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Introduction: Spinal bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron disorder caused by the presence of ≥38 CAG repeats in the androgen receptor gene. Existing literature indicates a relationship between CAG repeat number and the onset age of some motor symptoms of SBMA. This review explores the effect of larger versus shorter CAG repeats on the age of weakness onset in male SBMA patients. Methods: Three databases (October 2021; MEDLINE, SCOPUS, and Web of Science), Cambridge University Press, and Annals of Neurology were searched. 514 articles were initially identified, of which 13 were included for qualitative synthesis. Results: Eleven of the thirteen articles identified a statistically significant inverse correlation between CAG repeat length and age of weakness onset in SBMA. Five studies indicated that SBMA patients with between 35 and 37 CAG repeats had an older age of weakness onset than patients with over 40 CAG repeats. The minimum number of CAG repeats associated with weakness was in the mid-to-late thirties. Conclusion: Identification of a relationship between CAG repeat number and age of weakness may enable earlier detection and intervention for SBMA. In the future, studies should use interviews, chart reviews, and standardized scoring methods to reduce effects of retrospective bias.
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Calcium mobilization from the endoplasmic reticulum (ER) induced by, for example, IP3 receptor (IP3R) stimulation, and its subsequent crosstalk with extracellular Ca2+ influx mediated through voltage-gated calcium channels (VGCCs) and neuronal store-operated calcium entry (nSOCE), is essential for normal neuronal signaling and cellular homeostasis. However, several studies suggest that chronic calcium dysregulation may play a key role in the onset and/or progression of neurodegenerative conditions, particularly Alzheimer's disease (AD). Here, using early postnatal hippocampal tissue from two transgenic murine models of AD, we provide further evidence that not only are crucial calcium signaling pathways dysregulated, but also that such dysregulation occurs at very early stages of development. Utilizing epifluorescence calcium imaging, we investigated ER-, nSOCE- and VGCC-mediated calcium signaling in cultured primary hippocampal neurons from two transgenic rodent models of AD: 3xTg-AD mice (PS1M146V/APPSWE/TauP301L) and TgF344-AD rats (APPSWE/PS1ΔE9) between 2 and 9 days old. Our results reveal that, in comparison to control hippocampal neurons, those from 3xTg-AD mice possessed significantly greater basal ER calcium levels, as measured by larger responses to I-mGluR-mediated ER Ca2+ mobilization (amplitude; 4 (0-19) vs 21(12-36) a.u., non-Tg vs 3xTg-AD; median difference (95 % Cl) = 14 a.u. (11-18); p = 0.004)) but reduced nSOCE (15 (4-22) vs 8(5-11) a.u., non-Tg vs 3xTg-AD; median difference (95 % Cl) = -7 a.u. (-3- -10 a.u.); p < 0.0001). Furthermore, unlike non-Tg neurons, where depolarization enhanced the amplitude, duration and area under the curve (A.U.C.) of I-mGluR-evoked ER-mediated calcium signals when compared with basal conditions, this was not apparent in 3xTg-AD neurons. Whilst the amplitude of depolarization-enhanced I-mGluR-evoked ER-mediated calcium signals from both non-Tg F344 and TgF344-AD neurons was significantly enhanced relative to basal conditions, the A.U.C. and duration of responses were enhanced significantly upon depolarization in non-Tg F344, but not in TgF344-AD, neurons. Overall, the nature of basal I-mGluR-mediated calcium responses did not differ significantly between non-Tg F344 and TgF344-AD neurons. In summary, our results characterizing ER- and nSOCE-mediated calcium signaling in neurons demonstrate that ER Ca2+ dyshomeostasis is an early and potentially pathogenic event in familial AD.
