A comparative study of cortical computations in the mammalian visual cortex

textA common feature of all mammals is the cerebral cortex, which is essential for higher-order functions and processing information to generate motor actions. While cortical circuits exhibit a striking uniformity in anatomical organization, it is unknown whether these circuits preform similar computations across mammalian species. In this dissertation I compare the emergence of two computations in the primary visual cortex (V1) of carnivores and rodents. A cortical computation is a transformation in neural representation, such that the spiking output of a cortical neuron exhibits a selectivity not present in the inputs from upstream neurons. Here I explore two computations: orientation selectivity, the preference of neurons for oriented edges in the visual world, and binocularity, the integration of signals from the two eyes. In the first section, I compare the emergence of orientation selectivity in the early visual pathway of mouse and cat. Recordings from thalamic relay cells and V1 neurons in both species reveal orientation selectivity in mouse V1 is not emergent, and could be inherited subcortically. In a second set of experiments, I measure orientation selectivity and the organization of V1 orientation preference in a grasshopper mouse with predatory behavior, compared to the scavenger lab mouse. Here I find the same functional properties. In the second section, I focus on the integration of ocular inputs in V1 of mouse and cat. I first compare disparity selectivity in cats, where convergence of ocular inputs has long been established, with mice, where ocular integration had not previously been investigated. Similar to cats, mouse V1 neurons were sensitive to binocular disparity, albeit to a lesser degree, and could be described by a linear feed-forward model. I next explore the disruption of binocular disparity tuning in both animals. In cats, strabismus induced during development causes increased monocularity in V1 and a loss of disparity selectivity. In mice, monocular deprivation causes increased ocular input, which also manifests as decreased disparity selectivity. Finally, I explore how excitatory and inhibitory neurons in mouse V1 integrate binocular signals. Paravalbumin-expressing inhibitory interneurons are more binocular but less disparity tuned than surrounding cortical neurons, providing a canonical mechanism explaining loss of disparity selectivity in both carnivores and rodents.Neuroscienc

MEK2 Is Sufficient but Not Necessary for Proliferation and Anchorage-Independent Growth of SK-MEL-28 Melanoma Cells

Mitogen-activated protein kinase kinases (MKK or MEK) 1 and 2 are usually treated as redundant kinases. However, in assessing their relative contribution towards ERK-mediated biologic response investigators have relied on tests of necessity, not sufficiency. In response we developed a novel experimental model using lethal toxin (LeTx), an anthrax toxin-derived pan-MKK protease, and genetically engineered protease resistant MKK mutants (MKKcr) to test the sufficiency of MEK signaling in melanoma SK-MEL-28 cells. Surprisingly, ERK activity persisted in LeTx-treated cells expressing MEK2cr but not MEK1cr. Microarray analysis revealed non-overlapping downstream transcriptional targets of MEK1 and MEK2, and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore, LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results indicate in SK-MEL-28 cells MEK1 and MEK2 signaling pathways are not redundant and interchangeable for cell proliferation. We conclude that in the absence of other MKK, MEK2 is sufficient for SK-MEL-28 cell proliferation. MEK1 conditionally compensates for loss of MEK2 only in the presence of other MKK

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc