Incidence of subsequent cholangiocarcinomas after another malignancy: trends in a population-based study.
Cholangiocarcinoma (CCA) characterized by late diagnosis and poor outcomes represents the commonest malignancy of biliary tract. Understanding metachronous cancer associations may achieve earlier detection. We aimed to evaluate the risk of subsequent CCAs among common cancer survivors. The National Cancer Institute's Surveillance, Epidemiology, and End Results database (1973-2010) was reviewed for patients with 1 of the 25 primary cancers. Standardized incidence ratios (SIRs) were calculated as an approximation of relative risk for subsequent CCAs after primary malignancy. Data were stratified by age at primary cancer diagnosis, latency period, and application of radiation. A total of 1487 patients developed subsequent CCAs. For patients diagnosed with primary cancers between the ages 20 and 39 years, the risk was increased among colon (SIR 14.65), gallbladder (129.29), and uterus (7.29) cancer survivors. At ages of 40 to 59 years, oral cavity and pharynx (1.89), stomach (3.24), colon (1.76), gallbladder (11.78), and lung cancers (1.75) were associated with increased risk. We found persistently elevated SIRs after colon and gallbladder cancer between ages 60 and 79 years. The SIR remained significant among gallbladder cancer survivors diagnosed after 80 years. Gallbladder cancer showed elevated risk at all of the latency periods except first 6 to 11 months. Increased risk of lung cancer (1.66) was detected after 120 months. However, radiation therapy did not contribute to increased risk. This population-based study suggests that several initial cancers are associated with elevated risk of CCA. The increased risk may be due to shared genetic or environmental etiological factors between these malignancies. Lower threshold for CCA surveillance may be warranted in high-risk patients.


Characterization of a receptor for interleukin 5 on human eosinophils: variable expression and induction by granulocyte/macrophage colony-stimulating factor.
Interleukin 5 (IL-5) acts on eosinophil differentiation and activation, suggesting the existence of a membrane receptor for IL-5 on eosinophils. Here, we report that 125I-labeled recombinant human IL-5 bound, at 4 degrees C, to high affinity receptors on human eosinophils. The association constant was higher for hypodense eosinophils (1.93 x 10(9) M-1) than for normodense cells (0.39 x 10(9) M-1), with a closely related number of receptor sites per cell. No specific binding occurred on neutrophils. The specific binding of IL-5 was induced by overnight incubation at 37 degrees C of human eosinophils with granulocyte/macrophage (GM)-CSF. The levels of increase were significantly higher for normodense than for hypodense eosinophils, suggesting a previous in vivo activation of the later subpopulation by GM-CSF. IL-3 was ineffective by itself but synergistically enhanced the effect of GM-CSF. Specificity studies showed that the binding of 125I-labeled IL-5 was inhibited by IL-5, but not by other cytokines, on human eosinophils. These results show the existence of a specific binding site for IL-5 on human eosinophils with a variable affinity on eosinophil hypodense or normodense subpopulations, as previously reported for other membrane receptors.


GLUT3 expression in cystic change induced by hypoxia in pituitary adenomas.
Tumor cells require large amounts of energy to sustain growth. Through the mediated transport of glucose transporters, the uptake and utilization of glucose by tumor cells are significantly enhanced in the hypoxic microenvironment. Pituitary adenomas are benign tumors with high-energy metabolisms. We aimed to investigate the role of expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1) in pituitary adenomas, including effects on size, cystic change and hormone type. Pituitary adenomas from 203 patients were collected from January 2013 to April 2017, and immunohistochemical analysis was used to detect the expression of GLUT3 and GLUT1 in tumor specimens. GLUT3-positive expression in the cystic change group was higher than that in the non-cystic change group (P = 0.018). Proportions of GLUT3-positive staining of microadenomas, macroadenomas, and giant adenomas were 22.7 (5/22), 50.4 (66/131) and 54.0% (27/50), respectively (P = 0.022). In cases of prolactin adenoma, GLUT3-positive staining was predominant in cell membranes (P = 0.000006), while in cases of follicle-stimulating hormone or luteotropic hormone adenoma, we found mainly paranuclear dot-like GLUT3 staining (P = 0.025). In other hormonal adenomas, GLUT3 was only partially expressed, and the intensity of cell membrane or paranuclear punctate staining was weak. In contrast to GLUT3, GLUT1 expression was not associated with pituitary adenomas. Thus, our results indicate that the expression of GLUT3 in pituitary adenomas is closely related to cystic change and hormonal type. This study is the first to report a unique paranuclear dot-like GLUT3 staining pattern in pituitary adenomas.


Whole-cell and single-channel calcium currents of isolated smooth muscle cells from saphenous vein.
Whole-cell and single-channel calcium currents in enzymatically isolated dog saphenous vein cells were recorded by the patch-clamp method. Test pulses to negative potentials from holding potentials of -90 to -40 mV elicited currents that inactivated quickly and in a voltage-dependent manner (called I low for low threshold). A second calcium current persisted even at relatively positive holding potentials of -30 to -10 mV, required stronger depolarizations for maximum current, and inactivated slowly (I high for high threshold). I high transported barium more than calcium, whereas I low transported the two ions equally. Single-channel current records (90 mM barium) showed a larger conductance that activated at relatively positive potentials and a smaller (about one-third) conductance that activated at weak depolarizations. Nitrendipine suppressed I high, and the effect was voltage dependent as observed in cardiac cells, although block of resting channels was much greater in vein cells (KR approximately 10(-8) M). Exposure to the stereoisomer (-)Bay K 8644 increased I high but not I low. The (-)Bay K 8644 also increased the channel activity and prolonged the open time of the larger conductance current. Thus, two types of calcium channels, differing in potential-dependence of activation and inactivation, calcium/barium selectivity, single-channel conductance, and sensitivities to dihydropyridines were identified in smooth muscle cells isolated from a large cutaneous vein.


Sinonasal-type hemangiopericytoma: a clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation.
Sinonasal-type hemangiopericytoma is an uncommon upper aerodigestive tract tumor of uncertain cellular differentiation. We report 104 cases of sinonasal-type hemangiopericytoma diagnosed between 1970 and 1995 from the files of the Armed Forces Institute of Pathology. There were 57 females and 47 males ranging in age from 5 to 86 years (mean 62.6 years). The most common clinical presentation was airway obstruction (n = 57) and/or epistaxis (n = 54), with symptoms averaging 10 months in duration. The tumors involved the nasal cavity alone (n = 47) or also a paranasal sinus (n = 26), were polypoid, and measured an average of 3.1 cm. Histologically, the tumors were submucosal and unencapsulated and showed a diffuse growth with fascicular (n = 37) to solid (n = 50) to focally whorled (n = 7) patterns. The tumor cells were uniform in appearance with minimal pleomorphism and had spindle-shaped (n = 82) to round/oval (n = 18) nuclei with vesicular to hyperchromatic chromatin and eosinophilic to amphophilic to clear-appearing cytoplasm with indistinct cell borders. Multinucleated (tumor) giant cells were identified in a minority of cases (n = 5). Mitotic figures were inconspicuous and necrosis was absent. The tumors were richly vascularized, including staghorn-appearing vessels that characteristically had prominent perivascular hyalinization (n = 92). An associated inflammatory cell infiltrate that included mast cells and eosinophils was noted in the majority of cases (n = 87). The immunohistochemical profile included reactivity with vimentin (98%), smooth muscle actin (92%), muscle specific actin (77%), factor XIIIa (78%), and laminin (52%). Surgery was the treatment of choice for all of the patients; adjunctive radiotherapy was given to four patients. Recurrences developed in 18 patients within 1-12 years from diagnosis. Ninety-seven patients were either alive (n = 51, mean 16.5 years) or dead (n = 46, mean 9.6 years) but free of disease. Four patients had disease at the last follow-up: three died with disease (mean 3.6 years) and one patient is alive with disease (28.3 years). Recurrent tumor (17.8%) can be managed by additional surgery. The majority of sinonasal-type hemangiopericytomas behave in a benign manner with excellent long-term prognosis (88% raw 5-year survival) following surgery alone. Sinonasal-type hemangiopericytomas have a characteristic light microscopic appearance with an immunophenotypic profile resembling that of glomus tumors.


Intensity, phase, and polarization of a vector Bessel vortex beam through multilayered isotropic media.
This paper investigates the characteristics of reflected and transmitted fields of a vector Bessel vortex beam through multilayered isotropic media on the basis of the vector angular spectrum expansion and presents the effects of media on intensity, phase, and polarization. The method is verified by studying the reflection and transmission on a single interface at vertical incidence. For both paraxial and nonparaxial incident beam cases, numerical simulations of the field components and the time-averaged Poynting vector power density of the reflected and transmitted beams for the three-layered media are presented and discussed in detail. It is shown that as the incident angle increases, the magnitude distribution of the reflected beams illustrates significant distortions and no longer represents similar patterns to that of the incident beam, whereas the magnitude distribution of the transmitted beams can maintain similar profiles to the incident beam, apart from the notable distortion of the central ring. For the same incident angle, the effects of media on the magnitude distribution for the nonparaxial case are more evident than those for the paraxial case. The results of phase distribution and polarization of the reflected and transmitted fields show that as the incident angle increases, the distortion of the phase distribution and polarization for the reflected fields are more significant and the topological charge cannot be preserved.


