Plant components can reduce methylmercury toxication: A mini-review.
Methylmercury (MeHg) is a ubiquitous environmental pollutant, with the nervous system as its main target; however, the neurotoxic mechanisms of MeHg have not been fully elucidated, and no effective therapeutic and preventive drugs are available to mitigate its toxicity. Recent evidence suggests a reduction in the toxicity of MeHg by natural plant extracts. The aim of this review is to provide an overview of effective natural plant extracts and their putative biochemical mechanisms for blocking gut absorption, enhancing excretion and minimizing toxic effects of MeHg. Natural plant extracts may act as potential therapeutics in response to MeHg exposure. The roles plant components play in the reduction of MeHg toxicity may be multifaceted including: (1) attenuating neurobehavioral deficits; (2) facilitating demethylation of MeHg to inorganic mercury; (3) reducing MeHg absorption from the gastrointestinal tract; (4) redistributing MeHg to less sensitive target organs and tissues; (5) promoting enterohepatic circulation of MeHg to increase its biliary and intestinal excretion; (6) restoring intracellular redox status. The possible protective effects of natural plant components contribute to the understanding of mechanisms of MeHg toxicity and to the development of novel therapeutic strategies.


Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth.
The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/- mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/- mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.


The effects of intensified training on resting metabolic rate (RMR), body composition and performance in trained cyclists.
Recent research has demonstrated decreases in resting metabolic rate (RMR), body composition and performance following a period of intensified training in elite athletes, however the underlying mechanisms of change remain unclear. Therefore, the aim of the present study was to investigate how an intensified training period, designed to elicit overreaching, affects RMR, body composition, and performance in trained endurance athletes, and to elucidate underlying mechanisms. Thirteen (n = 13) trained male cyclists completed a six-week training program consisting of a "Baseline" week (100% of regular training load), a "Build" week (~120% of Baseline load), two "Loading" weeks (~140, 150% of Baseline load, respectively) and two "Recovery" weeks (~80% of Baseline load). Training comprised of a combination of laboratory based interval sessions and on-road cycling. RMR, body composition, energy intake, appetite, heart rate variability (HRV), cycling performance, biochemical markers and mood responses were assessed at multiple time points throughout the six-week period. Data were analysed using a linear mixed modeling approach. The intensified training period elicited significant decreases in RMR (F(5,123.36) = 12.0947, p = <0.001), body mass (F(2,19.242) = 4.3362, p = 0.03), fat mass (F(2,20.35) = 56.2494, p = <0.001) and HRV (F(2,22.608) = 6.5212, p = 0.005); all of which improved following a period of recovery. A state of overreaching was induced, as identified by a reduction in anaerobic performance (F(5,121.87) = 8.2622, p = <0.001), aerobic performance (F(5,118.26) = 2.766, p = 0.02) and increase in total mood disturbance (F(5, 110.61) = 8.1159, p = <0.001). Intensified training periods elicit greater energy demands in trained cyclists, which, if not sufficiently compensated with increased dietary intake, appears to provoke a cascade of metabolic, hormonal and neural responses in an attempt to restore homeostasis and conserve energy. The proactive monitoring of energy intake, power output, mood state, body mass and HRV during intensified training periods may alleviate fatigue and attenuate the observed decrease in RMR, providing more optimal conditions for a positive training adaptation.


Structure and mechanism in site-specific recombination.
Three-dimensional structural information on the integrase family of site-specific recombinases has only recently become available, with the crystal structures of catalytic domains, full-length proteins and protein-DNA complexes of this family reported over the past two years. These results have led to a model for the overall architecture and active site stereochemistry of the recombination pathway that addresses a number of interesting mechanistic issues.


Association of nerve growth factor receptors with the triton X-100 cytoskeleton of PC12 cells.
Triton X-100 solubilizes membranes of PC12 cells and leaves behind a nucleus and an array of cytoskeletal filaments. Nerve growth factor (NGF) receptors (10% of those found in intact cells) are associated with this Triton X-100-insoluble residue. Two classes of NGF receptors are found on PC12 cells which display rapid and slow dissociating kinetics. Although rapidly dissociating binding is predominant (greater than 75%) in intact cells, the majority of binding to the Triton X-100 cytoskeleton is slowly dissociating (greater than 75%). Rapidly dissociating NGF binding on intact cells can be converted to a slowly dissociating form by the plant lectin wheat germ agglutinin (WGA). This lectin also increases the number of receptors which associate with the Triton X-100 cytoskeleton by more than 10-fold. 125I-NGF bound to receptors can be visualized by light microscopy autoradiography in Triton X-100-insoluble residues of cell bodies, as well as growth cones and neurites. The WGA-induced association with the cytoskeleton, however, is not specific for the NGF receptor, since greater than 90% of cell surface glycoprotein receptors for WGA become associated with Triton X-100-insoluble material at lectin concentrations greater than 33 micrograms/ml. Concentrations of WGA which change the Triton X-100 solubility of membrane glycoproteins are similar to those required to alter the kinetic state of the NGF receptor. Both events may be related to the crossbridging of cell surface proteins induced by this multivalent lectin.


High-energy diets, fatty acids and endothelial cell function: implications for atherosclerosis.
Diets high in fat and/or calories can lead to hypertriglyceridemia and postprandial lipemia and thus are considered a risk factor for the development of atherosclerosis. Plasma chylomicron levels are elevated in humans after consuming a high-fat meal, and hepatic synthesis of VLDL is increased when caloric intake is in excess of body needs. High lipoprotein lipase activity and subsequent hydrolysis of triglyceride-rich lipoproteins may be an important source of elevated concentrations of fatty acid anions in the proximity to the endothelium and hence a major risk factor for atherosclerosis. We have shown that selected fatty acids, as well as lipoprotein lipase-derived remnants of lipoproteins isolated from hypertriglyceridemic subjects, can activate vascular endothelial cells and disrupt endothelial integrity. Our studies suggest that omega-6 fatty acids, and especially linoleic acid, cause endothelial cell dysfunction most markedly as well as can potentiate TNF-mediated endothelial cell injury. We propose that high-energy diets, and especially diets rich in linoleic acid, are atherogenic by contributing to an imbalance in cellular oxidative stress/antioxidant status of the endothelium, which can lead to activation of oxidative stress-responsive transcription factors, inflammatory cytokine production and the expression of adhesion molecules. Our data also suggest that nutrients, which have antioxidant and/or membrane stabilizing properties, can protect endothelial cells. These findings contribute to the understanding of the interactive role of high fat/calorie diets and subsequent hypertriglyceridemia with inflammatory components and nutrients that exhibit antiatherogenic properties in the development of atherosclerosis. Moreover, results from our research further support the concept that high-fat/calorie diets and associated postprandial hypertriglyceridemia are significant risk factors for atherosclerosis.


Understanding the population consequences of disturbance.
Managing the nonlethal effects of disturbance on wildlife populations has been a long-term goal for decision makers, managers, and ecologists, and assessment of these effects is currently required by European Union and United States legislation. However, robust assessment of these effects is challenging. The management of human activities that have nonlethal effects on wildlife is a specific example of a fundamental ecological problem: how to understand the population-level consequences of changes in the behavior or physiology of individual animals that are caused by external stressors. In this study, we review recent applications of a conceptual framework for assessing and predicting these consequences for marine mammal populations. We explore the range of models that can be used to formalize the approach and we identify critical research gaps. We also provide a decision tree that can be used to select the most appropriate model structure given the available data. Synthesis and applications: The implementation of this framework has moved the focus of discussion of the management of nonlethal disturbances on marine mammal populations away from a rhetorical debate about defining negligible impact and toward a quantitative understanding of long-term population-level effects. Here we demonstrate the framework's general applicability to other marine and terrestrial systems and show how it can support integrated modeling of the proximate and ultimate mechanisms that regulate trait-mediated, indirect interactions in ecological communities, that is, the nonconsumptive effects of a predator or stressor on a species' behavior, physiology, or life history.


From egocentric to exocentric spatial orientation: development of posture control in bimanual and trunk inclination tasks.
The authors investigated the emergence of independent control of body segments in bimanual tasks involving either voluntary or involuntary trunk motion by tracking the transition from an ego- to an exocentric mode of postural control during childhood (i.e., from body-referenced orientation to externally referenced action). A paradigm combining a seated manual task and various trunk manipulations described the coordination strategies used by 24 children at different ages (2 to 9 years) and by adults. The following questions were asked: (a) When do children begin to dissociate upper limb movements from those of the trunk? (b) What segmental strategies are exhibited by each age group (2-3, 4-6, and 7-9 years, and adults)? Kinematic analyses revealed that younger children (2-6 years) used either the trunk or the support surface as reference to orient the limbs. Older children (7-9 years) began to use a gravitational reference frame similar to that of adults; they uncoupled upper limb motion from the trunk in either voluntary or imposed conditions. Young children patterned the forearm trajectory after the initiating segment (support surface or the trunk), thus reducing the degrees of freedom during the dual task. Echoing previous reports, 7-9 years of age appears to be a critical period in which children master postural control and develop an internal representation of body scheme.


