenesis of human umbilical vascular endothelial cells (HUVECs). We prepared STC1 or STC2 lentiviral particles to transduce the cells to reveal their effects on the processes of cell proliferation, migration and tube formation. The stimulatory effects of STCs on these processes were demonstrated, supporting the notion of STCs in angiogenesis. To dissect the molecular components involved, STC1 or STC2 transduction led to significant increases in the expression levels of cell cycle regulators (i.e. cyclin-D and phospho-retinoblastoma), matrix metalloproteinase (MMP)-2 but a decrease of tissue inhibitors of metalloproteases (TIMP)-1. The expression levels of the cell adhesion/junctional proteins vimentin and VE-cadherin, were significantly induced. Moreover the transduction induced both mRNA and protein levels of eNOS, VEGF and VEGFR2 (KDR mRNA and pKDR), highlighting the stimulatory effects of STCs on VEGF-signaling pathway. Furthermore STC2 transduction but not STC1, activated angiopoietin (Ang)-2 pathway. Taken together, STC1 and STC2 play positive roles in angiogenic sprouting. The action of STC1 was mediated via VEGF/VEGFR2 pathway while STC2 were mediated via VEGF/VEGFR2 and Ang-2 pathways.

Testes are sensitive to toxicants, such as cadmium and phthalates, which disrupt a local functional axis in the seminiferous epithelium known as the “apical ectoplasmic specialization (apical ES)-blood-testis-barrier (BTB)-basement membrane (BM)”. Following exposure, toxicants contact the basement membrane and activate the Sertoli cell, which perturbs its signaling function. Thus, toxicants can modulate signaling and/or cellular events at the apical ES-BTB-BM axis, perturbing spermatogenesis without entering the epithelium. Toxicants also enter the epithelium via drug transporters to potentiate their damaging effects, and downregulation of efflux transporters by toxicants impedes BTB function such that toxicants remain in the epithelium and efficiently disrupt spermatogenesis. These findings support a novel model of toxicant-induced disruption of spermatogenesis that could be interfered with using small molecules.

Previous studies revealed that food, particularly fish products, is the major source for human exposure to organochlorine pesticides (OCPs). Our previous studies revealed that contamination of Hong Kong market fish with DDT was 0.74–131 with a mean of 12.2 ng g−1, ww, a result suggested that local people might be exposed to hazardous concentrations of OCPs. Therefore, the present systematic study was conducted to determine concentrations of OCPs in blood plasma of Hong Kong residents, develop marker substances and evaluate sources of 19 individual OCPs from fish. Concentrations of ∑OCPs, ∑DDTs and ∑HCHs ranged from 294 to 9732, 172 to 8842, and 115 to 1616 ng g−1 lipid weight (lw), respectively. These concentrations were greater than those in blood of people from most developed countries but lower than those from most developing countries. The upper age group (>50 years) had significant (p

In order to evaluate effects of exposure to mercury (tHg) and methylmercury (MeHg) of Hong Kong residents via consumption of fish, total and bioaccessible concentrations of tHg and MeHg were measured in 10 freshwater and 10 marine fishes collected from markets in Hong Kong. Concentrations of tHg and MeHg in fishes ranged from 27.2 to 311ngg(-1) (median 88.9ngg(-1)) and ND to 116ngg(-1) (median 45.0ngg(-1)), respectively. Concentrations of MeHg in marine fishes (64.4±28.5ngg(-1)) were significantly greater than those in freshwater fishes (40.3±26.0ngg(-1)). Bioaccessibility tHg and MeHg was predicted for edible flesh of twenty fishes by use of an in vitro gastrointestinal assay. Bioaccessibilities of tHg and MeHg ranged from 21.4 to 51.7% (mean 37.4%) and 19.5 to 59.2% (mean 43.7%), respectively. Based on total concentrations, diets of 36% of adults and 51% of children exceeded the reference dose (RfD, 100ngkg(-1)bodymass(bm)d(-1)) for MeHg, but when bioaccessibility was considered, consumption of local market fish would not result in an EDIbio exceeded the RfD of MeHg for Hong Kong adults. These contradictory results suggested that risk assessments based on total concentrations would overestimate exposure because not all of contaminants consumed are bioaccessible. Furthermore, 9% of children had EDIbio for MeHg that exceeded the RfD, which suggests that more attention should be paid to consumption of local fish on health and development of children in Hong Kong.

The outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved slowly over the past 25 years. This improvement may be due to early aneurysm repair by endovascular or open means, use of nimodipine, and better critical care management. Despite this improvement, mortality remains at about 40%, and many survivors have permanent neurologic, cognitive, and neuropsychologic deficits. Randomized clinical trials have tested pharmacologic therapies, but few have been successful. There are numerous explanations for the failure of these trials, including ineffective interventions, inadequate sample size, treatment side effects, and insensitive or inappropriate outcome measures. Outcome often is evaluated on a good-bad dichotomous scale that was developed for traumatic brain injury 40 years ago. To address these issues, we established the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository. The primary aim of the SAHIT data repository is to provide a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase III trials in aneurysmal SAH. With this aim in mind, we convened a multinational investigator meeting to explore merging individual patient data from multiple clinical trials and observational databases of patients with SAH and to create an agreement under which such a group of investigators could submit data and collaborate. We welcome collaboration with other investigators.

Managing microtia patients is always a challenge. Multidisciplinary approach, good family support, well established doctor–patient relationship and well organised patient-support groups are the essential elements for success. With the advancement of implantable hearing devices, more options will be available for the microtia patients. Otologists play a leading role in the whole management process. They not only provide proper guidance to the patients in choosing the correct path of the treatment, but also play a key role in organising and maintaining a cost-effective multidisciplinary rehabilitation team for the microtia patients.

Perfluorinated compounds (PFCs) are man-made fluorinated hydrocarbons, which are very persistent in the environment. Since the early 1980s, the usage of PFCs has sharply increased for a wide array of industrial and commercial applications. Being the most important PFC, perfluorooctane sulfonate (PFOS) has received much attention. In the past decades, increasing surveys have been focused on this compound, to study its sources, fates and effects in the environment. According to the large production volume and wide usage in industrial and commercial products in the past, PFOS can be detected in various environmental media and matrix, even in human tissues. This article attempted to review the current status of PFOS contaminations in Asia, focusing on water systems, sediments, wide animals and human tissues. A special section is devoted to examine the pathways of human exposure to this compound, as well as human body loadings of PFOS and their possible association with diseases.

Bisphenol A (BPA), identified as an endocrine disruptor, is an industrially important chemical that is used as a raw material in the manufacture of many products such as engineering plastics (e.g., epoxy resins/polycarbonate plastics), food cans (i.e., lacquer coatings), and dental composites/sealants. The demand and production capacity of BPA in China have grown rapidly. This trend will lead to much more BPA contamination in the environmental media and in the general population in China. This paper reviews the current literature concerning the pollution status of BPA in China (the mainland, Hong Kong, and Taiwan) and its potential impact on human health. Due to potential human health risks from long-term exposure to BPA, body burden of the contaminant should be monitored. Keywords: Bisphenol A, Endocrine-disruptor, Environmental exposure, Potential impact, China

