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Results for “Deep generative models”

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PubMed2001

Changes in cannabinoid CB(1) receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis.

Data, initially anecdotal, but recently supported on more solid experimental evidence, suggest that cannabinoids might be beneficial in the treatment of some of the symptoms of multiple sclerosis (MS). Despite this evidence, there are no data on the possible changes in cannabinoid CB(1) or CB(2) receptors, the main molecular targets for the action of cannabinoids, either in the postmortem brain of patients with MS or in animal models of this disease. The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) in Lewis rats generated by inoculation of guinea pig myelin basic protein in Freund's adjuvant. After inoculation, animals were examined daily to detect the appearance of neurological signs. The first signs appeared around day 10 after inoculation, reaching the highest degree by day 13, when animals were sacrificed and their brains removed and used for analysis of CB(1) receptor binding, mRNA levels, and activation of GTP-binding proteins. CB(1) receptor binding and mRNA levels were not affected in EAE rats in brain areas such as the hippocampus, limbic structures, and cerebellum. However, there was a marked decrease in both parameters in the caudate-putamen, both in the lateral and medial parts, although this decrease did not correspond with decreases in binding in the nuclei recipient of striatal output neurons, which suggests that changes in CB(1) receptors are exclusively located in the cell bodies of striatal neurons. In addition, CB(1) receptor binding, but not mRNA levels, also decreased in the cerebral cortex, both in the deep and the superficial layers. The analysis of [(35)S]GTPgammaS binding after activation of CB(1) receptors with WIN55,212-2, a synthetic agonist, revealed that, despite the decrease in the number of CB(1) receptors in EAE rats, these were more efficiently coupled to GTP-binding protein-mediated signaling mechanisms in both the caudate-putamen and the cerebral cortex of these animals. In summary, these data suggest that the generation of EAE in Lewis rats would be associated with changes in CB(1) receptors in striatal and cortical neurons, which might be related to the alleviation of some motor signs observed after the treatment with cannabinoid receptor agonists in similar models of MS in rodents.

Animals↗

PubMed2003

Experimental deep tissue pain in wrist extensors--a model of lateral epicondylalgia.

The aim of this experimental study was to develop an in vivo model demonstrating sensory and motor interactions comparable to those seen in patients presenting with lateral epicondylalgia (i.e., deep tissue pain and hyperalgesia localised to specific sites in the wrist extensors, attenuation of wrist extension force). The effect of saline-induced deep pain combined with delayed onset muscle soreness (DOMS) on deep tissue sensitivity and motor function in wrist extensors was examined. Muscle pain intensity (visual analogue scale: VAS), distribution, and quality were assessed in 12 subjects. Pressure pain thresholds (PPTs) were recorded at five different sites around the elbow. Maximal wrist extension force was recorded. In the absence of DOMS, hypertonic saline administrated into different parts of the wrist extensors (extensor carpi radialis brevis, supinator, common extensor origin) induced significantly (P<0.05) higher VAS scores and larger pain areas compared with a control injection of isotonic saline. The typical quality of saline-induced pain was described as "drilling", "taut", "nagging" and "intense". In non-exercised wrist extensors, hyperalgesia to pressure was not detected during saline-induced pain but maximal wrist extensor force decreased significantly (P<0.05) compared with pre-pain recordings and recordings post isotonic saline. DOMS induced by eccentric wrist extension contractions generated moderate levels of soreness but no resting pain up to 24h post exercise. PPTs and maximal wrist extension force were significantly decreased (P<0.05) during DOMS compared with baseline and 7 days post exercise (P<0.05). VAS scores to injection of hypertonic saline into the DOMS arm were significantly increased (P<0.05) compared with injections into the unexercised arm. This is another manifestation of muscle hyperalgesia. Saline-induced pain combined with DOMS further decreased maximal wrist extension force (P<0.05). The simultaneous deep tissue pain and hyperalgesia linked with force attenuation support the use of the saline-induced deep tissue pain combined with DOMS as an experimental model simulating the clinical sensorimotor correlates of lateral epicondylalgia.

Adult↗

PubMedDate not supplied

Lactate efflux and the neuroenergetic basis of brain function.

