Search

Huntington's disease is caused by expression of a mutant form of Huntingtin protein containing an expanded polyglutamine repeat. One possible treatment for Huntington's disease may be to reduce expression of mutant Huntingtin in the brain via RNA interference. Unless the therapeutic molecule is designed to be allele-specific, both wild-type and mutant protein will be suppressed by an RNA interference treatment. A key question is whether suppression of wild-type as well as mutant Huntingtin in targeted brain regions can be tolerated and result in a net benefit to patients with Huntington's disease. Whether Huntingtin performs essential functions in the adult brain is unclear. Here, we tested the hypothesis that the adult primate brain can tolerate moderately reduced levels of wild-type Huntingtin protein for an extended period of time. A serotype 2 adeno-associated viral vector encoding for a short hairpin RNA targeting rhesus huntingtin messenger RNA (active vector) was bilaterally injected into the striatum of four adult rhesus monkeys. Four additional animals received a comparable vector encoding a scrambled control short hairpin RNA (control vector). General health and motor behaviour were monitored for 6 months. Upon termination, brain tissues were sampled and assessed blindly for (i) huntingtin messenger RNA knockdown; (ii) Huntingtin protein expression; and (iii) neuropathological changes. Reduction in wild-type huntingtin messenger RNA levels averaging ∼30% was measured in the striatum of active vector recipients 6 months post-injection. A widespread reduction in Huntingtin protein levels was also observed by immunohistochemistry in these animals, with an average protein reduction of ∼45% relative to controls measured by western blot analysis in the putamen of active vector recipients. As with control vector recipients, no adverse effects were observed behaviourally, and no neurodegeneration was found on histological examination of active vector recipients. Our results suggest that long-term partial suppression of wild-type Huntingtin may be safe, and thus if a comparable level of suppression of mutant Huntingtin is beneficial, then partial suppression of both wild-type and mutant Huntingtin may result in a net benefit in patients with heterozygous Huntington's disease.

Walleyes Sander vitreus are extensively cultured across Michigan, with highly variable success resulting in substantial differences in growth and survival. The present study was undertaken in 2005 and 2006 to determine the relationship between abiotic components (temperature, dissolved oxygen, and nutrient levels), prey (zooplankton and benthic macroinvertebrate) availability, and stocking density in ponds in the Lower Peninsula of Michigan and the growth and survival of walleyes in these ponds. Besides fertilization of some of the ponds, there was no management of the ponds until harvest. Ponds were grouped by similarity of abiotic and biotic factors. Correlations among walleye length, weight, and stocking density, as well as between walleye percent survival and stocking density, provided contradictory results between years. Walleye growth and survival were correlated with planktonic prey densities and nutrient levels. Although these interactions among abiotic variables, prey availability, and w...

Purpose This field trial examined the process of assigning drug-involved offenders to dispositions based on their criminogenic risks and needs. Methods Probation officers administered the Risk and Needs Triage (RANT)™ to 627 felony drug and property offenders at the pre-trial stage or shortly after sentencing to probation. The RANT™ was evaluated for internal scale consistency, factor structure, and predictive validity for re-arrest and re-conviction rates within 12 months of case disposition. Exploratory analyses examined whether recidivism was lower for participants who were assigned to an appropriate disposition given their assessment results. Results The RANT™ demonstrated acceptable internal consistency and factorial validity, and significantly predicted re-arrest and re-conviction rates within 12 months of case disposition. There was no racial or gender bias in the prediction of recidivism. Non-significant trends favored better outcomes for participants who were assigned to the indicated dispositions. Conclusions The results lend support for the RANT™ as a dispositional triage tool for drug-involved defendants and probationers at or near the point of arrest. The results also lend tentative support to the hypothesis that outcomes might be better if drug-involved offenders were matched to appropriate dispositions based on their risk-and-need profiles. Directions for future research are discussed.

Multiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3–23.5 μg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2–13 μm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aβ levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 μg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD.

We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance. We now report a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype with in vivo imaging showing reduced cerebellar-cortical inhibition. 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction. The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels.

