bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial dysfunction and HIF1α stabilization in inflammation
Authors: Garedew Assegid , Moncada Salvador
Published: October 2008

Activation of murine-derived J774.A1 macrophages with interferon γ and lipopolysaccharide leads to a progressive mitochondrial defect characterized by inhibition of oxygen consumption and a decrease in the generation of ATP by oxidative phosphorylation. These changes are dependent on the generation of nitric oxide (NO) by an inducible NO synthase that becomes a significant consumer of oxygen. Furthermore, in these activated cells there is a biphasic stabilization of the hypoxia-inducible factor HIF1α, the second phase of which is also dependent on the presence of NO. The mitochondrial defect and stabilization of HIF1α synergize to activate glycolysis, which, at its maximum, generates quantities of ATP greater than those produced by non-activated cells. Nevertheless, the amount of ATP generated is not sufficient to fulfil the energy requirements of the activated cells, probably leading to a progressive energy deficit with the consequent inhibition of cell proliferation and death.
The protein phosphatase PP2A-B′ subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism inDrosophila
Authors: Vereshchagina Natalia , Ramel Marie-Christine , Bitoun Emmanuelle , Wilson Clive
Published: October 2008

Inappropriate regulation of the PI3-kinase/PTEN/Akt kinase-signalling cassette, a key downstream target of insulin/insulin-like growth factor signalling (IIS), is associated with several major human diseases such as diabetes, obesity and cancer. In Drosophila, studies have recently revealed that different subcellular pools of activated, phosphorylated Akt can modulate different IIS-dependent processes. For example, a specific pool of activated Akt within the cytoplasm alters aspects of lipid metabolism, a process that is misregulated in both obesity and diabetes. However, it remains unclear how this pool is regulated. Here we show that the protein phosphatase PP2A-B′ regulatory subunit Widerborst (Wdb), which coimmunoprecipitates with Akt in vivo, selectively modulates levels of activated Akt in the cytoplasm. It alters lipid droplet size and expression of the lipid storage perilipin-like protein LSD2 in the Drosophila ovary, but not in epithelial cells of the eye imaginal discs. We conclude that isoforms of PP2A-B′ can act as subcellular-compartment-specific regulators of PI3-kinase/PTEN/Akt kinase signalling and IIS, potentially providing new targets for modulating individual subcellular pools of activated Akt in insulin-linked disease.
Human kidney anion exchanger 1 localisation in MDCK cells is controlled by the phosphorylation status of two critical tyrosines
Authors: Williamson Rosalind C. , Brown Alice C. N. , Mawby William J. , Toye Ashley M.
Published: October 2008

An important question in renal physiology is how the α-intercalated cells of the kidney regulate the distribution of the basolateral kidney anion exchanger 1 (kAE1) according to systemic acid-base status. Previous work using a MDCKI model system demonstrated that kAE1 basolateral targeting requires an N-terminal determinant and a critical C-terminal tyrosine (Y904). Here, we show that the N-terminal determinant is residue Y359, because a Y359A substitution mutant was mistargeted to the apical membrane. Further determinants might exist because a range of N-terminal kAE1 truncations that contained Y359 were incorrectly targeted to the TGN. Y359 and Y904 in kAE1 are phosphorylated upon pervanadate treatment and this phosphorylation is sensitive to specific Src kinase family inhibitors. We tested a range of stimuli on this model system and only the application of high nonphysiological concentrations of extracellular bicarbonate, and to a lesser extent hypertonicity or hyperosmolarity, induced tyrosine phosphorylation of kAE1. Treatment with pervanadate caused internalisation of kAE1 from the plasma membrane, but treatment with high concentrations of bicarbonate did not, because of the hypertonicity of the solution. We propose that α-intercalated cells control the distribution of kAE1 by reversible phosphorylation of tyrosine residues Y359 and Y904.
SHP-2 is a novel target of Abl kinases during cell proliferation
Authors: Mitra Sayan , Beach Carol , Feng Gen-Sheng , Plattner Rina
Published: October 2008

Previously, we showed that Abl family tyrosine kinases are activated by growth factors, and Abl is required for transition from G1 to S phase during PDGF-mediated proliferation. Here, we show that the SHP-2 tyrosine phosphatase, which acts to promote proliferation in response to cytokines and growth factors, is a novel substrate of endogenous Abl kinases during growth factor-mediated cellular proliferation. Using a pharmacological inhibitor and RNAi, we show that endogenous Abl kinases phosphorylate SHP-2 on Y580, and induce sustained activation of ERK kinases in response to growth factor stimulation in fibroblasts. Consistent with these data, SHP-2 is required for Abl-dependent PDGF-mediated proliferation since expression of an activated form of SHP-2 rescues the ability of Abl-Arg null fibroblasts to transit from G1 to S phase, whereas inhibition of SHP-2 signaling reduces the ability of Abl kinases to rescue the proliferation defect. Abl kinases also indirectly mediate phosphorylation of SHP-2 on Y63 and Y279, which are frequent sites of germline mutation in two cancer susceptibility syndromes. Significantly, we demonstrate that phosphorylation of SHP-2 on Y279 downregulates growth factor-induced sustained ERK activation and proliferation, supporting a role for Abl kinases not only in potentiating growth factor-mediated SHP-2 signaling, but also in negative-feedback regulation.
The Role of Cognitive Skills in Economic Development
Authors: Hanushek Eric A , Woessmann Ludger
Published: October 2008

