bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of transcriptome dynamics during watermelon fruit development: sequencing, assembly, annotation and gene expression profiles
Authors: Guo Shaogui , Liu Jingan , Zheng Yi , Huang Mingyun , Zhang Haiying , Gong Guoyi , He Hongju , Ren Yi , Zhong Silin , Fei Zhangjun , Xu Yong
Published: September 2011

Background

Cultivated watermelon [Citrullus lanatus (Thunb.) Matsum. & Nakai var. lanatus] is an important agriculture crop world-wide. The fruit of watermelon undergoes distinct stages of development with dramatic changes in its size, color, sweetness, texture and aroma. In order to better understand the genetic and molecular basis of these changes and significantly expand the watermelon transcript catalog, we have selected four critical stages of watermelon fruit development and used Roche/454 next-generation sequencing technology to generate a large expressed sequence tag (EST) dataset and a comprehensive transcriptome profile for watermelon fruit flesh tissues.

Results

We performed half Roche/454 GS-FLX run for each of the four watermelon fruit developmental stages (immature white, white-pink flesh, red flesh and over-ripe) and obtained 577,023 high quality ESTs with an average length of 302.8 bp. De novo assembly of these ESTs together with 11,786 watermelon ESTs collected from GenBank produced 75,068 unigenes with a total length of approximately 31.8 Mb. Overall 54.9% of the unigenes showed significant similarities to known sequences in GenBank non-redundant (nr) protein database and around two-thirds of them matched proteins of cucumber, the most closely-related species with a sequenced genome. The unigenes were further assigned with gene ontology (GO) terms and mapped to biochemical pathways. More than 5,000 SSRs were identified from the EST collection. Furthermore we carried out digital gene expression analysis of these ESTs and identified 3,023 genes that were differentially expressed during watermelon fruit development and ripening, which provided novel insights into watermelon fruit biology and a comprehensive resource of candidate genes for future functional analysis. We then generated profiles of several interesting metabolites that are important to fruit quality including pigmentation and sweetness. Integrative analysis of metabolite and digital gene expression profiles helped elucidating molecular mechanisms governing these important quality-related traits during watermelon fruit development.

Conclusion

We have generated a large collection of watermelon ESTs, which represents a significant expansion of the current transcript catalog of watermelon and a valuable resource for future studies on the genomics of watermelon and other closely-related species. Digital expression analysis of this EST collection allowed us to identify a large set of genes that were differentially expressed during watermelon fruit development and ripening, which provide a rich source of candidates for future functional analysis and represent a valuable increase in our knowledge base of watermelon fruit biology.
Influence of viral hepatitis status on prognosis in patients undergoing hepatic resection for hepatocellular carcinoma: a meta-analysis of observational studies
Authors: Zhou Yanming , Si Xiaoying , Wu Lupeng , Su Xu , Li Bin , Zhang Zhiming
Published: September 2011

Background

The influence of viral hepatitis status on prognosis in patients undergoing hepatic resection for hepatocellular carcinoma (HCC) remains a matter of debate. This study is a meta-analysis of the available evidence.

Methods

A literature search was performed to identify comparative studies reporting postoperative survival of HCC in different types of viral hepatitis. Pooled odds ratios (OR) and weighted mean differences (WMD with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model.

Results

Twenty studies matched the selection criteria and reported on 4744 subjects, of whom 2008 in the HBV-positive (B-HCC) group, 2222 in the HCV-positive (C-HCC) group, and 514 in the hepatitis B- and C-negative (NBNC-HCC). Meta-analysis showed that patients with HBV or HCV infection had a worse 5-year disease-free survival when compared to patients with NBNC-HCC (respectively: OR: 0.39, 95% CI: 0.28 to 0.53, P < 0.001; WMD: 0.37, 95% CI: 0.22 to 0.64, P < 0.001). There was a tendency toward higher 5-year overall survival rates in the NBNC-HCC group compared to those in the other two groups, although these differences were not statistically significant. Both the 5-year overall survival and disease-free survival were not different among the B-HCC and C-HCC groups.

Conclusions

Patients with positive serology for hepatitis B or C undergoing resection for HCC had a poor prognosis compared to patients with negative serology.
C-reactive protein-derived peptide 201–206 inhibits neutrophil adhesion to endothelial cells and platelets through CD32
Authors: El Kebir Driss , Zhang Ying , Potempa Lawrence A , Wu Yi , Fournier Alain , Filep János G
Published: September 2011