We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Using the Career Key as a criterion measure, the validity of the Strong Interest Explorer was tested with a sample of Latino junior high school and senior high school students. A total of 85 Hispanic youth were administered the Strong Interest Explorer and the Career Key in counterbalanced order. Separate correlational analyses were conducted for (a) the total sample, (b) junior high/senior high students, and (c) males/females. Results generally offered support for the validity of the Strong Interest Explorer Artistic, Social and Enterprising scales but not the Investigative, Conventional or Realistic scales. Cautions regarding use of the Strong Interest Explorer with Latino youth are discussed. ********** Latinos are the largest minority group in the United States. According to the 2000 Census, there are 35.3 million Latinos living in the U. S. It is expected that by 2050, Latinos will represent approximately 25 percent of the total U.S. population. Latinos are also one of the youngest population groups in the United States. One-third of Latinos are under 18 years of age, and they represent approximately 15 percent of the K-12 population (2002 National Directory, 2002). Furthermore, between the years 2000 and 2025, the U.S. Census Bureau projects that the number of working-age Latino Americans will increase by 18 million. However, only 57 percent of Latinos 25 years and older have completed high school. Twenty-seven percent of Latinos have less than a high school education. College-qualified Latino students are the only racial/ethnic group significantly less likely than other college-qualified students to pursue post-secondary education (2002 National Directory, 2002). According to the National Educational Longitudinal Survey (NELS), only 55% of Latino eighth graders expect to get college degrees (Our Nation on the Fault Line, 1996). Latino youth continue to be underrepresented in higher education. According to the 2000 Census, only 10.6 percent of Hispanics have attained a bachelor's degree. In 1996, Latinos represented only 4 percent of students in graduate school and approximately 8 percent of first-year professional students. Latino American high school graduates still trail other population groups in attaining college degrees, according to a report recently released by the Pew Hispanic Center (PHC) (Fry, 2002). Only 35% of Latino high school graduates 18 to 24 years old are enrolled in college compared to 46% of whites. The Baccalaureate degree completion rate for Latinos is currently at 10%. This combines to produce the lowest completion rates and highest dropout rates for the fastest growing minority group in the US (McGlynn, 2001). Latinos also tend to be over-represented in occupational categories such as farming, labor, factory-type work, and service industry occupations. Only 28% of males of Latino descent hold upper-level managerial, technical, and administrative positions, compared to 48% of nonLatino males. As the level of education or skill increases for a particular job, the percentage of Latinos in that position diminishes (U.S. Bureau of the Census, 1988). Under-representation of Latino workers is especially severe in high-tech jobs that require college or graduate degrees, due to unequal access to the types of postsecondary education required for science and technology jobs. Only 1.3% of Latinos had college-educated technical jobs. Latinos are also underrepresented in education, health care, management, accounting, sales, and marketing (Our Nation on the Fault Line, 1996). Similarly, Latinos remain severely underrepresented in science and engineering education, and male Latinos are disproportionately represented among the lower levels of employment in manufacturing. In academic settings, Latinos represented only 2.7% of doctoral science and engineering faculty in 1995 (Muller-Karger, 2000). Clearly, such dismal statistics offer strong evidence that this population of students is in dire need of career development services and career planning assistance. …

We evaluated relationships between climatological variables and abundance of larval yellow perch (Perca flavescens) in eastern South Dakota glacial lakes. Age-0 yellow perch were collected using a 0.75 m diameter ichthyoplankton net from May through mid-June at 7 to 10 d intervals. Highest correlation coefficients with larval yellow perch abundance were for April total precipitation (r-0.95–0.99; P=0.09–0.01; three lakes), mean March wind speed (r=-0.98 to −0.99; P=0.02–0.006; two lakes), mean of May average daily temperatures (1-0.78; P=0.12; one lake) and mean May wind speed (r=-0.82; P=0.02; one lake). Given the low number of years in some samples, individual years at times had undue influence on the relationship, resulting in high correlation coefficients. Multiple regression modeling resulted in improved models for only two of the seven lakes (R2=0.90–0.98; P=0.05–0.02). However, March through May weather patterns in some combination were related to larval yellow perch abundance in all seven...

