Inhibition of sustained gamma oscillations (35-80 Hz) by fast transient responses in cat visual cortex.

Interactions between stimulus-induced oscillations (35-80 Hz) and stimulus-locked nonoscillatory responses were investigated in the visual cortex areas 17 and 18 of anaesthetized cats. A single square-wave luminance grating was used as a visual stimulus during simultaneous recordings from up to seven electrodes. The stimulus movement consisted of a superposition of a smooth movement with a sequence of dynamically changing accelerations. Responses of local groups of neurons at each electrode were studied on the basis of multiple unit activity and local slow field potentials (13-120 Hz). Oscillatory and stimulus-locked components were extracted from multiple unit activity and local slow field potentials and quantified by a combination of temporal and spectral correlation methods. We found fast stimulus-locked components primarily evoked by sudden stimulus accelerations, whereas oscillatory components (35-80 Hz) were induced during slow smooth movements. Oscillations were gradually reduced in amplitude and finally fully suppressed with increasing amplitudes of fast stimulus-locked components. It is argued that suppression of oscillations is necessary to prevent confusion during sequential processing of stationary and fast changing retinal images.     

Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit

Activin ligands are formed by dimerization of activin ss(A)- and/or ss(B)-subunits to produce activins A, AB, or B. These ligands are members of the transforming growth factor-ss superfamily and act as growth and differentiation factors in many cells and tissues. New additions to this family include activin ss(C)-, ss(D)-, and ss(E)-subunits. The aim of this investigation was to examine the localization of and dimerization among activin subunits; the results demonstrate that activin ss(C) can form dimers with activin ss(A) and ss(B) in vitro, but not with the inhibin alpha-subunit. Using a specific antibody, activin ss(C) protein was localized to human liver and prostate and colocalized with ss(A)- and ss(B)-subunits to specific cell types in benign and malignant prostate tissues. Activin C did not alter DNA synthesis of the prostate tumor cell line, LNCaP, or the liver tumor cell line, HepG2, in vitro when added alone or with activin A. Therefore, the capacity to form novel activin heterodimers (but not inhibin C) resides in the human liver and prostate. Activin A, AB, and B have diverse actions in many tissues, including liver and prostate, but there is no known biological activity for activin C. Thus, the evidence of formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biological activity of other activins in these tissues.     

beta(1)- and beta(2)-Adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men

The aim of this study was to elucidate the roles of the beta(1)- and the beta(2)-adrenoceptors in thermogenesis and lipid utilization in obesity. The beta(1)-adrenoceptor study was performed in 9 obese and 10 lean men and consisted of 4 30-min periods during which subjects received consecutive infusions of 0, 3, 6, and 9 microg/kg fat-free mass (FFM).min dobutamine. Energy expenditure, lipid oxidation, and plasma nonesterified fatty acids and glycerol concentrations increased similarly in both groups during beta(1)-adrenergic stimulation. The beta(2)-adrenoceptor study was performed in 10 obese and 11 lean men and involved 3 45-min periods during which 0, 50, and 100 ng/kg FFM.min salbutamol were given in combination 1.2 microg/kg FFM.min atenolol (bolus, 50 microg/kg FFM). During beta(2)-adrenergic stimulation, the increases in energy expenditure and plasma nonesterified fatty acids and glycerol concentrations were reduced in the obese group. Furthermore, lipid oxidation significantly increased in the normal weight group, but remained similar in the overweight group. In conclusion, these data suggest that beta(1)-adrenoceptor-mediated metabolic processes are similar in both groups, but beta(2)-adrenoceptor-mediated increases in thermogenesis and lipid utilization are impaired in the obese.     

Autoimmune reactivity against the 20S-proteasome includes immunosubunits LMP2 (beta1i), MECL1 (beta2i) and LMP7 (beta5i)