The role of improved schooling, a central part of most development strategies, has become controversial because expansion of school attainment has not guaranteed improved economic conditions. This paper reviews the role of cognitive skills in promoting economic well-being, with a particular focus on the role of school quality and quantity. It concludes that there is strong evidence that the cognitive skills of the population—rather than mere school attainment—are powerfully related to individual earnings, to the distribution of income, and to economic growth. New empirical results show the importance of both minimal and high level skills, the complementarity of skills and the quality of economic institutions, and the robustness of the relationship between skills and growth. International comparisons incorporating expanded data on cognitive skills reveal much larger skill deficits in developing countries than generally derived from just school enrollment and attainment. The magnitude of change needed makes clear that closing the economic gap with developed countries will require major structural changes in schooling institutions.
Real Business Cycle Views of the Great Depression and Recent Events: A Review of Timothy J. Kehoe and Edward C. Prescott's Great Depressions of the Twentieth Century
Authors: Temin Peter
Published: October 2008

This book collects essays, most of which were published earlier, into an advertisement for real business cycle (RBC) analysis. Half of the essays discuss the Great Depression; half discuss events of the 1980s and 1990s. They all use the general equilibrium model of economic growth to analyze short-run fluctuations in the rate of economic growth of various countries. I find that the use of closed economy models without frictions is not useful for the analysis of short-run variations in the rate of economic growth. Almost all of these essays end by claiming that variations in the rate of GDP growth were due to changes in the rate of total factor productivity (TFP) growth. They do not provide any explanation for fluctuations in the rate of TFP growth, leaving the reader no closer to understanding these periods of depression and slow growth. I discuss in turn the essays on the Great Depression, the essays on more recent fluctuations, and the definition of “great depressions” used in this volume.
The Efficacy of Information Policy: A Review of Archon Fung, Mary Graham, and David Weil's Full Disclosure: The Perils and Promise of Transparency
Authors: Winston Clifford
Published: October 2008

The economics of information has identified an important role for government to correct situations where competition is not sufficient to reveal valuable information to consumers. Archon Fung, Mary Graham, and David Weil's Full Disclosure: The Perils and Promise of Transparency provides a thorough discussion of government-mandated disclosure policies. I use their book to frame an empirical assessment of whether these—and other information policies—have significantly reduced the costs to consumers created by imperfect information. My conclusion, which calls for more research, is that government information policies have amounted to weak solutions in search of a problem.
Metrics—When and Why Nonaveraging Statistics Work
Authors: Shugan Steven M. , Mitra Debanjan
Published: October 2008

Good metrics are well-defined formulae (often involving averaging) that transmute multiple measures of raw numerical performance (e.g., dollar sales, referrals, number of customers) to create informative summary statistics (e.g., average share of wallet, average customer tenure). Despite myriad uses (benchmarking, monitoring, allocating resources, diagnosing problems, explanatory variables), most uses require metrics that contain information summarizing multiple observations. On this criterion, we show empirically (with people data) that although averaging has remarkable theoretical properties, supposedly inferior nonaveraging metrics (e.g., maximum, variance) are often better. We explain theoretically (with exact proofs) and numerically (with simulations) when and why. For example, when the environment causes a correlation between observed sample sizes (e.g., number of past purchases, projects, observations) and latent underlying parameters (e.g., the likelihood of favorable outcomes), the maximum statistic is a better metric than the mean. We refer to this environmental effect as the Muth effect, which occurs when rational markets provide more opportunities (i.e., more observations) to individuals and organizations with greater innate ability. Moreover, when environments are adverse (e.g., failure-rich), nonaveraging metrics correctly overweight favorable outcomes. We refer to this environmental effect as the Anna Karenina effect, which occurs when less-favorable outcomes convey less information. These environmental effects impact metric construction, selection, and employment.
Patents and the Performance of Voluntary Standard-Setting Organizations
Authors: Rysman Marc , Simcoe Timothy
Published: October 2008

