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1.  Developmental Delays and Reduced Pup Ultrasonic Vocalizations but Normal Sociability in Mice Lacking the Postsynaptic Cell Adhesion Protein Neuroligin2 
Behavioural brain research  2012;251:50-64.
Mutations in neurexin and neuroligin genes have been associated with neurodevelopmental disabilities including autism. Autism spectrum disorder is diagnosed by aberrant reciprocal social interactions, deficits in social communication, and repetitive, stereotyped patterns of behaviors, along with narrow restricted interests. Mouse models have been successfully used to study physiological and behavioral outcomes of mutations in the trans-synaptic neurexin-neuroligin complex. To further understand the behavioral consequences of NEUROLIGIN2 (NLGN2) mutations, we assessed several behavioral phenotypes relevant to autism in neuroligin2 null (Nlgn2-/-), heterozygote (Nlgn2+/-), and wildtype (Nlgn2+/+) littermate control mice. Reduced breeding efficiency and high reactivity to handling was observed in Nlgn2-/- mice, resulting in low numbers of adult mice available for behavioral assessment. Consistent with previous findings, Nlgn2-/- mice displayed normal social behaviors, concomitant with reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones. No spontaneous stereotypies or repetitive behaviors were detected. Acoustic, tactile, and olfactory sensory information processing as well as sensorimotor gating were not affected. Nlgn2-/- pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2+/+ littermate controls. The present findings add to the growing literature on the role of neurexins and neuroligins in physiology and behavior relevant to neurodevelopmental disorders.
PMCID: PMC3979986  PMID: 22820233
Neuroligin; GABA; inhibition; autism; schizophrenia; anxiety; social behavior; communication; ultrasonic vocalization
2.  Time-Dependent Compensatory Responses to Chronic Neuroinflammation in Hippocampus and Brainstem: The Potential Role of Glutamate Neurotransmission 
Chronic neuroinflammation is characteristic of neurodegenerative diseases and is present during very early stages, yet significant pathology and behavioral deficits do not manifest until advanced age. We investigated the consequences of experimentally-induced chronic neuroinflammation within the hippocampus and brainstem of young (4 mo) F-344 rats. Lipopolysaccharide (LPS) was infused continuously into the IVth ventricle for 2, 4 or 8 weeks. The number of MHC II immunoreactive microglia in the brain continued to increase throughout the infusion period. In contrast, performance in the Morris water maze was impaired after 4 weeks but recovered by 8 weeks. Likewise, a transient loss of tyrosine hydroxylase immunoreactivity in the substantia nigra and locus coeruleus was observed after 2 weeks, but returned to control levels by 4 weeks of continuous LPS infusion. These data suggest that direct activation of microglia is sufficient to drive, but not sustain, spatial memory impairment and a decrease in tyrosine hydroxylase production in young rats. Our previous studies suggest that chronic neuroinflammation elevates extracellular glutamate and that this elevation underlies the spatial memory impairment. In the current study, increased levels of GLT1 and SNAP25 in the hippocampus corresponded with the resolution of performance deficit. Increased expression of SNAP25 is consistent with reduced glutamate release from axonal terminals while increased GLT1 is consistent with enhanced clearance of extracellular glutamate. These data demonstrate the capacity of the brain to compensate for the presence of chronic neuroinflammation, despite continued activation of microglia, through changes in the regulation of the glutamatergic system.
PMCID: PMC3939715  PMID: 24600537
Neuroinflammation; Rat; Lipopolysaccharide; Alzheimer; Parkinson; Glutamate; Excitatory amino acid transporter; SNAP25
3.  A Randomized Trial of Rectal Indomethacin to Prevent Post-ERCP Pancreatitis 
The New England Journal of Medicine  2012;366(15):1414-1422.
Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).
In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.
A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03).
Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; number, NCT00820612.)
PMCID: PMC3339271  PMID: 22494121
4.  Sociability and Motor Functions in Shank1 Mutant Mice 
Brain research  2010;1380:120-137.