Retroviral Gag proteins perform important functions in viral assembly, but are also involved in other steps in the viral life cycle. Conventional mutational analysis has yielded considerable information about domains essential for these functions, yet many regions of gag remain uncharacterized. We used genetic footprinting, a technique that permits the generation and simultaneous analysis of large numbers of mutations, to perform a near-saturation mutagenesis and functional analysis of 639 nucleotides in the gag region of Moloney murine leukemia virus. We report here the resulting functional map defined by eight footprints representing regions of Moloney murine leukemia virus gag , some previously uncharacterized, that are essential for replication. We found that significant portions of matrix and p12 proteins were tolerant of insertions, in contrast to the N-terminal half of capsid, which was not. We analyzed 30 mutants from our library by using conventional methods to validate the footprints. Six of these mutants were characterized in detail, identifying the precise stage at which their replication is blocked. In addition to providing the most comprehensive functional map of a retroviral gag gene, our study demonstrates the abundance of information that can be gleaned by genetic footprinting of viral sequences.

A simulation model for detailed micro-level examination of ongoing and proposed probation-and-parole operations was developed and exercised for a wide variety of external conditions and alternative internal-decision scenarios. We describe the system and model, report on statistical experimental-design and sensitivity analyses, and discuss implications for public policy and implementation issues. We also illustrate some general simulation-methodological practices in this application.

Alewives were collected by nighttime gill netting during summer 1999 from 12 Connecticut lakes that support landlocked populations to determine relationships between population characteristics and physicochemical lake variables. Mean catch-per-unit-effort (CPUE) ranged from 0.2 to 16.4 age-1 and older alewives per net hour. Maximum ages of alewives among lakes ranged from two to five years, and mean back-calculated length-at-age-1, used to index growth rate, ranged from 78 to 146 mm. Mean back-calculated length-at-age-1 was positively correlated with mean relative condition factor (Kn), watershed area:lake surface area ratio, watershed area:lake volume ratio, lake surface area:lake volume ratio, conductivity, total nitrogen, alkalinity, calcium, magnesium, and chlorophyll a, and negatively correlated with retention time, maximum lake depth, mean lake depth, and transparency. Mean Kn ranged from 0.93 to 1.23 and was positively correlated with mean back-calculated length-at-age-1, watershed area:la...

Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection. Congenital HCMV infection occurs in 0.2–1% of all births, and causes birth defects and developmental abnormalities, including sensorineural hearing loss and developmental delay. Several key studies have established the guinea pig as a tractable model for the study of congenital HCMV infection and have shown that polyclonal antibodies can be protective [1]–[3]. In this study, we demonstrate that an anti-guinea pig CMV (GPCMV) glycoprotein H/glycoprotein L neutralizing monoclonal antibody protects against fetal infection and loss in the guinea pig. Furthermore, we have delineated the kinetics of GPCMV congenital infection, from maternal infection (salivary glands, seroconversion, placenta) to fetal infection (fetus and amniotic fluid). Our studies support the hypothesis that a neutralizing monoclonal antibody targeting an envelope GPCMV glycoprotein can protect the fetus from infection and may shed light on the therapeutic intervention of HCMV congenital infection in humans., Author Summary Human cytomegalovirus (HCMV) is the most common cause of congenital virus infection and causes developmental abnormalities, including hearing loss and developmental delay. Although there is no therapy for congenital HCMV disease, there is evidence from both human and animal studies that antibodies can have efficacy in this setting. Such studies have focused exclusively on polyclonal antibodies, in which the targets of protective antibodies are unknown. Guinea pigs have been used as a model of human maternal fetal transmission of infection because of similarities in placental anatomy between human and guinea pig. Furthermore, guinea pig CMV (GPCMV) has been demonstrated to cross the placenta and cause fetal infection and loss, similar to the effects of infection with HCMV. However, the kinetics of maternal and fetal infection in this model has not been carefully investigated. In this work, we have delineated the kinetics of maternal to fetal infection and found that congenital infection is rapid following maternal infection. Importantly, we demonstrate that a monoclonal antibody against a protein critical for viral entry protects pregnant guinea pigs against fetal infection. Thus, our studies may be informative for development of a therapeutic intervention to treat congenital HCMV infection in humans.

