Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the ...evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.
Ferroelectric ceramics are widely used as sensors and actuators for their electro-mechanical properties, and in electronic applications for their dielectric properties. Domain switching--the ...phenomenon wherein the ferroelectric material changes from one spontaneously polarized state to another under electrical or mechanical loads--is an important attribute of these materials. However, this is a complex collective process in commercially used polycrystalline ceramics that are agglomerations of a very large number of variously oriented grains. As the domains in one grain attempt to switch, they are constrained by the differently oriented neighbouring grains. Here we use a combined theoretical and experimental approach to establish a relation between crystallographic symmetry and the ability of a ferroelectric polycrystalline ceramic to switch. In particular, we show that equiaxed polycrystals of materials that are either tetragonal or rhombohedral cannot switch; yet polycrystals of materials where these two symmetries co-exist can in fact switch.
Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, ...and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
G protein-coupled receptors (GPCRs) and their downstream signaling cascades contribute to most physiological processes and a variety of human diseases. Isolating the effects of GPCR activation in an ...in vivo experimental setting is challenging as exogenous ligands have off-target effects and endogenous ligands constantly modulate the activity of native receptors. Highly specific designer drug-designer receptor complexes are a valuable tool for elucidating the effects of activating particular receptors and signaling pathways within selected cell types in vivo. In this study, we describe a generic protocol for the directed molecular evolution of designer receptors exclusively activated by designer drugs (DREADDs). First, the yeast system is validated with the template receptor. Second, a mutant library is generated by error-prone PCR. Third, the library is screened by drug-dependent yeast growth assays. Mutants exhibiting the desired properties are selected for further rounds of mutagenesis or for characterization in mammalian systems. In total, these steps should take 6-8 weeks of experimentation and should result in the evolution of a receptor to be activated by the chosen ligand. This protocol should help improve the experimental targeting of select cell populations.
Within primary progressive aphasia the logopenic variant remains less understood than the two other main variants, namely semantic and non-fluent progressive aphasia. This may be because of the ...relatively small number of explored patients and because of the lack of investigations with a comprehensive three-level characterization of cognitive, brain localization and biological aspects. The aim of the present study was to decipher the logopenic variant through a multimodal approach with a large cohort of 19 patients (age 66.5 ± 8.7 years, symptom duration 3.2 ± 0.6 years) using detailed cognitive and linguistic assessments, magnetic resonance imaging and perfusion single-photon emission computed tomography as well as cerebrospinal fluid biomarkers screening for Alzheimer pathology. The linguistic assessment unveiled that language dysfunction is not limited to the typical feature of word finding and verbal working memory impairments but that it extends into the language system affecting to some degree syntactic production, phonological encoding and semantic representations. Perfusion tomography revealed damage of the temporal-parietal junction with a peak of significance in the superior temporal gyrus (Brodmann area 42), and of some less significant prefrontal areas (Brodmann areas 8, 9 and 46), whereas hippocampal cortices were unaffected. Magnetic resonance imaging, which was visually assessed in a larger group of 54 patients with logopenic, non-fluent, semantic variants as well as with posterior cortical atrophy, confirmed that the logopenic variant demonstrates predominant atrophy of left temporal-parietal junction, but that this atrophy pattern has a relatively poor sensitivity and specificity for clinical diagnosis. Finally, the biomarker study revealed that two-thirds of the logopenic patients demonstrated a profile indicative of Alzheimer pathology whereas one-third had a non-Alzheimer profile. Splitting the two groups showed that logopenic aphasia due to probable Alzheimer pathology is a more aggressive variant characterized by more extensive language/cognitive disorders affecting, in addition to lexical processes and verbal working memory, also phoneme sequencing, semantic processing and ideomotor praxis. Concordantly, logopenic aphasia due to probable Alzheimer pathology demonstrated more extensive brain hypoperfusion involving larger regions throughout the inferior parietal, the posterior-superior and the middle temporal cortex. These findings allow for unfolding logopenic aphasia into two subvariants differing by disease severity, lesion nature and lesion distribution, which has important implications for diagnosis, patient management and for potential future trials with anti-Alzheimer drugs. The present data therefore provide novel insight into the cognition and brain damage of logopenic patients while unveiling the existence of distinct diseases constituting a 'logopenic aphasia complex'.
Purpose
Few studies examine whether maternal and neonatal outcomes differ by time from metabolic and bariatric surgery (MBS) to conception. We describe maternal and neonatal outcomes among women with ...pregnancy after Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) overall and by whether conception occurred during the period when pregnancy is not recommended (< 18 months postoperative) versus later.
Materials and Methods
A prospective cohort study enrolled 135 US adult women (median age, 30 years, body mass index BMI, 47.2 kg/m
2
) who underwent RYGB or SG (2006–2009) and subsequently reported ≥ 1 pregnancy within 7 years. Participants self-reported pregnancy-related information annually. Differences in prevalence of maternal and neonatal outcomes by postoperative conception timeframe (< 18 versus ≥ 18 months) were assessed.
