Withania somnifera modulates cancer cachexia associated inflammatory cytokines and cell death in leukaemic THP-1 cells and peripheral blood mononuclear cells (PBMC's).
Cancer and inflammation are associated with cachexia. Withania somnifera (W. somnifera) possesses antioxidant and anti-inflammatory potential. We investigated the potential of an aqueous extract of the root of W. somnifera (WRE) to modulate cytokines, antioxidants and apoptosis in leukaemic THP-1 cells and peripheral blood mononuclear cells (PBMC's). Cytotoxcity of WRE was determined at 24 and 72 h (h). Oxidant scavenging activity of WRE was evaluated (2, 2-diphenyl-1 picrylhydrazyl assay). Glutathione (GSH) levels, caspase (- 8, - 9, - 3/7) activities and adenosine triphosphate (ATP) levels (Luminometry) were thereafter assayed. Tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and IL-10 levels were also assessed using enzyme-linked immunosorbant assay. At 24 h, WRE (0.2-0.4 mg/ml) decreased PBMC viability between 20 and 25%, whereas it increased THP-1 viability between 15 and 23% (p < 0.001). At 72 h, WRE increased PBMC viability by 27-39% (0.05, 0.4 mg/ml WRE) whereas decreased THP-1 viability between 9 and 16% (0.05-0.4 mg/ml WRE) (p < 0.001). Oxidant scavenging activity was increased by WRE (0.05-0.4 mg/ml, p < 0.0001). PBMC TNF-α and IL-10 levels were decreased by 0.2-0.4 mg/ml WRE, whereas IL-1β levels were increased by 0.05-0.4 mg/ml WRE (p < 0.0001). In THP-1 cells, WRE (0.05-0.4 mg/ml) decreased TNF-α, IL-1β and IL-6 levels (p < 0.0001). At 24 h, GSH levels were decreased in PBMC's, whilst increased in THP-1 cells by 0.2-0.4 mg/ml WRE (p < 0.0001). At 72 h, WRE (0.1-0.4 mg/ml) decreased GSH levels in both cell lines (p < 0.0001). At 24 h, WRE (0.2-0.4 mg/ml) increased PBMC caspase (-8, -3/7) activities whereas WRE (0.05, 0.1, 0.4 mg/ml) increased THP-1 caspase (-9, -3/7) activities (p < 0.0001). At 72 h, PBMC caspase (-8, -9, -3/7) activities were increased at 0.05-0.1 mg/ml WRE (p < 0.0001). In THP-1 cells, caspase (-8, -9, -3/7) activities and ATP levels were increased by 0.1-0.2 mg/ml WRE, whereas decreased by 0.05 and 0.4 mg/ml WRE (72 h, p < 0.0001). In PBMC's and THP-1 cells, WRE proved to effectively modulate antioxidant activity, inflammatory cytokines and cell death. In THP-1 cells, WRE decreased pro-inflammatory cytokine levels, which may alleviate cancer cachexia and excessive leukaemic cell growth.


Aromatic Decoration Determines the Formation of Anthocyanic Vacuolar Inclusions.
Anthocyanins are some of the most widely occurring secondary metabolites in plants, responsible for the orange, red, purple, and blue colors of flowers and fruits and red colors of autumn leaves. These pigments accumulate in vacuoles, and their color is influenced by chemical decorations, vacuolar pH, the presence of copigments, and metal ions. Anthocyanins are usually soluble in the vacuole, but in some plants, they accumulate as discrete sub-vacuolar structures. Studies have distinguished intensely colored intra-vacuolar bodies observed in the cells of highly colored tissues, termed anthocyanic vacuolar inclusions (AVIs), from more globular, membrane-bound anthocyanoplasts. We describe a system in tobacco that adds additional decorations to the basic anthocyanin, cyanidin 3-O-rutinoside, normally formed by this species. Using this system, we have been able to establish which decorations underpin the formation of AVIs, the conditions promoting AVI formation, and, consequently, the mechanism by which they form.


Association between particulate matter air pollution and risk of depression and suicide: systematic review and meta-analysis.
Some recent studies examined the effect of ambient particulate matter (PM) pollution on depression and suicide. However, the results have been inconclusive.AimsTo determine the overall relationship between PM exposure and depression/suicide in the general population. We conducted a systematic review and meta-analysis of case-crossover and cohort studies to assess the association between PM2.5 (particles with an aerodynamic diameter of 2.5 µm or less) or PM10 (particles with an aerodynamic diameter between 2.5 and 10 µm) exposure and depression/suicide. A total of 14 articles (7 for depression and 7 for suicide) with data from 684 859 participants were included in the meta-analysis. With a 10 µg/m3 increase in PM2.5 we found a 19% (odds ratio [95% CI] 1.19 [1.07, 1.33]) increased risk of depression and a marginally increased risk of suicide (odds ratio [95% CI] 1.05 [0.99, 1.11]) in the general population. We did not observe any significant associations between increasing exposure to PM10 and depression/suicide. Sensitivity and subgroup analyses were used to determine the robustness of results. The strongest estimated effect of depression associated with PM2.5 appeared in a long-term lag pattern (odds ratio [95% CI] 1.25 [1.07, 1.45], P < 0.01) and cumulative lag pattern (odds ratio [95% CI] 1.26 [1.07, 1.48], P < 0.01). The meta-analysis suggested that an increase in ambient PM2.5 concentration was strongly associated with increased depression risk in the general population, and the association appeared stronger at long-term lag and cumulative lag patterns, suggesting a potential cumulative exposure effect over time.Declaration of interestNone.


Novel Ca2+ currents in mammalian CNS neurons.
Voltage-dependent Ca2+ currents (ICa) in neurons can be classified into T-, N- and L-types. In the CA1 pyramidal neurons freshly dissociated from rat hippocampus we found an additional tetrodotoxin (TTX)-sensitive Ca2+ current (termed 'TTX-ICa'). The TTX-ICa showed a heterogeneous distribution, preferentially in the dorsal site of CA1 region. Activation and inactivation processes of the TTX-ICa were highly potential-dependent, and the latter was fitted by a double exponential function. The TTX-ICa was activated at a threshold potential of about -55 mV and reached full activation at -30 mV. The steady-state inactivation of TTX-ICa could be fitted by a Boltzmann equation with a slope factor of 6.0 mV and a half-inactivation voltage of -72.5 mV. When the peak amplitudes of TTX-ICa were plotted as a function of extracellular Ca2+ concentration ([Ca2+]o), the current amplitude increased linearly without showing any saturation. The ratio of peak amplitude in the individual I-V relationships of Ca2+, Sr2+ and Ba2+ currents passing through the TTX-sensitive Ca(2+)-conducting channel was 1:0.33:0.05, although the current kinetics were much the same. TTX inhibited the TTX-ICa in time- and concentration-dependent manner without affecting the current kinetics. Lignocaine inhibited the TTX-ICa in a second in a concentration-dependent manner, with accelerating the inactivation process. The concentrations of half-inhibition (IC50) were 3.5 x 10(-9) M for TTX and 3.6 x 10(-4) M for lignocaine. Scorpion toxin prolonged the inactivation phase of TTX-ICa in a time- and concentration-dependent manner. In the toxin-treated neurons, both the slow time constant of inactivation (tau is) and its functional contribution to the total current increased with increasing the toxin concentration.


Sayette Group Formation Task (GFT) Spontaneous Facial Expression Database.
Despite the important role that facial expressions play in interpersonal communication and our knowledge that interpersonal behavior is influenced by social context, no currently available facial expression database includes multiple interacting participants. The Sayette Group Formation Task (GFT) database addresses the need for well-annotated video of multiple participants during unscripted interactions. The database includes 172,800 video frames from 96 participants in 32 three-person groups. To aid in the development of automated facial expression analysis systems, GFT includes expert annotations of FACS occurrence and intensity, facial landmark tracking, and baseline results for linear SVM, deep learning, active patch learning, and personalized classification. Baseline performance is quantified and compared using identical partitioning and a variety of metrics (including means and confidence intervals). The highest performance scores were found for the deep learning and active patch learning methods. Learn more at http://osf.io/7wcyz.


Reversal of cell fate determination in Caenorhabditis elegans vulval development.
In Caenorhabditis elegans, the fates of the multipotent vulval precursor cells (VPCs) are specified by intercellular signals. The VPCs divide in the third larval stage (L3) of the wild type, producing progeny of determined cell types. In lin-28 mutants, vulva development is similar to wild-type vulva development except that it occurs precociously, in the second larval stage (L2). Consequently, when lin-28 hermaphrodites temporarily arrest development at the end of L2 in the dauer larva stage, they have partially developed vulvae consisting of VPC progeny. During post-dauer development, these otherwise determined VPC progeny become reprogrammed back to the multipotent, signal-sensitive state of VPCs. Our results indicate that VPC fate determination by intercellular signals is reversible by dauer larva developmental arrest and post-dauer development.


Transcranial direct current stimulation improves isometric time to exhaustion of the knee extensors.
Transcranial direct current stimulation (tDCS) can increase cortical excitability of a targeted brain area, which may affect endurance exercise performance. However, optimal electrode placement for tDCS remains unclear. We tested the effect of two different tDCS electrode montages for improving exercise performance. Nine subjects underwent a control (CON), placebo (SHAM) and two different tDCS montage sessions in a randomized design. In one tDCS session, the anodal electrode was placed over the left motor cortex and the cathodal on contralateral forehead (HEAD), while for the other montage the anodal electrode was placed over the left motor cortex and cathodal electrode above the shoulder (SHOULDER). tDCS was delivered for 10min at 2.0mA, after which participants performed an isometric time to exhaustion (TTE) test of the right knee extensors. Peripheral and central neuromuscular parameters were assessed at baseline, after tDCS application and after TTE. Heart rate (HR), ratings of perceived exertion (RPE), and leg muscle exercise-induced muscle pain (PAIN) were monitored during the TTE. TTE was longer and RPE lower in the SHOULDER condition (P<0.05). Central and peripheral parameters, and HR and PAIN did not present any differences between conditions after tDCS stimulation (P>0.05). In all conditions maximal voluntary contraction (MVC) significantly decreased after the TTE (P<0.05) while motor-evoked potential area (MEP) increased after TTE (P<0.05). These findings demonstrate that SHOULDER montage is more effective than HEAD montage to improve endurance performance, likely through avoiding the negative effects of the cathode on excitability.