Perfluorooctane sulfonate (PFOS) was produced by various industries and was widely used in diverse consumer products. Human sample analysis indicated PFOS contamination in body fluids. Animal studies revealed that PFOS tends to accumulate in livers and is able to induce hepatomegaly. However the underlying mechanism of PFOS-elicited hepatotoxicity has not yet been fully addressed. The objective of this study is to identify the cellular target of PFOS and to reveal the mechanisms of PFOS-induced toxicity.In this study, mature 8-week old male CD-1 mice were administered 0, 1, 5 or 10 mg/kg/day PFOS for 3, 7, 14 or 21 days. Histological analysis of liver sections, and biochemical/molecular analysis of biomarkers for hepatic lipid metabolism were assessed.PFOS-induced steatosis was observed in a time- and dose-dependent manner. The gene expression levels of fatty acid translocase (FAT/CD36) and lipoprotein lipase (Lpl) were significantly increased by 10 and/or 5 mg/kg PFOS. Serum levels of very-low density lipoprotein were decreased by 14 days of PFOS exposure (p0.05). The rate of mitochondrial β-oxidation was also found to be significantly reduced, leading to the restriction of fatty acid oxidation for energy production.Taken together, the disturbance of lipid metabolism leads to the accumulation of excessive fatty acids and triglycerides in hepatocytes.Since PFOS-elicited pathological manifestation resembles one of the most common human liver diseases-nonalcoholic fatty liver disease, environmental exposure to PFOS may attribute to the disease progression.

Ecological assessments over large spatial scales require that anthropogenic impacts be distinguishable above natural variation, and that monitoring tools are implemented to maximise impact detection and minimise cost. For three heavily modified and four relatively 'pristine' estuaries (disturbance category), chemical indicators (metals and PAHs) of anthropogenic stress were measured in benthic sediments, suspended sediments and deployed oysters, together with other environmental variables. These were compared with infaunal and hard-substrate invertebrate communities. Univariate analyses were useful for comparing contaminant loads between different monitoring tools and identified the strongest relationships between benthic and suspended sediments. However, multivariate analyses were necessary to distinguish ecological response to anthropogenic stressors from environmental "noise" over a large spatial scale and to identify sites that were being impacted by contaminants. These analyses provide evidence that suspended sediments are a useful alternative monitoring tool to detect potential anthropogenic impacts on benthic (infaunal and hard-substrate) communities. © 2011 Elsevier Ltd. All rights reserved.

In fish, stanniocalcin-1 (STC1) is a key endocrine factor that acts on gill, intestine and kidney to regulate serum calcium and phosphate homeostasis. The recent identification and study of mammalian STCs (STC1 and STC2) revealed that the hormones are made in virtually all tissues and they act primarily as paracrine/autocrine factors to regulate various biological functions. Based on their ubiquitous expression patterns and generally undetectable levels in blood serum, it is unlikely that the mammalian STCs play important roles in serum Ca 2+ /P i homeostasis. However current evidences still support the local action of STCs in Ca 2+ and P i transport, probably via their action on Ca 2+ -channels and Na + /P i co-transporter. At present, information about the sequence, expression and distribution of the STC receptor(s) is lacking. However, recent emerging evidence hints the involvement of STC1 and STC2 in the sub-cellular functions of mitochondria and endoplasmic reticulum respectively, particularly responding to oxidative stress and unfolded protein response. With increasing evidence that demonstrates the local actions of STCs, the focus of the research has been moved to cellular inflammation and carcinogenesis. This review integrates the information available on STCs in fish and mammals, focusing mainly on their embryonic origin, tissue distribution, their potential regulatory mechanisms and the modes of action, and their physiological and pathophysiological functions, particularly in cancer biology.

The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects embryo development, implantation and fertility in humans. The underlying molecular mechanism by which TCDD suppresses implantation remains largely unknown. We used the trophoblastic spheroids (embryo surrogate)–endometrial cells co-culture assay to study the attachment of trophoblastic spheroids (BeWo and Jeg-3) onto the endometrial epithelial (RL95-2 and Ishikawa) cells. TCDD dose-dependently induced cytochrome P450 1A1 (Cyp1A1) expression in trophoblastic and endometrial epithelial cells. Moreover, TCDD at 1 and 10 nM suppressed β-catenin (a Wnt-signaling molecule) and E-cadherin expression, as well as spheroids attachment onto endometrial cells. Interestingly, activation of the canonical Wnt-signaling pathway via Wnt3a or lithium chloride reverted the suppressive effect of TCDD on β-catenin and E-cadherin expressions in the BeWo and RL95-2 cells, and restored the spheroids attachment rate to be comparable to the untreated controls. Taken together, TCDD induces Cyp1A1 expression, modulates the Wnt-signaling pathway and suppresses spheroids attachment onto endometrial cells.