Contracting state mental hospital systems.
The predominant approach to contracting state mental hospital systems has been to close individual hospitals. Such a policy creates conflict between state government and the affected workers and communities. Closing of hospitals has been motivated by an implicit assumption on the part of state policy-makers that there are increasing returns to scale in mental hospitals. The bulk of empirical evidence suggests that returns to scale are constant. Thus, in many cases one may forego the political conflict inherent in closing hospitals by shrinking them with no loss in economic efficiency.


Nucleotide variations in the 3' A gamma enhancer region are linked to beta-gene cluster haplotypes and are unrelated to fetal hemoglobin expression.
Molecular cloning and sequence analysis of a nondeletion form of Sicilian beta o hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C----T at -158 5' to G gamma, T----C at +2285, C----A at +2476, and A----G at +2676, all 3' to A gamma. The latter three variations in the putative A gamma enhancer are identical to those observed in the case of Seattle HPFH. However, a severe beta o-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variation, albeit an inefficient HbF production. We conclude that the variations in the A gamma enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the beta-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black beta c-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between A gamma and psi beta, which is thus in linkage disequilibrium with the variations in the A gamma enhancer.(ABSTRACT TRUNCATED AT 250 WORDS)


Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics.
The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786 .


Climate change leads to increasing population density and impacts of a key island invader.
The considerable threats of invasive rodents to island biodiversity are likely to be compounded by climate change. Forecasts for such interactions have been most pronounced for the Southern Ocean islands where ameliorating conditions are expected to decrease thermal and resource restrictions on rodents. Firm evidence for changing rodent populations in response to climate change, and demonstrations of associated impacts on the terrestrial environment, are nonetheless entirely absent for the region. Using data collected over three decades on sub-Antarctic Marion Island, we tested empirically whether mouse populations have changed through time and whether these changes can be associated significantly with changing abiotic conditions. Changes in invertebrate populations, which have previously been attributed to mouse predation, but with little explicit demographic analysis, were also examined to determine whether they can be associated with changing mouse populations. The total number of mice on the island at annual peak density increased by 430.0% between 1979-1980 and 2008-2011. This increase was due to an advanced breeding season, which was robustly related to the number of precipitation-free days during the non-breeding season. Mice directly reduced invertebrate densities, with biomass losses of up to two orders of magnitude in some habitats. Such invertebrate declines are expected to have significant consequences for ecosystem processes over the long term. Our results demonstrate that as climate change continues to create ameliorating conditions for invasive rodents on sub-Antarctic islands, the severity of their impacts will increase. They also emphasize the importance of rodent eradication for the restoration of invaded islands.


Potentiation of lead-induced cell death in PC12 cells by glutamate: protection by N-acetylcysteine amide (NACA), a novel thiol antioxidant.
Oxidative stress has been implicated as an important factor in many neurological diseases. Oxidative toxicity in a number of these conditions is induced by excessive glutamate release and subsequent glutamatergic neuronal stimulation. This, in turn, causes increased generation of reactive oxygen species (ROS), oxidative stress, excitotoxicity, and neuronal damage. Recent studies indicate that the glutamatergic neurotransmitter system is involved in lead-induced neurotoxicity. Therefore, this study aimed to (1) investigate the potential effects of glutamate on lead-induced PC12 cell death and (2) elucidate whether the novel thiol antioxidant N-acetylcysteine amide (NACA) had any protective abilities against such cytotoxicity. Our results suggest that glutamate (1 mM) potentiates lead-induced cytotoxicity by increased generation of ROS, decreased proliferation (MTS), decreased glutathione (GSH) levels, and depletion of cellular adenosine-triphosphate (ATP). Consistent with its ability to decrease ATP levels and induce cell death, lead also increased caspase-3 activity, an effect potentiated by glutamate. Exposure to glutamate and lead elevated the cellular malondialdehyde (MDA) levels and phospholipase-A(2) (PLA(2)) activity and diminished the glutamine synthetase (GS) activity. NACA protected PC12 cells from the cytotoxic effects of glutamate plus lead, as evaluated by MTS assay. NACA reduced the decrease in the cellular ATP levels and restored the intracellular GSH levels. The increased levels of ROS and MDA in glutamate-lead treated cells were significantly decreased by NACA. In conclusion, our data showed that glutamate potentiated the effects of lead-induced PC12 cell death by a mechanism involving mitochondrial dysfunction (ATP depletion) and oxidative stress. NACA had a protective role against the combined toxic effects of glutamate and lead by inhibiting lipid peroxidation and scavenging ROS, thus preserving intracellular GSH.


Disparity in the natural cycles of Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis.
We studied the prevalence of Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis (HGE) among questing nymphal and adult Ixodes scapularis ticks of the same generation and the infectivity of wild white-footed mice for ticks feeding on them. The prevalence of B. burgdorferi infection in host-seeking ticks increased less than twofold from nymphal (31% to 33%) to adult (52% to 56%) stage, and 52% of white-footed mice were infected. Prevalence of the agent of HGE increased 4.5- to 10.6-fold from nymphal (1.5% to 1.8%) to adult stage (7.6% to 19.0%), while only 18% of mice were infectious to ticks. B. burgdorferi infection was more common in mouse-fed ticks than in ticks collected from vegetation, whereas the agent of HGE was half as common in mouse-fed ticks as in ticks collected from vegetation. The different prevalence in nature of these pathogens in ticks suggests that their maintenance cycles are also different.


Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study.
Since the release of the first global hepatitis elimination targets in 2016, and until the COVID-19 pandemic started in early 2020, many countries and territories were making progress toward hepatitis C virus (HCV) elimination. This study aims to evaluate HCV burden in 2020, and forecast HCV burden by 2030 given current trends. This analysis includes a literature review, Delphi process, and mathematical modelling to estimate HCV prevalence (viraemic infection, defined as HCV RNA-positive cases) and the cascade of care among people of all ages (age ≥0 years from birth) for the period between Jan 1, 2015, and Dec 31, 2030. Epidemiological data were collected from published sources and grey literature (including government reports and personal communications) and were validated among country and territory experts. A Markov model was used to forecast disease burden and cascade of care from 1950 to 2050 for countries and territories with data. Model outcomes were extracted from 2015 to 2030 to calculate population-weighted regional averages, which were used for countries or territories without data. Regional and global estimates of HCV prevalence, cascade of care, and disease burden were calculated based on 235 countries and territories. Models were built for 110 countries or territories: 83 were approved by local experts and 27 were based on published data alone. Using data from these models, plus population-weighted regional averages for countries and territories without models (n=125), we estimated a global prevalence of viraemic HCV infection of 0·7% (95% UI 0·7-0·9), corresponding to 56·8 million (95% UI 55·2-67·8) infections, on Jan 1, 2020. This number represents a decrease of 6·8 million viraemic infections from a 2015 (beginning of year) prevalence estimate of 63·6 million (61·8-75·8) infections (0·9% [0·8-1·0] prevalence). By the end of 2020, an estimated 12·9 million (12·5-15·4) people were living with a diagnosed viraemic infection. In 2020, an estimated 641 000 (623 000-765 000) patients initiated treatment. At the beginning of 2020, there were an estimated 56·8 million viraemic HCV infections globally. Although this number represents a decrease from 2015, our forecasts suggest we are not currently on track to achieve global elimination targets by 2030. As countries recover from COVID-19, these findings can help refocus efforts aimed at HCV elimination. John C Martin Foundation, Gilead Sciences, AbbVie, ZeShan Foundation, and The Hepatitis Fund.


In Vivo Wound Healing and In Vitro Anti-Inflammatory Activity Evaluation of Phlomis russeliana Extract Gel Formulations.
The air-dried aerial parts of Phlomis russeliana (Sims) Lag. Ex Benth. was extracted by methanol and fractionated by n-hexane, dichloromethane, and ethyl acetate, respectively. The wound healing properties of P. russeliana extract gel was evaluated using the in vivo excisional wound model using Balb-c mice. Initially, the P. russeliana methanol extract showed LOX inhibitory activity at IC50 = 23.2 µg/mL, whereas the DPPH• assay showed IC50 = 0.89 mg/mL, and the ABTS• assay showed IC50 = 0.99 mg/mL, respectively. In addition, a remarkable anti-inflammatory activity was observed in the cell culture assay. Thereafter, activity-guided fractionation was performed by LOX enzyme inhibition assays, and the structures of the two most active fractions were revealed by both GC-FID and GC/MS analyses, simultaneously. Phytol and 1-heptadecanoic acid were characterized as the active constituents. Moreover, the P. russeliana extract gel formulation was applied for in vivo tests, where the new gel formulation supported the in vitro anti-inflammatory activity findings. As a conclusion, this experimental results support the wound healing evidence based on the ethnobotanical application of Phlomis species with further potential.