Voluntary standard-setting organizations (SSOs) are a common feature of systems industries, where firms supply interoperable components for a shared technology platform. These institutions promote coordinated innovation by providing a forum for collective decision making and a potential solution to the problem of fragmented and overlapping intellectual property rights. This paper examines the economic and technological significance of SSOs by analyzing the flow of citations to a sample of U.S. patents disclosed during the standard-setting process. Our main results show that the age distribution of SSO patent citations is shifted toward later years (relative to an average patent) and that citations increase substantially following standardization. These results suggest that SSOs identify promising technologies and influence their subsequent adoption.
Blood Pressure Control with Amlodipine Add-on Therapy in Patients with Hypertension and Diabetes: Results of the Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial
Authors: Kloner Robert A , Neutel Joel , Roth Eli M , Weiss Robert , Weinberger Myron H , Thakker Kamlesh M , Schwartz Brian , Shi Harry , Gregg Anne-Marie
Published: October 2008

Background:

Attainment of blood pressure (BP) goals in patients with diabetes is critical both to reduce the risk of cardiovascular events and to delay the progression of renal disease. While therapeutic guidelines advise initial therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, monotherapy with these agents may not be sufficient to attain target BP.

Objective:

The ADHT (Amlodipine Diabetic Hypertension Efficacy Response Evaluation Trial) evaluated the efficacy and safety of adding amlodipine to the treatment regimen of patients with hypertension and diabetes who were already receiving either quinapril or losartan as monotherapy.

Methods:

ADHT was a double-blind, double-dummy, 22-week trial conducted in the US, After a washout period of 7–13 days, patients (aged 30–75 y) with hypertension and diabetes were randomized to receive quinapril 20 mg/day plus placebo or losartan 50 mg/day plus placebo for 4 weeks, titrated to 40 mg or 100 mg (if required), respectively, for an additional 4 weeks to achieve their BP goals (<130/60 mm Hg), At week 8, either amlodipine 5 mg/day or placebo was added for an additional 12 weeks, with titration to 10 mg at week 14 if the BP goal was not achieved.

Results:

Efficacy of add-on therapy was evaluated in 411 patients (amlodipine 211, placebo 200). BP goal was reached by 27.5% of patients when amlodipine was added to quinapril or losartan monotherapy, compared with 12.5% when placebo was added (OR 2.73; 95% CI 1.61 to 4.64; p < 0.001), When added to quinapril or losartan monotherapy, amlodipine reduced BP by 8.1/5.4 mm Hg, compared with a 1.6/0.7 mm Hg decrease with add-on placebo (p < 0.001). Amlodipine, quinapril, and losartan were well tolerated.

Conclusions:

Amlodipine is safe and effective when added to quinapril or losartan monotherapy to help lower BP toward therapeutic targets in patients with hypertension and diabetes.
Comparison of the Impact of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management Trial on Prescribing Patterns: A Time-Series Analysis
Authors: Choudhry Niteesh K , Zagorski Brandon , Avorn Jerry , Levin Raisa , Sykora Kathy , Laupacis Andreas , Mamdani Muhammad
Published: October 2008

Background:

The AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial demonstrated that rate control and rhythm control strategies result in similar survival and quality of life for patients with atrial fibrillation (AF). Because of superior safety and lower cost, rate control is now the recommended strategy (or the management of most elderly, high-risk AF patients.

Objective:

To determine the extent to which the AFFIRM trial results have been adopted into actual practice.

Methods:

We conducted a time-series analysis of 3 population-based cohorts of patients with AF who were 66 years of age or older in Pennsylvania and Ontario. We stratified patients in Ontario by socioeconomic status (SES) and examined changes in quarterly prescription rates for rate control and rhythm controlling medications as well as cardioversion procedures before and after publication of the AFFIRM trial.

Results:

The publication of the AFFIRM trial resulted in statistically significant reductions in the use of rhythm controlling medications in all 3 cohorts (p < 0.01). The magnitude of these changes in the non-low SES Canadian cohort was approximately 1% per quarter and was greater than the magnitude observed in the other cohorts (p < 0.001). The use of cardioversion procedures also decreased in all study regions (p < 0.01). In contrast, AFFIRM publication was also associated with a small increase in the use of rate controlling medications in Canada (p < 0.01) but not in the US (p = 0.23).

Conclusions:

Publication of the AFFIRM trial resulted in small but statistically significant changes in the care of patients with AF.
Males Do Not Reduce the Fitness of Their Female Co-Twins in Contemporary Samples
Authors: Medland Sarah E. , Loehlin John C. , Willemsen Gonneke , Hatemi Peter K. , Keller Mathew C. , Boomsma Dorret I. , Eaves Lindon J. , Martin Nicholas G.
Published: October 2008

