A MOPEVAC multivalent vaccine induces sterile protection against New World arenaviruses in non-human primates.

Pathogenic New World arenaviruses (NWAs) cause haemorrhagic fevers and can have high mortality rates, as shown in outbreaks in South America. Neutralizing antibodies (Abs) are critical for protection from NWAs. Having shown that the MOPEVAC vaccine, based on a hyperattenuated arenavirus, induces neutralizing Abs against Lassa fever, we hypothesized that expression of NWA glycoproteins in this platform might protect against NWAs. Cynomolgus monkeys immunized with MOPEVACMAC, targeting Machupo virus, prevented the lethality of this virus and induced partially NWA cross-reactive neutralizing Abs. We then developed the pentavalent MOPEVACNEW vaccine, expressing glycoproteins from all pathogenic South American NWAs. Immunization of cynomolgus monkeys with MOPEVACNEW induced neutralizing Abs against five NWAs, strong innate followed by adaptive immune responses as detected by transcriptomics and provided sterile protection against Machupo virus and the genetically distant Guanarito virus. MOPEVACNEW may thus be efficient to protect against existing and potentially emerging NWAs.

Development and validation of a new method for visual acuity assesment on tablet in pediatric population: eMOVA test.

BACKGROUND: Amblyopia is a major public health concern. Its screening and management require reliable methods of visual acuity assessment. New technologies offer nowadays many tests available on different app stores for smartphone or tablet but most of them often lack of scientific validation for a medical use. The aim of our study was to attempt validating a tablet-based near visual acuity test adapted to the pediatric population: the eMOVA test (electronic Measurement Of Visual Acuity) by comparing visual acuity measured with more conventional test. METHODS: A cohort of 100 children aged 3 to 8 attending the ophthalmic-pediatric for eye examination between September 2016 and June 2017 were included in the study. Near visual acuity was assessed on participants using both the eMOVA test and a Standard test (Rossano-Weiss test). Duration of each test, its comprehension, its acceptability and the attention of the child during the test was also investigated. RESULTS: The eMOVA test overestimated near visual acuity by 0.06 logMAR. This difference, statistically significant, was not clinically relevant. The duration of the eMOVA test was longer than the reference test, but less discomfort and preferred by children and their parents compared to standard tests. CONCLUSION: The eMOVA test appears as a reliable test to assess near visual acuity in children. By its portability and efficiency, this application proved to be a relevant tool to be used for children eye examination in daily routine at the hospital.

A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains.

A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.

A new visual acuity test on touchpad for vision screening in children.

AIM: To validate a visual acuity (VA) test application on touchpad in the screening of pediatric population by comparing VA results obtained with conventional tests. METHODS: A cohort of 101 patients, 44 girls and 57 boys with a median of 6.5 years old (3-10 years of age), presenting for eye examinations in Ophthalmology Department (Strasbourg, France) between November 1st, 2018, and February 1st, 2019 were enrolled. Monocular and binocular VA testing was performed on the subject using both a standard test and the touchpad application (Monoyer, "E" or, Pigassou depending of children's capacities). Patients were excluded if they were physically or mentally unable to use the touchpad. The duration of each tests, the painfulness, the comprehension, the attention of children during the test and test's preferences were also evaluated. RESULTS: There was a good linear correlation and intra-class correlation coefficient [ICC=0.50 (0.34, 0.64) for binocular acuity, 0.74 (0.64, 0.82) for right eyes and 0.525 (0.37, 0.66) for left eye]. The standard errors of measurement were very low (0.08, 0.05, 0.08 for binocular VA, right eyes VA and left eyes VA, respectively). There was no difference between two tests for right eye (P=0.126), left eye (P=0.098) and binocular acuity (P=0.085). Non inferiority was proved for all binocular [-0.06 (-0.09, -0.03)], right eye [-0.04 (-0.07, -0.01)] and left eye [-0.06 (-0.09, -0.02)] VA. The sensitivity and specificity, which correspond to the ability for our app to detect amblyopia, were 92% and 80% respectively. CONCLUSION: Our touchpad application represents an efficient and valid test of VA in children with a high specificity to detect visual impairment.

ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice.

The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimer's disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.

Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze.

Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with sham-operated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21 h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal-dependent memory.

Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice.

G protein-coupled receptor (GPCR) associated sorting protein 1 (GASP-1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP-1 has been shown to regulate dopamine (D(2)) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP-1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP-1 knockout (KO) mice and have examined the consequences of the absence of GASP-1 on chronic cocaine treatments. GASP-1 KO and wild-type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self-administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self-administration. Acute and sensitized cocaine-locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self-administration was also observed in GASP-1-deficient mice, which was associated with pronounced down-regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP-1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP-1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP-1 stimulates recycling rather than receptor degradation.

Coexisting cholinergic and parahippocampal degeneration: a key to memory loss in dementia and a challenge for transgenic models?

One century after Alzheimer's initial report, a variety of animal models of Alzheimer's disease (AD) are being used to mimic one or more pathological signs viewed as critical for the evolution of cognitive decline in dementia. Among the most common are, (a) traditional lesion models aimed at reproducing the degeneration of one of two key brain regions affected in AD, namely the cholinergic basal forebrain (CBF) and the transentorhinal region, and (b) transgenic mouse models aimed at reproducing AD histopathological hallmarks, namely amyloid plaques and neurofibrillary tangles. These models have provided valuable insights into the development and consequences of the pathology, but they have not consistently reproduced the severity of memory deficits exhibited in AD. The reasons for this lack of correspondence with the severity of expected deficits may include the limited replication of multiple neuropathology in potentially key brain regions. A recent lesion model in the rat found that severe memory impairment was obtained only when the two traditional lesions were combined together (i.e. conjoint CBF and entorhinal cortex lesions), indicative of a dramatic impact on cognitive function when there is coexisting, rather than isolated, damage in these two brain regions. It is proposed that combining AD transgenic mouse models with additional experimental damage to both the CBF and entorhinal regions might provide a unique opportunity to further understand the evolution of the disease and improve treatments of severe cognitive dysfunction in neurodegenerative dementias.

Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.

Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.

Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice.

The selective lesion of basal forebrain cholinergic neurons (BFCNs) is an unestimable tool to study the implication of these neurons in cognition, an interest widely motivated by their degeneration in Alzheimer's disease. Here we evaluated the histochemical and behavioral effects of a selective lesion of BFCNs in C57BL/6J mice treated intracerebroventricularly (ICV) with a novel version of the immunotoxin mu p75-saporin (0.4 mug/mouse). There was a 100% postsurgical survival rate, no abnormal loss of weight, no disruption of sensorimotor coordination, and no noncognitive bias in a water-maze test. This immunotoxin induced a loss of choline acetyltransferase-positive neurons in the medial septum (-82%) and in the nucleus basalis (-55%). Preserved parvalbumine-immunostaining suggests that the lesion was specific to BFCNs. Septo-hippocampal and basalo-cortical projections of BFCNs degenerated as suggested by massive loss of acetylcholinesterase-positive staining in the hippocampus and the cortical mantle. Moreover, anticalbindin immunostaining showed no damage to cerebellar Purkinje cells. Lesioned mice displayed increased diurnal and nocturnal locomotor activity. Their spatial learning/memory performances in a water maze and in a Barnes maze were significantly impaired: learning was substantially slowed down, although not obliterated, and memory retention was altered. These behavioral consequences are comparable, with fewer side effects, to those reported after ICV 192 IgG-saporin in rats. In conclusion, the new version of mu p75-saporin provides a safe and powerful tool for BFCN lesion in mice.