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Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Postnatal brain plasticity is associated with increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Over the past decade, its application has expanded to infant populations providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal states. However, many methodological issues of rs-fMRI analysis need to be resolved prior to standardization of the technique to infant populations. As a primary goal, this methodological manuscript will (1) present a robust methodological protocol to extract and assess resting-state networks in early infancy using independent component analysis (ICA), such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature; (2) review the current methodological challenges and ethical considerations associated with emerging field of infant rs-fMRI analysis; and (3) discuss the significance of rs-fMRI application in infants for future investigations of neurodevelopment in the context of early life stressors and pathological processes. The overarching goal is to catalyze efforts toward development of robust, infant-specific acquisition, and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used.

Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life-threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine-binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7-10 days old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS1 treatment resulted in liver-specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1. [ABSTRACT FROM AUTHOR]

Estrogens can signal through either estrogen receptor α (ERα) or β (ERβ) to ameliorate experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERα on astrocytes, but not neurons, was critical for ERα ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we determined whether ERβ on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERβ from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERβ ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERβ on either astrocytes or neurons and did not involve a reduction in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERα versus ERβ on astrocytes, we looked for molecules within astrocytes that were affected by signaling through ERα, but not ERβ. We found that ERα ligand treatment, but not ERβ ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERβ signaling does not require ERβ on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERα signaling requires ERα on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERα and ERβ in EAE. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia inducible factor (HIF) is a transcription factor that under low environmental oxygen regulates the expression of suites of genes involved in metabolism, angiogenesis, erythropoiesis, immune function, and growth. Here, we isolated and sequenced partial cDNAs encoding hif-α and arnt/hif-β from the Atlantic blue crab, Callinectes sapidus, an estuarine species that frequently encounters concurrent hypoxia (low O2) and hypercapnia (elevated CO2). We then examined the effects of acute exposure (1h) to hypoxia (H) and hypercapnic hypoxia (HH) on relative transcript abundance for hif-α and arnt/hif-β in different tissues (glycolytic muscle, oxidative muscle, hepatopancreas, gill, and gonads) using quantitative real-time RT-PCR. Our results indicate that hif-α and arnt/hif-β mRNAs were constitutively present under well-aerated normoxia (N) conditions in all tissues examined. Further, H and HH exposure resulted in both tissue-specific and muscle fiber type-specific effects on relative hif-α transcript abundance. In the gill and glycolytic muscle, relative hif-α mRNA levels were significantly lower under H and HH, compared to N, while no change (or a slight increase) was detected in oxidative muscle, hepatopancreas and gonadal tissues. H and HH did not affect relative transcript abundance for arnt/hif-β in any tissue or muscle fiber type. Thus, in crustaceans the HIF response to H and HH appears to involve changes in hif transcript abundance, with variation in hif-α and arnt/hif-β transcriptional dynamics occurring in both a tissue- and muscle fiber type-dependent manner. [Copyright &y& Elsevier]

The application of spatial-temporal stochastic rainfall models to semi-arid or arid areas is expected to be particularly challenging because of the high variability of rainfall, sparse rain gauge networks with significant periods of missing rainfall and potential data quality issues. In this article, a generalized linear model (GLM) has been fitted to daily rainfall data from the period 1975-1999 for 13 gauges in a 7660 km2 sub-basin of the Limpopo basin in Botswana, with the objective of exploring applicability of the GLM for infilling historic records and for climate change analysis. Several relevant statistics of rainfall space-time variability were used to analyse model performance, including use of an independent validation period and sites that were not used in the fitting. The GLM was considered to simulate rainfall adequately for the purpose of sub-basin-scale water resource studies, although the model uncertainty is high. The main factors affecting rainfall space-time variability were found to be seasonality, autocorrelation of daily rainfall, altitude, latitude and longitude. Addition of large-scale drivers of rainfall (pressure, humidity and temperature) further improved representation of inter-annual variability, and this link to large-scale climate potentially facilitates downscaling of global climate model outputs. Although the model was locally sensitive to data quality issues, there was no evidence that these issues affected sub-basin scale analysis. Copyright © 2011 Royal Meteorological Society [ABSTRACT FROM AUTHOR]