Quantum Hall states stabilized in semi-magnetic bilayers of topological insulators.
By breaking the time-reversal symmetry in three-dimensional topological insulators with the introduction of spontaneous magnetization or application of magnetic field, the surface states become gapped, leading to quantum anomalous Hall effect or quantum Hall effect, when the chemical potential locates inside the gap. Further breaking of inversion symmetry is possible by employing magnetic topological insulator heterostructures that host non-degenerate top and bottom surface states. Here we demonstrate the tailored-material approach for the realization of robust quantum Hall states in the bilayer system, in which the cooperative or cancelling combination of the anomalous and ordinary Hall responses from the respective magnetic and non-magnetic layers is exemplified. The appearance of quantum Hall states at filling factor 0 and +1 can be understood by the relationship of energy band diagrams for the two independent surface states. The designable heterostructures of magnetic topological insulator may explore a new arena for intriguing topological transport and functionality.


A Low-Cost Method of Skin Swabbing for the Collection of DNA Samples from Small Laboratory Fish.
Fin clipping of live fish under anesthesia is widely used to collect samples for DNA extraction. An alternative, potentially less invasive, approach involves obtaining samples by swabbing the skin of nonanesthetized fish. However, this method has yet to be widely adopted for use in laboratory studies in the biological and biomedical sciences. Here, we compare DNA samples from zebrafish Danio rerio and three-spined sticklebacks Gasterosteus aculeatus collected via fin clipping and skin swabbing techniques, and test a range of DNA extraction methods, including commercially available kits and a lower-cost, in-house method. We verify the method for polymerase chain reaction analysis, and examine the potential risk of cross contamination between individual fish that are netted together. We show that swabbing, which may not require the use of anesthesia or analgesics, offers a reliable alternative to fin clipping. Further work is now required to determine the relative effects of fin clipping and swabbing on the stress responses and subsequent health of fish, and hence the potential of swabbing as a refinement to existing DNA sampling procedures.


Experiences of acupuncturists in a placebo-controlled, randomized clinical trial.
This paper describes the experiences of 8 licensed acupuncturists in a placebo-controlled randomized clinical trial (RCT). This information is important to the design and conduct of high-quality trials. We conducted a RCT (N=135) with a 2-week placebo run-in followed by 4 weeks of twice-weekly treatments comparing genuine to sham acupuncture (using the Streitberger placebo needle) in the treatment of arm pain caused by repetitive use. At the end of this study, we conducted written structured interviews with 8 participating acupuncturists. The acupuncturists were not aware of the study's results at the time of these interviews. The questions focused on their experiences in the study, adherence to study protocols, their thoughts about the technical and ethical issues involved in using a sham needling device, and their expectations of trial outcomes. The questions were motivated by expressions of concerns the acupuncturists raised in feedback groups during the course of the study, and our desire to improve further trials. The acupuncturists differed widely in their comfort levels with the research methods used, their adherence to the study protocol, and their expectations of trial outcomes. We conclude that careful monitoring of acupuncturists, including observation of treatments and frequent meetings to support them throughout the trial, is necessary to maintain a high degree of quality control.


The Neurobiological Effects of Electroconvulsive Therapy Studied Through Magnetic Resonance: What Have We Learned, and Where Do We Go?
Electroconvulsive therapy (ECT) is an established treatment choice for severe, treatment-resistant depression, yet its mechanisms of action remain elusive. Magnetic resonance imaging (MRI) of the human brain before and after treatment has been crucial to aid our comprehension of the ECT neurobiological effects. However, to date, a majority of MRI studies have been underpowered and have used heterogeneous patient samples as well as different methodological approaches, altogether causing mixed results and poor clinical translation. Hence, an association between MRI markers and therapeutic response remains to be established. Recently, the availability of large datasets through a global collaboration has provided the statistical power needed to characterize whole-brain structural and functional brain changes after ECT. In addition, MRI technological developments allow new aspects of brain function and structure to be investigated. Finally, more recent studies have also investigated immediate and long-term effects of ECT, which may aid in the separation of the therapeutically relevant effects from epiphenomena. The goal of this review is to outline MRI studies (T1, diffusion-weighted imaging, proton magnetic resonance spectroscopy) of ECT in depression to advance our understanding of the ECT neurobiological effects. Based on the reviewed literature, we suggest a model whereby the neurobiological effects can be understood within a framework of disruption, neuroplasticity, and rewiring of neural circuits. An improved characterization of the neurobiological effects of ECT may increase our understanding of ECT's therapeutic effects, ultimately leading to improved patient care.


Characterization of non-olfactory GPCRs in human sperm with a focus on GPR18.
G protein-coupled receptors (GPCRs) transduce external chemical cues into intracellular signals and are involved in a plethora of physiological processes, but knowledge regarding the function of these receptors in spermatozoa is limited. In the present study, we performed RNA-Seq and analyzed the expression of the all GPCRs except olfactory receptors in human spermatozoa. We revealed the expression of up to 223 different GPCR transcripts in human spermatozoa (FPKM > 0.1) and identified GPR18, a newly described cannabinoid receptor, together with GPR137 and GPR135, as one of the three most highly expressed GPCRs. To date, the expression of GPR18 was completely unknown in human spermatozoa. We confirmed GPR18 expression using RT-PCR and immuncytochemistry experiments and localized the GPR18 protein in the midpiece of human spermatozoa. Stimulation of human spermatozoa with the GPR18 ligand N-arachidonoylglycine induced the phosphorylation of 12 protein kinases, some of them are for example known to be involved in the acrosome reaction. In line with this, N-arachidonoylglycine affected the cytoskeleton by changing levels of F-actin and inducing the acrosome reaction in human spermatozoa in a concentration-dependent manner. Our results indicate that GPR18 might be involved in physiological processes of human spermatozoa, suggesting GPR18 to be a potential player in sperm physiology.


Multilevel non-volatile data storage utilizing common current hysteresis of networked single walled carbon nanotubes.
The characteristic source-drain current hysteresis frequently observed in field-effect transistors with networked single walled carbon-nanotube (NSWNT) channels is problematic for the reliable switching and sensing performance of devices. But the two distinct current states of the hysteresis curve at a zero gate voltage can be useful for memory applications. In this work, we demonstrate a novel non-volatile transistor memory with solution-processed NSWNTs which are suitable for multilevel data programming and reading. A polymer passivation layer with a small amount of water employed on the top of the NSWNT channel serves as an efficient gate voltage dependent charge trapping and de-trapping site. A systematic investigation evidences that the water mixed in a polymer passivation solution is critical for reliable non-volatile memory operation. The optimized device is air-stable and temperature-resistive up to 80 °C and exhibits excellent non-volatile memory performance with an on/off current ratio greater than 10(4), a switching time less than 100 ms, data retention longer than 4000 s, and write/read endurance over 100 cycles. Furthermore, the gate voltage dependent charge injection mediated by water in the passivation layer allowed for multilevel operation of our memory in which 4 distinct current states were programmed repetitively and preserved over a long time period.


Violation of Heisenberg's measurement-disturbance relationship by weak measurements.
While there is a rigorously proven relationship about uncertainties intrinsic to any quantum system, often referred to as "Heisenberg's uncertainty principle," Heisenberg originally formulated his ideas in terms of a relationship between the precision of a measurement and the disturbance it must create. Although this latter relationship is not rigorously proven, it is commonly believed (and taught) as an aspect of the broader uncertainty principle. Here, we experimentally observe a violation of Heisenberg's "measurement-disturbance relationship", using weak measurements to characterize a quantum system before and after it interacts with a measurement apparatus. Our experiment implements a 2010 proposal of Lund and Wiseman to confirm a revised measurement-disturbance relationship derived by Ozawa in 2003. Its results have broad implications for the foundations of quantum mechanics and for practical issues in quantum measurement.


Response of soybean to seed inoculation with Bradyrhizobium japonicum and with mixed inoculants of B. japonicum and Azotobacter chroococcum.
Effects of pre-sowing soybean seed inoculation with Bradyrhizobium japonicum alone or with mixed inoculants containing soybean rhizobia and Azotobacter chroococcum were compared. In the pot experiment all the tested strains of soybean rhizobia in pure cultures or in mixtures with A. chroococcum significantly improved nodulation of soybean plants and seed yields of this crop. In micro-plot experiments pre-sowing soybean seeds treatment with the inoculant containing the most effective strain 94P of B. japonicum alone or with the mixed inoculant of strain 94P and A. chroococcum were equally effective in improving nodulation intensity and seed yields of soybean in comparison to the uninoculated soybean.


