Multicentre phase II trial of cabozantinib in patients with hepatocellular carcinoma after immune checkpoint inhibitor treatment.

BACKGROUND & AIMS: Prospective data on treatment after immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) are lacking. We conducted a phase II multicentre study on cabozantinib after ICI treatment in HCC. METHODS: This is an investigator-initiated, single-arm, clinical trial involving academic centres in Hong Kong and Korea. Key eligibility criteria included diagnosis of HCC, refractoriness to prior ICI-based treatment, and Child-Pugh A liver function. A maximum of two prior lines of therapy were allowed. All patients were commenced on cabozantinib at 60 mg/day. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were recruited from Oct 2020 to May 2022; 27 and 20 patients had received one and two prior therapies, respectively. Median follow-up was 11.2 months. The median PFS was 4.1 months (95% CI 3.3-5.3). The median overall survival (OS) was 9.9 months (95% CI 7.3-14.4), and the 1-year OS rate was 45.3%. Partial response and stable disease occurred in 3 (6.4%) and 36 (76.6%) patients, respectively. When used as a second-line treatment (n = 27), cabozantinib was associated with a median PFS and OS of 4.3 (95% CI 3.3-6.7) and 14.3 (95% CI 8.9-NR) months, respectively. The corresponding median PFS and OS were 4.3 (95% CI 3.3-11.0) and 14.3 (95% CI 9.0-NR) months, respectively, for those receiving ICI-based regimens with proven benefits (n = 17). The most common grade 3-4 treatment-related adverse event was thrombocytopenia (6.4%). The median dose of cabozantinib was 40 mg/day. The number of prior therapies was an independent prognosticator (one vs. two; hazard ratio = 0.37; p = 0.03). CONCLUSIONS: Cabozantinib demonstrated efficacy in patients who had received prior ICI regimens; survival data for second-line cabozantinib following first-line ICI regimens provide a reference for future clinical trial design. The number of prior lines of treatment may be considered a stratification factor in randomised studies. IMPACT AND IMPLICATIONS: Prospective data on systemic treatment following prior immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) are lacking. This phase II clinical trial provides efficacy and safety data on cabozantinib in patients who had received prior ICI-based treatment. Exploratory analyses showed that the performance of cabozantinib differed significantly when used as a second- or third-line treatment. The above data could be used as a reference for clinical practice and the design of future clinical trials on subsequent treatment lines following ICIs. GOV IDENTIFIER: NCT04588051.

Multiscale Modeling of Macromolecular Interactions between Tau-Amylin Oligomers and Asymmetric Lipid Nanodomains That Link Alzheimer's and Diabetic Diseases.

The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer's and diabetes, respectively. Recent studies suggest that tau and amylin can form hetero-tau-amylin oligomers. Those hetero-oligomers are more neurotoxic than homo-tau oligomers. So far, the detailed interactions between the hetero-oligomers and the neuronal membrane are unknown. Using multiscale MD simulations, the lipid binding and protein folding behaviors of hetero-oligomers on asymmetric lipid nanodomains or raft membranes were examined. Our raft membranes contain phase-separated phosphatidylcholine (PC), cholesterol, and anionic phosphatidylserine (PS) or ganglioside (GM1) in one leaflet of the lipid bilayer. The hetero-oligomers bound more strongly to the PS and GM1 than other lipids via the hydrophobic and hydrophilic interactions, respectively, in the raft membranes. The hetero-tetramer disrupted the acyl chain orders of both PC and PS in the PS-containing raft membrane, but only the GM1 in the GM1-containing raft membrane as effectively as the homo-tau-tetramer. We discovered that the alpha-helical content in the heterodimer was greater than the sum of alpha-helical contents from isolated tau and amylin monomers on both raft membranes, indicative of a synergetic effect of tau-amylin interactions in surface-induced protein folding. Our results provide new molecular insights into understanding the cross-talk between Alzheimer's and diabetes.

Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics.

Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design.

Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands.

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418-a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 µM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer's disease (AD).

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations.

The aggregation of human Islet Amyloid Polypeptide (hIAPP) on cell membranes is linked to amyloid diseases. However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases.

Quality of Life Associated with Nausea and Vomiting from Anthracycline-Based Chemotherapy: A Pooled Data Analysis from Three Prospective Trials.