Methylmalonic acidemia (MMA), an inherited metabolic disorder caused by deficient activity of methylmalonyl-CoA mutase, carries a poor prognosis for long-term survival. While administration of a recombinant adeno-associated virus serotype 8 vector (rAAV8) can rescue Mut−/− mice from neonatal lethality and provide sustained phenotypic correction, translation of gene therapy to human subjects will likely require multiple rounds of systemic administration and, ideally, the use of a vector that transduces the kidney. To examine the effectiveness of alternative rAAVs in the treatment of MMA, a serotype 9 rAAV expressing the Mut cDNA was constructed and delivered to newborn Mut−/− mice (n=11). rAAV9 gene therapy directed hepatic transgene expression within 24 h and effectively rescued the Mut−/− mice from lethality, conferred long-term survival, markedly improved metabolism and resulted in striking preservation of renal function and histology. Systemic readministration of the vector at a dose similar to that used in human clinical trials (2.5 × 109 GC of rAAV9 per gram) to older, treated Mut−/− mice (n=5) lowered circulating metabolites, increased in vivo propionate oxidative capacity and produced transgene expression in the kidney and liver. Our data support the use of an rAAV9 vector in the acute and chronic treatment of MMA, and highlight the renal tropism afforded by this novel serotype. [ABSTRACT FROM AUTHOR]

Background: Although research suggests that socio-sexual behavior changes in conjunction with the menstrual cycle, several potential factors are rarely taken into consideration. We investigated the role of changing hormone concentrations on self-reported physical discomfort, sleep, exercise and socio-sexual interest in young, healthy women. Methods: Salivary hormones (dehydroepiandrosterone sulfate-DHEAS, progesterone, cortisol, testosterone, estradiol and estriol) and socio-sexual variables were measured in 20 women taking oral contraceptives (OC group) and 20 not using OCs (control group). Outcome measures were adapted from questionnaires of menstrual cycle-related symptoms, physical activity, and interpersonal relations. Testing occurred during menstruation (T1), mid-cycle (T2), and during the luteal phase (T3). Changes in behavior were assessed across time points and between groups. Additionally, correlations between hormones and socio-behavioral characteristics were determined. Results: Physical discomfort and sleep disturbances peaked at T1 for both groups. Exercise levels and overall sociosexual interest did not change across the menstrual cycle for both groups combined. However, slight mid-cycle increases in general and physical attraction were noted among the control group, whereas the OC group experienced significantly greater socio-sexual interest across all phases compared to the control group. Associations with hormones differed by group and cycle phase. The estrogens were correlated with socio-sexual and physical variables at T1 and T3 in the control group; whereas progesterone, cortisol, and DHEAS were more closely associated with these variables in the OC group across test times. The direction of influence further varies by behavior, group, and time point. Among naturally cycling women, higher concentrations of estradiol and estriol are associated with lower attraction scores at T1 but higher scores at T3. Among OC users, DHEAS and progesterone exhibit opposing relationships with attraction scores at T1 and invert at T3. Conclusions: Data from this study show no change across the cycle in socio-sexual interest among healthy, reproductive age women but higher social and physical attraction among OC users. Furthermore, a broader range of hormones may be associated with attraction than previously thought. Such relationships differ by use of oral contraceptives, and may either reflect endogenous hormone modulation by OCs and/or self-selection of sexually active women to practice contraceptive techniques. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To develop and perform psychometric testing on an instrument designed to assess cognitive/emotional responses among men receiving HPV testing. METHODS: Men enrolled in an HPV natural history study (N = 139) completed a computer-assisted survey instrument based on Leventhal's parallel processing/common-sense model. Data were analyzed using SPSS and Mplus. RESULTS: Reliability analyses resulted in Cronbach alpha of 0.72 (knowledge), 0.86 (perceived threat), 0.83 (self-efficacy), and 0.55 (response efficacy). A revised measurement model exhibited evidence of construct validity, as indicated by acceptable model fit statistics. CONCLUSION: To our knowledge, this is the only validated instrument assessing men's reactions to an HPV test result. [ABSTRACT FROM AUTHOR]