Autism is a neurodevelopmental disorder characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. While the etiology remains unclear, strong evidence exists for a genetic component, and several synaptic genes have been implicated. SHANK genes encode a family of synaptic scaffolding proteins located postsynaptically on excitatory synapses. Mutations in SHANK genes have been detected in several autistic individuals. To understand the consequences of SHANK mutations relevant to the diagnostic and associated symptoms of autism, comprehensive behavioral phenotyping on a line of Shank1 mutant mice was conducted on multiple measures of social interactions, social olfaction, repetitive behaviors, anxiety-related behaviors, motor functions, and a series of control measures for physical abilities. Results from our comprehensive behavioral phenotyping battery indicated that adult Shank1 null mutant mice were similar to their wildtype and heterozygous littermates on standardized measures of general health, neurological reflexes and sensory skills. Motor functions were reduced in the null mutants on open field activity, rotarod, and wire hang, replicating and extending previous findings (Hung et al., 2008). A partial anxiety-like phenotype was detected in the null mutants in some components of the light ↔ dark task, as previously reported (Hung et al., 2008) but not in the elevated plus-maze. Juvenile reciprocal social interactions did not differ across genotypes. Interpretation of adult social approach was confounded by a lack of normal sociability in wildtype and heterozygous littermates. All genotypes were able to discriminate social odors on an olfactory habituation/dishabituation task. All genotypes displayed relatively high levels of repetitive self-grooming. Our findings support the interpretation that Shank1 null mice do not demonstrate autism-relevant social deficits, but confirm and extend a role for Shank1 in motor functions.
PMCID: PMC3041833  PMID: 20868654
5.  Low Stress Reactivity and Neuroendocrine Factors in the BTBR T+tf/J Mouse Model of Autism 
Neuroscience  2010;171(4):1197-1208.
Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that displays robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including low social interactions, reduced vocalizations in social settings, and high levels of repetitive self-grooming. Autism-relevant phenotypes in BTBR offer translational tools to discover neurochemical mechanisms underlying unusual mouse behaviors relevant to symptoms of autism. Because repetitive self-grooming in mice may be a displacement behavior elevated by stressors, we investigated neuroendocrine markers of stress and behavioral reactivity to stressors in BTBR mice, as compared to C57BL/6J, a standard inbred strain with high sociability. Radioimmunoassays replicated previous findings that circulating corticosterone is higher in the BTBR than in B6. Higher basal glucocorticoid receptor mRNA and higher oxytocin peptide levels were detected in the brains of BTBR as compared to B6. No significant differences were detected in corticotrophin releasing factor (CRF) peptide or CRF mRNA. In response to behavioral stressors, BTBR and B6 were generally similar on behavioral tasks including stress-induced hyperthermia, elevated plus-maze, light ↔ dark exploration, tail flick, acoustic startle and prepulse inhibition. BTBR displayed less reactivity than B6 to a noxious thermal stimulus in the hot plate, and less immobility than B6 in both the forced swim and tail suspension depression-related tasks. BTBR, therefore, exhibited less depression-like scores than B6 on two standard tests sensitive to antidepressants, did not differ from B6 on two well-validated anxiety-like behaviors, and did not exhibit unusual stress reactivity to sensory stimuli. Our findings support the interpretation that autism-relevant social deficits, vocalizations, and repetitive behaviors are not the result of abnormal stress reactivity in the BTBR mouse model of autism.
PMCID: PMC2991427  PMID: 20888890
autism; mouse models; BTBR
6.  Endometrial carcinoma diagnosed by scapular biopsy: A case report 
► Endometrial cancer diagnosed by scapular biopsy. ► Advanced cancer may present with metastatic disease to the bone.
PMCID: PMC3857686  PMID: 24371590
Endometrial carcinoma; Bone metastases; Lytic bone lesion; Scapular mass
7.  Why Have College Completion Rates Declined? An Analysis of Changing Student Preparation and Collegiate Resources† 
Rising college enrollment over the last quarter century has not been met with a proportional increase in college completion. Comparing the high school classes of 1972 and 1992, we show declines in college completion rates have been most pronounced for men who first enroll in less selective public universities and community colleges. We decompose the decline into the components due to changes in preparedness of entering students and due to changes in collegiate characteristics, including type of institution and resources per student. While both factors play some role, the supply-side characteristics are most important in explaining changes in college completion. (JEL I23)
PMCID: PMC3140225  PMID: 21785668
8.  A Randomized Controlled Trial of Whole Body Vibration Exposure on Markers of Bone Turnover in Postmenopausal Women 
Journal of Osteoporosis  2011;2011:710387.