Lummaa et al. (2007) presented historical data collected from twins born in Finland between 1734 and 1888 which suggested that females (N= 31) born as part of an opposite sex (OS) twin pair were 25% less likely to reproduce than female twins (N= 35) born as part of a same sex (SS) pair. They hypothesized that this reduction in fitness was due to masculinization of the female fetus via prenatal effects of the hormones of a male fetus. Because such masculinization would presumably take place in modern populations as well, it would seem important to establish to what degree it does so, and if so, whether reproduction is affected. We therefore address the question of reproduction differences in individual female twins from same-sex (N= 1979) and opposite-sex (N= 913) dizygotic pairs in studies carried out in Australia, the Netherlands, and the United States. In all three samples, there were no differences in the number of children or age of first pregnancies in women from same sex pairs compared to those from opposite sex pairs. Similarly, there were no differences in psychological femininity between women from pairs of the same or opposite sex.
Vitamin D Receptor Gene Polymorphisms Have Negligible Effect on Human Height
Authors: Macgregor Stuart , Hottenga Jouke-Jan , Lind Penelope A. , Suchiman H. Eka D. , Willemsen Gonneke , Slagboom P. Eline , Montgomery Grant W. , Martin Nicholas G. , Visscher Peter M. , Boomsma Dorret I.
Published: October 2008

Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian samples from Australia (N= 3906) and the Netherlands (N= 1689) for polymorphisms in VDR. The Australian samples were twin families with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height — this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.
Anthropometry, Carbohydrate and Lipid Metabolism in the East Flanders Prospective Twin Survey: Linkage of Candidate Genes Using Two Sib-Pair Based Variance Components Analyses
Authors: Souren Nicole Y. , Zeegers Maurice P. , Janssen Rob G. J. H. , Steyls Anja , Gielen Marij , Loos Ruth J. F. , Beunen Gaston , Fagard Robert , Stassen Alphons P. M. , Aerssens Jeroen , Derom Catherine , Vlietinck Robert , Paulussen Aimee D. C.
Published: October 2008

Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARγ and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.
Adhesion Molecule Polymorphisms and Pulse Wave Velocity in American Youth
Authors: Zhu Haidong , Yan Weili , Tan Yuande , Li Ke , Kapuku Gaston , Treiber Frank A. , Su Shaoyong , Harshfield Gregory A. , Snieder Harold , Dong Yanbin
Published: October 2008

Background:Our research group recently reported that aorto-radial (radial) and aorto-dorsalis-pedis (foot) pulse wave velocity (PWV) as proxies of arterial stiffness are substantially heritable in healthy youth. This article aimed at uncovering the genetic contributions of adhesion molecules, key members in the inflammatory process, to PWV in these young individuals.Methods:Radial and foot PWV were noninvasively measured with applanation tonometry in 702 black and white subjects (42% blacks, mean age 17.7 ± 3.3 years) from the Georgia Cardio vascular Twin Study. Eight functional polymorphisms from genes for E-selectin (SELE), P-selectin (SELP), intercellular adhesion molecules-1 (ICAM1), and vascular cell adhesion molecules-1 (VCAM1) were genotyped.Results:Youth with Ser290Asn or Asn290Asn genotype (SELP) compared to those with Ser290Ser had an increase in both radial and foot PWV (6.61 ± 0.07 vs. 6.41 ± 0.05 m/s,p= .026; 7.22 ± 0.05 vs. 7.04 ± 0.04 m/s,p= .007). TT homozygotes of rs2244529 (SELP) had higher foot PWV (7.28 ± 0.07 vs. 7.06 ± 0.03 m/s,p= .002) than CT heterozygotes and CC homozygotes. There appeared to be a decrease in foot PWV in youth with the 241Arg allele (ICAM1) as compared to those without (6.96 ± 0.08 vs. 7.14 ± 0.03 m/s,p= .005). For the Asp693Asp (C to T) polymorphism (VCAM1), CC genotype had higher foot PWV than CT and TT genotypes (7.18 ± 0.04 vs. 6.95 ± 0.06 m/s,p< .0001). There was an epistatic interaction between Ser290Asn, Gly241Arg, and Asp693Asp on foot PWV (p= .017), explaining 3.6% variance of the foot PWV.Conclusion:Genetic variation of adhesion molecules may be implicated in the development of arterial stiffness. Screening for adhesion molecule polymorphisms may help identify high-risk youth.
Sleep During a Regular Week Night: A Twin-Sibling Study
Authors: Boomsma Dorret I. , van Someren Eus J. W. , Beem A. Leo , de Geus Eco J. C. , Willemsen Gonneke
Published: October 2008

Previous genetic investigations of variation in normal sleep have focused on measures that describe sleep over longer periods of time. We undertook a study with the aim of evaluating whether heritability can be found in single-night sleep traits. A classical twin study design of monozygotic and dizygotic twins, enriched with siblings of twins was employed. The study included adult twin pairs and their siblings (N= 813 subjects from 342 families). A subsample of 66 individuals participated twice. For a single night, bedtime, awakening time and subjective sleep quality were assessed using a diary. The diary also assessed smoking, alcohol and coffee consumption, and the subjective evaluation of stress. Resemblance between family members was used to estimate the heritability of bedtime, awakening time, sleep problems and sleep quality as a function of sex. Most sleep measures showed familial clustering, but results differed for men and women. Heritability for bedtime and sleep problems was seen in women; and for awakening time in men. We conclude that heritability can be demonstrated for bedtime and subjective evaluation of even a single night of sleep. The contribution of the genetic make-up is sex specific. In women variance in awakening time is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible. In contrast, for males, variance in the evening bedtime is so affected by environmental circumstances, that the genetic contribution to the variance becomes negligible.
Maternal Age and Temporal Effects on Stillbirth Rates
Authors: Fellman Johan , Eriksson Aldur W.
Published: October 2008

