Publications by authors named "Alexander Jackson"

71 Publications

Cellular taxonomy and spatial organization of the murine ventral posterior hypothalamus.

Elife 2020 10 29;9. Epub 2020 Oct 29.

Department of Physiology and Neurobiology, University of Connecticut, Storrs, United States.

The ventral posterior hypothalamus (VPH) is an anatomically complex brain region implicated in arousal, reproduction, energy balance, and memory processing. However, neuronal cell type diversity within the VPH is poorly understood, an impediment to deconstructing the roles of distinct VPH circuits in physiology and behavior. To address this question, we employed a droplet-based single-cell RNA sequencing (scRNA-seq) approach to systematically classify molecularly distinct cell populations in the mouse VPH. Analysis of >16,000 single cells revealed 20 neuronal and 18 non-neuronal cell populations, defined by suites of discriminatory markers. We validated differentially expressed genes in selected neuronal populations through fluorescence in situ hybridization (FISH). Focusing on the mammillary bodies (MB), we discovered transcriptionally-distinct clusters that exhibit neuroanatomical parcellation within MB subdivisions and topographic projections to the thalamus. This single-cell transcriptomic atlas of VPH cell types provides a resource for interrogating the circuit-level mechanisms underlying the diverse functions of VPH circuits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.58901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595735PMC
October 2020

Conscious prone positioning during non-invasive ventilation in COVID-19 patients: experience from a single centre.

F1000Res 2020 31;9:859. Epub 2020 Jul 31.

General Intensive Care unit, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, SO16 6YD, UK.

Critically ill patients admitted to hospital following SARS-CoV-2 infection often experience hypoxic respiratory failure and a proportion require invasive mechanical ventilation to maintain adequate oxygenation. The combination of prone positioning and non-invasive ventilation in conscious patients may have a role in improving oxygenation. The purpose of this study was to assess the effect of prone positioning in spontaneously ventilating patients receiving non-invasive ventilation admitted to the intensive care.  Clinical data of 81 patients admitted with COVID 19 pneumonia and acute hypoxic respiratory failure were retrieved from electronic medical records and examined. Patients who had received prone positioning in combination with non-invasive ventilation were identified. A total of 20 patients received prone positioning in conjunction with non-invasive ventilation. This resulted in improved oxygenation as measured by a change in PaO /FiO (P/F) ratio of 28.7 mmHg while prone, without significant change in heart rate or respiratory rate. Patients on average underwent 5 cycles with a median duration of 3 hours. There were no reported deaths, 7 of the 20 patients (35%) failed non-invasive ventilation and subsequently required intubation and mechanical ventilation. In our cohort of 20 COVID-19 patients with moderate acute hypoxic respiratory failure, prone positioning with non-invasive ventilation resulted in improved oxygenation. Prone positioning with non-invasive ventilation may be considered as an early therapeutic intervention in COVID-19 patients with moderate acute hypoxic respiratory failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.25384.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578762PMC
October 2020

Noninvasive ventilation for COVID-19-associated acute hypoxaemic respiratory failure: experience from a single centre.

Br J Anaesth 2020 10 21;125(4):e368-e371. Epub 2020 Jul 21.

Respiratory Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK; General Intensive Care Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Acute Perioperative and Critical Care Group, Southampton NIHR Biomedical Research Centre, University Hospital Southampton/University of Southampton, Southampton, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373070PMC
October 2020

GABA receptor density alterations revealed in a mouse model of early moderate prenatal ethanol exposure using [F]AH114726.

Nucl Med Biol 2020 Jul 25;88-89:44-51. Epub 2020 Jul 25.

Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia. Electronic address:

Introduction: Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABA receptors (GABAR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABAR levels in the adult offspring.

Methods: C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry.

Results: In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABAR in the olfactory bulbs. Immunohistochemistry detected reduced GABAR in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE.

Conclusion: Early moderate PEE may induce long-term alterations in the GABAR system that persisted into adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nucmedbio.2020.07.005DOI Listing
July 2020

Procalcitonin as an antibiotic stewardship tool in COVID-19 patients in the intensive care unit.

J Glob Antimicrob Resist 2020 09 25;22:782-784. Epub 2020 Jul 25.

