Combined visual and motor disorganization in patients with schizophrenia

Cognitive impairments are difficult to relate to clinical symptoms in schizophrenia, partly due to insufficient knowledge on how cognitive impairments interact with one another. Here, we devised a new sequential pointing task requiring both visual organization and motor sequencing. Six circles were presented simultaneously on a touch screen around a fixation point. Participants pointed with the finger each circle one after the other, in synchrony with auditory tones. We used an alternating rhythmic 300/600 ms pattern so that participants performed pairs of taps separated by short intervals of 300 ms. Visual organization was manipulated by using line-segments that grouped the circles two by two, yielding three pairs of connected circles, and three pairs of unconnected circles that belonged to different pairs. This led to three experimental conditions. In the “congruent condition,” the pairs of taps had to be executed on circles grouped by connecters. In the “non congruent condition,” they were to be executed on the unconnected circles that belonged to different pairs. In a neutral condition, there were no connecters. Twenty two patients with schizophrenia with mild symptoms and 22 control participants performed a series of 30 taps in each condition. Tap pairs were counted as errors when the produced rhythm was inverted (expected rhythm 600/300 = 2; inversed rhythm <1). Error rates in patients with a high level of clinical disorganization were significantly higher in the non-congruent condition than in the two other conditions, contrary to controls and the remaining patients. The tap-tone asynchrony increased in the presence of connecters in both patient groups, but not in the controls. Patients appeared not to integrate the visual organization during the planning phase of action, leading to a large difficulty during motor execution, especially in those patients revealing difficulties in visual organization. Visual motor tapping tasks may help detect those subgroups of patients

Motor Agency: A New and Highly Sensitive Measure to Reveal Agency Disturbances in Early Psychosis

Background: Early diagnosis of young adults at risk of schizophrenia is essential for preventive approaches of the illness. Nevertheless, classic screening instruments are difficult to use because of the non-specific nature of the signs at this preonset phase of illness. The objective of the present contribution was to propose an innovating test that can probe the more specific symptom of psychosis, i.e., the sense of agency, which is defined as being the immediate experience of oneself as the cause of an action. More specifically, we tested whether motor agency is abnormal in early psychosis. Methods: Thirty-two young symptomatic patients and their age-matched controls participated in the study. 15 of these patients were at ultra high-risk for developing psychosis (UHR), and 17 patients were suffering from first-episode psychosis (FEP). Patients ’ neurocognitive capacities were assessed through the use of seven neuropsychological tests. A motor agency task was also introduced to obtain an objective indicator of the degree of sense of agency, by contrasting force levels applied during other and self-produced collisions between a hand-held objet and a pendulum. Results: As reported in the literature for adult controls, healthy adolescents used more efficient force levels in self than in other-imposed collisions. For both UHR and FEP patients, abnormally high levels of grip force were used for self-produced collisions, leading to an absence of difference between self and other. The normalized results revealed that motor agency differentiated patients from controls with a higher level of sensitivity than the more classic neuropsychological test battery

Grip Force Reveals the Context Sensitivity of Language-Induced Motor Activity during “Action Words

Studies demonstrating the involvement of motor brain structures in language processing typically focus on \ud time windows beyond the latencies of lexical-semantic access. Consequently, such studies remain inconclusive regarding whether motor brain structures are recruited directly in language processing or through post-linguistic conceptual imagery. In the present study, we introduce a grip-force sensor that allows online measurements of language-induced motor activity during sentence listening. We use this tool to investigate whether language-induced motor activity remains constant or is modulated in negative, as opposed to affirmative, linguistic contexts. Our findings demonstrate that this simple experimental paradigm can be used to study the online crosstalk between language and the motor systems in an ecological and economical manner. Our data further confirm that the motor brain structures that can be called upon during action word processing are not mandatorily involved; the crosstalk is asymmetrically\ud governed by the linguistic context and not vice versa

Functional Interaction between Type III-Secreted Protein IncA of Chlamydophila psittaci and Human G3BP1

Chlamydophila (Cp.) psittaci, the causative agent of psittacosis in birds and humans, is the most important zoonotic pathogen of the family Chlamydiaceae. These obligate intracellular bacteria are distinguished by a unique biphasic developmental cycle, which includes proliferation in a membrane-bound compartment termed inclusion. All Chlamydiaceae spp. possess a coding capacity for core components of a Type III secretion apparatus, which mediates specific delivery of anti-host effector proteins either into the chlamydial inclusion membrane or into the cytoplasm of target eukaryotic cells. Here we describe the interaction between Type III-secreted protein IncA of Cp. psittaci and host protein G3BP1 in a yeast two-hybrid system. In GST-pull down and co-immunoprecipitation experiments both in vitro and in vivo interaction between full-length IncA and G3BP1 were shown. Using fluorescence microscopy, the localization of G3BP1 near the inclusion membrane of Cp. psittaci-infected Hep-2 cells was demonstrated. Notably, infection of Hep-2 cells with Cp. psittaci and overexpression of IncA in HEK293 cells led to a decrease in c-Myc protein concentration. This effect could be ascribed to the interaction between IncA and G3BP1 since overexpression of an IncA mutant construct disabled to interact with G3BP1 failed to reduce c-Myc concentration. We hypothesize that lowering the host cell c-Myc protein concentration may be part of a strategy employed by Cp. psittaci to avoid apoptosis and scale down host cell proliferation

