PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (127)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences 
Nature genetics  2016;48(6):593-599.
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including SNVs, MNVs, indels, STRs, and CNVs. Of these, CNVs contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree based on binary SNVs and projected the more complex variants onto it, estimating the numbers of mutations for each class. Our phylogeny reveals bursts of extreme expansions in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.
doi:10.1038/ng.3559
PMCID: PMC4884158  PMID: 27111036
2.  From Savannas to Settlements: Exploring Cognitive Foundations for the Design of Urban Spaces 
Frontiers in Psychology  2016;7:1607.
Urban configurations in developing countries have become the subject of urban design, with good design promoting economic benefits. Yet, the common practice of urban design lacks a principled scientific foundation. In this respect, cognitive neuroscience could provide a unique perspective and potential foundational insights regarding how embodied cognition links configuration with movement. Although the neural networks that underlie navigation abilities in the brain have been extensively studied, the manner in which these networks might best constrain urban configurations has not been examined specifically. Moreover, it remains an open issue whether the neurological development and functional topographies in the brain that could potentially constrain such urban configurations might also replicate the geometric structures of those environments that were the cradle of human evolution. We propose urban grid-form settlement patterns may be a result of the naturally evolved structures of the human brain. We suggest then that a potential agenda for experimentation and debate could focus on neurological underpinnings of movement choices in urban places. Such an agenda would benefit from bridging a gap between C.P. Snow’s two cultures, i.e., among architects and neuroscientists. Here, we provide a perspective to engender such further dialog on the design of embodied urban spaces and the potential neural systems that may constrain their design.
doi:10.3389/fpsyg.2016.01607
PMCID: PMC5078783  PMID: 27826264
urban design; embodied space; prospect-refuge theory; grid-form streets; hippocampal cells; system 1 heuristics
3.  Commissural functional topography of the inferior colliculus assessed in vitro 
Hearing research  2015;328:94-101.
The inferior colliculus (IC) receives ascending and descending information from several convergent neural sources. As such, exploring the neural pathways that converge in the IC is crucial to uncovering their multi-varied roles in the integration of auditory and other sensory information. Among these convergent pathways, the IC commissural connections represent an important route for the integration of bilateral information in the auditory system. Here, we describe the preparation and validation of a novel in vitro slice preparation for examining the functional topography and synaptic properties of the commissural and intrinsic projections in the IC of the mouse. This preparation, in combination with modern genetic approaches in the mouse, enables the specific examination of these pathways, which potentially can reveal cell-type specific processing channels in the auditory midbrain.
doi:10.1016/j.heares.2015.08.011
PMCID: PMC4582000  PMID: 26319767
inferior colliculus; commissural; GABA; inhibition; auditory; disinhibition
4.  Nicotinic alteration of functional thalamocortical topography 
Neuroreport  2015;26(12):688-694.
The thalamocortical pathways form highly topographic connections from the primary sensory thalamic nuclei to the primary cortical areas. The synaptic properties of these thalamocortical connections are modifiable by activation from various neuromodulators, such as acetylcholine. Cholinergic activation can alter functional properties in both the developing and mature nervous system. Moreover, environmental factors, such as nicotine, can activate these receptors, although the circuit-level alterations resulting from such nicotinic activation of sensory neural circuits remain largely unexplored. Therefore, we examined alterations to the functional topography of thalamocortical circuits in the developing sensory pathways of the mouse. Photostimulation via uncaging of glutamate was used to map these functional thalamocortical alterations in response to nicotinic receptor activation. As a result, we found that activation of forebrain nicotinic acetylcholine receptors results in an expansion and enhancement of functional thalamocortical topographies as assessed in brain slice preparations using laser-scanning photostimulation via uncgaing of glutamate. These physiological changes were correlated with the neuroanatomical expression of nicotinic acetylcholine receptor subtypes (α7 and β2). These circuit level alterations may provide a neural substrate underlying the plastic development and reshaping of thalamocortical circuitry in response to nicotinic receptor activation.
doi:10.1097/WNR.0000000000000409
PMCID: PMC4506132  PMID: 26164456
nicotine; thalamus; cortex; layer 4; medial geniculate body; auditory; somatosensory; ventrobasal nucleus; thalamocortical; nicotinic acetylcholine receptor
5.  Engineering microdeletions and microduplications by targeting segmental duplications with CRISPR 
Nature neuroscience  2016;19(3):517-522.