The article discusses an analysis method for stress-concentration factor in rotary-shouldered connections used in oil well drilling. The method in this study uses finite-element analysis as a tool to investigate the maximum peak-stress behavior in rotary-shouldered connections. It compares maximum peak-stress behaviors and stress-concentration factor values among rotary-shouldered connections. Furthermore, the paper describes the stress-concentration factor in rotary-shouldered connections and offers a discussion regarding the stress-concentration factor-analysis method.

Objective: To validate photographic bioimaging for evaluating the severity of herpes simplex virus keratitis. Methods: Stromal keratitis of patients in the Herpetic Eye Disease Study was clinically measured with a slitbeam micrometer and then photographed at trial entry. Calibrated images of 169 eyes were analyzed for the size, location, and density of stromal keratitis and endotheliitis, with shape factor as a function of area and perimeter. Validity was assessed by comparing clinical and computerized measurements and by correlating the keratitis area with visual acuity. Logistic regression explored characteristics associated with larger or denser corneal inflammation. Results: Stromal keratitis had a median area of 22.4mm² (interquartile range, 12.8-31.6mm2) with a median shape factor of 0.69 (interquartile range, 0.56-0.79); 126 eyes (75%) had their midpoint within 2mmof the cornea's geometric center. Photoanalytical area estimates of herpetic stromal keratitis correlated closely with clinical measurements (correlation coefficient, 0.83). Eyes with larger stromal keratitis had worse vision (correlation coefficient, 0.32) and were more likely to have iritis (P=.01). Necrotizing stromal keratitis was significantly whiter (P=.02). Conclusions: Image analysis validly assesses the disciform geometry of herpetic stromal keratitis and confirms that increased severity is associated with uveitis and reduced vision. [ABSTRACT FROM AUTHOR]

The article discusses the drillstring technology innovations of ultradeep drilling for oil wells in the U.S. It states that drilling ultra-deep (UD) wells sets significant requirements on the drillstring. Lengthy drill stems lead to high tensile loads, which can contribute to slip crushing and results to hoisting capacity issue and drill-pipe collapse capacity at the blowout preventor (BOP). It cites that BOP shear rams may have difficulty shearing high-strength and high-toughness drill-pipe. Moreover, bottomhole assembly (BHA) connection failures pose great risk and cost at UD well depths.

We investigate the capability of generalized linear models (GLMs) to simulate sequences of daily maximum wind speed (DMWS), at a selection of locations in NW Europe. Models involving both the gamma and Weibull distributions have been fitted to the NCEP reanalysis data for the period 1958–1998. In simulations, these models successfully reproduce the observed increasing trends up to 0.3 m/s per decade in coastal or oceanic locations for the wintertime and the decreasing trends down to –0.2 m/s per decade in inland Europe for the summertime. Annually extreme winds exhibit an increasing tendency (with median estimates up to 0.6 m/s per decade) at the studied locations. The gamma model slightly overestimates the upper percentiles of the wind speed distribution, but reproduces trends better than the Weibull model. In both the NCEP data and GLM simulations, local extreme DMWS events (defined in terms of threshold exceedances) have increased dramatically in frequency during winter; decreasing trends are more common in summer. The NCEP data indicate similar trends in the frequencies of large-scale windy events (defined via simultaneous exceedances at 2 or more locations). Overall, these events have increased in number; at the scale of the North Sea basin, their number may have changed from 3–5 days per year during the earlier decades, to 5–7 days per year during later decades based on observational estimates. An increase in the frequency of large-scale extreme winter storms is implied. The GLMs underestimate these large-scale event frequencies, and provide imprecise estimates of the corresponding secular trends. These problems could be rectified by using a better representation of spatial dependence. The present results suggest that GLMs offer a useful tool to study local climate extremes in the context of changing climate distributions; they also provide some pointers towards improving the representation of extremes at a regional scale. [ABSTRACT FROM AUTHOR]