Intracellular Bacteria Encode Inhibitory SNARE-Like Proteins

Pathogens use diverse molecular machines to penetrate host cells and manipulate intracellular vesicular trafficking. Viruses employ glycoproteins, functionally and structurally similar to the SNARE proteins, to induce eukaryotic membrane fusion. Intracellular pathogens, on the other hand, need to block fusion of their infectious phagosomes with various endocytic compartments to escape from the degradative pathway. The molecular details concerning the mechanisms underlying this process are lacking. Using both an in vitro liposome fusion assay and a cellular assay, we showed that SNARE-like bacterial proteins block membrane fusion in eukaryotic cells by directly inhibiting SNARE-mediated membrane fusion. More specifically, we showed that IncA and IcmG/DotF, two SNARE-like proteins respectively expressed by Chlamydia and Legionella, inhibit the endocytic SNARE machinery. Furthermore, we identified that the SNARE-like motif present in these bacterial proteins encodes the inhibitory function. This finding suggests that SNARE-like motifs are capable of specifically manipulating membrane fusion in a wide variety of biological environments. Ultimately, this motif may have been selected during evolution because it is an efficient structural motif for modifying eukaryotic membrane fusion and thus contribute to pathogen survival

SNARE Protein Mimicry by an Intracellular Bacterium

Many intracellular pathogens rely on host cell membrane compartments for their survival. The strategies they have developed to subvert intracellular trafficking are often unknown, and SNARE proteins, which are essential for membrane fusion, are possible targets. The obligate intracellular bacteria Chlamydia replicate within an intracellular vacuole, termed an inclusion. A large family of bacterial proteins is inserted in the inclusion membrane, and the role of these inclusion proteins is mostly unknown. Here we identify SNARE-like motifs in the inclusion protein IncA, which are conserved among most Chlamydia species. We show that IncA can bind directly to several host SNARE proteins. A subset of SNAREs is specifically recruited to the immediate vicinity of the inclusion membrane, and their accumulation is reduced around inclusions that lack IncA, demonstrating that IncA plays a predominant role in SNARE recruitment. However, interaction with the SNARE machinery is probably not restricted to IncA as at least another inclusion protein shows similarities with SNARE motifs and can interact with SNAREs. We modelled IncA's association with host SNAREs. The analysis of intermolecular contacts showed that the IncA SNARE-like motif can make specific interactions with host SNARE motifs similar to those found in a bona fide SNARE complex. Moreover, point mutations in the central layer of IncA SNARE-like motifs resulted in the loss of binding to host SNAREs. Altogether, our data demonstrate for the first time mimicry of the SNARE motif by a bacterium

Temporal Information Processing in Short- and Long-Term Memory of Patients with Schizophrenia

Cognitive deficits of patients with schizophrenia have been largely recognized as core symptoms of the disorder. One neglected factor that contributes to these deficits is the comprehension of time. In the present study, we assessed temporal information processing and manipulation from short- and long-term memory in 34 patients with chronic schizophrenia and 34 matched healthy controls. On the short-term memory temporal-order reconstruction task, an incidental or intentional learning strategy was deployed. Patients showed worse overall performance than healthy controls. The intentional learning strategy led to dissociable performance improvement in both groups. Whereas healthy controls improved on a performance measure (serial organization), patients improved on an error measure (inappropriate semantic clustering) when using the intentional instead of the incidental learning strategy. On the long-term memory script-generation task, routine and non-routine events of everyday activities (e.g., buying groceries) had to be generated in either chronological or inverted temporal order. Patients were slower than controls at generating events in the chronological routine condition only. They also committed more sequencing and boundary errors in the inverted conditions. The number of irrelevant events was higher in patients in the chronological, non-routine condition. These results suggest that patients with schizophrenia imprecisely access temporal information from short- and long-term memory. In short-term memory, processing of temporal information led to a reduction in errors rather than, as was the case in healthy controls, to an improvement in temporal-order recall. When accessing temporal information from long-term memory, patients were slower and committed more sequencing, boundary, and intrusion errors. Together, these results suggest that time information can be accessed and processed only imprecisely by patients who provide evidence for impaired time comprehension. This could contribute to symptomatic cognitive deficits and strategic inefficiency in schizophrenia

Membrane curvature in cell biology: An integration of molecular mechanisms.

Curving biological membranes establishes the complex architecture of the cell and mediates membrane traffic to control flux through subcellular compartments. Common molecular mechanisms for bending membranes are evident in different cell biological contexts across eukaryotic phyla. These mechanisms can be intrinsic to the membrane bilayer (either the lipid or protein components) or can be brought about by extrinsic factors, including the cytoskeleton. Here, we review examples of membrane curvature generation in animals, fungi, and plants. We showcase the molecular mechanisms involved and how they collaborate and go on to highlight contexts of curvature that are exciting areas of future research. Lessons from how membranes are bent in yeast and mammals give hints as to the molecular mechanisms we expect to see used by plants and protists