Perfluorinated compounds (PFCs) are man-made fluoro-surfactants that are identified as global pollutants and can pose health risks to humans and wildlife. Two aspects of risk assessment were conducted in this study, including exposure and response. Exposure was estimated by using the concentrations of PFCs in fish and applying standard exposure factors. Among different PFCs, PFOS, PFOA, PFNA, PFDA, PFUdA and PFTrDA were detected. Total concentrations of PFC in fish ranged from 0.27–8.4 ng g −1 to 0.37–8.7 ng g −1 respectively in Hong Kong and Xiamen. The calculated hazard ratio (HR) of PFOS for all fish was less than 1.0. However, the HR for mandarin fish in Hong Kong and bighead carp, grass carp and tilapia in Xiamen, had HR values of approximately 0.5, indicating that frequent consumption of these 4 more contaminated fish species might pose an unacceptable risk to human health. Our data support the notion that the released/disposed chemical pollutants into water systems make fish a source of environmental toxicants to humans. The risks and potential effects of PFCs to health of coastal population in the Pearl River Delta are of concern.

To assess organochlorine pesticide (OCP) contaminations and its possible adverse health impacts, different food samples were collected from three areas of Cambodia, one of the poorest countries in the world. The ∑OCP concentrations in Kampong Cham, Kratie and Kandal provinces ranged from 1.28 to 188 (median 3.11), 1.06 to 25.1 (5.59) and 2.20 to 103 (20.6) ng g −1 , respectively. The dichlorodiphenyltrichloroethanes (DDTs) were the predominant OCPs and accounted for 62.2% (median) among all foodstuffs. Congener profile analyses suggested that there were new input sources of DDTs and hexachlorocyclohexanes (HCHs) in Cambodia, particularly in Kandal province. The estimated daily intake of OCPs (330 ng kg −1 day −1 ) for residents in Kandal province ranked No. 1 among the 13 compared countries or regions. On the basis of 95th percentile concentrations, the carcinogenic hazard ratios (HRs) of most investigated individual OCPs in vegetable and fish in Cambodia exceeding unity. Particularly for α-HCH in vegetable, the 95th HR was as high as 186. The data revealed that there is a great cancer risk for the local residents with life time consumption of OCP contaminated vegetable and fish. To our knowledge, this the first study to evaluate the daily intakes of OCPs in Cambodia.

The oral bioaccessibility of dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexanes (HCHs) in twenty fish species were evaluated using an in vitro gastrointestinal model. Relatively high concentrations of ∑HCH (0.33–9.88 ng g−1, mean 1.57 ng g−1) and ∑DDT (0.74–131 ng g−1, mean 12.2 ng g−1) were observed in all market fish. The average bioaccessibilities for ∑HCHs were 3.35% and 8.73% in gastric and intestinal conditions, respectively, and for ∑DDTs were 5.48% and 17.6%, respectively. Significant (p

Fish consumption is known to be beneficial to human health. However since the age of industrialization, the released/disposed chemical pollutants into water systems make fish a source of various environmental toxicants to humans. In oceanic cities with heavy industrial activities, fish products contribute the greatest proportion of exposure to pollutants. In this study, risks and potential effects of dioxins to health of coastal populations in the Pearl River Delta were assessed. Concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs) were measured in common fish species purchased at local markets. Concentrations of total dioxins in fish ranged from 0.481 to 9.05 pg TEQ/g wet weight were similar to the lesser concentrations reported for fish from other countries. The greatest concentrations of dioxins were measured in mandarin fish, a carnivorous freshwater fish. Exposure of murine primary leydig and ovarian cells to 2,3,7,8-tetrachlorinated dibenzo-p-dioxins (2,3,7,8-TCDD) reduced the synthesis of progesterone, testosterone and/or estrogen. The reductions were probably via inhibitory effects on the expression of the steroidogenic enzymes, steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (P450scc). Based on these reproductive parameters, the concentrations of dioxins and dioxin-like residues represent a moderate health risk due to consumption of fish.

