Biomedical subjects

Fan Gao

Publications and source records attributed to Fan Gao.

26 records · Page 2Linked to original sources

PubMed2003

Matrix analyses of interaction among fingers in static force production tasks.

The fingers on a hand show interactions in force production tasks. The interfinger connection matrices (IFMs) quantify these interactions (Li et al. 2002; Zatsiorsky et al. 2002b; Danion et al. 2003). The goal of the present study was to explore the differences in the IFMs of individual subjects and, in particular, to establish a procedure that may be used in the future for diagnostic purposes. Subjects ( n=20) pressed downward maximally with ten different combinations of the four fingers, index (I), middle (M), ring (R), and little (L): I, M, R, L, IM, MR, RL, IMR, MRL, and IMRL. Voluntary activation of a subset of the four fingers was accompanied by an involuntary force production by fingers that were not intentionally activated (enslaving). Interfinger connection matrices were computed for each subject by the artificial neural network. The similarities/dissimilarities (proximities) between the individual matrices were determined. This procedure was performed twice: (a) for nonnormalized IFMs whose elements represented the amount of force (in newtons) exerted by a finger i in response to a unit command to a finger j; and (b) for normalized IFMs, after dividing the elements of each IFM by the total force produced by the four fingers acting together (the elements of the matrix are in percents). The 20x20 matrix of the proximities was subjected to multidimensional scaling (MDS) to reduce the number of dimensions and identify the major ones. To interpret the meaning of the computed dimensions, they were regressed on a set of finger force parameters described in the text. For the nonnormalized IFMs an interpretable dimension was the strength of the subjects. For the normalized IFMs two dimensions were interpreted: (a) the location of the point of resultant force application along the mediolateral axis that is defined by the pattern of force sharing among the fingers and (b) the total contribution of the enslaved forces into the total finger force. We speculate that the similarity of typical everyday tasks across the population promotes the similarity of the IMFs reflecting optimal hand functioning over these tasks.

Adult↗

PubMed2003

Light-evoked excitatory and inhibitory synaptic inputs to ON and OFF alpha ganglion cells in the mouse retina.

Bipolar cell and amacrine cell synaptic inputs to alpha ganglion cells (alphaGCs) in dark-adapted mouse retinas were studied by recording the light-evoked excitatory cation current (DeltaIC) and inhibitory chloride current (DeltaICl) under voltage-clamp conditions, and the cell morphology was revealed by Lucifer yellow fluorescence with a confocal microscope. Three types of alphaGCs were identified. (1) ONalphaGCs exhibits no spike activity in darkness, increased spikes in light, sustained inward DeltaIC, sustained outward DeltaICl of varying amplitude, and large soma (20-25 microm in diameter) with alpha-cell-like dendritic field approximately 180-350 microm stratifying near 70% of the inner plexiform layer (IPL) depth. (2) Transient OFFalphaGCs (tOFFalphaGCs) exhibit no spike activity in darkness, transient increased spikes at light offset, small sustained outward DeltaIC in light, a large transient inward DeltaIC at light offset, a sustained outward DeltaICl, and a morphology similar to the ONalphaGCs except for that their dendrites stratified near 30% of the IPL depth. (3) Sustained OFFalphaGCs exhibit maintained spike activity of 5-10 Hz in darkness, sustained decrease of spikes in light, sustained outward DeltaIC, sustained outward DeltaICl, and a morphology similar to the tOFFalphaGCs. By comparing the response thresholds and dynamic ranges of alphaGCs with those of the preganglion cells, our data suggest that the light responses of each type of alphaGCs are mediated by different sets of bipolar cells and amacrine cells. This detailed physiological analysis complements the existing anatomical results and provides new insights on the functional roles of individual synapses in the inner mammalian retina.

Action Potentials↗

PubMed2003

Curariform antagonists bind in different orientations to the nicotinic receptor ligand binding domain.