Effect of factory effluents on physiological and biochemical contents of Gossypium hirsutum l.
The effect of sago and sugar factory effluents was studied on Gossypium hirsutum L. var. MCU 5 and MCU 11. Plants were irrigated with 0, 25, 50, 75 and 100% of effluents of both factories. At lower concentration (25%) of sugar factory effluents had stimulatory effect on all biochemical contents observed. Moreover, all concentration of sago factory effluents were found to have inhibitory effect on all biochemical contents except proline content which increased with increasing concentration of both the effluents. Plants growing on adjacent to sago and sugar factories or they irrigated with such type of polluted water, may accumulate the heavy metals found in both the effluents, at higher levels in plant products and if consumed may have similar effect on living organisms.


Retention in publicly funded methadone maintenance treatment in two Western States.
This study examined individual and system characteristics associated with retention in methadone maintenance treatment among Medicaid-eligible adults in treatment for opiate use in Oregon and Washington. Logistic regression was used to examine the contributions of predisposing, need, and enabling characteristics on 365 day retention in methadone maintenance treatment. Older patients, patients with a history of methadone maintenance treatment, and persons with stable Medicaid eligibility had higher rates of retention than did patients with disabilities, polysubstance users, and those with an arrest record. In Oregon, which delivers methadone maintenance treatment through managed care, retention rose sharply from 28% to 51% between 1994 and 1998 and then leveled off. During the same time period, retention in Washington State grew from 28% to 34%. The higher rates of retention in Oregon, in part, can be explained by differences in service delivery influenced by financing. Faced with long waiting lists, Washington providers were more than twice as likely to administratively discharge patients for rule violations as their Oregon counterparts. Given the importance of retention, policies and practices that influence retention should be carefully considered. Because Medicaid eligibility has a dramatic impact on retention, policies that help extend eligibility or stabilize eligibility among individuals actively engaged in treatment should be carefully considered.


A novel Kunitz protein with proposed dual function from Eudiplozoon nipponicum (Monogenea) impairs haemostasis and action of complement in vitro.
Serine peptidases are involved in many physiological processes including digestion, haemostasis and complement cascade. Parasites regulate activities of host serine peptidases to their own benefit, employing various inhibitors, many of which belong to the Kunitz-type protein family. In this study, we confirmed the presence of potential anticoagulants in protein extracts of the haematophagous monogenean Eudiplozoon nipponicum which parasitizes the common carp. We then focused on a Kunitz protein (EnKT1) discovered in the E. nipponicum transcriptome, which structurally resembles textilinin-1, an antihemorrhagic snake venom factor from Pseudonaja textilis. The protein was recombinantly expressed, purified and biochemically characterised. The recombinant EnKT1 did inhibit in vitro activity of Factor Xa of the coagulation cascade, but exhibited a higher activity against plasmin and plasma kallikrein, which participate in fibrinolysis, production of kinins, and complement activation. Anti-coagulation properties of EnKT1 based on the inhibition of Factor Xa were confirmed by thromboelastography, but no effect on fibrinolysis was observed. Moreover, we discovered that EnKT1 significantly impairs the function of fish complement, possibly by inhibiting plasmin or Factor Xa which can act as a C3 and C5 convertase. We localised Enkt1 transcripts and protein within haematin digestive cells of the parasite by RNA in situ hybridisation and immunohistochemistry, respectively. Based on these results, we suggest that the secretory Kunitz protein of E. nipponicum has a dual function. In particular, it impairs both haemostasis and complement activation in vitro, and thus might facilitate digestion of a host's blood and protect a parasite's gastrodermis from damage by the complement. This study presents, to our knowledge, the first characterisation of a Kunitz protein from monogeneans and the first example of a parasite Kunitz inhibitor that impairs the function of the complement.


Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection.
The clinical spectrum, etiologies, and best therapeutic approaches of type II mixed cryoglobulinemia (MC) not associated with hepatitis C virus (HCV) infection have been poorly described to date. We studied the clinical presentation and outcome of patients with type II MC with no evidence of HCV. This was a multicenter retrospective study on the clinical presentation and outcome of patients with type II MC without evidence of HCV infection. Only patients with symptomatic MC were included. Thirty-three patients were included (median followup 67.2 mo). Extensive investigations for associated diseases were performed at presentation. MC was related to an autoimmune disease in 14 patients, to a lymphoid malignancy in 4 patients, and to an infectious disease in 2 patients, while MC was classified as essential (primary) in 13. Essential MC tended to be more severe than secondary disease with, in particular, more frequent renal and peripheral nerve involvement. Most patients were treated with steroid with or without immunosuppressive agents, mainly cyclophosphamide. These treatments were unable to induce sustained remission. One patient was successfully treated with lenalidomide. Seven patients with nonmalignant MC were treated with rituximab; 2 had a sustained complete remission, 3 improved greatly but relapsed within 5 months, and 2 experienced a disease flare. An important proportion of non HCV-related type II MC remains essential. Efforts should be made to find other etiologies than HCV, because treatments with steroid and immunosuppressants are not satisfactory, especially in severe forms. In these situations anti-CD20 therapy may present the best option but should be used with caution. New agents such as lenalidomide remain to be evaluated.


Immunologic and hormonal effects of prophylthiouracil treatment using maintenance dose in Graves' disease patients.
To assess immunologic remission in patients with Graves' disease following euthyroid condition at the end of treatment with maintenance dose of PTU. This is an intervention study using one-group pre-post design. Subjects were 25 Graves' disease patients visiting Metabolic Endocrinology Clinic at Dr. M.Djamil hospital Padang and met the inclusion criteria. Patients were given PTU treatment for 12 months. Blood samples were taken at the beginning and at the end of treatment to determine immunological remission reflected by differences in IL-4serum levels. After maintenance therapy, we found significant decrease of T3 levels (2.29±0.57 nmol/L vs. 1.87±0.34 nmol/L, p<0.05), significant decrease of T4 levels (118.15±25.99 nmol/L vs. 94.15±23.76 nmol/L, p<0.05), significant increase of TSH levels (0.379±0.548 vs. 0.859±0.990, p<0.05) and significant decreased levels of IL-4 (12.23±5.74 vs. 3.84±0.42, p<0.05). The IL-4 level, however, did not decrease to the normal levels. PTU administration in maintenance dose can significantly reduce thyroid hormonal parameter levels down to euthyroid condition, but cannot reduce immunological parameter (IL4) to normal limit.


Application of environmental DNA to detect an endangered marine skate species in the wild.
Environmental DNA (eDNA) techniques have only recently been applied in the marine environment to detect the presence of marine species. Species-specific primers and probes were designed to detect the eDNA of the endangered Maugean skate (Zearaja maugeana) from as little as 1 L of water collected at depth (10-15 m) in Macquarie Harbour (MH), Tasmania. The identity of the eDNA was confirmed as Z. maugeana by sequencing the qPCR products and aligning these with the target sequence for a 100% match. This result has validated the use of this eDNA technique for detecting a rare species, Z. maugeana, in the wild. Being able to investigate the presence, and possibly the abundance, of Z. maugeana in MH and Bathurst harbour (BH), would be addressing a conservation imperative for the endangered Z. maugeana. For future application of this technique in the field, the rate of decay was determined for Z. maugeana eDNA under ambient dissolved oxygen (DO) levels (55% saturation) and lower DO (20% saturation) levels, revealing that the eDNA can be detected for 4 and 16 hours respectively, after which eDNA concentration drops below the detection threshold of the assay. With the rate of decay being influenced by starting eDNA concentrations, it is recommended that samples be filtered as soon as possible after collection to minimize further loss of eDNA prior to and during sample processing.


Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model.
Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD) mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers). Moreover, numbers of immature neurons (DCX) were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker). A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(TM)), increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.


A Prospective Cohort Study of Muscular and Performance Fitness and Risk of Hearing Loss: The Niigata Wellness Study.
Several cross-sectional studies have linked higher physical fitness with better hearing sensitivity but have not established a causal relation; none have used a prospective design that is less susceptible to bias. We used a prospective cohort study to investigate the association between muscular and performance fitness and the incidence of hearing loss. A total of 21,907 participants without hearing loss received physical fitness assessments between April 2001 and March 2002. Muscular and performance fitness index, an age- and sex-specific summed z-score based on grip strength, vertical jump height, single-leg balance, forward bending, and whole-body reaction time was calculated. Participants were classified into quartiles according to the muscular and performance fitness index and each physical fitness test. They were followed up for the development of hearing loss, assessed by pure-tone audiometry at annual health examinations between April 2002 and March 2008. Hazard ratios and 95% confidence intervals for hearing loss incidence were estimated using Cox proportional hazards regression models. During follow-up, 2765 participants developed hearing loss. The hazard ratios (95% confidence intervals) for developing hearing loss across the muscular and performance fitness index quartiles (lowest to highest) were 1.00 (reference), 0.88 (0.79-0.97), 0.83 (0.75-0.93), and 0.79 (0.71-0.88) (Ptrend <.001). Among the various physical fitness components, a clear dose-response association with hearing loss incidence was observed for vertical jump height and single-leg balance (Ptrend <.001 for both). Higher muscular and performance fitness is associated with a lower incidence of hearing loss.


Toxicity and carcinogenicity mechanisms of fibrous antigorite.
We studied the effects of fibrous antigorite on mesothelial MeT-5A and monocyte-macrophage J774 cell lines to further understand cellular mechanisms induced by asbestos fibers leading to lung damage and cancer. Antigorite is a mineral with asbestiform properties, which tends to associate with chrysotile or tremolite, and frequently occurs as the predominant mineral in the veins of several serpentinite rocks found abundantly in the Western Alps. Particles containing antigorite are more abundant in the breathing air of this region than those typically found in urban ambient air. Exposure of MeT-5A and J774 cells to fibrous antigorite at concentrations of 5-100 microg/ml for 72 hr induced dose-dependent cytotoxicity. Antigorite also stimulated the ROS production, induced the generation of nitrite and PGE2. MeT-5A cells were more sensitive to antigorite than J774 cells. The results of this study revealed that the fibrous antigorite stimulates cyclooxygenase and formation of hydroxyl and nitric oxide radicals. These changes represent early cellular responses to antigorite fibers, which lead to a host of pathological and neoplastic conditions because free radicals and PGE2 play important roles as mediators of tumor pathogenesis. Understanding the mechanisms of the cellular responses to antigorite and other asbestos particles should be helpful in designing rational prevention and treatment approaches.