Surface and core sediments collected from six mariculture farms in the Pearl River Delta (PRD) were analyzed to evaluate contamination levels of polychlorinated biphenyls (PCBs). The ∑PCBs (37 congeners) concentrations ranged from 5.10 to 11.0 ng g(-1) (mean 7.96 ng g(-1)) in surface and 3.19 to 22.1 ng g(-1) (mean 7.75 ng g(-1)) in core sediments, respectively. The concentrations were significantly higher than that measured in the sediments of their corresponding reference sites, whereby the average enrichment percentages were 62.0% and 42.7% in surface and core sediments, respectively. Significant correlations (R2=0.77, p

The human glycoprotein, stanniocalcin-2 (STC2) is a HIF-1 target gene that is found to be associated with tumor development. The relationship of the prognostic outcome to the level of its expression in cancer tissues is controversial; however experimental evidence suggests that STC2 is a positive regulator of cancer progression. In the present study, we investigated if the expression of STC2 in hypoxic cells is associated with cancer invasion and metastasis. We studied the epithelial-mesenchymal transition (EMT) markers in STC2-silenced and over-expressed SKOV3 cells maintained in hypoxic condition. Western blot and immunocytochemical analysis revealed that the stable expression of exogenous STC2 promoted EMT, as revealed by the increase of N-cadherin/vimentin but a decrease of E-cadherin levels. This observation was further confirmed by colony formation assay where the STC2 stably transfected cells showed high degree of motility with fibroblast morphology under hypoxic condition. In conducting invasion assay in hypoxia, the STC2 stably transfected cells showed high degree of invasiveness. This observation was correlated with the significant increase of MMP2 and MMP9 expression in the STC2 stably transfected cells. In HUVEC/SKOV3 co-culture invasion study, endothelial invasion was found to be enhanced by the seeding of STC2 stably transfected cells in the lower compartment. These observations were possibly mediated by an increase of ROS and activated ERK1/2 levels in the cells. Collectively, the finding provides the first evidence that STC2 is a positive regulator in tumor progression at hypoxia.

Pharmacokinetics of melamine has not been studied in pregnancies despite of the many reports on the effect on renal damage in adult and neonates. In this study, Sprague-Dawley rats have been used as a model to study the single-dose effect of melamine administration in late pregnancy and in neonates within 24h. Melamine concentrations in maternal serum, breast milk, whole foetus, amniotic fluid, neonatal serum and neonatal kidney was measured by liquid chromatography coupled with mass spectrometry. Melamine was detected in all the samples, including foetal rats and amniotic fluid in utero. Melamine was able to pass through placenta and reach the foetus, and to accumulate in lactating mammary gland and neonatal kidney. Moreover, melamine was eliminated through the placenta of the foetus and the kidneys of the neonates, and later excreted into the amniotic fluid. The study characterised for the first time the distribution of melamine in foetuses and neonates, providing reference for toxicological study of melamine during pregnancy.

Surface and core sediments collected from six fish farms in Hong Kong and from reference sites were investigated for the enrichment and sources of polycyclic aromatic hydrocarbons (PAHs). Moderately high ∑PAH 16 levels (123–947 ng g −1 , mean: 450 ng g −1 ) were found in the surface aquaculture sediments. In comparison with the sediments from the reference sites, the average enrichment percentage of total organic carbon (TOC) and PAHs in surface sediments were 21.4 and 43.8%, respectively, and in the core sediments, 24.6 and 73.7%, respectively. Mathematical source apportionment analyses (i.e. isomer ratios, hierarchical cluster analysis, principal components analysis with multiple linear regression analysis) suggested a higher percentage of petrogenic sources in aquaculture sediments. The fish feeds might be the main source of the enriched PAHs in the aquaculture sediments. To our knowledge, this is the first study showing that PAHs in aquaculture sediments could be attributed to human aquaculture activities.