Postquantum Steering.
The discovery of postquantum nonlocality, i.e., the existence of nonlocal correlations that are stronger than any quantum correlations but nevertheless consistent with the no-signaling principle, has deepened our understanding of the foundations of quantum theory. In this work, we investigate whether the phenomenon of Einstein-Podolsky-Rosen steering, a different form of quantum nonlocality, can also be generalized beyond quantum theory. While post-quantum steering does not exist in the bipartite case, we prove its existence in the case of three observers. Importantly, we show that postquantum steering is a genuinely new phenomenon, fundamentally different from postquantum nonlocality. Our results provide new insight into the nonlocal correlations of multipartite quantum systems.


Metallization of the C60/Rh(100) interface revealed by valence photoelectron spectroscopy and density functional theory calculations.
The electronic structure of single and multiple layers of C(60) molecules deposited on a Rh(100) surface is investigated by means of valence photoemission spectroscopy and density functional theory calculations. The binding of the fullerene monolayer to the metal surface yields the appearance of a new state in the valence band spectrum crossing the Fermi level. Insight into the metallization of the metal/fullerene interface is provided by the calculated electronic structure that allows us to correlate the measured interface state with a strong hybridization between the Rh metal states and the highest and lowest molecular orbitals. This results in a net charge transfer of approximately 0.5e-0.6e from the metal to the p states of the interfacial C atoms. The charge transfer is shown to be very short range, involving only the C atoms bound to the metal. The electronic structure of the second C(60) layer is already insulating and resembles the one measured for C(60) multilayers supported by the same substrate or calculated for fullerenes isolated in vacuum. The discussion of the results in the context of other C(60)/metal systems highlights the distinctive electronic properties of the molecule/metal interface determined by the Rh support.


The ZKIR Assay, a Real-Time PCR Method for the Detection of Klebsiella pneumoniae and Closely Related Species in Environmental Samples.
Klebsiella pneumoniae is of growing public health concern due to the emergence of strains that are multidrug resistant, virulent, or both. Taxonomically, the K. pneumoniae complex ("Kp") includes seven phylogroups, with Kp1 (K. pneumoniaesensu stricto) being medically prominent. Kp can be present in environmental sources such as soils and vegetation, which could act as reservoirs of animal and human infections. However, the current lack of screening methods to detect Kp in complex matrices limits research on Kp ecology. Here, we analyzed 1,001 genome sequences and found that existing molecular detection targets lack specificity for Kp. A novel real-time PCR method, the ZKIR (zur-khe intergenic region) assay, was developed and used to detect Kp in 96 environmental samples. The results were compared to a culture-based method using Simmons citrate agar with 1% inositol medium coupled to matrix-assisted laser desorption ionization-time of flight mass spectrometry identification. Whole-genome sequencing of environmental Kp was performed. The ZKIR assay was positive for the 48 tested Kp reference strains, whereas 88 non-Kp strains were negative. The limit of detection of Kp in spiked soil microcosms was 1.5 × 10-1 CFU g-1 after enrichment for 24 h in lysogeny broth supplemented with ampicillin, and it was 1.5 × 103 to 1.5 × 104 CFU g-1 directly after soil DNA extraction. The ZKIR assay was more sensitive than the culture method. Kp was detected in 43% of environmental samples. Genomic analysis of the isolates revealed a predominance of phylogroups Kp1 (65%) and Kp3 (32%), a high genetic diversity (23 multilocus sequence types), a quasi-absence of antibiotic resistance or virulence genes, and a high frequency (50%) of O-antigen type 3. This study shows that the ZKIR assay is an accurate, specific, and sensitive novel method to detect the presence of Kp in complex matrices and indicates that Kp isolates from environmental samples differ from clinical isolates.IMPORTANCE The Klebsiella pneumoniae species complex Kp includes human and animal pathogens, some of which are emerging as hypervirulent and/or antibiotic-resistant strains. These pathogens are diverse and classified into seven phylogroups, which may differ in their reservoirs and epidemiology. Proper management of this public health hazard requires a better understanding of Kp ecology and routes of transmission to humans. So far, detection of these microorganisms in complex matrices such as food or the environment has been difficult due to a lack of accurate and sensitive methods. Here, we describe a novel method based on real-time PCR which enables detection of all Kp phylogroups with high sensitivity and specificity. We used this method to detect Kp isolates from environmental samples, and we show based on genomic sequencing that they differ in antimicrobial resistance and virulence gene content from human clinical Kp isolates. The ZKIR PCR assay will enable rapid screening of multiple samples for Kp presence and will thereby facilitate tracking the dispersal patterns of these pathogenic strains across environmental, food, animal and human sources.


A splice site mutation in laminin-α2 results in a severe muscular dystrophy and growth abnormalities in zebrafish.
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2). Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501), exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.


Bridging the gap between in silico and cell-based analysis of the nuclear factor-kappaB signaling pathway by in vitro studies of IKK2.
Previously, we have shown by sensitivity analysis, that the oscillatory behavior of nuclear factor (NF-kappaB) is coupled to free IkappaB kinase-2 (IKK2) and IkappaBalpha(IkappaBalpha), and that the phosphorylation of IkappaBalpha by IKK influences the amplitude of NF-kappaB oscillations. We have performed further analyses of the behavior of NF-kappaB and its signal transduction network to understand the dynamics of this system. A time lapse study of NF-kappaB translocation in 10,000 cells showed discernible oscillations in levels of nuclear NF-kappaB amongst cells when stimulated with interleukin (IL-1alpha), which suggests a small degree of synchronization amongst the cell population. When the kinetics for the phosphorylation of IkappaBalpha by IKK were measured, we found that the values for the affinity and catalytic efficiency of IKK2 for IkappaBalpha were dependent on assay conditions. The application of these kinetic parameters in our computational model of the NF-kappaB pathway resulted in significant differences in the oscillatory patterns of NF-kappaB depending on the rate constant value used. Hence, interpretation of in silico models should be made in the context of this uncertainty.


A non-hallucinogenic psychedelic analogue with therapeutic potential.
The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.


Quality of private and public ambulatory health care in low and middle income countries: systematic review of comparative studies.
In developing countries, the private sector provides a substantial proportion of primary health care to low income groups for communicable and non-communicable diseases. These providers are therefore central to improving health outcomes. We need to know how their services compare to those of the public sector to inform policy options. We summarised reliable research comparing the quality of formal private versus public ambulatory health care in low and middle income countries. We selected studies against inclusion criteria following a comprehensive search, yielding 80 studies. We compared quality under standard categories, converted values to a linear 100% scale, calculated differences between providers within studies, and summarised median values of the differences across studies. As the results for for-profit and not-for-profit providers were similar, we combined them. Overall, median values indicated that many services, irrespective of whether public or private, scored low on infrastructure, clinical competence, and practice. Overall, the private sector performed better in relation to drug supply, responsiveness, and effort. No difference between provider groups was detected for patient satisfaction or competence. Synthesis of qualitative components indicates the private sector is more client centred. Although data are limited, quality in both provider groups seems poor, with the private sector performing better in drug availability and aspects of delivery of care, including responsiveness and effort, and possibly being more client orientated. Strategies seeking to influence quality in both groups are needed to improve care delivery and outcomes for the poor, including managing the increasing burden of non-communicable diseases.


Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).
Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 μg/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN.


Neuroleptic malignant syndrome: a case responding to electroconvulsive therapy plus bupropion.
Neuroleptic malignant syndrome (NMS) is a severe motor syndrome occurring as a consequence of neuroleptic treatment. We present a case of a 67-year-old Caucasian woman with a history of a major depressive disorder with psychotic features. During her third hospital admission, symptoms of autonomic instability, hyperpyrexia, severe extrapyramidal side effects, and delirium appeared, suggesting NMS due to concomitant treatment with risperidone and quetiapine, among other drugs. Despite several consecutive pharmacological treatments (lorazepam, bromocriptine and amantadine) and prompt initiation of electroconvulsive therapy (ECT), clinical improvement was observed only after combining bupropion with ECT. The symptoms that had motivated the admission gradually remitted and the patient was discharged home. Bupropion increases dopaminergic activity in both the nucleus accumbens and the prefrontal cortex. Therefore, from a physiopathological standpoint, bupropion has a potential role in treating NMS. However, there is scarce evidence supporting this approach and therefore future cases should be carefully considered.


Synergy between experimental and theoretical methods in the exploration of homogeneous transition metal catalysis.
In this Perspective, we will focus on the use of both experimental and theoretical methods in the exploration of reaction mechanisms in homogeneous transition metal catalysis. We briefly introduce the use of Hammett studies and kinetic isotope effects (KIE). Both of these techniques can be complemented by computational chemistry - in particular in cases where interpretation of the experimental results is not straightforward. The good correspondence between experiment and theory is only possible due to recent advances within the applied theoretical framework. We therefore also highlight the innovations made in the last decades with emphasis on dispersion-corrected DFT and solvation models. The current state-of-the-art is highlighted using examples from the literature with particular focus on the synergy between experiment and theory.


