Transient inactivation of perirhinal cortex disrupts encoding, retrieval, and consolidation of object recognition memory.

Damage to perirhinal cortex (PRh) impairs object recognition memory in humans, monkeys, and rats when tested in tasks such as delayed nonmatching to sample, visual paired comparison, and its rodent analog, the spontaneous object recognition task. In the present study, we have capitalized on the discrete one-trial nature of the spontaneous object recognition task to investigate the role of PRh in several distinct stages of object recognition memory. In a series of experiments, transient inactivation of PRh was accomplished with bilateral infusions of lidocaine directly into PRh immediately before the sample phase (encoding), immediately before the choice phase (retrieval), or within the retention delay after the sample phase (storage-consolidation). Compared with performance on trials in which they received saline infusions, rats were significantly impaired when lidocaine was infused before the sample phase, regardless of the length of the retention delay. Similarly, delay-independent deficits were observed after immediate pre-choice infusions of lidocaine. Finally, PRh inactivation immediately and 20 min after the sample phase, but not 40, 60, or 80 min after, also disrupted subsequent object recognition when the retention delay was sufficiently long to ensure the dissipation of the actions of lidocaine during the choice phase. The effects of pre-sample and pre-choice inactivation indicate involvement of PRh in encoding and retrieval stages of object recognition, and the time course of post-sample inactivation effects suggests a role for PRh in the maintenance of the object trace during memory consolidation

Glutamate receptors in perirhinal cortex mediate encoding, retrieval, and consolidation of object recognition memory.

Object recognition is consistently impaired in human amnesia and animal models thereof. Results from subjects with permanent brain damage have revealed the importance of the perirhinal cortex to object recognition memory. Here, we report evidence from rats for interdependent but distinct stages in object recognition memory (encoding, retrieval, and consolidation), which require glutamate receptor activity within perirhinal cortex. Transient blockade of AMPA receptor-mediated synaptic transmission within perirhinal cortex disrupted encoding for short- and long-term memory as well as retrieval and consolidation. In contrast, transient NMDA receptor blockade during encoding affected only long-term object recognition memory; NMDA receptor activity was also necessary for consolidation but not retrieval. These results further demonstrate the importance of perirhinal cortex for object recognition memory and suggest that, as in the hippocampus, AMPA and NMDA receptors mediate synaptic transmission and activity-dependent synaptic plasticity, respectively, in several stages of memory processing

Paradoxical facilitation of object recognition memory after infusion of scopolamine into perirhinal cortex: implications for cholinergic system function.

The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions directly before the retrieval stage had no discernible effect on object recognition. However, postsample infusions of scopolamine with sample-to-infusion delays of up to 20 h significantly facilitated performance relative to postsample saline infusion trials. Additional analysis suggested that the infusion episode could cause retroactive or proactive interference with the sample object trace and that scopolamine blocked the acquisition of this interfering information, thereby facilitating recognition memory. This is, to our knowledge, the first example of improved recognition memory after administration of scopolamine. The overall pattern of results is inconsistent with a direct role for cortical acetylcholine in declarative memory consolidation or retrieval. Rather, the cholinergic input to the perirhinal cortex may facilitate acquisition by enhancing the cortical processing of incoming stimulus information

Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe.

It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri-postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe

Dissociable cognitive impairments in two strains of transgenic Alzheimer\u27s disease mice revealed by a battery of object-based tests

Object recognition tasks detect cognitive deficits in transgenic Alzheimer\u27s disease (AD) mouse models. Object recognition, however, is not a unitary process, and there are many uncharacterized facets of object processing with relevance to AD. We therefore systematically evaluated object processing in 5xFAD and 3xTG AD mice to clarify the nature of object recognition-related deficits. Twelve-month-old male and female 5xFAD and 3xTG mice were assessed on tasks for object identity recognition, spatial recognition, and multisensory object perception. Memory and multisensory perceptual impairments were observed, with interesting dissociations between transgenic AD strains and sex that paralleled neuropathological changes. Overreliance on the widespread object recognition task threatens to slow discovery of potentially significant and clinically relevant behavioural effects related to this multifaceted cognitive function. The current results support the use of carefully designed object-based test batteries to clarify the relationship between object recognition impairments and specific aspects of AD pathology in rodent models

Surveying the Agents of Galaxy Evolution in the Tidally-Stripped, Low Metallicity Small Magellanic Cloud (SAGE-SMC) II. Cool Evolved Stars