Curariform alkaloids competitively inhibit muscle acetylcholine receptors (AChR) by bridging the alpha and non-alpha subunits that form the ligand-binding site. Here we delineate bound orientations of d-tubocurarine (d-TC) and its methylated derivative metocurine using mutagenesis, ligand binding measurements, and computational methods. When tested against a series of lysine mutations in the epsilon subunit, the two antagonists show marked differences in the consequences of the mutations on binding affinity. The mutations epsilon L117K, epsilon Y111K, and epsilon L109K decrease affinity of metocurine by up to 3 orders of magnitude but only slightly alter affinity of d-TC. At the alpha subunit face of the binding site, the mutation alpha Y198T decreases affinity of both antagonists, but alpha Y198F preferentially enhances affinity of d-TC. Computation of antagonist docking orientations, based on our structural model of the alpha-epsilon site of the human AChR, indicates distinct orientations of each antagonist; the flatter metocurine fits into a pocket formed principally by the epsilon subunit, whereas the more compact d-TC spans the narrower crevasse between alpha and epsilon subunits. The side chains of epsilon Tyr-111 and epsilon Thr-117 juxtapose one of two quaternary nitrogens in metocurine but are remote from the equivalent quaternary nitrogen in d-TC, which instead closely approaches alpha Tyr-198. The different docked orientations arise through tilt of the curariform scaffold by approximately 60 degrees normal to the nitrogen-nitrogen axis, together with a 20 degrees rotation about the axis. The overall mutagenesis and computational results show that despite their similar structures, d-TC and metocurine bind in distinctly different orientations to the adult human AChR.

Alkaloids↗

PubMed2003

Curariform antagonists bind in different orientations to acetylcholine-binding protein.

Acetylcholine-binding protein (AChBP) recently emerged as a prototype for relating structure to function of the ligand binding domain of nicotinic acetylcholine receptors (AChRs). To understand interactions of competitive antagonists at the atomic structural level, we studied binding of the curare derivatives d-tubocurarine (d-TC) and metocurine to AChBP using computational methods, mutagenesis, and ligand binding measurements. To account for protein flexibility, we used a 2-ns molecular dynamics simulation of AChBP to generate multiple snapshots of the equilibrated dynamic structure to which optimal docking orientations were determined. Our results predict a predominant docking orientation for both d-TC and metocurine, but unexpectedly, the bound orientations differ fundamentally for each ligand. At one subunit interface of AChBP, the side chain of Tyr-89 closely approaches a positively charged nitrogen in d-TC but is farther away from the equivalent nitrogen in metocurine, whereas, at the opposing interface, side chains of Trp-53 and Gln-55 closely approach the metocurine scaffold but not that of d-TC. The different orientations correspond to approximately 170 degrees rotation and approximately 30 degrees degree tilt of the curare scaffold within the binding pocket. Mutagenesis of binding site residues in AChBP, combined with measurements of ligand binding, confirms the different docking orientations. Thus structurally similar ligands can adopt distinct orientations at receptor binding sites, posing challenges for interpreting structure-activity relationships for many drugs.

Amino Acid Sequence↗

PubMed2003

Finger force vectors in multi-finger prehension.

In a majority of studies on grasp, only normal forces were measured and only when a zero torque was exerted on a hand-held object. This study concerns finger force vectors during the torque production tasks. Subjects (n=8) stabilized a handle with an attachment that allowed for change of external torque from -1.5 to 1.5 Nm. Forces and moments exerted by the digit tips on the object were recorded. At the large (>-0.375 Nm) supination torques the index/middle and ring/little pairs of fingers generated oppositely directed tangential forces. The index and middle finger produced forces in a downward direction and therefore did not support the load. At a zero torque and pronation torques, the middle, ring and little fingers produced forces along nearly the same direction. The vector of the index finger force was always directed differently from the vectors of other finger forces, the angles ranged from 19 degrees 30' to 47 degrees 40'. The points of force application were systematically displaced with the torque, with the exception of the little finger. Tangential finger forces contributed substantially to the total torque exerted on the hand-held object.

Adult↗

PubMed2002

Segregation and integration of visual channels: layer-by-layer computation of ON-OFF signals by amacrine cell dendrites.