Purpose. To examine the effects of two doses of low-frequency (12 Hz), low-magnitude (0.3 g), whole body vibration on markers of bone formation and resorption in postmenopausal women. Methods. Women were recruited and randomized into a sham vibration control group, one time per week vibration group (1×/week), or three times per week vibration group (3×/week). Vibration exposure consisted of 20 minutes of intermittent vibration for the 1×/week and 3×/week groups, and sham vibration (<0.1 g) for the control group for eight weeks. Double-blinded primary outcome measures were urine markers of bone resorption: N-telopeptide X normalised to creatinine (NTx/Cr) and bone formation: bone-specific alkaline phosphatase (ALP). Results. Forty-six women (59.8 ± 6.2 years, median 7.3 years since menopause) were enrolled. NTx/Cr was significantly reduced (34.6%) in the 3×/wk vibration group but not in the 1×/wk vibration group compared with sham control (P < .01) group. No effect of time or group allocation was observed on the bone formation marker ALP (P = .27). Conclusion. We have shown for the first time that low-frequency, low-magnitude vibration 3×/week for eight weeks in postmenopausal women results in a significant reduction in NTx/Cr, a marker of bone resorption, when compared with sham vibration exposure.
PMCID: PMC3135216  PMID: 21772975
9.  Sequence-based analysis of pQBR103; a representative of a unique, transfer-proficient mega plasmid resident in the microbial community of sugar beet 
The ISME journal  2007;1(4):331-340.
The plasmid pQBR103 was found within Pseudomonas populations colonizing the leaf and root surfaces of sugar beet plants growing at Wytham, Oxfordshire, UK. At 425 kb it is the largest self-transmissible plasmid yet sequenced from the phytosphere. It is known to enhance the competitive fitness of its host, and parts of the plasmid are known to be actively transcribed in the plant environment. Analysis of the complete sequence of this plasmid predicts a coding sequence (CDS)-rich genome containing 478 CDSs and an exceptional degree of genetic novelty; 80% of predicted coding sequences cannot be ascribed a function and 60% are orphans. Of those to which function could be assigned, 40% bore greatest similarity to sequences from Pseudomonas spp, and the majority of the remainder showed similarity to other c-proteobacterial genera and plasmids. pQBR103 has identifiable regions presumed responsible for replication and partitioning, but despite being tra+ lacks the full complement of any previously described conjugal transfer functions. The DNA sequence provided few insights into the functional significance of plant-induced transcriptional regions, but suggests that 14% of CDSs may be expressed (11 CDSs with functional annotation and 54 without), further highlighting the ecological importance of these novel CDSs. Comparative analysis indicates that pQBR103 shares significant regions of sequence with other plasmids isolated from sugar beet plants grown at the same geographic location. These plasmid sequences indicate there is more novelty in the mobile DNA pool accessible to phytosphere pseudomonas than is currently appreciated or understood.
PMCID: PMC2656933  PMID: 18043644
Pseudomonas; phytosphere; environmental; plasmid; sequence
10.  Heterogeneous Selection in a Spatially Structured Environment Affects Fitness Tradeoffs of Plasmid Carriage in Pseudomonads▿  
Applied and Environmental Microbiology  2008;74(10):3189-3197.
Environmental conditions under which fitness tradeoffs of plasmid carriage are balanced to facilitate plasmid persistence remain elusive. Periodic selection for plasmid-encoded traits due to the spatial and temporal variation typical in most natural environments (such as soil particles, plant leaf and root surfaces, gut linings, and the skin) may play a role. However, quantification of selection pressures and their effects is difficult at a scale relevant to the bacterium in situ. The present work describes a novel experimental system for such fine-scale quantification, with conditions designed to mimic the mosaic of spatially variable selection pressures present in natural surface environments. The effects of uniform and spatially heterogeneous mercuric chloride (HgCl2) on the dynamics of a model community of plasmid-carrying, mercury-resistant (Hgr) and plasmid-free, mercury-sensitive (Hgs) pseudomonads were compared. Hg resulted in an increase in the surface area occupied by, and therefore an increase in the fitness of, Hgr bacteria relative to Hgs bacteria. Uniform and heterogeneous Hg distributions were demonstrated to result in different community structures by epifluorescence microscopy, with heterogeneous Hg producing spatially variable selection landscapes. The effects of heterogeneous Hg were only apparent at scales of a few hundred micrometers, emphasizing the importance of using appropriate analysis methods to detect effects of environmental heterogeneity on community dynamics. Heterogeneous Hg resulted in negative frequency-dependent selection for Hgr cells, suggesting that sporadic selection may facilitate the discontinuous distribution of plasmids through host populations in complex, structured environments.
