A computational model of antibiotic-resistance mechanisms in methicillin-resistant Staphylococcus aureus (MRSA)

An agent-based model of bacteria-antibiotic interactions has been developed that incorporates the antibiotic-resistance mechanisms of Methicillin-Resistant Staphylococcus aureus (MRSA). The model, called the Micro-Gen Bacterial Simulator, uses information about the cell biology of bacteria to produce global information about population growth in different environmental conditions. It facilitates a detailed systems-level investigation of the dynamics involved in bacteria-antibiotic interactions and a means to relate this information to traditional high-level properties such as the Minimum Inhibitory Concentration (MIC) of an antibiotic. The two main resistance strategies against β-lactam antibiotics employed by MRSA were incorporated into the model: β-lactamase enzymes, which hydrolytically cleave antibiotic molecules, and penicillin-binding proteins (PBP2a) with reduced binding affinities for antibiotics. Initial tests with three common antibiotics (penicillin, ampicillin and cephalothin) indicate that the model can be used to generate quantitatively accurate predictions of MICs for antibiotics against different strains of MRSA from basic cellular and biochemical information. Furthermore, by varying key parameters in the model, the relative impact of different kinetic parameters associated with the two resistance mechanisms to β-lactam antibiotics on cell survival in the presence of antibiotics was investigated.     

Reaction of neurons of the medial geniculate body to acoustic stimulation

Responses of medial geniculate body (MGB) neurons to pure tones and clicks were studied in acute experiments in immobilized cats, preliminary operations being performed under calypsol anaesthesia. MGB units were identified by their reactions to cortical zone AI and brachium of inferior colliculus stimulations. When tonal stimuli were applied relay neurons of pars principalis of MGB usually demonstrated either unimodal tuning curves with narrow frequency band or fragmental ones with several narrow bands. On-response with subsequent inhibition of the background activity or without such an inhibitory period was most frequent type of the reaction (66.6%) of relay MGB neurons to tonal stimulation. The group of relay neurons with the tonic type of reaction (9.1%) was classified for which the duration of tonic response depends on the duration of tonal stimulus. Change of the excitatory reaction to the inhibitory one when the characteristic tone frequency is changed by non-characteristic++ ones is supposed to be a mechanism supplying sharpness of tuning at relay MGB neurons. It is concluded that responses of acoustic cortical neurons to sound stimulation depend to a great extent on the pattern of impulsation that comes from MGB relay units.     

内侧膝状体解剖与生理学研究进展

内侧膝状体 (medialgeniculatebody ,MGB)是听觉系统在丘脑的重要接替核团。MGB的丘脑 皮层神经元 (thalamocorticalneuron)发出上行性纤维投射至听皮层 ,同时接受听皮层的皮层 丘脑神经元 (corticothalamicneuron)发出的下行性纤维投射。因此 ,听觉信息既受到MGB上行听觉通路的编码和整合 ,也接受皮层下行通路的调控。同时 ,MGB还参与声音定位、听觉可塑性等过程。本文总结近年MGB的解剖与生理学研究进展 ,着重叙述MGB与听皮层的纤维联系及其在听觉信息调控中的作用。     

Unit responses in the cat auditory cortex to medial geniculate body stimulation

Responses of 98 auditory cortical neurons to electrical stimulation of the medial geniculate body (MGB) were recorded (45 extracellulary, 53 intracellularly) in experiments on cats immobilized with tubocurarine. Responses of the same neurons to clicks were recorded for comparison. Of the total number of neurons, 75 (76%) responded both to MGB stimulation and to clicks, and 23 (24%) to MGB stimulation only. The latent period of extracellularly recorded action potentials of auditory cortical neurons in response to clicks varied from 7 to 28 msec (late responses were disregarded), and that to MGB stimulation varied from 1.5 to 12.5 msec. For EPSPs these values were 8–13 and 1–4 msec respectively. The latent period of IPSPs arising in response to MGB stimulation varied from 2.2 to 6.5 msec; for 34% of neurons it did not exceed 3 msec. The difference between the latent periods of responses to clicks and to MGB stimulation varied for different neurons from 6 to 21 msec. Responses of 11% of neurons to MGB stimulation, recorded intracellularly, consisted of sub-threshold EPSPs, while responses of 23% of neurons began with an EPSP which was either followed by an action potential and subsequent IPSP or was at once cut off by an IPSP; 66% of neurons responded with primary IPSPs. Neurons responding to MGB stimulation by primary IPSPs are distributed irregularly in the depth of the cortex: there are very few in layers III and IV and many more at a depth of 1.6–2 mm. Conversely, excited neurons are predominant in layer III and IV, and they are few in number at a depth of 1.6–2 mm. It is concluded that the afferent volley reaching the auditory cortex induces excitation of some neurons therein and, at the same time, by the principle of reciprocity, induces inhibition of others. This afferent inhibition takes place with the participation of inhibitory interneurons, and in some cells the inhibition is recurrent. The existence of reciprocal relationships between neurons in different layers of the auditory cortex is postulated.A. A. Bogomolets' Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 4, No. 1, pp. 23–31, January–February, 1972.     