In the unstimulated brain energy is primarily supplied by the oxidation of glucose. However the oxygen-to-glucose index (OGI), which is the ratio of metabolic rates of oxygen to glucose, CMR(O2)/CMR(glc), diverges from the theoretical value of 6 as activity is increased. In vivo measurements of brain lactate show its concentration to increase with stimulation. The decreasing OGI with stimulation had led to the suggestion that activation, unlike resting activity, is supported by anaerobic glycolysis. To date a unifying concept that accommodates glucose oxidation at rest with lactate generation and OGI decrease during stimulation of brain is lacking. Furthermore, energetics that change with increasing activity are not consistent with a neuroenergetic model that has been proposed from 1-(13)C-glucose MRS experiments. That model, based upon in vivo MRS measurements and cellular studies by Pellerin and Magistretti, showed that glutamate neurotransmitter cycling was coupled to glucose oxidation over a wide range of brain activities from rest down to deep anesthesia. Here we reconcile these paradoxical observations by suggesting that anaerobic glucose consumption (which can provide energy rapidly) increases with activation to meet the power requirements of millisecond neuronal firing. It is proposed, in accord with our neuroenergetic model, that the extra glucose mobilized rapidly for glial clearance of glutamate, is not needed for the oxidative processes that are responsible for neuronal firing and glutamate release, and consequently it is effluxed as lactate. A stoichiometric relation between OGI and lactate concentration is derived from the neuroenergetic model, showing that the enhanced glucose uptake during activation is consistent with neuronal activity being energetically supported by glucose oxidation.

Adenosine Triphosphate↗

PubMedDate not supplied

A computational model for heat generation in a radially layered tissue inside a 'coaxial TEM' applicator.

The electromagnetic heat dissipation in a radially layered biological tissue inside a circular cylinder has been investigated theoretically. The theory is based on a three-dimensional model and the electromagnetic field is assumed to be generated by a prescribed electric field along a ring-shaped aperture. The method of computation employs the spatial Fourier transform of all field quantities with respect to the axial coordinate, after which the field equations are solved in the spectral domain. Subsequently, an inverse Fourier transform is carried out to compute the quantities that are of interest to the clinical deep-body hyperthermia system at hand. For a number of representative configurations numerical results at 70 MHz are given.

Body Temperature↗

PubMed1998

Nociceptive integration in the rat spinal cord: role of non-linear membrane properties of deep dorsal horn neurons.

Deep dorsal horn neurons (DHNs) involved in nociception can relay long-lasting inputs and generate prolonged afterdischarges believed to enhance the transfer of nociceptive responses to the brain. We addressed the role of neuronal membrane properties in shaping these responses, by recording lamina V DHNs in a slice preparation of the rat cervical spinal cord. Of 256 neurons, 102 produced accelerating discharges in response to depolarizing current pulses, whereas the other neurons showed spike frequency adaptation. Two mechanisms mediated the firing acceleration: a slow inactivation of a K+ current expressed upon activation of the neuron from hyperpolarized holding potentials, and the expression of a regenerative plateau potential activating around resting membrane potential. The increase in firing frequency was much stronger when sustained by the plateau potential (71 DHNs, 28%). A few neurons produced adaptation and both types of acceleration, in different membrane potential domains, showing that the firing pattern of a deep DHN is not a rigid characteristic. Plateau potentials could be elicited by stimulation of nociceptive primary afferent fibres. The bistability associated with plateau potentials permitted afterdischarges. Because plateau potentials had slow activation kinetics and were voltage-dependent, the neurons had non-linear input-output relationships in both the amplitude and time domains. Nociceptive primary afferent stimulation elicited intense and prolonged responses in plateau-generating DHNs, while brief bursts of spikes were evoked otherwise. These results indicate that in a population of deep DHNs, intense firing and prolonged afterdischarges in response to nociceptive stimulation depend on non-linear intrinsic membrane properties.

4-Aminopyridine↗

PubMed2006

Imaging renin content and release in the living kidney.

Renin release is the first, and at least initially, the rate-limiting step in the activation of the renin-angiotensin system, which helps to maintain body salt and water balance. Recent advances in our understanding of pathophysiology have generated a renewed interest in the multiple roles of renin and prorenin as a hormone, enzyme, and signaling molecule. The assays available to measure renin content, release and tissue activity are complex, indirect and work with significant internal errors. We developed an imaging approach to directly visualize renin content and study the dynamics of both the release and tissue activity of renin. Our experimental model uses multiphoton fluorescence microscopy, which is ideal for deep optical sectioning of the living renal tissue. Here we review the application of this renin imaging approach to the dissected, in vitro microperfused glomerulus as well as in the intact kidney in vivo.