Objectives. Autoantibodies against the 20S-proteasome displaya broad diversity with a remarkably low frequency of individualcross-reactivity against the different subunits of the proteasome.Although their pathogenic and diagnostic significance remainsobscure, an involvement in the clearance of circulating proteasomesas well as an interaction with the activity of the proteolyticcomplex was assumed in previous studies. Methods. To investigate the anti-proteasome response in moredetail and to disclose reactivities against former neglectedsubunits, two-dimensional electrophoresis followed by immunoblottingwas used. As a novel antigen source, the immunosubunits LMP2(β1i) and LMP7 (β5i) were expressed as recombinantproteins and employed in ELISA. Results. The subunits Iota (1) and Zeta (5) of the outer ringsas well as the catalytic subunit Delta (β1) and all threeimmunosubunits [MECL-1 (β2i), LMP2 (β1i) and LMP7(β5i)] of the inner rings of the proteasome were identifiedas autoantigens for the first time. Using a panel of anti-proteasomeantibody-positive sera of patients with SLE, autoimmune myositis(PM/DM) and primary Sjögren's syndrome (pSS), an autoimmuneresponse was documented against LMP2 (β1i) and LMP7 (β5i)in all three patient groups in ELISA. Conclusions. The frequent autoimmune response against LMP2 (β1i)and LMP7 (β5i) might indicate a role of inflammatory processesin the primary induction of the anti-proteasomal immune reaction,while the diversity of the humoral response against the proteasomesystem supports the assumption of a specific antigen-drivenprocess leading to these extended autoimmune reactivities. KEY WORDS: Proteasome, Immunosubunits, Autoantibodies, Autoimmunity Submitted 18 September 2007; revised version accepted 16 January 2008.     

Instrumental conditioning of fast (20- to 50-Hz) oscillations in corticothalamic networks

Cats were instrumentally conditioned to generate grouped fast (20- to 50-Hz) oscillations in motor cortex (area 4). Over seven experimental sessions, there was a spatially selective increased generation of grouped fast oscillations in that electroencephalogram lead. This locally increased generation of fast oscillations in cortex was associated with a widespread increase in synchrony of fast oscillations in thalamocortical networks, as demonstrated by cross-correlations between intracortical, corticothalamic, and intrathalamic field potentials. A three-session extinction period abolished the local increase in generation of grouped fast oscillations and reset the thalamocortical synchrony of fast oscillations to control values. A subsequent series of seven sessions with instrumental conditioning of fast oscillations in visual cortex (area 17) reproduced the results from area 4, with a spatially selective increased generation of grouped fast oscillations in the criterion lead, associated with a widespread increase in thalamocortical synchrony of fast oscillations. In addition to their presence during the conditioning sessions, the changes in synchrony of fast oscillations were expressed during periods of quiet waking, rapid-eye-movement sleep, and nonrapid-eye-movement sleep recorded during the first hour after the end of the conditioning.     

Fast oscillations (20-40 Hz) in thalamocortical systems and their potentiation by mesopontine cholinergic nuclei in the cat.

Previous investigations in various motor and sensory cortical areas have shown that fast oscillations (20-80 Hz) of focal electroencephalogram and multiunit activities occur spontaneously during increased alertness or are dependent upon optimal sensory stimuli. We now report the presence of 20- to 40-Hz rhythmic activities in intracellularly recorded thalamocortical cells of the cat. In some neurons, subthreshold oscillations were triggered by depolarizing pulses and eventually gave rise to action potentials. In other neurons, the oscillations consisted of fast prepotentials, occasionally generating full spikes that arose from the resting or even from hyperpolarized membrane potential levels, and leading to trains of spikes at more depolarized levels. The rhythmic nature of these fast prepotentials was confirmed by means of an autocorrelation study, which demonstrated clear peaks at 25-ms intervals (40 Hz). In view of the recent evidence that mesopontine cholinergic nuclei trigger and maintain activation processes in thalamocortical systems, we tested the possibility that stimulation of these brainstem nuclei potentiates the 40-Hz waves on the background of the cortical electroencephalogram. This was indeed the case. The potentiation outlasted the stimulation by 10-20 s. The brainstem-induced facilitation of cortical 40-Hz oscillations was blocked by scopolamine, a muscarinic antagonist. That this facilitation was transmitted by brainstem-thalamic cholinergic projections was confirmed by persistence of the phenomenon after large excitotoxic lesions of the nucleus basalis of Meynert.     

Contributions of beta2-microglobulin-dependent molecules and lymphocytes to iron regulation: insights from HfeRag1(-/-) and beta2mRag1(-/-) double knock-out mice

Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a beta2-microglobulin (beta2m)-associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of beta2mRag1(-/-) double-deficient mice, lacking all beta2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with beta2m single knock-out mice. To evaluate whether the observed phenotype in beta2mRag1(-/-) mice was due solely to the absence of Hfe or to other beta2m-dependent molecules, we generated HfeRag1(-/-) double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with beta2mRag1(-/-) mice. These results suggest that other beta2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity.     

