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[Formation of a generator of excitation in the gigantocellular nucleus of the medulla oblongata during disruption of inhibitory processes].

Neuronal activity in the gigantocellular nucleus after injection of tetanus toxin was studied on decerebrated cats. The toxin was used as a substance producing a deep and continuous suppression of inhibitory processes. The increase in the amplitude and rate of neuronal discharges, in the integral background and evoked activity as well as in the number of active neurons and that of neurons with burst activity was recorded in the "poisoned" nucleus. The enhanced activity in the investigated regions of the poisoned nucleus might be temporarily suppressed by a strong direct electrical shock and by glycin administrations to those regions. The obtained data indicate that a pool of neurons with disturbed inhibitory processes forms a generator of enhanced excitation. The mechanisms and characteristic features of the activity of such generators are discussed. The possibility of modelling neurological syndromes by production of similar generators in various parts of the central nervous system and their relation to the earlier described phenomenon of "dispatch station" are considered.

Animals↗

Numerical phase algorithm for decompression computers and application.

Present generation decompression computers employ a simplified algorithm, limiting dissolved gas build-up in tissue and blood according to a method proposed by Haldane 80 years ago. Such a model works well for single dives, but is usually liberal and theoretically incomplete for multiple exposures within 24 hr spans. Using the critical phase hypothesis in a bubble model, we have extended the classical model of Haldane to multi-exposures. This model is discussed, and a decomputer algorithm described for multi-diving. The focus is permissible bubble excess, not just dissolved gas per se, with phase constraints affecting all tissues, fast and slow, and requiring a systematic lowering of repetitive tissue tensions. Deep repetitive and shallow multi-day exposures are impacted most by the procedure. Within nucleation theory deeper-than-first dives are also treated. A set of multi-diving fractions, xi, accounting for micronuclei excitation and regeneration, reduced bubble elimination in repetitive activity, and coupled effects on tissue tension, are proposed, with xi representing a set of multiplicative factors (less than one) applied to critical tissue tensions for multi-exposures. These factors affect repetitive activity over short time spans, deeper-than-previous and continuous multi-day activities, compared to standard computer software, and are easily encoded into existing decompression meters, potentially extending their range and flexibility over exposure regimes.

Algorithms↗

A prototype epithermal neutron beam for boron neutron capture therapy.

An epithermal neutron beam has been designed and tested at the Georgia Institute of Technology's 5-MW Research Reactor. The prototype facility consists of aluminum and sulfur disks in a tangential beam port for fast neutron filtration. A cadmium sheet at the port exit removes the thermal neutrons from the transmitted beam, leaving an intensely epithermal neutron beam spanning five energy decades, each contributing to the flux demanded by boron neutron capture therapy. The thermal neutron flux generated by the incident epithermal neutrons in a polyethylene head phantom peaks at a depth of 3 cm and remains above the incident thermal flux to a 7-cm depth. The beam thus provides the penetration required for treating deep-seated gliomas. Photon contamination in the prototype facility is high, and a number of basic modifications are proposed for reducing it to safer levels.

Boron↗

Orthopaedic nursing research priorities: a replication and extension.

