Spontaneously emerging internal models of visual sequences combine abstract and event-specific information in the prefrontal cortex.

When exposed to sensory sequences, do macaque monkeys spontaneously form abstract internal models that generalize to novel experiences? Here, we show that neuronal populations in macaque ventrolateral prefrontal cortex jointly encode visual sequences by separate codes for the specific pictures presented and for their abstract sequential structure. We recorded prefrontal neurons while macaque monkeys passively viewed visual sequences and sequence mismatches in the local-global paradigm. Even without any overt task or response requirements, prefrontal populations spontaneously form representations of sequence structure, serial order, and image identity within distinct but superimposed neuronal subspaces.

Decoding rapidly presented visual stimuli from prefrontal ensembles without report nor post-perceptual processing.

The role of the primate prefrontal cortex (PFC) in conscious perception is debated. The global neuronal workspace theory of consciousness predicts that PFC neurons should contain a detailed code of the current conscious contents. Previous research showed that PFC is indeed activated in paradigms of conscious visual perception, including no-report paradigms where no voluntary behavioral report of the percept is given, thus avoiding a conflation of signals related to visual consciousness with signals related to the report.

Anatomo-Functional Mapping of the Primate Mesencephalic Locomotor Region Using Stereotactic Lesions.

Background: Dysfunction of the mesencephalic locomotor region has been implicated in gait disorders. However, the role of its 2 components, the pedunculopontine and the cuneiform nuclei, in locomotion is poorly understood in primates.

Objectives: To analyze the effect of cuneiform lesions on gait and balance in 2 monkeys and to compare them with those obtained after cholinergic pedunculopontine lesions in 4 monkeys and after lesions in both the cuneiform and pedunculopontine nuclei in 1 monkey.

New piperazine multi-effect drugs prevent neurofibrillary degeneration and amyloid deposition, and preserve memory in animal models of Alzheimer's disease.

Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property.

A phenotypic approach to the discovery of compounds that promote non-amyloidogenic processing of the amyloid precursor protein: Toward a new profile of indirect β-secretase inhibitors.

Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid β peptides (Aβ) is central to Alzheimer's disease (AD) etiology. Aβ peptides are produced by sequential cleavage of APP by β-secretase (BACE-1) and γ-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Aβ peptide production.

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism.

The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease.

Perinatal Exposure to the Cyanotoxin β-N-Méthylamino-L-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring-Potential Involvement of DNA Damage and Oxidative Stress.

We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg three times a week from embryonic days 7-10 to postnatal day 21.

The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.

Herein we describe the discovery of IDX21437 35b, a novel Rd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes.

Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.

The penicillinase-resistant antibiotics (PRAs), especially the highly prescribed flucloxacillin, caused frequent liver injury via mechanisms that remain largely non-elucidated. We first showed that flucloxacillin, independently of cytotoxicity, could exhibit cholestatic effects in human hepatocytes in the absence of an immune reaction, that were typified by dilatation of bile canaliculi associated with impairment of the Rho-kinase signaling pathway and reduced bile acid efflux. Then, we analyzed the sequential molecular events involved in flucloxacillin-induced cholestasis.