The role of CRP as a regulator of inflammation is not fully understood. Structural rearrangement in CRP results in expression of potent proinflammatory actions. Proteolysis of CRP yields the C-terminal peptide Lys201-Pro-Gln-Leu-Trp-Pro206. Here, we investigated the impact of this peptide on neutrophil interactions with endothelial cells and platelets, critical inflammatory events triggering acute coronary artery disease. CRP peptide 201–206 induced L-selectin shedding from human neutrophils and inhibited L-selectin-mediated neutrophil adhesion to TNF-α-activated HCAECs under nonstatic conditions. CRP peptide 201–206 also attenuated shear-induced up-regulation of platelet P-selectin expression, platelet capture of neutrophils, and subsequent homotypic neutrophil adhesion in human whole blood. Anti-CD32 but not anti-CD16 or anti-CD64 mAb effectively prevented the inhibitory actions of CRP peptide 201–206. Substitution of Lys201, Gln203, or Trp205 with Ala in CRP peptide 201–206 resulted in loss of the biological activities, whereas peptides in which Pro202, Leu204, or Pro206 was substituted with Ala retained biological activity. We identified amino acid residues involved in CRP peptide 201–206-FcγRII (CD32) interactions, which mediate potent antineutrophil and antiplatelet adhesion actions, and these findings open up new perspectives for limiting inflammation and thrombosis underlying coronary artery disease.
Higher proportions of circulating FOXP3+ and CTLA-4+ regulatory T cells are associated with lower fractions of memory CD4+ T cells in infants
Authors: Rabe Hardis , Lundell Anna-Carin , Andersson Kerstin , Adlerberth Ingegerd , Wold Agnes E , Rudin Anna
Published: September 2011

In adults, a majority of FOXP3+ Tregs expresses CTLA-4, and this costimulatory molecule is essential to control the expansion of other T cells. However, it remains to be investigated whether FOXP3+ and/or CTLA-4+ Tregs are associated with the expression of memory markers and homing receptors on CD4+ T cells. Thus, in a prospective newborn-infant cohort study, we examined the proportions of FOXP3+ and CTLA-4+ Tregs within the CD4+CD25+ T cell population and the fractions of CD4+ T cells that expressed CD45RA, CD45RO, HLA-DR, α4β7, CD62L, and CCR4 at several time-points during the first 3 years of life using flow cytometry. With the use of multivariate factor analysis, we found that a high proportion of FOXP3+ or CTLA-4+ Tregs during the first 18 months of life was associated positively with the fraction of T cells that expressed a naïve phenotype (CD45RA and α4β7) and inversely related to the fraction of T cells that expressed a memory phenotype (CD45RO and CCR4) later in childhood. In conclusion, FOXP3+ or CTLA-4+ Tregs may modulate CD4+ T cell activation and homing receptor expression in children.
Facilitated antigen uptake and timed exposure to TLR ligands dictate the antigen-presenting potential of plasmacytoid DCs
Authors: Kool Mirjam , GeurtsVanKessel Corine , Muskens Femke , Madeira Fillipe Branco , van Nimwegen Menno , Kuipers Harmjan , Thielemans Kris , Hoogsteden Henk C , Hammad Hamida , Lambrecht Bart N
Published: September 2011

Subsets of antigen-presenting cDCs have a differential capacity to present exogenous and endogenous protein antigens to CD4+ and/or CD8+ T lymphocytes, depending on expression of antigen-uptake receptors, processing machinery, and microbial instruction. pDCs are also capable of antigen presentation, but the conditions under which they do this have not been systematically addressed. Highly purified cDCs and pDCs were exposed to exogenous, soluble OVA peptide or whole protein. Alternatively, they were made to express cytoplasmic or endosomal OVA by retroviral transduction or by infection with influenza virus containing OVA epitopes. Like cDCs, pDCs expressed the MHC I processing machinery and could present endogenous or cross-present exogenous OVA to CD8+ T cells, provided they had been stimulated by CpG motif TLR9 ligands or by influenza. Unlike cDCs, the cross-priming activity of pDCs was enhanced, not decreased, by simultaneous TLR stimulation. Processing and presentation of exogenous OVA to CD4+ T cells required TLR9 ligation prior to antigen encounter and addition of OVA-specific Igs. These stimuli up-regulated critical MHC II processing machinery and enhanced routing to acidic endosomal organelles in a FcγRII-dependent manner. Endogenous antigen was not presented to CD4+ T cells when expressed in the cytoplasm of pDCs by retrovirus or contained in influenza, unless an Ii-chain-derived endosomal routing signal was present. Thus, timing of TLR ligation and facilitated antigen uptake dictate the potential of pDCs to present endogenous or exogenous antigen by influencing endosomal traffic and antigen-processing machinery.
Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK-M, SHIP-1, and A20
Authors: Xiong Yanbao , Medvedev Andrei E
Published: September 2011