PURPOSE: This study identified current orthopaedic nursing research priorities that should be investigated to advance the practice of orthopaedic nursing. The study was accomplished by the National Association of Orthopaedic Nurses' (NAON) Research Committee via a national survey of selected NAON members. DESIGN: A descriptive design was used to determine research priorities. SAMPLE: The sample consisted of a random sample of 133 NAON members. The sample was stratified for either graduate degrees (> or = master's), other than a graduate degree (< or = bachelor's) (to insure representation from "frontline" practicing nurses), and registrants in the NAON Researcher Database and recipients of NAON Foundation or American Academy of Orthopaedic Surgeons (AAOS)/NAON grants. METHOD: A three round Delphi survey technique was used to build consensus by systematically generating, synthesizing, and analyzing opinions of a group of experts while maintaining confidentiality of the individuals. MAIN RESEARCH CLASSIFICATIONS: Nursing research priorities, Delphi method, Orthopaedic nursing. FINDINGS: The nine target research questions for orthopaedic nursing identified as high priority were grouped into the following categories: patient acuity, care delivery models, staffing issues, patient complications, pain management (in the elderly and those with altered mental status), and patient mobility. These research priority items are intended to direct the orthopaedic nurse researcher to study specific questions within these categories. CONCLUSION: Results reflect the dramatic changes occurring in orthopaedic nursing practice. Research priorities reveal the need for more research on pain and patient complications (e.g., deep vein thrombosis (DVT)) despite a preponderance of existing, published research on these topics. IMPLICATIONS FOR NURSING RESEARCH: This study identified target research questions for orthopaedic nursing. These questions may be used by orthopaedic nurses to develop nursing research proposals as well as collaborative research endeavors with other members of the orthopaedic health care team. An ongoing and wider dissemination of results of existing research to the NAON membership needs to be implemented.

Delphi Technique↗

A generic morphological model of the anatomic variability in the m. flexor digitorum profundus, m. flexor pollicis longus and mm. lumbricales complex.

In the present study a generic model is presented of the anatomic variability in the muscle group formed by the m. flexor digitorum profundus, m. flexor pollicis longus and mm. lumbricales. This model provides a hypothesis about the structural causes of the frequent interdependence of tendons and muscle bellies in this muscle group. The model considers the muscle group as composed of two simple elementary building blocks: the monogastric contractile units of the FDP-FPL, and the digastric contractile elements of the lumbrical, and shows that these units can be assembled into complex entities, to which in reality a third structural element, the synovial membranes, not discussed in the present paper, adds a further complexity. The model allows to generate homologues of the existing anatomical variants, which are illustrated by typical dissection results. The present study should be of relevance to the morphologist, embryologist, surgeon, and musician/pedagogue. To the morphologist, it presents an alternative method of description or understanding of anatomic variability, based on (i) the 'atomary' concept that the anatomic structure is assembled from simple basic elements, and (ii) the local spatial constraints. To the embryologist, it raises the question to what degree the 'atomary' anatomical components of this model, which describes the macroscopic anatomy of the muscle group in detail, have an embryological basis. To the surgeon, the study presents detailed information about the scope of the variability in the deep flexor group, and the nature of its intertendinous connections. To the musician/pedagogue, it presents a visual illustration of the congenital interdependence of the muscles and tendons of an important finger motor group, as a possible cause of lack in finger independence which may hamper a fluent instrumental technique.

Dissection↗

Three-dimensional reconstruction of microleakage pattern using a sequential grinding technique.

Dye penetration tests are very commonly used to detect the absence of a fluid seal at the tooth-restoration interface. Airlocks in the marginal gap, leaching of water-soluble tracers during processing, and the failure of only a few sections to allow interpretation of the full pattern, limit these tests to low reproducibility and precision. The purpose of this present study was to generate high-resolution three-dimensional images of waterfast tracer patterns. Cylindrical class V (3 mm diameter, 2 mm deep) dentine-bonded resin composite restorations in buccal coronal dentine were thermally cycled (1000 x, 8 degrees C, 55 degrees C, 30 s dwell at each temperature) and then silver stained using an initial vacuum (100 mmHg pressure). Each restoration was sequentially abraded from the free surface on wet 180 grit silicon carbide paper, producing up to 30 parallel surfaces at approximately 0.15 mm separation through the restoration down to the pulp. Images of the ground surfaces were captured, and assembled by a computer image analyser program to give a three-dimensional model of the tracer pattern. The maximum depths of tracer penetration below the reference surfaces were 3.00 mm, 2.09 mm, 3.16 mm and > 2.29 mm for the four specimens. Projections of the models were viewed from several directions with sections in various locations to allow investigation of the full tracer pattern. This method allows the creation of high-resolution three-dimensional tracer patterns.