Stable Cu nanoclusters: from an aggregation-induced emission mechanism to biosensing and catalytic applications.
Highly luminescent and stable Cu nanoclusters (NCs) have been prepared, displaying an intriguing aggregation-induced emission (AIE) feature. The attractive AIE feature allowed the CuNCs to serve as pH stimuli-responsive functional materials. Additionally, we explored the utility of CuNCs for biosensing and catalysis applications.


Alcohol Regulates BK Surface Expression via Wnt/β-Catenin Signaling.
It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify β-catenin as a primary necessary protein. Alcohol increases β-catenin, and blocking accumulation of β-catenin blocks alcohol-induced internalization in these neurons. In transfected HEK293 cells, suppression of Wnt/β-catenin signaling blocks ethanol-induced internalization. Conversely, activation of Wnt/β-catenin reduces BK current density. A point mutation in a putative glycogen synthase kinase phosophorylation site within the S10 region of BK blocks internalization, suggesting that Wnt/β-catenin directly regulates alcohol-induced BK internalization via glycogen synthase kinase phosphorylation. These findings establish de novo protein synthesis and Wnt/β-catenin signaling as critical in mediating a persistent form of BK molecular alcohol tolerance establishing a commonality with other forms of long-term plasticity. Alcohol tolerance is a key step toward escalating alcohol consumption and subsequent dependence. Our research aims to make significant contributions toward novel, therapeutic approaches to prevent and treat alcohol misuse by understanding the molecular mechanisms of alcohol tolerance. In our current study, we identify the role of a key regulatory pathway in alcohol-induced persistent molecular changes within the hippocampus. The canonical Wnt/β-catenin pathway regulates BK channel surface expression in a protein synthesis-dependent manner reminiscent of other forms of long-term hippocampal neuronal adaptations. This unique insight opens the possibility of using clinically tested drugs, targeting the Wnt/β-catenin pathway, for the novel use of preventing and treating alcohol dependency.


Challenges and opportunities in implementing managed relocation for conservation of freshwater species.
The rapidity of climate change is predicted to exceed the ability of many species to adapt or to disperse to more climatically favorable surroundings. Conservation of these species may require managed relocation (also called assisted migration or assisted colonization) of individuals to locations where the probability of their future persistence may be higher. The history of non-native species throughout the world suggests managed relocation may not be applicable universally. Given the constrained existence of freshwater organisms within highly dendritic networks containing isolated ponds, lakes, and rivers, managed relocation may represent a useful conservation strategy. Yet, these same distinctive properties of freshwater ecosystems may increase the probability of unintended ecological consequences. We explored whether managed relocation is an ecologically sound conservation strategy for freshwater systems and provided guidelines for identifying candidates and localities for managed relocation. A comparison of ecological and life-history traits of freshwater animals associated with high probabilities of extirpation and invasion suggests that it is possible to select species for managed relocation to minimize the likelihood of unintended effects to recipient ecosystems. We recommend that translocations occur within the species' historical range and optimally within the same major river basin and that lacustrine and riverine species be translocated to physically isolated seepage lakes and upstream of natural or artificial barriers, respectively, to lower the risk of secondary spread across the landscape. We provide five core recommendations to enhance the scientific basis of guidelines for managed relocation in freshwater environments: adopt the term managed translocation to reflect the fact that individuals will not always be reintroduced within their historical native range; examine the trade-off between facilitation of individual movement and the probability of range expansion of non-native species; determine which species and locations might be immediately considered for managed translocation; adopt a hypothetico-deductive framework by conducting experimental trials to introduce species of conservation concern into new areas within their historical range; build on previous research associated with species reintroductions through communication and synthesis of case studies.


Statins use and its impact in EGFR-TKIs resistance to prolong the survival of lung cancer patients: A Cancer registry cohort study in Taiwan.
Statins have been shown to be a beneficial treatment as chemotherapy and target therapy for lung cancer. This study aimed to investigate the effectiveness of statins in combination with epidermal growth factor receptor-tyrosine kinase inhibitor therapy for the resistance and mortality of lung cancer patients. A population-based cohort study was conducted using the Taiwan Cancer Registry database. From January 1, 2007, to December 31, 2012, in total 792 non-statins and 41 statins users who had undergone EGFR-TKIs treatment were included in this study. All patients were monitored until the event of death or when changed to another therapy. Kaplan-Meier estimators and Cox proportional hazards regression models were used to calculate overall survival. We found that the mortality was significantly lower in patients in the statins group compared with patients in the non-statins group (4-y cumulative mortality, 77.3%; 95% confidence interval (CI), 36.6%-81.4% vs. 85.5%; 95% CI, 78.5%-98%; P = .004). Statin use was associated with a reduced risk of death in patients the group who had tumor sizes <3 cm (hazard ratio [HR], 0.51, 95% CI, 0.29-0.89) and for patients in the group who had CCI scores <3 (HR, 0.6; 95% CI, 0.41-0.88; P = .009). In our study, statins were found to be associated with prolonged survival time in patients with lung cancer who were treated with EGFR-TKIs and played a synergistic anticancer role.


A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder?
In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.


White light emission in Bi3+/Mn2+ ion co-doped CsPbCl3 perovskite nanocrystals.
Colloidal perovskite nanocrystals (NCs), especially the fully inorganic cesium lead halide (CsPbX3, X = Cl, Br, I) NCs, have been considered as promising candidates for lighting and display applications due to their narrow band emission, tunable band gap and high photoluminescence quantum yields (QYs). However, owing to the anion exchange in the CsPbX3 NCs, stable multi-color and white light emissions are difficult to achieve, thus limiting their practical optoelectronic applications. In this work, dual ion Bi3+/Mn2+ codoped CsPbCl3 perovskite NCs were prepared through the hot injection method for the first time to the best of our knowledge. Through simply adjusting the doping ion concentrations, the codoped NCs exhibited tunable emissions spanning the wide range of correlated color temperature (CCT) from 19 000 K to 4250 K under UV excitation. This interesting spectroscopic behaviour benefits from efficient energy transfer from the perovskite NC host to the intrinsic energy levels of Bi3+ or Mn2+ doping ions. Finally, taking advantage of the cooperation between the excitonic transition of the CsPbCl3 perovskite NC host and the intrinsic emissions from Bi3+ and Mn2+ ions, white light emission with the Commission Internationale de l'Eclairage (CIE) color coordinates of (0.33, 0.29) was developed in the codoped CsPbCl3 NCs.


Perceived neighbourhood social cohesion and myocardial infarction.
The main strategy for alleviating heart disease has been to target individuals and encourage them to change their health behaviours. Although important, emphasis on individuals has diverted focus and responsibility away from neighbourhood characteristics, which also strongly influence people's behaviours. Although a growing body of research has repeatedly demonstrated strong associations between neighbourhood characteristics and cardiovascular health, it has typically focused on negative neighbourhood characteristics. Only a few studies have examined the potential health enhancing effects of positive neighbourhood characteristics, such as perceived neighbourhood social cohesion. Using multiple logistic regression models, we tested whether higher perceived neighbourhood social cohesion was associated with lower incidence of myocardial infarction. Prospective data from the Health and Retirement Study--a nationally representative panel study of American adults over the age of 50--were used to analyse 5276 participants with no history of heart disease. Respondents were tracked for 4 years and analyses adjusted for relevant sociodemographic, behavioural, biological and psychosocial factors. In a model that adjusted for age, gender, race, marital status, education and total wealth, each SD increase in perceived neighbourhood social cohesion was associated with a 22% reduced odds of myocardial infarction (OR=0.78, 95% CI 0.63 to 0.94. The association between perceived neighbourhood social cohesion and myocardial infarction remained even after adjusting for behavioural, biological and psychosocial covariates. Higher perceived neighbourhood social cohesion may have a protective effect against myocardial infarction.


A Three-Dimensional Skeletal Reconstruction of the Stem Amniote Orobates pabsti (Diadectidae): Analyses of Body Mass, Centre of Mass Position, and Joint Mobility.
Orobates pabsti, a basal diadectid from the lower Permian, is a key fossil for the understanding of early amniote evolution. Quantitative analysis of anatomical information suffers from fragmentation of fossil bones, plastic deformation due to diagenetic processes and fragile preservation within surrounding rock matrix, preventing further biomechanical investigation. Here we describe the steps taken to digitally reconstruct MNG 10181, the holotype specimen of Orobates pabsti, and subsequently use the digital reconstruction to assess body mass, position of the centre of mass in individual segments as well as the whole animal, and study joint mobility in the shoulder and hip joints. The shape of most fossil bone fragments could be recovered from micro-focus computed tomography scans. This also revealed structures that were hitherto hidden within the rock matrix. However, parts of the axial skeleton had to be modelled using relevant isolated bones from the same locality as templates. Based on the digital fossil, mass of MNG 10181 was estimated using a model of body shape that was varied within a plausible range to account for uncertainties of the dimension. In the mean estimate model the specimen had an estimated mass of circa 4 kg. Varying of the mass distribution amongst body segments further revealed that Orobates carried most of its weight on the hind limbs. Mostly unrestricted joint morphology further suggested that MNG 10181 was able to effectively generate propulsion with the pelvic limbs. The digital reconstruction is made available for future biomechanical studies.