Prevalence and Risk of Mild Cognitive Impairment in Low and Middle-Income Countries: A Systematic Review.
Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs and were included as long as MCI was clearly defined. 5,568 articles were screened, and 78 retained. In total, n = 23 different LMICs were represented; mostly from China (n = 55 studies). Few studies were from countries defined as lower-middle income (n = 14), low income (n = 4), or from population representative samples (n = 4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n = 26). Prevalence of amnesic MCI (aMCI) (Petersen criteria) ranged from 0.6%to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5%to 18.3%) and all-MCI (range 6.1%to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning.


Effects of leachate from tree leaves and grass litter on tadpoles.
Tree species composition can change as a result of succession, climate change, fire suppression, and invasive species. These changes clearly affect forests, but they can also affect aquatic ecosystems based on differences in the input quality of leaf litter, such as plant secondary compounds. These compounds vary in type and concentration depending on species and can be toxic to aquatic organisms. To examine toxic effects on Pseudacris maculata and Pseudacris crucifer tadpoles, we conducted 60-d laboratory experiments to compare leaf litter leachate from a dominant canopy species (red oak) and nonnative species (white pine) with an aquatic grass (prairie cordgrass) and plain water control. An additional experiment examined the effects of white pine on Bufo americanus, Hyla versicolor, and tannin concentrations in natural ponds. Compared with the control and grass, tree leaf extracts resulted in reduced tadpole survival. Leached compounds from pine reduced tadpole survival to 3 d or less. Tadpoles were able to metamorphose in significant numbers only from the two controls. The lowered survival with the red oak treatment might have been caused by lowered dissolved oxygen or high tannin concentrations. However, pine is known to have high concentrations of toxic monoterpenes, which should be investigated further. We found that tannin concentrations in natural ponds were much lower than the test concentrations, indicating that these results may represent worst-case scenarios or unrealistic concentrations.


Genome-wide linkage scan for submaximal exercise heart rate in the HERITAGE family study.
The purpose of this study was to identify regions of the human genome linked to submaximal exercise heart rates in the sedentary state and in response to a standardized 20-wk endurance training program in blacks and whites of the HERITAGE Family Study. A total of 701 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan, with 328 sibling pairs from 99 white nuclear families and 102 pairs from 115 black family units. Steady-state heart rates were measured at the relative intensity of 60% maximal oxygen uptake (HR60) and at the absolute intensity of 50 W (HR50). Baseline phenotypes were adjusted for age, sex, and baseline body mass index (BMI) and training responses (posttraining minus baseline, Delta) were adjusted for age, sex, baseline BMI, and baseline value of the phenotype. Two analytic strategies were used, a multipoint variance components and a regression-based multipoint linkage analysis. In whites, promising linkages (LOD > 1.75) were identified on 18q21-q22 for baseline HR50 (LOD = 2.64; P = 0.0002) and DeltaHR60 (LOD = 2.10; P = 0.0009) and on chromosome 2q33.3 for DeltaHR50 (LOD = 2.13; P = 0.0009). In blacks, evidence of promising linkage for baseline HR50 was detected with several markers within the chromosomal region 10q24-q25.3 (peak LOD = 2.43, P = 0.0004 with D10S597). The most promising regions for fine mapping in the HERITAGE Family Study were found on 2q33 for HR50 training response in whites, on 10q25-26 for baseline HR60 in blacks, and on 18q21-22 for both baseline HR50 and DeltaHR60 in whites.


Magnetic Resonance evaluation of disease activity in Graves' ophthalmopathy: T2-time and signal intensity of extraocular muscles.
It is accepted that T2-weighted imaging can demonstrate the extent of an inflammatory process in Graves' ophthalmopathy (GO). This aim of this study was a comparative evaluation of the most commonly used indicators of extraocular muscle pathophysiology, i.e. signal intensity (SI) and T2-time (T2-t) in correlation with muscle volume (MV), and to determine the need to make the above indicators objective with regards to clinical practice. MRI examinations in a 1.5 T scanner of 40 orbits formed the study group. Quantitative assessment of the muscles was carried out using a numerical segmentation imaging technique (NSI). SI and T2-t were measured for each muscle. A standardization algorithm was applied based on T2-t and IS from the ipsilateral white matter of the frontal lobes. The correlation between T2-t and MV for the medial rectus and inferior rectus muscles (IRM) was at a comparatively high level (R: 0.49 and 0.47), with a value as high as R=0.58 for the superior rectus muscle. Correlation between SI and volume for these muscles was found to be at R-levels of 0.37, 0.48, and 0.46. Correction of the T2-t and SI values with use of a standardization algorithm in most cases did not change the above correlations, except for IRM. The parameter with the higher correlation to the symptoms of GO is T2 The value of SI as an indicator of disease intensity in GO that can be used without the use of multiple echo sequences was confirmed. It is necessary to make the above parameters objective relative to white matter when calculating IS for the inferior rectus muscle.


Oxidative removal of arsenite by Fe(II)- and polyoxometalate (POM)-amended zero-valent aluminum (ZVAl) under oxic conditions.
Abiotic transformation of As(III) to As(V) is possible which would decrease As toxicity. This study investigated the potential applications of zero-valent Al (ZVAl) or Al wastes, such as Al beverage cans, for converting As(III) to As(V) in an acidic solution under aerobic conditions. Results showed that As(III) could not be oxidized by ZVAl within 150 min reaction at pH 1 because of the presence of an oxide layer on ZVAl. However, 85 μM As(III) could be completely oxidized with the addition of Fe(II) or POM due to the generation of a Fenton reaction or the enhancement of H2O2 production, respectively, on the ZVAl surfaces. Because Fe(II) or polyoxometalate (POM) exhibited more stable at low pH and scavenged rapidly the H2O2 produced on the aerated ZVAl surfaces, OH radical productions were more efficient and As(III) was rapidly oxidized in the ZVAl/O2 system with theses two catalysts. The catalytic oxidation kinetics of As(III) in the presence of Fe(II) or POM were best described by zero-order reaction, and the rate constants increased with a decrease of pH from 2 to 1. Following the oxidative conversion of As(III) to As(V) in the ZVAl/Fe/O2 system, As(V) was removed by the newly formed hydrous Al/Fe precipitates by increasing the solution pH to 6. Nonetheless, the As(V) removal was incomplete in the ZVAl/POM/O2 system because the hydrolyzed products of POM, e.g., PO4(3-), inhibited As(V) removal due to the competitive adsorption of the oxyanion on Al precipitates. Discarded Al-based beverage cans exhibit a higher efficiency for As(III) oxidation and final As removal compared with that of ZVAl, and thus, the potential application of Al beverage cans to scavenge As in solutions is feasible.


Autoimmunity in neuropsychiatric disorders.
The immune system's role in the pathophysiology of several neuropsychiatric disorders has been the subject of research for many decades. Despite suggestive evidence from genetic, epidemiologic, and immunologic studies, those findings did not translate into clinical practice. Recent recognition of antibody-mediated central nervous system (CNS) disorders has fueled the search for a subgroup of patients with an antibody-mediated psychiatric illness. This chapter focuses on the current understanding of autoimmune CNS disorders and how they may be relevant to psychiatric disorders, particularly schizophrenia and autism. We review the results provided by antibody screening in psychiatric patient groups and discuss future directions to establish whether those findings will be meaningful in clinical practice.


Gallstone is correlated with an increased risk of idiopathic sudden sensorineural hearing loss: a retrospective cohort study.
This study aims to test the hypothesis that gallstone disease (GSD) is a risk factor for the development of idiopathic sudden sensorineural hearing loss (ISSNHL). Research has shown risks of cardiovascular and cerebrovascular events in patients with GSD; however, well-conducted English studies on the association between GSD and the development of ISSNHL are lacking. Retrospective cohort study using the Taiwan Longitudinal Health Insurance Database. We compared 26,449 patients diagnosed with GSD between 1 January 2001 and 31 December 2007, with 52,898 age-matched, gender-matched and comorbidities propensity scores-matched controls. We followed each patient until the end of 2011 and evaluated the incidence of ISSNHL for at least 4 years after the initial GSD diagnosis. The incidence of ISSNHL was 1.42 times higher in the GS cohort than in the non-GS cohort (9.27 vs 6.52/10,000 person-years). Using Cox proportional hazard regressions, the adjusted HR was 1.44 (95% CI 1.19 to 1.74). In the cohort of patients with GSD who needed a cholecystectomy, 37 patients suffered from ISSNHL. Among those patients, 31 (83.7%) patients sustained ISSNHL before cholecystectomy and 6 (16.2%) patients sustained ISSNHL after cholecystectomy. A diagnosis of GSD may be an independent risk for ISSNHL. This finding suggests that an underlying vascular and inflammatory mechanism may contribute to the development of ISSNHL. Physicians may want to counsel patients with GSD to seek medical attention if they have hearing impairments, because patients may be at an increased risk of developing ISSNHL.