Animals↗

PubMed1998

Microsurgical treatment of arteriovenous malformations: analysis and comparison with stereotactic radiosurgery.

OBJECT: To compare microsurgical and stereotactic radiosurgical treatment of arteriovenous malformations (AVMs), the authors analyzed a prospective series of 72 consecutive patients who were treated microsurgically for cerebral AVMs by one neurosurgeon. The authors then compared the results of microsurgical treatment with published results of stereotactic radiosurgical treatment of small AVMs. METHODS: Patients were categorized by age, gender, presentation, and preoperative neurological status. The AVMs were categorized by size, location, presence of deep venous drainage, and Spetzler-Martin grade. Outcome was assessed for angiographic obliteration, hemorrhage following treatment, presence of a new, persistent postoperative neurological deficit, and Glasgow Outcome Scale (GOS) score. Ordinal logistic regression was used to model the GOS score and to predict new postoperative deficits. Generalized estimating equations were used to compare published results of microsurgical and stereotactic radiosurgical treatment of AVMs. Kaplan-Meier event-free survival plots were generated to compare the two modalities with respect to hemorrhage following treatment. Overall, six patients (8.3%) exhibited a new persistent neurological deficit postoperatively. Sixty-five patients (90.3%) had a GOS score of 5. Three patients were moderately disabled and four patients were severely disabled. No patient was observed to be in a vegetative state and there were no treatment-related deaths. Seventy-one patients (98.6%) underwent intra- or postoperative angiography. Total excision of the AVM was angiographically confirmed in 70 patients (98.6% of those who underwent angiography). To date no patient has suffered from hemorrhage since the microsurgical treatment. When analysis was confined to patients whose AVMs were smaller than 3 cm in maximum diameter, the authors found a 100% angiographic obliteration rate, no new postoperative neurological deficit, and a good recovery in all patients. An analysis of all patients with Spetzler-Martin Grades I to III resulted in a 100% rate of angiographic obliteration, one patient with a new postoperative neurological deficit, and good recovery in 93% of the patients. Size of the AVM, preoperative neurological status, and patient age are associated with GOS score (for all, p < 0.02). The Spetzler-Martin grading system as well as each component of this system are associated with the development of a new postoperative neurological deficit (for all, p < 0.01). For the entire series there were fewer postoperative hemorrhages and deaths than those mentioned in published series of small AVMs treated with stereotactic radiosurgery. When these patients and published series of patients with microsurgically treated AVMs classified as Grade I to III were compared with similar patients treated radiosurgically there were significantly fewer postoperative hemorrhages (odds ratio = 0.210, p = 0.001), fewer deaths (odds ratio = 0.659, p = 0.019), fewer new posttreatment neurological deficits (odds ratio = 0.464, p = 0.013), and a higher incidence of obliteration (odds ratio = 28.2, p = 0.001) for the microsurgical group. Lifetable analysis confirms the statistically significant difference in hemorrhage-free survival time between the two groups (p = 0.002). CONCLUSIONS: Based on this analysis, microsurgical treatment of Grades I to III AVMs is superior to stereotactic radiosurgery.

Adolescent↗

PubMed2005

Water-rich basalts at mid-ocean-ridge cold spots.

Although water is only present in trace amounts in the suboceanic upper mantle, it is thought to play a significant role in affecting mantle viscosity, melting and the generation of crust at mid-ocean ridges. The concentration of water in oceanic basalts has been observed to stay below 0.2 wt%, except for water-rich basalts sampled near hotspots and generated by 'wet' mantle plumes. Here, however, we report unusually high water content in basaltic glasses from a cold region of the mid-ocean-ridge system in the equatorial Atlantic Ocean. These basalts are sodium-rich, having been generated by low degrees of melting of the mantle, and contain unusually high ratios of light versus heavy rare-earth elements, implying the presence of garnet in the melting region. We infer that water-rich basalts from such regions of thermal minima derive from low degrees of 'wet' melting greater than 60 km deep in the mantle, with minor dilution by melts produced by shallower 'dry' melting--a view supported by numerical modelling. We therefore conclude that oceanic basalts are water-rich not only near hotspots, but also at 'cold spots'.