The distribution and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in surface sediments of freshwater fishponds and mariculture rafts around the Pearl River Delta (PRD) were investigated. Twenty-one sample sites were chosen, consisting of fifteen freshwater fishponds and six mariculture rafts. The total PAH ( summation SigmaPAH) concentrations measured in all the sediment samples ranged from 52.7 to 717 ng g(-1), with mean of 184 ng g(-1). The marine sediment samples contained higher levels of summation SigmaPAH, high molecular weight (HMW) PAHs and carcinogenic PAHs than freshwater sediments (p

In this study we aimed to assess the dioxin- and estrogen-like activities of contaminants extracted from twenty species of freshwater and seawater fishes, using luciferase reporter assays. Transfected MCF7 cells were treated with sample extracts and luciferase activities were then measured at 24-h of post-treatment. The mean values of the detected dioxin- and estrogen-like activities in the freshwater fishes were 25.3 pg TEQ/g ww and 102.3 pM EEQ/g ww whereas in the seawater fishes, the values were 46.2 pg TEQ/g ww and 118.8 pM EEQ/g ww. Using sample-relevant dosage of estrogen, inductions of cell proliferation markers (i.e. retinoblastoma, cyclin D) and stimulations of cell growth were revealed by Western blotting, colony formation and BrdU uptake assays. A cotreatment with TCDD significantly reduced these effects. Using the sample extracts with different dioxin- and estrogen-like activities, similar observation was revealed. The data highlighted the mixture effect of food contaminants on human health.

Nine groups of food items (freshwater fish, marine fish, pork, chicken, chicken eggs, leafy, non-leafy vegetables, rice and flour) and three types of human samples (human milk, maternal serum and cord serum) were collected for the analysis of PCDD/Fs. Results of chemical analysis revealed PCDD/Fs concentrations (pg g−1 fat) in the following ascending order: pork (0.289 pg g−1 fat), grass carp (Ctenopharyngodon idellus) (freshwater fish) (0.407), golden thread (Nemipterus virgatus) (marine fish) (0.511), chicken (0.529), mandarin fish (Siniperca kneri) (marine fish) (0.535), chicken egg (0.552), and snubnose pompano (Trachinotus blochii) (marine fish) (1.219). The results of micro-EROD assay showed relatively higher PCDD/Fs levels in fish (2.65 pg g−1 fat) when compared with pork (0.47), eggs (0.33), chicken (0.13), flour (0.07), vegetables (0.05 pg g−1 wet wt) and rice (0.05). The estimated average daily intake of PCDD/Fs of 3.51 pg EROD-TEQ/kg bw/day was within the range of WHO Tolerable Daily Intake (1–4 pg WHO-TEQ/kg bw/day) and was higher than the Provisional Tolerable Daily Intake (PMTL) (70 pg for dioxins and dioxin-like PCBs) recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) [Joint FAO/WHO Expert Committee on Food Additives (JECFA), Summary and conclusions of the fifty-seventh meeting, JECFA, 2001.]. Nevertheless, the current findings were significantly lower than the TDI (14 pg WHO-TEQ/kg/bw/day) recommended by the Scientific Committee on Food of the Europe Commission [European Scientific Committee on Food (EU SCF), Opinions on the SCF on the risk assessment of dioxins and dioxin-like PCBs in food, 2000.]. However, it should be noted that micro-EROD assay overestimates the PCDD/Fs levels by 2 to 7 folds which may also amplify the PCDD/Fs levels accordingly. Although the levels of PCDD/Fs obtained from micro-EROD assay were much higher than those obtained by chemical analysis by 2 to 7 folds, it provides a cost-effective and rapid screening of dioxin levels in food and human samples. Keywords: PCDD/Fs, Human tissues, Body loadings, Fish, Vegetables

