The Time Course of Activation of Object Shape and Shape+Colour Representations during Memory Retrieval

Little is known about the timing of activating memory for objects and their associated perceptual properties, such as colour, and yet this is important for theories of human cognition. We investigated the time course associated with early cognitive processes related to the activation of object shape and object shape+colour representations respectively, during memory retrieval as assessed by repetition priming in an event-related potential (ERP) study. The main findings were as follows: (1) we identified a unique early modulation of mean ERP amplitude during the N1 that was associated with the activation of object shape independently of colour; (2) we also found a subsequent early P2 modulation of mean amplitude over the same electrode clusters associated with the activation of object shape+colour representations; (3) these findings were apparent across both familiar (i.e., correctly coloured – yellow banana) and novel (i.e., incorrectly coloured - blue strawberry) objects; and (4) neither of the modulations of mean ERP amplitude were evident during the P3. Together the findings delineate the timing of object shape and colour memory systems and support the notion that perceptual representations of object shape mediate the retrieval of temporary shape+colour representations for familiar and novel objects.     

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1^−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1^+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer     

Biochemical properties of alligator (Alligator mississippiensis) bone collagen

Acid-soluble collagen (ASC) and pepsin solubilized collagen (PSC) isolated and purified from alligator (Alligator mississippiensis) bone were studied for molecular size, amino acid profile, secondary structure, and denaturation temperature by SDS-PAGE, HPLC, circular dichroism, and viscometry. Two collagen subunits, alpha1 and alpha2 were identified by SDS-PAGE. The molecular masses for alpha1 and alpha2 chains of ASC were 124 kDa and 111 kDa, respectively. The molecular masses were 123 kDa for alpha1 and 110 kDa for alpha2 chains of the PSC preparation. The molecular masses for ([alpha1](2) alpha2) of ASC and PSC were 359 kDa and 356 kDa, respectively. The major composition of alligator bone ASC and PSC was found to be typical type I collagen. The amino acid profiles of alligator ASC and PSC were similar to amino acid profile of subtropical fish black drum (Pogonias cromis, Sciaenidae) bone. Comparison of amino acid profiles with shark cartilage PSC, showed differences in alanine, hydroxylysine, lysine, and histidine contents. The denaturation temperatures (T(d)) of alligator ASC and PSC collagen measured by viscometry were 38.1 and 38.2 degrees C, respectively. Thermal denaturation temperatures, measured by melting point using circular dichroism, were 37.6 and 37.9 degrees C, respectively. Taken together, these results suggest that alligator bone collagen may find a wide range of applications in biological research, functional foods and nutraceuticals, and biomedical and pharmaceutical research.     

Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons

The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q < 0.05; enrichment range 1.40–9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans?nosology pathways in diabetes and its co-morbidities.     

ABSENCE OF POLLEN DISCOUNTING IN A GENOTYPE OF IPOMOEA PURPUREA EXHIBITING INCREASED SELFING

Throughout southeastern North America, the annual morning glory Ipomoea purpurea exhibits a polymorphism at a locus that influences the intensity of floral pigmentation. Previous studies have shown that when rare, the homozygous white genotype has a greater selfing rate than the homozygous dark genotype. In the absence of pollen discounting (a reduction in transmission of pollen to other plants by genotypes that exhibit increased selfing) and inbreeding depression, this increased selfing rate should favor the white allele. Experiments reported here confirm that the white genotype has elevated selfing rates when rare but indicate pollen discounting is not associated with elevated selfing. Rather, white genotypes contribute more pollen to the outcross pollen pool. The disparity between genotypes in both selfing rates and success at pollen contribution to other plants disappears at intermediate to high frequencies of the white allele. Pollinator movements are consistent with the pattern of selfing. These results suggest that elevated selfing and enhanced success at pollen donation contribute to maintenance of the white allele in natural populations of morning glories.     

Conformational dynamics of a lipid-interacting protein: MD simulations of saposin B

Saposin B is a water soluble alpha-helical protein which can bind to membranes and extract selected lipids, especially cerebroside sulfates. The X-ray structure of saposin B is homodimeric. There are two conformations of the dimer in the crystal-one with a closed central cavity (the AB dimer) and one (the CD dimer) with a more open cavity. We have conducted a series of short (5 ns) molecular dynamics simulations of saposin B, starting from both the AB and CD conformations and with/without bound lipid and/or water molecules within the central hydrophobic cavity. The more open (CD) dimer showed greater conformational drift than the AB dimer. The conformational drift was also somewhat higher in the absence of bound lipid. Two more extended (30 ns) simulations of AB and CD dimers were performed and analyzed in terms of changes in intersubunit packing within the dimers. The AB dimer remained largely unchanged in conformation over the duration of the extended simulation. In contrast, the CD dimer underwent a substantial conformational change corresponding to a 'scissor' motion of the two monomers so as to compress the central cavity to a more closed conformation than that seen in the AB dimer structure. A H-bond between the Q53 and Y54 side chains of the alpha3 helices of the two opposing monomers seems to hold the dimer in this 'scissor-closed' conformation. We suggest that a cycle of conformational changes, expanding and compressing the central cavity of the saposin B dimer, may play a key role in facilitating lipid extraction from bilayers.     

Caenorhabditis nematodes colonize ephemeral resource patches in neotropical forests

Factors shaping the distribution and abundance of species include life‐history traits, population structure, and stochastic colonization–extinction dynamics. Field studies of model species groups help reveal the roles of these factors. Species of Caenorhabditis nematodes are highly divergent at the sequence level but exhibit highly conserved morphology, and many of these species live in sympatry on microbe‐rich patches of rotten material. Here, we use field experiments and large‐scale opportunistic collections to investigate species composition, abundance, and colonization efficiency of Caenorhabditis species in two of the world''s best‐studied lowland tropical field sites: Barro Colorado Island in Panamá and La Selva in Sarapiquí, Costa Rica. We observed seven species of Caenorhabditis, four of them known only from these collections. We formally describe two species and place them within the Caenorhabditis phylogeny. While these localities contain species from many parts of the phylogeny, both localities were dominated by globally distributed androdiecious species. We found that Caenorhabditis individuals were able to colonize baits accessible only through phoresy and preferentially colonized baits that were in direct contact with the ground. We estimate the number of colonization events per patch to be low.