PMCID: PMC2394952  PMID: 18378654
11.  The minimum information about a genome sequence (MIGS) specification 
Nature biotechnology  2008;26(5):541-547.
With the quantity of genomic data increasing at an exponential rate, it is imperative that these data be captured electronically, in a standard format. Standardization activities must proceed within the auspices of open-access and international working bodies. To tackle the issues surrounding the development of better descriptions of genomic investigations, we have formed the Genomic Standards Consortium (GSC). Here, we introduce the minimum information about a genome sequence (MIGS) specification with the intent of promoting participation in its development and discussing the resources that will be required to develop improved mechanisms of metadata capture and exchange. As part of its wider goals, the GSC also supports improving the ‘transparency’ of the information contained in existing genomic databases.
PMCID: PMC2409278  PMID: 18464787
12.  Transferable Antibiotic Resistance Elements in Haemophilus influenzae Share a Common Evolutionary Origin with a Diverse Family of Syntenic Genomic Islands 
Journal of Bacteriology  2004;186(23):8114-8122.
Transferable antibiotic resistance in Haemophilus influenzae was first detected in the early 1970s. After this, resistance spread rapidly worldwide and was shown to be transferred by a large 40- to 60-kb conjugative element. Bioinformatics analysis of the complete sequence of a typical H. influenzae conjugative resistance element, ICEHin1056, revealed the shared evolutionary origin of this element. ICEHin1056 has homology to 20 contiguous sequences in the National Center for Biotechnology Information database. Systematic comparison of these homologous sequences resulted in identification of a conserved syntenic genomic island consisting of up to 33 core genes in 16 β- and γ-Proteobacteria. These diverse genomic islands shared a common evolutionary origin, insert into tRNA genes, and have diverged widely, with G+C contents ranging from 40 to 70% and amino acid homologies as low as 20 to 25% for shared core genes. These core genes are likely to account for the conjugative transfer of the genomic islands and may even encode autonomous replication. Accessory gene clusters were nestled among the core genes and encode the following diverse major attributes: antibiotic, metal, and antiseptic resistance; degradation of chemicals; type IV secretion systems; two-component signaling systems; Vi antigen capsule synthesis; toxin production; and a wide range of metabolic functions. These related genomic islands include the following well-characterized structures: SPI-7, found in Salmonella enterica serovar Typhi; PAP1 or pKLC102, found in Pseudomonas aeruginosa; and the clc element, found in Pseudomonas sp. strain B13. This is the first report of a diverse family of related syntenic genomic islands with a deep evolutionary origin, and our findings challenge the view that genomic islands consist only of independently evolving modules.
PMCID: PMC529066  PMID: 15547285
13.  The Common Nodulation Genes of Astragalus sinicus Rhizobia Are Conserved despite Chromosomal Diversity 
The nodulation genes of Mesorhizobium sp. (Astragalus sinicus) strain 7653R were cloned by functional complementation of Sinorhizobium meliloti nod mutants. The common nod genes, nodD, nodA, and nodBC, were identified by heterologous hybridization and sequence analysis. The nodA gene was found to be separated from nodBC by approximately 22 kb and was divergently transcribed. The 2.0-kb nodDBC region was amplified by PCR from 24 rhizobial strains nodulating A. sinicus, which represented different chromosomal genotypes and geographic origins. No polymorphism was found in the size of PCR products, suggesting that the separation of nodA from nodBC is a common feature of A. sinicus rhizobia. Sequence analysis of the PCR-amplified nodA gene indicated that seven strains representing different 16S and 23S ribosomal DNA genotypes had identical nodA sequences. These data indicate that, whereas microsymbionts of A. sinicus exhibit chromosomal diversity, their nodulation genes are conserved, supporting the hypothesis of horizontal transfer of nod genes among diverse recipient bacteria.
PMCID: PMC92101  PMID: 10877796

Results 1-13 (13)