The visual system analyzes images through parallel channels, and our data suggest that the first set of parallel representations of the visual world is embodied in the inner plexiform layer (IPL) of the retina, in which light-evoked excitatory inputs of the ON and OFF bipolar cells to amacrine cells (ACs) are organized in a layer-by-layer manner. Approximately 30% of ACs have narrowly monostratified dendrites in 1 of the 10 strata of the IPL, and they receive segregated bipolar cell inputs: the light-evoked excitatory cation current, DeltaI(C), in strata 1, 2, and 4 is OFF (predominantly mediated by the OFF bipolar cells), the current in strata 3 and 7-10 is ON (predominantly mediated by ON bipolar cells), and the current in strata 5 and 6 is ON-OFF (mediated by both ON and OFF bipolar cells). The remaining 70% of ACs have broadly monostratified, multistratified, or diffuse dendrites, and they integrate bipolar cell signals through layer-by-layer summation: ACs with dendrites ramified in multiple strata exhibit DeltaI(C)s that are sums of DeltaI(C)s of individual strata. The light-evoked inhibitory chloride current, DeltaI(Cl), in strata 1, 2, and 4-6 is ON-OFF (mediated predominantly by ON-OFF ACs or ON ACs plus OFF ACs), and the DeltaI(Cl) in strata 3 and 7-10 is ON (mediated predominantly by ON ACs). This indicates that the amacrine-amacrine inhibitory synaptic circuitry in the IPL is asymmetrical in favor of the ON channels.

Amacrine Cells↗

PubMed2002

Non-linear, high-gain and sustained-to-transient signal transmission from rods to amacrine cells in dark-adapted retina of Ambystoma.

In darkness, On-Off amacrine cells (ACs) of the tiger salamander retina exhibited large spontaneous transient depolarizing potentials (sTDPs) with average peak amplitude of 5.05 +/- 2.5 mV and average frequency of 0.42 +/- 0.25 s(-1). Under voltage-clamp conditions the cell displayed large spontaneous postsynaptic currents (sPSCs) with average peak amplitude of 98 +/- 39 pA and average frequency of 0.45 +/- 0.22 s(-1). To a light step, ACs gave rise to a transient 'On' response at the light onset and a transient 'Off' response at light offset, followed by a train of TDPs ('After' response). Near the response threshold (0.3 activated rhodopsin molecules per rod per second), light-evoked TDPs (leTDPs) of similar amplitude and kinetics as the large sTDPs observed in darkness were seen, and about half of these leTDPs elicited a regenerative potential (RP). Brighter light steps gave rise to more leTDPs and higher rates of RPs in the On, Off and After responses. Within the linear response range of the rods, the AC response was non-linear, with the highest gain (676 +/- 429) near the dark potential. The amplitude of Off responses increased with the duration of the light step, and ACs may use this to encode speeds of moving stimuli: the faster the light object moves, the smaller the AC Off response. Moreover, the number of leTDPs in the AC After response increased with light intensity, and the onset of the After response coincides with bipolar cell tail response recovery. One possible origin of the large sTDPs and leTDPs is the spontaneous and depolarization-induced regenerative calcium potentials (RCaPs) in bipolar cell synaptic terminals. RCaPs in bipolar cell synaptic terminals cause transient glutamate release that results in the sTDPs in darkness, and leTDPs in On, Off and After responses in ACs.

Amacrine Cells↗

PubMed2002

Relative contributions of bipolar cell and amacrine cell inputs to light responses of ON, OFF and ON-OFF retinal ganglion cells.

Light-evoked postsynaptic currents (lePSCs) were recorded from ON, OFF and ON-OFF ganglion cells in dark-adapted salamander retinal slices under voltage clamp conditions, and the cell morphology was examined using Lucifer yellow fluorescence with confocal microscopy. The current-voltage relations of the lePSCs in all three types of ganglion cells are approximately linear within the cells' physiological range. The average chloride/cation conductance ratio (Deltag(Cl)(NR)/Deltag(C)(NR)) of the lePSCs is near 3, suggesting that ganglion cell light responses are associated with a greater postsynaptic conductance change at the amacrine-ganglion cell inhibitory synapses than at the bipolar-ganglion cell excitatory synapses. By comparing the charge transfer of lePSCs in normal Ringer's and in picrotoxin+strychnine+Imidazole-4-acidic acid, we found that the GABAergic and glycinergic amacrine-bipolar cell feedback synapses decreased the light-induced glutamatergic vesicle release from bipolar cells to all ganglion cells, and the degree of release reduction varied widely from ganglion cell to ganglion cell, with a range of 3-28 fold.

Ambystomatidae↗