The Drosophila melanogaster Suppressor of deltex gene, a regulator of the Notch receptor signaling pathway, is an E3 class ubiquitin ligase.

During development, the Notch receptor regulates many cell fate decisions by a signaling pathway that has been conserved during evolution. One positive regulator of Notch is Deltex, a cytoplasmic, zinc finger domain protein, which binds to the intracellular domain of Notch. Phenotypes resulting from mutations in deltex resemble loss-of-function Notch phenotypes and are suppressed by the mutation Suppressor of deltex [Su(dx)]. Homozygous Su(dx) mutations result in wing-vein phenotypes and interact genetically with Notch pathway genes. We have previously defined Su(dx) genetically as a negative regulator of Notch signaling. Here we present the molecular identification of the Su(dx) gene product. Su(dx) belongs to a family of E3 ubiquitin ligase proteins containing membrane-targeting C2 domains and WW domains that mediate protein-protein interactions through recognition of proline-rich peptide sequences. We have identified a seven-codon deletion in a Su(dx) mutant allele and we show that expression of Su(dx) cDNA rescues Su(dx) mutant phenotypes. Overexpression of Su(dx) also results in ectopic vein differentiation, wing margin loss, and wing growth phenotypes and enhances the phenotypes of loss-of-function mutations in Notch, evidence that supports the conclusion that Su(dx) has a role in the downregulation of Notch signaling.     

Phylogenetic analysis of the 5-aminolevulinate synthase gene.

The evolution of 5-aminolevulinate synthase (ALS) was studied by acquiring sequence data and generating phylogenetic trees. Gene sequences were already available for a variety of vertebrates (which have both a housekeeping and an erythroid form of the gene), fungi, alpha-proteobacteria, and one protist and one protostome. In order to generate representative trees, ALS sequence data were acquired from various deuterostomes and protostomes. The species and tissues selected for study were beluga whale liver, hagfish blood, sea urchin gonadal tissue, cuttlefish hepatopancreas, horseshoe crab hepatopancreas, and bloodworm blood. The new sequences and those previously published were examined for the presence of heme-regulatory motifs (HRMs) and iron-responsive elements (IREs). The HRMs are present in almost all eukaryotic species, which suggests their fundamental role in the regulation of ALS. The IREs are present in all vertebrate erythroid forms of ALS, which indicates that in those animals, expression of the erythroid form of the enzyme and, hence, hemoglobin production can be influenced by the intracellular content of iron. The new sequences were aligned with previously reported ALS sequences, and phylogenetic analyses were performed. The resulting trees provided evidence regarding the timing of the gene duplication event that led to the two forms of the ALS gene in vertebrates. It appears that the housekeeping and erythroid forms of ALS probably arose before the divergence of hagfish from the deuterostome line leading to the vertebrates. The data also add to the evidence indicating that alpha-proteobacteria are the nearest contemporary relatives of mitochondria.     

Black students’ experiences of transformation at a previously “white only” South African university: a photovoice study

South African higher education has faced much structural transformation since the dismantling of apartheid, and yet remains a racialized space. Despite a stated commitment to transformation in university policy nationally, lay discourses of transformation are highly contested. In these debates, black students are often represented in stigmatizing ways; which affect students’ self-esteem and academic performance. This paper explores black students’ experiences of transformation at the University of Cape Town (UCT), a previously “white only” university, based on the results of a photovoice project. The data analysed are drawn from focus groups, personal reflections, photographs and written stories exploring their experiences at UCT. The findings suggest that there is a failure of transformation at UCT, characterized by the dominance of whiteness in the institution. The paper also discusses how many students internalize the negative stereotypes they encounter whilst others use coping mechanisms and strategies to resist the discourse of black inferiority.     