Journal Article↗

PubMed1993

[A new procedure for removal of foreign bodies in the area of the head].

Identification and extraction of penetrating cranial foreign bodies can cause problems in some cases. Small fragments localized deep in the orbit or cerebrum can be especially hard to detect. Severe bleeding and traumatized anatomy can make orientation difficult. We used a new localizing device, computer-assisted surgery (CAS), to good effect in six such cases. CAS is a localizing technique designed to assist the head surgeon during surgery, providing real-time position information. The method is based upon a three-dimensional volume model of the patient's skull generated by preceding computed tomography imaging procedures (CT or MRI). Intraoperative correlation of a 3D-model and the patient's skull allows for real-time position display of a surgical instrument on the monitor screen. Thereby the surgeon is able to localize even small foreign bodies without extensive exploration. In the case of multiple foreign bodies the surgeon calls up a simple documentation facility recording which of the visible fragments have already been extracted. We successfully used the system for extraction of orbital foreign bodies in four and intracerebral foreign bodies in two cases. In a 4-year-old child with gunshot injury the bullet was located in the precentral region and was easily extracted with the CAS system. In a 21-year-old man 39 glass fragments were extracted from the left orbit. In a 36-year-old man a bone fragment was dislocated to the apex of the orbit directly under the optic nerve. Location and extraction were achieved without damage to the orbital structures with the help of the CAS system.

Adult↗

PubMed2004

A CoMFA study of COX-2 inhibitors with receptor based alignment.

A diverse set of 53 cyclooxygenase-2 (COX-2) inhibitors which were aligned in two different ways were subjected to CoMFA analysis. The first method of alignment of the molecules was based on the binding information sourced from the crystallographic study, from which CoMFA Model 1 was derived. The second mode of alignment was generated by docking the inhibitors in the binding pocket using the DOCK and AFFINITY suite of programs; this gave a second model. The CoMFA Model 2 was slightly better than Model 1 in terms of the statistical parameters r(2) and q(2). The two models could predict very well the activity of a test set of diverse molecules, with a predictive r(2) of 0.593 and 0.768, respectively. Besides the QSAR results, the docking studies give a deep insight into the H-bonding interactions between the inhibitors and residues in the active site of the enzyme, which can be exploited in designing better inhibitors. Useful ideas on activity improvement could be gleaned from these models.

Binding Sites↗

PubMed2002

Self-contained microelectrochemical immunoassay for small volumes using mouse IgG as a model system.

A self-contained, microelectrochemical immunoassay on the smallest volumes reported to date (1 microL for the antigen, 1 microL for the secondary antibody-enzyme conjugate, and 200 nL for the electrochemically detected species) has been developed using mouse IgG as a model system in a sandwich-type enzyme-linked immunosorbant assay, which takes less than 30 min to both complete the assembly of immunoassay components onto the antibody-modified surface and detect enzymatically generated species (excluding time for electrochemical cleaning of electrodes). These studies demonstrate the advantage of the close proximity of electrodes to modified surfaces and their application in the analysis of small volumes. Using a 50 microm diameter x 8 microm deep cavity with individually addressable electrodes on a microfabricated chip, the primary antibody was selectively and covalently attached at a gold, recessed microdisk (RMD) at the bottom of the microcavity to the free end of SAMs of either 11-mercaptoundecanoic acid or 11-mercapto-1-undecanol using 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride. Nonspecific adsorption to the surrounding material, polyimide, of the microcavity device was eliminated. Electrochemical desorption was used to confine the immunoassay activity at the RMD. Enzymatic conversion of the substrate p-aminophenyl phosphate top-aminophenol is detectable in less than 30 s using cyclic voltammetry at a gold, tubular nanoband electrode, which is on the wall of the microcavity and immediately adjacent to the modified RMD. A third electrode, also within the region of the microcavity, served as the pseudoreference/auxiliary electrode. Calibration curves obtained for 1-microL solutions of 5-100 ng/mL of IgG and for 200 nL-solutions of 5 microM to 4 mM of PAPR gave detection limits of 4.4 nM (6.4 ng/mL) or 880 fmol (129 pg) for PAPR and 56 fM (9 pg/mL) or 56 zmol (9 fg) for IgG. It is expected that the device may be suitable for analysis with volumes down to tens of picoliters.