Methionine sulfoxide profiling of milk proteins to assess the influence of lipids on protein oxidation in milk.
Thermal treatment of milk and milk products leads to protein oxidation, mainly the formation of methionine sulfoxide. Reactive oxygen species, responsible for the oxidation, can be generated by Maillard reaction, autoxidation of sugars, or lipid peroxidation. The present study investigated the influence of milk fat on methionine oxidation in milk. For this purpose, quantitative methionine sulfoxide profiling of all ten methionine residues of β-lactoglobulin, α-lactalbumin, and αs1-casein was carried out by ultrahigh-performance liquid chromatography-electrospray ionization tandem mass spectrometry with scheduled multiple reaction monitoring (UHPLC-ESI-MS/MS-sMRM). Analysis of defatted and regular raw milk samples after heating for up to 8 min at 120 °C and analysis of ultrahigh-temperature milk samples with 0.1%, 1.5%, and 3.5% fat revealed that methionine oxidation of the five residues of the whey proteins and of residues M 123, M 135, and M 196 of αs1-casein was not affected or even suppressed in the presence of milk fat. Only the oxidation of residues M 54 and M 60 of αs1-casein was promoted by lipids. In evaporated milk samples, formation of methionine sulfoxide was hardly influenced by the fat content of the samples. Thus, it can be concluded that lipid oxidation products are not the major cause of methionine oxidation in milk.


Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study.
Allergic rhinitis (AR) is a disease characterized by IgE-mediated, allergic inflammation of the nasal mucosa. T helper (Th) 2 cells play an important role in the development of IgE-mediated diseases such as AR, with local overproduction of Th2 cytokines (IL-4, IL-5 and IL-13) at the site of allergic inflammation. Th1 cytokines (IL-12 and IFN-gamma) are known to suppress this Th2 immune response, aiding the treatment of these diseases. Beta-1,3-1,6-glucan (Glucan) is an immunomodulator stimulating particularly the antitumor response. An efficient antitumor stimulation can be achieved through a Th1-mediated immune response. The aim of this study was to investigate the effects of Glucan on the immunopathogenic processes in the microenvironment to determine if it reverses the Th2-mediated immune response in AR to Th1-mediated response. 24 Olea europea mono-sensitized patients with AR were randomized into Glucan and placebo groups. The Glucan group consisted of 12 patients who received Glucan treatment for 12 weeks, while the placebo group of 12 patients received placebo during the same period. A nasal provocation test (NPT) with Olea europea was performed at the beginning and end of treatment, and nasal lavage followed the positive NPT. IL-4, IL-5, IFN-gamma and IL-12 levels and the eosinophil count (%) were measured in nasal lavage fluid (NLF) samples. Simultaneously, peripheral blood eosinophil % values were measured. After treatment, IL-4 and IL-5 levels in NLF from the Glucan group were found to have decreased significantly (p = 0.027, p = 0.04; respectively), while IL-12 levels were found to have significantly increased (p = 0.008). However, IFN-gamma levels had not changed. On the other hand, none of the cytokine levels had changed significantly in the placebo group following treatment. Moreover, the percentage of eosinophils in the NLF was found to have decreased significantly after treatment in the Glucan group (p = 0.01), while that of the placebo group did not change. Peripheral blood percentage eosinophil levels had not changed significantly in any group. Th2-originated IL-4 and IL-5 levels responsible for the allergic inflammatory response in the microenvironment of patients with AR, are decreased with Glucan while levels of Th1-originated IL-12 are increased. Moreover, eosinophils, which are important effector cells of the inflammatory response, are decreased in the microenvironment. As a result, Glucan may have a role as an adjunct to standard treatment in patients with AR.


Polymorphisms of 5-HTT LPR and GNβ3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.
The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNβ3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNβ3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNβ3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. GNβ3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNβ3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). GNβ3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.


Comparison of different statistical approaches for urinary peptide biomarker detection in the context of coronary artery disease.
When combined with a clinical outcome variable, the size, complexity and nature of mass-spectrometry proteomics data impose great statistical challenges in the discovery of potential disease-associated biomarkers. The purpose of this study was thus to evaluate the effectiveness of different statistical methods applied for urinary proteomic biomarker discovery and different methods of classifier modelling in respect of the diagnosis of coronary artery disease in 197 study subjects and the prognostication of acute coronary syndromes in 368 study subjects. Computing the discovery sub-cohorts comprising [Formula: see text] of the study subjects based on the Wilcoxon rank sum test, t-score, cat-score, binary discriminant analysis and random forests provided largely different numbers (ranging from 2 to 398) of potential peptide biomarkers. Moreover, these biomarker patterns showed very little overlap limited to fragments of type I and III collagens as the common denominator. However, these differences in biomarker patterns did mostly not translate into significant differently performing diagnostic or prognostic classifiers modelled by support vector machine, diagonal discriminant analysis, linear discriminant analysis, binary discriminant analysis and random forest. This was even true when different biomarker patterns were combined into master-patterns. In conclusion, our study revealed a very considerable dependence of peptide biomarker discovery on statistical computing of urinary peptide profiles while the observed diagnostic and/or prognostic reliability of classifiers was widely independent of the modelling approach. This may however be due to the limited statistical power in classifier testing. Nonetheless, our study showed that urinary proteome analysis has the potential to provide valuable biomarkers for coronary artery disease mirroring especially alterations in the extracellular matrix. It further showed that for a comprehensive discovery of biomarkers and thus of pathological information, the results of different statistical methods may best be combined into a master pattern that then can be used for classifier modelling.


Nitrogen supplementation of corn silages. 2. Assessing rumen function using fatty acid profiles of bovine milk.
The effects of N supplementation strategies on milk fatty acid profiles of dairy cows and their use as a noninvasive technique to diagnose rumen function, and to guide protein feeding decisions on-farm were evaluated in three experiments. Each experiment was designed according to three 3 x 3 Latin squares with 9 Holstein cows receiving total mixed rations based on corn silage. Experiment 1 was designed to study effects of diets with different ratios of effective rumen-degradable protein (ERDP; g) to fermentable metabolizable energy (FME; j) providing, respectively, a large deficiency, a slight deficiency, and a slight excess in relation to the target level of 11 g of ERDP/MJ FME for lactating cows. Experiment 2 evaluated effects of different proportions of quickly and slowly rumen-degradable protein achieved by replacing soybean meal with urea in the concentrates (0, 0.5, and 1% urea for U0, U5, and U10, respectively). Experiment 3 investigated effects of synchronizing the availability of FME and ERDP in rumen by offering the protein-rich concentrate once or twice per day before the meal (corn silage, ryegrass hay, and energy-rich concentrate), or included in the total mixed ration. Milk fatty acid profiles were significantly affected by dietary N and carbohydrate supply. Principal component factor analysis provided a reasonable description of the data, clearly discriminating between fatty acids that are synthesized by different metabolic pathways. Several sources/pathways were distinguished: de novo synthesis in the mammary gland (short- and medium-chain fatty acids), delta9-desaturase activity (monoenoic fatty acids), direct absorption from the blood stream (long-chain fatty acids), and de novo synthesis by the rumen microbial populations (odd-chain fatty acids). Discriminant canonical analysis showed that milk odd-chain fatty acids had a higher ability to discriminate between diets than even-chain fatty acids. The anteiso C15:0 increased in line with increasing sugar supply, and C17:0 appears to be a marker of protein deficiency. Additionally, iso C17:0 and anteiso C17:0 were associated with the NDF and CP contents of diets. The results suggests that milk odd-chain fatty acids have the potential to be used as a noninvasive technique to assess rumen function in terms of microbial populations, substrates and interactions.


Rapid transcriptome responses of maize (Zea mays) to UV-B in irradiated and shielded tissues.
Depletion of stratospheric ozone has raised terrestrial levels of ultraviolet-B radiation (UV-B), an environmental change linked to an increased risk of skin cancer and with potentially deleterious consequences for plants. To better understand the processes of UV-B acclimation that result in altered plant morphology and physiology, we investigated gene expression in different organs of maize at several UV-B fluence rates and exposure times. Microarray hybridization was used to assess UV-B responses in directly exposed maize organs and organs shielded by a plastic that absorbs UV-B. After 8 hours of high UV-B, the abundance of 347 transcripts was altered: 285 were increased significantly in at least one organ and 80 were downregulated. More transcript changes occurred in directly exposed than in shielded organs, and the levels of more transcripts were changed in adult compared to seedling tissues. The time course of transcript abundance changes indicated that the response kinetics to UV-B is very rapid, as some transcript levels were altered within 1 hour of exposure. Most of the UV-B regulated genes are organ-specific. Because shielded tissues, including roots, immature ears, and leaves, displayed altered transcriptome profiles after exposure of the plant to UV-B, some signal(s) must be transmitted from irradiated to shielded tissues. These results indicate that there are integrated responses to UV-B radiation above normal levels. As the same total UV-B irradiation dose applied at three intensities elicited different transcript profiles, the transcriptome changes exhibit threshold effects rather than a reciprocal dose-effect response. Transcriptome profiling highlights possible signaling pathways and molecules for future research.