TLRs mediate host defense against microbial pathogens by eliciting production of inflammatory mediators and activating expression of MHC, adhesion, and costimulatory molecules. Endotoxin tolerance limits excessive TLR-driven inflammation during sepsis and reprograms macrophage responses to LPS, decreasing expression of proinflammatory cytokines without inhibiting anti-inflammatory and antimicrobial mediators. Molecular mechanisms of reprogramming of TLR4 signaling upon in vivo induction of endotoxin tolerance are incompletely understood. We used an in vivo model of endotoxin tolerance, whereby C57BL/6 mice were i.p.-inoculated with LPS or PBS, followed by in vitro challenge of peritoneal or splenic macrophages with LPS to examine activation of IRAK4 and expression of negative regulatory molecules. Administration of LPS in vivo-induced endotoxin tolerance in peritoneal and splenic macrophages, as evidenced by decreased degradation of IκBα, suppressed phosphorylation of p38 and reduced expression of TNF-α, IL-6, and KC mRNA upon in vitro LPS challenge. Macrophages from control and endotoxin-tolerant mice exhibited comparable TLR4 mRNA levels and similar expression of IL-1RA and IL-10 genes. Endotoxin tolerization in vivo blocked TLR4-driven IRAK4 phosphorylation and activation in macrophages, while increasing expression of IRAK-M, SHIP-1, A20 mRNA, and A20 protein. Thus, induction of endotoxin tolerance in vivo inhibits expression of proinflammatory mediators via impaired activation of IRAK4, p38, and NF-κB and increases expression of negative regulators of TLR4 pathways.
Estimation of Estradiol in Mouse Serum Samples: Evaluation of Commercial Estradiol Immunoassays
Authors: Haisenleder Daniel J. , Schoenfelder Aleisha H. , Marcinko Elizabeth S. , Geddis Lisa M. , Marshall John C.
Published: September 2011

The University of Virginia Center for Research in Reproduction Ligand Core performed an evaluation of nine commercial estradiol (E2) immunoassays for use with mouse serum. The evaluation had two components. 1) Recovery Studies: a mouse pool was spiked with E2 concentrations across the assay range, and percent recovery and parallelism to the assay standard curve were determined. 2) Correlation Studies: serum pools were collected from intact females, ovariectomized (OVX) and OVX-E2 treated mice and E2 assayed, then measured by gas chromatography/tandem mass spectrometry (GC/MSMS) for comparison to a gold standard method. Recovery results showed that E2 recovery from spiked mouse pools varied greatly (from <18% to >640%) among kits tested. However, three kits (DiaSorin Radioimmunoassay, Siemens Double Antibody RIA, and CalBiotech Enzyme Immunoassay) showed reasonable recoveries and parallelism. Data collected from the Correlation Study showed that values from intact, OVX and OVX-E2-treated mouse pools varied by several fold vs. GC/MSMS for most of the kits tested. The DiaSorin RIA and CalBiotech Enzyme Immunoassay Kits showed the best correlation to GC/MSMS. Unfortunately, while this evaluation was ongoing, the DiaSorin Kit was discontinued. In summary, the CalBiotech Kit was the only available assay tested that demonstrated good E2 parallelism to the assay standard curve and accuracy vs. a gold standard method (i.e. GC/MSMS). Also of note, the CalBiotech assay is sensitive and requires minimal sample volume. Therefore, based on these findings the CalBiotech E2 assay has been implemented for use in mouse serum samples within the Ligand Core.
Laypeople's Ethical Concerns About a New Israeli Organ Transplantation Prioritization Policy Aimed to Encourage Organ Donor Registration among the Public
Authors: Guttman Nurit , Ashkenazi Tamar , Gesser-Edelsburg Anat , Seidmann Vered
Published: September 2011

A new policy recently enacted in Israel promises preferred status in receiving organs for transplantation to individuals who register to be organ donors and to their close family members. Proponents believe it will increase the supply of organs for transplantation from the deceased. Ethical issues were raised in government committees appointed to discuss the policy before its approval, but discussions among laypeople were not solicited. This study aimed to elicit laypeople's views about the policy by conducting thirteen group interviews and thirty-six individual interviews. Participants included religious and nonreligious people, immigrants, and Arabs. Some participants thought the law would contribute to fairness by prioritizing those willing to give, but others articulated ethical concerns that were not emphasized by scholars, in particular that the policy would add to the erosion of social solidarity, increase divisiveness, and enable people to abuse the system. Mistrust in the health care system emerged as a prominent reason for not registering as an organ donor. Implications about the importance of transparency in the organ transplantation system as a basis for an information campaign, social norms regarding organ donation, and the public's involvement in policy issues on organ donation are discussed.
Addressing the Shortage of Kidneys for Transplantation: Purchase and Allocation Through Chain Auctions
Authors: Rosen Lara , Vining Aidan R. , Weimer David L.
Published: September 2011

Transplantation is generally the treatment of choice for those suffering from kidney failure. Not only does transplantation offer improved quality of life and increased longevity relative to dialysis, it also reduces end-stage renal disease program expenditures, providing savings to Medicare. Unfortunately, the waiting list for kidney transplants is long, growing, and unlikely to be substantially reduced by increases in the recovery of cadaveric kidneys. Another approach is to obtain more kidneys through payment to living “donors,” or vendors. Such direct commodification, in which a price is placed on kidneys, has generally been opposed by medical ethicists. Much of the ethical debate, however, has been in terms of commodification through market exchange. Recognizing that there are different ethical concerns associated with the purchase of kidneys and their allocation, it is possible to design a variety of institutional arrangements for the commodification of kidneys that pose different sets of ethical concerns. We specify three such alternatives in detail sufficient to allow an assessment of their likely consequences and we compare these alternatives to current policy in terms of the desirable goals of promoting human dignity, equity, efficiency, and fiscal advantage. This policy analysis leads us to recommend that kidneys be purchased at administered prices by a nonprofit organization and allocated to the transplant centers that can organize the longest chains of transplants involving willing-but-incompatible donor-patient dyads.
Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development
Authors: Wang Baiping , Harrison Wilbur , Overbeek Paul A. , Zheng Hui
Published: September 2011