Absorption↗

PubMed2005

An olivine-free mantle source of Hawaiian shield basalts.

More than 50 per cent of the Earth's upper mantle consists of olivine and it is generally thought that mantle-derived melts are generated in equilibrium with this mineral. Here, however, we show that the unusually high nickel and silicon contents of most parental Hawaiian magmas are inconsistent with a deep olivine-bearing source, because this mineral together with pyroxene buffers both nickel and silicon at lower levels. This can be resolved if the olivine of the mantle peridotite is consumed by reaction with melts derived from recycled oceanic crust, to form a secondary pyroxenitic source. Our modelling shows that more than half of Hawaiian magmas formed during the past 1 Myr came from this source. In addition, we estimate that the proportion of recycled (oceanic) crust varies from 30 per cent near the plume centre to insignificant levels at the plume edge. These results are also consistent with volcano volumes, magma volume flux and seismological observations.

Journal Article↗

PubMed2004

A model of spectral filtering to reduce photochemical damage in age-related macular degeneration.

BACKGROUND/PURPOSE: Cumulative sunlight exposure and cataract surgery are reported risk factors for advanced age-related macular degeneration (AMD). Laboratory studies suggest that accumulation and photochemical reactions of A2E (N-retinylidene-N-retinylethanolamine) and its epoxides, components of lipofuscin, are important in AMD. To relate this data to the clinical setting, we modeled the effects of macular irradiance and spectral filtering on production of A2E and reactive oxygen intermediates (ROIs) in pseudophakic eyes with a clear or "yellow" intraocular lens (IOL) and in phakic eyes. METHODS: We calculated relative changes of macular irradiance as a function of light (390 to 700 nm) intensity, pupil size, age, and lens status, and modeled resulting all-trans-retinal concentration and rates of production of A2E-related photochemicals and photon-induced ROIs in rods and retinal pigment epithelium (RPE). We compared these photoproducts following cataract surgery and IOL implantation with and without spectral sunglasses to normal age-related nuclear sclerotic lens changes. RESULTS: Following cataract and IOL surgery, all-trans-retinal and lipofuscin photochemistry would theoretically increase average generation of 1) A2E-related photochemicals, 2) ROI in rods and 3) ROI in RPE, respectively, 2.6-, 15- and 6.6-fold with a clear IOL, and 2.1-, 4.1- and 2.6 fold with a yellow IOL, but decrease approximately 30-, approximately 20- and 4-fold with a vermillion filter sunglass and clear IOL compared to an average 70 year old phakic eye. CONCLUSION: Sunglasses that strongly decrease both deep blue light and rod photobleaching, while preserving photopic sensitivity and color perception, would provide upstream protection from potential photochemical damage in subjects at risk for AMD progression after cataract surgery.

Aged↗

PubMed2006

Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Deep Brain Stimulation↗

PubMed2001

Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice.

OBJECTIVE: To map aggrecan cleavage by matrix metalloproteinases (MMPs) and aggrecanases in normal murine tibial articular cartilage (CBA strain) and in the development of spontaneous osteoarthritis (OA) in the STR/ort mouse and to assess the influence of sex hormone status on these conditions in gonadectomized STR/ort mice. METHODS: The distributions of neoepitopes of aggrecan generated by MMP (VDIPEN) and aggrecanase (NITEGE) cleavage were investigated by immunohistochemistry. RESULTS: VDIPEN neoepitope was detected mainly in the pericellular matrix of deep-zone chondrocytes in normal tibial cartilage from STR/ort and CBA mice. In early OA, VDIPEN immunostaining also localized to the pericellular matrix of chondrocytes at the site of the lesion. With increasing severity of OA lesions, VDIPEN immunostaining was also detected in the interterritorial matrix, close to the site of the lesion. In contrast, NITEGE mapped most strongly to the pericellular matrix of upper-zone chondrocytes in normal tibial cartilage. As with VDIPEN, NITEGE was strongly expressed in the pericellular matrix at the site of early OA lesions. With advancing OA, NITEGE colocalized with VDIPEN in both the pericellular and interterritorial matrices of chondrocytes adjacent to OA lesions and in those of the deep zones. Hormone status did not appear to influence the development of OA or the distribution of aggrecan neoepitopes in STR/ort mice. CONCLUSION: MMP- and aggrecanase-generated neoepitopes map predominantly to different regions in normal murine tibial cartilage. However, both groups of enzymes generate increased amounts of neoepitopes in pericellular and interterritorial matrix adjacent to histopathologic lesions of OA. Aggrecan degradation and the development of OA appear to be independent of sex hormone status in this model.