Composite Resins↗

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition.

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.

Action Potentials↗

The localisation and characterisation of insulin-like growth factor-I receptors and the investigation of melatonin receptors on the hair follicles of seasonal and non-seasonal fibre-producing goats.

To define the hormonal influences that are directly involved in the hair follicle cycles of animals with differing patterns of fibre growth and moulting, we have investigated the possible presence of IGF-I and melatonin receptors on the dermis and hair follicles of cashmere and Angora goats, sampled in February. March and June, using quantitative in vitro autoradiography. The presence of IGF-I receptors in the dermis of both breeds of goat was determined using cryostat sections incubated with 50 pM 125I-labelled IGF-I in the presence or absence of 50 nM IGF-I. Sections of the growing tip of deep antlers concerning the cartilaginous zone, a tissue known to contain high concentrations of specific IGF-I receptors, were used as a positive control. As the production of antler velvet uniquely involves the generation of hair follicles de novo, the presence of IGF-I receptors in the velvet-producing region was also investigated. In both breeds of goat, specific 125I-IGF-I binding was localised over the inner and outer root sheath, the matrix, the germinal matrix, the dermal papilla and the sebaceous glands and satisfied the basic kinetic criteria considered to be representative of a specific IGF-I receptor. Analysis of saturation isotherms using a one-site binding model revealed dissociation constants (Kd) in the range 0.1-0.9 nM and theoretical maximal numbers of binding sites (Bmax) between 21.4 and 45.6 fmol/mg tissue. Kd and Bmax values derived from cashmere and Angora goats sampled at different times of the year did not differ significantly between breeds or sampling times. Specific 125I-IGF-I binding was also localised to the developing follicles on the deer antler dermis. The presence of melatonin receptors within the goat dermis was also investigated. Sections were incubated with 100 pM 2-[125I]iodomelatonin with or without 0.1 microM melatonin, along with sections of sheep pars tuberalis which are known to contain high levels of high-affinity melatonin receptors. No displaceable 2-[125I]iodomelatonin binding was found on any sections of the cashmere or Angora skin analysed. It is therefore concluded that melatonin receptors are not present on the hair follicles or associated structures. IGF-I receptors are present on the hair follicle and sebaceous gland and may be involved in the growth of both seasonally and non-seasonally produced fibre and in the development of antler velvet.

Animals↗

[New functional cerebral cartography: studies of plasticity of the human brain].

The non-invasive brain scanning techniques, introduced a quarter of a century ago, have become crucial for diagnosis in clinical neurology. They have also been used to investigate brain function and have provided information about normal activity and pathogenesis. They have been used to investigate functional specialisation in the brain and how specialised areas communicate to generate complex integrated functions such as speech, memory, the emotions and so on. Brain plasticity is a generic term that has now come to be used to signify any changes in brain structure or function. The phenomenon is poorly understood, and yet clinical neurologists are aware that spontaneous recovery from brain lesions is not uncommon. An improved understanding of the mechanisms of recovery may generate new therapeutic strategies and indicate ways of modulating mechanisms that promote plastic compensation for loss of function. The main methods used to investigate these issues are positron emission tomography and magnetic resonance imaging (MRI). The techniques of functional brain mapping and computational morphometrics depend on high performance scanners and a validated set of analytic statistical procedures that generate reproducible data and meaningful inferences from them. The motor system presents a good paradigm to illustrate advances made by scanning towards an understanding of plasticity at the level of brain areas. The normal motor system is organised in a nested hierarchy. Recovery from paralysis caused by internal capsule strokes involves functional reorganisation manifesting as changed patterns of activity in the component brain areas of the normal motor system. The pattern of plastic modification depends in part on patterns of residual or disturbed connectivity after brain injury. Therapeutic manipulations in patients with Parkinson's disease using deep brain stimulation, dopaminergic agents or foetal mesencephalic transplantation provide a means to examine mechanisms underpinning plastic change. Other models of plastic change, such as normal visuospatial learning or re-establishing speech comprehension after cochlear implantation in the deaf illustrate how patterns of brain function adapt over time. Limitations of the scanning techniques and prospects for the future are discussed in relation to new developments in the neuroimaging field.

