Biology subjects

Cohen, I.

Publications and source records attributed to Cohen, I..

6 recordsLinked to original sources

bioRxiv2018

Total lung capacity without plethysmography

BackgroundAmong the most basic measures of respiratory function is the total lung capacity (TLC). TLC is the pulmonary gas volume at maximal lung inflation, which is the sum of the volume of gas that can be exhaled -the vital capacity (VC)- and the volume of gas that cannot -the residual volume (RV). Determination of VC requires only spirometry whereas determination of RV or TLC requires body plethysmography, gas dilution or washout, or thoracic imaging, each of which is more complex than spirometry, and none of which is suited to routine office practice, population screening, or community medicine. To fill this gap, we describe here a new approach to determine TLC without plethysmography.\n\nMethodsIn a heterogeneous population of 434 volunteers (265 male, 169 female; 201 healthy, 170 with airflow obstruction, and 63 with ventilatory restriction), we determined TLC in the standard fashion using conventional body plethysmography (TLCpleth). In the same individuals, we also determined TLC in a novel fashion using the MiniBox (TLCMB). To obtain TLCMB, population-based data from traditional spirometry together with flow-interruption transients were subjected to data mining and machine-learning to create for each individual subject an unbiased statistical determination of TLC.\n\nResultsFor the combined heterogeneous population, we found TLCpleth = 1.02TLCMB -0.091 L, adjusted r2=0.824. For the heterogeneous population as a whole, and for each subpopulation, TLCMB closely tracked TLCpleth. For 26 healthy subjects measured on different days, the coefficient of variation for repeated measurements in was 3.3% for TLCpleth versus 1.6% for TLCMB.\n\nConclusionsThese results establish the validity and potential utility of a new method for rapid, accurate, and repeatable determination of TLC in a heterogeneous patient population, but without the need of a plethysmograph.

bioengineering↗

bioRxiv2018

Desiccation-induced changes in recombination rate and interference in fruit flies: an evidence for fitness-dependent plasticity

Meiotic recombination is evolutionarily ambiguous, giving both benefits and costs to its bearers, with the resultant depending on a variety of conditions. The existing theoretical models explain why recombination does exist while the existence of its essential features remains underexplored. Here we test whether recombination plasticity and interference plasticity are fitness dependent. We compare effects of desiccation on recombination and interference in chromosome 3 in desiccation-sensitive and desiccation-tolerant Drosophila lines. We show that in desiccation-sensitive genotypes the treatment causes significant segment-specific increase in single- and double-crossover frequencies while in desiccation-tolerant genotypes changes are less pronounced, if seen at all. These results indicate that desiccation is a recombinogenic factor, and that desiccation-induced changes in both recombination and interference are fitness dependent, with a negative-feedback pattern implying the tendency of less fitted individuals to produce more variable progeny. Such dependence may play an important role in regulation of genetic variation in population experiencing environmental challenges.

genetics↗

bioRxiv2018

Cortical control of kinematic primitives in mice performing a hold-still-center-out reach task

Motor sequences are constructed from primitives, hypothesized building blocks of movement, but mechanisms of primitive generation remain unclear. Using automated homecage training and a novel forelimb sensor, we trained freely-moving mice to initiate forelimb sequences with clearly resolved submillimeter-scale micromovements followed by millimeter-scale reaches to learned spatial targets. Hundreds of thousands of trajectories were decomposed into millions of kinematic primitives, while closed-loop photoinhibition was used to test roles of motor cortical areas. Inactivation of contralateral motor cortex reduced primitive peak speed but, surprisingly, did not substantially affect primitive direction, initiation, termination, or complexity, resulting in isomorphic, spatially contracted trajectories that undershot targets. Our findings demonstrate separable loss of a single kinematic parameter, speed, and identify conditions where loss of cortical drive reduces the gain of motor primitives but does not affect their generation, timing or direction. The combination of high precision forelimb sensing with automated training and neural manipulation provides a system for studying how motor sequences are constructed from elemental building blocks.

neuroscience↗

bioRxiv2018

Anterior thalamic excitation and feed-forward inhibition of presubicular neurons projecting to medial entorhinal cortex

The presubiculum contains head direction cells that are crucial for spatial navigation. Here, we examined the connectivity and strengths of thalamic inputs to presubicular layer 3 neurons projecting to the medial entorhinal cortex in the mouse. We recorded pairs of projection neurons and interneurons while optogenetically stimulating afferent fibers from the anterior thalamic nuclei (ATN). Thalamic input differentially affects presubicular neurons: layer 3 pyramidal neurons and fast-spiking parvalbumin expressing (PV) interneurons are directly and monosynaptically activated, with depressing dynamics, while somatostatin (SST) expressing interneurons are indirectly excited, during repetitive ATN activity. This arrangement ensures that the thalamic excitation of layer 3 cells is often followed by disynaptic inhibition. Feed-forward inhibition is largely mediated by PV interneurons which have a high probability of connection to presubicular pyramidal cells. Our data point to a specific role of presubicular microcircuits in shaping thalamic head-direction signals transmitted to medial entorhinal cortex: Short-latency PV cell activation may enforce temporally precise head direction tuning during fast turns. However, depression at ATN-PV synapses during repeated activation tends to facilitate pyramidal cell firing when head direction is maintained. Operations performed in presubicular layer 3 circuits seem well-adapted for spatial fine-tuning of head direction signals sent to the medial entorhinal cortex.\n\nSIGNIFICANCE STATEMENTHow microcircuits participate in shaping neural inputs is crucial to understanding information processing in the brain. Here, we show how the presubiculum may process thalamic head directional information before transmitting it to the medial entorhinal cortex. Synaptic inputs from the anterior thalamic nuclei (ATN) excite layer 3 pyramidal cells (PC) and parvalbumin (PV) interneurons, which mediate disynaptic feed-forward inhibition. Somatostatin (SST) interneurons are excited indirectly. Presubicular circuits may switch between two regimes according to the angular velocity of head movements. During immobility, SST-PC interactions support maintained head directional firing with attractor-like dynamics. During rapid head turns, in contrast, PV mediated feed-forward inhibition acts to tune the head direction signal transmitted to medial entorhinal cortex.

neuroscience↗

bioRxiv2017

Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14

MMP-14 and MMP-9 are two well established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a non-specific MMP inhibitor, N-TIMP2. The engineered purified N-TIMP2 variants showed enhanced specificity towards MMP-14 and MMP-9 relative to a panel of off-target MMPs. MMP-specific N-TIMP2 sequence signatures were obtained that could be understood from the structural perspective of MMP/N-TIMP2 interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities.

biophysics↗

bioRxiv2017

How activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum

Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modeled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal - Martinotti cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum.

neuroscience↗