Bursts of beta oscillation differentiate postperformance activity in the striatum and motor cortex of monkeys performing movement tasks

Studies of neural oscillations in the beta band (13–30 Hz) have demonstrated modulations in beta-band power associated with sensory and motor events on time scales of 1 s or more, and have shown that these are exaggerated in Parkinson’s disease. However, even early reports of beta activity noted extremely fleeting episodes of beta-band oscillation lasting <150 ms. Because the interpretation of possible functions for beta-band oscillations depends strongly on the time scale over which they occur, and because of these oscillations’ potential importance in Parkinson’s disease and related disorders, we analyzed in detail the distributions of duration and power for beta-band activity in a large dataset recorded in the striatum and motor-premotor cortex of macaque monkeys performing reaching tasks. Both regions exhibited typical beta-band suppression during movement and postmovement rebounds of up to 3 s as viewed in data averaged across trials, but single-trial analysis showed that most beta oscillations occurred in brief bursts, commonly 90–115 ms long. In the motor cortex, the burst probabilities peaked following the last movement, but in the striatum, the burst probabilities peaked at task end, after reward, and continued through the postperformance period. Thus, what appear to be extended periods of postperformance beta-band synchronization reflect primarily the modulated densities of short bursts of synchrony occurring in region-specific and task-time-specific patterns. We suggest that these short-time-scale events likely underlie the functions of most beta-band activity, so that prolongation of these beta episodes, as observed in Parkinson’s disease, could produce deleterious network-level signaling.Oscillations of brain activity in the beta band (13–30 Hz) have been implicated in sensorimotor control and integration (1–5) and are pathologically synchronized and exaggerated in Parkinson''s disease (6–11). Although reports have published examples of very brief (<150 ms) bursts of beta-band oscillation (12–15), the analysis of beta-band activity has focused primarily on data averaged over trials, which show variations in average beta-band power occurring on a time scale of seconds.To address the apparent discrepancy in time scales between the single-trial results and the trial-averaged results, we analyzed the relationship of brief beta bursts as viewed at a single-trial level to the substantially slower variations in trial-averaged power that are conventionally referred to as periods of “synchronization” or “desynchronization” of beta-band activity. We examined beta-band activity recorded in two regions of prime clinical interest, the motor-premotor regions of the neocortex and the striatum, in macaque monkeys performing well-learned movement sequences. Our findings suggest that these regions exhibit different peak times of synchronization of beta bursting during the classic postmovement period, comprising differentially timed alignments of beta bursts within a desynchronized background of beta activity. Such brief, one to several cycle alignments of beta oscillation are suitable for realignment of circuit activity according to contextual demands. We suggest that the prolongation of beta bursts known to occur in Parkinson’s disease could blunt or abolish such flexibility in the neural control of behavior.     

Hemoglobin Sunshine Seth - alpha 2 (94 (G1) Asp replaced by His) beta 2.

Hemoglobin Sunshine Seth in which a histidyl is substituted for an aspartyl residue at position 94 of the alpha chain was detected at birth in a Caucasian male infant during cord blood screening and is present also in the mother and a male sibling. Although the substitution is in the alpha 1 beta 2 contact, it is without obvious deleterious effect on the hematological parameters or the health of the affected individuals.     

Hemoglobin Gavello - alpha 2 beta 2 47 (CD6) Asp replaced by Gly. A new hemoglobin variant from Polesine (Italy)

During a survey for abnormal hemoglobins in Polesine (a region north of the Po river, where beta-thalassemia is very frequent) a slow moving variant was noted in a 79-yr-old woman living in Gavello, a small town in the province of Rovigo. Structural studies demonstrated a previously undescribed amino acid substitution, beta47 Asp replaced by Gly. This new variant has been named Hb Gavello.     

The beta(2)-adrenergic receptor Arg16-gly polymorphism and interactions involving beta(2)- and beta(3)-adrenergic receptor polymorphisms are associated with variations in longitudinal serum lipid profiles: the Bogalusa Heart Study