BACKGROUND: There is limited work on the impact of chemotherapy-induced nausea and vomiting (CINV) on quality of life (QoL) in adriamycin-cyclophosphamide (AC)-treated patients with breast cancer. The objectives of the study were the following: (a) to confirm if symptoms of CINV led to lower QoL during AC; (b) to evaluate the pattern of changes in patients' QoL during multiple cycles of AC; and (c) to assess if the QoL in an earlier cycle affected the QoL in subsequent cycles of AC. MATERIALS AND METHODS: This is a secondary pooled data analysis that included 303 Chinese patients with breast cancer who received 1,177 cycles of adjuvant AC in three prospective antiemetic studies. QoL data were based on Functional Living Index-emesis (FLIE) scored over three to four AC cycles. CINV symptoms assessed included "no significant nausea" (NSN), "significant nausea" (SN), "no vomiting" (NoV), "vomiting" (V), and complete response (CR). RESULTS: Across all AC cycles, the mean scores for the FLIE nausea domain for patients who experienced NSN versus SN were 10.92 versus 53.92, respectively (p < .0001), with lower scores indicating better QoL; the mean scores for the FLIE vomiting domain for patients who experienced NoV versus V were 1.44 versus 19.11, respectively (p < .0001), with similar results across subsequent cycles. Analysis of the effect of the QoL in cycle 1 on the QoL of subsequent cycles revealed the following: for the nausea domain, among patients who had cycle 1 FLIE scores ≥ versus < the mean, the corresponding scores in cycle 2 were 6.87 versus 36.71 (p < .0001); whereas those for cycle 3 were 7.07 versus 36.87 (p < .0001); and those for cycle 4 were 5.92 versus 21.48 (p < .0001). Similar findings were observed for the vomiting domain. Netupitant + palonosetron- or aprepitant/olanzapine-based antiemetics had significantly better QoL outcomes. CONCLUSION: CINV had a significant impact on the QoL of patients with breast cancer treated with AC over multiple cycles. IMPLICATIONS FOR PRACTICE: In this post-hoc analysis of three prospective studies on chemotherapy-induced nausea and vomiting (CINV), quality of life (QoL) using contemporary antiemetic regimens in Chinese breast cancer patients receiving doxorubicin-cyclophosphamide (AC) was evaluated. During the first and subsequent AC cycles, QoL was significantly better for patients who did not experience vomiting or significant nausea. QoL in an earlier cycle affected the QoL in subsequent AC cycles. Furthermore, recent regimens involving olanzapine/aprepitant or netupitant-palonosetron were associated with a positive impact in QoL. Antiemetic guideline-consistent practice and higher clinician awareness of the impact of CINV on QoL can further mitigate the negative effects of CINV on QoL.

VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy.

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper-permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF-A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen-induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho-functional responses of the ischemic retina to anti-angiogenic therapies. Using this model, we investigated the retinal responses to VEGF-Trap (Aflibercept), an anti-angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age-related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light-responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743.

Effects of Cholesterol in Stress-Related Neuronal Death-A Statistical Analysis Perspective.

The association between plasma cholesterol levels and the development of dementia continues to be an important topic of discussion in the scientific community, while the results in the literature vary significantly. We study the effect of reducing oxidized neuronal cholesterol on the lipid raft structure of plasma membrane. The levels of plasma membrane cholesterol were reduced by treating the intact cells with methyl-ß-cyclodextrin (MßCD). The relationship between the cell viability with varying levels of MßCD was then examined. The viability curves are well described by a modified form of the empirical Gompertz law of mortality. A detailed statistical analysis is performed on the fitting results, showing that increasing MßCD concentration has a minor, rather than significant, effect on the cellular viability. In particular, the dependence of viability on MßCD concentration was found to be characterized by a ~25% increase per 1 µM of MßCD concentration.

Dynamic Fingering in Adhered Lipid Membranes.

Artificial lipid membranes incorporating proteins have frequently been used as models for the dynamic organization of biological structures in living cells as well as in the development of biology-inspired technologies. We report here on the experimental demonstration and characterization of a pattern-forming process that occurs in a lipid bilayer membrane adhered via biotin-avidin binding to a second lipid membrane that is supported by a solid substrate. Adhesion regions are roughly circular with a diameter of about 25 µm. Using confocal fluorescence microscopy, we record time series of dynamic fingering patterns that grow in the upper lipid membrane and intermembrane biotin-avidin bonds. The fingers are micrometer-scale elongated pores that grow from the edge of an already-stabilized hole. Finger growth is saltatory on the scale of tens of seconds. We find that as the fingers grow and the density of adhesion proteins increases, the rate of finger growth decreases exponentially and the width of newly formed fingers decreases linearly. We show that these findings are consistent with a thermodynamic description of dynamic pore formation and stabilization.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

This corrects the article DOI: 10.1038/hdy.2015.89.