PubFocus: semantic MEDLINE/PubMed citations analytics through integration of controlled biomedical dictionaries and ranking algorithm.
Understanding research activity within any given biomedical field is important. Search outputs generated by MEDLINE/PubMed are not well classified and require lengthy manual citation analysis. Automation of citation analytics can be very useful and timesaving for both novices and experts. PubFocus web server automates analysis of MEDLINE/PubMed search queries by enriching them with two widely used human factor-based bibliometric indicators of publication quality: journal impact factor and volume of forward references. In addition to providing basic volumetric statistics, PubFocus also prioritizes citations and evaluates authors' impact on the field of search. PubFocus also analyses presence and occurrence of biomedical key terms within citations by utilizing controlled vocabularies. We have developed citations' prioritisation algorithm based on journal impact factor, forward referencing volume, referencing dynamics, and author's contribution level. It can be applied either to the primary set of PubMed search results or to the subsets of these results identified through key terms from controlled biomedical vocabularies and ontologies. NCI (National Cancer Institute) thesaurus and MGD (Mouse Genome Database) mammalian gene orthology have been implemented for key terms analytics. PubFocus provides a scalable platform for the integration of multiple available ontology databases. PubFocus analytics can be adapted for input sources of biomedical citations other than PubMed.


High resolution 1H-detected solid-state NMR spectroscopy of protein aliphatic resonances: access to tertiary structure information.
Biological magic angle spinning (MAS) solid-state nuclear magnetic resonance spectroscopy has developed rapidly over the past two decades. For the structure determination of a protein by solid-state NMR, routinely (13)C,(13)C distance restraints as well as dihedral restraints are employed. In protonated samples, this is achieved by growing the bacterium on a medium which contains [1,3]-(13)C glycerol or [2]-(13)C glycerol to dilute the (13)C spin system. Labeling schemes, which rely on heteronuclei, are insensitive both for detection and in terms of quantification of distances, since they are relying on low-γ nuclei. Proton detection can in principle provide a gain in sensitivity by a factor of 8 and 31, compared to the (13)C or (15)N detected version of the experiment. We report here a new labeling scheme, which enables (1)H-detection of aliphatic resonances with high resolution in MAS solid-state NMR spectroscopy. We prepared microcrystals of the SH3 domain of chicken α-spectrin with 5% protonation at nonexchangeable sites and obtained line widths on the order of 25 Hz for aliphatic (1)H resonances. We show further that (13)C resolved 3D-(1)H,(1)H correlation experiments yield access to long-range proton-proton distances in the protein.


A Complex Code of Extrinsic Influences on Cortical Progenitor Cells of Higher Mammals.
Development of the cerebral cortex depends critically on the regulation of progenitor cell proliferation and fate. Cortical progenitor cells are remarkably diverse with regard to their morphology as well as laminar and areal position. Extrinsic factors, such as thalamic axons, have been proposed to play key roles in progenitor cell regulation, but the diversity, extent and timing of interactions between extrinsic elements and each class of cortical progenitor cell in higher mammals remain undefined. Here we use the ferret to demonstrate the existence of a complex set of extrinsic elements that may interact, alone or in combination, with subpopulations of progenitor cells, defining a code of extrinsic influences. This code and its complexity vary significantly between developmental stages, layer of residence and morphology of progenitor cells. By analyzing the spatial-temporal overlap of progenitor cell subtypes with neuronal and axonal populations, we show that multiple sets of migrating neurons and axon tracts overlap extensively with subdivisions of the Subventricular Zones, in an exquisite lamina-specific pattern. Our findings provide a framework for understanding the feedback influence of both intra- and extra-cortical elements onto progenitor cells to modulate their dynamics and fate decisions in gyrencephalic brains.


Purification and characterization of two protein kinases acting on the aquaporin SoPIP2;1.
Aquaporins are water channel proteins that facilitate the movement of water and other small solutes across biological membranes. Plants usually have large aquaporin families, providing them with many ways to regulate the water transport. Some aquaporins are regulated post-translationally by phosphorylation. We have previously shown that the water channel activity of SoPIP2;1, an aquaporin in the plasma membrane of spinach leaves, was enhanced by phosphorylation at Ser115 and Ser274. These two serine residues are highly conserved in all plasma membrane aquaporins of the PIP2 subgroup. In this study we have purified and characterized two protein kinases phosphorylating Ser115 and Ser274 in SoPIP2;1. By anion exchange chromatography, the Ser115 kinase was purified from the soluble protein fraction isolated from spinach leaves. The Ca2+-dependent Ser274 kinase was purified by peptide affinity chromatography using plasma membranes isolated from spinach leaves. When characterized, the Ser115 kinase was Mg2+-dependent, Ca2+-independent and had a pH-optimum at 6.5. In accordance with previous studies using the oocyte expression system, site-directed mutagenesis and kinase and phosphatase inhibitors, the phosphorylation of Ser274, but not of Ser115, was increased in the presence of phosphatase inhibitors while kinase inhibitors decreased the phosphorylation of both Ser274 and Ser115. The molecular weight of the Ser274 kinase was approximately 50 kDa. The identification and characterization of these two protein kinases is an important step towards elucidating the signal transduction pathway for gating of the aquaporin SoPIP2;1.


'We'd like to have a family'--young women doctors' opinions of maternity leave and part-time training.
Maternity leave and part-time training should facilitate the integration of the family and professional lives of young women doctors - whom the NHS cannot afford to lose as their numbers rise to half the number of the graduates of UK medical schools. Women doctors' planned professional activity is high, but to what extent do the maternity leave and part-time training arrangements assist them in fulfilling their plans? One hundred and forty-five young women doctors reported their experiences of and views on maternity leave and part-time training. Most had children between 6 and 10 years after qualification, to fit with career development. Seventy-one per cent of the confinements had qualified for maternity leave and pay, but there were complaints about the working of the regulations, particularly in relation to junior hospital doctors' short contracts. When asked to comment about part-time training, most (77%) expressed themselves as broadly in favour - only three actively opposing it. It was perceived as difficult to organize by 20% of respondents, as difficult to undertake by 29%, and as being of low status by 15%. This study concludes that the arrangements for maternity leave need to be improved and that the availability and status of part-time training need enhancing - especially to encourage women doctors to enter careers in hospital medicine.


The Assessment and Non-Pharmacologic Treatment of Procedural Pain From Infancy to School Age Through a Developmental Lens: A Synthesis of Evidence With Recommendations.
The 2011 IOM report stated that pain management in children is often lacking especially during routine medical procedures. The purpose of this review is to bring a developmental lens to the challenges in assessment and non-pharmacologic treatment of pain in young children. A synthesis of the findings from an electronic search of PubMed and the university library using the keywords pain, assessment, treatment, alternative, complementary, integrative, infant, toddler, preschool, young, pediatric, and child was completed. A targeted search identified additional sources for best evidence. Assessment of developmental cues is essential. For example, crying, facial expression, and body posture are behaviors in infancy that indicate pain: however in toddlers these same behaviors are not necessarily indicative of pain. Preschoolers need observation scales in combination with self-report while for older children self-report is the gold standard. Pain management in infants includes swaddling and sucking. However for toddlers, preschoolers and older children, increasingly sophisticated distraction techniques such as easily implemented non-pharmacologic pain management strategies include reading stories, watching cartoons, or listening to music. A developmental approach to assessing and treating pain is critical. Swaddling, picture books, or blowing bubbles are easy and effective when used at the appropriate developmental stage and relieve both physical and emotional pain. Untreated pain in infants and young children may lead to increased pain perception and chronic pain in adolescents and adults. Continued research in the non-pharmacological treatment of pain is an important part of the national agenda.


Strength gains after resistance training: the effect of stressful, negative life events.
This study was designed to examine the effect of self-reported, stressful life events on strength gains after 12 weeks of resistance training. Participants were 135 undergraduates enrolled in weight training classes that met for 1.5 hours, two times per week. After a 2-week period to become familiar with weight training, participants completed the college version of the Adolescent Perceived Events Scale (APES), the Social Support Inventory, and one-repetition maximal lifts (1RM) for the bench press and squat. Maximal lifts were repeated after 12 weeks of training. Median splits for stress and social support were used to form groups. Results indicated that the low stress participants experienced a significantly greater increase in bench press and squat than their high stress counterparts. Strength gains were, however, unrelated to social support scores in either the low or high stress group. High life stress may lessen a person's ability to adapt to weight training. It may benefit coaches to monitor their athletes' stress both within and outside the training setting to maximize their recovery and adaptation.


Biological reactivity of TiO2 nanoparticles assessed by ex vivo testing.
Isolated digestive gland epithelium from a model invertebrate organism was used in an ex vivo system to assess the potential of nanoparticulate TiO(2) to disrupt cell membranes. Primary particle size, surface area, concentration of particles in a suspension, and duration of exposure to TiO(2) particles were all found to have effects, which are observed at concentrations of nano-TiO(2) as low as 1 μg mL(-1). The test system employed here can be used as a fast screening tool to assess biological potential of nanoparticles with similar chemical composition but different size, concentration, or duration of exposure. We discuss the potential of ex vivo tests to avoid some of the limitations of conventional in vitro tests.


Re-examining the directional-ordering transition in the compass model with screw-periodic boundary conditions.
We study the directional-ordering transition in the two-dimensional classical and quantum compass models on the square lattice by means of Monte Carlo simulations. An improved algorithm is presented which builds on the Wolff cluster algorithm in one-dimensional subspaces of the configuration space. This improvement allows us to study classical systems up to L=512. Based on this algorithm, we give evidence for the presence of strongly anomalous scaling for periodic boundary conditions which is much worse than anticipated before. We propose and study alternative boundary conditions for the compass model which do not make use of extended configuration spaces and show that they completely remove the problem with finite-size scaling. In the last part, we apply these boundary conditions to the quantum problem and present a considerably improved estimate for the critical temperature which should be of interest for future studies on the compass model. Our investigation identifies a strong one-dimensional magnetic ordering tendency with a large correlation length as the cause of the unusual scaling and moreover allows for a precise quantification of the anomalous length scale involved.


Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial.
Pioglitazone increases the insulin sensitivity of peripheral tissues and may provide an alternative first-line treatment for type 2 diabetes. This study compared metabolic control in drug-naive type 2 diabetes patients given either pioglitazone or metformin. Eleven hundred and ninety-nine patients with poorly controlled type 2 diabetes mellitus [glycosylated hemoglobin (HbA1c), 7.5-11%; normal, 4.3-6.1%] were randomized to receive either pioglitazone (< or =45 mg/d) or metformin (< or =850 mg, three times daily). HbA1c, fasting plasma glucose (FPG), insulin levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, triglycerides, free fatty acids, and urinary albumin/creatinine ratio were measured. Mean HbA1c decreased in both treatment groups from baseline to wk 52 (-1.4% and -1.5%). Significantly greater mean reductions in FPG were observed in the pioglitazone group (-45.0 mg/dl; -2.5 mmol/liter) than in the metformin (-39.6 mg/dl; -2.2 mmol/liter) group (P = 0.016). Favorable changes in triglycerides and HDL-C were more pronounced with pioglitazone. Although low density lipoprotein cholesterol and TC levels increased with pioglitazone, TC/HDL-C ratios decreased similarly with both treatments. The urinary albumin/creatinine ratio was reduced by 19% with pioglitazone treatment, but remained unchanged with metformin therapy (-1%; P = 0.002). There was an increase in body weight of 1.9 kg in the pioglitazone group and a decrease of 2.5 kg in the metformin group. The overall frequency of adverse events was similar between treatment groups, but adverse event profiles were different between treatment groups. HbA1c reduction is similar after pioglitazone and metformin monotherapies, but differences in FPG, plasma lipids, and adverse effects between the two compounds may influence decision-making in individual prescribers.


The development of global and domain-specific self-esteem from age 13 to 31.
This study examines the development of global self-esteem and self-esteem in 6 specific domains across adolescence and young adulthood. Using a cohort-sequential design, we analyzed longitudinal data on 3,116 Norwegian men and women from 13 to 31 years of age by means of growth curve modeling. Questionnaire data provided information on global self-esteem and self-esteem in social, academic, athletic, and appearance domains. Data on important life outcomes was provided by register linkages. Results showed increasing levels of global self-esteem and self-esteem in most domains with increasing age. Being male, higher parental education, and reported higher levels of parental care were related to higher levels of global self-esteem and self-esteem in several domains. Self-esteem in the appearance domain showed high and stable correlations with global self-esteem, whereas in social domains, correlations with global self-esteem increased over age, with a particularly steep increase for romantic appeal self-esteem. As to the prospective relationship between self-esteem and important life outcomes, results showed that participants high in academic self-esteem attained higher education levels and higher income, but most of the relationship was explained by covariates such as parents' socioeconomic status and school grades. Low global self-esteem predicted later prescription of antidepressants, even after controlling for covariates. This study is the first to provide a comprehensive picture of the development of global and domain-specific self-esteem throughout adolescence and young adulthood using long-term longitudinal data. The results underscore the importance of examining development of self-esteem in specific domains in addition to global self-esteem.


Tetranuclear homo- (Zn(II)4 and Cd(II)4) and hetero-metal (Zn(II)2Tb(III)2 and Cd(II)2Tb(III)2) complexes with a pair of carboxylate ligands in a rare η2:η2:μ4-bridging mode: syntheses, structures and emission properties.
Four tetranuclear complexes involving both homo- and hetero-metal combinations, viz. [Zn(II)(2)L(2)(μ(4)-PhCOO)(2)Zn(II)(2)(hfac)(2)] (1), [Cd(II)(2)L(2)(μ(4)-PhCOO)(2)Cd(II)(2)(hfac)(2)] (2), [Zn(II)(2)L(2)(μ(4)-PhCOO)(2)Tb(III)(2)(hfac)(4)] (3), and [Cd(II)(2)L(2)(μ(4)-PhCOO)(2)Tb(III)(2)(hfac)(4)] (4) have been prepared following a single-pot synthesis protocol using N,N'-dimethyl-N,N'-bis(2-hydroxy-3,5-dimethylbenzyl)ethylenediamine (H(2)L) as a primary ligand. Both benzoate and hexafluoroacetylacetonate (hfac(-)), used here as ancillary ligands, play crucial roles in generating a tetranuclear core with high thermodynamic stability. Oxygen atoms of each carboxylate moiety bind all the four metal centers together in a rare η(2):η(2):μ(4)-bridging mode as confirmed by X-ray crystallography. In the homo-metallic complexes (1 and 2), the metal centers are all lying in a square plane, each occupying a corner, and remain connected together by oxygen bridges forming octagonal metallacrowns. These structures remain intact in solution as confirmed by (1)H NMR spectroscopy and photoluminescent studies. In the hetero-metal complexes (3 and 4), the metal centers are arrayed in alternate positions of the tetranuclear core. The Tb(III) centers have eight coordinate bi-capped trigonal prismatic coordination environments with different degrees of distortions. The all oxygen O(8) core surrounding each Tb(III) center is devoid of solvent molecules that make fluorescent emission from these molecules (3 and 4) quite interesting. The hfac(-)-based (1)(π-π*) emissions observed in 1 and 2 are quenched in 3 and 4. These sensitized Tb(III) emissions [(5)D(4)→(7)F(j); j = 6, 5, 4, and 3] are influenced by the local environments surrounding the 4f-metal center. The lifetime for the luminescence decay of 3 ((5)D(4)→(7)F(5) transition) is about 1.5 times longer than that of 4 in all the solvents studied at 298 K.


Vertical saccades in superior oblique palsy.
Vertical saccadic velocities in 10 patients who had unilateral superior oblique muscle palsy and 14 normal subjects were measured with the magnetic scleral search coil. The authors sought to determine whether downward saccades in patients who had superior oblique palsy are slow. Peak velocities of 10 degrees and 20 degrees saccades performed in the superior and inferior fields of the orbit, and 10 degrees, 20 degrees, and 30 degrees saccades performed across the center of the orbit were recorded with the eye in center gaze, 30 degrees of adduction, and 30 degrees of abduction. Paired t-tests did not show statistically significant differences between upward and downward saccades in patients with superior oblique palsy; no effects of orbital field or position of horizontal gaze were found (P greater than 0.01). Comparison of similar saccades between normal subjects and patients with superior oblique palsy by two-sample t-tests did not show significant differences between the two groups (P greater than 0.01).


Embolization before stereotactic radiosurgery for the treatment of brain arteriovenous malformations.
Embolization is commonly used for the treatment of brain arteriovenous malformations (AVMs) prior to stereotactic radiosurgery (SRS). Due to mixed outcomes, however, its use remains controversial. This article is a review of recent studies assessing the efficacy of pre-radiosurgical embolization for brain AVMs. Articles published between 1990 and 2017 on the subject of pre-radiosurgical AVM embolization were retrieved from PubMed. A literature review was performed on the selected studies to compare obliteration, hemorrhage, and complication rates from groups treated with embolization prior to radiosurgery to those treated without embolization. Overall, the studies reviewed demonstrate mixed results on the efficacy of pre-radiosurgical AVM embolization. For large, complex AVMs, embolization prior to radiosurgery may have a role in carefully selected patients performed by experienced practitioners.


Massage therapy for people with HIV/AIDS.
Infection with human immunodeficency virus (HIV) and acquired immunodeficency syndrome (AIDS) is a pandemic that has affected millions of people globally. Although major research and clinical initiatives are addressing prevention and cure strategies, issues of quality of life for survivors have received less attention. Massage therapy is proposed to have a positive effect on quality of life and may also have a positive effect on immune function through stress mediation. The objective of this systematic review was to examine the safety and effectiveness of massage therapy on quality of life, pain and immune system parameters in people living with HIV/AIDS. A comprehensive search strategy was devised incorporating appropriate terms for HIV/AIDS, randomised controlled trials (RCTs), massage therapy and the pertinent measures of benefit. All electronic databases identified were searched in November 2008, including Cochrane Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, SCIENCE CITATION INDEX, AIDSLINE, AIDSearch, CINAHL, HEALTHSTAR, PsycLIT, AMED, Current Contents, AMI, NLM GATEWAY, LILACS, IndMed, SOCIOFILE, SCI, SSCI, ERIC and DAI. We also reviewed relevant published and unpublished conference abstracts and proceedings and scrutinised reference lists from pertinent journals. There were no language or date restrictions. Studies were identified by two reviewers based on trial design (RCTs) and participants (ie, people of any age with HIV/AIDS, at any stage of the disease) who had undergone an intervention that included massage therapy for the identified aims of improving quality of life and activity and participation levels, improving immune function, reducing pain and improving other physiological or psychological impairments. Two reviewers independently identified included studies and extracted relevant data. Two other reviewers independently reviewed the included studies for risk of bias. All data and risk of bias judgements were entered into Revman (v5) and meta-analyses were conducted where appropriate. Twelve papers were identified, from which four were included. The remaining eight papers were excluded predominantly due to inappropriate methodology. The four included studies were highly clinically heterogenous, investigating a range of age groups (ie, children, adolescents and adults) across the disease spectrum from early HIV through late-stage AIDS. The settings were either community or palliative care, and the outcome measures were a combination of quality of life and immunological function. The trials were judged to be at moderate risk of bias mostly because of incomplete reporting. For quality of life measures, the studies reported that massage therapy in combination with other modalities, such as meditation and stress reduction, are superior to massage therapy alone or to the other modalities alone. The quality of life domains with significant effect sizes included self-reported reduced use of health care resources, improvement in self-perceived spiritual quality of life and improvement in total quality of life scores. One study also reported positive changes in immune function, in particular CD4+ cell count and natural killer cell counts, due to massage therapy, and one study reported no difference between people given massage therapy and controls in immune parameters. Adverse or harmful effects were not well reported. There is some evidence to support the use of massage therapy to improve quality of life for people living with HIV/AIDS (PLWHA), particularly in combination with other stress-management modalities, and that massage therapy may have a positive effect on immunological function. The trials are small, however, and at moderate risk of bias. Further studies are needed using larger sample sizes and rigorous design/reporting before massage therapy can be strongly recommended for PLWHA.