Within the group of botanical products there is a large range of variation with regard to their properties. Some products are identical to foods while others come close to or are medicines. Botanical products are regulated differently within the different member states of the European Union (EU) and globally. They are regulated either as food or as medicinal products, and in the latter case often with simplified registration procedures. These differences are caused by differences in traditional use, in cultural and historical background, in scientific substantiation and in enforcement of current legislation. One may expect that in the future differences will remain, unless EU legislation is enacted with sufficient room for different approaches. The strengths and weaknesses of the different regulatory procedures have been reviewed and evaluated as well as the current methods for quality, efficacy and safety evaluation. Criteria to categorize botanical products have been defined, such that botanical products can be regulated under the current food and medicinal regulations. Furthermore, a decision tree has been developed as a tool to distinguish herbal medicinal products from botanical health products and vice versa, and to provide a stepwise framework for the assessment of safety and efficacy. [Copyright &y& Elsevier]

Simple Summary: Human breast tissue extracellular matrix (ECM) is a microenvironment essential for the survival and biological activities of mammary epithelial cells. The ECM structural features of human breast tissues remain poorly defined. In this study, we identified the structural and mechanical properties of human normal breast and invasive ductal carcinoma tissue ECM using histological methods and atomic force microscopy. Additionally, a protein hydrogel was generated using human breast tissue ECM and defined for its microstructural features using immunofluorescence imaging and machine learning. Furthermore, we examined the three-dimensional growth of normal mammary epithelial cells or breast cancer cells cultured on the ECM protein hydrogel, where the cells exhibited biological phenotypes like those seen in native breast tissues. Our data provide novel insights into cancer cell biology, tissue microenvironment mimicry and engineering, and native tissue ECM-based biomedical and pharmaceutical applications. Tissue extracellular matrix (ECM) is a structurally and compositionally unique microenvironment within which native cells can perform their natural biological activities. Cells grown on artificial substrata differ biologically and phenotypically from those grown within their native tissue microenvironment. Studies examining human tissue ECM structures and the biology of human tissue cells in their corresponding tissue ECM are lacking. Such investigations will improve our understanding about human pathophysiological conditions for better clinical care. We report here human normal breast tissue and invasive ductal carcinoma tissue ECM structural features. For the first time, a hydrogel was successfully fabricated using whole protein extracts of human normal breast ECM. Using immunofluorescence staining of type I collagen (Col I) and machine learning of its fibrous patterns in the polymerized human breast ECM hydrogel, we have defined the microstructural characteristics of the hydrogel and compared the microstructures with those of other native ECM hydrogels. Importantly, the ECM hydrogel supported 3D growth and cell-ECM interaction of both normal and cancerous mammary epithelial cells. This work represents further advancement toward full reconstitution of the human breast tissue microenvironment, an accomplishment that will accelerate the use of human pathophysiological tissue-derived matrices for individualized biomedical research and therapeutic development. [ABSTRACT FROM AUTHOR]

The process of establishing and evaluating an industrial social work programme in a small distillery using a third party university model is described. The programme is based on a participatory philosophy and the importance of joint management and union "ownership" of the programme is emphasized. The evaluation examined health and attitudes of employees, absenteeism and productivity, cost effectiveness and reduction in grievances. The overall finding was that both the employees and the corporation benefitted substantially from the project. [ABSTRACT FROM PUBLISHER]