Brain↗

Fast rhythmic bursting can be induced in layer 2/3 cortical neurons by enhancing persistent Na+ conductance or by blocking BK channels.

Fast rhythmic bursting (or "chattering") is a firing pattern exhibited by selected neocortical neurons in cats in vivo and in slices of adult ferret and cat brain. Fast rhythmic bursting (FRB) has been recorded in certain superficial and deep principal neurons and in aspiny presumed local circuit neurons; it can be evoked by depolarizing currents or by sensory stimulation and has been proposed to depend on a persistent g(Na) that causes spike depolarizing afterpotentials. We constructed a multicompartment 11-conductance model of a layer 2/3 pyramidal neuron, containing apical dendritic calcium-mediated electrogenesis; the model can switch between rhythmic spiking (RS) and FRB modes of firing, with various parameter changes. FRB in this model is favored by enhancing persistent g(Na) and also by measures that reduce [Ca(2+)](i) or that reduce the conductance of g(K(C)) (a fast voltage- and Ca(2+)-dependent conductance). Axonal excitability plays a critical role in generating fast bursts in the model. In vitro experiments in rat layer 2/3 neurons confirmed (as shown previously by others) that RS firing could be switched to fast rhythmic bursting, either by buffering [Ca(2+)](i) or by enhancing persistent g(Na). In addition, our experiments confirmed the model prediction that reducing g(KC) (with iberiotoxin) would favor FRB. During the bursts, fast prepotentials (spikelets) could occur that did not originate in apical dendrites and that appear to derive from the axon. We suggest that modulator-induced regulation of [Ca(2+)] dynamics or of BK channel conductance, for example via protein kinase A, could play a role in determining the firing pattern of neocortical neurons; specifically, such modulation could play a role in regulating whether neurons respond to strong stimulation with fast rhythmic bursts.

Action Potentials↗

A molecular scheme for the reaction between gamma-aminobutyric acid and the most abundant chloride channel on crayfish deep extensor abdominal muscle.

Single-channel measurements were performed with the aim of constructing a detailed molecular scheme for the reaction between gamma-aminobutyric acid (GABA) and a chloride channel of crayfish deep extensor abdominal muscle (DEAM). GABA was applied in pulses to outside-out patches of muscle membrane, and, based on the dose-response of the peak currents and of their rise times, a linear model with five binding steps has been proposed. Evaluation of the single-channel kinetics indicated at least three open states. Two of them originate most probably from the fully liganded receptor state and are grouped in mixed bursts due to their different life times. The third one appears independently, outside the bursts, and originates from a lower liganded receptor state. Simulations of the dose-responses and the open time distributions with this model led to a set of rate constants which generated relatively optimal fits.

Abdominal Muscles↗

Forthergillian Lecture. Imaging human brain function.