Correct development of the cerebellum requires coordinated sonic hedgehog (Shh) signaling from Purkinje to granule cells. How Shh expression is regulated in Purkinje cells is poorly understood. Using a novel tyrosinase minigene-tagged Sleeping Beauty transposon-mediated mutagenesis, which allows for coat color-based genotyping, we created mice in which the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene is deleted. Loss of Skor2 leads to defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Skor2 is specifically expressed in Purkinje cells in the brain, where it is required for proper expression of Shh. Skor2 overexpression suppresses BMP signaling in an HDAC-dependent manner and stimulates Shh promoter activity, suggesting that Skor2 represses BMP signaling to activate Shh expression. Our study identifies an essential function for Skor2 as a novel transcriptional regulator in Purkinje cells that acts upstream of Shh during cerebellum development.
Nephronectin regulates atrioventricular canal differentiation via Bmp4-Has2 signaling in zebrafish
Authors: Patra Chinmoy , Diehl Florian , Ferrazzi Fulvia , van Amerongen Machteld J. , Novoyatleva Tatyana , Schaefer Liliana , Mühlfeld Christian , Jungblut Benno , Engel Felix B.
Published: September 2011

The extracellular matrix is crucial for organogenesis. It is a complex and dynamic component that regulates cell behavior by modulating the activity, bioavailability and presentation of growth factors to cell surface receptors. Here, we determined the role of the extracellular matrix protein Nephronectin (Npnt) in heart development using the zebrafish model system. The vertebrate heart is formed as a linear tube in which myocardium and endocardium are separated by a layer of extracellular matrix termed the cardiac jelly. During heart development, the cardiac jelly swells at the atrioventricular (AV) canal, which precedes valve formation. Here, we show that Npnt expression correlates with this process. Morpholino-mediated knockdown of Npnt prevents proper valve leaflet formation and trabeculation and results in greater than 85% lethality at 7 days post-fertilization. The earliest observed phenotype is an extended tube-like structure at the AV boundary. In addition, the expression of myocardial genes involved in cardiac valve formation (cspg2, fibulin 1, tbx2b, bmp4) is expanded and endocardial cells along the extended tube-like structure exhibit characteristics of AV cells (has2, notch1b and Alcam expression, cuboidal cell shape). Inhibition of has2 in npnt morphants rescues the endocardial, but not the myocardial, expansion. By contrast, reduction of BMP signaling in npnt morphants reduces the ectopic expression of myocardial and endocardial AV markers. Taken together, our results identify Npnt as a novel upstream regulator of Bmp4-Has2 signaling that plays a crucial role in AV canal differentiation.
Preference Reversals Under Ambiguity
Authors: Maafi Hela
Published: September 2011

Preference reversals have been widely studied using risky or riskless gambles. However, little is known about preference reversals under ambiguity (unknown probabilities). Subjects were asked to make a binary choice between ambiguous P-bets (big likelihood of giving small prize) and ambiguous $-bets (small likelihood of giving large prize) and their willingness to accept was elicited. Subjects then performed the same two tasks with risky bets, where the probability of winning for a given risky bet is the center of the probability interval of the corresponding ambiguous bet. Preference reversals are not only replicated under ambiguity but are even stronger than are those under risk. This is due to higher elicited prices for the $-bet and lower elicited prices for the P-bet under ambiguity than under risk. This result can be explained by the shape of the weighting function for different levels of uncertainty and for different elicitation modes.

This paper was accepted by Peter Wakker, decision analysis.
How Do Acquirers Retain Successful Target CEOs? The Role of Governance
Authors: Wulf Julie , Singh Harbir
Published: September 2011

The resource-based view argues that acquisitions can build competitive advantage partially through retention of valuable human capital of the target firm. However, making commitments to retain and motivate successful top managers is a challenge when contracts are not enforceable. Investigating the conditions under which target chief executive officers (CEOs) are retained in a sample of mergers in the 1990s, we find greater retention of better-performing and higher-paid CEOs—both measures of valuable human capital. We also show that the performance-retention link is stronger when the acquirer's governance provisions support managers and when the acquirer's CEO owns more equity. Although it is not common for acquirers to retain target CEOs, we argue that they are more likely to do so when their governance environment maintains managerial discretion. Based on a joint analysis of retention and governance, our findings are largely consistent with a managerial human capital explanation of retention.