Wnt/ß-catenin and ERK pathway activation: A possible mechanism of photobiomodulation therapy with light-emitting diodes that regulate the proliferation of human outer root sheath cells.

BACKGROUND: Outer root sheath cells (ORSCs) play important roles in maintaining hair follicle structure and provide support for the bulge area. The hair growth promoting effects of photobiomodulation therapy (PBMT) have been reported, but the mechanisms for this in human ORCs (hORSCs) have rarely been studied. OBJECTIVE: The aim of this study was to investigate the effect of various wavelengths of light-emitting diode (LED) irradiation on human ORSCs (hORSCs). METHODS: LED irradiation effects on hORSC proliferation and migration were examined with MTT assay, BrdU incorporation assay and migration assays. hORSCs were irradiated using four LED wavelengths (415, 525, 660, and 830 nm) with different low energy levels. LED irradiation effects on the expression of molecules associated with the Wnt/ß-catenin signaling and ERK pathway, hair stem cell markers, and various growth factors and cytokines in hORSCs were examined with real-time PCR and Western blot assay. The effect of the LED-irradiated hORSCs on cell proliferation of human dermal papilla cells (hDPCs) was examined with co-culture and MTT assay. RESULTS: PBMT with LED light variably promoted hORSC proliferation and suppressed cell apoptosis depending on energy level. LED irradiation induced Wnt5a, Axin2, and Lef1 mRNA expression and ß-catenin protein expression in hORSCs. Phosphorylation of ERK, c-Jun, and p38 in hORSCs was observed after LED light irradiation, and ERK inhibitor treatment before irradiation reduced ERK and c-Jun phosphorylation. Red light-treated hORSCs showed substantial increase in IL-6, IL-8, TNF-a, IGF-1, TGF-ß1, and VEGF mRNA. Light irradiation at 660 and 830 nm projected onto hORSCs accelerated in vitro migration. LED-irradiated hORSCs increased hDPCs proliferation when they were co-cultured. The conditioned medium from LED-irradiated hORSCs was sufficient to stimulate hDPCs proliferation. CONCLUSION: These results demonstrate that LED light irradiation induced hORSC proliferation and migration and inhibited apoptosis in vitro. The growth-promoting effects of LEDs on hORSCs appear to be associated with direct stimulation of the Wnt5a/ß-catenin and ERK signaling pathway. Lasers Surg. Med. 49:940-947, 2017. © 2017 Wiley Periodicals, Inc.

Ancestral whole-genome duplication in the marine chelicerate horseshoe crabs.

Whole-genome duplication (WGD) results in new genomic resources that can be exploited by evolution for rewiring genetic regulatory networks in organisms. In metazoans, WGD occurred before the last common ancestor of vertebrates, and has been postulated as a major evolutionary force that contributed to their speciation and diversification of morphological structures. Here, we have sequenced genomes from three of the four extant species of horseshoe crabs-Carcinoscorpius rotundicauda, Limulus polyphemus and Tachypleus tridentatus. Phylogenetic and sequence analyses of their Hox and other homeobox genes, which encode crucial transcription factors and have been used as indicators of WGD in animals, strongly suggests that WGD happened before the last common ancestor of these marine chelicerates >135 million years ago. Signatures of subfunctionalisation of paralogues of Hox genes are revealed in the appendages of two species of horseshoe crabs. Further, residual homeobox pseudogenes are observed in the three lineages. The existence of WGD in the horseshoe crabs, noted for relative morphological stasis over geological time, suggests that genomic diversity need not always be reflected phenotypically, in contrast to the suggested situation in vertebrates. This study provides evidence of ancient WGD in the ecdysozoan lineage, and reveals new opportunities for studying genomic and regulatory evolution after WGD in the Metazoa.

TIOtropium Safety and Performance In Respimat® (TIOSPIRTM ): Analysis of Asian cohort of COPD patients.

