Multiple controls exerted by 5-HT2C receptors upon basal ganglia function: from physiology to pathophysiology

Serotonin2C (5-HT_2C) receptors are expressed in the basal ganglia, a group of subcortical structures involved in the control of motor behaviour, mood and cognition. These receptors are mediating the effects of 5-HT throughout different brain areas via projections originating from midbrain raphe nuclei. A growing interest has been focusing on the function of 5-HT_2C receptors in the basal ganglia because they may be involved in various diseases of basal ganglia function notably those associated with chronic impairment of dopaminergic transmission. 5-HT_2C receptors act on numerous types of neurons in the basal ganglia, including dopaminergic, GABAergic, glutamatergic or cholinergic cells. Perhaps inherent to their peculiar molecular properties, the modality of controls exerted by 5-HT_2C receptors over these cell populations can be phasic, tonic (dependent on the 5-HT tone) or constitutive (a spontaneous activity without the presence of the ligand). These controls are functionally organized in the basal ganglia: they are mainly localized in the input structures and preferentially distributed in the limbic/associative territories of the basal ganglia. The nature of these controls is modified in neuropsychiatric conditions such as Parkinson’s disease, tardive dyskinesia or addiction. Most of the available data indicate that the function of 5-HT_2C receptor is enhanced in cases of chronic alterations of dopamine neurotransmission. The review illustrates that 5-HT_2C receptors play a role in maintaining continuous controls over the basal ganglia via multiple diverse actions. We will discuss their interest for treatments aimed at ameliorating current pharmacotherapies in schizophrenia, Parkinson’s disease or drugs abuse.     

Candida guilliermondii: biotechnological applications, perspectives for biological control, emerging clinical importance and recent advances in genetics

Candida guilliermondii (teleomorph Meyerozyma guilliermondii) is an ascomycetous species belonging to the Saccharomycotina CTG clade which has been studied over the last 40 years due to its biotechnological interest, biological control potential and clinical importance. Such a wide range of applications in various areas of fundamental and applied scientific research has progressively made C. guilliermondii an attractive model for exploring the potential of yeast metabolic engineering as well as for elucidating new molecular events supporting pathogenicity and antifungal resistance. All these research fields now take advantage of the establishment of a useful molecular toolbox specifically dedicated to C. guilliermondii genetics including the construction of recipient strains, the development of selectable markers and reporter genes and optimization of transformation protocols. This area of study is further supported by the availability of the complete genome sequence of the reference strain ATCC 6260 and the creation of numerous databases dedicated to gene ontology annotation (metabolic pathways, virulence, and morphogenesis). These genetic tools and genomic resources represent essential prerequisites for further successful development of C. guilliermondii research in medical mycology and in biological control by facilitating the identification of the multiple factors that contribute to its pathogenic potential. These genetic and genomic advances should also expedite future practical uses of C. guilliermondii strains of biotechnological interest by opening a window into a better understanding of the biosynthetic pathways of valuable metabolites.     

Do reading processes differ in transparent versus opaque orthographies? A study of acquired dyslexia in Welsh/English bilinguals

In English, the relationship between the written and spoken forms of words is relatively opaque, leading to proposals that skilled reading requires two procedures: (a) a sublexical grapheme/phoneme conversion process allowing the correct reading of regular words (CAT) and new or pseudowords (ZAT); (b) a lexical process necessary to read irregular words accurately (TWO) and assumed to be the dominant process for familiar words. However, it has been argued that the sublexical process may be sufficient in highly transparent languages such as Welsh. If this is the case, damage to the sublexical process may lead to more severe deficits in transparent languages due to the lack of an alternative lexical process. To test this hypothesis, we compared Welsh and English oral reading and written-word recognition and comprehension in seven bilingual stroke participants with comparably impaired pseudoword reading in English and Welsh. Performance was remarkably similar across languages. Irrespective of the language tested, words were read more accurately than pseudowords. Lexical decision and word comprehension were as accurate in Welsh and in English, and when imageability effects were present they were of a similar size in both languages. This study does not support the hypothesis that orthographic transparency determines the nature of cognitive reading processes, but rather suggests that readers develop a sight vocabulary through reading experience irrespective of orthographic transparency.     

Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B

The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg.     

Blood Pressure Variations During a Working Day at Age 28: Effects of Different Types of Work and Blood Pressure Level at Age 18

Abstract

During an ordinary work day blood pressure was self-monitored once every hour in two samples of asymptomatic nonmedicating 28-year-old men. They were selected on the basis of previous compulsory blood pressure recordings made at the age of 18 when they had been drafted for military service. Subjects in the ?original hypertensive sample” with ?strain” occupations (hectic and uncontrollable, such as waiter, driver and cook) had more marked elevations of systolic blood pressure during work hours than other subjects.     

Life Change Events,Ballistocardiography and Coronary Death

Abstract

Thirty-six men and women who experienced a documented myocardial infarction, half of whom ultimately died from their disease and half of whom survived over a six-year period, provided longitudinal recent life changes and ballistocardiographic data. The 18 patients who died from their coronary disease indicated a significant buildup in life changes which peaked approximately one year prior to death; their serial ballistocardiograms indicated a significant buildup in average force of contraction which was seen to peak approximately six months prior to death. The 18 post-infarction patients who survived the six-year follow-up showed neither a buildup in life change nor a buildup in the ballistocardiographic index of cardiac contraction force. These findings of a life change peak preceding ballistocardiographic evidence of an “overworked” heart are discussed in terms of their possible medical and psychophysiological significances.     