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Enfermedad de Alzheimer , Receptores de Glutamato Metabotrópico , Ratones , Ratas , Animales , Enfermedad de Alzheimer/metabolismo , Roedores/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Calcio/metabolismo , Ratas Endogámicas F344 , Neuronas/metabolismo , Retículo Endoplásmico/metabolismo , Señalización del Calcio/fisiologíaRESUMEN
Both summative and formative assessments are known to facilitate student learning and understanding and help students to identify areas of weakness. However, few studies have investigated students' preference for either summative or formative evaluations, particularly in the area of preclinical medicine. The current study addresses this deficit by surveying 137 first-year graduate entry to medicine (GEM) preclinical medical students from 2 consecutive years (2018-2019 and 2019-2020), for their thoughts on the 6 summative (i.e., for a small percentage of marks), proctored and the 5 informal, formative (i.e., no marks available) continuous assessments in physiology that they encountered in semesters 1 and 2, respectively. Our survey revealed that between 75 and 90% of students felt that both evaluation formats were roughly equally useful (i.e., selecting options, "agree" or "strongly agree") both for providing feedback about their understanding of physiology and for identifying deficits in their physiology knowledge. However, although a significantly larger number of students felt that summative evaluations motivated them to study more than the formative evaluations (P = 0.006), overall, more students favored formative over summative assessments. Notably, however, GEM students from nonbiomedical backgrounds were significantly more in favor of summative assessments than those from either biomedical backgrounds (P = 0.003) or the whole GEM survey cohort (P = 0.01). The implications of these findings will be discussed, with suggestions as to how the student views outlined here might be facilitated within an academic program to maximize both student learning as well as their motivation to study and keep up with taught material.NEW & NOTEWORTHY Although several studies have investigated the relative effectiveness of regular summative versus formative assessments as tools to facilitate student learning and understanding, ours is the first to explicitly solicit students' views on, and preferences for, either regular formative or summative assessment in preclinical medicine. We demonstrate that, overall, students preferred formative- to summative-type assessments, due to the immediacy of feedback, but also that summative tests incentivized them to study and keep up with material more.
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Educación de Pregrado en Medicina , Estudiantes de Medicina , Humanos , Evaluación Educacional , Aprendizaje , RetroalimentaciónRESUMEN
Interleukin-6 (IL-6) is a pro-inflammatory cytokine, classically associated with orchestrating an immune response to invading pathogens. However, IL-6 can also directly or indirectly modify central nervous system function, and thereby alter higher-order functions, such as learning and the consolidation of memories. IL-6 is chronically elevated in Duchenne Muscular Dystrophy (DMD), a neuromuscular disorder arising when a mutation causes the loss of the structural protein, dystrophin. Absence of dystrophin leads to progressive immobility, chronic inflammation and premature death. However, the role of dystrophin as a mechano-transducing signalling molecule is unnecessary in non-contracting cells such as neurons, where it may play a role in synapse formation. Specific brain regions, including the hippocampus, which is the site of memory acquisition, expresses dystrophin and therefore, loss of this protein may underlie variable deficits in cognitive function that are common in individuals with DMD. This review will evaluate the potential role of IL-6 in cognitive dysfunction in dystrophin-deficient DMD.
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Disfunción Cognitiva/metabolismo , Citocinas/metabolismo , Interleucina-6/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Neuronas/metabolismo , Animales , Encéfalo/metabolismo , HumanosRESUMEN
Medical students increasingly utilize social media platforms to supplement their preclinical learning; however, the prevalence of social media use for physiology learning in medical education remains unclear. The aim of the present study was to determine how first-year medical students from both direct entry medicine and graduate entry medicine interacted with social media as a learning tool by assessing its prevalence, perceived benefits, favored platforms, and reason(s) for its use. Seventy-one percent of surveyed students (out of 139 participants) stated that they interacted with social media in general more than 12 times per week. However, 98% had previously used internet platforms to source physiology information, with 89.2% doing so at least once per week during term. YouTube was the primary source of learning for 76% of students. Significantly, 94% of students indicated that they would first search for answers online if they did not understand something in physiology rather than contacting their instructor in person or by e-mail. However, only 31% of students "fact-checked" physiology information obtained from online sources, by using textbooks, papers, and/or instructors. Our study has revealed that most preclinical medical students utilize social media extensively to study physiology. However, the absence of academic and ethical oversight, paired with students' lack of critical appraisal of possibly inaccurate information, does raise concerns about the overall utility of social media as part of physiology education.
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Internet/tendencias , Fisiología/educación , Medios de Comunicación Sociales/tendencias , Estudiantes de Medicina/psicología , Encuestas y Cuestionarios , Adolescente , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain networks, including those pivotal to the motor control of breathing. The aim of this study was to examine respiratory control in the TgF344-AD transgenic rat model of AD. At 8-11 months of age, basal minute ventilation and ventilatory responsiveness to chemostimulation were equivalent in conscious wild-type (WT) and TgF344-AD rats. Under urethane anesthesia, basal diaphragm and genioglossus EMG activities were similar in WT and TgF344-AD rats. The duration of phenylbiguanide-induced apnoea was significantly shorter in TgF344-AD rats compared with WT. Following bilateral cervical vagotomy, diaphragm and genioglossus EMG responsiveness to chemostimulation were intact in TgF344-AD rats. Amyloid precursor protein C-terminal fragments were elevated in the TgF344-AD brainstem, in the absence of amyloid-ß accumulation or alterations in tau phosphorylation. Brainstem pro-inflammatory cytokine concentrations were not increased in TgF344-AD rats. We conclude that neural control of breathing is preserved in TgF344-AD rats at this stage of the disease.