The non-invasive brain scanning techniques introduced a quarter of a century ago have become crucial for diagnosis in clinical neurology. They have also been used to investigate brain function and have provided information about normal activity and pathogenesis. They have been used to investigate functional specialization in the brain and how specialized areas communicate to generate complex integrated functions such as speech, memory, the emotions and so on. The phenomenon of brain plasticity is poorly understood and yet clinical neurologists are aware, from everyday observations, that spontaneous recovery from brain lesions is common. An improved understanding of the mechanisms of recovery may generate new therapeutic strategies and indicate ways of modulating mechanisms that promote plastic compensation for loss of function. The main methods used to investigate these issues are positron emission tomography and magnetic resonance imaging (M.R.I.). M.R.I. is also used to map brain structure. The techniques of functional brain mapping and computational morphometrics depend on high performance scanners and a validated set of analytic statistical procedures that generate reproducible data and meaningful inferences from brain scanning data. The motor system presents a good paradigm to illustrate advances made by scanning towards an understanding of plasticity at the level of brain areas. The normal motor system is organized in a nested hierarchy. Recovery from paralysis caused by internal capsule strokes involves functional reorganization manifesting itself as changed patterns of activity in the component brain areas of the normal motor system. The pattern of plastic modification depends in part on patterns of residual or disturbed connectivity after brain injury. Therapeutic manipulations in patients with Parkinson's disease using deep brain stimulation, dopaminergic agents or fetal mesencephalic transplantation provide a means to examine mechanisms underpinning plastic change. Other models of plastic change, such as normal visuospatial learning or re-establishing speech comprehension after cochlear implantation in the deaf illustrate how patterns of brain function adapt over time. Limitations of the scanning techniques and prospects for the future are discussed in relation to new developments in the neuroimaging field.

Brain↗

Organic-inorganic interactions in petroleum-producing sedimentary basins.

Petroleum deposits form as a consequence of the increased temperatures that accompany progressive burial of organic matter deep within sedimentary basins. Recent advances in petroleum geochemistry suggest that inorganic sedimentary components participate in organic transformations associated with this process. Water is particularly important because it facilitates reaction mechanisms not available in dry environments, and may contribute hydrogen and oxygen for the formation of hydrocarbons and oxygenated alteration products. These findings suggest that petroleum generation and stability is influenced by subsurface chemical environments, and is a simple function of time, temperature and the composition of sedimentary organic matter.

Evolution, Chemical↗

Diagnostic performance of machine learning models versus established risk stratification for intracranial aneurysm rupture: a systematic review and bivariate meta-analysis.

BACKGROUND: Machine learning (ML) models have been proposed to improve the discrimination of intracranial aneurysm rupture status beyond established clinical risk stratification tools. However, reported performance is heterogeneous and the relative contribution of model architecture and feature dominance remains unclear. METHODS: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-diagnostic test accuracy systematic review and diagnostic meta-analysis of studies evaluating ML models for intracranial aneurysm rupture discrimination. PubMed, Embase and CENTRAL were searched to February 2026. Sensitivity and specificity were pooled using a bivariate random-effects model, with summary receiver operating characteristic curves generated across training, internal testing and external validation datasets. Models were compared with regression-based approaches and Population, Hypertension, Age, Size of aneurysm, Earlier subarachnoid haemorrhage, Site of aneurysm (PHASES) scores. Subgroup and meta-regression analyses explored associations between algorithm family and feature domain. RESULTS: Sixty-two retrospective cohorts (29&#x2009;709 patients 209 models) met the inclusion criteria. In training datasets, pooled sensitivity and specificity for ML were 0.81 (95% CI 0.75 to 0.85)&#x2009;and 0.83 (0.80-0.86), with an area under the curve (AUC) of 0.878, exceeding PHASES (AUC 0.667). In testing datasets, ML retained higher discrimination (AUC 0.837) than regression models (0.806) and PHASES (0.646). In external validation, sensitivity was preserved (0.82), but specificity declined (0.66). Deep learning demonstrated the highest AUCs (training and testing). Incorporation of haemodynamic or radiomic features improved pooled discrimination relative to morphology alone. Evidence of small-study effects and mostly unclear Prediction Model Risk Of Bias Assessment Tool ratings were observed. CONCLUSIONS: ML approaches demonstrate higher pooled discrimination for aneurysm rupture status than conventional risk scores in retrospective datasets, but reduced external validation specificity and heterogeneity limit confidence for clinical translation. Prospective, externally validated, calibrated models are required before integration into routine cerebrovascular risk stratification.

Humans↗

Seismic imaging of structural heterogeneity in Earth's mantle: evidence for large-scale mantle flow.