Recurrent, reciprocal genomic disorders resulting from non-allelic homologous recombination (NAHR) between near-identical segmental duplications (SDs) are a major cause of human disease, often producing phenotypically distinct syndromes. The genomic architecture of flanking SDs presents a significant challenge for modeling these syndromes; however, the capability to efficiently generate reciprocal copy number variants (CNVs) that mimic NAHR would represent an invaluable modeling tool. We describe here a CRISPR/Cas9 genome engineering method, Single-guide-CRISPR/Cas-targeting-Of-Repetitive-Elements (SCORE), to model reciprocal genomic disorders and demonstrate its capabilities by generating reciprocal CNVs of 16p11.2 and 15q13.3, including alteration of one copy-equivalent of the SDs that mediate NAHR in vivo. The method is reproducible and RNAseq reliably clusters transcriptional signatures from human subjects with in vivo CNV and their corresponding in vitro models. This new approach will provide broad applicability for the study of genomic disorders and, with further development, may also permit efficient correction of these defects.
doi:10.1038/nn.4235
PMCID: PMC4903018  PMID: 26829649
CRISPR; Cas9; Genomic Disorder; 16p11.2; NAHR; Genome Editing; Copy Number Variation (CNV); Structural Variation; Homology
6.  Impact of pay-for-performance on mortality in diabetes patients in Taiwan 
Medicine  2016;95(27):e4197.
Supplemental Digital Content is available in the text
Abstract
Background:
The impact of pay-for-performance (P4P) programs on long-term mortality for chronic illnesses, especially diabetes mellitus, has been rarely reported. Several studies described the favorable impact of P4P for diabetes mellitus on medical utilizations or intermediate outcomes. Therefore, this study aimed to investigate the impact of a P4P program on mortality in patients with type 2 diabetes.
Methods:
The P4P group in this population-based cohort study was 2090 individuals with a primary diagnosis of type 2 diabetes who had been newly enrolled in the P4P program of Taiwan between January 1, 2004 and December 31, 2004. Matched by 1:1 ratio, patients in the non-P4P group were selected by propensity score matching (PSM) for sex, age, the first year of diagnosis as diabetes, and 32 other potential confounding factors. Mean (SD) age was 60.91 (12.04) years when diabetes was first diagnosed and mean (SD) duration of diabetes was 4.3 (1.9) years at baseline. The time-dependent Cox regression model was used to explore the impact of P4P on all-cause mortality.
Results:
During a mean of 5.13 years (SD = 1.07 years) of follow-up, 206 and 263 subjects died in the P4P group and the non-P4P group, respectively. After adjusting for the potential confounding factors at baseline, survival was significantly longer in the P4P group than in the non-P4P group (hazard ratio, 0.76 [95% confidence interval, 0.64–0.92], P = 0.004, by log-rank test). This decrease in mortality is equivalent to one less death for every 37 patients who were treated in the P4P program for 5.13 years. In this study, the P4P program significantly increased the medical utilization of physician visits and diabetes-related examinations, improved the adherence of oral hypoglycemic drugs during the first 3 years and that of insulin during the second 3 years, and was negatively associated with risk of cancer and chronic kidney disease. In annual health expense, there was no significant difference between P4P and non-P4P groups, P = 0.430.
Conclusions:
As compared with control, pay-for-performance program significantly improved survival in patients with diabetes without increasing the medical cost. The P4P group had significantly lower risk of cancer and chronic kidney disease.
doi:10.1097/MD.0000000000004197
PMCID: PMC5058873  PMID: 27399144
mortality; pay-for-performance; type 2 diabetes
7.  Inhibition of mammillary body neurons by direct activation of Group II metabotropic glutamate receptors 
The mammillary body is an important neural component of limbic circuitry implicated in learning and memory. Excitatory and inhibitory inputs, primarily mediated by glutamate and gamma-amino butyric acid (GABA), respectively, converge and integrate in this region, before sending information to the thalamus. One potentially overlooked mechanism for inhibition of mammillary body neurons is through direct activation of Group II metabotropic glutamate receptors (mGluRs). Here, whole-cell patch clamp recordings of in vitro slice preparations containing the mammillary body nuclei of the mouse were employed to record responses to bath application of pharmacological agents to isolate the direct effect of activating Group II mGluRs. Application of the Group II mGluR specific agonist, APDC, resulted in a hyperpolarization of the membrane potential in mammillary body neurons, likely resulting from the opening of a potassium conductance. These data suggest that glutamatergic inputs to the mammillary body may be attenuated via Group II mGluRs and implicates a functional role for these receptors in memory-related circuits and broadly throughout the central nervous system.
PMCID: PMC4933320  PMID: 27390777
mammillary body; glutamate; inhibition; Group II mGluR; metabotropic glutamate receptor; limbic system
8.  Development of a new diabetes medication self-efficacy scale and its association with both reported problems in using diabetes medications and self-reported adherence 
Patient preference and adherence  2016;10:1003-1010.
Background
Although there are several different general diabetes self-efficacy scales, there is a need to develop a self-efficacy scale that providers can use to assess patient’s self-efficacy regarding medication use. The purpose of this study was to: 1) develop a new diabetes medication self-efficacy scale and 2) examine how diabetes medication self-efficacy is associated with patient-reported problems in using diabetes medications and self-reported adherence.
Patients and methods
Adult English-speaking patients with type 2 diabetes were recruited from a family medicine clinic and a pharmacy in Eastern North Carolina, USA. The patients were eligible if they reported being nonadherent to their diabetes medicines on a visual analog scale. Multivariable regression was used to examine the relationship between self-efficacy and the number of reported diabetes medication problems and adherence.
Results
The diabetes medication self-efficacy scale had strong reliability (Cronbach’s alpha =0.86). Among a sample (N=51) of mostly African-American female patients, diabetes medication problems were common (6.1±3.1) and a greater number of diabetes medications were associated with lower medication adherence (odds ratio: 0.35; 95% confidence interval: 0.13, 0.89). Higher medication self-efficacy was significantly related to medication adherence (odds ratio: 1.17; 95% confidence interval: 1.05, 1.30) and inversely related to the number of self-reported medication problems (β=−0.13; P=0.006).
Conclusion
Higher diabetes medication self-efficacy was associated with fewer patient-reported medication problems and better medication adherence. Assessing medication-specific self-efficacy may help to identify medication-related problems that providers can help the patients address, potentially improving adherence and patient outcomes.
doi:10.2147/PPA.S101349
PMCID: PMC4908948  PMID: 27354769
diabetes; adherence; self-efficacy; literacy
9.  Wisteria Floribunda Agglutinin-Labeled Perineuronal Nets in the Mouse Inferior Colliculus, Thalamic Reticular Nucleus and Auditory Cortex 
Brain Sciences  2016;6(2):13.
Perineuronal nets (PNNs) are specialized extracellular matrix molecules that are associated with the closing of the critical period, among other functions. In the adult brain, PNNs surround specific types of neurons, however the expression of PNNs in the auditory system of the mouse, particularly at the level of the midbrain and forebrain, has not been fully described. In addition, the association of PNNs with excitatory and inhibitory cell types in these structures remains unknown. Therefore, we sought to investigate the expression of PNNs in the inferior colliculus (IC), thalamic reticular nucleus (TRN) and primary auditory cortex (A1) of the mouse brain by labeling with wisteria floribunda agglutinin (WFA). To aid in the identification of inhibitory neurons in these structures, we employed the vesicular GABA transporter (VGAT)-Venus transgenic mouse strain, which robustly expresses an enhanced yellow-fluorescent protein (Venus) natively in nearly all gamma-amino butyric acid (GABA)-ergic inhibitory neurons, thus enabling a rapid and unambiguous assessment of inhibitory neurons throughout the nervous system. Our results demonstrate that PNNs are expressed throughout the auditory midbrain and forebrain, but vary in their local distribution. PNNs are most dense in the TRN and least dense in A1. Furthermore, PNNs are preferentially associated with inhibitory neurons in A1 and the TRN, but not in the IC of the mouse. These data suggest regionally specific roles for PNNs in auditory information processing.