Daytime Cheyne-Stokes respiration in ambulatory patients with severe congestive heart failure is associated with increased mortality.
Cheyne-Stokes respiration (CSR) frequently occurs in patients with severe heart failure during sleep and may increase mortality. Daytime CSR supposedly poses an even greater risk, but its prevalence and prognostic importance remain elusive. Therefore, we investigated the circadian prevalence of CSR and its influence on survival in patients with heart failure. In 60 consecutive ambulatory patients (mean age+/-SE, 58.0+/-1.5 years; 6 women) with stable severe heart failure (left ventricular ejection fraction, 26+/-1%; New York Heart Association [NYHA] class, 2.6+/-0.1), the breathing pattern was unobtrusively monitored during 24 h of usual activities with a portable respiratory inductive plethysmograph. During nights, 62% of patients had >or=15 periodic breathing cycles per hour; during days, the corresponding prevalence was 16%. CSR prevailed in 32+/-3% of the night and in 10+/-2% of the day, with peaks at 4:00 am, 2:00 pm, and 6:00 pm. Eighteen patients with CSR during >or=10% of the daytime lived shorter without heart transplantation than 42 patients with <10% of daytime CSR (p<0.05) during 836+/-27 days of follow-up. CSR during >or=10% of the daytime was an independent predictor of mortality (hazard ratio, 3.8; 95% confidence interval, 1.1 to 12.7; p<0.05) when controlling for age, sex, brain natriuretic peptide, left ventricular ejection fraction, and NYHA class. CSR occurs in 62% of patients with severe heart failure at night and in 16% during the day. Since daytime CSR is associated with reduced survival, solely performing sleep studies may not allow to adequately assess prognosis and tailor treatment in patients with severe heart failure.


Including older patients in cancer trials: A qualitative study of collaboration between geriatricians and oncologists.
The under-representation of older patients in cancer trials remains an important obstacle to the generation of data on efficacy and safety in this growing patient population. In France, geriatric oncology coordination units (UCOGs) have been created to help oncologists and geriatricians work together on research, best practice, and continuing medical education. Taking these units as a case study, this paper sheds light on the collaboration between geriatricians and oncologists in the inclusion process of older patients in cancer trials. Empirical data were gathered in a series of sociological interviews with all 16 oncologists, geriatricians and unit coordinators in the five UCOGs in the greater Paris region of France. The case of French geriatric oncology coordination units shows the gap between professional research cultures in oncology and geriatrics that may account for the low observed inclusion rates. It is easier to include patients in randomized clinical trials than in observational studies. UCOGs have the potential to improve research in geriatric oncology by catalyzing the development and implementation of effective collaboration tools (such as frailty assessments). The units also have the potential to promote Phase IV trials and observational research that are suitable for older patients with cancer. Bridging the cultural gap between oncologists (the dominant force in setting the cancer research agenda) and geriatricians (a source of specific knowledge and know-how) is essential for producing relevant trial protocols that match the specific yet diverse features of older patient populations.


Effect of exercise on thicknesses of mature hyaline cartilage, calcified cartilage, and subchondral bone of equine tarsi.
OBJECTIVE-To investigate effects of exercise on hyaline cartilage (HC), calcified cartilage (CC), and subchondral bone (SCB) thickness patterns of equine tarsi. SAMPLE POPULATION-30 tarsi from cadavers of horses with known exercise history. PROCEDURES-Tarsi were assigned to 3 groups according to known exercise history as follows: pasture exercise only (PE tarsi), low-intensity general-purpose riding exercise (LE tarsi), and high-intensity elite competition riding exercise (EE tarsi). Osteochondral tissue from distal tarsal joints underwent histologic preparation. Hyaline cartilage, CC, and SCB thickness were measured at standard sites at medial, midline, and lateral locations across joints with a histomorphometric technique. RESULTS-HC, CC, and SCB thickness were significantly greater at all sites in EE tarsi, compared with PE tarsi; this was also true when LE tarsi were compared with PE tarsi. At specific sites, HC, CC, and SCB were significantly thicker in EE tarsi, compared with LE tarsi. Along the articular surface of the proximal aspect of the third metatarsal bone, SCB was thickest in EE tarsi and thinnest in LE tarsi; increases were greatest at sites previously reported to undergo peak strains and osteochondral damage. CONCLUSIONS AND CLINICAL RELEVANCE-Increased exercise was associated with increased HC, CC, and SCB thickness in mature horses. At sites that undergo high compressive strains, with a reported predisposition to osteoarthritic change, there was increased CC and SCB thickness. These results may provide insight into the interaction between adaptive response to exercise and pathological change.


Testing for gluten-related disorders in clinical practice: the role of serology in managing the spectrum of gluten sensitivity.
Immunoglobulin A tissue transglutaminase is the single most efficient serological test for the diagnosis of celiac disease. It is well known that immunoglobulin A tissue transglutaminase levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with celiac disease. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Antigliadin tests are no longer recommended for the diagnosis of classical celiac disease. However, our understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. Studies are needed to determine the clinical utility of antigliadin serology in the diagnosis of gluten sensitivity.


Rituals, Repetitiveness and Cognitive Load : A Competitive Test of Ritual Benefits for Stress.
A central hypothesis to account for the ubiquity of rituals across cultures is their supposed anxiolytic effects: rituals being maintained because they reduce existential anxiety and uncertainty. We aimed to test the anxiolytic effects of rituals by investigating two possible underlying mechanisms for it: cognitive load and repetitive movement. In our pre-registered experiment (osf.io/rsu9x), 180 undergraduates took part in either a stress or a control condition and were subsequently assigned to either control, cognitive load, undirected movement, a combination of undirected movement and cognitive load, or a ritualistic intervention. Using both repeated self-report measures and continuous physiological indicators of anxiety, we failed to find direct support for a cognitive suppression effect of anxiety through ritualistic behavior. Nevertheless, we found that induced stress increased participants' subsequent repetitive behavior, which in turn reduced physiological arousal. This study provides novel evidence for plausible underlying effects of the proposed anxiolytic effect of rituals: repetitive behavior but not cognitive load may decrease physiological stress responses during ritual.


RAS-related protein 1: an estrogen-responsive gene involved in development and molting-mediated regeneration of the female reproductive tract in chickens.
It is important to identify molecular candidates involved in morphological and functional changes in the female reproductive system. We have discovered several candidate genes that were significantly altered in chick oviducts by exogenous estrogen and those candidates included dexamethasone (DEX)-induced RAS-related protein 1 (RASD1). RAS-related protein 1, a member of the Ras family of monomeric G proteins, is involved in various cellular processes including cell growth, proliferation and differentiation, as well as a cell-signaling protein regulating hormonal actions. Although the RASD1 gene was first identified as a DEX (a corticosteroid) inducible gene, there is evidence that it is also an estrogen-responsive gene. However, hormone-mediated expression and biological functions of RASD1 in the avian female reproductive system are poorly understood. Therefore, we tested the hypothesis that RASD1 may be involved in the development and remodeling of the chicken reproductive system as an estrogen-responsive gene. Here we demonstrate differential expression of RASD1 gene and candidate microRNAs (miRNAs) targeting chicken RASD1 transcripts in chicken oviducts in response to diesthylstilbestrol (DES, a synthetic non-steroidal estrogen) and the estrogen-mediated molting process. Result of the present study indicated that expression of RASD1 messenger RNA (mRNA) increased in the developing oviducts of chicks treated with DES, particularly in the glandular (GE) and luminal (LE) epithelia of the magnum and the shell gland. Also, during induced molting by zinc feeding, RASD1 expression changed in concert with changes in concentrations of estrogen in blood of laying hens. Our results revealed that expression of RASD1 mRNA decreased as the oviduct regressed and then increased as the oviduct underwent re-growth and recrudescence in hens. Furthermore, RASD1 mRNA was expressed predominantly in GE and LE of the oviduct of laying hens during regeneration of the oviduct after induced molting, but not during the period of regression of the oviduct during molting. In addition, the relative expression of candidate miRNAs (miR-30a-5p, miR-30b-5p, miR-30c-5p and miR-30d) regulating RASD1 transcripts changed in response to estrogen stimulation of chick oviducts. These results indicate that transcription of the RASD1 gene and miRNAs regulating post-transcriptional aspects of expression of RASD1 are modulated by estrogen which is critical for growth, development, remodeling and maintenance of function of the chicken oviduct.


