The organization and development of cortical interneuron presynaptic circuits are area specific.

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

Expression of a human variant of CHMP2B linked to neurodegeneration in Drosophila external sensory organs leads to cell fate transformations associated with increased Notch activity.

Proper function of cell signaling pathways is dependent upon regulated membrane trafficking events that lead to the endocytosis, recycling, and degradation of cell surface receptors. The endosomal complexes required for transport (ESCRT) genes play a critical role in the sorting of ubiquitinated cell surface proteins. CHMP2BIntron5 , a truncated form of a human ESCRT-III protein, was discovered in a Danish family afflicted by a hereditary form of frontotemporal dementia (FTD). Although the mechanism by which the CHMP2B mutation in this family causes FTD is unknown, the resulting protein has been shown to disrupt normal endosomal-lysosomal pathway function and leads to aberrant regulation of signaling pathways. Here we have misexpressed CHMP2BIntron5 in the developing Drosophila external sensory (ES) organ lineage and demonstrate that it is capable of altering cell fates. Each of the cell fate transformations seen is compatible with an increase in Notch signaling. Furthermore, this interpretation is supported by evidence that expression of CHMP2BIntron5 in the notum environment is capable of raising the levels of Notch signaling. As such, these results add to a growing body of evidence that CHMP2BIntron5 can act rapidly to disrupt normal cellular function via the misregulation of critical cell surface receptor function.

Large-scale mouse knockouts and phenotypes.

Standardized phenotypic analysis of mutant forms of every gene in the mouse genome will provide fundamental insights into mammalian gene function and advance human and animal health. The availability of the human and mouse genome sequences, the development of embryonic stem cell mutagenesis technology, the standardization of phenotypic analysis pipelines, and the paradigm-shifting industrialization of these processes have made this a realistic and achievable goal. The size of this enterprise will require global coordination to ensure economies of scale in both the generation and primary phenotypic analysis of the mutant strains, and to minimize unnecessary duplication of effort. To provide more depth to the functional annotation of the genome, effective mechanisms will also need to be developed to disseminate the information and resources produced to the wider community. Better models of disease, potential new drug targets with novel mechanisms of action, and completely unsuspected genotype-phenotype relationships covering broad aspects of biology will become apparent. To reach these goals, solutions to challenges in mouse production and distribution, as well as development of novel, ever more powerful phenotypic analysis modalities will be necessary. It is a challenging and exciting time to work in mouse genetics.

Mouse models of ciliopathies: the state of the art.

The ciliopathies are an apparently disparate group of human diseases that all result from defects in the formation and/or function of cilia. They include disorders such as Meckel-Grüber syndrome (MKS), Joubert syndrome (JBTS), Bardet-Biedl syndrome (BBS) and Alström syndrome (ALS). Reflecting the manifold requirements for cilia in signalling, sensation and motility, different ciliopathies exhibit common elements. The mouse has been used widely as a model organism for the study of ciliopathies. Although many mutant alleles have proved lethal, continued investigations have led to the development of better models. Here, we review current mouse models of a core set of ciliopathies, their utility and future prospects.

miR-9a prevents apoptosis during wing development by repressing Drosophila LIM-only.

Loss of Drosophila mir-9a induces a subtle increase in sensory bristles, but a substantial loss of wing tissue. Here, we establish that the latter phenotype is largely due to ectopic apoptosis in the dorsal wing primordium, and we could rescue wing development in the absence of this microRNA by dorsal-specific inhibition of apoptosis. Such apoptosis was a consequence of de-repressing Drosophila LIM-only (dLMO), which encodes a transcriptional regulator of wing and neural development. We observed cell-autonomous elevation of endogenous dLMO and a GFP-dLMO 3'UTR sensor in mir-9a mutant wing clones, and heterozygosity for dLMO rescued the apoptosis and wing defects of mir-9a mutants. We also provide evidence that dLMO, in addition to senseless, contributes to the bristle defects of the mir-9a mutant. Unexpectedly, the upregulation of dLMO, loss of Cut, and adult wing margin defects seen with mir-9a mutant clones were not recapitulated by clonal loss of the miRNA biogenesis factors Dicer-1 or Pasha, even though these mutant conditions similarly de-repressed miR-9a and dLMO sensor transgenes. Therefore, the failure to observe a phenotype upon conditional knockout of a miRNA processing factor does not reliably indicate the lack of critical roles of miRNAs in a given setting.

Lethal effects of treatment with a special dimeticone formula on head lice and house crickets (Orthoptera, Ensifera: Acheta domestica and Anoplura, phthiraptera: Pediculus humanus). Insights into physical mechanisms.