Systematic analyses of earthquake-generated seismic waves have resulted in models of three-dimensional elastic wavespeed structure in Earth's mantle. This paper describes the development and the dominant characteristics of one of the most recently developed models. This model is based on seismic wave travel times and wave shapes from over 100,000 ground motion recordings of earthquakes that occurred between 1980 and 1998. It shows signatures of plate tectonic processes to a depth of about 1,200 km in the mantle, and it demonstrates the presence of large-scale structure throughout the lower 2,000 km of the mantle. Seismological analyses make it increasingly more convincing that geologic processes shaping Earth's surface are intimately linked to physical processes in the deep mantle.

Disasters↗

Progressive neurodegeneration in aspartylglycosaminuria mice.

Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375-1378). Our current findings demonstrate that after the age of 10 months, the general condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particularly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacuolation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU.

Acetylglucosamine↗

Screening for venous thromboembolism in traumatic brain injury: limitations of D-dimer assay.

OBJECTIVES: To assess whether 2 different D-dimer fibrin degradation assays-a second-generation latex immunosorbent agglutination (LIA) and an enzyme-linked immunosorbent assay (ELISA)-are predictive for the development of deep venous thrombosis (DVT) at the currently accepted level of 500 microg/L of D-dimer assay during the first weeks after traumatic brain injury (TBI) and to correlate over 8 weeks the second-generation LIA assay with the ELISA assay after acute TBI. DESIGN: A case series of persons with TBI were screened for DVT at 2 weeks (+/-3d) using real-time, spectral Doppler ultrasound, as well as D-dimer fibrin split products. All persons were rescreened at 4, 6, and 8 weeks (+/-3d) after injury using D-dimer LIA and ELISA assays. SETTING: A university hospital with a directly connected comprehensive in- and outpatient rehabilitation center that are part of the Traumatic Brain Injury Model Systems. PARTICIPANTS: Over 3 years, 35 TBI subjects with a mean Glasgow Coma Scale score of 6.5 were consecutively enrolled into the trial while on acute care. Persons were at least 16 years of age with no history of treatment for DVT. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data were analyzed for the levels of D-dimer and risk as established by a predictive value of 500 microg/L. Changes in D-dimer values over time and within subjects were assessed by analysis of variance (ANOVA) with repeated measures, and the methods were correlated. RESULTS: The mean LIA level at 2 weeks was 4.3mg/L and averaged 1.6 mg/L at 8 weeks from injury (P=.012, ANOVA), and the ELISA dropped from 4,748 microg/L to 1.695 microg/L (P=.0022, ANOVA). Except for 1 ELISA value in 1 patient, D-dimer levels were elevated beyond 500 microg/L at 2 weeks. There was a very good correlation between the LIA and the ELISA at 2, 4, 6, and 8 weeks after TBI (P<.0001). In individual cases, there were only occasional discrepancies between the LIA and ELISA methods. There were no positive DVTs at 2 weeks using ultrasound, so prediction of the sensitivity and the specificity of D-dimer with DVT was not possible. CONCLUSION: Using the currently recommended levels of D-dimer to predict DVT is not clinically useful in the acute TBI population.

Adolescent↗

Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex.

Gene-specific targeting of the Sin3 corepressor complex by DNA-bound repressors is an important mechanism of gene silencing in eukaryotes. The Sin3 corepressor specifically associates with a diverse group of transcriptional repressors, including members of the Mad family, that play crucial roles in development. The NMR structure of the complex formed by the PAH2 domain of mammalian Sin3A with the transrepression domain (SID) of human Mad1 reveals that both domains undergo mutual folding transitions upon complex formation generating an unusual left-handed four-helix bundle structure and an amphipathic alpha helix, respectively. The SID helix is wedged within a deep hydrophobic pocket defined by two PAH2 helices. Structure-function analyses of the Mad-Sin3 complex provide a basis for understanding the underlying mechanism(s) that lead to gene silencing.

Amino Acid Sequence↗