This paper was accepted by Bruno Cassiman, business strategy.
Decadal-scale changes in the shallow subtidal benthos of an Irish marine reserve
Authors: Trowbridge Cynthia D. , Little Colin , Pilling Graham M. , Stirling Penny , Miles Alison
Published: September 2011

Long-term annual monitoring of rocky intertidal and shallow subtidal shores of an Irish sea lough (1990–2010) documented major regime shifts in the past decade. When population densities of the purple urchin Paracentrotus lividus plummeted in Lough Hyne Marine Reserve in southwestern Ireland, the warm-water fucalean alga Cystoseira foeniculacea and ephemeral algae proliferated shortly after. We discuss the possible influences of release from herbivory and climate change on this algal proliferation, which blanketed the benthos. Smothering of the benthos led to high levels of shallow subtidal anoxia. Furthermore, the invasive fucalean alga Sargassum muticum has made repeated incursions into the reserve. Although being reduced by persistent eradication efforts (2003–2011), Sargassum is spreading within the lough. Limited seawater flushing and propagule dispersal within the lough and eutrophication in coastal waters may have contributed to community-level changes. Whether the regime change is cyclical (contingent on re-establishment of urchins within the lough and continued eradication of S. muticum) or irreversible (the result of critical transitions) remains unclear.
Measurement of granulocyte maturation may improve the early diagnosis of the septic state
Authors: Bernstein Larry H. , Rucinski James
Published: September 2011

Sepsis is a costly diagnosis in hospitalized patients. Failure to diagnose sepsis in a timely manner creates a potential financial and safety hazard. The use of transthyretin, C-reactive protein and procalcitonin measurement as early markers of systemic inflammatory response syndrome (SIRS) and sepsis in association with admission of emergency department patients to the intensive care unit (ICU) has been studied. In these studies the SIRS criteria as well as the use of an elevated neutrophil count with granulocyte precursors (left shift) have proved to be problematic. Despite the validity of procalcitonin measurement (PCT, Brahms) in the early diagnosis of SIRS the cost and time for testing are limiting considerations. Immature granulocyte (IG) measurement has been proposed as a more readily available indicator of the presence of granulocyte precursors (left shift).

This study calibrates and validates the measurement of granulocyte maturation [Immature granulocytes (IG)] to the identification of sepsis, a study carried out on a Sysmex Analyzer, model XE 2100 (Kobe, Japan). The Sysmex IG parameter is a crucial measure of immature granulocyte counts and includes metamyelocytes and myelocytes, but not band neutrophils.

We found agreement with previous work that designated an IG measurement cut-off of 3.2 as optimal. The analysis was then carried a step further with a multivariable discriminator.
Singular value decomposition and its application to numerical inversion for ray transforms in 2D vector tomography
Authors: Derevtsov Evgeny Y. , Efimov Anton V. , Louis Alfred K. , Schuster Thomas
Published: September 2011

The operators of longitudinal and transverse ray transforms acting on vector fields on the unit disc are considered in the paper. The goal is to construct SVD-decompositions of the operators and invert them approximately by means of truncated decomposition for the parallel scheme of data acquisition. The orthogonal bases in the initial spaces and the image spaces are constructed using harmonic, Jacobi and Gegenbauer polynomials. Based on the obtained decompositions inversion formulas are derived and the polynomial approximations for the inverse operators are obtained. Numerical tests for data sets with different noise levels of smooth and discontinuous fields show the validity of the approach for the reconstruction of solenoidal or potential parts of vector fields from their ray transforms.
Asymptotic inversion formulas in 3D vector field tomography for different geometries
Authors: Kazantsev Sergey G. , Schuster Thomas
Published: September 2011

We study the problem of recovering scalar fields and solenoidal vector fields supported in the unit ball in from tomographic data. We consider three different measurement settings: the case of full data, where the ray sources cover the entire unit sphere and the rays spread in all directions, the case of parallel geometry which is to be understood slice-by-slice as well as the case of cone beam data where the sources are located on a trajectory surrounding the object and the rays are emitted in directions that are bounded by a cone. We formulate an asymptotic inversion formula for the case of full data using an expansion of the searched object in orthogonal polynomials and show how this inversion formula remains valid even for the parallel and cone beam geometry, where for the latter one the source trajectory has to satisfy a certain Tuy condition for vector fields.
Morphological and Functional Continuum Underlying Heterogeneity in the Spiking Fidelity at the Calyx of Held SynapseIn Vitro
Authors: Grande Giovanbattista , Wang Lu-Yang
Published: September 2011

Reliable neuronal spiking is critical for a myriad of computations performed by neural circuits. This is particularly evident for sound localization cues in the auditory brainstem circuits that detect timing and intensity differences of sounds arriving at two ears. The calyx of Held–principal neuron synapse in the medial nucleus of the trapezoid body (MNTB) in this circuit is traditionally viewed as a reliable relay, which converts contralateral excitatory inputs to inhibitory outputs to ipsilateral superior olive neurons that code interaural timing and intensity differences. However, recent studies demonstrated large variability in the incidence of postsynaptic spike failures at this synapse, challenging the view that this synapse is a fail-safe relay. Using combined imaging and paired recordings in mature (P16–P19) mouse brainstem slices, we show that spike failure rates of MNTB neurons are strongly correlated with differences in gross morphology of the calyx terminal and quantal properties under standardin vitro-andin vivo-like conditions. MNTB neurons innervated by calyces with simple morphologies (mainly digits) express strong short-term synaptic depression and a high incidence of spike failures after high-frequency stimulation. Conversely, MNTB neurons innervated by structurally complex calyces (digits and numerous bouton-like swellings) exhibit initial facilitation followed by slow depression and very few spike failures. Our results indicate that the calyx of Held–MNTB synapse is likely organized as a structural and functional continuum, in that correlated heterogeneities in calyx morphology and short-term plasticity serve as a filter for regulating the inhibition delivered to superior olive neurons during sound localization.
Transfer of Learned Manipulation following Changes in Degrees of Freedom
Authors: Fu Qiushi , Hasan Ziaul , Santello Marco
Published: September 2011