The present study provides the first convincing explanation of the mode of action of the medical device NYDA, a special dimeticone (CAS 9006-65-9) formula containing 92% of two dimeticones with different viscosities specifically designed for the physical treatment of head lice infestations (pediculosis capitis) by suffocation. Both, lice (Pediculus humanus) and house crickets (Acheta domestica) treated with this anti-head lice product are knocked out to the status "of no major vital signs" within less than 1 min that in consequence is accompanied irreversibly with the death of the respective insects. Scanning electron microscopical investigations have revealed that the cuticle is coated by a thin closed layer of the dimeticone formula that also enters the stigmata. In vivo observations and dissections of Acheta domestica have shown that application of the medical device to the thoracic stigmata invariably leads to rapid death; this is strongly correlated with the influx of the special dimeticone formula into the head trachea, whereby the solution effectively blocks the oxygen supply of the central nervous system. Dissections after application of the stained product show that it also enters the finest tracheal branches. Analogous in vivo observations in Pediculus humanus have confirmed the correlation between the disappearance of major vital signs and the displacement of air by the dimeticone formula in the tracheal system of the head. For both insect species, statistical data are provided for the chronological sequence of the filling of the tracheal system in relation to the respective vitality conditions of the Insects. On average, the special dimeticone formula reaches the insect's head tracheae within 0.5 min in house crickets and in less than 1 min in lice with a complete filling of the entire head tracheal system of lice within 3.5 min. In addition, a timed sequence of images illustrates this process for lice. The experiments clearly reveal the exclusive and pure physical mode of action of the tested dimeticone formula.

Signaling the brain in systemic inflammation: role of sensory circumventricular organs.

The sensory circumventricular organs (CVOs) are specialized brain regions that lack a tight blood-brain barrier. A role for these brain structures in signaling the brain during systemic inflammation is based on the following sets of observations. In spite of some conflicting data from literature, lesions of CVOs have been shown to block several components of brain controlled illness responses (i.e. fever or neuroendocrine modifications). Receptors for inflammatory cytokines and for bacterial fragments are constitutively expressed in cells within the sensory CVOs. The expression of most of these receptors is upregulated under conditions of systemic inflammation. Cellular responses in theses brain areas can be recorded and documented after stimulation of these respective receptors. Such responses include changes in electrical activity of neurons, induction of transcription factors leading to modifications in gene expression during inflammation and to a localized release of secondary signal molecules. These molecules may influence or even gain access to neural structures inside the blood-brain barrier, which can normally not directly be reached by circulating cytokines or bacterial fragments.

WAY-100635, an antagonist of 5-HT(1A) receptor, causes malformations of the CNS in ascidian embryos.

Serotonin (5-HT) is a neurotransmitter which is supposed to play a key role during development. In the last few years 5-HT receptors have been cloned in many animal species, and there is evidence that different 5-HT receptors are also present in ascidians. Ascidians and vertebrates are both members of the phylum Chordata and both have a dorsal tubular central nervous system. Embryos of the ascidian Phallusia mammillata have been treated with WAY-100635, a potent and selective 5-HT(1A) receptor antagonist. The larvae developed from treated embryos showed a dramatic reduction of their anterior sensory vesicles and the pigment of two sensory organs, the ocellus and the otolith. Immunofluorescence experiments with an anti beta-tubulin monoclonal antibody specific for the neural system showed that the anterior neural system of treated animals was radically altered by the action of the drug in a dose-dependent way. These results suggest that 5-HT plays a role in the development of the neural system in ascidians and its action is mediated by receptors similar to the members of the 5-HT(1A) receptor subtype of mammals.

Tumour of the juxtaoral organ.

The juxtaoral organ is a normal and constant structure of the oral cavity. It consists of benign epithelial nests. We describe an intraoral tumour of the juxtaoral organ in a child. The tumour was not diagnosed after clinical and radiological examinations because it is extremely rare. A histological examination revealed a tumour of the juxtaoral organ, presumed to be neuroid hamartoma. This is only the second time that a tumour of the juxtaoral organ has been described in a child. We also describe the location, the embryology, the histology and the function of this organ. This is important because this structure can be confused with carcinomas of the oral cavity when examining frozen sections.