The global burden of congenital toxoplasmosis: a systematic review.
To estimate the global burden of congenital toxoplasmosis (CT), which results from infection of pregnant women with Toxoplasma gondii. The authors systematically searched 9 major databases for published and unpublished sources and established direct contact with the authors of source materials. Searches were country-specific. To be included, studies had to report on the incidence of CT, on positivity to Toxoplasma-specific IgM in infants and pregnant women (including seroconversion results) or on positivity to Toxoplasma-specific IgG in the general population. Various modelling techniques were used, depending on the country-specific data available, to estimate the CT incidence and burden in each country. These data were then synthesized into an estimate of the global incidence of CT and of the global burden of CT in disability-adjusted life years (DALYs). The global annual incidence of congenital toxoplasmosis was estimated to be 190,100 cases (95% credible interval, CI: 179,300-206,300). This was equivalent to a burden of 1.20 million DALYs (95% CI: 0.76-1.90). High burdens were seen in South America and in some Middle Eastern and low-income countries. Congenital toxoplasmosis poses a substantial burden of poor health globally. Toxoplasmosis should be included in future updates of the global burden of disease and the corresponding data should be used to support public health interventions to reduce disease burden.


Bradykinin does not modulate the natriuretic response to atrial natriuretic factor in rats with aortocaval fistula.
Rats with aortocaval fistula, an experimental model of congestive heart failure (CHF), display two distinct patterns of sodium excretion: some rats develop marked sodium retention and worsening edema with urinary excretion of sodium (UNaV) < 200 microEq per 24 hours, i.e., uncompensated CHF, whereas in others sodium balance rapidly returns to normal (UNaV > 1,400 microEq per 24 hours), i.e., compensated CHF. Similar patterns of sodium excretion are found in patients with CHF. The mechanisms underlying these responses are not fully understood. The present study was designed to assess whether bradykinin plays a role in the compensatory response to CHF. Infusions of either 10 or 50 micrograms/kg per minute of synthetic atrial natriuretic factor (ANF)8-33 into sham-operated control animals produced significant increases in urine flow and fractional excretion of sodium (FENa). Infusions of ANF at the same doses into rats with compensated CHF increased FENa from 0.11 +/- 0.03% to a maximum of 6.10 +/- 1.30%, whereas the rise in FENa in animals with uncompensated CHF was significantly reduced (0.05 +/- 0.01% to 0.59 +/- 0.18%) compared with sham-operated controls (0.23 +/- 0.05% to 8.32 +/- 1.0%) or the group with compensated CHF. Treatment of the compensated rats with the bradykinin antagonist HOE-140 (D-Arg,[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) given at a rate of 100 nmol/kg per hour did not affect their renal response to the ANF. In addition, infusion of the bradykinin antagonist alone into compensated rats with aortocaval fistula had no significant effect on their basal urinary flow rate or sodium excretion during the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)


Spatially resolved ultrafast magnetic dynamics initiated at a complex oxide heterointerface.
Static strain in complex oxide heterostructures has been extensively used to engineer electronic and magnetic properties at equilibrium. In the same spirit, deformations of the crystal lattice with light may be used to achieve functional control across heterointerfaces dynamically. Here, by exciting large-amplitude infrared-active vibrations in a LaAlO3 substrate we induce magnetic order melting in a NdNiO3 film across a heterointerface. Femtosecond resonant soft X-ray diffraction is used to determine the spatiotemporal evolution of the magnetic disordering. We observe a magnetic melt front that propagates from the substrate interface into the film, at a speed that suggests electronically driven motion. Light control and ultrafast phase front propagation at heterointerfaces may lead to new opportunities in optomagnetism, for example by driving domain wall motion to transport information across suitably designed devices.


Parental attitudes towards mandatory vaccination; a systematic review.
Uptake of childhood vaccines is decreasing. While mandatory vaccination schemes can increase vaccine uptake rates, they can also cause backlash among some parents. We conducted a systematic review investigating parental beliefs about vaccine mandates and factors associated with support for mandatory vaccination schemes. We searched Embase, Ovid MEDLINE, Global Health, APA PsycINFO and Web of Science from inception to 17th September 2020. Seventeen studies (five qualitative, twelve quantitative) were eligible for inclusion. We synthesised results of qualitative and quantitative studies separately. As quantitative studies were heterogeneous in the mandatory vaccination schemes and associated factors investigated, there was no scope to conduct a meta-analysis. Instead, data were narratively synthesised, considering risk of bias ratings. Qualitative data were synthesised using meta-ethnography, synthesising themes reported across studies included. Quantitative studies reported that support for mandatory vaccination schemes was reasonably high (73% to 88%). However, due to heterogeneity, there was little evidence for any factors being consistently associated with support for mandatory vaccination. Qualitative studies gave an insight into how parents perceive mandatory vaccination. Studies found that parents perceived mandatory vaccination schemes as an infringement of their rights, and particularly disliked schemes offering financial incentives for vaccination. Nevertheless, some parents felt that schemes limiting access to schooling of unvaccinated children gave them "peace of mind." Results should be taken with caution due to the purposive use of non-representative samples. Before deciding to mandate vaccination, it is important to understand the impact it could have on parental beliefs and attitudes about vaccination.


Prominent Neutralizing Antibody Response Targeting the Ebolavirus Glycoprotein Subunit Interface Elicited by Immunization.
The severe death toll caused by the recent outbreak of Ebola virus disease reinforces the importance of developing ebolavirus prevention and treatment strategies. Here, we have explored the immunogenicity of a novel immunization regimen priming with vesicular stomatitis virus particles bearing Sudan Ebola virus (SUDV) glycoprotein (GP) that consists of GP1 & GP2 subunits and boosting with soluble SUDV GP in macaques, which developed robust neutralizing antibody (nAb) responses following immunizations. Moreover, EB46, a protective nAb isolated from one of the immune macaques, is found to target the GP1/GP2 interface, with GP-binding mode and neutralization mechanism similar to a number of ebolavirus nAbs from human and mouse, indicating that the ebolavirus GP1/GP2 interface is a common immunological target in different species. Importantly, selected immune macaque polyclonal sera showed nAb specificity similar to EB46 at substantial titers, suggesting that the GP1/GP2 interface region is a viable target for ebolavirus vaccine.Importance: The elicitation of sustained neutralizing antibody (nAb) responses against diverse ebolavirus strains remains as a high priority for the vaccine field. The most clinically advanced rVSV-ZEBOV vaccine could elicit moderate nAb responses against only one ebolavirus strain, EBOV, among the five ebolavirus strains, which last less than 6 months. Boost immunization strategies are desirable to effectively recall the rVSV vector-primed nAb responses to prevent infections in prospective epidemics, while an in-depth understanding of the specificity of immunization-elicited nAb responses is essential for improving vaccine performance. Here, using non-human primate animal model, we demonstrated that booster immunization with a stabilized trimeric soluble form of recombinant glycoprotein derived from the ebolavirus Sudan strain following the priming rVSV vector immunization led to robust nAb responses that substantially map to the subunit interface of ebolavirus glycoprotein, a common B cell repertoire target of multiple species including primates and rodents.


NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner.
The N-terminal 198 residues of NS3 (NS3-N) of Hepatitis C virus (HCV) subtype 1b obtained from 29 patients, as well as full-length NS3 (NS3-Full), were analysed for their subcellular localization, interaction with the tumour suppressor p53 and serine protease activity in the presence and absence of the viral cofactor NS4A. Based on the subcellular-localization patterns in the absence of NS4A, NS3-N sequences were classified into three groups, with each group exhibiting either dot-like, diffuse or a mixed type of localization. Chimeric NS3-Full sequences, each consisting of an individual NS3-N and a shared C-terminal sequence, showed the same localization patterns as those of the respective NS3-N. Site-directed mutagenesis experiments revealed that a single or a few amino acid substitutions at a particular position(s) of NS3-N altered the localization pattern. Interestingly, NS3 of the dot-like type, either NS3-N or NS3-Full, interacted with p53 more strongly than that of the diffuse type, in both the presence and the absence of NS4A. Moreover, NS3-N of the dot-like type suppressed trans-activating activity of p53 more strongly than that of the diffuse type. Serine protease activity did not differ significantly between the two types of NS3. In HCV RNA replicon-harbouring cells, physical interaction between NS3 and p53 was observed consistently and p53-mediated transcriptional activation was suppressed significantly compared with HCV RNA-negative control cells. Our results collectively suggest the possibility that NS3 plays an important role in the hepatocarcinogenesis of HCV by interacting differentially with p53 in an NS3 sequence-dependent manner.


Left ventricular performance before and after aortocoronary artery bypass surgery.
Left ventricular performance was studied before and late (mean 12-17 months) after aortocoronary artery bypass surgery by quantitative, computer-based videoangiography. We measured total function (left ventricular ejection fraction, volumes and end-diastolic pressure) at rest (in 60 patients) and before and after exercise (abnormal exercise hemodynamics preoperatively in 32 patients) and regional function (peak rate of systolic wall thickening) at rest (in 60 patients) and before and after administration of nitroglycerin (in 19 patients). Total left ventricular function at rest is usually unchanged postoperatively. Exercise hemodynamics are more sensitive indexes of performance and, if abnormal, usually improve postoperatively if revascularization has been complete and extensive myocardial infarction has not occurred. Regional myocardial function usually improves postoperatively if the bypass graft to the region is patent and has a blood flow of more than 60 ml/min (measured late postoperatively by videodensitometry) and if no previous infarction was present in the region. Myocardial infarction and graft blood flow of 40 ml/min or less are the two main factors that prevent improvement in abnormal regions defined by the regional wall thickening method when bypass grafts are patent. Regions supplied by occluded grafts show decreases in regional function. The preoperative wall-thickening response to administration of nitroglycerin can be used to distinguish ischemia and significant myocardial infarction and to predict the successful response to aortocoronary bypass graft surgery.