doi:10.3390/brainsci6020013
PMCID: PMC4931490  PMID: 27089371
auditory; thalamus; cortex; midbrain; thalamic reticular nucleus; inferior colliculus; auditory cortex; wisteria floribunda agglutinin
10.  An integrated map of structural variation in 2,504 human genomes 
Sudmant, Peter H. | Rausch, Tobias | Gardner, Eugene J. | Handsaker, Robert E. | Abyzov, Alexej | Huddleston, John | Zhang, Yan | Ye, Kai | Jun, Goo | Fritz, Markus Hsi-Yang | Konkel, Miriam K. | Malhotra, Ankit | Stütz, Adrian M. | Shi, Xinghua | Casale, Francesco Paolo | Chen, Jieming | Hormozdiari, Fereydoun | Dayama, Gargi | Chen, Ken | Malig, Maika | Chaisson, Mark J.P. | Walter, Klaudia | Meiers, Sascha | Kashin, Seva | Garrison, Erik | Auton, Adam | Lam, Hugo Y. K. | Mu, Xinmeng Jasmine | Alkan, Can | Antaki, Danny | Bae, Taejeong | Cerveira, Eliza | Chines, Peter | Chong, Zechen | Clarke, Laura | Dal, Elif | Ding, Li | Emery, Sarah | Fan, Xian | Gujral, Madhusudan | Kahveci, Fatma | Kidd, Jeffrey M. | Kong, Yu | Lameijer, Eric-Wubbo | McCarthy, Shane | Flicek, Paul | Gibbs, Richard A. | Marth, Gabor | Mason, Christopher E. | Menelaou, Androniki | Muzny, Donna M. | Nelson, Bradley J. | Noor, Amina | Parrish, Nicholas F. | Pendleton, Matthew | Quitadamo, Andrew | Raeder, Benjamin | Schadt, Eric E. | Romanovitch, Mallory | Schlattl, Andreas | Sebra, Robert | Shabalin, Andrey A. | Untergasser, Andreas | Walker, Jerilyn A. | Wang, Min | Yu, Fuli | Zhang, Chengsheng | Zhang, Jing | Zheng-Bradley, Xiangqun | Zhou, Wanding | Zichner, Thomas | Sebat, Jonathan | Batzer, Mark A. | McCarroll, Steven A. | Mills, Ryan E. | Gerstein, Mark B. | Bashir, Ali | Stegle, Oliver | Devine, Scott E. | Lee, Charles | Eichler, Evan E. | Korbel, Jan O.
Nature  2015;526(7571):75-81.
Summary
Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype-blocks in 26 human populations. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.
doi:10.1038/nature15394
PMCID: PMC4617611  PMID: 26432246
11.  Shared Acquired Genomic Changes in Zebrafish and Human T-ALL 
Oncogene  2011;30(41):4289-4296.
T cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover genetic changes occurring in T-ALL, and those contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from 4 zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) to a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in >3 zebrafish cancers and ≥4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with 3 zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies to aCGH results from 50 human T-ALL patients who failed induction, relapsed, or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, 9 recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution.
doi:10.1038/onc.2011.138
PMCID: PMC4811672  PMID: 21552289
T cell acute lymphoblastic leukemia (T-ALL); array comparative genome hybridization (aCGH); zebrafish; copy number aberration (CNA); leukemogenesis
12.  An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts 
Molecules and Cells  2016;39(2):77-86.
Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients’ tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.
doi:10.14348/molcells.2016.2350
PMCID: PMC4757806  PMID: 26831452
cancer drug development; cancer genomics; patient-derived xenografts; precision medicine
13.  Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms 
Nature communications  2015;6:7256.
Investigating genomic structural variants at basepair resolution is crucial for understanding their formation mechanisms. We identify and analyze 8,943 deletion breakpoints in 1,092 samples from the 1000 Genomes Project. We find breakpoints have more nearby SNPs and indels than the genomic average, likely a consequence of relaxed selection. By investigating the correlation of breakpoints with DNA methylation, Hi-C interactions, and histone marks and the substitution patterns of nucleotides near them, we find that breakpoints with the signature of non-allelic homologous recombination (NAHR) are associated with open chromatin. We hypothesize that some NAHR deletions occur without DNA replication and cell division, in embryonic and germline cells. In contrast, breakpoints associated with non-homologous (NH) mechanisms often have sequence micro-insertions, templated from later replicating genomic sites, spaced at two characteristic distances from the breakpoint. These micro-insertions are consistent with template-switching events and suggest a particular spatiotemporal configuration for DNA during the events.
doi:10.1038/ncomms8256
PMCID: PMC4451611  PMID: 26028266
14.  Asthma and Risk of Prostate Cancer 
Medicine  2015;94(36):e1371.