Microbiology Innovation and Research Unit (MIRU), Department of Microbiology, University Hospitals Southampton NHS Foundation Trust, and University of Southampton School of Medicine, Southampton, UK; International Society of Antimicrobial Chemotherapy (ISAC), Chair of Rapid Diagnostics and Biomarker Working Group. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgar.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381395PMC
September 2020

A general strategy for degradable single-chain nanoparticles via cross-linker mediated chain collapse of radical copolymers.

Chem Commun (Camb) 2020 Sep 27;56(68):9838-9841. Epub 2020 Jul 27.

Agency for Science, Technology and Research (A*Star) Singapore, Institute of Chemical and Engineering Sciences (ICES), 1 Pesek Road, Jurong Island, 627833, Singapore.

Radical ring-opening copolymerization (rROP) between 2-methylene-1,3-dioxepane (MDO) and methacrylic acid N-hydroxysuccinimide ester (NHSMA) furnishes a reactive polyester-based linear copolymer precursor. Subsequent cross-linker mediated chain collapse affords degradable single-chain nanoparticles (DSCNPs). This methodology is an experimentally robust and straightforward route to main-chain degradable polymeric nanoparticles in the sub-30 nm size range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cc03792cDOI Listing
September 2020

Perylene Diimide Nanoprobes for In Vivo Tracking of Mesenchymal Stromal Cells Using Photoacoustic Imaging.

ACS Appl Mater Interfaces 2020 Jun 12;12(25):27930-27939. Epub 2020 Jun 12.

Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L69 7ZD, U.K.

Noninvasive bioimaging techniques are critical for assessing the biodistribution of cellular therapies longitudinally. Among them, photoacoustic imaging (PAI) can generate high-resolution images with a tissue penetration depth of ∼4 cm. However, it is essential and still highly challenging to develop stable and efficient near-infrared (NIR) probes with low toxicity for PAI. We report here the preparation and use of perylene diimide derivative (PDI) with NIR absorbance (around 700 nm) as nanoprobes for tracking mesenchymal stromal cells (MSCs) in mice. Employing an in-house synthesized star hyperbranched polymer as a stabilizer is the key to the formation of stable PDI nanoparticles with low toxicity and high uptake by the MSCs. The PDI nanoparticles remain within the MSCs as demonstrated by in vitro and in vivo assessments. The PDI-labeled MSCs injected subcutaneously on the flanks of the mice are clearly visualized with PAI up to 11 days postadministration. Furthermore, bioluminescence imaging of PDI-labeled luciferase-expressing MSCs confirms that the administered cells remain viable for the duration of the experiment. These PDI nanoprobes thus have good potential for tracking administered cells in vivo using PAI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c03857DOI Listing
June 2020

Unraveling the History and Revisiting the Synthesis of Degradable Polystyrene Analogues via Radical Ring-Opening Copolymerization with Cyclic Ketene Acetals.

Materials (Basel) 2020 May 19;13(10). Epub 2020 May 19.

Institute of Chemical and Engineering Sciences (ICES), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore.

Degradable analogues of polystyrene are synthesized via radical ring-opening (co)polymerization (rROP) between styrene and two cyclic ketene acetals, namely 2-methylene-1,3-dioxepane (MDO) and 5,6-benzo-2-methylene-1,3-dioxepane (BMDO). This approach periodically inserts ester bonds throughout the main chain of polystyrene, imparting a degradation pathway via ester hydrolysis. We discuss the historical record of this approach, with careful attention paid to the conflicting findings previously reported. We have found a common H NMR characterization error, repeated throughout the existing body of work. This misinterpretation is responsible for the discrepancies within the cyclic ketene acetal (CKA)-based degradable polystyrene literature. These inconsistencies, for the first time, are now understood and resolved through optimization of the polymerization conditions, and detailed characterization of the degradable copolymers and their corresponding oligomers after hydrolytic degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma13102325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287801PMC
May 2020

Biochemical Characterization of Yeast Xrn1.

Biochemistry 2020 04 13;59(15):1493-1507. Epub 2020 Apr 13.

Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States.

Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries out 5' → 3' processive, hydrolytic degradation of RNA molecules using divalent metal ion catalysis. To initiate studies of the 5' → 3' RNA decay machinery in our lab, we expressed a C-terminally truncated version of Xrn1 and explored its enzymology using a second-generation, time-resolved fluorescence RNA degradation assay. Using this system, we quantitatively explored Xrn1's preference for 5'-monophosphorylated RNA substrates, its pH dependence, and the importance of active site mutations in the molecule's conserved catalytic core. Furthermore, we explore Xrn1's preference for RNAs containing a 5' single-stranded region both in an intermolecular hairpin structure and in an RNA-DNA hybrid duplex system. These results both expand and solidify our understanding of Xrn1, a centrally important enzyme whose biochemical properties have implications in numerous RNA degradation and processing pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biochem.9b01035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780157PMC
April 2020

A Roadmap towards Successful Nanocapsule Synthesis via Vesicle Templated RAFT-Based Emulsion Polymerization.

Polymers (Basel) 2018 Jul 15;10(7). Epub 2018 Jul 15.

Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island 627833, Singapore.

Vesicle templated emulsion polymerization is a special form of emulsion polymerization where the polymer is grown from the outside of the vesicle, leading to nanocapsules. Cost effective nanocapsules synthesis is in high demand due to phasing out of older methods for capsule synthesis. Although the first indications of this route being successful were published some 10 years ago, until now a thorough understanding of the parameters controlling the morphologies resulting from the template emulsion polymerization was lacking. Most often a mixture of different morphologies was obtained, ranging from solid particles to pro-trusion structures to nanocapsules. A high yield of nanocapsules was not achieved until now. In this paper, the influence of initial vesicle dispersion, choice of the Reversible Addition-Fragmentation chain Transfer (RAFT) species and oligomer, monomer and crosslinker have been investigated. It turns out that good initial vesicle dispersion, molecular control of the RAFT process, a not too hydrophobic monomer and some crosslinking is needed to result in high yield of nanocapsules. In previous work, the level of RAFT control was often suboptimal and not properly verified and although nanocapsules were shown, other morphologies were also present. We now believe we have a full understanding of vesicle templated nanocapsules synthesis, relevant to many applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/polym10070774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403744PMC
July 2018

Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons.

Nat Neurosci 2019 04 11;22(4):642-656. Epub 2019 Mar 11.

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA.

The lateral hypothalamic area (LHA) coordinates an array of fundamental behaviors, including sleeping, waking, feeding, stress and motivated behavior. The wide spectrum of functions ascribed to the LHA may be explained by a heterogeneous population of neurons, the full diversity of which is poorly understood. We employed a droplet-based single-cell RNA-sequencing approach to develop a comprehensive census of molecularly distinct cell types in the mouse LHA. Neuronal populations were classified based on fast neurotransmitter phenotype and expression of neuropeptides, transcription factors and synaptic proteins, among other gene categories. We define 15 distinct populations of glutamatergic neurons and 15 of GABAergic neurons, including known and novel cell types. We further characterize a novel population of somatostatin-expressing neurons through anatomical and behavioral approaches, identifying a role for these neurons in specific forms of innate locomotor behavior. This study lays the groundwork for better understanding the circuit-level underpinnings of LHA function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-019-0349-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043322PMC
April 2019

Histamine: neural circuits and new medications.

Sleep 2019 01;42(1)

Centre National de Référence Narcolepsie Hypersomnies, Unité des Troubles du Sommeil, Service de Neurologie, Hôpital Gui-de-Chauliac, Université Montpellier, INSERM, Montpellier, France.

Histamine was first identified in the brain about 50 years ago, but only in the last few years have researchers gained an understanding of how it regulates sleep/wake behavior. We provide a translational overview of the histamine system, from basic research to new clinical trials demonstrating the usefulness of drugs that enhance histamine signaling. The tuberomammillary nucleus is the sole neuronal source of histamine in the brain, and like many of the arousal systems, histamine neurons diffusely innervate the cortex, thalamus, and other wake-promoting brain regions. Histamine has generally excitatory effects on target neurons, but paradoxically, histamine neurons may also release the inhibitory neurotransmitter GABA. New research demonstrates that activity in histamine neurons is essential for normal wakefulness, especially at specific circadian phases, and reducing activity in these neurons can produce sedation. The number of histamine neurons is increased in narcolepsy, but whether this affects brain levels of histamine is controversial. Of clinical importance, new compounds are becoming available that enhance histamine signaling, and clinical trials show that these medications reduce sleepiness and cataplexy in narcolepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsy183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335869PMC
January 2019

The Reciprocal Relationships Between Escalation, Anger, and Confidence in Investment Decisions Over Time.

Front Psychol 2018 5;9:1136. Epub 2018 Jul 5.