Toward a better understanding of the regional causes of local community richness

Despite widespread acknowledgement that local ecological communities are profoundly shaped by regional-scale influences, including evolutionary and biogeographic processes, this perspective has yet to be widely incorporated into ecological research. Drawing on recent research, we propose four steps towards making regional influences a stronger part of research on the richness of local communities: (1) identifying the regional-scale causes of variation in species richness in the systems ecologists study; (2) testing for effects of regional richness on local richness, using improved observational and experimental analyses to overcome earlier problems; (3) simultaneously analysing environmental influences on regional and local species richness as well as the influence of regional richness on local richness and (4) considering the potential reciprocal effects of local processes on regional richness. In conclusion, we suggest some ways that similar approaches could be applied to other aspects of community structure beyond species richness.     

Laryngeal elevation achieved by neuromuscular stimulation at rest.

During swallowing, airway protection is achieved in part by laryngeal elevation. Although multiple muscles are normally active during laryngeal elevation, neuromuscular stimulation of select muscles was evaluated to determine which single muscle or muscle pair best elevates the larynx and should be considered during future studies of neuromuscular stimulation in dysphagic patients. Hooked-wire monopolar electrodes were inserted into mylohyoid, thyrohyoid, and geniohyoid muscle regions in 15 healthy men selected for having a highly visible thyroid prominence for videotaping. During trials of single, bilateral, and combined muscle stimulations, thyroid prominence movements were video recorded, digitized, and normalized relative to elevation during a 2-ml water swallow. Individual muscle stimulation induced approximately 30% of the elevation observed during a swallow and approximately 50% of swallow velocity, whereas paired muscle stimulation resulted in approximately 50% of the elevation and approximately 80% of the velocity produced during a swallow. Paired muscle stimulation produced significantly greater elevation than single muscle stimulation and could assist with laryngeal elevation in dysphagic patients with reduced or delayed laryngeal elevation.     

Structural basis for α-conotoxin potency and selectivity

Parkinson’s disease is a debilitating movement disorder characterized by altered levels of α₆β₂1 (1 indicates the possible presence of additional subunits) nicotinic acetylcholine receptors (nAChRs) localized on presynaptic striatal catecholaminergic neurons. α-Conotoxin MII (α-CTx MII) is a highly useful ligand to probe α₆β₂ nAChRs structure and function, but it does not discriminate among closely related α₆1 nAChR subtypes. Modification of the α-CTx MII primary sequence led to the identification of α-CTx MII[E11A], an analog with 500–5300-fold discrimination between α₆1 subtypes found in both human and non-human primates. α-CTx MII[E11A] binds most strongly (femtomolar dissociation constant) to the high affinity α₆ nAChR, a subtype that is selectively lost in Parkinson’s disease. Here, we present the three-dimensional solution structure for α-CTx MII[E11A] as determined by two-dimensional ¹H NMR spectroscopy to 0.13 ± 0.09 ? backbone and 0.45 ± 0.08 ? heavy atom root-mean-square deviation from mean structure. Structural comparisons suggest that the increased hydrophobic area of α-CTx MII[E11A] relative to other members of the α-CTx family may be responsible for its exceptionally high affinity for α6α4β21 nAChR as well as discrimination between α₆β₂ and α₃β₂ containing nAChRs. This finding may enable the rational design of novel peptide analogs that demonstrate enhanced specificity for α₆1 nAChR subunit interfaces and provide a means to better understand nAChR structural determinants that modulate brain dopamine levels and the pathophysiology of Parkinson’s disease.     

Viral Persistence and Chronic Immunopathology in the Adult Central Nervous System following Coxsackievirus Infection during the Neonatal Period