During summer 1999, 5,004 landlocked alewives (Alosa pseudoharengus) were captured from 12 Connecticut lakes using horizontal gill nets with mesh sizes of 9.5, 12.7, 15.9, 19.1, 25.4, and 31.8 mm (bar measure). The most effective mesh size was 12.7-mm, capturing 3,035 alewives. The modal length of alewives caught in each mesh size increased as the mesh size increased from 9.5 to 25.4 mm. No alewives less than 70 mm total length or greater than 245 mm were captured. Modal lengths of selectivity curves estimated indirectly using the Holt model were 85, 114, 143, 172, and 228 mm for the 9.5-, 12.7–15.9-, 19. 1-, and 25.4-mm mesh sizes, respectively. Adding a 22.3-mm mesh and removing the 31.8-mm mesh is suggested to sample landlocked alewives between 100 and 245 mm in Connecticut lakes.

The primary sequence of the long unique region L-DNA (L for low GC) of rhesus monkey rhadinovirus (RRV) isolate 26-95 was determined. The L-DNA consists of 130,733 bp that contain 84 open reading frames (ORFs). The overall organization of the RRV26-95 genome was found to be very similar to that of human Kaposi sarcoma-associated herpesvirus (KSHV). BLAST search analysis revealed that in almost all cases RRV26-95 coding sequences have a greater degree of similarity to corresponding KSHV sequences than to other herpesviruses. All of the ORFs present in KSHV have at least one homologue in RRV26-95 except K3 and K5 (bovine herpesvirus-4 immediate-early protein homologues), K7 (nut-1), and K12 (Kaposin). RRV26-95 contains one MIP-1 and eight interferon regulatory factor (vIRF) homologues compared to three MIP-1 and four vIRF homologues in KSHV. All homologues are correspondingly located in KSHV and RRV with the exception of dihydrofolate reductase (DHFR). DHFR is correspondingly located near the left end of the genome in RRV26-95 and herpesvirus saimiri (HVS), but in KSHV the DHFR gene is displaced 16,069 nucleotides in a rightward direction in the genome. DHFR is also unusual in that the RRV26-95 DHFR more closely resembles HVS DHFR (74% similarity) than KSHV DHFR (55% similarity). Of the 84 ORFs in RRV26-95, 83 contain sequences similar to the recently determined sequences of the independent RRV isolate 17577. RRV26-95 and RRV17577 sequences differ in that ORF 67.5 sequences contained in RRV26-95 were not found in RRV17577. In addition, ORF 4 is significantly shorter in RRV26-95 than was reported for RRV17577 (395 versus 645 amino acids). Only four of the corresponding ORFs between RRV26-95 and RRV17577 exhibited less than 95% sequence identity: glycoproteins H and L, uracil DNA glucosidase, and a tegument protein (ORF 67). Both RRV26-95 and RRV17577 have unique ORFs between positions 21444 to 21752 and 110910 to 114899 in a rightward direction and from positions 116524 to 111082 in a leftward direction that are not found in KSHV. Our analysis indicates that RRV26-95 and RRV17577 are clearly independent isolates of the same virus species and that both are closely related in structural organization and overall sequence to KSHV. The availability of detailed sequence information, the ability to grow RRV lytically in cell culture, and the ability to infect monkeys experimentally with RRV will facilitate the construction of mutant strains of virus for evaluating the contribution of individual genes to biological properties.

All members of the Herpesviridae family contain sequences for a highly conserved glycoprotein B (gB) gene. We investigated the phylogenetic relationships of gB sequences from eight independent rhadinovirus isolates obtained from three species: rhesus ( Macaca mulatta ), cynomologus ( Macaca fasicularis ), and pig-tailed ( Macaca nemestrina ) macaques. Samples were derived from monkeys housed at four separate facilities. Analysis of these eight independent gB sequences revealed five regions of heterogeneity within the 823- to 829-amino-acid polypeptides: residues 1 to 65, 120 to 185, 255 to 300, 352 to 393, and 412 to 457. The remaining regions of gB were highly conserved among the different macaque isolates. Overall divergence among these gene sequences ranged from 0.1 to 7.2% at the amino acid level. Phylogenetic trees constructed with our macaque rhadinovirus gB sequences and those derived from additional subfamilies or genera (alpha, beta, gamma-1, and gamma-2) revealed that the macaque gB sequences branched with other gamma-2 herpesvirus gB sequences and that within the gamma-2 genera, the macaque gB sequences clustered as a distinct branch. The eight macaque rhadinovirus gB sequences were all approximately equidistant from Kaposi sarcoma-associated herpesvirus (KSHV) gB sequences and had a shorter evolutionary distance to KSHV gB sequences than to any other herpesvirus, including the gamma-2 herpesvirus saimiri (HVS) of New World squirrel monkeys. The macaque gB sequences did not cluster according to the facility of origin, but did cluster according to the species of origin, displaying less intraspecies divergence (0.1 to 2.9%) than interspecies divergence (3.3 to 7.2%). These results demonstrate a close relatedness of rhadinovirus isolates from different macaque species.