We examined the effects of combined genotypes of the beta(2)-adrenergic receptor (AR) Arg(16)-Gly and beta(3)-AR Trp(64)-Arg polymorphisms on longitudinal serum total (T-C) and low-density lipoprotein cholesterol (LDL-C) profiles in 1,198 subjects examined multiple times (6,488 observations) from 1973 to 1996 in the Bogalusa Heart Study, at ages from 4.5 to 38 years. Within 5-year age groups, T-C was significantly (P <.05) higher in beta(2)-AR Arg(16)/Arg(16) homozygotes than in Gly(16) carriers among those 4 to 8 (171.4 +/- 30.0 v 161.5 +/- 27.7 mg/dL), 9 to 13 (167.7 +/- 28.6 v 162.4 +/- 27.4 mg/dL), and 14 to 18 (158.8 +/- 29.6 v 154.7 +/- 27.5 mg/dL) years of age, but not in those 19 to 23, 24 to 28, 29 to 33, or 34 to 38 years of age. The beta(3)-AR polymorphism was not associated with variation in either T-C or LDL-C. In multilevel polynomial growth curve models, the combination of the beta(2)-AR Arg(16)/Arg(16) genotype with either the beta(3)-AR Arg(64)/Arg(64) or Trp(64)/Arg(64) genotypes, denoted AA/AX, was associated with variation in longitudinal T-C (P <.01) and LDL-C (P <.01) profiles. The association between combined beta(2)/beta(3)-AR genotype and lipid profiles differed among race/sex groups, being most marked in black females, in whom the AA/AX combination was associated with higher T-C and LDL-C profiles across all ages. In White males, the AA/AX combination was most strongly associated with higher lipids in adults. In black males and white females, lipid profiles differed little between genotype groups. Our findings suggest that the beta(2)-AR Arg(16)-Gly genotype influences T-C and LDL-C levels in an age-specific manner, that it may interact with beta(3)-AR Trp(64)-Arg genotypes to influence longitudinal T-C and LDL-C profiles, and that the effect of combined beta(2)/beta(3)-AR genotypes on T-C and LDL-C profiles may differ among race/sex groups.     

Polymerization and solubility of recombinant hemoglobins alpha 2 beta 2 (6Val) (Hb S) and alpha 2 beta 2(6Leu) (Hb Leu).

In an effort to clarify the role of amino acid hydrophobicity at the beta 6 position in sickling we have made recombinant hemoglobin tetramers containing beta 6 Val (Hb S) and beta 6 Leu (Hb Leu). Recombinant Hb S and Hb Leu had the same electrophoretic mobility, chromatographic behavior, and absorption spectrum. The deoxy form of both tetramers polymerized in high phosphate buffer (1.8 M) and exhibited distinct delay times prior to polymerization. The kinetics of polymerization for recombinant and native Hb S were similar, while recombinant Hb Leu polymerized more readily. The solubility of deoxy Hb Leu was less than deoxy Hb S, indicating that rapid polymerization and decreased solubility of deoxyhemoglobin is accelerated with increasing hydrophobicity at the beta 6 position.     

Defective platelet response to arachidonic acid and thromboxane A(2) in subjects with Pl(A2) polymorphism of beta(3) subunit (glycoprotein IIIa)

The membrane complex alpha(IIb)beta(3) is the major receptor for fibrinogen and is involved in platelet adhesion and aggregation. Evidence has been presented that the Pl(A2) allele of the beta(3) Pl(A1/A2) gene polymorphism might be an independent risk factor for coronary thrombosis, but the matter is still controversial. We investigated the relationship between this polymorphism and possible alterations of platelet functions in vitro. The platelet adhesion to fibrinogen-coated microplate wells and the aggregation induced by several different agonists were tested in 63 healthy volunteers, among them, 49 subjects with Pl(A1/A1) polymorphism, 12 subjects with Pl(A1/A2) polymorphism and two subjects with (PlA2/A2) polymorphism. Subjects with PlA1/A2 polymorphism or with Pl(A2/A2) polymorphism showed significantly lower platelet responses as compared with Pl(A1/A1) subjects when either arachidonic acid or the thromboxane A(2) analogue, U46619, were used as agonists. In resting condition and after thrombin or ADP stimulation, platelet function was normal in all the subjects. An increased sensitivity to the anti-aggregatory effect of acetylsalicylic acid was observed in platelets from subjects with the Pl(A2) allele. Finally, using a flow-cytometric evaluation and determining the beta-thromboglobulin plasma levels, we did not find any evidence of a Pl(A2) platelet hyper-reactivity ex vivo. Our findings are not consistent with the hypothesis that the purported increase of cardiovascular risk in these subjects may be as a result of platelet hyperactivation. On the contrary, the Pl(A2) allele is associated with a platelet functional deficiency, specifically linked to the activation of the fibrinogen receptor by thromboxane A(2).