Stillbirth rates among single and multiple births show markedly decreasing temporal trends. In addition, several studies have demonstrated that the stillbirth rates are dependent on maternal age, in general, showing a U- or J-shaped association with maternal age. In this study, the temporal trends in and the effect of maternal age on the stillbirth rate were considered simultaneously. Our goal was to split the variation into temporal trends and maternal age effects. We applied two-dimensional analysis of variance because no linear association between maternal age and stillbirth rate can be assumed. The temporal trends of stillbirth rates also were not clearly linear. However, the possibility of applying regression analyses based on linear time trends was also considered. Our study is mainly based on official data from England and Wales for the period between 1927 and 2004. These results were compared with registered birth data from Finland between 1937 and 1997. The best fit was obtained when the models were built for the logarithm of the stillbirth rate. Our interpretation of this result is that an association exists between the effects of the factors and the mean stillbirth rate, and consequently, a multiplicative model was applied. Relatively high stillbirth rates were observed among twin births of young mothers and among all births of older mothers.
Dramatically Different Dizygotic Twins: Will We Include Them in Research? / Twin Research Reviews: Congenital Anomalies, Mirror-Image Effects in Conjoined Twins, Older Mothers of Twins; / Twin Statistics: 'Massachusetts, Land of Twins'; / Tribute: Dr Victor A. McKusick
Authors: Segal Nancy L.
Published: October 2008

The increased frequency of interracial marriage is a likely source of unusual-looking dizygotic (DZ) twins. Some members of DZ twin pairs born to mixed-race couples inherit very different physical features from their parents. This raises several questions, such as: Will researchers wish to include such twins in their ongoing studies? Next, new twin research concerned with congenital anomalies, mirror-image effects in conjoined twins and older mothers of twins will be reviewed. New statistics on twinning rates in Massachusetts will also be summarized, followed by a tribute to the late medical geneticist Dr. Victor A. McKusick.
A Local Circuit Model of Learned Striatal and Dopamine Cell Responses under Probabilistic Schedules of Reward
Authors: Tan Can Ozan , Bullock Daniel
Published: October 2008

Recently, dopamine (DA) neurons of the substantia nigra pars compacta (SNc) were found to exhibit sustained responses related to reward uncertainty, in addition to the phasic responses related to reward-prediction errors (RPEs). Thus, cue-dependent anticipations of the timing, magnitude, and uncertainty of rewards are learned and reflected in components of DA signals. Here we simulate a local circuit model to show how learned uncertainty responses are generated, along with phasic RPE responses, on single trials. Both types of simulated DA responses exhibit the empirically observed dependencies on conditional probability, expected value of reward, and time since onset of the reward-predicting cue. The model's three major pathways compute expected values of cues, timed predictions of reward magnitudes, and uncertainties associated with these predictions. The first two pathways' computations refine those modeled by Brown et al. (1999). The third, newly modeled, pathway involves medium spiny projection neurons (MSPNs) of the striatal matrix, whose axons corelease GABA and substance P, both at synapses with GABAergic neurons in the substantia nigra pars reticulata (SNr) and with distal dendrites (in SNr) of DA neurons whose somas are located in ventral SNc. Corelease enables efficient computation of uncertainty responses that are a nonmonotonic function of the conditional probability of reward, and variability in striatal cholinergic transmission can explain observed individual differences in the amplitudes of uncertainty responses. The involvement of matricial MSPNs and cholinergic transmission within the striatum implies a relation between uncertainty in cue–reward contingencies and action-selection functions of the basal ganglia.
Aminoglycoside-Induced Phosphatidylserine Externalization in Sensory Hair Cells Is Regionally Restricted, Rapid, and Reversible
Authors: Goodyear Richard J. , Gale Jonathan E. , Ranatunga Kishani M. , Kros Corné J. , Richardson Guy P.
Published: October 2008