Abstract
Several epidemiologic studies in Western countries have examined the association between asthma and prostate cancer risk, but the results have been inconclusive. We investigated this association in a large, nationwide, population-based case-cohort study. Using the Taiwan National Health Insurance Research Database from 1997 to 2008, we collected data from 12,372 men, including 4124 with asthma and 8248 age-, residence-, and insurance premium-matched control subjects, who were never diagnosed with asthma. Competing risk-adjusted Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% confidence interval (CI) for determining the association between prostate cancer and asthma. During a mean follow-up of 5.05 years (standard deviation, 2.10), there were 74 cases of prostate cancer. The incidence of prostate cancer was 163.0/100,000 person-years (95% CI: 113.0–228.0) in the asthma patients. Asthma was significantly associated with prostate cancer (HR: 2.36; 95% CI: 1.22–4.57; P = 0.011) after adjusting for age, residential area, insurance premium, hypertriglyceridemia, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, duration of hospitalization, and mortality. In the subgroup analysis, independent risk factors for prostate cancer among men with asthma were age (HR: 1.09; 95% CI: 1.05–1.21; P < 0.001) and hypertension (HR: 2.75; 95% CI: 1.24–7.80; P = 0.047). The results of our study suggest that men with asthma have an increased risk of prostate cancer.
doi:10.1097/MD.0000000000001371
PMCID: PMC4616655  PMID: 26356691
15.  Brown Pine Leaf Extract and Its Active Component Trans-Communic Acid Inhibit UVB-Induced MMP-1 Expression by Targeting PI3K 
PLoS ONE  2015;10(6):e0128365.
Japanese red pine (Pinus densiflora) is widely present in China, Japan, and Korea. Its green pine leaves have traditionally been used as a food as well as a coloring agent. After being shed, pine leaves change their color from green to brown within two years, and although the brown pine leaves are abundantly available, their value has not been closely assessed. In this study, we investigated the potential anti-photoaging properties of brown pine leaves for skin. Brown pine leaf extract (BPLE) inhibited UVB-induced matrix metalloproteinase-1 (MMP-1) expression to a greater extent than pine leaf extract (PLE) in human keratinocytes and a human skin equivalent model. HPLC analysis revealed that the quantity of trans-communic acid (TCA) and dehydroabietic acid (DAA) significantly increases when the pine leaf color changes from green to brown. BPLE and TCA elicited reductions in UVB-induced MMP-1 mRNA expression and activator protein-1 (AP-1) transactivation by reducing DNA binding activity of phospho-c-Jun, c-fos and Fra-1. BPLE and TCA also inhibited UVB-induced Akt phosphorylation, but not mitogen activated protein kinase (MAPK), known regulators of AP-1 transactivation. We additionally found that BPLE and TCA inhibited phosphoinositide 3-kinase (PI3K), the upstream kinase of Akt, in vitro. In summary, both BPLE and its active component TCA exhibit protective effects against UVB-induced skin aging. Taken together, these findings underline the potential for BPLE and TCA to be utilized as anti-wrinkling agents and cosmetic ingredients, as they suppress UVB-induced MMP-1 expression.