BACKGROUND AND OBJECTIVE: The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here. METHODS: TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 µg with HandiHaler 18 µg in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW). RESULTS: In Asia (n = 2356), time to death was similar for Respimat 5 and 2.5 µg versus HandiHaler 18 µg (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 µg, but increased for 2.5 µg versus HandiHaler 18 µg (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions. CONCLUSION: Similar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 µg and HandiHaler 18 µg in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW.

Time-resolved neutron reflectometry and photovoltaic device studies on sequentially deposited PCDTBT-fullerene layers.

We have used steady-state and time-resolved neutron reflectometry to study the diffusion of fullerene derivatives into the narrow optical gap polymer poly[N-9″-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (PCDTBT) to explore the sequential processing of the donor and acceptor for the preparation of efficient organic solar cells. It was found that when [6,6]-phenyl-C61-butyric-acid-methyl-ester (60-PCBM) was deposited onto a thin film of PCDTBT from dichloromethane (DCM), a three-layer structure was formed that was stable below the glass-transition temperature of the polymer. When good solvents for the polymer were used in conjunction with DCM, both 60-PCBM and [6,6]-phenyl-C71-butyric-acid-methyl-ester (70-PCBM) were seen to form films that had a thick fullerene layer containing little polymer and a PCDTBT-rich layer near the interface with the substrate. Devices composed of films prepared by sequential deposition of the polymer and fullerene had efficiencies of up to 5.3%, with those based on 60-PCBM close to optimized bulk heterojunction (BHJ) cells processed in the conventional manner. Sequential deposition of pure components to form the active layer is attractive for large-area device fabrication, and the results demonstrate that this processing method can give efficient solar cells.

Determination of fullerene scattering length density: a critical parameter for understanding the fullerene distribution in bulk heterojunction organic photovoltaic devices.

Fullerene derivatives are commonly used as electron acceptors in combination with (macro)molecular electron donors in bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. Understanding the BHJ structure at different electron donor/acceptor ratios is critical to the continued improvement and development of OPVs. The high neutron scattering length densities (SLDs) of the fullerenes provide effective contrast for probing the distribution of the fullerene within the blend in a nondestructive way. However, recent neutron scattering studies on BHJ films have reported a wide range of SLDs ((3.6-4.4) × 10(-6) Å(-2)) for the fullerenes 60-PCBM and 70-PCBM, leading to differing interpretations of their distribution in thin films. In this article, we describe an approach for determining more precisely the scattering length densities of the fullerenes within a polymer matrix in order to accurately quantify their distribution within the active layers of OPV devices by neutron scattering techniques.

In silico analysis reveals the prospects of renal anisotropy in improving chronic kidney disease detection using ultrasound shear wave elastography.

Renal anisotropy is a complex property of the kidney and often poses a challenge in obtaining consistent measurements when using shear wave elastography to detect chronic kidney disease. To circumvent the challenge posed by renal anisotropy in clinical settings, a dimensionless biomarker termed the 'anisotropic ratio' was introduced to establish a correlation between changes in degree of renal anisotropy and progression of chronic kidney disease through an in silico perspective. To achieve this, an efficient model reduction approach was developed to model the anisotropic property of kidneys. Good agreement between the numerical and experimental data were obtained, as percentage errors of less than 5.5% were reported when compared against experimental phantom measurement from the literature. To demonstrate the applicability of the model to clinical measurements, the anisotropic ratio of sheep kidneys was quantified, with both numerical and derived experimental results reporting a value of .667. Analysis of the anisotropic ratio with progression of chronic kidney disease demonstrated that patients with normal kidneys would have a lower anisotropic ratio of .872 as opposed to patients suffering from renal impairment, in which the anisotropic ratio may increase to .904, as determined from this study. The findings demonstrate the potential of the anisotropic ratio in improving the detection of chronic kidney disease using shear wave elastography.

Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1.