The high variability in reported lengths of larval yellow perch Perca flavescens at hatching, dietary shift, and morphometric transformation may be partly caused by shrinkage that occurs after preservation. Larval yellow perch were captured, randomly assigned to one of six preservative treatments (100%, 95%, 80%, and 50% ethyl alcohol and 5% and 10% formalin), and measured (before preservation) for total length (TL). Larval yellow perch total lengths were then recorded on days 1, 7, 14, and 21 after storage in each of the six preservatives. Significant reductions in TL (11.5–14.3%) occurred during the first 24 h after fixation and larvae continued to contract at a lesser rate through day 7 in all four ethyl alcohol treatments. Total length reductions of up to 2.5% also occurred during the first 24 h in each formalin concentration. Our findings report the total length reductions of larval yellow perch at a length range used by some biologists when indexing year-class strength and during studies of...

In human cytomegalovirus (HCMV), the UL128-131A locus plays an essential role in cellular tropism and spread. Here, we report the complete annotation of the GP129-133 locus from guinea pig cytomegalovirus (GPCMV) and the discovery of the UL131A homolog, named GP133. We have found that similar to HCMV the GP129-133 proteins form a pentamer complex with the GPCMV glycoproteins gH and gL. In addition, we find that the GP129-133 proteins play a critical role in entry as the GP129-133 deletion mutant shows a defect in both endothelial and fibroblast cell entry. Although the GP129-133 deletion strain can propagate in vitro, we find that the deletion fails to spread in vivo. Interestingly, the wildtype strain can spontaneously give rise to the GP129-133 deletion strain during in vivo spread, suggesting genetic instability at this locus.

In this study, we used bioluminescence imaging (BLI) to track long-term transgene activity following the transfection of brain cells using a nonviral gene therapy technique. Formulations of deoxyribonucleic acid (DNA) combined with 30-mer lysine polymers (substituted with 10 kDa polyethylene glycol) form nanoparticles that transfect brain cells in vivo and produce transgene activity. Here we show that a single intracerebral injection of these DNA nanoparticles (DNPs) into the rat cortex, striatum, or substantia nigra results in long-term and persistent luciferase transgene activity over an 8- to 11-week period as evaluated by in vivo BLI analysis, and single injections of DNPs into the mouse striatum showed stable luciferase transgene activity for 1 year. Compacted DNPs produced in vivo signals 7- to 34-fold higher than DNA alone. In contrast, ex vivo BLI analysis, which is subject to less signal quenching from surrounding tissues, demonstrated a DNP to DNA alone ratio of 76- to 280-fold. Moreover, the ex vivo BLI analysis confirmed that signals originated from the targeted brain structures. In summary, BLI permits serial analysis of luciferase transgene activity at multiple brain locations following gene transfer with DNPs. Ex vivo analysis may permit more accurate determination of relative activities of gene transfer vectors.

Although immunization against amyloid-β (Aβ) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-Aβ immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular ( icv ) versus systemic delivery of anti-Aβ antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged icv infusions of anti-Aβ antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10- to 50-fold lower than used with systemic delivery of the same antibody. Both icv and systemic anti-Aβ antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-Aβ antibodies that aggravated vascular pathology, icv -infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of icv -delivered anti-Aβ antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-Aβ antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, icv -targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.