On the parameterization of rigid base and basepair models of DNA from molecular dynamics simulations.
A method is described to extract a complete set of sequence-dependent material parameters for rigid base and basepair models of DNA in solution from atomistic molecular dynamics simulations. The method is properly consistent with equilibrium statistical mechanics, leads to effective shape, stiffness and mass parameters, and employs special procedures for treating spontaneous torsion angle flips and H-bond breaks, both of which can have a significant effect on the results. The method is accompanied by various analytical consistency checks that can be used to assess the equilibration of statistical averages, and different modeling assumptions pertaining to the rigidity of the bases and basepairs and the locality of the quadratic internal energy. The practicability of the approach is verified by estimating complete parameter sets for the 16-basepair palindromic oligomer G(TA)(7)C simulated in explicit water and counterions. Our results indicate that the method is capable of resolving sequence-dependent variations in each of the material parameters. Moreover, they show that the assumptions of rigidity and locality hold rather well for the base model, but not for the basepair model. For the latter, it is shown that the non-local nature of the internal energy can be understood in terms of a certain compatibility relation involving Schur complements.


Acute toxicity associated with the recreational use of the novel dissociative psychoactive substance methoxphenidine.
Methoxphenidine is a novel dissociative designer drug of the diarylethylamine class which shares structural features with phencyclidine (PCP), and is not at present subject to restrictive regulations. There is very limited information about the acute toxicity profile of methoxphenidine and the only sources are anonymous internet sites and a 1989 patent of the Searle Company. We report a case of analytically confirmed oral methoxphenidine toxicity. A 53-year-old man was found on the street in a somnolent and confusional state. Observed signs and symptoms such as tachycardia (112 bpm), hypertension (220/125 mmHg), echolalia, confusion, agitation, opisthotonus, nystagmus and amnesia were consistent with phencyclidine-induced adverse effects. Temperature (99.1°F (37.3°C)) and peripheral oxygen saturation while breathing room air (99%) were normal. Laboratory analysis revealed an increase of creatine kinase (max 865 U/L), alanine aminotransferase (72 U/L) and gamma-glutamyl transpeptidase (123 U/L). Methoxphenidine was identified by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction in plasma and urine samples collected on admission. The clinical course was favourable and signs and symptoms resolved with symptomatic treatment. Based on this case report and users' web reports, and compatible with the chemical structure, methoxphenidine produces effects similar to those of the arylcyclohexylamines, as PCP.


Association of Accelerometer-Measured Light-Intensity Physical Activity With Brain Volume: The Framingham Heart Study.
Dementia risk may be attenuated by physical activity (PA); however, the specific activity levels optimal for dementia prevention are unclear. Moreover, most older adults are unable to meet the nationally recommended PA guidelines, set at 150 minutes of moderate to vigorous PA per week. To assess the association of total steps walked per day and total dose (intensity × duration) of PA with brain volumes on magnetic resonance imaging (MRI) among Framingham Heart Study participants. This cross-sectional, community-based cohort study of the association of accelerometry-determined PA with brain MRI measures in Framingham, Massachusetts, included the Framingham Heart Study third-generation (examination 2, 2008-2011) and offspring (examination 9, 2011-2014) cohorts. Of 4021 participants who agreed to wear an accelerometer and had valid data (≥10 hours/day for ≥3 days), 1667 participants who did not undergo brain MRI (n = 1604) or had prevalent dementia or stroke (n = 63) were excluded. Data analysis began in 2016 and was completed in February 2019. Physical activity achieved using accelerometry-derived total activity (steps per day) and 2 intensity levels (light intensity and moderate to vigorous intensity). Differences in total brain volume and other MRI markers of brain aging. The study sample of 2354 participants had a mean (SD) age of 53 (13) years, 1276 (54.2%) were women, and 1099 (46.7%) met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging (β estimate, 0.22; SD, 0.07; P = .003). Among individuals not meeting the PA guidelines, each hour of light-intensity PA (β estimate, 0.28; SD, 0.11; P = .01) and achieving 7500 steps or more per day (β estimate, 0.44; SD, 0.18; P = .02) were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume. Every additional hour of light-intensity PA was associated with higher brain volumes, even among individuals not meeting current PA guidelines. These data are consistent with the notion that the potential benefits of PA on brain aging may accrue at a lower, more achievable level of intensity or duration.


Reassessing Serosurvey-Based Estimates of the Symptomatic Proportion of Zika Virus Infections.
Since the 2007 Zika epidemic in the Micronesian state of Yap, it has been apparent that not all people infected with Zika virus (ZIKV) experience symptoms. However, the proportion of infections that result in symptoms remains unclear. Existing estimates have varied in their interpretation of symptoms due to other causes and the case definition used, and they have assumed perfect test sensitivity and specificity. Using a Bayesian model and data from ZIKV serosurveys in Yap (2007), French Polynesia (2013-2014), and Puerto Rico (2016), we found that assuming perfect sensitivity and specificity generally led to lower estimates of the symptomatic proportion. Incorporating reasonable assumptions for assay sensitivity and specificity, we estimated that 27% (95% credible interval (CrI): 15, 37) (Yap), 44% (95% CrI: 26, 66) (French Polynesia), and 50% (95% CrI: 34, 92) (Puerto Rico) of infections were symptomatic, with variation due to differences in study populations, study designs, and case definitions. The proportion of ZIKV infections causing symptoms is critical for surveillance system design and impact assessment. Here, we accounted for key uncertainties in existing seroprevalence data and found that estimates for the symptomatic proportion ranged from 27% to 50%, suggesting that while the majority of infections are asymptomatic or mildly symptomatic, symptomatic infections might be more common than previously estimated.


Approach of empirical antibiotic treatment: analyzing bacterial resistance of community-acquired bacteremia.
Nosocomial bacterial resistance has been advanced and well studied in Taiwan, but there were few reports describing the antibiotic susceptibility of community-acquired pathogens. Through collecting data from those who received blood cultures in emergency department, we presented an epidemiological study to analyze appropriate empirical therapy for the community-acquired bacteremia in Southern Taiwan. From July 1998 to June 1999, patients presented at emergency department of Kaohsiung Veterans General Hospital with fever, chills or symptoms of sepsis were routinely performed two sets of blood cultures. Those of positive blood cultures without prior admission history to the hospital within 2 weeks were further analyzed for the etiologic pathogens, antibiotic susceptibility, and risk factors of community-acquired bacteremia. A total of 303 episodes were enrolled for analysis, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus accounted for 76.3% of the isolates. Most of the community-acquired bacteremia was secondary bacteremia. Eighty-four percents of E. coli, 89% of K. pneumoniae, and 76% of S. aureus were susceptible to cefazolin. Susceptible rates of the three major pathogens to gentamicin were 72%, 92%, and 68% respectively. While treating community-acquired bacteremia in Southern Taiwan, the first generation antibiotic, cefazolin plus gentamicin, was effective in vitro for the majority of cases. However, since the community-acquired bacteremia is mostly secondary in origin, it is necessary to explore the underlying primary lesions to attain therapeutic success. Further on-going epidemiological surveillance on bacterial resistance of community-acquired bacteremia is necessary to provide evidence-based appropriateness of empirical therapy.


Long-term genetic stability and a high-altitude East Asian origin for the peoples of the high valleys of the Himalayan arc.
The high-altitude transverse valleys [>3,000 m above sea level (masl)] of the Himalayan arc from Arunachal Pradesh to Ladahk were among the last habitable places permanently colonized by prehistoric humans due to the challenges of resource scarcity, cold stress, and hypoxia. The modern populations of these valleys, who share cultural and linguistic affinities with peoples found today on the Tibetan plateau, are commonly assumed to be the descendants of the earliest inhabitants of the Himalayan arc. However, this assumption has been challenged by archaeological and osteological evidence suggesting that these valleys may have been originally populated from areas other than the Tibetan plateau, including those at low elevation. To investigate the peopling and early population history of this dynamic high-altitude contact zone, we sequenced the genomes (0.04×-7.25×, mean 2.16×) and mitochondrial genomes (20.8×-1,311.0×, mean 482.1×) of eight individuals dating to three periods with distinct material culture in the Annapurna Conservation Area (ACA) of Nepal, spanning 3,150-1,250 y before present (yBP). We demonstrate that the region is characterized by long-term stability of the population genetic make-up despite marked changes in material culture. The ancient genomes, uniparental haplotypes, and high-altitude adaptive alleles suggest a high-altitude East Asian origin for prehistoric Himalayan populations.


Allogeneic beta-islet cells correct diabetes and resist immune rejection.
Allogeneic MHC-incompatible organ or cell grafts are usually promptly rejected by immunocompetent hosts. Here we tested allogeneic beta-islet cell graft acceptance by immune or naive C57BL/6 mice rendered diabetic with streptozotocin (STZ). Fully MHC-mismatched insulin-producing growth-regulated beta-islet cells were transplanted under the kidney capsule or s.c. Although previously or simultaneously primed mice rejected grafts, STZ-treated diabetic mice accepted islet cell grafts, and hyperglycemia was corrected within 2-4 weeks in absence of conventional immunosuppression. Allogeneic grafts that controlled hyperglycemia expressed MHC antigens, were not rejected for >100 days, and resisted a challenge by allogeneic skin grafts or multiple injections of allogeneic cells. Importantly, the skin grafts were rejected in a primary fashion by the grafted and corrected host, indicating neither tolerization nor priming. Such strictly extralymphatic cell grafts that are immunologically largely ignored should be applicable clinically.