The fruit of Swietenia macrophylla is commonly known as “sky fruit”. The fruit, which contains flavonoids and saponins, is processed commercially into a wide range of health foods and healthcare products. The fruit concentrate is used traditionally to improve blood circulation and impart a healthy skin. In this paper, we describe the isolation and structure elucidation of three new phragmalin ortho esters, named swietephragmin H-J ( 1 – 3 ), and a new polyhydroxylated phragmalin, named swietemacrophine ( 4 ), from the leaves of S. macrophylla . The structures of the compounds were elucidated by spectroscopic methods, including HRESIMS, 1 H NMR, 13 C NMR, DEPT, 1 H– 1 H COSY, HMQC, HMBC and NOESY spectra. This is the first report of phragmalin ortho esters and a polyhydroxylated phragmalin from this plant.

Mammalian stanniocalcin-2 (STC2) is a secreted glycoprotein hormone with a putative role in unfolded protein response and apoptosis. Here we reported that STC2 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines revealed that CpG dinucleotides in STC2 promoter was methylated in human ovarian epithelial cancer (SKOV3, OVCAR3 and CaOV3), pancreatic cancer (BxP3), colon adenoma (HT29), and leukemia (Jurkat cells). STC2 CpG island hypermethylation was accompanied with a low basal STC2 expression level. Treatment of these cancer cells with 5-aza-2'-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation significantly induced STC2 expression. Using SKOV3 cells as a model, the link between DNA demethylation and STC2 expression was consistently demonstrated with hydralazine treatment, which was shown to reduce the protein level of DNA methyltransferase 1 (DNMT1) but stimulated STC2 expression. Two human normal surface ovarian cell-lines (i.e. IOSE 29 and 398) showed no methylation at CpG dinucleotides in the examined promoter region and were accompanied with high basal STC2 levels. Hypoxia stimulated STC2 expression in SKOV3 cells was markedly increased in 5-aza-CdR pretreated cells, showing that DNA methylation may hinder the HIF-1 mediated activation. To elucidate this possibility, RNA interference studies confirmed that endogenous HIF-1 alpha was a key factor for STC2 gene activation as well as in the synergistic induction of STC2 expression in 5-aza-CdR pretreated cells. Chromatin immunoprecipitation (ChIP) assay demonstrated the binding of HIF-1 alpha to STC2 promoter. The binding was increased in 5-aza-CdR pretreated cells. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression.

Classification of data with imbalanced class distribution has posed a significant drawback of the performance attainable by most standard classifier learning algorithms, which assume a relatively balanced class distribution and equal misclassification costs. The significant difficulty and frequent occurrence of the class imbalance problem indicate the need for extra research efforts. The objective of this paper is to investigate meta-techniques applicable to most classifier learning algorithms, with the aim to advance the classification of imbalanced data. The AdaBoost algorithm is reported as a successful meta-technique for improving classification accuracy. The insight gained from a comprehensive analysis of the AdaBoost algorithm in terms of its advantages and shortcomings in tacking the class imbalance problem leads to the exploration of three cost-sensitive boosting algorithms, which are developed by introducing cost items into the learning framework of AdaBoost. Further analysis shows that one of the proposed algorithms tallies with the stagewise additive modelling in statistics to minimize the cost exponential loss. These boosting algorithms are also studied with respect to their weighting strategies towards different types of samples, and their effectiveness in identifying rare cases through experiments on several real world medical data sets, where the class imbalance problem prevails.

