Enzymes produced by autoactivation of blood factor XII in buffer: A contribution from the Hematology at Biomaterial Interfaces Research Group

High-resolution electrophoresis of FXII-derived proteins produced by contact activation of FXII in buffer solutions (i.e. in absence of plasma proteins) with hydrophilic and silanized-glass activators spanning the observable range of water wettability (hydrophilic to hydrophobic), shows no evidence of proteolytic cleavage of FXII into αFXIIa or βFXIIa. The autoactivation mixture contains only a single-chain protein with a molecular weight of ∼80 kDa, confirming Oscar Ratnoff's previous finding of a single-chain activated form of FXII that he called ‘HF_ea’. Functional assays have shown that these autoactivation products exhibit procoagulant potential (protease activity inducing clotting of blood) or amidolytic potential (cleaves amino bonds in s-2302 chromogen but do not cause coagulation of plasma) or both amidolytic potential and procoagulant potential. Some of these proteins also have the remarkable potential to ‘suppress autoactivation’ (i.e. suppress creation of enzymes with procoagulant potential). It is thus hypothesized that autoactivation of FXII in the absence of plasma proteins generates not just a single type of activated conformer, as suggested by previous researchers, but rather an ensemble of conformer products with collective activity that varies with activator surface energy used in contact activation of FXII. Furthermore, reaction of αFXIIa with FXII in buffer solution does not produce additional αFXIIa by the putative autoamplification reaction FXIIa + FXII → 2FXIIa as has been proposed in past literature to account for the discrepancy between chromogenic and plasma-coagulation assays for αFXIIa in buffer solution. Instead, net procoagulant activity measured directly by plasma-coagulation assays, decreases systematically with increasing FXII solution concentration. Under the same reaction conditions, chromogenic assay reveals that net amidolytic activity increases with increasing FXII solution concentration. Thus, although autoamplification does not occur it appears that there is some form of “FXII self reaction” that influences products of αFXIIa reaction with FXII. Electrophoretic measurements indicate that no proteolytic cleavage takes in this reaction leading us to conclude that change in activity is most likely due to change(s) in FXII conformation (with related change in enzyme activity).     

Characterization of factor XII Tenri, a rare CRM-negative factor XII deficiency

Factor XII Tenri (Y34C), a rare cross-reacting material (CRM)-negative factor XII deficiency, was identified in a 71-yr-old Japanese woman with angina pectoris. In the patient's plasma, factor XII activity and antigen levels were only 1.6% and 5.0%, respectively, of those seen in a normal subject. Immunoblot analysis showed that the secreted factor XII Tenri existed not only as a monomer (76 kDa), but also in complexes with apparent molecular weights of approximately 115, 140, 190, 215, and 225 kDa. After reduction with 2-mercaptoethanol, the factor XII Tenri contained in the complexes was completely converted to monomeric form on immunoblot patterns. It appeared that some of the secreted factor XII Tenri formed several types of disulfide-linked complexes, including a factor XII-alpha1-microglobulin complex, through a newly generated Cys residue. The monomeric form of factor XII Tenri, like normal factor XII, was degraded into 2 major fragments with molecular weights of approximately 45 kDa and 30 kDa following mixing with activated partial-thromboplastin-time measuring reagent (cephalin and ellagic acid), whereas the factor XII Tenri that formed the complexes was not. This indicates that the factor XII Tenri present in disulfide-linked complexes with other proteins (and itself) is not converted to active forms, suggesting that attached proteins obstruct or delay the activation of factor XII via an inhibition of its binding to a negatively charged surface in vitro.     

Optimal feedback control and the long-latency stretch response

There has traditionally been a separation between voluntary control processes and the fast feedback responses which follow mechanical perturbations (i.e., stretch “reflexes”). However, a recent theory of motor control, based on optimal control, suggests that voluntary motor behavior involves the sophisticated manipulation of sensory feedback. We have recently proposed that one implication of this theory is that the long-latency stretch “reflex”, like voluntary control, should support a rich assortment of behaviors because these two processes are intimately linked through shared neural circuitry including primary motor cortex. In this review, we first describe the basic principles of optimal feedback control related to voluntary motor behavior. We then explore the functional properties of upper-limb stretch responses, with a focus on how the sophistication of the long-latency stretch response rivals voluntary control. And last, we describe the neural circuitry that underlies the long-latency stretch response and detail the evidence that primary motor cortex participates in sophisticated feedback responses to mechanical perturbations.     