Using Black Hole Algorithm to Improve EEG-Based Emotion Recognition.
Emotions are a critical aspect of human behavior. One widely used technique for research in emotion measurement is based on the use of EEG signals. In general terms, the first step of signal processing is the elimination of noise, which can be done in manual or automatic terms. The next step is determining the feature vector using, for example, entropy calculation and its variations to generate a classification model. It is possible to use this approach to classify theoretical models such as the Circumplex model. This model proposes that emotions are distributed in a two-dimensional circular space. However, methods to determine the feature vector are highly susceptible to noise that may exist in the signal. In this article, a new method to adjust the classifier is proposed using metaheuristics based on the black hole algorithm. The method is aimed at obtaining results similar to those obtained with manual noise elimination methods. In order to evaluate the proposed method, the MAHNOB HCI Tagging Database was used. Results show that using the black hole algorithm to optimize the feature vector of the Support Vector Machine we obtained an accuracy of 92.56% over 30 executions.


Competing islands limit the rate of adaptation in structured populations.
Beneficial mutations can co-occur when population structure slows down adaptation. Here, we consider the process of adaptation in asexual populations distributed over several locations ("islands"). New beneficial mutations arise at constant rate ub, and each mutation has the same selective advantage s>0. We assume that populations evolve within islands according to the successional mutations regime of Desai and Fisher (2007), that is, the time to local fixation of a mutation is short compared to the expected waiting time until the next mutation occurs. To study the rate of adaptation, we introduce an approximate model, the successional mutations (SM) model, which can be simulated efficiently and yields accurate results for a wide range of parameters. In the SM model, mutations fix instantly within islands, and migrants can take over the destination island if they are fitter than the residents. For the special case of a population distributed equally across two islands with population size N, we approximate the model further for small and large migration rates in comparison to the mutation rate. These approximations lead to explicit formulas for the rate of adaptation which fit the original model for a large range of parameter values. For the d island case we provide some heuristics on how to extend the explicit formulas and check these with computer simulations. We conclude that the SM model is a good approximation of the adaptation process in a structured population, at least if mutation or migration is limited.


Protein folding on rugged energy landscapes: conformational diffusion on fractal networks.
We perform simulations of model proteins to study folding on rugged energy landscapes. We construct "first-passage" networks as the system transitions from unfolded to native states. The nodes and bonds in these networks correspond to basins and transitions between them in the energy landscape. We find power-law relations between the folding time and the number of nodes and bonds. We show that these scalings are determined by the fractal properties of first-passage networks. Thus, we have identified a possible mechanism--the small fractal dimension of first passage networks--which can give rise to reliable folding in proteins with rugged energy landscapes.


Blending education, research, and service missions: the Arkansas model.
Creating school and community partnerships with academic health centers (AHC) offers one strategy for initiating and sustaining broad-based change in health systems. This article describes the development, initial evaluation, and current iteration of the Arkansas Partners in Behavioral Health Sciences Model, a collaboration between personnel from an AHC and K-12 schools to address behavioral health issues in children. The model's focus on education, research, and service provides an opportunity for AHC faculty and school personnel to collaborate to promote mental health in school-aged youth. Quantitative and qualitative methods have been used to inform development and confirm effectiveness of the program. From 2001 through 2005, more than 2,700 school personnel from 72 of the 75 counties in Arkansas participated in more than 30,000 hours of continuing education. The programs have also targeted students using interactive televideo presentations, supplemental classroom curricula, and an exhibit in a state science museum, resulting in an outreach to more than 2,500 youths. Results of longitudinal and randomized studies also show changes in knowledge, attitudes, and behaviors. In an era of extraordinary need and finite resources for school systems, AHCs are poised to provide the critical link to improve the scientific knowledge and understanding of behavioral health conditions. The current program targets behavioral health, but AHCs also can incorporate other health conditions, scientific topics, and medical interventions to provide a important service for the public and to accomplish an important mission toward health leadership in the community.


A model of chronic pain in the rat: response of multiple opioid systems to adjuvant-induced arthritis.
Chronic arthritic pain was induced by intradermally inoculating rats at the tail-base with Mycobacterium butyricum, which results in swelling, inflammation, and hyperalgesia of the joints. These symptoms peak at 3 weeks after inoculation and disappear by 10 weeks. The following changes were seen at 3 weeks. Immunoreactive dynorphin (ir-Dyn) and ir-alpha-neo-endorphin (alpha-NE) manifested comparable patterns of change. Their levels were increased in the anterior, but not neurointermediate, pituitary. The thalamus showed a rise in ir-Dyn and ir-alpha-NE, but no alterations were seen in other brain regions. In each case, cervical, thoracic, and lumbosacral sections of the spinal cord showed a rise in ir-Dyn and ir-alpha-NE: This was most pronounced in the lumbosacral region, where the magnitude of these shifts correlated with the intensity of arthritic symptoms. In addition, a moderate elevation in ir-methionine-enkephalin (ME) was seen in lumbosacral spinal cord. In brain, ir was not changed. The level of ir-beta-endorphin (beta-EP) was elevated both in the plasma and the anterior, but not the neurointermediate, pituitary. In addition, the content of messenger RNA encoding the beta-EP precursor, proopiomelanocortin (POMC), was enhanced in the anterior lobe. Thus, there was a selective activation of synthesis of beta-EP in, and its secretion from, the anterior lobe. In no brain tissue did levels of ir-beta-EP change. At 10 weeks postinoculation, the above changes were no longer apparent, indicating their reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)


A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster.
Two major problems have to be solved in studies of genes near breakpoints of chromosome abnormalities and in large-scale genomic mapping projects: (i) the identification of genes within the large amount on nontranscribed DNA and (ii) the determination of the tissues in which the identified genes are transcribed. In situ hybridization to mRNA is ideally suited to assess gene expression in all tissues but probe preparation presents major difficulties for adapting the technique for rapid screening. Here, we present a procedure to easily generate strand-specific DNA probes for in situ hybridization. In this method, a DNA fragment to be tested in uniformly labeled, denatured, and prehybridized to an excess of competitor single-stranded DNA corresponding to either positive or negative strands of the test fragment. No sequence information is needed. The prehybridized mixture is used directly for hybridization to whole embryo or tissue sections. We demonstrate the utility of this approach for any nonrepetitive fragment by using cDNA probes, intronless genomic probes, or genomic probes comprising transcribed and nontranscribed DNA. As an example, we show that mRNA for the recombination-activating genes (RAG) RAG-1 and RAG-2 is found in thymus of dE16 mouse embryos. Within the thymus, high levels of expression of RAG-1 and RAG-2 are detectable in the cortex but not in the medullary region. This supports the view that RAG-1 and RAG-2 expression is associated with cells known to actively rearrange antigen receptor loci.


Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development.
Sirt3 is a mitochondrial NAD(+)-dependent deacetylase that governs mitochondrial metabolism and reactive oxygen species homeostasis. Sirt3 deficiency has been reported to accelerate the development of the metabolic syndrome. However, the role of Sirt3 in atherosclerosis remains enigmatic. We aimed to investigate whether Sirt3 deficiency affects atherosclerosis, plaque vulnerability, and metabolic homeostasis. Low-density lipoprotein receptor knockout (LDLR(-/-)) and LDLR/Sirt3 double-knockout (Sirt3(-/-)LDLR(-/-)) mice were fed a high-cholesterol diet (1.25 % w/w) for 12 weeks. Atherosclerosis was assessed en face in thoraco-abdominal aortae and in cross sections of aortic roots. Sirt3 deletion led to hepatic mitochondrial protein hyperacetylation. Unexpectedly, though plasma malondialdehyde levels were elevated in Sirt3-deficient mice, Sirt3 deletion affected neither plaque burden nor features of plaque vulnerability (i.e., fibrous cap thickness and necrotic core diameter). Likewise, plaque macrophage and T cell infiltration as well as endothelial activation remained unaltered. Electron microscopy of aortic walls revealed no difference in mitochondrial microarchitecture between both groups. Interestingly, loss of Sirt3 was associated with accelerated weight gain and an impaired capacity to cope with rapid changes in nutrient supply as assessed by indirect calorimetry. Serum lipid levels and glucose tolerance were unaffected by Sirt3 deletion in LDLR(-/-) mice. Sirt3 deficiency does not affect atherosclerosis in LDLR(-/-) mice. However, Sirt3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation. Thus, Sirt3 may contribute to postponing cardiovascular risk factor development.