Department of Psychology, Middle Tennessee State University, Murfreesboro, TN, United States.

Research on escalation of commitment has predominantly been studied in the context of a single decision without consideration for the psychological consequences of escalating. This study sought to examine (a) the extent to which people escalate their commitment to a failing course of action in a sequential decision-making task, (b) confidence and anger as psychological consequences of escalation of commitment, and (c) the reciprocal relationship between escalation of commitment and confidence and anger. Participants were 110 undergraduate students who completed a series of investment decisions regarding a failing endeavor. Results revealed that although a high proportion of individuals escalate through all decisions, the extent to which they escalated decreased with each decision as they were less willing to invest money in the project. Furthermore, as participants escalated, confidence in one's decision decreased and anger increased. Lastly, the analyses revealed that the relationship between escalation and confidence is reciprocal. Escalation was negatively associated with confidence, and confidence predicted escalation in the subsequent decision. These results highlight the importance of considering both the determinants and psychological consequences of escalation of commitment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2018.01136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041483PMC
July 2018

Thromboelastometry and Platelet Function during Acclimatization to High Altitude.

Thromb Haemost 2018 01 5;118(1):63-71. Epub 2018 Jan 5.

Apex (Altitude Physiology Expeditions), Edinburgh, United Kingdom.

Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at high altitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of specific coagulation factors in hypoxic humans have yielded conflicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to high altitude (5,200 m) using thromboelastometry and assays of platelet function to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent profiles, we detected a significant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter finding may be accounted for by the significant rise in platelet count and fibrinogen concentration that occurred during acclimatization. Platelet function assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normalization of coagulation following descent to sea level. These robust findings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH17-02-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260116PMC
January 2018

Neurochemical Heterogeneity Among Lateral Hypothalamic Hypocretin/Orexin and Melanin-Concentrating Hormone Neurons Identified Through Single-Cell Gene Expression Analysis.

eNeuro 2017 Sep-Oct;4(5). Epub 2017 Sep 22.

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269.

The lateral hypothalamic area (LHA) lies at the intersection of multiple neural and humoral systems and orchestrates fundamental aspects of behavior. Two neuronal cell types found in the LHA are defined by their expression of hypocretin/orexin (Hcrt/Ox) and melanin-concentrating hormone (MCH) and are both important regulators of arousal, feeding, and metabolism. Conflicting evidence suggests that these cell populations have a more complex signaling repertoire than previously appreciated, particularly in regard to their coexpression of other neuropeptides and the machinery for the synthesis and release of GABA and glutamate. Here, we undertook a single-cell expression profiling approach to decipher the neurochemical phenotype, and heterogeneity therein, of Hcrt/Ox and MCH neurons. In transgenic mouse lines, we used single-cell quantitative polymerase chain reaction (qPCR) to quantify the expression of 48 key genes, which include neuropeptides, fast neurotransmitter components, and other key markers, which revealed unexpected neurochemical diversity. We found that single MCH and Hcrt/Ox neurons express transcripts for multiple neuropeptides and markers of both excitatory and inhibitory fast neurotransmission. Virtually all MCH and approximately half of the Hcrt/Ox neurons sampled express both the machinery for glutamate release and GABA synthesis in the absence of a vesicular GABA release pathway. Furthermore, we found that this profile is characteristic of a subpopulation of LHA glutamatergic neurons but contrasts with a broad population of LHA GABAergic neurons. Identifying the neurochemical diversity of Hcrt/Ox and MCH neurons will further our understanding of how these populations modulate postsynaptic excitability through multiple signaling mechanisms and coordinate diverse behavioral outputs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0013-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617207PMC
May 2018

Formation of hydrophobic drug nanoparticles via ambient solvent evaporation facilitated by branched diblock copolymers.

Int J Pharm 2017 Nov 28;533(1):245-253. Epub 2017 Sep 28.

Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK. Electronic address:

Hydrophobic drug nanoparticles have been prepared by ambient solvent evaporation from ethanol at room temperature. Poly(ethylene glycol)-b-(N-isopropylacrylamide) (PEG-b-PNIPAm) branched diblock copolymers are employed to prevent drug crystallization during solvent evaporation and to stabilize the drug nanoparticles once suspended in aqueous media. After the initial solvent evaporation the dry materials obtained exhibit excellent stability during storage and can be readily dissolved in water to produce aqueous drug nanoparticles suspensions. Among the hydrophobic compounds investigated, Ketoprofen nanoparticles (D≈200nm, stable up to 9 months in solution) can be produced with a drug suspension yield of 96% at a drug:polymer ratio of 0.33:1 or a drug suspension yield of 80% at a drug:polymer ratio of 1:1. UV-vis spectroscopy has been used to determine the yield of drug suspended in aqueous media while cryo-TEM, dynamic light scattering (DLS) and powder x-ray diffraction (PXRD) are used to characterize the drug nanoparticles prepared.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.09.067DOI Listing
November 2017

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability.

J Neurosci 2017 09 5;37(39):9574-9592. Epub 2017 Sep 5.

Departments of Physiology and Neurobiology and

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0580-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618271PMC
September 2017

Simultaneously Occurring Elevated Metabolic States Expose Constraints in Maximal Levels of Oxygen Consumption in the Oviparous Snake Lamprophis fuliginosus.

Physiol Biochem Zool 2017 May/Jun;90(3):301-312. Epub 2017 Feb 15.

African house snakes (Lamprophis fuliginosus) were used to compare the metabolic increments associated with reproduction, digestion, and activity both individually and when combined simultaneously. Rates of oxygen consumption ([Formula: see text]) and carbon dioxide production ([Formula: see text]) were measured in adult female (nonreproductive and reproductive) and adult male snakes during rest, digestion, activity while fasting, and postprandial activity. We also compared the endurance time (i.e., time to exhaustion) during activity while fasting and postprandial activity in males and females. For nonreproductive females and males, our results indicate that the metabolic increments of digestion (∼3-6-fold) and activity while fasting (∼6-10-fold) did not interact in an additive fashion; instead, the aerobic scope associated with postprandial activity was 40%-50% lower, and animals reached exhaustion up to 11 min sooner. During reproduction, there was no change in digestive [Formula: see text], but aerobic scope for activity while fasting was 30% lower than nonreproductive values. The prioritization pattern of oxygen delivery exhibited by L. fuliginosus during postprandial activity (in both males and females) and for activity while fasting (in reproductive females) was more constrained than predicted (i.e., instead of unchanged [Formula: see text], peak values were 30%-40% lower). Overall, our results indicate that L. fuliginosus's cardiopulmonary system's capacity for oxygen delivery was not sufficient to maintain the metabolic increments associated with reproduction, digestion, and activity simultaneously without limiting aerobic scope and/or activity performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/691094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485249PMC
July 2017

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X receptor antagonists.

Eur J Med Chem 2017 Apr 2;130:433-439. Epub 2017 Mar 2.

School of Chemistry, The University of Sydney, NSW, 2006, Australia. Electronic address:

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2XR antagonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.02.060DOI Listing
April 2017

Totally percutaneous versus surgical cut-down femoral artery access for elective bifurcated abdominal endovascular aneurysm repair.

Cochrane Database Syst Rev 2017 02 21;2:CD010185. Epub 2017 Feb 21.

Northern Vascular Centre, Freeman Hospital, Freeman Road, Newcastle upon Tyne, UK, NE7 7DN.

Background: Abdominal aortic aneurysms (AAAs) are a vascular condition with significant risk attached, particularly if they rupture. It is, therefore, critical to identify and repair these as an elective procedure before they rupture and require emergency surgery. Repair has traditionally been an open surgical technique that required a large incision across the abdomen. Endovascular abdominal aortic aneurysm repairs (EVARs) are now a common alternative. In this procedure, the common femoral artery is exposed via a cut-down approach and a graft introduced to the aneurysm in this way. This review examines a totally percutaneous approach to EVAR. This technique gives a minimally invasive approach to femoral artery access that may reduce groin wound complication rates and improve recovery time. The technique may, however, be less applicable in people with, for example, groin scarring or arterial calcification. This is an update of the review first published in 2014.

Objectives: This review aims to compare the clinical outcomes of percutaneous access with surgical cut-down femoral artery access in elective bifurcated abdominal endovascular aneurysm repair (EVAR).

Search Methods: For this update the Cochrane Vascular Information Specialist (CIS) searched their Specialised Register (last searched October 2016) and CENTRAL (2016, Issue 9). We also searched clinical trials registries and checked the reference lists of relevant retrieved articles.