Analysis of the step response of the saccadic feedback: system behavior

We used prolonged stimulation of the monkey superior colliculus to elicit staircase eye movements. By changing the parameters of the stimulating current we were able to obtain movements with different dynamics. An increase in the current frequency resulted in the shortening of the intersaccadic interval and a decrease of the amplitudes in the staircase. In cases of high stimulation, after an initial saccade of fixed metrics, the eyes moved in an apparently smooth fashion. The movement was conjugate and in the same direction as the first saccade. By analyzing the velocity trace we found that the movement consisted of a chain of small saccades, each of which started before the previous one ended. We conducted a quantitative analysis of the staircase movements including the cases of apparently smooth movement of the eyes. We conclude that all of the movements elicited by prolonged SC stimulation were generated by the saccadic feedback circuitry. The dynamic profiles of the elicited movements changed continuously with the stimulating current parameters. On one end of the continuum we observed the classically described staircase movements with individual movements separated in time. On the other end of the continuum we saw the apparent smooth movement as the limit case produced by high stimulation of the SC.     

Dynamic performance of accommodating intraocular lenses in a negative feedback control system: a simulation-based study

A dynamic model of ocular accommodation is used to simulate the stability and dynamic performance of accommodating intraocular lenses (A-IOLs) that replace the hardened natural ocular lens that is unable to change focus. Accommodation simulations of an older eye with A-IOL materials having biomechanical properties of a younger eye illustrate overshoots and oscillations resulting from decreased visco-elasticity of the A-IOL. Stable dynamics of an A-IOL are restored by adaptation of phasic and tonic neural-control properties of accommodation. Simulations indicate that neural control must be recalibrated to avoid unstable dynamic accommodation with A-IOLs. An interactive web-model of A-IOL illustrating these properties is available at http://schorlab.berkeley.edu.     

脑电反馈控制系统的研制

本文介绍了基于IBM PC/XT计算机的新型双闭环脑电反馈控制系统的研制及在系统中抑制噪声干扰、使系统具有临床实用性的具体措施。该系统将脑电生物反馈和物理刺激的反馈控制加以结合,能有效地进行脑电反馈控制,并具备多种脑电指标的CRT显示和打印机输出。     

Continuous flow total artificial heart: modeling and feedback control in a mock circulatory system

We developed a mock circulatory loop and used mathematical modeling to test the in vitro performance of a physiologic flow control system for a total artificial heart (TAH). The TAH was constructed from two continuous flow pumps. The objective of the control system was to maintain loop flow constant in response to changes in outflow resistance of either pump. Baseline outflow resistances of the right (pulmonary vascular resistance) and the left (systemic vascular resistance) pumps were set at 2 and 18 Wood units, respectively. The corresponding circuit flow was 4 L/min. The control system consisted of two digital integral controllers, each regulating the voltage, hence, the rotational speed of one of the pumps. The in vitro performance of the flow control system was validated by increasing systemic and pulmonary vascular resistances in the mock loop by 4 and 8 Wood units (simulating systemic and pulmonary hypertension conditions), respectively. For these simulated hypertensive states, the flow controllers regulated circuit flow back to 4 L/min within seconds by automatically adjusting the rotational speed of either or both pumps. We conclude that this multivariable feedback mechanism may constitute an adequate supplement to the inherent pressure sensitivity of rotary blood pumps for the automatic flow control and left-right flow balance of a dual continuous flow pump TAH system.     

Implementation of natural sensory feedback in a portable control system for a hand grasp neuroprosthesis

This paper presents the design and implementation of the first generation of a portable system for a hand grasp neuroprosthesis that is controlled by means of signals from natural sensors in the skin of the index finger. To reduce development time and costs, we based our design on readily available, standardised modules such as a 486DX100 compatible CPU, a data acquisition board, a flash disk storage unit, and a high-efficiency DC/DC switch-mode power supply. Additionally, we designed and built a telemeter to supply an implanted muscle stimulator with power and control data. The signal from the natural sensors was recorded with a cuff electrode implanted around the palmar digital nerve innervating the radial aspect of the index finger. For amplification of the recorded nerve signal, we added an external low-noise nerve signal amplifier. For pre-processing of the recorded nerve signal, an optimised band-pass filter was used. A data-recording unit allowed storage and off-line analysis of the stimulator command and the recorded nerve signal. The portable system was used by a tetraplegic volunteer to test the feasibility of including natural sensors in a hand grasp neuroprosthesis for activities of daily living. The flexibility of the presented system allows rapid prototyping of experimental FES hand grasp systems intended for portable use.     