Disfunción del olfato / Disfunction of the sense of smell

Objetivo: reportar los resultados obtenidos con el abordaje sistematizado (fisiopatológico, de diagnóstico y tratamiento) de la disfunción del olfato que puede afectar la vida del paciente en forma significativa. Material y método: se evaluaron 58 pacientes que acudieron a la clínica con alteraciones en la olfación o el gusto, o ambos. El protocolo incluye un cuestionario orientado, pruebas de identificación de olores y umbral olfatorio, rinomanometría, histograma nasal, estudio radiológico simple de las vías respiratorias superiores y senos paranasales, además de tomografía axial computada y endoscopia. Resultados: la causa más frecuente de la disfunción olfatoria fue la obstrucción mecánica debida a procesos inflamatorios, como sinusitis crónica y poliposis nasal, las cuales obstruyen el nicho olfatorio como complicación; de los 58 pacientes, 48 por ciento pertenecieron a este grupo. Esta enfermedad inflamatoria se dividió, a su vez, en alergia pura 25 por ciento, infecciosa 21 por ciento y patrón mixto 54 por ciento. Las pruebas olfatorias mostraron hiposmia severa. En el análisis general el resto de la disfunción olfatoria se clasificó como postviral en 20 por ciento, postraumática en 12.1 por ciento, un grupo misceláneo 8.6 por ciento, provocada por toxinas 6-9 por ciento, quedando un grupo de causa idiopática en 3.4 por ciento.

Evaluación sensitiva y sensorial postglosectomía parcial en procedimientos de cirugía ortognática

El propósito de este esudio fue evaluar sensorialmente y sensitivamente la glosectomía parcial (tecnica de Obwegeser modificada) como intervención complementaria a la cirugía ortognática.Material y Método. Fue estudiado un universo de 30 pacientes. El grupo experimental estuvo formado por 15 pacientes operados. El grupo control lo constituyen 15 pacientes sanos, no operados y de similares características etarias. Se evaluó el postoperatorio a través de un exámen que abarcó pruebas sensitivas y sensoriales. Además se aplicó un cuestionario a los pacientes operados sobre su percepción comparativa pre y postoperatoria de los aspectos estudiados experimentalmente. Los resultados fueron analizados estadísticamente a través de tests paramétricos (test "T" de Student no apareado) y no paramétricos (chi-cuadrado y Mann-Whitney), utilizando una p <0,05.Resultados. En la muestra estudiada, la percepción gustativa y térmica no se muestran alteradas. Puede presentarse una disminución post- quirúrgica leve de la sensibilidad dolorosa. Los pacientes después de operados quedan conformes con los resultados (AU)

Stress-induced phenocopy of C. elegans defines functional steps of sensory organ differentiation.

The differentiation of male specific sensory rays in the nematode Caenorhabditis elegans is a complex process regulated by multiple genetic components. A novel approach with heat shock treatment was employed to show that multistep regulation is involved in this process. Intervention in this stepwise regulation resulted in phenocopy of specific gene mutations. The results suggest that differential gene function acting at a precise time frame is necessary to guide the normal differentiation of sensory rays.

Fusarium solani fungal infection of the lateral line canal system in captive scalloped hammerhead sharks (Sphyrna lewini) in Hawaii.

Two of five scalloped hammerhead sharks (Sphyrna lewini) captured May 1987 in Hawaii (USA) developed granulomatous exudative mycotic dermatitis localized in the lateral line canal system. The lesion initially was noted in the cephalic canals, but over a period of months extended into the lateral canal. Fusarium solani and Vibrio spp. were isolated from the canal exudate of both sharks. Bacterial colonies were not observed in the canal walls or surrounding tissues. Fusarium solani infection resulted in a chronic physical and behavioral deterioration of the two sharks; one shark was euthanized in September 1988 and the other in July 1989. This is the first report of Fusarium solani infection in the lateral line canal system and the third account in hammerhead sharks.

Vitamin A deficiency and sensory function.

Morphological investigation of tongue, olfactory epithelia, trachea and inner ear in vitamin A deficiency are reported. The results support assumptions concerning the loss of sensory function as been at least a secondary effect of alterations of the neighbourhood of the sensory cells caused by vitamin A deficiency. Taste buds are hindered in function by a dense layer of squamous cells and olfaction is decreased by atrophy of the surrounding respiratory epithelium. Inner ear functionality seems to be affected by vitamin A status via a stabilizing effect on the endolymph-perilymph barrier.

Schwannoma of the inferior alveolar nerve in association with the organ of Chievitz.

A benign neural sheath neoplasm arising from the investing tissues of the inferior alveolar nerve and presenting as a facial swelling is described. Of interest and importance was the associated finding of the so-called organ of Chievitz within the initial biopsy specimen. Its recognition as a vestigal structure and not a pathological entity is emphasized.