Discourse of 'transformational leadership' in infection control.
The article explores the impact of the ;transformational leadership' style in the role of modern matron with regards to infection control practices. Policy and guidance on the modern matron role suggest that it is distinctive in its combination of management and clinical components, and in its reliance on transformational leadership. Senior nurses are therefore expected to motivate staff by creating high expectations, modelling appropriate behaviour, and providing personal attention to followers by giving respect and responsibility. In this article, we draw on policy documents and interview data to explore the potential impact of this new management style on infection control practices. Combining the techniques of discourse analysis and corpus linguistics, we identify examples where matrons appear to disassociate themselves from the role of ;an empowered manager' who has control over human and financial resources to resolve problems in infection control efficiently.


Multidisciplinary team care in rehabilitation: an overview of reviews.
To systematically investigate current scientific evidence about the effectiveness of multidisciplinary team rehabilitation for different health problems. A comprehensive literature search was conducted in Cochrane, Medline, DARE, Embase, and Cinahl databases, and research from existing systematic reviews was critically appraised and summarized. Using the search terms "rehabilitation", "multidisciplinary teams" or "team care", references were identified for existing studies published after 2000 that examined multidisciplinary rehabilitation team care for adults, without restrictions in terms of study population or outcomes. The most recent reviews examining a study population were selected. Two reviewers independently extracted information about study populations, sample sizes, study designs, rehabilitation settings, the team, interventions, and findings. A total of 14 reviews were included to summarize the findings of 12 different study populations. Evidence was found to support improved functioning following multidisciplinary rehabilitation team care for 10 of 12 different study population: elderly people, elderly people with hip fracture, homeless people with mental illness, adults with multiple sclerosis, stroke, acquired brain injury, chronic arthropathy, chronic pain, low back pain, and fibromyalgia. Whereas evidence was not found for adults with amyetrophic lateral schlerosis, and neck and shoulder pain. Although these studies included heterogeneous patient groups the overall conclusion was that multidisciplinary rehabilitation team care effectively improves rehabilitation intervention. However, further research in this area is needed.


Implications of prostacyclin generation for modulation of vascular tone.
1. The biotransformation of arachidonic acid and prostacyclin in the circulation was studied in anaesthetized dogs, using the blood-bathed organ technique. 2. In passage through the lungs, arachidonate (50-800 microgram kg-1 min-1) was transformed into prostacyclin. No thromboxane A2 or prostaglandin E2 could be detected in arterial blood. 3. In dogs treated with indomethacin (5 mg/kg), intravenous infusions of arachidonate had no cardiovascular effects and no prostacyclin was produced. Therefore, the vasodilator effects of arachidonate in vivo may be attributable to prostacyclin formation. 4. Prostacyclin, unlike prostaglandin E2, is not inactivated by passage across the lungs, and only about 50% disappears in one passage through peripheral vascular beds. 5. Thus prostacyclin released from the lungs could function as a circulating vasodilator and contribute to the regulation of blood vessel tone and blood pressure.


Recurrence of Pancreatic Neuroendocrine Tumors and Survival Predicted by Ki67.
Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs) and adjuvant treatment currently is not indicated. This study investigated the role of Ki67 with regard to recurrence and survival after curative resection of panNET. Patients with resected non-functioning panNET diagnosed between 1992 and 2016 from three institutions were retrospectively analyzed. Patients who had G1 or G2 tumor without distant metastases or hereditary syndromes were included in the study. The patients were re-categorized into Ki67 0-5 and Ki67 6-20%. Cox regression analysis with log-rank testing for recurrence and survival was performed. The study enrolled 241 patients (86%) with Ki67 0-5% and 39 patients (14%) with Ki67 6-20%. Recurrence was seen in 34 patients (14%) with Ki67 0-5% after a median period of 34 months and in 16 patients (41%) with Ki67 6-20% after a median period of 16 months (p < 0.001). The 5-year recurrence-free and 10-year disease-specific survival periods were respectively 90 and 91% for Ki67 0-5% and respectively 55 and 26% for Ki67 6-20% (p < 0.001). The overall survival period after recurrence was 44.9 months, which was comparable between the two groups (p = 0.283). In addition to a Ki67 rate higher than 5%, tumor larger than 4 cm and lymph node metastases were independently associated with recurrence. Patients at high risk for recurrence after curative resection of G1 or G2 panNET can be identified by a Ki67 rate higher than 5%. These patients should be more closely monitored postoperatively to detect recurrence early and might benefit from adjuvant treatment. A clear postoperative follow-up regimen is proposed.


Susceptibility of Anopheles hermsi to Plasmodium vivax.
Two outbreaks of Plasmodium vivax malaria have occurred recently in southern California, and Anopheles hermsi, a newly described species closely related to A freeborni, has been implicated as the vector. To assess the competence of A. hermsi as a vector, its susceptibility to P. vivax was compared with that of the efficient vector A. freeborni by allowing 150 females of each species to feed to repletion on infected squirrel monkeys. Oocyst density was greater in A. hermsi than in A. freeborni, and the frequency and density of sporozoites were similar. A. hermsi was susceptible to P. vivax and readily supported development to the sporozoite stage.


Sampling solution traces for the problem of sorting permutations by signed reversals.
Traditional algorithms to solve the problem of sorting by signed reversals output just one optimal solution while the space of all optimal solutions can be huge. A so-called trace represents a group of solutions which share the same set of reversals that must be applied to sort the original permutation following a partial ordering. By using traces, we therefore can represent the set of optimal solutions in a more compact way. Algorithms for enumerating the complete set of traces of solutions were developed. However, due to their exponential complexity, their practical use is limited to small permutations. A partial enumeration of traces is a sampling of the complete set of traces and can be an alternative for the study of distinct evolutionary scenarios of big permutations. Ideally, the sampling should be done uniformly from the space of all optimal solutions. This is however conjectured to be ♯P-complete. We propose and evaluate three algorithms for producing a sampling of the complete set of traces that instead can be shown in practice to preserve some of the characteristics of the space of all solutions. The first algorithm (RA) performs the construction of traces through a random selection of reversals on the list of optimal 1-sequences. The second algorithm (DFALT) consists in a slight modification of an algorithm that performs the complete enumeration of traces. Finally, the third algorithm (SWA) is based on a sliding window strategy to improve the enumeration of traces. All proposed algorithms were able to enumerate traces for permutations with up to 200 elements. We analysed the distribution of the enumerated traces with respect to their height and average reversal length. Various works indicate that the reversal length can be an important aspect in genome rearrangements. The algorithms RA and SWA show a tendency to lose traces with high average reversal length. Such traces are however rare, and qualitatively our results show that, for testable-sized permutations, the algorithms DFALT and SWA produce distributions which approximate the reversal length distributions observed with a complete enumeration of the set of traces.


National perspective on in-hospital emergency units in Iraq.
Hospitals play a crucial role in providing communities with essential medical care during times of disasters. The emergency department is the most vital component of hospitals' inpatient business. In Iraq, at present, there are many casualties that cause a burden of work and the need for structural assessment, equipment updating and evaluation of process. To examine the current pragmatic functioning of the existing set-up of services of in-hospital emergency departments within some general hospitals in Baghdad and Mosul in order to establish a mechanism for future evaluation for the health services in our community. A cross-sectional study was employed to evaluate the structure, process and function of six major hospitals with emergency units: four major hospitals in Baghdad and two in Mosul. The six surveyed emergency units are distinct units within general hospitals that serve (collectively) one quarter of the total population. More than one third of these units feature observation unit beds, laboratory services, imaging facilities, pharmacies with safe storage, and ambulatory entrance. Operation room was found only in one hospital's reception and waiting area. Consultation/track area, cubicles for infection control, and discrete tutorial rooms were not available. Patient assessment was performed (although without adequate privacy). The emergency specialist, family medicine specialist and interested general practitioner exist in one-third of the surveyed units. Psychiatrist, physiotherapists, occupational therapists, and social work links are not available. The shortage in medication, urgent vaccines and vital facilities is an obvious problem. Our emergency unit's level and standards of care are underdeveloped. The inconsistent process and inappropriate environments need to be reconstructed. The lack of drugs, commodities, communication infrastructure, audit and training all require effective build up.


The purification of fructose 1,6-diphosphatase from ox liver and its activation by ethylenediaminetetra-acetate.
1.A procedure for the purification of ox liver fructose 1,6-kiphosphatase is described. A number of criteria indicate that the enzyme was not subjected to any significant degree of proteolytic attack during the purification. 2. The molecular weight, amino acid composition and subunit molecular weight are reported. 3. The activation by EDTA was shown to be due to the chelation heavy metals rather than by a more complex interaction with the enzyme as had previously been suggested.


