bluuebunny/crossref_metadata_2025 huggingface dataset:
MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4
Authors: Huijbers Maartje G. , Zhang Wei , Klooster Rinse , Niks Erik H. , Friese Matthew B. , Straasheijm Kirsten R. , Thijssen Peter E. , Vrolijk Hans , Plomp Jaap J. , Vogels Pauline , Losen Mario , Van der Maarel Silvère M. , Burden Steven J. , Verschuuren Jan J.
Published: December 2013

Significance

MuSK myasthenia gravis (MG) is a debilitating autoimmune disease: one-third of MuSK MG patients experience a life-threatening respiratory crisis, and long-term immunosuppression is the only current treatment option. Here we show that pathogenic human IgG4 MuSK antibodies bind to the first Ig-like domain in MuSK and prevent Lrp4 from binding MuSK, thereby inhibiting Agrin-stimulated MuSK phosphorylation. This inhibitory mechanism is likely responsible for disrupting the structure of the synapse, compromising synaptic transmission and causing disease. Our findings therefore suggest that therapeutic strategies designed to increase MuSK activity may prove effective in treating MuSK MG. Moreover, our studies provide mechanistic understanding of an IgG4-mediated autoimmune disease and may shed light on the mechanisms of other IgG4-mediated autoimmune diseases.
Crystallographic insights into sodium-channel modulation by the β4 subunit
Authors: Gilchrist John , Das Samir , Van Petegem Filip , Bosmans Frank
Published: December 2013

Significance

Voltage-gated sodium (Na
v
) channels are members of a large complex that plays a crucial role in rapid electrical signaling throughout the human body. As prominent members of this complex, β-subunits modify Na
v
channel function and cause debilitating disorders when mutated. Collectively, the functional and crystallographic results reported in this work uncover intricate interactions of these elements within the Na
v
-channel signaling complex and establish a key role for β-subunits in shaping Na
v
1.2 pharmacology. An important concept emerging from our results is that β-subunits provide exciting opportunities for designing new therapeutic strategies to correct their abnormal behaviors.
Sensitivity to ocean acidification parallels natural pCO
2
gradients experienced by Arctic copepods under winter sea ice
Authors: Lewis Ceri N. , Brown Kristina A. , Edwards Laura A. , Cooper Glenn , Findlay Helen S.
Published: December 2013

Significance

The Arctic Ocean is a bellwether for ocean acidification, yet few direct Arctic studies have been carried out and limited observations exist, especially in winter. We present unique under-ice physicochemical data showing the persistence of a mid water column area of high CO
2
and low pH through late winter, Zooplankton data demonstrating that the dominant copepod species are distributed across these different physicochemical conditions, and empirical data demonstrating that these copepods show sensitivity to pCO
2
that parallels the range of natural pCO
2
they experience through their daily vertical migration behavior. Our data, collected as part of the Catlin Arctic Survey, provide unique insight into the link between environmental variability, behavior, and an organism’s physiological tolerance to CO
2
in key Arctic biota.
Predicting the X-ray lifetime of protein crystals
Authors: Zeldin Oliver B. , Brockhauser Sandor , Bremridge John , Holton James M. , Garman Elspeth F.
Published: December 2013

Significance

Most atomic-resolution protein structures are determined by growing protein crystals, then exposing them to intense X-ray beams. The pattern of scattered X-rays can be used to find the atomic structure of the protein. A major drawback of this technique is that absorbed X-rays damage the fragile protein crystals. We present a method for determining how long a protein crystal will last in the X-ray beam, and for evaluating specific data-collection strategies in terms of how many data are acquired per unit damage caused. By way of example, we show that a small change in the typical experimental geometry can allow large crystals to be exposed for longer, giving better data quality and resulting in lower levels of damage.
Sex differences in the structural connectome of the human brain
Authors: Ingalhalikar Madhura , Smith Alex , Parker Drew , Satterthwaite Theodore D. , Elliott Mark A. , Ruparel Kosha , Hakonarson Hakon , Gur Raquel E. , Gur Ruben C. , Verma Ragini
Published: December 2013

Significance

Sex differences are of high scientific and societal interest because of their prominence in behavior of humans and nonhuman species. This work is highly significant because it studies a very large population of 949 youths (8–22 y, 428 males and 521 females) using the diffusion-based structural connectome of the brain, identifying novel sex differences. The results establish that male brains are optimized for intrahemispheric and female brains for interhemispheric communication. The developmental trajectories of males and females separate at a young age, demonstrating wide differences during adolescence and adulthood. The observations suggest that male brains are structured to facilitate connectivity between perception and coordinated action, whereas female brains are designed to facilitate communication between analytical and intuitive processing modes.
Male contraception via simultaneous knockout of α
1A
-adrenoceptors and P2X1-purinoceptors in mice
Authors: White Carl W. , Choong Yan-Ting , Short Jennifer L. , Exintaris Betty , Malone Daniel T. , Allen Andrew M. , Evans Richard J. , Ventura Sabatino
Published: December 2013