The aminophospholipid phosphatidylserine (PS) is normally restricted to the inner leaflet of the plasma membrane. During certain cellular processes, including apoptosis, PS translocates to the outer leaflet and can be labeled with externally applied annexin V, a calcium-dependent PS-binding protein. In mouse cochlear cultures, annexin V labeling reveals that the aminoglycoside antibiotic neomycin induces rapid PS externalization, specifically on the apical surface of hair cells. PS externalization is observed within ∼75 s of neomycin perfusion, first on the hair bundle and then on membrane blebs forming around the apical surface. Whole-cell capacitance also increases significantly within minutes of neomycin application, indicating that blebbing is accompanied by membrane addition to the hair cell surface. PS externalization and membrane blebbing can, nonetheless, occur independently. Pretreating hair cells with calcium chelators, a procedure that blocks mechanotransduction, or overexpressing a phosphatidylinositol 4,5-biphosphate (PIP2)-binding pleckstrin homology domain, can reduce neomycin-induced PS externalization, suggesting that neomycin enters hair cells via transduction channels, clusters PIP2, and thereby activates lipid scrambling. The effects of short-term neomycin treatment are reversible. After neomycin washout, PS is no longer detected on the apical surface, apical membrane blebs disappear, and surface-bound annexin V is internalized, distributing throughout the supranuclear cytoplasm of the hair cell. Hair cells can therefore repair, and recover from, neomycin-induced surface damage. Hair cells lacking myosin VI, a minus-end directed actin-based motor implicated in endocytosis, can also recover from brief neomycin treatment. Internalized annexin V, however, remains below the apical surface, thereby pinpointing a critical role for myosin VI in the transport of endocytosed material away from the periphery of the hair cell.
Bidirectional Regulation of the cAMP Response Element Binding Protein Encodes Spatial Map Alignment in Prism-Adapting Barn Owls
Authors: Nichols Grant S. , DeBello William M.
Published: October 2008

The barn owl midbrain contains mutually aligned maps of auditory and visual space. Throughout life, map alignment is maintained through the actions of an instructive signal that encodes the magnitude of auditory-visual mismatch. The intracellular signaling pathways activated by this signal are unknown. Here we tested the hypothesis that CREB (cAMP response element-binding protein) provides a cell-specific readout of instructive information. Owls were fitted with prismatic or control spectacles and provided rich auditory-visual experience: hunting live mice. CREB activation was analyzed within 30 min of hunting using phosphorylation state-specific CREB (pCREB) and CREB antibodies, confocal imaging, and immunofluorescence measurements at individual cell nuclei. In control owls or prism-adapted owls, which experience small instructive signals, the frequency distributions of pCREB/CREB values obtained for cell nuclei within the external nucleus of the inferior colliculus (ICX) were unimodal. In contrast, in owls adapting to prisms or readapting to normal conditions, the distributions were bimodal: certain cells had received a signal that positively regulated CREB and, by extension, transcription of CREB-dependent genes, whereas others received a signal that negatively regulated it. These changes were restricted to the subregion of the inferior colliculus that received optically displaced input, the rostral ICX, and were not evident in the caudal ICX or central nucleus. Finally, the topographic pattern of CREB regulation was patchy, not continuous, as expected from the actions of a topographically precise signal encoding discrete events. These results support a model in which the magnitude of CREB activation within individual cells provides a readout of the instructive signal that guides plasticity and learning.
Top-Down Control of Human Visual Cortex by Frontal and Parietal Cortex in Anticipatory Visual Spatial Attention
Authors: Bressler Steven L. , Tang Wei , Sylvester Chad M. , Shulman Gordon L. , Corbetta Maurizio
Published: October 2008

Advance information about an impending stimulus facilitates its subsequent identification and ensuing behavioral responses. This facilitation is thought to be mediated by top-down control signals from frontal and parietal cortex that modulate sensory cortical activity. Here we show, using Granger causality measures on blood oxygen level-dependent time series, that frontal eye field (FEF) and intraparietal sulcus (IPS) activity predicts visual occipital activity before an expected visual stimulus. Top-down levels of Granger causality from FEF and IPS to visual occipital cortex were significantly greater than both bottom-up and mean cortex-wide levels in all individual subjects and the group. In the group and most individual subjects, Granger causality was significantly greater from FEF to IPS than from IPS to FEF, and significantly greater from both FEF and IPS to intermediate-tier than lower-tier ventral visual areas. Moreover, top-down Granger causality from right IPS to intermediate-tier areas was predictive of correct behavioral performance. These results suggest that FEF and IPS modulate visual occipital cortex, and FEF modulates IPS, in relation to visual attention. The current approach may prove advantageous for the investigation of interregional directed influences in other human brain functions.
Neural Circuitry of Stress-Induced Insomnia in Rats
Authors: Cano Georgina , Mochizuki Takatoshi , Saper Clifford B.
Published: October 2008

