Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits

Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have shown a role for this molecule and its LPA₁ receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA₁ receptor is involved in behavior. In this study, we studied the phenotype of maLPA₁-null mice, which bear a targeted deletion at the lpa ₁ locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA₁-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor co-ordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes and co-ordinated limb use. At behavioral level, maLPA₁-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA₁ receptor may play a major role in both spatial memory and response to anxiety-like conditions.     

Ecohydrology of a seasonal wetland in the Rift Valley: ecological characterization of Lake Solai

The following research describes through an ecohydrological approach, the first assessment of the ecology of Lake Solai, with a particular emphasis on the vegetation. Lake Solai is located 50 km north of Nakuru in the Rift Valley in Kenya at E36°80'–36°84' to N00°05'–00°08'. It is a shallow lake that follows a very peculiar seasonal water regime, and that faces conflicts between agriculture and conservation water users. In the upper catchment, an overview of the agricultural practices was implemented and river water uses were identified to assess river flows. Crops/grassland and woodland/shrubland were the major land uses, covering c. 65% of the catchment. Closer to the lake, vegetation samples were collected around the lake together with samples of environmental factors such as soil and water quality. Thirteen vegetation communities were identified within four main zonations: forest, grassland, river inlet and rocky outcrop. These communities showed abundance, distribution and diversity determined mostly by the human pressures, the flooding periods and the salinity. Cynodon , Cyperus and Sporobolus genera were the most abundant.     

Immune Regulatory Neural Stem/Precursor Cells Protect from Central Nervous System Autoimmunity by Restraining Dendritic Cell Function

Background

The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.

Methodology/Principal Findings

To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific–BMP-4-dependent–mechanism hindering the DC maturation.

Conclusion/Significance

The study described herein, identifies the first member of the TGF β/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.     

Stereospecific synthesis of "para-hydroxymexiletine" and sodium channel blocking activity evaluation

Both enantiomers of "para-hydroxymexiletine" (PHM), one of the main metabolites of mexiletine, were synthesized and fully characterized. Properties of (R)- and (S)-PHM, in terms of blocking potency and stereoselectivity on frog skeletal muscle Na(+) channels, were evaluated. The presence of a hydroxy group on the aryloxy moiety in the 4-position, as in PHM, reduced potency with respect to mexiletine in reducing I(Na max). However, PHM showed clear use-dependent behavior similar to that of mexiletine and, in contrast with what is observed with the parent compound, maintained its stereoselectivity during the use-dependent block. Chirality 16:72-78, 2004.     

Synthesis and antiviral evaluation of benzimidazoles, quinoxalines and indoles from dehydroabietic acid

Several heterocycles, such as benzimidazoles, quinoxalines and indoles incorporated into a hydrophenanthrene and naphthalene skeleton, were synthesised from two useful ortho-bromonitro precursors derived from dehydroabietic acid: methyl 12-bromo-13-nitro-deisopropyldehydroabietate and methyl 12-bromo-13,14-dinitro-deisopropyldehydroabietate. The new heterocycles were evaluated for their activity in vitro against several RNA and DNA viruses.     

Alkaloids of Antizoma angustifolia (Menispermaceae)

The main alkaloids in leaves, stems and rhizomes of Antizoma angustifolia, a traditional medicinal plant of the family Menispermaceae, were isolated and identified. The main compound in leaves is almost invariably crotsparine, while stems and rhizomes have several other alkaloids (glaziovine, pronuciferine, bulbocapnine, salutaridine, cissacapine, insularine) in lower yields. These results do not agree with a previous study, where salutaridine was identified as the main alkaloid. Salutaridine was detected as a minor constituent of the rhizomes of only one of the samples. Alkaloids appear to be quite variable within different plant parts and different provenances of A. angustifolia, a fact that may explain the apparent absence of salutaridine in our samples.     