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Enfermedad de Alzheimer/fisiopatología , Apnea/fisiopatología , Tronco Encefálico/metabolismo , Diafragma/fisiopatología , Síntomas Prodrómicos , Reflejo/fisiología , Respiración , Lengua/fisiopatología , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Anestesia General , Animales , Modelos Animales de Enfermedad , Electromiografía , Presenilina-1/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Transgénicas , VagotomíaRESUMEN
BACKGROUND: There is increasing concern amongst educators that the provision of recorded lectures may reduce student attendance of live lectures. We therefore sought to determine if the provision of prerecorded lecture video podcasts (VODcasts) to first-year Graduate Entry to Medicine (GEM) students, affected attendance at 21 Physiology lectures within three separate pre-clinical modules. METHODS: Data on lecture attendance, utilization of VODcasts, and whether VODcasts should replace live lectures were drawn from three surveys conducted in academic years 2014-2015 and 2015-2016 on all first-year GEM students in two first-year pre-clinical modules where prerecorded Physiology VODcasts were available for viewing or downloading prior to scheduled live lectures. RESULTS: A total of 191/214 (89%) students responded to the three surveys, with 84.3% of students attending all 21 lectures in the study. Only 4% of students missed more than one lecture in each of the three lecture series, with 79% indicating that VODcasts should not replace lectures. CONCLUSION: Therefore, we conclude that the attendance of pre-clinical GEM students at live lectures is not significantly impacted upon by the provision of lecture VODcasts, with most students viewing them as useful revision tools rather than as a replacement for live lectures.
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Educación de Pregrado en Medicina , Internet , Enseñanza , Grabación de Cinta de Video , Adulto , Femenino , Humanos , Masculino , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals.
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Antihipertensivos/uso terapéutico , Antioxidantes/uso terapéutico , Catalasa/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Catalasa/administración & dosificación , Catalasa/efectos adversos , Bovinos , Óxidos N-Cíclicos/administración & dosificación , Óxidos N-Cíclicos/efectos adversos , Quimioterapia Combinada/efectos adversos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipodermoclisis , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/fisiopatología , Médula Renal/irrigación sanguínea , Médula Renal/efectos de los fármacos , Médula Renal/metabolismo , Médula Renal/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Endogámicas SHR , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Marcadores de Spin , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resistencia Vascular/efectos de los fármacosRESUMEN
NEW FINDINGS: What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.
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Colon/efectos de los fármacos , Colon/metabolismo , Citocinas/metabolismo , Interleucina-6/metabolismo , Leptina/farmacología , Adolescente , Adulto , Anciano , Animales , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Síndrome del Colon Irritable/metabolismo , Masculino , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Adulto JovenRESUMEN
Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility, and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein that connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit nonprogressing cognitive dysfunction, with deficits in verbal, short-term, and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient, and specific deficits in synaptogenesis and channel clustering at synapses has been noted. Little consideration has been devoted to the cognitive deficits associated with DMD compared with the research conducted into the peripheral effects of dystrophin deficiency. Therefore, this review focuses on what is known about the role of full-length dystrophin (Dp427) in hippocampal neurons. The importance of dystrophin in learning and memory is assessed, and the potential importance that inflammatory mediators, which are chronically elevated in dystrophinopathies, may have on hippocampal function is also evaluated.