Significance

The search for a viable male contraceptive target has been a medical challenge for many years. Most strategies have focused on hormonal or germ-line strategies to produce dysfunctional sperm that are incapable of fertilization. The problem with such approaches is that they have intolerable side effects such as affecting male sexual activity or causing long-term irreversible effects on fertility. In addition, some strategies may transmit detrimental changes to future offspring. This manuscript describes a male contraceptive target within the autonomic nervous system, which would not affect the long-term viability of sperm nor the sexual or general health of males. In addition, due to the nature of the target, the contraceptive has the potential to be orally administered.
Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling
Authors: Louria-Hayon Igal , Frelin Catherine , Ruston Julie , Gish Gerald , Jin Jing , Kofler Michael M. , Lambert Jean-Philippe , Adissu Hibret A. , Milyavsky Michael , Herrington Robert , Minden Mark D. , Dick John E. , Gingras Anne-Claude , Iscove Norman N. , Pawson Tony
Published: December 2013

Significance

Recurrence of cancer in patients treated with radiation therapy infers that tumor cells have the capacity to escape the lethal effects of irradiation. Surviving tumor cells rely on signaling pathways triggered by hematopoietic interleukins in a mechanism that is poorly understood. We find that the adaptor protein Lnk is key in this process, acting as a negative regulator of interleukin 11 survival signaling. In Lnk knockout derived mice, hematopoietic stem cells have a marked level of irradiation resistance, causing B-cell malignancies. Such observations are consistent with the physiology seen in a subset of human leukemia patients that have Lnk gene mutations. Inhibition of interleukin 11 signaling in the mouse model circumvented this irradiation-resistance phenomenon and is suggestive of a potential for therapeutic intervention.
A maximum entropy framework for nonexponential distributions
Authors: Peterson Jack , Dixit Purushottam D. , Dill Ken A.
Published: December 2013

Significance

Many statistical distributions, particularly among social and biological systems, have “heavy tails,” which are situations where rare events are not as improbable as would have been guessed from more traditional statistics. Heavy-tailed distributions are the basis for the phrase “the rich get richer.” Here, we propose a basic principle underlying systems with heavy-tailed distributions. We show that it is the same principle (maximum entropy) used in statistical physics and statistics to estimate probabilistic models from relatively few constraints. The heavy-tail principle can be expressed in terms of shared costs and economies of scale. The probability distribution we derive is a mathematical digamma function, and we show that it accurately fits 13 real-world data sets.
RH5–Basigin interaction plays a major role in the host tropism of
Plasmodium falciparum
Authors: Wanaguru Madushi , Liu Weimin , Hahn Beatrice H. , Rayner Julian C. , Wright Gavin J.
Published: December 2013

Significance

Plasmodium falciparum
is responsible for almost all malaria-related deaths and belongs to a family of parasites that infect African apes. In their native habitat, these parasites exhibit strict host tropism, with human
P
.
falciparum
having never been found in wild-living chimpanzees and gorillas. Our research provides a molecular explanation for this phenomenon by showing that the interaction between a parasite protein (RH5) and its erythrocyte cell surface receptor (Basigin) is species specific and mirrors the observed host–parasite tropism. Our findings also reveal how a parasite responsible for one of the world’s major health problems has evolved its relationship with the human host and identify specific changes in the Basigin receptor that could make human erythrocytes resistant to infection by
P
.
falciparum
.
CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis
Authors: Dondossola Eleonora , Rangel Roberto , Guzman-Rojas Liliana , Barbu Elena M. , Hosoya Hitomi , St. John Lisa S. , Molldrem Jeffrey J. , Corti Angelo , Sidman Richard L. , Arap Wadih , Pasqualini Renata
Published: December 2013

Significance

The progression of many solid tumors is associated with increased vascularization. We previously recognized involvement in tumor development and angiogenesis of tumor stromal cells expressing the CD13 protease aminopeptidase. The basic biological concept of participation of nontumor cells in the cancer stroma microenvironment is strengthened in the present study by our finding that a CD11b
+
CD13
+
myeloid subset of bone marrow-derived cells affects pericyte biology and angiogenesis and thereby influences tumor growth and metastasis. Therapeutic implications of the identification of specific CD11
+
CD13
+
myeloid bone marrow-derived cells as participants in the mechanism of tumor angiogenesis merit further investigation.
Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection
Authors: Grady Sarah L. , Purdy John G. , Rabinowitz Joshua D. , Shenk Thomas
Published: December 2013