doi:10.1371/journal.pone.0128365
PMCID: PMC4465834  PMID: 26066652
16.  Benthic microbial communities of coastal terrestrial and ice shelf Antarctic meltwater ponds 
The numerous perennial meltwater ponds distributed throughout Antarctica represent diverse and productive ecosystems central to the ecological functioning of the surrounding ultra oligotrophic environment. The dominant taxa in the pond benthic communities have been well described however, little is known regarding their regional dispersal and local drivers to community structure. The benthic microbial communities of 12 meltwater ponds in the McMurdo Sound of Antarctica were investigated to examine variation between pond microbial communities and their biogeography. Geochemically comparable but geomorphologically distinct ponds were selected from Bratina Island (ice shelf) and Miers Valley (terrestrial) (<40 km between study sites), and community structure within ponds was compared using DNA fingerprinting and pyrosequencing of 16S rRNA gene amplicons. More than 85% of total sequence reads were shared between pooled benthic communities at different locations (OTU0.05), which in combination with favorable prevailing winds suggests aeolian regional distribution. Consistent with previous findings Proteobacteria and Bacteroidetes were the dominant phyla representing over 50% of total sequences; however, a large number of other phyla (21) were also detected in this ecosystem. Although dominant Bacteria were ubiquitous between ponds, site and local selection resulted in heterogeneous community structures and with more than 45% of diversity being pond specific. Potassium was identified as the most significant contributing factor to the cosmopolitan community structure and aluminum to the location unique community based on a BEST analysis (Spearman's correlation coefficient of 0.632 and 0.806, respectively). These results indicate that the microbial communities in meltwater ponds are easily dispersed regionally and that the local geochemical environment drives the ponds community structure.
doi:10.3389/fmicb.2015.00485
PMCID: PMC4444838  PMID: 26074890
biogeography; Antarctic; benthic; microbial; pond
17.  Functional Annotation of Proteome Encoded by Human Chromosome 22 
Journal of Proteome Research  2014;13(6):2749-2760.
As part of the chromosome-centric human proteome project (C-HPP) initiative, we report our progress on the annotation of chromosome 22. Chromosome 22, spanning 51 million base pairs, was the first chromosome to be sequenced. Gene dosage alterations on this chromosome have been shown to be associated with a number of congenital anomalies. In addition, several rare but aggressive tumors have been associated with this chromosome. A number of important gene families including immunoglobulin lambda locus, Crystallin beta family, and APOBEC gene family are located on this chromosome. On the basis of proteomic profiling of 30 histologically normal tissues and cells using high-resolution mass spectrometry, we show protein evidence of 367 genes on chromosome 22. Importantly, this includes 47 proteins, which are currently annotated as “missing” proteins. We also confirmed the translation start sites of 120 chromosome 22-encoded proteins. Employing a comprehensive proteogenomics analysis pipeline, we provide evidence of novel coding regions on this chromosome which include upstream ORFs and novel exons in addition to correcting existing gene structures. We describe tissue-wise expression of the proteins and the distribution of gene families on this chromosome. These data have been deposited to ProteomeXchange with the identifier PXD000561.
doi:10.1021/pr401169d
PMCID: PMC4059257  PMID: 24669763
human proteome; “missing” proteins; genome annotation; uORF
18.  Clonal evolution enhances leukemia propagating cell frequency in T-cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation 
Cancer cell  2014;25(3):366-378.
SUMMARY
Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T-cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection.
doi:10.1016/j.ccr.2014.01.032
PMCID: PMC3992437  PMID: 24613413
20.  Aspirin Use Associated With Amyotrophic Lateral Sclerosis: a Total Population-Based Case-Control Study 
Journal of Epidemiology  2015;25(2):172-177.
Background
The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan.
Methods
A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives.
Results
Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years.
Conclusions
The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people.
doi:10.2188/jea.JE20140070
PMCID: PMC4310879  PMID: 25721071
amyotrophic lateral sclerosis; aspirin; case-control study
21.  Exploring functions for the non-lemniscal auditory thalamus 
The functions of the medial geniculate body (MGB) in normal hearing still remain somewhat enigmatic, in part due to the relatively unexplored properties of the non-lemniscal MGB nuclei. Indeed, the canonical view of the thalamus as a simple relay for transmitting ascending information to the cortex belies a role in higher-order forebrain processes. However, recent anatomical and physiological findings now suggest important information and affective processing roles for the non-primary auditory thalamic nuclei. The non-lemniscal nuclei send and receive feedforward and feedback projections among a wide constellation of midbrain, cortical, and limbic-related sites, which support potential conduits for auditory information flow to higher auditory cortical areas, mediators for transitioning among arousal states, and synchronizers of activity across expansive cortical territories. Considered here is a perspective on the putative and unresolved functional roles of the non-lemniscal nuclei of the MGB.
doi:10.3389/fncir.2015.00069
PMCID: PMC4631820  PMID: 26582978
auditory; thalamus; cortex; corticothalamic; thalamocortical; amygdala
22.  Federal Regulation of Unapproved Chelation Products 
Journal of Medical Toxicology  2013;9(4):313-317.