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Disfunción Cognitiva/etiología , Disfunción Cognitiva/inmunología , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/inmunología , Animales , Hipocampo/inmunología , Humanos , Masculino , Distrofia Muscular de Duchenne/psicologíaRESUMEN
Group I metabotropic glutamate receptors (I-mGluRs) modulate numerous cellular functions such as specific membrane currents and neurotransmitter release linked to their ability to mobilize calcium from intracellular calcium stores. As such, most I-mGluR research to date has focused on the coupling of these receptors to phospholipase C (PLC)-dependent and inositol (1,4,5) trisphosphate (IP3)-mediated calcium release via activation of IP3 receptors located upon the sarco/endoplasmic reticulum. However, there are now numerous examples of PLC- and IP3-independent I-mGluR-evoked signals, which may instead be mediated by activation of ryanodine receptors (RyRs). A prime candidate for mediating this coupling between I-mGluR activation and RyR opening is cyclic ADP ribose (cADPR) and, indeed, several of these PLC-/IP3-independent I-mGluR-evoked calcium signals have now been shown to be mediated wholly or partly by cADPR-evoked activation of RyRs. The contribution of cADPR signalling to I-mGluR-mediated responses is relatively complex, dependent as it is on factors such as cell type, excitation state of the cell and location of I-mGluRs on the cell. However, these factors notwithstanding, I-mGluR-mediated cADPR signalling remains poorly characterized, with several key aspects yet to be fully elucidated such as (1) the range of stimuli which evoke cADPR production, (2) the specific molecular mechanism(s) coupling cADPR to RyR activation and (3) the contribution of cADPR-mediated responses to downstream outputs such as synaptic plasticity. Furthermore, it is possible that the cADPR pathway may play a role in diseases underpinned by dysregulated calcium homoeostasis such as Alzheimer's disease (AD).
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Enfermedad de Alzheimer/genética , Señalización del Calcio/genética , ADP-Ribosa Cíclica/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Calcio/metabolismo , ADP-Ribosa Cíclica/genética , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Glutamato Metabotrópico/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismoRESUMEN
The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.
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Sistema Nervioso Entérico/fisiopatología , Interleucina-6/fisiología , Síndrome del Colon Irritable/fisiopatología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Adolescente , Adulto , Anciano , Animales , Anticuerpos Monoclonales/administración & dosificación , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Motilidad Gastrointestinal/fisiología , Humanos , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/terapia , Masculino , Persona de Mediana Edad , Plexo Mientérico/fisiopatología , Neuroinmunomodulación/fisiología , Sistemas Neurosecretores/fisiopatología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/fisiología , Dolor Visceral/etiología , Dolor Visceral/fisiopatología , Dolor Visceral/terapia , Adulto JovenRESUMEN
1. The effects of changes in mean and pulsatile shear stress on the diameter of the iliac of the anaesthetized pig were investigated in the presence of clazosentan and tezosentan. 2. A total of 17 pigs were used. Mean shear stress was increased by infusing acetylcholine downstream (2-20 µg/min) through the deep femoral artery. Pulsatile shear stress was enhanced first by injecting varying volumes (1-10 mL) of calcium gluconate (stock 10 mg/mL) directly into the left ventricle. Second, by electrical stimulation of the left sympathetic nerves to the heart (1-16 Hz, 4 min duration, supramaximal voltage). 3. An increase in mean shear stress induced a vasodilation that was not altered significantly by the selective endothelin A antagonist clazosentan (10 mg/kg i.v.). Similarly, the vasoconstriction induced by an increase in pulsatile shear stress brought about by either calcium gluconate injections or left sympathetic nerve stimulation was unaffected by clazosentan. However, tezosentan (10 mg/kg i.v.), significantly attenuated the vasoconstriction induced by an increase in pulsatile shear stress. 4. In conclusion, an increase in pulsatile shear stress causes vasoconstriction of the pig iliac artery, which is attenuated by dual endothelin receptor antagonism, but not by specific endothelin A blockade.
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Dioxanos/farmacología , Antagonistas de los Receptores de Endotelina , Arteria Ilíaca/efectos de los fármacos , Piridinas/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Tetrazoles/farmacología , Vasoconstricción/efectos de los fármacos , Vasodilatadores/farmacología , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Antagonistas de los Receptores de la Endotelina A , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Arteria Ilíaca/lesiones , Arteria Ilíaca/fisiología , Flujo Pulsátil/efectos de los fármacos , Estrés Mecánico , Porcinos , Vasoconstricción/fisiologíaRESUMEN
After injury GABA(A) receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA(A)-α2 and -α3 receptor function within the spinal cord. GABA can also act at GABA(A) receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABA(A) receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1-10 mg/kg) and TPA023 (3-30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenan-inflamed and nerve-injured rats. The non-selective PAM diazepam (1-5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3-30 mg/kg) and the α5-selective NAM α5IA-II (10-60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenan-inflamed rats α5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA(A) receptors might be more complex than previously anticipated, and is worthy of further exploration.