Results
Thirty-one women reported ≥ 2 postoperative pregnancies. At time of postoperative conception (median 26 IQR:22–52 months postoperative) median BMI was 31 (IQR:27–36) kg/m
2
. Excessive gestational weight gain (55%), cesarean section (42%) and preterm labor or rupture of membranes (40%) were the most common maternal outcomes. Forty percent of neonates had a composite outcome of still birth (1%), preterm birth (26%), small for gestational age (11%), or neonatal intensive care unit admission (8%). Prevalence of outcomes did not statistically significantly differ by timeframe.
Conclusion
In US women who conceived ≤ 7 years following RYGB or SG, 40% of neonates had the composite neonatal outcome. The prevalence of maternal and neonatal outcomes post-MBS were not statistically significant by conception timeframe.
Graphical Abstract
Viral infections are common complications of pregnancy. Although some infections have maternal sequelae, many viral infections can be perinatally transmitted to cause congenital or chronic infection ...in fetuses or infants. Treatments of such infections are geared toward reducing maternal symptoms and complications and toward preventing maternal-to-child transmission of viruses. This article reviews the treatment of herpes simplex virus, cytomegalovirus, hepatitis B and C viruses, and human immunodeficiency virus during pregnancy.
An experimental programme is presented, examining the turbulent wake of a monopile foundation in a current. Velocity was recorded across an extensive domain downstream of a model monopile in a 0.5 m ...deep basin, using an acoustic Doppler velocimeter array. The distribution of turbulent kinetic energy (TKE) is examined across the entire domain. Tests were undertaken using several combinations of pile diameter (D = 0.1 and 0.2 m) and mean flow velocity (u0¯ = 0.08–0.24 m/s), representing typical prototype conditions at a scale of 1:50. It is shown that turbulence can be predicted using the distance downstream (x) and off axis (y), the pile diameter, and the mean flow velocity. Two new parameters are introduced to simplify assessment of proposed structures. Relative Excess Turbulence (RET) is the extra turbulence generated by the pile, normalised by the ambient turbulence. Turbulence Recovery Lengthscale (TRL) is the distance downstream (normalised by D) required for RET to fall below a given threshold. Results show that RET decays exponentially with distance downstream. Across the wake, RET fitted a Gaussian function with peak values at the wake centreline. TRL is estimated at 40 for an RET threshold of 1.0 and 400 for an RET threshold of 0.1.
•Distribution of turbulence was measured in the wake of a model monopile foundation.•Turbulence decays exponentially with distance downstream of the pile.•Turbulence can be normalised by pile diameter and mean flow velocity squared.•Two new parameters are introduced to characterise the distribution of turbulence.•Results suggest that the effect on turbulence is small at typical pile spacing in offshore wind farms.
A significant challenge for neuroscientists is to determine how both electrical and chemical signals affect the activity of cells and circuits and how the nervous system subsequently translates that ...activity into behavior. Remote, bidirectional manipulation of those signals with high spatiotemporal precision is an ideal approach to addressing that challenge. Neuroscientists have recently developed a diverse set of tools that permit such experimental manipulation with varying degrees of spatial, temporal, and directional control. These tools use light, peptides, and small molecules to primarily activate ion channels and G protein-coupled receptors (GPCRs) that in turn activate or inhibit neuronal firing. By monitoring the electrophysiological, biochemical, and behavioral effects of such activation/inhibition, researchers can better understand the links between brain activity and behavior. Here, we review the tools that are available for this type of experimentation. We describe the development of the tools and highlight exciting in vivo data. We focus primarily on designer GPCRs (receptors activated solely by synthetic ligands, designer receptors exclusively activated by designer drugs) and microbial opsins (e.g., channelrhodopsin-2, halorhodopsin, Volvox carteri channelrhodopsin) but also describe other novel techniques that use orthogonal receptors, caged ligands, allosteric modulators, and other approaches. These tools differ in the direction of their effect (activation/inhibition, hyperpolarization/depolarization), their onset and offset kinetics (milliseconds/minutes/hours), the degree of spatial resolution they afford, and their invasiveness. Although none of these tools is perfect, each has advantages and disadvantages, which we describe, and they are all still works in progress. We conclude with suggestions for improving upon the existing tools.
The prevailing paradigm of locoregional chemotherapy has been centred around delivering chemotherapy as close to the tumour as possible and in some cases incorporating vascular isolation techniques. ...Strategically, the development of these techniques has been rudimentary without consideration for the interdependencies between macrovascular manipulation and the microvascular effects. This review focuses on how new capabilities offered by recent advances in vascular access technology could be exploited to facilitate the mass fluid transfer (MFT) of anticancer agents to solid tumours. A haemodynamic model of MFT is proposed using the physical laws of fluid flow, flux, and diffusion that describe the microvascular effects anticancer agents may have upon tumours through the manipulation of macrovascular blood flow control. Finally, the possible applications of this technique for several organs are discussed.
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•New technology now enables organ isolation via repeatable multi-catheter access.•Technique utilized for controlled release of chemotherapy via mass fluid transfer.•Allows manipulation of physical laws to control tumour microvasculature•Applicable to various solid organ tumours; liver, pancreas, breast, lung, prostate
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