The hair follicle: a paradoxical androgen target organ

Androgens are the main regulator of normal human hair growth. After puberty, they promote transformation of vellus follicles, producing tiny, unpigmented hairs, to terminal ones, forming larger pigmented hairs, in many areas, e.g. the axilla. However, they have no apparent effect on the eyelashes, but can cause the opposite transformation on the scalp leading to the replacement of terminal hairs by vellus ones and the gradual onset of androgenetic alopecia. This paradox appears to be an unique hormonal effect. Hair follicles are mainly epithelial tissues, continuous with the epidermis, which project into the dermis. A mesenchyme-derived dermal papilla enclosed within the hair bulb at the base controls many aspects of follicle function. In the current hypothesis for androgen regulation, the dermal papilla is also considered the main site of androgen action with androgens from the blood binding to receptors in dermal papilla cells of androgen-sensitive follicles and causing an alteration of their production of paracrine factors for target cells e.g. keratinocytes. Studies of cultured dermal papilla cells from sites with different responses to androgens in vivo have confirmed the paradoxical responses. All dermal papilla cells from androgen-sensitive sites contain low capacity, high affinity androgen receptors. However, only some cells formed 5alpha-dihydrotestosterone, e.g. beard but not axillary cells, in line with hair growth in 5alpha-reductase deficiency. Incubation with androgens also stimulated the mitogenic capacity of beard cell media, but inhibited that produced by scalp cells. This suggests that the paradoxical differences are due to differential gene expression within hair follicles, presumably caused during embryogenesis.     

Phylogenetics of Asphodelaceae (Asparagales): An Analysis of Plastid rbcL and trnL-F DNA Sequences

Phylogenetic relationships of Asphodelaceae were investigatedby parsimony analysis of 57 monocotrbcL nucleotide sequences,including 17 genera that have at some time been assigned tothe family. All genera of Asphodelaceae except for three (Hemiphylacus,Paradisea and Simethis) form a strongly supported monophyleticgroup with Hemerocallidaceae and Xanthorrhoeaceae as their immediatesister taxa. In a second analysis, we added 34 plastid trnL-Fsequences (an intron and a spacer between two transfer RNA genes)for the Asphodelaceae clade and nearest outgroup families (Doryanthaceae,Hemerocallidaceae, Iridaceae, Ixioliriaceae, Tecophilaeaceaeand Xanthorrhoeaceae) in an attempt to improve resolution andlevels of internal support. The results from the separate analysesproduced highly similar although not identical results. No stronglysupported incongruent groups occurred, and we combined bothsequence regions in one analysis, which demonstrated improvedresults. Strong support exists for a monophyletic subfamilyAlooideae, but this leaves a paraphyletic subfamily Asphodeloideaebecause Bulbine/Jodrellia alone are strongly supported as thesister group of Alooideae. Characters that have been used toseparate Alooideae as a distinct group (either as here a subfamilyor as a separate family by other authors), such as secondarygrowth and bimodal karyotypes, are found in at least some membersof Asphodeloideae, particularly in Bulbine and Jodrellia forthe karyotypes, making Alooideae less easily recognized. Copyright2000 Annals of Botany Company Alooideae, Asphodeloideae, Asphodelaceae, Asparagales, phylogenetic analysis, rbcL, trnL-F, molecular systematics     

Notch signaling regulates the pattern of auditory hair cell differentiation in mammals

The development of the mammalian cochlea is an example of patterning in the peripheral nervous system. Sensory hair cells and supporting cells in the cochlea differentiate via regional and cell fate specification. The Notch signaling components shows both distinct and overlapping expression patterns of Notch1 receptor and its ligands Jagged1 (Jag1) and Jagged2 (Jag2) in the developing auditory epithelium of the rat. On embryonic day 16 (E16), many precursor cells within the K?lliker's organ immunostained for the presence of both Notch1 and Jag1, while the area of hair cell precursors did not express either Notch1 and Jag1. During initial events of hair cell differentiation between E18 and birth, Notch1 and Jag1 expression predominated in supporting cells and Jag2 in nascent hair cells. Early after birth, Jag2 expression decreased in hair cells while the pattern of Notch1 expression now included both supporting cells and hair cells. We show that the normal pattern of hair cell differentiation is disrupted by alteration of Notch signaling. A decrease of either Notch1 or Jag1 expression by antisense oligonucleotides in cultures of the developing sensory epithelium resulted in an increase in the number of hair cells. Our data suggest that the Notch1 signaling pathway is involved in a complex interplay between the consequences of different ligand-Notch1 combinations during cochlear morphogenesis and the phases of hair cell differentiation.