The present study was designed to determine whether manipulation learned with a set of digits can be transferred to grips involving a different number of digits, and possible mechanisms underlying such transfer. The goal of the task was to exert a torque and vertical forces on a visually symmetrical object at object lift onset to balance the external torque caused by asymmetrical mass distribution. Subjects learned this manipulation through consecutive practice using one grip type (two or three digits), after which they performed the same task but with another grip type (e.g., after adding or removing one digit, respectively). Subjects were able to switch grip type without compromising the behavioral outcome (i.e., the direction, timing, and magnitude of the torque exerted on the object was unchanged), despite the use of significantly different digit force-position coordination patterns in the two grip types. Our results support the transfer of learning for anticipatory control of manipulation and indicate that the CNS forms an internal model of the manipulation task independent of the effectors that are used to learn it. We propose that sensory information about the new digit placement—resulting from adding or removing a digit immediately after the switch in grip type—plays an important role in the accurate modulation of new digit force distributions. We discuss our results in relation to studies of manipulation reporting lack of learning transfer and propose a theoretical framework that accounts for failure or success of motor learning generalization.
Default Mode Network Connectivity Predicts Sustained Attention Deficits after Traumatic Brain Injury
Authors: Bonnelle Valerie , Leech Robert , Kinnunen Kirsi M. , Ham Tim E. , Beckmann Cristian F. , De Boissezon Xavier , Greenwood Richard J. , Sharp David J.
Published: September 2011

Traumatic brain injury (TBI) frequently produces impairments of attention in humans. These can result in a failure to maintain consistent goal-directed behavior. A predominantly right-lateralized frontoparietal network is often engaged during attentionally demanding tasks. However, lapses of attention have also been associated with increases in activation within the default mode network (DMN). Here, we study TBI patients with sustained attention impairment, defined on the basis of the consistency of their behavioral performance over time. We show that sustained attention impairments in patients are associated with an increase in DMN activation, particularly within the precuneus and posterior cingulate cortex. Furthermore, the interaction of the precuneus with the rest of the DMN at the start of the task, i.e., its functional connectivity, predicts which patients go on to show impairments of attention. Importantly, this predictive information is present before any behavioral evidence of sustained attention impairment, and the relationship is also found in a subgroup of patients without focal brain damage. TBI often results in diffuse axonal injury, which produces cognitive impairment by disconnecting nodes in distributed brain networks. Using diffusion tensor imaging, we demonstrate that structural disconnection within the DMN also correlates with the level of sustained attention. These results show that abnormalities in DMN function are a sensitive marker of impairments of attention and suggest that changes in connectivity within the DMN are central to the development of attentional impairment after TBI.
The Functional Link between Area MT Neural Fluctuations and Detection of a Brief Motion Stimulus
Authors: Smith Jackson E. T. , Zhan Chang'an A. , Cook Erik P.
Published: September 2011

Fluctuations of neural firing rates in visual cortex are known to be correlated with variations in perceptual performance. It is important to know whether these fluctuations are functionally linked to perception in a causal manner or instead reflect non-causal processes that arise after the perceptual decision is made. We recorded from middle temporal (MT) neurons from monkey subjects while they detected the random occurrence of a brief 50 ms motion pulse that occurred in either of two (or simultaneously in both) random dot patches located in the same hemisphere. The receptive field parameters of the motion pulse were matched to that preferred by each MT neuron under study. This task contained uncertainty in both space and time because, on any given trial, the subjects did not know which patch would contain the motion pulse or when the motion pulse would occur. Covariations between MT activity and behavior began just before the motion pulse onset and peaked at the maximum neural response. These neural–behavioral covariations were strongest when only one patch contained the motion pulse and were still weakly present when a patch did not contain a motion pulse. A feedforward temporal integration model with two independent detector channels captured both the detection performance and evolution of the neural–behavior covariations over time and stimulus condition. The results suggest that, when detecting a brief visual stimulus, there is a causal relationship between fluctuations in neural activity and variations in behavior across trials.
IL-1 Receptor Accessory Protein-Like 1 Associated with Mental Retardation and Autism Mediates Synapse Formation byTrans-Synaptic Interaction with Protein Tyrosine Phosphatase δ
Authors: Yoshida Tomoyuki , Yasumura Misato , Uemura Takeshi , Lee Sung-Jin , Ra Moonjin , Taguchi Ryo , Iwakura Yoichiro , Mishina Masayoshi
Published: September 2011