Sleep architecture is often disturbed after a stressful event; nevertheless, little is known about the brain circuitry responsible for the sleep perturbations induced by stress. We exposed rats to a psychological stressor (cage exchange) that initially causes an acute stress response, but several hours later generates a pattern of sleep disturbances similar to that observed in stress-induced insomnia in humans: increased sleep latency, decreased non-REM (nREM) and REM sleep, increased fragmentation, and high-frequency EEG activity during nREM sleep. We examined the pattern of Fos expression to identify the brain circuitry activated, and found increased Fos in the cerebral cortex, limbic system, and parts of the arousal and autonomic systems. Surprisingly, there was simultaneous activation of the sleep-promoting areas, most likely driven by ongoing circadian and homeostatic pressure. The activity in the cerebral cortex and arousal system while sleeping generates a novel intermediate state characterized by EEG high-frequency activity, distinctive of waking, during nREM sleep. Inactivation of discrete limbic and arousal regions allowed the recovery of specific sleep components and altered the Fos pattern, suggesting a hierarchical organization of limbic areas that in turn activate the arousal system and subsequently the cerebral cortex, generating the high-frequency activity. This high-frequency activity during nREM was eliminated in the stressed rats after inactivating parts of the arousal system. These results suggest that shutting down the residual activity of the limbic-arousal system might be a better approach to treat stress-induced insomnia, rather than potentiation of the sleep system, which remains fully active.
Synchronous Bursts of Neuronal Activity in the Developing Hippocampus: Modulation by Active Sleep and Association with Emerging Gamma and Theta Rhythms
Authors: Mohns Ethan J. , Blumberg Mark S.
Published: October 2008

The neonatal hippocampus exhibits regularly recurring waves of synchronized neuronal activityin vitro. Because active sleep (AS), characterized by bursts of phasic motor activity in the form of myoclonic twitching, may provide conditions that are conducive to activity-dependent development of hippocampal circuits, we hypothesized that the waves of synchronous neuronal activity that have been observedin vitrowould be associated with AS-related twitching. Using unanesthetized 1- to 12-d-old rats, we report here that the majority of neurons in CA1 and the dentate gyrus (DG) are significantly more active during AS than during either quiet sleep or wakefulness. Neuronal activity typically occurs in phasic bursts, during which most neurons are significantly cross-correlated both within and across the CA1 and DG fields. All AS-active neurons increase their firing rates during periods of myoclonic twitching of the limbs, and a subset of these neurons exhibit a burst of activity immediately after limb twitches, suggesting that the twitches themselves provide sensory feedback to the infant hippocampus, as occurs in the infant spinal cord and neocortex. Finally, the synchronous bursts of neuronal activity are coupled to the emergence of the AS-related hippocampal gamma rhythm during the first postnatal week, as well as the emergence of the AS-related theta rhythm during the second postnatal week. We hypothesize that the phasic motor events of active sleep provide the developing hippocampus with discrete sensory stimulation that contributes to the development and refinement of hippocampal circuits as well as the development of synchronized interactions between hippocampus and neocortex.
Sleep Accelerates the Improvement in Working Memory Performance
Authors: Kuriyama Kenichi , Mishima Kazuo , Suzuki Hiroyuki , Aritake Sayaka , Uchiyama Makoto
Published: October 2008

Working memory (WM) performance, which is an important factor for determining problem-solving and reasoning ability, has been firmly believed to be constant. However, recent findings have demonstrated that WM performance has the potential to be improved by repetitive training. Although various skills are reported to be improved by sleep, the beneficial effect of sleep on WM performance has not been clarified. Here, we show that improvement in WM performance is facilitated by posttraining naturalistic sleep. A spatial variant of then-back WM task was performed by 29 healthy young adults who were assigned randomly to three different experimental groups that had different time schedules of repetitiven-back WM task sessions, with or without intervening sleep. Intergroup and intersession comparisons of WM performance (accuracy and response time) profiles showed thatn-back accuracy after posttraining sleep was significantly improved compared with that after the same period of wakefulness, independent of sleep timing, subject's vigilance level, or circadian influences. On the other hand, response time was not influenced by sleep or repetitive training schedules. The present study indicates that improvement inn-back accuracy, which could reflect WM capacity, essentially benefits from posttraining sleep.
Rhythmically Active Enkephalin-Expressing GABAergic Cells in the CA1 Area of the Hippocampus Project to the Subiculum and Preferentially Innervate Interneurons
Authors: Fuentealba Pablo , Tomioka Ryohei , Dalezios Yannis , Márton László F. , Studer Michele , Rockland Kathleen , Klausberger Thomas , Somogyi Peter
Published: October 2008

