Learning and memory in individuals with agenesis of the corpus callosum

Damage to long white matter pathways in the cerebral cortex is known to affect memory capacity. However, the specific contribution of interhemispheric connectivity in memory functioning is only beginning to become understood. The present study examined verbal and visual memory processing in individuals with agenesis of the corpus callosum (AgCC) using the Wechsler Memory Scale-Third Edition (WMS-III; Wechsler, 1997b). Thirty participants with AgCC (FSIQ >78) were compared against 30 healthy age and IQ matched controls on auditory/verbal (Logical Memory, Verbal Paired Associates) and visual (Visual Reproduction, Faces) memory subtests. Performance was worse in AgCC than controls on immediate and delayed verbal recall for rote word pairs and on delayed recall of faces, as well as on percent recall for these tasks. Immediate recall for thematic information from stories was also worse in AgCC, but groups did not differ on memory for details from narratives or on recall for thematic information following a time delay. Groups also did not differ on memory for abstract figures or immediate recall of faces. On all subtests, individuals with AgCC had greater frequency of clinically significant impairments than predicted by the normal distribution. Results suggest less efficient overall verbal and visual learning and memory with relative weaknesses processing verbal pairs and delayed recall for faces. These findings suggest that the corpus callosum facilitates more efficient learning and recall for both verbal and visual information, that individuals with AgCC may benefit from receiving verbal information within semantic context, and that known deficits in facial processing in individuals with AgCC may contribute to their impairments in recall for faces

Abnormal Glycosylation of Procathepsin L Due to N-terminal Point Mutations Correlates with Failure to Sort to Lysosomes

A single point mutation in the lysosomal proenzyme receptor-inhibiting sequence near the N terminus of mouse procathepsin L can result in glycosylation of a normally cryptic site near its C terminus. When alanine replaced His36, Arg38, or Tyr40, the nascent chain of the mutant protein cotranslationally acquired a high mannose oligosaccharide chain at Asn268. In contrast, when alanine replaced Ser34, Arg37, or Leu39, this second carbohydrate chain was not added. This alternating pattern of abnormal glycosylation suggested that propeptide residues 36-40 normally assume an extended conformation having the side chains of residues 36, 38, and 40 facing in the same direction. When tyrosine conservatively replaced His36 or lysine replaced Arg38, Asn268 was not glycosylated. But the procathepsin L mutant having phenylalanine in place of Tyr40 was glycosylated at Asn268, which indicates that the hydrogen bond between the hydroxyl group of Tyr40 and the carboxylate group of Asp82 is necessary for normal folding of the nascent proenzyme chain. Mutation of the adjacent alpha2p (ERININ) helix of the propeptide or addition of a C-terminal epitope tag sequence to procathepsin L also induced misfolding of the proenzyme, as indicated by addition of the second oligosaccharide chain. In contrast, the propeptide mutation KAKK99-102AAAA had no effect on carbohydrate modification even though it reduced the positive charge of the proenzyme. Misfolded mutant mouse procathepsin L was not efficiently targeted to lysosomes on expression in human HeLa cells, even though it acquired phosphate on mannose residues. The majority of the mutant protein was secreted after undergoing modification with complex sugars. Similarly, epitope-tagged mouse procathepsin L was not targeted to lysosomes in homologous mouse cells but was efficiently secreted. Since production of mature endogenous protease was not reduced in cells expressing the tagged protein, the tagged protein did not compete with endogenous procathepsin L for targeting to lysosomes

Comparison of wet and dry distillers grains plus solubles to corn as an energy source in forage-based diets

Four experiments compared wet or dry distillers grains plus solubles (WDGS or DDGS) to corn as energy sources in forage-based diets. In Exp. 1, 66 individually fed steers (268 kg of initial BW) were fed a 60:40 blend of sorghum silage and alfalfa hay and supplemented at 0, 0.33, 0.67, or 1.0% of BW with either WDGS or DDGS. In Exp. 2, 160 steers (286 kg of initial BW) were fed 25% WDGS or 33.6% dry rolled corn (DRC) in 35% sorghum silage and grass hay diets (DM basis). In Exp. 3, 60 individually fed steers (231 kg of initial BW) were fed DRC at 22.0, 41.0, or 60.0%, or WDGS at 15.0, 25.0, or 35.0% of diet DM in 30% sorghum silage and grass hay diets. In Exp. 4, 120 individually fed steers (282 kg of initial BW) were fed DDGS, WDGS (15 or 30% of diet DM), or DRC (22 or 50% of diet DM) in sorghum silage and grass hay diets. In Exp. 1, 3, and 4, increasing DGS inclusion increased ADG (P \u3c 0.01) in forage-based diets. In Exp. 3, cattle consuming WDGS gained more BW than cattle fed DRC (P \u3c 0.01). Using regression analysis, data from Exp. 2, 3, and 4 were pooled to calculate the energy value of WDGS relative to DRC in forage diets. The energy value of WDGS was 137% and 136% of DRC when fed at 15 and 30% of diet DM, respectively

Comparison of wet and dry distillers grains plus solubles to corn as an energy source in forage-based diets