We investigate the infrared (IR) properties of cool, evolved stars in the Small Magellanic Cloud (SMC), including the red giant branch (RGB) stars and the dust-producing red supergiant (RSG) and asymptotic giant branch (AGB) stars using observations from the Spitzer Space Telescope Legacy program entitled: "Surveying the Agents of Galaxy Evolution in the Tidally-stripped, Low Metallicity SMC", or SAGE-SMC. The survey includes, for the first time, full spatial coverage of the SMC bar, wing, and tail regions at infrared (IR) wavelengths (3.6 - 160 microns). We identify evolved stars using a combination of near-IR and mid-IR photometry and point out a new feature in the mid-IR color-magnitude diagram that may be due to particularly dusty O-rich AGB stars. We find that the RSG and AGB stars each contribute ~20% of the global SMC flux (extended + point-source) at 3.6 microns, which emphasizes the importance of both stellar types to the integrated flux of distant metal-poor galaxies. The equivalent SAGE survey of the higher-metallicity Large Magellanic Cloud (SAGE-LMC) allows us to explore the influence of metallicity on dust production. We find that the SMC RSG stars are less likely to produce a large amount of dust (as indicated by the [3.6]-[8] color). There is a higher fraction of carbon-rich stars in the SMC, and these stars appear to able to reach colors as red as their LMC counterparts, indicating that C-rich dust forms efficiently in both galaxies. A preliminary estimate of the dust production in AGB and RSG stars reveals that the extreme C-rich AGB stars dominate the dust input in both galaxies, and that the O-rich stars may play a larger role in the LMC than in the SMC.Comment: Accepted for publication in AJ. 25 pages, 36 figures, Table 4 will be available electronically from A

K70Q Adds High-Level Tenofovir Resistance to “Q151M Complex” HIV Reverse Transcriptase through the Enhanced Discrimination Mechanism

HIV-1 carrying the “Q151M complex” reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations

Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors

<p>Abstract</p> <p>Background</p> <p>XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.</p> <p>Results</p> <p>We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy <it>in vitro</it>. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC₅₀values in the nanomolar range.</p> <p>Conclusions</p> <p>Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.</p

An Overview of the Management of Flexor Tendon Injuries

Flexor tendon injuries still remain a challenging condition to manage to ensure optimal outcome for the patient. Since the first flexor tendon repair was described by Kirchmayr in 1917, several approaches to flexor tendon injury have enabled successful repairs rates of 70-90%. Primary surgical repair results in better functional outcome compared to secondary repair or tendon graft surgery. Flexor tendon injury repair has been extensively researched and the literature demonstrates successful repair requires minimal gapping at the repair site or interference with tendon vascularity, secure suture knots, smooth junction of tendon end and having sufficient strength for healing. However, the exact surgical approach to achieve success being currently used among surgeons is still controversial. Therefore, this review aims to discuss the results of studies demonstrating the current knowledge regarding the optimal approach for flexor tendon repair. Post-operative rehabilitation for flexor tendon surgery is another area, which has caused extensive debate in hand surgery. The trend to more active mobilisation protocols seems to be favoured but further study in this area is needed to find the protocol, which achieves function and gliding but avoids rupture of the tendons. Lastly despite success following surgery complications commonly still occur post surgery, including adhesion formation, tendon rupture and stiffness of the joints. Therefore, this review aims to discuss the appropriate management of these difficulties post surgery. New techniques in management of flexor tendon will also be discussed including external laser devices, addition of growth factors and cytokines

Production of dust by massive stars at high redshift

The large amounts of dust detected in sub-millimeter galaxies and quasars at high redshift pose a challenge to galaxy formation models and theories of cosmic dust formation. At z > 6 only stars of relatively high mass (> 3 Msun) are sufficiently short-lived to be potential stellar sources of dust. This review is devoted to identifying and quantifying the most important stellar channels of rapid dust formation. We ascertain the dust production efficiency of stars in the mass range 3-40 Msun using both observed and theoretical dust yields of evolved massive stars and supernovae (SNe) and provide analytical expressions for the dust production efficiencies in various scenarios. We also address the strong sensitivity of the total dust productivity to the initial mass function. From simple considerations, we find that, in the early Universe, high-mass (> 3 Msun) asymptotic giant branch stars can only be dominant dust producers if SNe generate <~ 3 x 10^-3 Msun of dust whereas SNe prevail if they are more efficient. We address the challenges in inferring dust masses and star-formation rates from observations of high-redshift galaxies. We conclude that significant SN dust production at high redshift is likely required to reproduce current dust mass estimates, possibly coupled with rapid dust grain growth in the interstellar medium.Comment: 72 pages, 9 figures, 5 tables; to be published in The Astronomy and Astrophysics Revie