Demonstration that platelet-activating factor is capable of activating mast cells and inducing a chemotactic response

Platelet-activating factor (PAF) is generated in a variety of inflammatory conditions in which mast cells accumulate. However, little is known about the ability of PAF to influence mast cell function directly. In this study we examine the ability of PAF to activate mast cells and regulate mast cell chemotaxis. PAF was found to induce intracellular calcium mobilization and chemotactic responses in both murine and human mast cells. PAF induced transient increases in intracellular Ca2+ concentrations with a 50% effective dose of 1 nM and induced significant migratory responses at PAF concentrations of 1 nM to 1 microM in the human leukaemia mast cell line (HMC-1). Using signal transduction inhibitors, both PAF-induced calcium mobilization and migration of mast cells were shown to require activation of pertussis toxin-sensitive G proteins. PAF-induced calcium and chemotactic responses were cross-desensitized by C5a. Together, these data demonstrate that PAF is capable of activating distinct signalling pathways in mast cells associated with calcium mobilization and cell migration; and that PAF may thus contribute to the regulation of mast cell responses and hyperplasia at sites of inflammation.     

Grapheme-to-lexeme feedback in the spelling system: Evidence from a dysgraphic patient

This article presents an argument for grapheme-to-lexeme feedback in the cognitive spelling system, based on the impaired spelling performance of dysgraphic patient CM. The argument relates two features of CM's spelling. First, letters from prior spelling responses intrude into subsequent responses at rates far greater than expected by chance. This letter persistence effect arises at a level of abstract grapheme representations, and apparently results from abnormal persistence of activation. Second, CM makes many formal lexical errors (e.g., carpet?→?compute). Analyses revealed that a large proportion of these errors are “true” lexical errors originating in lexical selection, rather than “chance” lexical errors that happen by chance to take the form of words. Additional analyses demonstrated that CM's true lexical errors exhibit the letter persistence effect. We argue that this finding can be understood only within a functional architecture in which activation from the grapheme level feeds back to the lexeme level, thereby influencing lexical selection.     

Grapheme-to-lexeme feedback in the spelling system: Evidence from a dysgraphic patient

This article presents an argument for grapheme-to-lexeme feedback in the cognitive spelling system, based on the impaired spelling performance of dysgraphic patient CM. The argument relates two features of CM's spelling. First, letters from prior spelling responses intrude into subsequent responses at rates far greater than expected by chance. This letter persistence effect arises at a level of abstract grapheme representations, and apparently results from abnormal persistence of activation. Second, CM makes many formal lexical errors (e.g., carpet → compute). Analyses revealed that a large proportion of these errors are "true" lexical errors originating in lexical selection, rather than "chance" lexical errors that happen by chance to take the form of words. Additional analyses demonstrated that CM's true lexical errors exhibit the letter persistence effect. We argue that this finding can be understood only within a functional architecture in which activation from the grapheme level feeds back to the lexeme level, thereby influencing lexical selection.     

Antibodies to factor XII: a possible predictive marker for recurrent foetal loss

Antibodies to factor XII (FXIIabs) have been demonstrated in some patients with the anti-phospholipid syndrome (APS). The presence of these antibodies were shown to lead to statistically significantly reduced levels of FXII (p = 0.02). In an extension to this study forty female patients with either primary APS (n = 26) or systemic lupus erythematosus (APS positive) (n = 14) were investigated for levels of factor XII, the presence of lupus anticoagulant and antibodies to cardiolipin, beta 2-glycoprotein I and factor XII. Twenty one of the forty patients had a history of foetal loss (> 2, mean = 2.6). Lupus anticoagulant positivity showed a weak association with foetal loss (odds ratio = 1.1). While there was no association between the presence of antibodies to cardiolipin or beta 2-glycoprotein I with foetal loss, antibodies to factor XII showed a strong and statistically significant association (odds ratio = 5.4, p = 0.025).