Coxsackieviruses are significant human pathogens, and the neonatal central nervous system (CNS) is a major target for infection. Despite the extreme susceptibility of newborn infants to coxsackievirus infection and viral tropism for the CNS, few studies have been aimed at determining the long-term consequences of infection on the developing CNS. We previously described a neonatal mouse model of coxsackievirus B3 (CVB3) infection and determined that proliferating stem cells in the CNS were preferentially targeted. Here, we describe later stages of infection, the ensuing inflammatory response, and subsequent lesions which remain in the adult CNS of surviving animals. High levels of type I interferons and chemokines (in particular MCP-5, IP10, and RANTES) were upregulated following infection and remained at high levels up to day 10 postinfection (p.i). Chronic inflammation and lesions were observed in the hippocampus and cortex of surviving mice for up to 9 months p.i. CVB3 RNA was detected in the CNS up to 3 months p.i at high abundance (∼10⁶ genomes/mouse brain), and viral genomic material remained detectable in culture after two rounds of in vitro passage. These data suggest that CVB3 may persist in the CNS as a low-level, noncytolytic infection, causing ongoing inflammatory lesions. Thus, the effects of a relatively common infection during the neonatal period may be long lasting, and the prognosis for newborn infants recovering from acute infection should be reexplored.Early damaging events on the central nervous system (CNS) by infection can result not only in severe physical and intellectual disability but also in less obvious neurological deficits. For example, children who were thought to have fully recovered from neonatal CNS virus infections exhibited some deficiency in scholastic performance (12). Thus, the enduring harmful effects of childhood infections on the CNS may be greatly underappreciated. Picornaviruses including polioviruses, coxsackieviruses, and other unclassified enteroviruses frequently infect the CNS (60). Although these infections often are considered acute and self-limiting, evidence is emerging that these viruses—or at least the viral RNAs—may persist for months or years after the initial infection. For example, ∼50 years after the primary infection, a large percentage (∼30%) of polio victims are now experiencing new symptoms (postpolio syndrome), which some investigators have correlated with the presence of viral RNA in the CNS (43). Worldwide distribution of enterovirus infection is revealed by the detection of enterovirus-specific antibodies in the serum of approximately 75% of individuals within developed countries. For example, in 1996, approximately 10 to 15 million diagnosed cases of enterovirus infection occurred in the United States alone (49). Few studies have been done to determine if enteroviruses, or their close relatives, have the ability to persist and cause long-term damage in the CNS (10, 56) or whether previous infection of neurons may indirectly lead to the degeneration of aging motor neurons.Coxsackievirus, a member of the enterovirus genus, is a fairly frequent childhood infection and may cause severe morbidity and mortality in humans, predominantly in the very young. Infants infected with coxsackievirus have been shown to be extremely susceptible to meningitis and encephalitis. Severe demyelinating diseases may occur following infection, including acute disseminated encephalomyelitis (18) and acute transverse myelitis (27). Also, a number of delayed neuropathologies have been associated with previous coxsackievirus infection, including schizophrenia (47, 52), encephalitis lethargica (16), and amyotrophic lateral sclerosis (62, 63). If human neurotropic viruses persist, they could provide a chronic inflammatory stimulus, leading to regional cytokine induction and activation of autoreactive T cells through molecular mimicry and bystander activation (32, 45). This may be especially true for viruses, such as coxsackievirus, which have the ability to infect stem cells (24) and neurons (1). Recently, we have shown that coxsackievirus B3 (CVB3) targets proliferating cells in regions of the neonatal CNS supporting neurogenesis (24). Nonetheless, infected migratory neuronal progenitor cells were able to differentiate into mature neurons. Many neurons eventually underwent caspase-3-mediated apoptosis at later stages of disease (22).Intriguingly, viral RNA was detected in the CNS of surviving pups in the absence of infectious virus for up to 30 days postinfection (p.i.). The detection of CVB3 RNA in target tissues may have great significance for CVB3-mediated disease, given that the long-term presence of replication-restricted CVB3 RNA in the heart (generated using transgenic techniques) has been directly associated with dilated cardiomyopathy in a previous study by Wessely et al. (59). We were therefore interested in expanding this notable observation in the CNS by significantly increasing the number of animals examined, more precisely quantifying the amounts of viral RNA, and determining how long viral RNA might persist in the CNS. In addition, we thoroughly assessed the nature and degree of neuropathology in surviving animals harboring CVB3 RNA. These studies may help predict the lasting neurological sequelae of a previous viral infection on the developing host.