VEGF-A165b Is an Endogenous Neuroprotective Splice Isoform of Vascular Endothelial Growth Factor A in?Vivo and in?Vitro

Vascular endothelial growth factor (VEGF) A is generated as two isoform families by alternative RNA splicing, represented by VEGF-A₁₆₅a and VEGF-A₁₆₅b. These isoforms have opposing actions on vascular permeability, angiogenesis, and vasodilatation. The proangiogenic VEGF-A₁₆₅a isoform is neuroprotective in hippocampal, dorsal root ganglia, and retinal neurons, but its propermeability, vasodilatatory, and angiogenic properties limit its therapeutic usefulness. In contrast, a neuroprotective effect of endogenous VEGF-A₁₆₅b on neurons would be advantageous for neurodegenerative pathologies. Endogenous expression of human and rat VEGF-A₁₆₅b was detected in hippocampal and cortical neurons. VEGF-A₁₆₅b formed a significant proportion of total VEGF-A in rat brain. Recombinant human VEGF-A₁₆₅b exerted neuroprotective effects in response to multiple insults, including glutamatergic excitotoxicity in hippocampal neurons, chemotherapy-induced cytotoxicity of dorsal root ganglion neurons, and retinal ganglion cells (RGCs) in rat retinal ischemia-reperfusion injury in vivo. Neuroprotection was dependent on VEGFR2 and MEK1/2 activation but not on p38 or phosphatidylinositol 3–kinase activation. Recombinant human VEGF-A₁₆₅b is a neuroprotective agent that effectively protects both peripheral and central neurons in vivo and in vitro through VEGFR2, MEK1/2, and inhibition of caspase-3 induction. VEGF-A₁₆₅b may be therapeutically useful for pathologies that involve neuronal damage, including hippocampal neurodegeneration, glaucoma diabetic retinopathy, and peripheral neuropathy. The endogenous nature of VEGF-A₁₆₅b expression suggests that non–isoform-specific inhibition of VEGF-A (for antiangiogenic reasons) may be damaging to retinal and sensory neurons.Vascular endothelial growth factor (VEGF) A, originally described as a potent vascular permeability and growth factor for endothelial cells, is up-regulated in the brain during stroke and ischemic episodes¹ and has been linked with many neuronal diseases. The most widely studied isoform of VEGF-A, VEGF-A₁₆₅a, is up-regulated in hypoxia, induces increased vascular permeability in neuronal vasculature, and can stimulate angiogenesis after ischemic episodes. The resulting edema and hyperemia can be damaging, but VEGF-A₁₆₅a has also been found to have direct anticytotoxic effects on neurons, raising the possibility that it may act as an endogenous neuroprotective agent in neurodegenerative pathologies. VEGF-A exerts neurotrophic (survival) and neurotropic (neurogenesis and axon outgrowth) actions, which, although initially thought to be a function of increased angiogenesis and perfusion after neuronal injury,² are now appreciated as direct effects of VEGF-A on neurons.The vegfa gene encodes numerous products by differential splicing, but not all isoforms exert the same effects.³ Alternative splicing of exon 8 leads to two functionally distinct families: the proangiogenic VEGF-A_xxxa family and the counteracting VEGF-A_xxxb family.^4,5 VEGF-A₁₆₅b prevents the VEGF-A₁₆₅a effects on increased vascular permeability, blood vessel growth, and vasodilatation.^4–7The therapeutic potential of VEGF-A and anti–VEGF-A treatments are now widely recognized, and effective anti–VEGF-A treatments are available in ophthalmology⁸ and oncology.⁹ The finding that VEGF-A is implicated in neuronal disorders (eg, Alzheimer disease, Parkinson disease, Huntington disease, diabetic neuropathy, and amyotrophic lateral sclerosis¹⁰) provides a rationale for the use of VEGF-A as a therapeutic agent in neurodegenerative conditions. Although this rationale is supported by preclinical evidence,¹¹ the identification of the VEGF-A_xxxb family requires reexamination of VEGF-A isoforms in these contexts to allow for the clear evidence that VEGF-A splicing variants are not functionally equivalent³ and to determine whether augmentation of the proangiogenic isoform family (VEGF-A_xxxa) alone may have deleterious effects (eg, in occult malignancy and carcinoma in situ).The neuroprotective profile of the exon 8 alternatively spliced isoforms VEGF-A_xxxb remains unexplored. Interestingly, VEGF-A_xxxb isoforms do not exhibit the vascular effects seen with VEGF-A_xxxa isoforms, such as a sustained increase in capillary permeability or hypotension.^5,12 The lack of these potential adverse effects may make VEGF-A_xxxb isoforms more amenable as therapeutic agents in neurodegenerative diseases.We therefore tested the hypothesis that VEGF-A₁₆₅b is neuroprotective for central and peripheral neurons. We found that VEGF-A₁₆₅b is expressed in central neurons and is neuroprotective in vitro and in vivo. This finding indicates that VEGF-A₁₆₅b may prove to be a suitable therapeutic agent in neurodegenerative disorders, exhibiting fewer adverse effects than VEGF-A₁₆₅a.