Anthropogenic noise changes arthropod abundances.
Anthropogenic noise is a widespread and growing form of sensory pollution associated with the expansion of human infrastructure. One specific source of constant and intense noise is that produced by compressors used for the extraction and transportation of natural gas. Terrestrial arthropods play a central role in many ecosystems, and given that numerous species rely upon airborne sounds and substrate-borne vibrations in their life histories, we predicted that increased background sound levels or the presence of compressor noise would influence their distributions. In the second largest natural gas field in the United States (San Juan Basin, New Mexico, USA), we assessed differences in the abundances of terrestrial arthropod families and community structure as a function of compressor noise and background sound level. Using pitfall traps, we simultaneously sampled five sites adjacent to well pads that possessed operating compressors, and five alternate, quieter well pad sites that lacked compressors, but were otherwise similar. We found a negative association between sites with compressor noise or higher levels of background sound and the abundance of five arthropod families and one genus, a positive relationship between loud sites and the abundance of one family, and no relationship between noise level or compressor presence and abundance for six families and two genera. Despite these changes, we found no evidence of community turnover as a function of background sound level or site type (compressor and noncompressor). Our results indicate that anthropogenic noise differentially affects the abundances of some arthropod families. These preliminary findings point to a need to determine the direct and indirect mechanisms driving these observed responses. Given the diverse and important ecological functions provided by arthropods, changes in abundances could have ecological implications. Therefore, we recommend the consideration of arthropods in the environmental assessment of noise-producing infrastructure.


Chemiluminescent examination of abiotic oxidative stress of watercress.
Watercress (Nasturtium officinale) is an aquatic plant that readily bioaccumulates heavy metals that may be found in contaminated aquatic systems. Toxic effects of contaminants on the physiological processes cause changes in oxidase enzymatic activity in watercress, which can be measured using a luminometer. The luminometer uses the reaction produced when peroxidases break down hydrogen peroxide into water and an oxygen radical. The resulting oxyradical binds to and oxidizes phenolic groups producing a measureable luminescent reaction. N. officinale plants were exposed to three different concentrations of heavy metals including lead, nickel, copper, and manganese for 24, 48, and 72 hour exposures. Aquatic exposure to the four heavy metals caused a significant increase in oxidative enzyme production. Fluorometric and morphometric measurements were also conducted in order to compare plant stress to the oxidative enzyme analyses. Fluorometric measurements performed on plants stressed by exposure to heavy metals revealed no significant decreases in photosystem II efficiency. Morphometric measurements of root length showed decreased root growth resulting from exposures to nickel, copper, and manganese. Environ Toxicol Chem © 2013 SETAC.


Matrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation.
Factors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.


Real-Time Functional Magnetic Resonance Imaging Amygdala Neurofeedback Changes Positive Information Processing in Major Depressive Disorder.
In participants with major depressive disorder who are trained to upregulate their amygdalar hemodynamic responses during positive autobiographical memory recall with real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training, depressive symptoms diminish. This study tested whether amygdalar rtfMRI-nf also changes emotional processing of positive and negative stimuli in a variety of behavioral and imaging tasks. Patients with major depressive disorder completed two rtfMRI-nf sessions (18 received amygdalar rtfMRI-nf, 16 received control parietal rtfMRI-nf). One week before and following rtfMRI-nf training, participants performed tasks measuring responses to emotionally valenced stimuli including a backward-masking task, which measures the amygdalar hemodynamic response to emotional faces presented for traditionally subliminal duration and followed by a mask, and the Emotional Test Battery in which reaction times and performance accuracy are measured during tasks involving emotional faces and words. During the backward-masking task, amygdalar responses increased while viewing masked happy faces but decreased to masked sad faces in the experimental versus control group following rtfMRI-nf. During the Emotional Test Battery, reaction times decreased to identification of positive faces and during self-identification with positive words and vigilance scores increased to positive faces and decreased to negative faces during the faces dot-probe task in the experimental versus control group following rtfMRI-nf. rtfMRI-nf training to increase the amygdalar hemodynamic response to positive memories was associated with changes in amygdalar responses to happy and sad faces and improved processing of positive stimuli during performance of the Emotional Test Battery. These results may suggest that amygdalar rtfMRI-nf training alters responses to emotional stimuli in a manner similar to antidepressant pharmacotherapy.


Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate.
Calcium stone (renal) formation in patients with hyperuricosuria has been ascribed to the urate-induced crystallization of calcium oxalate. Citrate (0.5mM), added to synthetic medium metastably supersaturated with respect to calcium oxalate, was shown to inhibit heterogeneous nucleation of calcium oxalate by monosodium urate (2 mg/mL). Long-term trial with potassium citrate (60 to 80 mEq/day) was therefore undertaken to determine whether induced hypercitraturia would prevent calcium oxalate stone formation in 19 patients with hyperuricosuria. The treatment produced a sustained rise in urinary pH by 0.55 to 0.85 to the high normal range (6.5 to 7.0). Urinary citrate levels rose by 249 to 402 mg/day to approximate the normal mean value of 643 mg/day. Commensurate with these changes, urinary saturation of calcium oxalate (relative saturation ratio) and the amount of undissociated uric acid declined significantly. However, the urinary uric acid and saturation of monosodium urate remained elevated. Stone formation declined from 1.55 +/- 2.70 per patient-year to 0.38 +/- 1.22 per patient-year during mean treatment period of 2.35 +/- 0.88 years. Stones ceased to form in 16 of 19 patients during treatment. The results provide physicochemical and clinical evidence for the utility of potassium citrate in the management of hyperuricosuric calcium oxalate nephrolithiasis.


An Improved Fuzzy Brain Emotional Learning Model Network Controller for Humanoid Robots.
The brain emotional learning (BEL) system was inspired by the biological amygdala-orbitofrontal model to mimic the high speed of the emotional learning mechanism in the mammalian brain, which has been successfully applied in many real-world applications. Despite of its success, such system often suffers from slow convergence for online humanoid robotic control. This paper presents an improved fuzzy BEL model (iFBEL) neural network by integrating a fuzzy neural network (FNN) to a conventional BEL, in an effort to better support humanoid robots. In particular, the system inputs are passed into a sensory and emotional channels that jointly produce the final outputs of the network. The non-linear approximation ability of the iFBEL is achieved by taking the BEL network as the emotional channel. The proposed iFBEL works with a robust controller in generating the hand and gait motion of a humanoid robot. The updating rules of the iFBEL-based controller are composed of two parts, including a sensory channel followed by the updating rules of the conventional BEL model, and the updating rules of the FNN and the robust controller which are derived from the "Lyapunov" function. The experiments on a three-joint robot manipulator and a six-joint biped robot demonstrated the superiority of the proposed system in reference to a conventional proportional-integral-derivative controller and a fuzzy cerebellar model articulation controller, based on the more accurate and faster control performance of the proposed iFBEL.


Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.


A feasibility study of expert patient and community mental health team led bipolar psychoeducation groups: implementing an evidence based practice.
Group psychoeducation is a cost effective intervention which reduces relapse and improves functioning in bipolar disorder but is rarely implemented. The aim of this study was to identify the acceptability and feasibility of a group psychoeducation programme delivered by community mental health teams (CMHTs) and peer specialist (PS) facilitators. Organisational learning was used to identify and address systematically barriers and enablers, at organisational, health professional and patient levels, to its implementation into a routine service. A systematic examination of barriers and enablers to a three day training process informed the delivery of a first treatment group and a similar process informed the delivery of the second treatment group. Triangulation of research methods improved its internal validity: direct observation of training, self-rated surveys of participant experiences, group discussion, and thematically analysed individual participant and facilitator interviews were employed. Barriers and enablers were identified at organisational, educational, treatment content, facilitator and patient levels. All barriers under the control of the research team were addressed with subsequent improvements in patient knowledge about the condition and about local service. In addition, self-management, agency and altruism were enhanced. Barriers that could not be addressed required senior clinical and education leadership outside the research team's control. PS and professional facilitators were successfully trained and worked together to deliver groups which were generally reported as being beneficial. Psychoeducation groups involving CMHT and PS facilitators is acceptable and feasible but their sustainment requires senior leadership within and outside the organisation that control finance and education services.


Atlantic hurricane surge response to geoengineering.
Devastating floods due to Atlantic hurricanes are relatively rare events. However, the frequency of the most intense storms is likely to increase with rises in sea surface temperatures. Geoengineering by stratospheric sulfate aerosol injection cools the tropics relative to the polar regions, including the hurricane Main Development Region in the Atlantic, suggesting that geoengineering may mitigate hurricanes. We examine this hypothesis using eight earth system model simulations of climate under the Geoengineering Model Intercomparison Project (GeoMIP) G3 and G4 schemes that use stratospheric aerosols to reduce the radiative forcing under the Representative Concentration Pathway (RCP) 4.5 scenario. Global mean temperature increases are greatly ameliorated by geoengineering, and tropical temperature increases are at most half of those temperature increases in the RCP4.5. However, sulfate injection would have to double (to nearly 10 teragrams of SO2 per year) between 2020 and 2070 to balance the RCP4.5, approximately the equivalent of a 1991 Pinatubo eruption every 2 y, with consequent implications for stratospheric ozone. We project changes in storm frequencies using a temperature-dependent generalized extreme value statistical model calibrated by historical storm surges and observed temperatures since 1923. The number of storm surge events as big as the one caused by the 2005 Katrina hurricane are reduced by about 50% compared with no geoengineering, but this reduction is only marginally statistically significant. Nevertheless, when sea level rise differences in 2070 between the RCP4.5 and geoengineering are factored into coastal flood risk, we find that expected flood levels are reduced by about 40 cm for 5-y events and about halved for 50-y surges.