Ras inhibitors and radiation therapy.
Local recurrence after a definitive course of radiation therapy remains a significant clinical problem and represents a common pattern of failure for many solid tumors. The sensitivity of tumor cells to the cytotoxicity of ionizing radiation is thought to be one of the major determinants of local control for tumors in patients treated with radiation therapy. There is substantial experimental evidence to demonstrate that increased radiation resistance is associated with the expression of activated oncogenes, including Ras. Mutated forms of Ras are found in 30% of human cancers including a substantial proportion of pancreatic and colon adenocarcinomas. Mutated Ras produces proteins that remain locked in a constitutively active state, thereby relaying uncontrolled signals. Ras proteins are guanosine triphosphate-binding proteins that play a pivotal role in the control of many cellular processes, including growth and differentiation. Preclinical studies have shown that expression of mutant Ras increases cellular radioresistance. Ras function is dependent on its localization to the plasma membrane. This is achieved by posttranslational modifications, including the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). This enzyme has become an important target for the design of new agents that target Ras. FTase inhibitors (FTIs) block the farnesylation of Ras and reverse Ras-mediated radioresistance in human cell lines. FTIs have been well tolerated in animal studies and appear not to cause generalized cytotoxicity. There are ongoing clinical trials to determine the optimal therapeutic schedules and dose for FTIs. A phase 1 trial of the FTI L778-123 and radiotherapy has recently been completed.


Adaptive Integration of the Compressed Algorithm of CS and NPC for the ECG Signal Compressed Algorithm in VLSI Implementation.
Compressed sensing (CS) is a promising approach to the compression and reconstruction of electrocardiogram (ECG) signals. It has been shown that following reconstruction, most of the changes between the original and reconstructed signals are distributed in the Q, R, and S waves (QRS) region. Furthermore, any increase in the compression ratio tends to increase the magnitude of the change. This paper presents a novel approach integrating the near-precise compressed (NPC) and CS algorithms. The simulation results presented notable improvements in signal-to-noise ratio (SNR) and compression ratio (CR). The efficacy of this approach was verified by fabricating a highly efficient low-cost chip using the Taiwan Semiconductor Manufacturing Company's (TSMC) 0.18-μm Complementary Metal-Oxide-Semiconductor (CMOS) technology. The proposed core has an operating frequency of 60 MHz and gate counts of 2.69 K.


Hypoxia reduces the inhibitory effect of IL-1beta on chondrogenic differentiation of FCS-free expanded MSC.
Mesenchymal stromal cells (MSC) are a promising tool for tissue engineering of the intervertebral disc (ID). The IDs are characterized by hypoxia and, after degeneration, by an inflammatory environment as well. We therefore investigated the effects of inflammation induced with interleukin (IL)-1beta and of hypoxia (2% O(2)) on the chondrogenic differentiation of MSC. Bone-marrow-derived MSC (bmMSC) were cultured in a fetal-calf-serum-free medium and characterized according to the minimal criteria for multipotent MSC. Chondrogenic differentiation of MSC was induced following standard protocols, under hypoxic conditions, with or without IL-1beta supplementation. After 28 days of differentiation, micromasses were analyzed by histochemical staining and immunohistochemistry and by determining the mRNA level of chondrogenic marker genes utilizing quantitative RT-PCR. Micromasses differentiated under IL-1beta supplementation are smaller and express less extracellular matrix (ECM) protein. Micromasses differentiated under hypoxia appear larger in size, display a denser ECM and express marker genes comparable to controls. The combination of hypoxia and IL-1beta supplementation improved chondrogenesis compared to IL-1beta supplementation alone. Micromasses differentiated under standard conditions served as controls. Inflammatory processes inhibit the chondrogenic differentiation of MSC. This may lessen the regenerative potential of MSC in situ. Thus, for the cell therapy of IDs using MSC to be effective it will be necessary to manage the inflammatory conditions in situ. In contrast, hypoxic conditions exert beneficial effects on chondrogenesis and phenotype stability of transplanted MSC, and may improve the quality of the generated ECM.


Posttraumatic stress and posttraumatic stress disorder after termination of pregnancy and reproductive loss: a systematic review.
The aims of this systematic review were to integrate the research on posttraumatic stress (PTS) and posttraumatic stress disorder (PTSD) after termination of pregnancy (TOP), miscarriage, perinatal death, stillbirth, neonatal death, and failed in vitro fertilisation (IVF). Electronic databases (AMED, British Nursing Index, CINAHL, MEDLINE, SPORTDiscus, PsycINFO, PubMEd, ScienceDirect) were searched for articles using PRISMA guidelines. Data from 48 studies were included. Quality of the research was generally good. PTS/PTSD has been investigated in TOP and miscarriage more than perinatal loss, stillbirth, and neonatal death. In all reproductive losses and TOPs, the prevalence of PTS was greater than PTSD, both decreased over time, and longer gestational age is associated with higher levels of PTS/PTSD. Women have generally reported more PTS or PTSD than men. Sociodemographic characteristics (e.g., younger age, lower education, and history of previous traumas or mental health problems) and psychsocial factors influence PTS and PTSD after TOP and reproductive loss. This systematic review is the first to investigate PTS/PTSD after reproductive loss. Patients with advanced pregnancies, a history of previous traumas, mental health problems, and adverse psychosocial profiles should be considered as high risk for developing PTS or PTSD following reproductive loss.


Late brain stem radionecrosis seventeen years after fractionated radiotherapy.
The appearance of a new lesion several years after radiation treatment for a primary brain tumor may represent different kind of pathologies. We present a 24-year-old patient who suffered from right-sided hemiparesis and ataxic gait with a history of an operation due to left frontoparieal grade II fibrillary astrocytoma and fractioned radiotherapy. His cranial MRI study showed heterogeneous signal intensity of brain stem radionecrosis in the pons spreading through the mesencephalon and left brachium pontis. The leading diagnosis was high-grade glial tumor. The patient underwent stereotaxic biopsy and histopathological examination revealed radionecrosis. Radiation necrosis has a radiological appearance similar to various important pathologies. Tissue sampling for histopathological examination is mandatory for definite diagnosis and correct treatment of the disease.


Can enrichment make Brazilian tapir spend more time on view to the public?
One common visitor complaint in zoos is that the nonhuman animals are not visible. This problem needs to be resolved without compromising the animals' welfare; environmental enrichment could solve the problem. This study investigated whether enrichment would increase public exposure time of lowland tapir (Tapirus terrestris) in the Belo Horizonte Zoo in Minas Gerais, Brazil. Observations were made before (62 hr) and during (62 hr) the introduction of enrichment using focal animal sampling with instantaneous recording of behavior. The 5 enrichment items were a bamboo fence covered in vines, logs, a sandbox, dry leaves, and bamboo bushes. Before the enrichments were applied, the tapir was not visible to the public for more than 85% of the time. In addition, during the analysis of the enrichment treatment, other variables were considered--such as weekday, time of day, and weather conditions--which could influence the animals' interaction with the enrichments. The enrichments increased and decreased the expression of some behaviors; however, public viewing time of the animals did not increase. Thus, the enrichment applied was not strong enough to overcome the animals' crepuscular behavior.


Interaction webs in arctic ecosystems: Determinants of arctic change?
How species interact modulate their dynamics, their response to environmental change, and ultimately the functioning and stability of entire communities. Work conducted at Zackenberg, Northeast Greenland, has changed our view on how networks of arctic biotic interactions are structured, how they vary in time, and how they are changing with current environmental change: firstly, the high arctic interaction webs are much more complex than previously envisaged, and with a structure mainly dictated by its arthropod component. Secondly, the dynamics of species within these webs reflect changes in environmental conditions. Thirdly, biotic interactions within a trophic level may affect other trophic levels, in some cases ultimately affecting land-atmosphere feedbacks. Finally, differential responses to environmental change may decouple interacting species. These insights form Zackenberg emphasize that the combination of long-term, ecosystem-based monitoring, and targeted research projects offers the most fruitful basis for understanding and predicting the future of arctic ecosystems.


Deuterium content of water increases depression susceptibility: the potential role of a serotonin-related mechanism.
Environmental factors can significantly affect disease prevalence, including neuropsychiatric disorders such as depression. The ratio of deuterium to protium in water shows substantial geographical variation, which could affect disease susceptibility. Thus the link between deuterium content of water and depression was investigated, both epidemiologically, and in a mouse model of chronic mild stress. We performed a correlation analysis between deuterium content of tap water and rates of depression in regions of the USA. Next, we used a 10-day chronic stress paradigm to test whether 2-week deuterium-depleted water treatment (91 ppm) affects depressive-like behavior and hippocampal SERT. The effect of deuterium-depletion on sleep electrophysiology was also evaluated in naïve mice. There was a geographic correlation between a content of deuterium and the prevalence of depression across the USA. In the chronic stress model, depressive-like features were reduced in mice fed with deuterium-depleted water, and SERT expression was decreased in mice treated with deuterium-treated water compared with regular water. Five days of predator stress also suppressed proliferation in the dentate gyrus; this effect was attenuated in mice fed with deuterium-depleted water. Finally, in naïve mice, deuterium-depleted water treatment increased EEG indices of wakefulness, and decreased duration of REM sleep, phenomena that have been shown to result from the administration of selective serotonin reuptake inhibitors (SSRI). Our data suggest that the deuterium content of water may influence the incidence of affective disorder-related pathophysiology and major depression, which might be mediated by the serotoninergic mechanisms.