Retroviral capsid (CA) proteins contain a structurally conserved N-terminal domain (NTD) consisting of a β-hairpin and six to seven α-helices. To examine the role of this domain in Moloney murine leukemia virus (MoMLV) replication, we analyzed 18 insertional mutations in this region. All mutants were noninfectious. Based on the results of this analysis and our previous studies on additional mutations in this domain, we were able to divide the NTD of MoMLV CA into three functional regions. The first functional region included the region near the N terminus that forms the β-hairpin and was shown to control normal maturation of virions. The second region included the helix 4/5 loop and was essential for the formation of spherical cores. The third region encompassed most of the NTD except for the above loop. Mutants of this region assembled imperfect cores, as seen by detailed electron microscopy analyses, yet the resulting particles were efficiently released from cells. The mutants were defective at a stage immediately following entry of the core into cells. Despite possessing functional reverse transcriptase machinery, these mutant virions did not initiate reverse transcription in cells. This block could be due to structural defects in the assembling core or failure of an essential host protein to interact with the mutant CA protein, both of which may prevent correct disassembly upon entry of the virus into cells. Future studies are needed to understand the mechanism of these blocks and to target these regions pharmacologically to inhibit retroviral infection at additional stages.

We sought to determine if abundance of larval yellow perch Perca flavescens could predict abundance of age-0 juvenile perch in late summer. Yellow perch larvae and juveniles were sampled from six eastern South Dakota glacial lakes in 1997. The number of age-0 yellow perch caught per seine haul in late summer was positively related to larval abundance in late May and early June (N = 6, r = 0.90, P = 0.01). When data collected from two eastern South Dakota lakes in 1995 and 1996 were added to this assessment, we also found a significant positive relation (N = 10, r = 0.88, P = 0.0009). Thus, biologists in eastern South Dakota can use larval yellow perch abundance as an early indicator to determine which water bodies are likely to have a weak naturally produced year-class and then can evaluate the success of fingerling perch stocking strategies.

We conducted a survey of the history of psychology course and received 357 undergraduate syllabi. Despite wide variation in the syllabi, several trends emerged. For instance, most instructors depend heavily on textbooks to organize their courses, and three textbooks accounted for more than 60% of book choices. Newer areas of historical interest did not appear in the course syllabi to any substantial degree.

Unique among primates, the colobine monkeys have adapted to a predominantly leaf-eating diet by evolving a foregut that utilizes bacterial fermentation to breakdown and absorb nutrients from such a food source. It has been hypothesized that pancreatic ribonuclease (pRNase) has been recruited to perform a role as a digestive enzyme in foregut fermenters, such as artiodactyl ruminants and the colobines. We present molecular analyses of 23 pRNase gene sequences generated from 8 primate taxa, including 2 African and 2 Asian colobine species. The pRNase gene is single copy in all noncolobine primate species assayed but has duplicated more than once in both the African and Asian colobine monkeys. Phylogenetic reconstructions show that the pRNase-coding and noncoding regions are under different evolutionary constraints, with high levels of concerted evolution among gene duplicates occurring predominantly in the noncoding regions. Our data suggest that 2 functionally distinct pRNases have been selected for in the colobine monkeys, with one group adapting to the role of a digestive enzyme by evolving at an increased rate with loss of positive charge, namely arginine residues. Conclusions relating our data to general hypotheses of evolution following gene duplication are discussed.

We report the identification of a novel domain in the Gag protein of Moloney murine leukemia virus (MoLV) that is important for the formation of spherical cores. Analysis of 18 insertional mutations in the N-terminal domain of the capsid protein (CA) identified 3 that were severely defective for viral assembly and release. Transmission electron microscopy of cells producing these mutants showed assembly of Gag proteins in large, flat or dome-shaped patches at the plasma membrane. Spherical cores were not formed, and viral particles were not released. This late assembly/release block was partially rescued by wild-type virus. All three mutations localized to the small loop between α-helices 4 and 5 of CA, analogous to the cyclophilin A-binding loop of human immunodeficiency virus type 1 CA. In the X-ray structure of the hexameric form of MLV CA, this loop is located at the periphery of the hexamer. The phenotypes of mutations in this loop suggest that formation of a planar lattice of Gag is unhindered by mutations in the loop. However, the lack of progression of these planar structures to spherical ones suggests that mutations in this loop may prevent formation of pentamers or of stable pentamer-hexamer interactions, which are essential for the formation of a closed, spherical core. This region in CA, focused to a few residues of a small loop, may offer a novel therapeutic target for retroviral diseases.