Two Wrongs Make a Right: Deficits in Reversal Learning after Orbitofrontal Damage Are Improved by Amygdala Ablation

Impaired cognitive flexibility after orbitofrontal damage has informed theories of orbitofrontal function and prefrontal cortex function generally. In this issue of Neuron, Stalnaker et al. demonstrate that reversal learning deficits after orbitofrontal damage in rats are eliminated by additional lesions of the basolateral amygdala. The involvement of orbitofrontal cortex in cognitive flexibility is via its interaction with the amygdala, and perhaps other brain areas, rather than an intrinsic property of this cortical region

Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection

To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex

Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia

Anesthetic protocols for behavioral neuroscience experiments are evolving as new anesthetics are developed and surgical procedures are refined to improve animal welfare. We tested whether neurotoxic dorsal hippocampal lesions produced under two different anesthetic protocols would have different behavioral and/or histo-pathological effects. Rats were anesthetized with either propofol, an intravenous anesthetic, or isoflurane, a gaseous anesthetic, and multiple injections of an excitotoxin (N-methyl-d-aspartate) were stereotaxically placed in the dorsal hippocampus bilaterally. Intraoperative physiological parameters were similar in the two surgical groups, as were the volumes of the lesions, although the profile of postoperative impairment in a spatial learning task differed between the lesion groups depending on the anesthetic regimen used. These results show that the choice of anesthetic protocol is a critical variable in designing behavioral neuroscience experiments using neurosurgical procedures. This factor should be considered carefully in experimental design and in cross-study comparisons of lesion effects on behavior. © 2007 Wiley-Liss, Inc

Pharmacological postconditioning against myocardial infarction with a slow-releasing hydrogen sulfide donor, GYY4137

Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30min of left coronary artery occlusion and 2h reperfusion. Infarct size was assessed by tetrazolium staining. In the first study, animals randomly received either no treatment or GYY4137 (26.6, 133 or 266μmolkg-1) by intravenous injection 10min before reperfusion. In a second series, involvement of PI3K and NO signalling were interrogated by concomitant administration of LY294002 or L-NAME respectively and the effects on the phosphorylation of Akt, eNOS, GSK-3β and ERK1/2 during early reperfusion were assessed by immunoblotting. GYY4137 266μmolkg-1 significantly limited infarct size by 47% compared to control hearts (P<0.01). In GYY4137-treated hearts, phosphorylation of Akt, eNOS and GSK-3β was increased 2.8, 2.2 and 2.2 fold respectively at early reperfusion. Co-administration of L-NAME and GYY4137 attenuated the cardioprotection afforded by GYY4137, associated with attenuated phosphorylation of eNOS. LY294002 totally abrogated the infarct-limiting effect of GYY4137 and inhibited Akt, eNOS and GSK-3β phosphorylation. These data are the first to demonstrate that GYY4137 protects the heart against lethal reperfusion injury through activation of PI3K/Akt signalling, with partial dependency on NO signalling and inhibition of GSK-3β during early reperfusion. H2S-based therapeutic approaches may have value as adjuncts to reperfusion in the treatment of acute myocardial infarction

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum

Towards on-farm pig face recognition using convolutional neural networks

© 2018 Elsevier B.V. Identification of individual livestock such as pigs and cows has become a pressing issue in recent years as intensification practices continue to be adopted and precise objective measurements are required (e.g. weight). Current best practice involves the use of RFID tags which are time-consuming for the farmer and distressing for the animal to fit. To overcome this, non-invasive biometrics are proposed by using the face of the animal. We test this in a farm environment, on 10 individual pigs using three techniques adopted from the human face recognition literature: Fisherfaces, the VGG-Face pre-trained face convolutional neural network (CNN) model and our own CNN model that we train using an artificially augmented data set. Our results show that accurate individual pig recognition is possible with accuracy rates of 96.7% on 1553 images. Class Activated Mapping using Grad-CAM is used to show the regions that our network uses to discriminate between pigs

Disruption of Decrements in Conditioned Stimulus Processing by Selective Removal of Hippocampal Cholinergic Input

The attention directed to environmental stimuli can be modified by experience. For example, preexposure of a conditioned stimulus (CS) in the absence of reinforcement can retard subsequent conditioning of that stimulus when it is paired directly with an unconditioned stimulus, a phenomenon referred to as latent inhibition. Similarly, consistent pairings of a CS with another event can slow the acquisition of new information about that CS. Such phenomena suggest that reductions in the processing of CSs occur when they are made behaviorally irrelevant or consistent predictors of other events. On the basis of the observation that hippocampal lesions prevented such reductions in CS processing, we hypothesized that damage to basal forebrain cholinergic neurons that project to the hippocampus, using microinjections of the selective immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB), also would disrupt normal reductions in CS processing. Lesions of hippocampal cholinergic input disrupted decreases in CS processing, manifested in both an absence of latent inhibition and a lack of reduced processing of a CS that had been a consistent predictor of another CS. These results indicate that cholinergic neurons in the MS/VDB play a role in the regulation of CS processing. Furthermore, these findings (in conjunction with previous findings) implicat

Lenvatinib and its use in the treatment of unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for approximately 90% of cases. Patients often present at an advanced stage when treatment options are limited. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been the first-line treatment in this setting for almost a decade. Several subsequent targeted therapies have failed to demonstrate significant improvement in survival. The results of the REFLECT study suggest that lenvatinib, a multikinase inhibitor, may have promised as a first-line treatment in patients with advanced HCC. This article will review the development of lenvatinib and the evidence behind its potential use in patients with advanced HCC

Ising-link Quantum Gravity

We define a simplified version of Regge quantum gravity where the link lengths can take on only two possible values, both always compatible with the triangle inequalities. This is therefore equivalent to a model of Ising spins living on the links of a regular lattice with somewhat complicated, yet local interactions. The measure corresponds to the natural sum over all 2^links configurations, and numerical simulations can be efficiently implemented by means of look-up tables. In three dimensions we find a peak in the ``curvature susceptibility'' which grows with increasing system size. However, the value of the corresponding critical exponent as well as the behavior of the curvature at the transition differ from that found by Hamber and Williams for the Regge theory with continuously varying link lengths.Comment: 11 page

Ap39, a mitochondria-targeting hydrogen sulfide (H2 s) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling

Background and Purpose H2S protects myocardium against ischaemia-reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of mitochondria-specific H2S donor, AP39, at reperfusion against ischaemia/reperfusion injury. Experimental Approach Anaesthetised rats underwent myocardial (30 min ischaemia/120 min reperfusion) with randomisation to receive interventions prior to reperfusion: vehicle, AP39 (0.01, 0.1, 1 µmol kg-1), or the control compounds AP219 or ADT-OH (1 µmol kg-1). LY294002, L-NAME or ODQ were used to interrogate the involvement of RISK pathway. Myocardial samples harvested 5 minutes after reperfusion were analysed for RISK protein phosphorylation and additional experiments were conducted on isolated cardiac mitochondria to examine the direct mitochondrial effects of AP39. Key Results AP39 exerted dose-dependent infarct size limitation. Inhibition of either PI3K/Akt, eNOS or sGC did not affect the infarct limitation of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK-3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Further, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibition of PTP. Conclusion and Implications AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. Cardioprotection could be mediated by inhibiting PTP via cyclophilin D-independent mechanism. Thus, selective delivery of H2S to mitochondria may be therapeutically applicable for harnessing the cardioprotective utility of H2S. This article is protected by copyright. All rights reserved