Expansion of Noncanonical V-Arm-Containing tRNAs in Eukaryotes.
Transfer RNA (tRNA) is essential for the translation of genetic information into proteins, and understanding its molecular evolution is important if we are to understand the genetic code. In general, long variable-arm (V-arm) structures form in tRNA(Leu), tRNA(Ser), and bacterial and organellar tRNA(Tyr). However, as we have previously reported, noncanonical V-arms occur in nematode tRNA(Gly) and tRNA(Ile), and potentially affect translational fidelity. Here, we comprehensively analyzed 69 eukaryotic genome sequences and examined the evolutionary divergence of the V-arm-containing tRNAs. In total, 253 V-arm-containing tRNAs, with neither leucine nor serine anticodons, were identified in organisms ranging from nematodes to fungi, plants, and vertebrates. We defined them as "noncanonical V-arm-containing tRNAs" (nov-tRNAs). Moreover, 2,415 nov-tRNA-like sequences lacking some of the conserved features of tRNAs were also identified, largely in vertebrate genomes. These nov-tRNA/nov-tRNA-like sequences can be categorized into three types, based on differences in their possible evolutionary origins. The type A nov-tRNAs in nematodes probably evolved not only from tRNA(Leu) but also from tRNA(Ser) and other isotypes on several independent occasions. The type B nov-tRNAs are dispersed abundantly throughout vertebrate genomes, and seem to have originated from retrotransposable elements. The type C nov-tRNAs may have been acquired from plant chloroplasts or from bacteria through horizontal transfer. Our findings provide unexpected insight into the evolution of the tRNA molecule, which was diverse and occurred independently in nematodes, vertebrates, and plants.


The experience of families with children with trisomy 13 and 18 in social networks.
Children with trisomy 13 and trisomy 18 (T13-18) have low survival rates and survivors have significant disabilities. For these reasons, interventions are generally not recommended by providers. After a diagnosis, parents may turn to support groups for additional information. We surveyed parents of children with T13-18 who belong to support groups to describe their experiences and perspectives. A total of 503 invitations to participate were sent and 332 questionnaires were completed (87% response rate based on site visits, 67% on invitations sent) by parents about 272 children. Parents reported being told that their child was incompatible with life (87%), would live a life of suffering (57%), would be a vegetable (50%), or would ruin their family (23%). They were also told by some providers that their child might have a short meaningful life (60%), however. Thirty percent of parents requested "full" intervention as a plan of treatment. Seventy-nine of these children with full T13-18 are still living, with a median age of 4 years. Half reported that taking care of a disabled child is/was harder than they expected. Despite their severe disabilities, 97% of parents described their child as a happy child. Parents reported these children enriched their family and their couple irrespective of the length of their lives. Parents who engage with parental support groups may discover an alternative positive description about children with T13-18. Disagreements about interventions may be the result of different interpretations between families and providers about the experiences of disabled children and their quality of life.


Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells.
Rspo2 was identified as a novel common integration site (CIS) for the mouse mammary tumor virus (MMTV) in viral induced mouse mammary tumors. Here we show that Rspo2 modulates Wnt signaling in mouse mammary epithelial cells. Co-expression of both genes resulted in an intermediate growth phenotype on plastic and had minor effects on the growth-promoting properties of Wnt1 in soft agar. However, individual Rspo2 and Wnt1 HC11 transfectants as well as the double transfectant were tumorigenic in athymic nude mice, with tumors from each line having distinctive histological characteristics. Rspo2 and Rspo2/Wnt1 tumors contained many spindle cells, consistent with an epithelial-mesenchymal transformation (EMT) phenotype. When Rspo2 and Rspo2/Wnt1 tumor cells were transferred into naïve mice, they exhibited greater metastatic activity than cells derived from Wnt1 tumors. For comparison, C57MG/Wnt1/Rspo2 co-transfectants exhibited invasive properties in three-dimensional (3D) Matrigel cultures that were not seen with cells transfected only with Wnt1 or Rspo2. Use of Dickkopf-1, a specific antagonist of the Wnt/β-catenin pathway, or short hairpin RNA targeting β-catenin expression demonstrated that the invasive activity was not mediated by β-catenin. Our results indicate that Rspo2 and Wnt1 have mutually distinct effects on mammary epithelial cell growth and these effects are context-dependent. While Rspo2 and Wnt1 act synergistically in the β-catenin pathway, other mechanisms are responsible for the invasive properties of stable double transfectants observed in 3D Matrigel cultures.


Inhibiting glycogen synthase kinase-3 decreases 12-O-tetradecanoylphorbol-13-acetate-induced interferon-γ-mediated skin inflammation.
Glycogen synthase kinase-3 (GSK-3) facilitates interferon (IFN)-γ signaling. Because IFN-γ is involved in inflammatory skin diseases, such as psoriasis, the aim of this study was to investigate the pathogenic role of GSK-3 in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IFN-γ-mediated ear skin inflammation. TPA (3 μg per ear) induced acute skin inflammation in the ears of C57BL/6 mice, including edema, infiltration of granulocytes but not T cells, and IFN-γ receptor 1-mediated deregulation of intercellular adhesion molecule 1 (CD54). TPA/IFN-γ induced GSK-3 activation, which in turn activated signal transducer and activator of transcription 1. Inhibiting GSK-3 pharmacologically, by administering 6-bromoindirubin-3'-oxime (1.5 μg per ear), and genetically, with lentiviral-based short-hairpin RNA, reduced TPA-induced acute skin inflammation but not T-cell infiltration. It is noteworthy that inhibiting GSK-3 decreased TPA-induced IFN-γ production and the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, in CD3-positive T cells. In chronic TPA-induced skin inflammation, inhibiting GSK-3 attenuated epidermis hyperproliferation and dermis angiogenesis. These results demonstrate the dual role of GSK-3 in TPA-induced skin inflammation that is not only to facilitate IFN-γ signaling but also to regulate IFN-γ production. Inhibiting GSK-3 may be a potential treatment strategy for preventing such effects.


Exploring symbioses by single-cell genomics.
Single-cell genomics has advanced the field of microbiology from the analysis of microbial metagenomes where information is "drowning in a sea of sequences," to recognizing each microbial cell as a separate and unique entity. Single-cell genomics employs Phi29 polymerase-mediated whole-genome amplification to yield microgram-range genomic DNA from single microbial cells. This method has now been applied to a handful of symbiotic systems, including bacterial symbionts of marine sponges, insects (grasshoppers, termites), and vertebrates (mouse, human). In each case, novel insights were obtained into the functional genomic repertoire of the bacterial partner, which, in turn, led to an improved understanding of the corresponding host. Single-cell genomics is particularly valuable when dealing with uncultivated microorganisms, as is still the case for many bacterial symbionts. In this review, we explore the power of single-cell genomics for symbiosis research and highlight recent insights into the symbiotic systems that were obtained by this approach.


Spill-SOS: Self-Pumping Siphon-Capillary Oil Recovery.
Oil spills remain a worldwide challenge and need emergency "spill-SOS" actions when they occur. Conventional methods suffer from complex processes and high cost. Here, we demonstrate a solar-heating siphon-capillary oil skimmer (S-SOS) that harvests solar energy, gravitational potential energy, and solid surface energy to enable efficient oil spill recovery in a self-pumping manner. The S-SOS is assembled by an inverted U-shape porous architecture combining solar-heating, siphon, and capillary effects, and works without any external power or manual interventions. Importantly, solid surface energy is used by capillary adsorption to enable the self-starting behavior, gravitational potential energy is utilized by siphon transport to drive the oil flow, and solar energy is harvested by solar-thermal conversion to facilitate the transport speed. In the proof-of-concept work, an all-carbon hierarchical architecture (VG/GF) is fabricated by growing vertically oriented graphene nanosheets (VGs) on a monolith of graphite felt (GF) via a plasma-enhanced method to serve as the U-shape architecture. Consequently, an oil-recovery rate of 35.2 L m-2 h-1 is obtained at ambient condition. When exposed to normal solar irradiation, the oil-recovery rate dramatically increases to 123.3 L m-2 h-1. Meanwhile, the solar-thermal energy efficiency is calculated to be 75.3%. Moreover, the S-SOS system presents excellent stability without obvious performance-degradation over 60 h. The outstanding performance is ascribed to the enhanced siphon action, capillary action, photonic absorption, and interfacial heating in the plasma-made graphene nanostructures. Multiple merits make the current S-SOS design and the VG/GF nanostructures promising for efficient oil recovery and transport of energy stored in chemical bonds.


A major quantitative trait locus for cadmium tolerance in Arabidopsis halleri colocalizes with HMA4, a gene encoding a heavy metal ATPase.
Cadmium (Cd) tolerance seems to be a constitutive species-level trait in Arabidopsis halleri sp. halleri. Therefore, an interspecific cross was made between A. halleri and its closest nontolerant interfertile relative, Arabidopsis lyrata sp. petraea, and a first-generation backcross population (BC1) was used to map quantitative trait loci (QTL) for Cd tolerance. Three QTL were identified, which explained 43%, 24%, and 16% of the phenotypic variation in the mapping population. Heavy metal transporting ATPases4 (HMA4), encoding a predicted heavy metal ATPase, colocalized with the peak of the major QTL Cdtol-1 and was consequently further studied. HMA4 transcripts levels were higher in the roots and the shoots of A. halleri than in A. lyrata sp. petraea. Furthermore, HMA4 was also more highly expressed in all BC1 genotypes harboring the HMA4 A. halleri allele at the QTL Cdtol-1, independently of the presence of an A. halleri allele at the two other QTL. Overexpression of AhHMA4 in yeast (Saccharomyces cerevisiae) supported a role of HMA4 in zinc (Zn) and Cd transport by reducing the Cd and Zn contents of the yeast cells. In epidermal tobacco (Nicotiana tabacum) cells, AhHMA4:green fluorescent protein was clearly localized in the plasma membrane. Taken together, all available data point to the elevated expression of HMA4 P(1B)-type ATPase as an efficient mechanism for improving Cd/Zn tolerance in plants under conditions of Cd/Zn excess by maintaining low cellular Cd(2+) and Zn(2+) concentrations in the cytoplasm.