Mental retardation (MR) and autism are highly heterogeneous neurodevelopmental disorders. IL-1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic MR and is associated with autism. Thus, the elucidation of the functional role of IL1RAPL1 will contribute to our understanding of the pathogenesis of these mental disorders. Here, we showed that knockdown of endogenous IL1RAPL1 in cultured cortical neurons suppressed the accumulation of punctate staining signals for active zone protein Bassoon and decreased the number of dendritic protrusions. Consistently, the expression of IL1RAPL1 in cultured neurons stimulated the accumulation of Bassoon and spinogenesis. The extracellular domain (ECD) of IL1RAPL1 was required and sufficient for the presynaptic differentiation-inducing activity, while both the ECD and cytoplasmic domain were essential for the spinogenic activity. Notably, the synaptogenic activity of IL1RAPL1 was specific for excitatory synapses. Furthermore, we identified presynaptic protein tyrosine phosphatase (PTP) δ as a major IL1RAPL1–ECD interacting protein by affinity chromatography. IL1RAPL1 interacted selectively with certain forms of PTPδ splice variants carrying mini-exon peptides in Ig-like domains. The synaptogenic activity of IL1RAPL1 was abolished in primary neurons from PTPδ knock-out mice. IL1RAPL1 showed robust synaptogenic activityin vivowhen transfected into the cortical neurons of wild-type mice but not in PTPδ knock-out mice. These results suggest that IL1RAPL1 mediates synapse formation throughtrans-synaptic interaction with PTPδ. Our findings raise an intriguing possibility that the impairment of synapse formation may underlie certain forms of MR and autism as a common pathogenic pathway shared by these mental disorders.
Surface Traffic of Dendritic CaV1.2 Calcium Channels in Hippocampal Neurons
Authors: Di Biase Valentina , Tuluc Petronel , Campiglio Marta , Obermair Gerald J. , Heine Martin , Flucher Bernhard E.
Published: September 2011

In neurons L-type calcium currents function in gene regulation and synaptic plasticity, while excessive calcium influx leads to excitotoxicity and neurodegeneration. The major neuronal CaV1.2 L-type channels are localized in clusters in dendritic shafts and spines. Whereas CaV1.2 clusters remain stable during NMDA-induced synaptic depression, L-type calcium currents are rapidly downregulated during strong excitatory stimulation. Here we used fluorescence recovery after photobleaching (FRAP), live cell-labeling protocols, and single particle tracking (SPT) to analyze the turnover and surface traffic of CaV1.2 in dendrites of mature cultured mouse and rat hippocampal neurons, respectively. FRAP analysis of channels extracellularly tagged with superecliptic pHluorin (CaV1.2-SEP) demonstrated ∼20% recovery within 2 min without reappearance of clusters. Pulse–chase labeling showed that membrane-expressed CaV1.2-HA is not internalized within1 h, while blocking dynamin-dependent endocytosis resulted in increased cluster density after 30 min. Together, these results suggest a turnover rate of clustered CaV1.2s on the hour time scale. Direct recording of the lateral movement in the membrane using SPT demonstrated that dendritic CaV1.2s show highly confined mobility with diffusion coefficients of ∼0.005 μm2s−1. Consistent with the mobile CaV1.2 fraction observed in FRAP, a ∼30% subpopulation of channels reversibly exchanged between confined and diffusive states. Remarkably, high potassium depolarization did not alter the recovery rates in FRAP or the diffusion coefficients in SPT analyses. Thus, an equilibrium of clustered and dynamic CaV1.2s maintains stable calcium channel complexes involved in activity-dependent cell signaling, whereas the minor mobile channel pool in mature neurons allows limited capacity for short-term adaptations.
The Relationship between Cortical Magnification Factor and Population Receptive Field Size in Human Visual Cortex: Constancies in Cortical Architecture
Authors: Harvey Ben M. , Dumoulin Serge O.
Published: September 2011

Receptive field (RF) sizes and cortical magnification factor (CMF) are fundamental organization properties of the visual cortex. At increasing visual eccentricity, RF sizes increase and CMF decreases. A relationship between RF size and CMF suggests constancies in cortical architecture, as their product, the cortical representation of an RF (point image), may be constant. Previous animal neurophysiology studies of this question yield conflicting results. Here, we use fMRI to determine the relationship between the population RF (pRF) and CMF in humans. In average and individual data, the product of CMF and pRF size, the population point image, is near constant, decreasing slightly with eccentricity in V1. Interhemisphere and subject variations in CMF, pRF size, and V1 surface area are correlated, and the population point image varies less than these properties. These results suggest a V1 cortical processing architecture of approximately constant size between humans. Up the visual hierarchy, to V2, V3, hV4, and LO1, the population point image decreases with eccentricity, and both the absolute values and rate of change increase. PRF sizes increase between visual areas and with eccentricity, but when expressed in V1 cortical surface area (i.e., corticocortical pRFs), they are constant across eccentricity in V2/V3. Thus, V2/V3, and to some degree hV4, sample from a constant extent of V1. This may explain population point image changes in later areas. Consequently, the constant factor determining pRF size may not be the relationship to the local CMF, but rather pRF sizes and CMFs in visual areas from which the pRF samples.
The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury
Authors: Mantuano Elisabetta , Henry Kenneth , Yamauchi Tomonori , Hiramatsu Nobuhiko , Yamauchi Kazuyo , Orita Sumihisa , Takahashi Kazuhisa , Lin Jonathan H. , Gonias Steven L. , Campana W. Marie
Published: September 2011