TrkB agonists prevent postischemic emergence of refractory neonatal seizures in mice.
Refractory neonatal seizures do not respond to first-line antiseizure medications like phenobarbital (PB), a positive allosteric modulator for GABAA receptors. GABAA receptor-mediated inhibition is dependent upon electroneutral cation-chloride transporter KCC2, which mediates neuronal chloride extrusion and its age-dependent increase and postnatally shifts GABAergic signaling from depolarizing to hyperpolarizing. Brain-derived neurotropic factor-tyrosine receptor kinase B activation (BDNF-TrkB activation) after excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. Here, the antiseizure efficacy of TrkB agonists LM22A-4, HIOC, and deoxygedunin (DG) on PB-refractory seizures and postischemic TrkB pathway activation was investigated in a mouse model (CD-1, P7) of refractory neonatal seizures. LM, a BDNF loop II mimetic, rescued PB-refractory seizures in a sexually dimorphic manner. Efficacy was associated with a substantial reduction in the postischemic phosphorylation of TrkB at Y816, a site known to mediate postischemic KCC2 hypofunction via PLCγ1 activation. LM rescued ischemia-induced phospho-KCC2-S940 dephosphorylation, preserving its membrane stability. Full TrkB agonists HIOC and DG similarly rescued PB refractoriness. Chemogenetic inactivation of TrkB substantially reduced postischemic neonatal seizure burdens at P7. Sex differences identified in developmental expression profiles of TrkB and KCC2 may underlie the sexually dimorphic efficacy of LM. These results support a potentially novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.


Attention modulates the responses of simple cells in monkey primary visual cortex.
Spatial attention has long been postulated to act as a spotlight that increases the salience of visual stimuli at the attended location. We examined the effects of attention on the receptive fields of simple cells in primary visual cortex (V1) by training macaque monkeys to perform a task with two modes. In the attended mode, the stimuli relevant to the animal's task overlay the receptive field of the neuron being recorded. In the unattended mode, the animal was cued to attend to stimuli outside the receptive field of that neuron. The relevant stimulus, a colored pixel, was briefly presented within a white-noise stimulus, a flickering grid of black and white pixels. The receptive fields of the neurons were mapped by correlating spikes with the white-noise stimulus in both attended and unattended modes. We found that attention could cause significant modulation of the visually evoked response despite an absence of significant effects on the overall firing rates. On further examination of the relationship between the strength of the visual stimulation and the firing rate, we found that attention appears to cause multiplicative scaling of the visually evoked responses of simple cells, demonstrating that attention reaches back to the initial stages of visual cortical processing.


Splice-site genetic polymorphism of the human kallikrein 12 (KLK12) gene correlates with no substantial expression of KLK12 protein having serine protease activity.
The human kallikrein 12 (KLK12) gene is a new member of the KLK gene family, some members of which are implicated in the initiation and progression of cancer. In this study, we examined 50 non-cancerous tissues from Japanese patients with primary gastric cancer to determine the presence of genetic polymorphisms in the KLK12 gene using polymerase chain reaction (PCR)-single-strand conformation polymorphism and sequencing. Four different types of genetic polymorphisms were identified: one at a splice-donor site of intron 4 (c.457+2T>C), two in exon 6 (c.618_619delTG:p.Cys206fsX72 and c.735G>A:p.Met245Ile), and one in intron 3. The c.457+2T>C polymorphism was observed at a high frequency (allele frequency:0.63), compared to the frequencies of the two polymorphisms in exon 6 (allele frequency:0.01). Reverse transcriptase (RT)-PCR and Western blot analyses revealed that the c.457+2T>C polymorphism was associated with a splicing abnormality and that the expression of the human KLK12 protein (hK12), corresponding to the putative serine protease, was absent in individuals with a c.457+2C/C genotype but not in individuals with the T/T or T/C genotypes. We also found that recombinant His6-tagged hK12 has activity that cleaves chromogenic substrate (H-D-Pro-L-Phe-L-Arg-p-nitroaniline dihydrochloride), that is, serine protease activity. These results indicate that individuals with the c.457+2C/C genotype have no substantial expression of hK12 serine protease.


Mammalian CBX7 isoforms p36 and p22 exhibit differential responses to serum, varying functions for proliferation, and distinct subcellular localization.
CBX7 is a polycomb group protein, and despite being implicated in many diseases, its role in cell proliferation has been controversial: some groups described its pro-proliferative properties, but others illustrated its inhibitory effects on cell growth. To date, the reason for the divergent observations remains unknown. While several isoforms for CBX7 were reported, no studies investigated whether the divergent roles of CBX7 could be due to distinct functions of CBX7 isoforms. In this study, we newly identified mouse CBX7 transcript variant 1 (mCbx7v1), which is homologous to the human CBX7 gene (hCBX7v1) and is expressed in various mouse organs. We revealed that mCbx7v1 and hCBX7v1 encode a 36 kDa protein (p36CBX7) whereas mCbx7 and hCBX7v3 encode a 22 kDa protein (p22CBX7). This study further demonstrated that p36CBX7 was localized to the nucleus and endogenously expressed in proliferating cells whereas p22CBX7 was localized to the cytoplasm, induced by serum starvation in both human and mouse cells, and inhibited cell proliferation. Together, these data indicate that CBX7 isoforms are localized in different locations in a cell and play differing roles in cell proliferation. This varying function of CBX7 isoforms may help us understand the distinct function of CBX7 in various studies.


Changing gender roles and attitudes and their implications for well-being around the new millennium.
Given evidence that gender role attitudes (GRAs) and actual gender roles impact on well-being, we examine associations between GRAs, three roles (marital status, household chore division, couple employment) and psychological distress in working-age men and women. We investigate time-trends reflecting broader social and economic changes, by focusing on three age groups at two dates. We used British Household Panel Survey data from 20- to 64-year-olds in heterosexual couple households in 1991 (N = 5,302) and 2007 (N = 6,621). We examined: levels of traditional GRAs according to gender, age, date, household and employment roles; associations which GRAs and roles had with psychological distress (measured via the GHQ-12); whether psychological distress increased when GRAs conflicted with actual roles; and whether any of these associations differed according to gender, age or date. Gender traditionalism was lower among women, younger people, those participating in 2007 and in 'less traditional' relationships and households. Psychological distress was higher among those with more traditional GRAs and, particularly among men, for those not employed, and there was some evidence of different patterns of association according to age-group. There was limited evidence, among women only, of increased psychological distress when GRAs and actual roles conflicted and/or reductions when GRAs and roles agreed, particularly in respect of household chores and paid employment. Although some aspects of gender roles and attitudes (traditionalism and paid employment) are associated with well-being, others (marital status and household chores), and attitude-role consistency, may have little impact on the well-being of contemporary UK adults.


Dark-field X-ray ptychography.
The dynamic range of X-ray detectors is a key factor limiting both the spatial resolution and sensitivity of X-ray ptychography as well as the coherent flux of incident X-rays. Here, we propose a method for high-resolution and high-sensitivity X-ray ptychography named "dark-field X-ray ptychography", which compresses the dynamic range of intensities of diffraction patterns. In this method, a small reference object is aligned upstream of the sample. The scattered X-rays from the object work as a reference beam for in-line holography. Ptychographic diffraction patterns including the in-line hologram are collected, and then the image of the sample is reconstructed by an iterative phasing method. This method allows us to obscure the low-Q region of the diffraction patterns using a beamstop since the in-line hologram complements structural information in the low-Q region, resulting in the compression of the dynamic range of intensities of diffraction patterns. A numerical study shows that the dynamic range of intensities of diffraction patterns is decreased by about three orders of magnitude.


Net use, care and repair practices following a universal distribution campaign in Mali.
The Government of Mali and the President's Malaria Initiative conducted a long-lasting, insecticidal net (LLIN) distribution campaign in April 2011 in the Sikasso region of Mali, with the aim of universal coverage, defined as one insecticide-treated net for every two persons. This study examines how households in post- and pre-campaign regions value and care for nets. The study was conducted in October 2012 in Sikasso and Kayes in the southeast and western regions of Mali, respectively. The regions were purposively selected to allow for comparison between areas that had already had a mass distribution campaign (Sikasso) and areas that had not yet had a mass distribution campaign (Kayes). Study sites and households were randomly selected. Sleeping space questionnaires and structured interviews with household heads were conducted to obtain information on net use, perceived value of free nets in relation to other malaria prevention activities, and net care and repair practices. The study included 40 households, split evenly across the two regions. Forty interviews were conducted with household heads and 151 sleeping spaces were inventoried using the sleeping space questionnaire. Nets obtained through the free distribution were reported to be highly valued in comparison to other malaria prevention strategies. Overall, net ownership and use were higher among households in areas that had already experienced a mass distribution. While participants reported using and valuing these nets, care and repair practices varied. National net use is high in Mali, and comparatively higher in the region covered by the universal distribution campaign than in the region not yet covered. While the Government of Mali and implementing partners have made strides to ensure high net coverage, some gaps remain related to communication messaging of correct and consistent net use throughout the year, and on improving net care and repair behaviour. By focusing on these areas as well as improved access to nets, coverage and use rates should continue to increase, contributing to improvements in malaria control.


In vitro allergenicity of cows' milk substitutes.
There are numerous alternatives to cows' milk formula for allergic children. We have investigated the allergenicity of several of these using RAST and RAST inhibition on serum from 16 patients with a known history of cows' milk protein intolerance (CMPI) and 16 atopic controls. A RAST grade of > or = 3 for cows' milk was present in all those with CMPI, whilst all the controls gave RAST of < or = 1. Modified cows' milk formula, goats' infant formula, sheep and goats' milk produced similar results to cows' milk. Only two patients had RAST > or = 3 for soya milk and the soy/beef hydrolysate gave positive results in only three patients. One had positive RAST to Nutramigen and two to Pregestimil. Of the whey hydrolysates investigated, Pepti-junior gave seven positive RASTs whilst we were unable to bind Alfare to the sepharose in sufficient quantities to interpret the results which were negative in all cases. RAST inhibition data on pooled sera from the same patients agreed with the RAST results. The inhibition curves showed high inhibition with goats', sheep, modified cows' milk formula and the casein formula, AL110 (50%). Soy and soy/beef hydrolysate showed a much lower inhibition pattern. Casein hydrolysates showed low inhibition while the whey hydrolysate produced higher inhibition. We have shown that despite claims of low allergenicity, some of these alternative formulae are antigenically recognized in vitro by some cows' milk intolerant patients.