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Analgésicos/uso terapéutico , Neuralgia/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Subunidades de Proteína/fisiología , Receptores de GABA-A/fisiología , Regulación Alostérica/fisiología , Analgésicos/farmacología , Animales , Diazepam/farmacología , Diazepam/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Neuralgia/fisiopatología , Dimensión del Dolor/métodos , Subunidades de Proteína/agonistas , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
Ensembl is a software project to automatically annotate large eukaryotic genomes and release them freely into the public domain. The project currently automatically annotates 10 complete genomes. This makes very large demands on compute resources, due to the vast number of sequence comparisons that need to be executed. To circumvent the financial outlay often associated with classical supercomputing environments, farms of multiple, lower-cost machines have now become the norm and have been deployed successfully with this project. The architecture and design of farms containing hundreds of compute nodes is complex and nontrivial to implement. This study will define and explain some of the essential elements to consider when designing such systems. Server architecture and network infrastructure are discussed with a particular emphasis on solutions that worked and those that did not (often with fairly spectacular consequences). The aim of the study is to give the reader, who may be implementing a large-scale biocompute project, an insight into some of the pitfalls that may be waiting ahead.
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Biología Computacional/métodos , Programas Informáticos , Sistemas de Computación , Sistemas de Administración de Bases de Datos , Bases de Datos Genéticas , Sistemas en Línea , Diseño de SoftwareRESUMEN
Using combined whole-cell voltage-clamp recording and Ca2+ imaging we have investigated further the characteristics and pharmacology of group I metabotropic l-glutamate receptor (mGluR)-mediated responses in CA1 pyramidal neurons of the rat hippocampus. The selective group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG), evoked a transient increase in intracellular Ca2+ levels ([Ca2+]i), within neuronal somas and apical dendrites, together with a relatively long lasting inward current (I(DHPG)). Both types of response were enhanced by depolarisation (-30 mV), and this condition was used for their characterisation. The DHPG-induced [Ca2+]i rise was much more sensitive to manipulations of Ca2+ homeostasis, such as using the Ca2+ store depleting agent, cyclopiazonic acid (50-100 microM), the fast Ca2+ buffer, BAPTA (intracellular; 20-40 mM) and Ca(2+)-free/EGTA (1 mM) bath solution, than I(DHPG), suggesting that these responses are, in the main part, mediated by distinct processes. The selective mGluR1 and mGluR5 antagonists, (S)-(+)-alpha-amino-a-methylbenzeneacetic acid (LY367385; 100 microM) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP;10 microM), respectively, markedly inhibited both I(DHPG) and the DHPG-evoked increase in [Ca2+]i. Moreover, these antagonists inhibited the Ca2+ response by more than 50% suggesting a synergistic interaction between mGluR1 and mGluR5. This study demonstrates that in CA1 pyramidal neurons group I mGluR-mediated inward currents and Ca2+ release from intracellular stores are enhanced under depolarising conditions and that mGluR1 and mGluR5 both contribute to these phenomena.
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Calcio/metabolismo , Células Piramidales/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
Ensembl (http://www.ensembl.org/) is a bioinformatics project to organize biological information around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of individual genomes, and of the synteny and orthology relationships between them. It is also a framework for integration of any biological data that can be mapped onto features derived from the genomic sequence. Ensembl is available as an interactive Web site, a set of flat files, and as a complete, portable open source software system for handling genomes. All data are provided without restriction, and code is freely available. Ensembl's aims are to continue to "widen" this biological integration to include other model organisms relevant to understanding human biology as they become available; to "deepen" this integration to provide an ever more seamless linkage between equivalent components in different species; and to provide further classification of functional elements in the genome that have been previously elusive.
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Biología Computacional/tendenciasAsunto(s)
Hipocampo/metabolismo , Leptina/farmacología , Neuronas/efectos de los fármacos , Canales de Potasio Calcio-Activados/metabolismo , Receptores de Superficie Celular , Animales , Calcio/metabolismo , Proteínas Portadoras/metabolismo , Células Cultivadas , Caribdotoxina/farmacología , Hipocampo/citología , Humanos , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio , Neuronas/metabolismo , Técnicas de Placa-Clamp , Fosfatidilinositol 3-Quinasas/metabolismo , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Ratas , Receptores de Leptina , Tetraetilamonio/farmacología , Tolbutamida/farmacologíaRESUMEN
We describe the challenges faced when developing a Linux/PC-based cluster to apply bioinformatics algorithms to the rapidly increasing raw genomics data available. The calculations, which take around two months to complete, result in a powerful resource that can be used for data mining--most obviously for the human genome. Our current infrastructure consists of a 1314 node cluster with 1734 processors supporting both production and research. This paper highlights the problems in achieving high data throughput with such systems and shows that raw computer power is only one component of a complex problem.