Aggrecans↗

PubMed1994

Development of a model of the premotor potential.

This study explored the sensory nature of the small negative premotor potential (PMP) that is often seen preceding the compound muscle action potential. We developed a model of the PMP, using the ulnar and superficial radial sensory (SRS) nerves. Standard conduction studies of the deep ulnar motor nerve recording over the first dorsal interosseous manus (FDIM) and of the SRS nerve recording over the same site were done separately, then simultaneously, on 20 normal hands. In all subjects, there was no FDIM PMP, but with simultaneous stimulation of both nerves, there was a potential in all subjects that appeared similar to their median thenar and ulnar hypothenar PMPs. Reference data for the median thenar, ulnar hypothenar, and model PMP were generated. Findings from this study are discussed and appear to support the concept of the PMP being either a sensory potential or a junctional potential.

Action Potentials↗

PubMed2026

Single-organ proteomics in Drosophila melanogaster larva.

The combination of genetic accessibility, organ complexity, evolutionary conservation, and cost-efficiency makes Drosophila melanogaster (Dm) a well-known model system for biomedical and fundamental biological research. Proteomic analysis of single organs enables the identification and quantification of proteins expressed in specific organs. This will help to uncover specific biological functions and unique protein profiles that are not detectable in whole-organism analyses. In this study we have isolated single organs form Dm larvae, and we have performed a deep proteomics mapping by following a minimal manipulation preparation procedure. The combined dataset across all organs comprised 9132 identified proteins. As anticipated, principal component analysis (PCA) revealed clear separation between the proteomes of most organs, confirming distinct protein profiles. These findings demonstrate the applicability of the sample preparation strategy for high-resolution proteomic characterization of individual organs in Drosophila. Given the extensive genetic tools available for this model organism, our approach has the potential to open new avenues for proteomic studies in Drosophila melanogaster and any other biological systems where the sample amount is limiting. SIGNIFICANCE STATEMENT: Drosophila melanogaster is a well-known model system for biomedical and fundamental biological research that serves as a valuable in vivo model organism due to its high degree of evolutionary conservation with higher vertebrates, tractable genetics, and logistical efficiency. However, the proteome of Drosophila at single organ level has been elusive to date, due to several factors like low sensitivity of previous generation mass spectrometers and sample preparation procedures, difficult isolation of some organs. In this study we have applied a compilation of advanced methods including minimal sample manipulation together with simple, straightforward and efficient protein extraction and digestion methods. Obtained peptides were minimally handled to be analyzed by applying specific and sensitive nLC methods coupled on-line to state-of-the-art MS/MS system. Altogether, the applied strategy allowed us to get the first single organ study to date for this animal. These datasets represent a significative resource for future genomic, transcriptomic and proteomic studies in Drosophila, as multi-omic integration requires deep proteomics to translate data into functional biochemistry, and serves as a critical bridge and an indispensable standalone resource across the genomic, transcriptomic, and proteomic landscapes.

Animals↗

PubMed2004

A separation-of-timescales approach to the coalescent in a continuous population.

This article presents an analysis of a model of isolation by distance in a continuous, two-dimensional habitat. An approximate expression is derived for the distribution of coalescence times for a pair of sequences sampled from specific locations in a rectangular habitat. Results are qualitatively similar to previous analyses of isolation by distance, but account explicitly for the location of samples relative to the habitat boundaries. A separation-of-timescales approach takes advantage of the fact that the sampling locations affect only the recent coalescent behavior. When the population size is larger than the number of generations required for a lineage to cross the habitat range, the long-term genealogical process is reasonably well described by Kingman's coalescent with time rescaled by the effective population size. This long-term effective population size is affected by the local dispersal behavior as well as the geometry of the habitat. When the population size is smaller than the time required to cross the habitat, deep branches in the genealogy are longer than would be expected under the standard neutral coalescent, similar to the pattern expected for a panmictic population whose population size was larger in the past.

Data Interpretation, Statistical↗