Gene expression profiling in human preadipocytes and adipocytes by microarray analysis.
Uncontrolled expansion of adipose tissue leads to obesity, a public health epidemic affecting >30% of adult Americans. Adipose mass increases in part through the recruitment and differentiation of an existing pool of preadipocytes (PA) into adipocytes (AD). Most studies investigating adipogenesis used primarily murine cell lines; much less is known about the relevant processes that occur in humans. Therefore, characterization of genes associated with adipocyte development is key to understanding the pathogenesis of obesity and developing treatments for this disorder. To address this issue, we performed large-scale analyses of human adipose gene expression using microarray technology. Differential gene expression between PA and AD was analyzed in 6 female patients using human cDNA microarray slides and data analyzed using the Stanford Microarray Database. Statistical analysis for the gene expression was performed using the SAS mixed models. Compared with PA, several genes involved in lipid metabolism were overexpressed in AD, including fatty acid binding protein, adipose differentiation-related protein, lipoprotein lipase, perilipin, and adipose most abundant transcript 1. Novel genes expressed in adipocytes included E2F5 transcriptional factor and SMARC (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin). PA predominantly expressed genes encoding extracellular matrix components such as fibronectin, matrix metalloprotein, and novel proteins such as lysyl oxidase. Despite the high differential expression of some of these genes, many did not differ significantly likely due to high variability and limited statistical power. A comprehensive list of differential gene expression is presented according to cellular function. In conclusion, these studies offer an overview of the gene expression profiles in PA and AD and identify new genes with potentially important functions in adipose tissue development and obesity that merit further investigation.


Microscopic and radiographic analysis of the effect of particle size of demineralized bovine cancellous bone matrix on the repair of bone defects in femurs of rabbits.
The bone tissue has a great regenerative potential, with ability to completely restore its structure and original functions. In some situations, though, bone defects cannot be self-repaired, thus requiring the use of grafts for a correct treatment and good prognosis. This work aimed at microscopically analyzing the effect of the particle size of demineralized bovine cancellous bone matrix in micro and macrogranular forms on the repair of bone defects in femurs of rabbits, with blood clot used as control. At 1, 3 and 6 months after implantation of the materials, the animals were killed and the anatomic specimens were removed. A foreign body-type granulomatous reaction containing macrophages and multinucleated giant cells in contact with the implanted particles was observed. These results suggest a failure in demineralization and/or interruption of the antigenic potential during production of the biomaterial. It is concluded that the size of the particles did not influence the evolution of the repair process of bone defects, acting only as bone-filler substances, and that the material implanted should be improved by quality control during production, since it may represent a good alternative for bone graft.


Deep Time Series Forecasting With Shape and Temporal Criteria.
This paper addresses the problem of multi-step time series forecasting for non-stationary signals that can present sudden changes. Current state-of-the-art deep learning forecasting methods, often trained with variants of the MSE, lack the ability to provide sharp predictions in deterministic and probabilistic contexts. To handle these challenges, we propose to incorporate shape and temporal criteria in the training objective of deep models. We define shape and temporal similarities and dissimilarities, based on a smooth relaxation of Dynamic Time Warping (DTW) and Temporal Distortion Index (TDI), that enable to build differentiable loss functions and positive semi-definite (PSD) kernels. With these tools, we introduce DILATE (DIstortion Loss including shApe and TimE), a new objective for deterministic forecasting, that explicitly incorporates two terms supporting precise shape and temporal change detection. For probabilistic forecasting, we introduce STRIPE++ (Shape and Time diverRsIty in Probabilistic for Ecasting), a framework for providing a set of sharp and diverse forecasts, where the structured shape and time diversity is enforced with a determinantal point process (DPP) diversity loss. Extensive experiments and ablations studies on synthetic and real-world datasets confirm the benefits of leveraging shape and time features in time series forecasting.


Coarse fibrillatory waves in atrial fibrillation predict success of electrical cardioversion.
To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (≥0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (χ2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors.


Specific light-up bioprobes based on AIEgen conjugates.
Driven by the high demand for sensitive and specific tools for optical sensing and imaging, bioprobes with various working mechanisms and advanced functionalities are flourishing at an incredible speed. Conventional fluorescent probes suffer from the notorious effect of aggregation-caused quenching that imposes limitation on their labelling efficiency or concentration to achieve desired sensitivity. The recently emerged fluorogens with an aggregation-induced emission (AIE) feature offer a timely remedy to tackle the challenge. Utilizing the unique properties of AIE fluorogens (AIEgens), specific light-up probes have been constructed through functionalization with recognition elements, showing advantages such as low background interference, a high signal to noise ratio and superior photostability with activatable therapeutic effects. In this tutorial review, we summarize the recent progress in the development of specific AIEgen-based light-up bioprobes. Through illustration of their operation mechanisms and application examples, we hope to provide guidelines for the design of more advanced AIE sensing and imaging platforms with high selectivity, great sensitivity and wide adaptability to a broad range of biomedical applications.


Alternative epigenetic chromatin states of polycomb target genes.
Polycomb (PcG) regulation has been thought to produce stable long-term gene silencing. Genomic analyses in Drosophila and mammals, however, have shown that it targets many genes, which can switch state during development. Genetic evidence indicates that critical for the active state of PcG target genes are the histone methyltransferases Trithorax (TRX) and ASH1. Here we analyze the repertoire of alternative states in which PcG target genes are found in different Drosophila cell lines and the role of PcG proteins TRX and ASH1 in controlling these states. Using extensive genome-wide chromatin immunoprecipitation analysis, RNAi knockdowns, and quantitative RT-PCR, we show that, in addition to the known repressed state, PcG targets can reside in a transcriptionally active state characterized by formation of an extended domain enriched in ASH1, the N-terminal, but not C-terminal moiety of TRX and H3K27ac. ASH1/TRX N-ter domains and transcription are not incompatible with repressive marks, sometimes resulting in a "balanced" state modulated by both repressors and activators. Often however, loss of PcG repression results instead in a "void" state, lacking transcription, H3K27ac, or binding of TRX or ASH1. We conclude that PcG repression is dynamic, not static, and that the propensity of a target gene to switch states depends on relative levels of PcG, TRX, and activators. N-ter TRX plays a remarkable role that antagonizes PcG repression and preempts H3K27 methylation by acetylation. This role is distinct from that usually attributed to TRX/MLL proteins at the promoter. These results have important implications for Polycomb gene regulation, the "bivalent" chromatin state of embryonic stem cells, and gene expression in development.


Impact of noncardiac congenital and genetic abnormalities on outcomes in hypoplastic left heart syndrome.
Hypoplastic left heart syndrome may coexist with noncardiac congenital defects or genetic syndromes. We explored the impact of such lesions on outcomes after staged univentricular palliation. Society of Thoracic Surgeons database 2002 to 2006: Children diagnosed with hypoplastic left heart syndrome who underwent stage 1 Norwood (n = 1,236), stage 2 superior cavopulmonary anastamosis (n = 702) or stage 3 Fontan (n = 553) procedures were studied. In-hospital mortality, postoperative complications, and length of stay were compared at each stage between those with and without noncardiac-genetic defects. Congenital Heart Surgeons' Society database 1994 to 2001: All 703 infants enrolled in the Congenital Heart Surgeons' Society critical left ventricular outflow tract obstruction study who underwent primary stage 1 palliation were reviewed. The impact of noncardiac defects-syndromes on survival was explored using multivariable parametric models with bootstrap bagging. Society of Thoracic Surgeons database: Stage 1 in-hospital mortality (26% vs 20%, p = 0.04) and mean postoperative length of stay (42 versus 31 days, p < 0.0001) were greater, and postoperative complications significantly more prevalent in infants with noncardiac-genetic defects. Congenital Heart Surgeons' Society database: Noncardiac-genetic defects were present in 55 (8%). Early hazard for death after Norwood was significantly worse in infants with noncardiac defects-syndromes (p = 0.008). Chromosomal defects (n = 14) were highly unfavorable: the early risk of death was doubled (10-year survival 25 +/- 9% vs 54 +/- 2%, p = 0.005). Turner syndrome accounted for the majority of chromosomal defects in this population (11 of 14, 79%). Mode of death was rarely attributable to the noncardiac-genetic defect. Survival in hypoplastic left heart syndrome is strongly influenced by the presence of noncardiac abnormalities. Strategies to improve mortality in infants with noncardiac abnormalities should be explored. Presence of chromosomal defects, especially Turner syndrome, should enter decision-management options for parents and physicians.


