Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones

In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression.     

Acoustic signals of baby black caimans

In spite of the importance of crocodilian vocalizations for the understanding of the evolution of sound communication in Archosauria and due to the small number of experimental investigations, information concerning the vocal world of crocodilians is limited. By studying black caimans Melanosuchus niger in their natural habitat, here we supply the experimental evidence that juvenile crocodilians can use a graded sound system in order to elicit adapted behavioral responses from their mother and siblings. By analyzing the acoustic structure of calls emitted in two different situations (‘undisturbed context’, during which spontaneous calls of juvenile caimans were recorded without perturbing the group, and a simulated ‘predator attack’, during which calls were recorded while shaking juveniles) and by testing their biological relevance through playback experiments, we reveal the existence of two functionally different types of juvenile calls that produce a different response from the mother and other siblings. Young black caimans can thus modulate the structure of their vocalizations along an acoustic continuum as a function of the emission context. Playback experiments show that both mother and juveniles discriminate between these ‘distress’ and ‘contact’ calls. Acoustic communication is thus an important component mediating relationships within family groups in caimans as it is in birds, their archosaurian relatives. Although probably limited, the vocal repertoire of young crocodilians is capable of transmitting the information necessary for allowing siblings and mother to modulate their behavior.     

One operational definition by population: the need for local evaluations of frailty

Frailty is a health problem that increases the probability of developing adverse health outcomes in the elderly. A frequently used way to operationalize frailty is the construction of a frailty index, which is built from the addition of several health deficits that describe biological aging. However, there is no consensus about the number of health deficits for building a frailty index and about which deficits must be chosen. This lack of a standardized frailty index is assumed to be an obstacle for the advancement of research on frailty. The focus of the present article is to propose a theoretically plausible alternative way of operationalizing frailty by means of frailty indexes composed of deficits selected at a local level. These deficits would therefore be different for each given population. This "anthropological approach" is on the opposite side from current trends in frailty research, which is characterized by the search for a standardized operational definition of frailty. The anthropological approach would generate more reliable data by taking into account the specificity of the population to be studied for selecting frailty deficits. In this approach, emotions, motives, and beliefs are as important to determine individuals' health vulnerability as chronic diseases and physical function. Physiological anthropologists are well positioned to contribute to research on frailty by carrying out studies on the selection of the best deficits to operationalize frailty in different populations, with different socio-cultural determinants of health, and living in different environmental life spaces.     

High-pressure analysis of a hammerhead ribozyme from Chrysanthemum chlorotic mottle viroid reveals two different populations of self-cleaving molecule

The activity of the full-length hammerhead ribozyme requires a tertiary interaction between its distal loops leading to the closure of the molecule and its stabilization in the active conformation. In this study, the conformational changes accompanying the cis-cleavage reaction of Chrysanthemum chlorotic mottle viroid hammerhead ribozyme were investigated by high-pressure experiments on the complete cleavage reaction. Two activation volumes (ΔV(≠)) were measured, pointing to the presence of two different populations of molecules corresponding to fast-cleaving and slow-cleaving ribozymes in the reaction mixture. The fast population, with a small ΔV(≠) of 2.6 mL·mol(-1), most likely represents molecules in the near-active conformation, whereas the slow population, with a larger ΔV(≠) of 11.6 mL·mol(-1 , represents molecules that need a larger conformational change to induce activity. In addition, pH-dependence experiments suggest that the group whose deprotonation is required for activity intervenes in the formation of the transition state or in the chemistry of the reaction, but not in the conformational change that precedes it.     

MRI Findings in 77 Children with Non-Syndromic Autistic Disorder

Background

The clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000 [1]. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences.

Methodology

MRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4±3.6) was performed. All met the DSM-IV and ADI –R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0±4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable.

Principal Findings

MRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow–Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients).

Conclusions

An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism.     

ARCHIPELAGO: a dedicated resource for exploiting past, present, and future genomic data on disease resistance regulation in rice

Large amounts of expression data dealing with biotic stresses in rice have been produced in the past 5 years. Here, we extensively review approximately 70 publications and gather together information on more than 2,500 genes of the rice defense arsenal. This information was integrated into the OryGenesDB database. Several genes (e.g., metallothioneins and PBZ1) appear to be hallmarks of rice-pathogen interactions. Cross-referencing this information with the rice kinome highlighted some defense genes and kinases as possible central nodes of regulation. Cross referencing defense gene expression and quantitative trait loci (QTL) information identified some candidate genes for QTL. Overall, pathogenesis-related genes and disease regulators were found to be statistically associated with disease QTL. At the genomic level, we observed that some regions are richer than others and that some chromosomes (e.g., 11 and 12), which contain a lot of resistance gene analogs, have a low content of defense genes. Finally, we show that classical defense genes and defense-related genes such as resistance genes are preferentially organized in clusters. These clusters are not always coregulated and individual paralogs can show specific expression patterns. Thus, the rice defense arsenal has an ARCHIPELAGO-like genome structure at the macro and micro level. This resource opens new possibilities for marker-assisted selection and QTL cloning.     

Crocodile egg sounds signal hatching time

Crocodilians are known to vocalize within the egg shortly before hatching [1,2]. Although a possible function of these calls - inducing hatching in siblings and stimulating the adult female to open the nest - has already been suggested, it has never been experimentally tested [1-5]. Here, we present the first experimental evidence that pre-hatching calls of Nile crocodile (Crocodylus niloticus) juveniles are informative acoustic signals which indeed target both siblings and mother.     

Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochrome c-Mediated Apoptosis Independently of Fas Signaling

Apoptosis of CD4(+) T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4(+) T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4(+) T-cell depletion in AIDS.     

Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: design, synthesis and structure-activity relationship studies

The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.     

A dual role of the GTPase Rac in cardiac differentiation of stem cells

The function of the GTPase Rac1, a molecular switch transducing intracellular signals from growth factors, in differentiation of a specific cell type during early embryogenesis has not been investigated. To address the question, we used embryonic stem (ES) cells differentiated into cardiomyocytes, a model that faithfully recapitulates early stages of cardiogenesis. Overexpression in ES cells of a constitutively active Rac (RacV12) but not of an active mutant (RacL61D38), which does not activate the NADPH oxydase generating ROS, prevented MEF2C expression and severely compromised cardiac cell differentiation. This resulted in poor expression of ventricular myosin light chain 2 (MLC2v) and its lack of insertion into sarcomeres. Thus ES-derived cardiomyocytes featured impaired myofibrillogenesis and contractility. Overexpression of MEF2C or addition of catalase in the culture medium rescued the phenotype of racV12 cells. In contrast, RacV12 specifically expressed in ES-derived ventricular cells improved the propensity of cardioblasts to differentiate into beating cardiomyocytes. This was attributed to both a facilitation of myofibrillogenesis and a prolongation in their proliferation. The dominant negative mutant RacN17 early or lately expressed in ES-derived cells prevented myofibrillogenesis and in turn beating of cardiomyocytes. We thus suggest a stage-dependent function of the GTPase during early embryogenesis.