Electron microscope study of sources in the cat primary auditory cortex (AI) projecting to the medial geniculate body

An electron microscope study of retrogradely labeled pyramidal neurons in layer VI of the primary auditory cortex (AI) after injecting horseradish peroxidase (HP) into the medial geniculate body was carried out in cats. Not less than 57.8±1.9% on average of the perimeter of perikaryon profiles of corticogeniculate neurons labeled with HP were found to be covered with astroglia processes. Between three and eight synapses occupying an average of 10.8±1.0% of the perimeter length were found on the perikaryon profiles of these neurons. Nearly all synapses (a total of 98.7%) at the soma of corticogeniculate neurons had symmetrical active zones, being made up of axonal terminals with flattened synaptic vesicles. Anterogradely HP-labeled axonal terminals of geniculocortical fibers were also found in the neuropil of layer VI in area AI, in addition to retrogradely labeled neurons. They contained large round synaptic vesicles and formed asymmetrical synapses. The potential role of axosomatic synapses in the shaping of corticogeniculate neuronal activity is discussed.A. A. Bogomolets Institute, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 2, pp. 171–178, March–April, 1990.     

Responses of medial geniculate body neurons to auditory cortical stimulation

Extracellular and intracellular unit responses of thepars principalis of the medial geniculate body to stimulation of the first (AI), second (AII), and third (AIII) auditory cortical areas were studied in cats immobilized with D-tubocurarine. In response to auditory cortical stimulation both antidromic (45–50%) and orthodromic (50–55%) responses occurred in the geniculate neurons. The latent period of the antidromic responses was 0.3–2.5 msec and of the orthodromic 2.0–18.0 msec. Late responses had a latent period of 30–200 msec. Of all neurons responding antidromically to stimulation of AII, 63% responded antidromically to stimulation of AI also, confirming the hypothesis that many of the same neurons of the medial geniculate body have projections into both auditory areas. Orthodromic responses of geniculate neurons consisted either of 1 or 2 spikes or of volleys of 8–12 spikes with a frequency of 300–600/sec. It is suggested that the volleys of spikes were discharges of inhibitory neurons. Intracellular responses were recorded in the form of antidromic spikes, EPSPs, EPSP-spike, EPSP-spike-IPSP, EPSP-IPSP, and primary IPSP. Over 50% of primary IPSP had a latent period of 2.0–4.0 msec. It is suggested that they arose through the participation of inhibitory interneurons located in the medial geniculate body.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 8, No. 1, pp. 5–12, January–February, 1976.     

Electrophysiological investigation of conduction of afferent impulses through the medial geniculate body

Extra- and intracellular reactions of 280 neurons of the pars principalis of the medial geniculate body (MGB) and of 408 auditory cortical neurons in area AI to stimulation of the inferior brachium of the midbrain and geniculocortical fibers were studied in cats immobilized with D-tubocurarine. Single electrical stimulation of the inferior brachium was shown to evoke a long and complex neuronal response in MGB in the form of excitation of some and inhibition of other neurons. The initial component of this response lasted 13 msec. Excitation of 72% of neurons participating in the response took place during the first 3 msec after the beginning of stimulation. In the same period 84% of IPSP arose. The inferior brachium was shown to contain a certain number of descending fibers. Some of them are axons of MGB neurons. Many fibers of the inferior brachium reach the auditory cortex without synaptic relay in MGB. Of all cells of MGB excited by stimulation of the inferior brachium monosynaptically, 76% are thalamocortical relay neurons; the rest are interneurons. Of the relay neurons of MGB 90% are excited monosynaptically, the rest by impulses passing through two or three synaptic relays in MGB. During stimulation of the inferior brachium, responses consisting of EPSP-IPSP and primary IPSP are recorded in many neurons of MGB. About 20% of primary IPSP arise monosynaptically, evidently in response to stimulation of inhibitory fibers of the inferior brachium. Most IPSP arise disynaptically, with the participation of an inhibitory interneuron located at the entrance to MGB. Inhibition observed in this case is direct afferent in nature.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 11, No. 6, pp. 515–523, November–December, 1979.     