Health literacy: health professionals' understandings and their perceptions of barriers that Indigenous patients encounter.
Despite the growing interest in health literacy, little research has been done around health professionals' knowledge of health literacy or understandings of the barriers to health literacy that patients face when navigating the health care system. Indigenous peoples in New Zealand (NZ), Canada and Australia experience numerous inequalities in health status and outcomes and international evidence reveals that Indigenous, minority, and socio-economically disadvantaged populations have greater literacy needs. To address concerns in Indigenous health literacy, a two-pronged approach inclusive of both education of health professionals, and structural reform reducing demands the system places on Indigenous patients, are important steps towards reducing these inequalities. Four Indigenous health care services were involved in the study. Interviews and one focus group were employed to explore the experiences of health professionals working with patients who had experienced cardiovascular disease (CVD) and were taking medications to prevent future events. A thematic analysis was completed and these insights were used in the development of an intervention that was tested as phase two of the study. Analysis of the data identified ten common themes. This paper concentrates on health professionals' understanding of health literacy and perceptions of barriers that their patients face when accessing healthcare. Health professionals' concepts of health literacy varied and were associated with their perceptions of the barriers that their patients face when attempting to build health literacy skills. These concepts ranged from definitions of health literacy that were focussed on patient deficit to broader definitions that focussed on both patients and the health system. All participants identified a combination of cultural, social and systemic barriers as impediments to their Indigenous patients improving their health literacy knowledge and practices. This study suggests that health professionals have a limited understanding of health literacy and of the consequences of low health literacy for their Indigenous patients. This lack of understanding combined with the perceived barriers to improving health literacy limit health professionals' ability to improve their Indigenous patients' health literacy skills and may limit patients' capacity to improve understanding of their illness and instructions on how to manage their health condition/s.


Positron emission tomography study of voluntary saccadic eye movements and spatial working memory.
1. The purpose of this study is to define the cortical regions that subserve voluntary saccadic eye movements and spatial working memory in humans. 2. Regional cerebral blood flow (rCBF) during performance of oculomotor tasks was measured with [15O]-H2O positron emission tomography (PET). Eleven well-trained, healthy young adults performed the following tasks: visual fixation, visually guided saccades, antisaccades (a task in which subjects made saccades away from rather than toward peripheral targets), and either an oculomotor delayed response (ODR, a task requiring memory-guided saccades after a delay period) or a conditional antisaccade task (a task in which the color of the peripheral target determined whether a saccade toward or away from the target was required). An additional six subjects performed a sequential hand movement task to compare localization of hand-related motor cortex and the frontal eye fields (FEFs) and of the hand- and eye-movement-related regions of the supplementary motor area (SMA). 3. Friston's statistical parametric mapping (SPM) method was used to identify significant changes in rCBF associated with task performance. Because SPM does not take advantage of the anatomic information available in magnetic resonance (MR) scans, each subject's PET scan was registered to that individual's MR scan, after which all PET and MR studies were transformed to conform to a standard reference MR image set. Subtraction images were visually inspected while overlayed on the reference MR scan to which PET images had been aligned, in order to confirm anatomic localization of significant rCBF changes. 4. Compared with visual fixation, performing visually guided saccades led to a significant bilateral activation in FEF, cerebellum, striate cortex, and posterior temporal cortex. Right posterior thalamus activation was also observed. 5. The visually guided saccade task served as the comparison task for the ODR, antisaccade, and conditional antisaccade tasks for identification of task-related changes in rCBF beyond those associated with saccade execution. Performance on the ODR task was associated with a bilateral increase of rCBF in FEFs, SMA, dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex. The cortical regions of increased regional blood flow during the ODR task also showed increased rCBF during the antisaccade task; however, FEF and SMA activations were significant only in the right hemisphere. These findings closely parallel those of single-cell recording studies with behaving monkeys in indicating that FEF, DLPFC, SMA, and posterior parietal cortex perform computational activity for voluntary purposive saccades. 6. Comparison of PET scans obtained during performance of eye movement and hand movement tasks indicated that peak activations in FEF were located approximately 2 cm lateral and 1 cm anterior to those of hand-related motor cortex. The oculomotor area of SMA, the supplementary eye field (SEF), was located approximately 7-8 mm anterior and superior to the hand-related area of SMA. 7. During performance of antisaccade and ODR tasks, rCBF was significantly lower in ventromedial prefrontal cortex (PFC), along the rectus gyrus, and in ventral anterior cingulate cortex than during the visually guided saccade and fixation tasks. During the antisaccade task, the ventral region of lower rCBF involved medial structures including left ventral striatum and bilateral medial temporal-limbic cortex. During the ODR task, the ventral aspect of the region of lower rCBF extended laterally, rather than medially, to include the temporal poles. The lower blood flow observed in ventromedial PFC during both the antisaccade and ODR tasks, relative to the visually guided saccade and fixation tasks, suggests that modulation of output from ventromedial PFC to limbic cortex and the striatum may play a role in the voluntary control of saccadic eye movements, possibly in the suppression of responses that would interrupt


Accurate, multi-kb reads resolve complex populations and detect rare microorganisms.
Accurate evaluation of microbial communities is essential for understanding global biogeochemical processes and can guide bioremediation and medical treatments. Metagenomics is most commonly used to analyze microbial diversity and metabolic potential, but assemblies of the short reads generated by current sequencing platforms may fail to recover heterogeneous strain populations and rare organisms. Here we used short (150-bp) and long (multi-kb) synthetic reads to evaluate strain heterogeneity and study microorganisms at low abundance in complex microbial communities from terrestrial sediments. The long-read data revealed multiple (probably dozens of) closely related species and strains from previously undescribed Deltaproteobacteria and Aminicenantes (candidate phylum OP8). Notably, these are the most abundant organisms in the communities, yet short-read assemblies achieved only partial genome coverage, mostly in the form of short scaffolds (N50 = ∼ 2200 bp). Genome architecture and metabolic potential for these lineages were reconstructed using a new synteny-based method. Analysis of long-read data also revealed thousands of species whose abundances were <0.1% in all samples. Most of the organisms in this "long tail" of rare organisms belong to phyla that are also represented by abundant organisms. Genes encoding glycosyl hydrolases are significantly more abundant than expected in rare genomes, suggesting that rare species may augment the capability for carbon turnover and confer resilience to changing environmental conditions. Overall, the study showed that a diversity of closely related strains and rare organisms account for a major portion of the communities. These are probably common features of many microbial communities and can be effectively studied using a combination of long and short reads.


Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice.
The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multimeric signaling unit that phosphorylates protein kinase B/Akt following hormonal and growth factor stimulation. Defective Akt phosphorylation at the mTORC2-catalyzed Ser473 site has been linked to schizophrenia. While human imaging and animal studies implicate a fundamental role for Akt signaling in prefrontal dopaminergic networks, the molecular mechanisms linking Akt phosphorylation to specific schizophrenia-related neurotransmission abnormalities have not yet been described. Importantly, current understanding of schizophrenia suggests that cortical decreases in DA neurotransmission and content, defined here as cortical hypodopaminergia, contribute to both the cognitive deficits and the negative symptoms characteristic of this disorder. We sought to identify a mechanism linking aberrant Akt signaling to these hallmarks of schizophrenia. We used conditional gene targeting in mice to eliminate the mTORC2 regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior. In addition, they show reduced prefrontal dopamine (DA) content, elevated cortical norepinephrine (NE), unaltered cortical serotonin (5-HT), and enhanced expression of the NE transporter (NET). In the cortex, NET takes up both extracellular NE and DA. Thus, we propose that amplified NET function in rictor KO mice enhances accumulation of both NE and DA within the noradrenergic neuron. This phenomenon leads to conversion of DA to NE and ultimately supports both increased NE tissue content as well as a decrease in DA. In support of this hypothesis, NET blockade in rictor KO mice reversed cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression, which we show is ultimately influenced by Akt phosphorylation status. These data illuminate a molecular link, Akt regulation of NET, between the recognized association of Akt signaling deficits in schizophrenia with a specific mechanism for cortical hypodopaminergia and hypofunction. Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex.


Inequalities in health: living conditions and infant mortality in Northeastern Brazil.
OBJECTIVE To analyze the variation of infant mortality as per condition of life in the urban setting. METHODS Ecological study performed with data regarding registered deaths of children under the age of one who resided in Aracaju, SE, Northeastern Brazil, from 2001 to 2010. Infant mortality inequalities were assessed based on the spatial distribution of the Living Conditions Index for each neighborhood, classified into four strata. The average mortality rates of 2001-2005 and 2006-2010 were compared using the Student's t-test. RESULTS Average infant mortality rates decreased from 25.3 during 2001-2005 to 17.7 deaths per 1,000 live births in 2006-2010. Despite the decrease in the rates in all the strata during that decade, inequality of infant mortality risks increased in neighborhoods with worse living conditions compared with that in areas with better living conditions. CONCLUSIONS Infant mortality rates in Aracaju showed a decline, but with important differences among neighborhoods. The assessment based on a living condition perspective can explain the differences in the risks of infant mortality rates in urban areas, highlighting health inequalities in infant mortality as a multidimensional issue.


Limb Occlusion Pressure: A Method to Assess Changes in Systolic Blood Pressure.
Although often used as a surrogate, comparisons between traditional blood pressure measurements and limb occlusion assessed via hand-held Doppler have yet to be completed. Using limb occlusion pressure as a method of assessing systolic pressure is of interest to those studying the acute effects of blood flow restriction, where the removal of the cuff may alter the physiological response. We sought to determine how changes in limb occlusion pressure track with changes in traditional assessments of blood pressure. Limb occlusion pressure measured by hand-held Doppler and blood pressure measured by an automatic blood pressure cuff were assessed at rest and following isometric knee extension (post and 5 minutes post). Each individual had a similar dispersion from the mean value for both the limb occlusion pressure measurement and traditional systolic blood pressure measurement [BF10: 0.33; median (95% credible interval): 0.02 (-6.0, 5.9) %]. In response to lower body isometric exercise, blood pressure changed across time. The difference between measurements was small at immediately post and 5 minutes post. The Bayes factors were in the direction of the null but did not exceed the threshold needed to accept the null hypothesis. However, at 5 minutes post, the differences were within the range of practical equivalence (within ± 4.6%). Our findings suggest that changes in limb occlusion pressure measured by hand-held Doppler track similarly to traditional measurements of brachial systolic blood pressure following isometric knee extension exercise.


The exposome and health: Where chemistry meets biology.
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.