The high density of A1 adenosine receptors in the brain results in significant potential for central nervous system (CNS)-related adverse effects with A1 agonists. Tecadenoson is a selective A1 adenosine receptor agonist with close similarity to adenosine. We studied the binding and transmembrane transport of tecadenoson by recombinant human equilibrative nucleoside transporters (hENTs) hENT1 and hENT2, and human concentrative nucleoside transporters (hCNTs) hCNT1, hCNT2, and hCNT3 in vitro and by mouse mENT1 in vivo. Binding affinities of the five recombinant human nucleoside transporters for tecadenoson differed (hENT1 > hCNT1 > hCNT3 > hENT2 > hCNT2), and tecadenoson was transported largely by hENT1. Pretreatment of mice with a phosphorylated prodrug of nitrobenzylmercaptopurine riboside, an inhibitor of mENT1, significantly decreased brain exposure to tecadenoson compared with that of the untreated (control) group, suggesting involvement of mENT1 in transport of tecadenoson across the blood-brain barrier (BBB). In summary, ENT1 was shown to mediate the transport of tecadenoson in vitro with recombinant and native human protein and in vivo with mice. The micromolar apparent Km value of tecadenoson for transport by native hENT1 in cultured cells suggests that hENT1 will not be saturated at clinically relevant (i.e., nanomolar) concentrations of tecadenoson, and that hENT1-mediated passage across the BBB may contribute to the adverse CNS effects observed in clinical trials. In contrast, in cases in which a CNS effect is desired, the present results illustrate that synthetic A1 agonists that are transported by hENT1 could be used to target CNS disorders because of enhanced delivery to the brain.

Hybrid optical system for three-dimensional shape acquisition.

Hybrid concepts are often used to improve existing methods in many fields. We developed a hybrid optical system that consists of multiple color cameras and one depth camera to make up the concavity problem of the visual hull construction. The heterogeneous data from the color cameras and the depth camera is fused in an effective way. The experimental results show that the proposed hybrid system can reconstruct concave objects successfully by combining the visual hull and the depth data.

Subcontractors and increased risk for work-related diseases and absenteeism.

BACKGROUND: Despite increasing reliance on subcontracting in many economic sectors, there is little information available on occupational health and safety issues among subcontractor employees. The purpose of this study was to investigate the effect of subcontracting on self-reported health problems and absences due to occupational accidents and sickness using a nationally representative sample from South Korea. METHODS: The data used were sampled from the second wave of the Korean Working Conditions Survey [2010]. Information on 3,282 parent firm employees and 728 subcontractor employees was obtained. For the logistic regression model, the outcomes were work-related health problems and absenteeism. The independent variables were personal and occupational characteristics, job aspects, and working hazards. RESULTS: Subcontractor employees were significantly more likely to experience health problems than the employee at parent firms. In particular, subcontractors' risk of injuries and anxiety/depression increased twofold (odd ratios, OR=2.01, 95% confidence interval, CIs, 1.24-3.26) and threefold (OR=2.95, 95% CIs 1.52-5.73), respectively, after controlling for potential variables. In addition, subcontractor employees were three times more likely than employees at parent firms to miss work due to illness (OR=3.56; 95% CIs 2.02-6.26). Working conditions, especially those related to job aspects and workplace exposures, attenuated these risks. CONCLUSION: Subcontracting workers were found to have a higher risk of work-related diseases and a higher absenteeism rate than parent firm workers. Our study highlights the need to protect and improve the occupational health and safety of subcontractor employees.

Insights into evolution of multicellular fungi from the assembled chromosomes of the mushroom Coprinopsis cinerea (Coprinus cinereus).

The mushroom Coprinopsis cinerea is a classic experimental model for multicellular development in fungi because it grows on defined media, completes its life cycle in 2 weeks, produces some 10(8) synchronized meiocytes, and can be manipulated at all stages in development by mutation and transformation. The 37-megabase genome of C. cinerea was sequenced and assembled into 13 chromosomes. Meiotic recombination rates vary greatly along the chromosomes, and retrotransposons are absent in large regions of the genome with low levels of meiotic recombination. Single-copy genes with identifiable orthologs in other basidiomycetes are predominant in low-recombination regions of the chromosome. In contrast, paralogous multicopy genes are found in the highly recombining regions, including a large family of protein kinases (FunK1) unique to multicellular fungi. Analyses of P450 and hydrophobin gene families confirmed that local gene duplications drive the expansions of paralogous copies and the expansions occur in independent lineages of Agaricomycotina fungi. Gene-expression patterns from microarrays were used to dissect the transcriptional program of dikaryon formation (mating). Several members of the FunK1 kinase family are differentially regulated during sexual morphogenesis, and coordinate regulation of adjacent duplications is rare. The genomes of C. cinerea and Laccaria bicolor, a symbiotic basidiomycete, share extensive regions of synteny. The largest syntenic blocks occur in regions with low meiotic recombination rates, no transposable elements, and tight gene spacing, where orthologous single-copy genes are overrepresented. The chromosome assembly of C. cinerea is an essential resource in understanding the evolution of multicellularity in the fungi.