In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.
Cocaine Alters BDNF Expression and Neuronal Migration in the Embryonic Mouse Forebrain
Authors: McCarthy Deirdre M. , Zhang Xuan , Darnell Shayna B. , Sangrey Gavin R. , Yanagawa Yuchio , Sadri-Vakili Ghazaleh , Bhide Pradeep G.
Published: September 2011

Prenatal cocaine exposure impairs brain development and produces lasting alterations in cognitive function. In a prenatal cocaine exposure mouse model, we found that tangential migration of GABA neurons from the basal to the dorsal forebrain and radial neuron migration within the dorsal forebrain were significantly decreased during the embryonic period. The decrease in the tangential migration occurred early in gestation and normalized by late gestation, despite ongoing cocaine exposure. The decrease in radial migration was associated with altered laminar positioning of neurons in the medial prefrontal cortex. The cocaine exposure led to transient decreases in the expression of Tbr2 and Tbr1, transcription factors associated with intermediate progenitor cells and newborn neurons of the dorsal forebrain, respectively, although neurogenesis was not significantly altered. Since cocaine can modulate brain derived neurotrophic factor (BDNF) expression in the mature brain, we examined whether cocaine can alter BDNF expression in the embryonic brain. We found a transient decrease in BDNF protein expression in the cocaine-exposed embryonic forebrain early in gestation. By late gestation, the BDNF expression recovered to control levels, despite ongoing cocaine exposure. In basal forebrain explants from cocaine-exposed embryos, cell migration was significantly decreased, corroborating thein vivodata on tangential GABA neuron migration. Since BDNF can influence tangential neuronal migration, we added BDNF to the culture medium and observed increased cell migration. Our data suggest that cocaine can alter tangential and radial neuronal migration as well as BDNF expression in the embryonic brain and that decreased BDNF may mediate cocaine's effects on neuronal migration.
Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory
Authors: Stone Scellig S. D. , Teixeira Cátia M. , DeVito Loren M. , Zaslavsky Kirill , Josselyn Sheena A. , Lozano Andres M. , Frankland Paul W.
Published: September 2011

Deep brain stimulation (DBS) is an established therapeutic modality for the treatment of movement disorders and an emerging therapeutic approach for the treatment of disorders of mood and thought. For example, recently we have shown that DBS of the fornix may ameliorate cognitive decline associated with dementia. However, like other applications of DBS, the mechanisms mediating these clinical effects are unknown. As DBS modulates neurophysiological activity in targeted brain regions, DBS might influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters analogous to clinical high-frequency DBS, here we addressed this question in mice. We found that acute stimulation of the entorhinal cortex (EC) transiently promoted proliferation in the dentate gyrus (DG). Cells generated as a consequence of stimulation differentiated into neurons, survived for at least several weeks, and acquired normal dentate granule cell (DGC) morphology. Importantly, stimulation-induced promotion of neurogenesis was limited to the DG and not associated with changes in apoptotic cell death. Using immunohistochemical approaches, we found that, once sufficiently mature, these stimulation-induced neurons integrated into hippocampal circuits supporting water-maze memory. Finally, formation of water-maze memory was facilitated 6 weeks (but not 1 week) after bilateral stimulation of the EC. The delay-dependent nature of these effects matches the maturation-dependent integration of adult-generated DGCs into dentate circuits supporting water-maze memory. Furthermore, because the beneficial effects of EC stimulation were prevented by blocking neurogenesis, this suggests a causal relationship between stimulation-induced promotion of adult neurogenesis and enhanced spatial memory.
Cdk5-Mediated Phosphorylation of Axin Directs Axon Formation during Cerebral Cortex Development
Authors: Fang Wei-Qun , Ip Jacque P. K. , Li Rui , Ng Yu Pong , Lin Sheng-Cai , Chen Yu , Fu Amy K. Y. , Ip Nancy Y.
Published: September 2011

Axon formation is critical for the establishment of connections between neurons, which is a prerequisite for the development of neural circuitry. Kinases such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase-3β (GSK-3β), have been implicated to regulate axon outgrowth. Nonetheless, thein vivoroles of these kinases in axon development and the underlying signaling mechanisms remain essentially unknown. We report here that Cdk5 is important for axon formation in mouse cerebral cortex through regulating the functions of axis inhibitor (Axin), a scaffold protein of the canonical Wnt pathway. Knockdown of Axinin uteroabolishes the formation and projection of axons. Importantly, Axin is phosphorylated by Cdk5, and this phosphorylation facilitates the interaction of Axin with GSK-3β, resulting in inhibition of GSK-3β activity and dephosphorylation of its substrate collapsin response mediator protein-2 (CRMP-2), a microtubule-associated protein. Specifically, both phosphorylation of Axin and its interaction with GSK-3β are critically required for axon formation in mouse cortex development. Together, our findings reveal a new regulatory mechanism of axon formation through Cdk5-dependent phosphorylation of Axin.