Selection Criteria: We considered only randomised controlled trials. The primary intervention was a totally percutaneous endovascular repair. We considered all device types. We compared this against surgical cut-down femoral artery access endovascular repair. We only considered studies investigating elective repairs. We excluded studies reporting emergency surgery for a ruptured abdominal aortic aneurysm and those reporting aorto-uni-iliac repairs.

Data Collection And Analysis: Two review authors independently collected all data. Owing to the small number of trials identified we did not conduct any formal sensitivity analysis. Heterogeneity was not significant for any outcome.

Main Results: Two studies with a total of 181 participants met the inclusion criteria, 116 undergoing the percutaneous technique and 65 treated by cut-down femoral artery access. One study had a small sample size and did not adequately report method of randomisation, allocation concealment or pre-selected outcomes. The second study was a larger study with few sources of bias and good methodology.We observed no significant difference in mortality between groups, with only one mortality occurring overall, in the totally percutaneous group (risk ratio (RR) 1.50; 95% confidence interval (CI) 0.06 to 36.18; 181 participants; moderate-quality evidence). Only one study reported aneurysm exclusion. In this study we observed only one failure of aneurysm exclusion in the surgical cut-down femoral artery access group (RR 0.17, 95% CI 0.01 to 4.02; 151 participants; moderate-quality evidence). No wound infections occurred in the cut-down femoral artery access group or the percutaneous group across either study (moderate-quality evidence).There was no difference in major complication rate between cut-down femoral artery access and percutaneous groups (RR 0.91, 95% CI 0.20 to 1.68; 181 participants; moderate-quality evidence); or in bleeding complications and haematoma (RR 0.94, 95% CI 0.31 to 2.82; 181 participants; high-quality evidence).Only one study reported long-term complication rates at six months, with no differences between the percutaneous and cut-down femoral artery access group (RR 1.03, 95% CI 0.34 to 3.15; 134 participants; moderate-quality evidence).We detected differences in surgery time, with percutaneous approach being significantly faster than cut-down femoral artery access (mean difference (MD) -31.46 minutes; 95% CI -47.51 minutes to -15.42 minutes; 181 participants; moderate-quality evidence). Only one study reported duration of ITU (intensive treatment unit) and hospital stay, with no difference found between groups.

Authors' Conclusions: This review shows moderate-quality evidence of no difference between the percutaneous approach compared with cut-down femoral artery access group for short-term mortality, aneurysm exclusion, major complications, wound infection and long-term (six month) complications, and high-quality evidence for no difference in bleeding complications and haematoma. There was a difference in operating time, with moderate-quality evidence showing that the percutaneous approach was faster than the cut-down femoral artery access technique. We downgraded the quality of the evidence to moderate as a result of the limited number of studies, low event numbers and imprecision. As the number of included studies were limited, further research into this technique would be beneficial. The search identified one ongoing study, which may provide an improved evidence base in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD010185.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464496PMC
February 2017

Unimolecular branched block copolymer nanoparticles in methanol for the preparation of poorly water-soluble drug nanoparticles.

J Mater Chem B 2017 Jan 23;5(3):423-427. Epub 2016 Dec 23.

School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, China.

Spherical unimolecular amphiphilic branched A-B block copolymer nanoparticles in methanol are fabricated via thermal annealing using the methanolic upper critical solution temperature (UCST) of the hydrophobic block segment. These polymer nanoparticles are then used to produce an aqueous poorly water-soluble drug nanoparticle suspension with a mass : drug ratio of 1 : 1 and 100% nanoparticle yield. The drug nanoparticles in the suspension are stabilized by multiple polymer nanoparticles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6tb02940jDOI Listing
January 2017

Octreotide Functionalized Nano-Contrast Agent for Targeted Magnetic Resonance Imaging.

Biomacromolecules 2016 12 1;17(12):3902-3910. Epub 2016 Dec 1.

Singapore Bioimaging Consortium , Agency for Science, Technology and Research (A* Star), 11 Biopolis Way, Helios, Singapore , 138667.