Monoclonal antibody against TNF-alpha such as infliximab has shown clinical efficacy in controlling the inflammatory signs and symptoms of rheumatoid arthritis (RA), but the detailed immunotherapeutic mechanism is not fully understood. We investigated 19 patients with active RA who were treated with infliximab (3 mg/kg) at weeks 0, 2, 6 and 14. Peripheral blood was obtained from the patients at weeks 0 and 14 and cultured with mitogens phytohaemagglutinin (PHA) and lipopolysaccharide (LPS). The concentrations of cytokines and soluble adhesion molecules (sICAM-1, sICAM-3, sE-selectin, sP-selectin, sVCAM-1 and sPECAM-1) in supernatant fluids or plasma were measured by flow cytometry and ELISA. After infliximab treatment, the absolute and percentage increases in release of inflammatory cytokine TNF-alpha and potent neutrophil chemoattractant IL-8 upon PHA and LPS activation were significantly decreased when compared to those of before treatment (all P0.01). The increased releases of IL-6, IL-1beta, IL-18 and IL-12 upon mitogen activation were similar before and after infliximab treatment (all P0.05). Plasma concentrations of these cytokines and soluble adhesion molecules did not differ significantly before and after infliximab treatment. Our study suggests that the reduction in synovial inflammation may be due to the decreased production of TNF-alpha and IL-8, and hence the number of neutrophils and other pro-inflammatory leukocytes infiltrating into the inflamed sites.

Our previous studies demonstrated that the ichthyotoxic Chattonella marina stimulated proliferation of branchial chloride cell (CC) and induced osmotic distress akin to hyperactive elimination of ions in fish (Rhabdosargus sarba). To ascertain the in vivo effects of C. marina on key CC ion transporters, the localization and expression of Na(+), K(+)-ATPase (NKA) and cystic fibrosis transmembrane conductance regulator (CFTR) proteins in response to C. marina exposure were investigated, using a quantitative immunocytochemical approach. The polarized distributions of NKA (alpha subunit) and CFTR proteins in branchial CCs of R. sarba remained unchanged under C. marina exposure. However, significant inductions of these two ion-transporters were detected in CCs of fish after 6h exposure. By real-time PCR, no significant changes in gill NKA and CFTR mRNA expressions were detected, suggesting a post-transcriptional pathway is likely involved in regulating the ion transporters abundance. This study is the first to demonstrate the in vivo effects of harmful algal toxin on NKA and CFTR protein expressions in gill transepithelial cells. Taken together, an augmentation of branchial CCs together with hyper-stimulation of NKA and CFTR in CCs attribute to the rapid development of osmotic distress in C. marina susceptible fish.

This paper introduces a new structured lighting scheme to obtain dense depth data fast and reliably. Its main idea is to use both features and continuous intensities organized in a hierarchical structure as the projection pattern. This hierarchical structure then guides the matching process. As a result, a dense depth map can be reliably acquired by grabbing only one image (or two images for better precision). Experimental results using a prototype system with two cameras and a lighting projector show that the proposed scheme is effective and efficient.

Among different mammalian tissues, testis is found to be one of the most sensitive organs to TCDD exposure. In this study, primary Sertoli cell culture was established. The purity of the cultured cells was verified using 3beta-hydroxysteroid dehydrogenase, alkaline phosphatase as well as testosterone induction assays. Effects of TCDD in modulating the expression of CYP1A1, aromatase, secretory products (i.e. Mullerian inhibiting substance (MIS), 17beta-estradiol (E(2)) and lactate) and markers for cell-cell interaction (i.e. sertolin and testin) were then examined. Our data demonstrated that Sertoli cells exposed to 0.2-2000 pg/ml of TCDD showed a dose dependent induction of CYP1A1 mRNA. The minimal dose of activation was 2 pg/ml, which indicated that the cell was very sensitive to TCDD exposure. However, there was little or no detectable level CYP1A1 protein and EROD activities found. Dose-dependent inductions of aromatase transcript (200%) and E(2) (20%) secretion were measured. In addition there was a significant reduction (40%) of MIS mRNA. No detectable change in the level of secreted lactate was observed. Sertolin and testin, the gene makers for cell-cell interactions were differentially modulated upon TCDD treatment. Taken together, the results implicated that TCDD exposure might interfere with the normal Sertoli cell functions.