Four experiments compared wet or dry distillers grains plus solubles (WDGS or DDGS) to corn as energy sources in forage-based diets. In Exp. 1, 66 individually fed steers (268 kg of initial BW) were fed a 60:40 blend of sorghum silage and alfalfa hay and supplemented at 0, 0.33, 0.67, or 1.0% of BW with either WDGS or DDGS. In Exp. 2, 160 steers (286 kg of initial BW) were fed 25% WDGS or 33.6% dry rolled corn (DRC) in 35% sorghum silage and grass hay diets (DM basis). In Exp. 3, 60 individually fed steers (231 kg of initial BW) were fed DRC at 22.0, 41.0, or 60.0%, or WDGS at 15.0, 25.0, or 35.0% of diet DM in 30% sorghum silage and grass hay diets. In Exp. 4, 120 individually fed steers (282 kg of initial BW) were fed DDGS, WDGS (15 or 30% of diet DM), or DRC (22 or 50% of diet DM) in sorghum silage and grass hay diets. In Exp. 1, 3, and 4, increasing DGS inclusion increased ADG (P \u3c 0.01) in forage-based diets. In Exp. 3, cattle consuming WDGS gained more BW than cattle fed DRC (P \u3c 0.01). Using regression analysis, data from Exp. 2, 3, and 4 were pooled to calculate the energy value of WDGS relative to DRC in forage diets. The energy value of WDGS was 137% and 136% of DRC when fed at 15 and 30% of diet DM, respectively

Learning and memory in individuals with agenesis of the corpus callosum

Damage to long white matter pathways in the cerebral cortex is known to affect memory capacity. However, the specific contribution of interhemispheric connectivity in memory functioning is only beginning to become understood. The present study examined verbal and visual memory processing in individuals with agenesis of the corpus callosum (AgCC) using the Wechsler Memory Scale-Third Edition (WMS-III; Wechsler, 1997b). Thirty participants with AgCC (FSIQ >78) were compared against 30 healthy age and IQ matched controls on auditory/verbal (Logical Memory, Verbal Paired Associates) and visual (Visual Reproduction, Faces) memory subtests. Performance was worse in AgCC than controls on immediate and delayed verbal recall for rote word pairs and on delayed recall of faces, as well as on percent recall for these tasks. Immediate recall for thematic information from stories was also worse in AgCC, but groups did not differ on memory for details from narratives or on recall for thematic information following a time delay. Groups also did not differ on memory for abstract figures or immediate recall of faces. On all subtests, individuals with AgCC had greater frequency of clinically significant impairments than predicted by the normal distribution. Results suggest less efficient overall verbal and visual learning and memory with relative weaknesses processing verbal pairs and delayed recall for faces. These findings suggest that the corpus callosum facilitates more efficient learning and recall for both verbal and visual information, that individuals with AgCC may benefit from receiving verbal information within semantic context, and that known deficits in facial processing in individuals with AgCC may contribute to their impairments in recall for faces

A Cathepsin L Isoform that Is Devoid of a Signal Peptide Localizes to the Nucleus in S Phase and Processes the CDP/Cux Transcription Factor

AbstractThe subclass of cysteine proteases termed lysosomal cathepsins has long been thought to be primarily involved in end-stage protein breakdown within lysosomal compartments. Furthermore, few specific protein substrates for these proteases have been identified. We show here that cathepsin L functions in the regulation of cell cycle progression through proteolytic processing of the CDP/Cux transcription factor. CDP/Cux processing in situ was increased following ectopic expression of cathepsin L but was reduced in Cat L−/− cells. Furthermore, catalytically active cathepsin L was localized to the nucleus during the G1-S transition as detected by immunofluorescence imaging and labeling using activity-based probes. Trafficking of cathepsin L to the nucleus is accomplished through a mechanism involving translation initiation at downstream AUG sites and the synthesis of proteases that are devoid of a signal peptide. Overall, these results uncover an as yet unsuspected role for cysteine proteases in the control of cell cycle progression

Invariant Chain Controls the Activity of Extracellular Cathepsin L

Secretion of proteases is critical for degradation of the extracellular matrix during an inflammatory response. Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of the p41 splice variant (p4165aa) of major histocompatibility complex class II–associated invariant chain (Ii) binds to the active site of CatL and permits the maintenance of a pool of mature enzyme in endosomal compartments of macro-phages and dendritic cells (DCs). Here we show that interaction of p4165aa with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p4165aa in culture supernatants from antigen-presenting cells (APCs). Extracellular accumulation of mature CatL is up-regulated by inflammatory stimuli as observed in interferon (IFN)-γ–treated macrophages and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the extracellular milieu, released CatL associated with p4165aa is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p4165aa stabilizes CatL in the extracellular environment and induces a local increase in the concentration of matrix-degrading enzymes during inflammation. Through its interaction with CatL, Ii may therefore control the migratory response of APCs and/or the recruitment of effectors of the inflammatory response

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design

Linkage analysis of von Recklinghausen neurofibromatosis to DNA markers on chromosome 17

Several recent studies indicate that the von Recklinghausen neurofibromatosis (NF1) gene is located near the centromere of chromosome 17 in some families. However, variable expressivity and a very high mutation rate suggest that defects at several different loci could result in phenotypes categorized as NF1. In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1. We ascertained a large Caucasian pedigree (33 individuals sampled, 17 NF1 affected) as well as eight smaller pedigrees and nuclear families (50 individuals sampled, 30 NF1 affected). Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum LOD = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum LOD = 0.57), both at a recombination fraction of zero. Since obligate crossovers with NF1 were not observed for either marker in any of the informative families tested, the possibility of NF1 locus heterogeneity is not supported.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26488/1/0000024.pd

A prevalence study and Description of alli® use by patients with eating disorders

This study examined the frequency and characteristics of alli® use among patients in eating disorder treatment facilities