Reversible addition-fragmentation chain transfer (RAFT) polymerization has been employed to synthesize branched block copolymer nanoparticles possessing 1,4,7,10-tetraazacyclododecane-N,N,'N,″N,‴-tetraacetic acid (DO3A) macrocycles within their cores and octreotide (somatostatin mimic) cyclic peptides at their periphery. These polymeric nanoparticles have been chelated with Gd and applied as magnetic resonance imaging (MRI) nanocontrast agents. This nanoparticle system has an r relaxivity of 8.3 mM s, which is 3 times the r of commercial gadolinium-based contrast agents (GBCAs). The in vitro targeted binding efficiency of these nanoparticles shows 5 times greater affinity to somatostatin receptor type 2 (SSTR2) with K = 77 pM (compared to somatostatin with K = 0.385 nM). We have also evaluated the tumor targeting molecular imaging ability of these branched copolymer nanoparticle in vivo using nude/NCr mice bearing AR42J rat pancreatic tumor (SSTR2 positive) and A549 human lung carcinoma tumor (SSTR2 negative) xenografts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biomac.6b01256DOI Listing
December 2016

Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour.

J Physiol 2016 11 19;594(22):6443-6462. Epub 2016 Jul 19.

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, 06269, USA.

The hypothalamus is among the most phylogenetically conserved regions in the vertebrate brain, reflecting its critical role in maintaining physiological and behavioural homeostasis. By integrating signals arising from both the brain and periphery, it governs a litany of behaviourally important functions essential for survival. In particular, the lateral hypothalamic area (LHA) is central to the orchestration of sleep-wake states, feeding, energy balance and motivated behaviour. Underlying these diverse functions is a heterogeneous assembly of cell populations typically defined by neurochemical markers, such as the well-described neuropeptides hypocretin/orexin and melanin-concentrating hormone. However, anatomical and functional evidence suggests a rich diversity of other cell populations with complex neurochemical profiles that include neuropeptides, receptors and components of fast neurotransmission. Collectively, the LHA acts as a hub for the integration of diverse central and peripheral signals and, through complex local and long-range output circuits, coordinates adaptive behavioural responses to the environment. Despite tremendous progress in our understanding of the LHA, defining the identity of functionally discrete LHA cell types, and their roles in driving complex behaviour, remain significant challenges in the field. In this review, we discuss advances in our understanding of the neurochemical and cellular heterogeneity of LHA neurons and the recent application of powerful new techniques, such as opto- and chemogenetics, in defining the role of LHA circuits in feeding, reward, arousal and stress. From pioneering work to recent developments, we review how the interrogation of LHA cells and circuits is contributing to a mechanistic understanding of how the LHA coordinates complex behaviour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP271946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108896PMC
November 2016

Orienting Oneself for Leadership: The Role of Goal Orientation in Leader Developmental Readiness.

New Dir Stud Leadersh 2016 ;2016(149):61-71

Kansas State University.

The ways in which individuals approach achievement situations influence their use of self-management activities such as goal setting, feedback seeking, and developmental strategies, and ultimately impact success in leader development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/yd.20162DOI Listing
January 2017

Nanoformulation and encapsulation approaches for poorly water-soluble drug nanoparticles.

Nanoscale 2016 Jan;8(4):1746-69

Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.

During the last few decades the nanomedicine sector has emerged as a feasible and effective solution to the problems faced by the high percentage of poorly water-soluble drugs. Decreasing the size of such drug compounds to the nanoscale can significantly change their physical properties, which lays the foundation for the use of nanomedicine for pharmaceutical applications. Various techniques have been developed to produce poorly water-soluble drug nanoparticles, mainly to address the poor water-soluble issues but also for the efficient and targeted delivery of such drugs. These techniques can be generally categorized into top-down, bottom-up and encapsulation approaches. Among them, the top-down approaches have been the main choice for industrial preparation of drug nanoparticles while other methods are actively investigated by researchers. In this review, we aim to give a comprehensive overview and latest progress of the top-down, bottom-up, and encapsulation methods for the preparation of poorly water-soluble drug nanoparticles and how solvents and additives can be selected for these methods. In addition to the more industrially applied top-down approaches, the review is focused more on bottom-up and encapsulation methods, particularly covering supercritical fluid-related methods, cryogenic techniques, and encapsulation with dendrimers and responsive block copolymers. Some of the approved and mostly used nanodrug formulations on the market are also covered to demonstrate the applications of poorly water-soluble drug nanoparticles. This review is complete with perspectives on the development and challenges of fabrication techniques for more effective nanomedicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5nr07161eDOI Listing
January 2016

Drug nanoparticles by emulsion-freeze-drying via the employment of branched block copolymer nanoparticles.

J Control Release 2016 Jan 15;222:141-50. Epub 2015 Dec 15.

Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. Electronic address:

A large percentage of drug compounds exhibit low water solubility and hence low bioavailability and therapeutic efficacy. This may be addressed by preparation of drug nanoparticles, leading to enhanced dissolution rate and direct use for treatment. Various methods have been developed to produce drug nanocrystals, including wet milling, homogenization, solution precipitation, emulsion diffusion, and the recently developed emulsion freeze-drying. The drawback for these methods may include difficult control in particles size, use of surfactants & polymer, and low ratio of drug to stabilizer. Here, biocompatible branched block copolymer nanoparticles with lightly-crosslinked hydrophobic core and hydrophilic surface groups are synthesized by the direct monomer-to-particle methodology, characterized, and then used as scaffold polymer/surfactant to produce drug nanoparticles via the emulsion-freeze-drying approach. This method can be used for model organic dye and different poorly water-soluble drugs. Aqueous drug nanoparticle dispersions can be obtained with high ratio of drug to stabilizer and relatively uniform nanoparticle sizes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2015.12.022DOI Listing
January 2016

Synthesis and in vivo magnetic resonance imaging evaluation of biocompatible branched copolymer nanocontrast agents.

Int J Nanomedicine 2015 18;10:5895-907. Epub 2015 Sep 18.

Institute of Chemical and Engineering Sciences (ICES), National University of Singapore, Singapore ; School of Chemistryand Chemical Engineering, HeFei University of Technology, Anhui, People's Republic of China.

Branched copolymer nanoparticles (D(h) =20-35 nm) possessing 1,4,7, 10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid macrocycles within their cores have been synthesized and applied as magnetic resonance imaging (MRI) nanosized contrast agents in vivo. These nanoparticles have been generated from novel functional monomers via reversible addition-fragmentation chain transfer polymerization. The process is very robust and synthetically straightforward. Chelation with gadolinium and preliminary in vivo experiments have demonstrated promising characteristics as MRI contrast agents with prolonged blood retention time, good biocompatibility, and an intravascular distribution. The ability of these nanoparticles to perfuse and passively target tumor cells through the enhanced permeability and retention effect is also demonstrated. These novel highly functional nanoparticle platforms have succinimidyl ester-activated benzoate functionalities within their corona, which make them suitable for future peptide conjugation and subsequent active cell-targeted MRI or the conjugation of fluorophores for bimodal imaging. We have also demonstrated that these branched copolymer nanoparticles are able to noncovalently encapsulate hydrophobic guest molecules, which could allow simultaneous bioimaging and drug delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S88764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583124PMC
August 2016

Patterns of oxygen consumption during simultaneously occurring elevated metabolic states in the viviparous snake Thamnophis marcianus.

J Exp Biol 2015 Nov 28;218(Pt 22):3570-9. Epub 2015 Sep 28.

Department of Ecology and Evolutionary Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA 92627, USA

Snakes exhibit large factorial increments in oxygen consumption during digestion and physical activity, and long-lasting sub-maximal increments during reproduction. Under natural conditions, all three physiological states may occur simultaneously, but the integrated response is not well understood. Adult male and female checkered gartersnakes (Thamnophis marcianus) were used to examine increments in oxygen consumption (i.e. V̇(O2)) and carbon dioxide production (i.e. V̇(CO2)) associated with activity (Act), digestion (Dig) and post-prandial activity (Act+Dig). For females, we carried out these trials in the non-reproductive state, and also during the vitellogenic (V) and embryogenic (E) phases of a reproductive cycle. Endurance time (i.e. time to exhaustion, TTE) was recorded for all groups during Act and Act+Dig trials. Our results indicate that male and non-reproductive female T. marcianus exhibit significant increments in V̇(O2) during digestion (∼5-fold) and activity (∼9-fold), and that Act+Dig results in a similar increment in V̇(O2) (∼9- to 10-fold). During reproduction, resting V̇(O2) increased by 1.6- to 1.7-fold, and peak increments during digestion were elevated by 30-50% above non-reproductive values, but values associated with Act and Act+Dig were not significantly different from non-reproductive values. During Act+Dig, endurance time remained similar for all of the groups in the present study. Overall, our results indicate that prioritization is the primary pattern of interaction in oxygen delivery exhibited by this species. We propose that the metabolic processes associated with digestion, and perhaps reproduction, are temporarily compromised during activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/jeb.115477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514467PMC
November 2015