A minimal mechanistic model for temporal signal processing in the lateral geniculate nucleus

The receptive fields of cells in the lateral geniculate nucleus (LGN) are shaped by their diverse set of impinging inputs: feedforward synaptic inputs stemming from retina, and feedback inputs stemming from the visual cortex and the thalamic reticular nucleus. To probe the possible roles of these feedforward and feedback inputs in shaping the temporal receptive-field structure of LGN relay cells, we here present and investigate a minimal mechanistic firing-rate model tailored to elucidate their disparate features. The model for LGN relay ON cells includes feedforward excitation and inhibition (via interneurons) from retinal ON cells and excitatory and inhibitory (via thalamic reticular nucleus cells and interneurons) feedback from cortical ON and OFF cells. From a general firing-rate model formulated in terms of Volterra integral equations, we derive a single delay differential equation with absolute delay governing the dynamics of the system. A freely available and easy-to-use GUI-based MATLAB version of this minimal mechanistic LGN circuit model is provided. We particularly investigate the LGN relay-cell impulse response and find through thorough explorations of the model’s parameter space that both purely feedforward models and feedback models with feedforward excitation only, can account quantitatively for previously reported experimental results. We find, however, that the purely feedforward model predicts two impulse response measures, the time to first peak and the biphasic index (measuring the relative weight of the rebound phase) to be anticorrelated. In contrast, the models with feedback predict different correlations between these two measures. This suggests an experimental test assessing the relative importance of feedforward and feedback connections in shaping the impulse response of LGN relay cells.     

Unit responses of the pericruciate cortex to stimulation of the medial geniculate body

Responses of 239 neurons of the pericruciate cortex to stimulation of the medial geniculate body and pyramidal tract were investigated (189 extracellularly, 50 intracellularly) in cats anesthetized with thiopental and immobilized with D-tubocurarine. In response to stimulation of the medial geniculate body, the mean spontaneous firing rate of 63.6% of neurons in the pericruciate cortex increased by 10–25%, in 23.6% of neurons it decreased within the same limits, and mixed effects were observed in 5.5% of neurons. Phasic responses to single stimulation of the medial geniculate body were observed in 20% of neurons of the pericruciate cortex. Responses with a latent period of 0.3–1.0 msec (16%) were classed as antidromic, those with a latent period of 1.5–2.0 msec (20%) as orthodromic, monosynaptic, and those with a latent period of 2.5–4.0 msec or more (64%) as polysynaptic. With intracellular recording, excitatory responses of the EPSP, EPSP-AP, and AP type with latent periods of between 1.3 and 19.5 msec developed in 78.2% of cells. IPSPs, which were recorded in 21.8% of neurons, were usually found as components of mixed responses; primary IPSPs were found in only two cases. Monosynaptic connection of the medial geniculate body was shown to take place with neurons of the pericruciate cortex that did not belong to the pyramidal tract.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 11, No. 1, pp. 18–24, January–February, 1979.     

Discharge properties of neurons in subdivisions of the medial geniculate body of the guinea pig

The activity of 194 neurons was recorded in three subdivisions of the medial geniculate body (74 neurons in the ventral, 62 in the medial and 44 neurons in the dorsal subdivision, i.e. vMGB, mMGB and dMGB) of guinea pigs anesthetized with ketamine-xylazine. The discharge properties of neurons were evaluated by means of peristimulus time histograms (PSTHs), interval histograms (INTHs) and auto-correlograms (ACGs). In the whole MGB, the most frequent PSTH responses to pure tone stimuli were onset (43%) or chopper (32%). The onset responses were mostly present in the vMGB, whereas chopper responses dominated in the dMGB. In the whole MGB Poisson-like and bimodal INTHs were found in 46% and 40% of neurons, respectively. The mMGB revealed fewer bimodal and more symmetrical types of INTH. In the whole MGB, 60% of units were found to have ACGs typical for short bursts (<100 ms), 23% for long bursts (>100 ms) and 15% of units fired without bursts. Neurons in the vMGB were characterized by short bursting, whereas those in the mMGB and dMGB expressed more activity in the long bursts. The results demonstrate that the type of information processing in the vMGB, which belongs to the "primary" auditory system, is different from that in two other subdivisions of the MGB.