Chelation products can be helpful in the treatment of metal poisoning. However, many unapproved products with unproven effectiveness and safety are marketed to consumers, frequently via the internet. This paper describes the primary responsibility of the Health Fraud and Consumer Outreach Branch of the United States Food and Drug Administration to identify and address health fraud products. Efforts to prevent direct and indirect hazards to the population’s health through regulatory actions are described.
doi:10.1007/s13181-013-0342-7
PMCID: PMC3846963  PMID: 24197664
Chelation products; FDA; Health fraud; FD&C Act; Federal regulatory action
23.  Differential expression of mGluR2 in the developing cerebral cortex of the mouse 
Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.
doi:10.4236/jbise.2014.713100
PMCID: PMC4235154  PMID: 25414764
metabotropic glutamate receptor; mouse; cortex; mGluR2; Group II mGluR
24.  Functional convergence of thalamic and intrinsic projections to cortical layers 4 and 6 
Neurophysiology  2013;45(5-6):396-406.
Ascending sensory information is conveyed from the thalamus to layers 4 and 6 of sensory cortical areas. Interestingly, receptive field properties of cortical layer 6 neurons are different from those in layer 4. Do such differences reflect distinct inheritance patterns from the thalamus or are they derived instead from local cortical circuits? To distinguish between these possibilities, we utilized in vitro slice preparations containing the thalamocortical pathways in the auditory and somatosensory systems. Responses from neurons in layers 4 and 6 that resided in the same column were recorded using whole-cell patch clamp. Laser-scanning photostimulation via uncaging of glutamate in the thalamus and cortex was used to map the functional topography of thalamocortical and intracortical inputs to each layer. In addition, we assessed the functional divergence of thalamocortical inputs by optical imaging of flavoprotein autofluorescence. We found that the thalamocortical inputs to layers 4 and 6 originated from the same thalamic domain, but the intracortical projections to the same neurons differed dramatically. Our results suggest that the intracortical projections, rather than the thalamic inputs, to each layer contribute more to the differences in their receptive field properties.
doi:10.1007/s11062-013-9385-2
PMCID: PMC3928022  PMID: 24563558
25.  The ecological dichotomy of ammonia-oxidizing archaea and bacteria in the hyper-arid soils of the Antarctic Dry Valleys 
The McMurdo Dry Valleys of Antarctica are considered to be one of the most physically and chemically extreme terrestrial environments on the Earth. However, little is known about the organisms involved in nitrogen transformations in these environments. In this study, we investigated the diversity and abundance of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in four McMurdo Dry Valleys with highly variable soil geochemical properties and climatic conditions: Miers Valley, Upper Wright Valley, Beacon Valley and Battleship Promontory. The bacterial communities of these four Dry Valleys have been examined previously, and the results suggested that the extremely localized bacterial diversities are likely driven by the disparate physicochemical conditions associated with these locations. Here we showed that AOB and AOA amoA gene diversity was generally low; only four AOA and three AOB operational taxonomic units (OTUs) were identified from a total of 420 AOA and AOB amoA clones. Quantitative PCR analysis of amoA genes revealed clear differences in the relative abundances of AOA and AOB amoA genes among samples from the four dry valleys. Although AOB amoA gene dominated the ammonia-oxidizing community in soils from Miers Valley and Battleship Promontory, AOA amoA gene were more abundant in samples from Upper Wright and Beacon Valleys, where the environmental conditions are considerably harsher (e.g., extremely low soil C/N ratios and much higher soil electrical conductivity). Correlations between environmental variables and amoA genes copy numbers, as examined by redundancy analysis (RDA), revealed that higher AOA/AOB ratios were closely related to soils with high salts and Cu contents and low pH. Our findings hint at a dichotomized distribution of AOA and AOB within the Dry Valleys, potentially driven by environmental constraints.
doi:10.3389/fmicb.2014.00515
PMCID: PMC4179728  PMID: 25324835
archaea; AOA; bacteria; AOB; ammonia oxidizers; Antarctica; Dry Valleys

Results 1-25 (127)