Enkephalins (ENKs) are endogenous opioids that regulate synaptic excitability of GABAergic networks in the cerebral cortex. Using retrograde tracer injections in the subiculum, we identified a hippocampal population of ENK-expressing projection neurons.In situhybridization for GAD shows that ENK-expressing cells are a small GABAergic subpopulation. Furthermore, by extracellular recording and juxtacellular labelingin vivo, we identified an ENK-expressing cell in stratum radiatum of the CA1 area by its complete axodendritic arborization and characteristic spike timing during network oscillations. The somatodendritic membrane was immunopositive for mGluR1α, and there was both a rich local axon in CA1 and subicular-projecting branches. The boutons showed cell-type- and layer-specific innervation, i.e., interneurons were the main targets in the alveus, both interneurons and pyramidal cell dendrites were innervated in the other layers, and interneurons were exclusive targets in the subiculum. Parvalbumin-, but not somatostatin-, calbindin-, or cholecystokinin-expressing interneurons were preferred synaptic targets. During network activity, the juxtacellularly labeled ENK-expressing cell was phase modulated throughout theta oscillations, but silenced during sharp-wave/ripple episodes. After these episodes the interneuron exhibited rebound activity of high-frequency spike bursts, presumably causing peptide release. The ENK-expressing interneurons innervating parvalbumin-positive interneurons might contribute to the organization of the sharp-wave/ripple episodes by decreased firing during and rebound activity after the ripple episodes, as well as to the coordination of activity between the CA1 and subicular areas during network oscillations.
Does Learned Shape Selectivity in Inferior Temporal Cortex Automatically Generalize Across Retinal Position?
Authors: Cox David D. , DiCarlo James J.
Published: October 2008

Biological visual systems have the remarkable ability to recognize objects despite confounding factors such as object position, size, pose, and lighting. In primates, this ability likely results from neuronal responses at the highest stage of the ventral visual stream [inferior temporal cortex (IT)] that signal object identity while tolerating these factors. However, for even the apparently simplest IT tolerance (“invariance”), tolerance to object position on the retina, little is known about how this feat is achieved. One possibility is that IT position tolerance is innate in that discriminatory power for newly learned objects automatically generalizes across position. Alternatively, visual experience plays a role in developing position tolerance. To test these ideas, we trained adult monkeys in a difficult object discrimination task in which their visual experience with novel objects was restricted to a single retinal position. After training, we recorded the spiking activity of an unbiased population of IT neurons and found that it contained significantly greater selectivity among the newly learned objects at the experienced position compared with a carefully matched, non-experienced position. Interleaved testing with other objects shows that this difference cannot be attributed to a bias in spatial attention or neuronal sampling. We conclude from these results that, at least under some conditions, full transfer of IT neuronal selectivity across retinal position is not automatic. This finding raises the possibility that visual experience plays a role in building neuronal tolerance in the ventral visual stream and the recognition abilities it supports.
Uncoordinated Firing Rate Changes of Striatal Fast-Spiking Interneurons during Behavioral Task Performance
Authors: Berke Joshua D.
Published: October 2008

Basal ganglia circuits make key contributions to decision making. Distributed, synchronous feedforward inhibition of striatal medium spiny neurons by fast-spiking GABAergic interneurons (FSIs) has been argued to be important for the suppression of unwanted actions, and a deficit in FSIs has been found in human patients with Tourette syndrome. However, no studies have yet examined how striatal FSIs change their activity during behavioral tasks. Here I describe 36 presumed striatal FSIs recorded in rats during well practiced performance of a radial maze win–stay task. Although most FSIs showed robust task-related activity, the temporal patterns of firing rate change were highly idiosyncratic. In contrast to other classes of striatal neurons, FSIs showed little or no coordinated population response to major task events such as instruction cues or rewards. Even when multiple FSIs were recorded simultaneously from the same local region of striatum, firing rate changes were dissimilar, and no clear evidence for synchronous firing was found using cross-correlograms (18 FSI pairs examined). These results suggest that FSIs play a more complex role in the information processing achieved by striatal microcircuits than supposed by current theoretical models.
Frequency-Selective Coding of Translation and Tilt in Macaque Cerebellar Nodulus and Uvula
Authors: Yakusheva Tatyana , Blazquez Pablo M. , Angelaki Dora E.
Published: October 2008

Spatial orientation depends critically on the brain's ability to segregate linear acceleration signals arising from otolith afferents into estimates of self-motion and orientation relative to gravity. In the absence of visual information, this ability is known to deteriorate at low frequencies. The cerebellar nodulus/uvula (NU) has been shown to participate in this computation, although its exact role remains unclear. Here, we show that NU simple spike (SS) responses also exhibit a frequency dependent selectivity to self-motion (translation) and spatial orientation (tilt). At 0.5 Hz, Purkinje cells encode three-dimensional translation and only weakly modulate during pitch and roll tilt (0.4 ± 0.05 spikes/s/°/s). But this ability to selectively signal translation over tilt is compromised at lower frequencies, such that at 0.05 Hz tilt response gains average 2.0 ± 0.3 spikes/s/°/s. We show that such frequency-dependent properties are attributable to an incomplete cancellation of otolith-driven SS responses during tilt by a canal-driven signal coding angular position with a sensitivity of 3.9 ± 0.3 spikes/s/°. This incomplete cancellation is brought about because otolith-driven SS responses are also partially integrated, thus encoding combinations of linear velocity and acceleration. These results are consistent with the notion that NU SS modulation represents an internal neural representation of similar frequency dependencies seen in behavior.