Nestin expression as an indicator of cervical cancer initiation.
Nestin is an intermediate filament protein expressed in proliferating cells during embryonic development of the central nervous system (CNS) and considered to be a neuronal stem cell/progenitor cell marker. This study investigated the difference of nestin expression between pre-cancer (carcinoma in situ - CIS) and cancer of cervix in 129 tissues (49 normal cervix, 41 CIS, and 39 invasive cervical cancer) through the use of a paraffin-embedded tissue array. Immunostaining was evaluated by intensity, proportion of stained cells, and pattern of expression. The expression of nestin was positive in 63.4% (26/41) for CIS and 43.6% (17/39) for invasive cervical cancer, but only 26.5% (13/49) for normal tissues (p = 0.002). Strong positive staining/large proportion staining were 53.7% (22/41) / 36.6% (15/41), 15.4% (6/39) / 61.5% (24/39) in the CIS and invasive cervical cancer tissues, respectively (p = 0.043, p < 0.001). The diffuse stain with basal layer was positive in 90.2% (37/41) for CIS, but only 24.5% (12/49) of the samples were positive in normal tissues (p < 0.001). Based on these results, the authors suggest that nestin expression seems to participate in the step of cancer initiation and could potentially be a useful marker in the early detection of cervical cancer.


Prevalence of Chlamydia trachomatis genital infection among persons aged 14-39 years--United States, 2007-2012.
Infection with the bacterium, Chlamydia trachomatis (often termed "chlamydia") is the most frequently reported sexually transmitted infection in the United States. The urethra is the most common site of infection in males, and the urethra and cervix are most commonly infected in females. Ascending infection in females can cause pelvic inflammatory disease, which can lead to infertility and ectopic pregnancy. Genital chlamydial infections are usually asymptomatic, and screening is necessary to identify most infections. Currently, chlamydia screening for sexually active women aged <25 years is recommended by the U.S. Preventive Services Task Force (grade B recommendation). Chlamydia is nationally notifiable; however, if females do not access care or clinicians do not screen, many infections go undiagnosed, unreported, and untreated. CDC monitors population prevalence of genital chlamydial infection through the National Health and Nutrition Examination Survey (NHANES), which tests a sample of the U.S. population aged 14-39 years for genital C. trachomatis and found that the overall chlamydia burden in the United States decreased during 1999-2008. Using data from the most recent cycles of NHANES (2007-2012), CDC estimated chlamydia prevalence among persons aged 14-39 years overall and by demographic characteristics and sexual behaviors. The prevalence of chlamydia among persons aged 14-39 years was 1.7% (95% confidence interval [CI] = 1.4%-2.0%). Chlamydia prevalence varied by age and race/ethnicity, with prevalence highest among non-Hispanic blacks (5.2%). Among sexually active females aged 14-24 years, the population targeted for routine screening, chlamydia prevalence was 4.7% overall and 13.5% among non-Hispanic black females. As chlamydia is common and infections are usually asymptomatic, health care providers should routinely screen sexually active young women aged <25 years for chlamydial infection, provide prompt treatment for infected persons, and ensure that infected patients' sex partners receive timely treatment to prevent reinfection.


A thorough evaluation of the Language Environment Analysis (LENA) system.
In the previous decade, dozens of studies involving thousands of children across several research disciplines have made use of a combined daylong audio-recorder and automated algorithmic analysis called the LENAⓇ system, which aims to assess children's language environment. While the system's prevalence in the language acquisition domain is steadily growing, there are only scattered validation efforts on only some of its key characteristics. Here, we assess the LENAⓇ system's accuracy across all of its key measures: speaker classification, Child Vocalization Counts (CVC), Conversational Turn Counts (CTC), and Adult Word Counts (AWC). Our assessment is based on manual annotation of clips that have been randomly or periodically sampled out of daylong recordings, collected from (a) populations similar to the system's original training data (North American English-learning children aged 3-36 months), (b) children learning another dialect of English (UK), and (c) slightly older children growing up in a different linguistic and socio-cultural setting (Tsimane' learners in rural Bolivia). We find reasonably high accuracy in some measures (AWC, CVC), with more problematic levels of performance in others (CTC, precision of male adults and other children). Statistical analyses do not support the view that performance is worse for children who are dissimilar from the LENAⓇ original training set. Whether LENAⓇ results are accurate enough for a given research, educational, or clinical application depends largely on the specifics at hand. We therefore conclude with a set of recommendations to help researchers make this determination for their goals.


Fatness mediates the influence of muscular fitness on metabolic syndrome in Colombian collegiate students.
The purpose of this study was two-fold: to analyze the association between muscular fitness (MF) and clustering of metabolic syndrome (MetS) components, and to determine if fatness parameters mediate the association between MF and MetS clustering in Colombian collegiate students. This cross-sectional study included a total of 886 (51.9% women) healthy collegiate students (21.4 ± 3.3 years old). Standing broad jump and isometric handgrip dynamometry were used as indicators of lower and upper body MF, respectively. Also, a MF score was computed by summing the standardized values of both tests, and used to classify adults as fit or unfit. We also assessed fat mass, body mass index, waist-to-height ratio, and abdominal visceral fat, and categorized individuals as low and high fat using international cut-offs. A MetS cluster score was derived by calculating the sum of the sample-specific z-scores from the triglycerides, HDL cholesterol, fasting glucose, waist circumference, and arterial blood pressure. Linear regression models were used to examine whether the association between MF and MetS cluster was mediated by the fatness parameters. Data were collected from 2013 to 2016 and the analysis was done in 2016. Findings revealed that the best profiles (fit + low fat) were associated with lower levels of the MetS clustering (p <0.001 in the four fatness parameters), compared with unfit and fat (unfit + high fat) counterparts. Linear regression models indicated a partial mediating effect for fatness parameters in the association of MF with MetS clustering. Our findings indicate that efforts to improve MF in young adults may decrease MetS risk partially through an indirect effect on improvements to adiposity levels. Thus, weight reduction should be taken into account as a complementary goal to improvements in MF within exercise programs.


No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits.
A 30 cM broad genomic region on the long arm of chromosome 10 at 80 cM shows significant and consistent linkage with AD and with plasma concentration of the beta-amyloid peptide 1-42 (Abeta42). The PLAU gene, which is involved in the production and degradation of Abeta42, maps to that region and is therefore a strong positional candidate for association with sporadic AD. We analyzed the non-synonymous single nucleotide polymorphism (SNP) rs2227564 in two independent case-control series from Switzerland and Greece and investigated the influence of this SNP on cognition in elderly individuals. Because PLAU modulates the cleavage of the amyloid precursor protein (APP) and the degradation of Abeta, we also determined the levels of Abeta in the brain, plasma and in the cerebrospinal fluid (CSF). We found no evidence for association of this SNP with AD or with AD-related traits such as beta-amyloid load in the medial temporal lobe or Abeta42 concentration in the CSF and in plasma. Our findings do not support a major role of PLAU polymorphisms as susceptibility factors for AD and suggest that large-scale association studies which combine genetic information from populations with similar genetic background might prevent the generation of spurious associations. Although PLAU may be pathophysiologially related to AD, the contribution of common genetic variants of this gene to the risk for developing AD is likely to be low.


The impact of outgroup choice and missing data on major seed plant phylogenetics using genome-wide EST data.
Genome level analyses have enhanced our view of phylogenetics in many areas of the tree of life. With the production of whole genome DNA sequences of hundreds of organisms and large-scale EST databases a large number of candidate genes for inclusion into phylogenetic analysis have become available. In this work, we exploit the burgeoning genomic data being generated for plant genomes to address one of the more important plant phylogenetic questions concerning the hierarchical relationships of the several major seed plant lineages (angiosperms, Cycadales, Gingkoales, Gnetales, and Coniferales), which continues to be a work in progress, despite numerous studies using single, few or several genes and morphology datasets. Although most recent studies support the notion that gymnosperms and angiosperms are monophyletic and sister groups, they differ on the topological arrangements within each major group. We exploited the EST database to construct a supermatrix of DNA sequences (over 1,200 concatenated orthologous gene partitions for 17 taxa) to examine non-flowering seed plant relationships. This analysis employed programs that offer rapid and robust orthology determination of novel, short sequences from plant ESTs based on reference seed plant genomes. Our phylogenetic analysis retrieved an unbiased (with respect to gene choice), well-resolved and highly supported phylogenetic hypothesis that was robust to various outgroup combinations. We evaluated character support and the relative contribution of numerous variables (e.g. gene number, missing data, partitioning schemes, taxon sampling and outgroup choice) on tree topology, stability and support metrics. Our results indicate that while missing characters and order of addition of genes to an analysis do not influence branch support, inadequate taxon sampling and limited choice of outgroup(s) can lead to spurious inference of phylogeny when dealing with phylogenomic scale data sets. As expected, support and resolution increases significantly as more informative characters are added, until reaching a threshold, beyond which support metrics stabilize, and the effect of adding conflicting characters is minimized.