Significance

Virus infection can trigger profound alterations in host cell metabolism, but the role of individual enzymes in this process is relatively unstudied. Here, we show that argininosuccinate synthetase 1 (AS1) antagonizes the production of herpes simplex virus 1 (HSV-1) in cultured fibroblasts. Infection reduces the level of AS1 protein, and further reduction induced by siRNA treatment enhances the production of HSV-1. AS1 deficiency mimics many of the metabolic changes induced by HSV-1 infection, demonstrating that a decrease in the activity of a single cellular enzyme is responsible for much of the metabolic reprogramming induced by HSV-1. These results underscore the dependence of HSV-1 replication on altered host cell metabolism.
β-Globin cis-elements determine differential nuclear targeting through epigenetic modifications
Authors: Bian Qian , Khanna Nimish , Alvikas Jurgis , Belmont Andrew S.
Published: December 2013

Increasing evidence points to nuclear compartmentalization as a contributing mechanism for gene regulation, yet mechanisms for compartmentalization remain unclear. In this paper, we use autonomous targeting of bacterial artificial chromosome (BAC) transgenes to reveal cis requirements for peripheral targeting. Three peripheral targeting regions (PTRs) within an HBB BAC bias a competition between pericentric versus peripheral heterochromatin targeting toward the nuclear periphery, which correlates with increased H3K9me3 across the β-globin gene cluster and locus control region. Targeting to both heterochromatin compartments is dependent on Suv39H-mediated H3K9me3 methylation. In different chromosomal contexts, PTRs confer no targeting, targeting to pericentric heterochromatin, or targeting to the periphery. A combination of fluorescent in situ hybridization, BAC transgenesis, and knockdown experiments reveals that peripheral tethering of the endogenous HBB locus depends both on Suv39H-mediated H3K9me3 methylation over hundreds of kilobases surrounding HBB and on G9a-mediated H3K9me2 methylation over flanking sequences in an adjacent lamin-associated domain. Our results demonstrate that multiple cis-elements regulate the overall balance of specific epigenetic marks and peripheral gene targeting.
CP110 exhibits novel regulatory activities during centriole assembly in Drosophila
Authors: Franz Anna , Roque Hélio , Saurya Saroj , Dobbelaere Jeroen , Raff Jordan W.
Published: December 2013

CP110 is a conserved centriole protein implicated in the regulation of cell division, centriole duplication, and centriole length and in the suppression of ciliogenesis. Surprisingly, we report that mutant flies lacking CP110 (CP110Δ) were viable and fertile and had no obvious defects in cell division, centriole duplication, or cilia formation. We show that CP110 has at least three functions in flies. First, it subtly influences centriole length by counteracting the centriole-elongating activity of several centriole duplication proteins. Specifically, we report that centrioles are ∼10% longer than normal in CP110Δ mutants and ∼20% shorter when CP110 is overexpressed. Second, CP110 ensures that the centriolar microtubules do not extend beyond the distal end of the centriole, as some centriolar microtubules can be more than 50 times longer than the centriole in the absence of CP110. Finally, and unexpectedly, CP110 suppresses centriole overduplication induced by the overexpression of centriole duplication proteins. These studies identify novel and surprising functions for CP110 in vivo in flies.
Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals
Authors: Heizmann Beate , Kastner Philippe , Chan Susan
Published: December 2013

Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C′ stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C′ and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.
Mortality among Patients with Methicillin-ResistantStaphylococcus aureusUSA300 versus Non-USA300 Invasive Infections: A Meta-Analysis
Authors: Nair Rajeshwari , Ammann Eric , Rysavy Matthew , Schweizer Marin L.
Published: December 2013

Background.

Community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) has been found to be epidemiologically and microbiologically distinct from healthcare-associated MRSA. Most CA-MRSA infections are not invasive; however, fatal outcomes have been reported among healthy people with CA-MRSA invasive infections. Epidemiological studies have attributed a major burden of CA-MRSA infections in the United States to the predominant clone USA300. We investigated the association between USA300 invasive infections and mortality by conducting a systematic review and meta-analysis of studies that reported mortality rates associated with USA300 strains.

Methods.

We searched PubMed, bibliographies of other publications, and gray literature between January 2001 and December 2013. Observational studies of patients with an invasive MRSA infection were included. The exposure of interest was presence of USA300 invasive infection. Studies were included only if they provided MRSA PFGE types and if corresponding mortality data were the measured outcome. We pooled crude odds ratios (cORs) using a random-effects model. Woolf test of homogeneity andQandI2statistics were assessed.

Results.

Of 574 articles identified by the search strategy, 8 met the inclusion criteria. Risk of mortality was significantly lower among patients with USA300 MRSA infections (pooled cOR, 0.63 [95% confidence interval (CI)], 0.49–0.81). There was a moderate degree of heterogeneity among study results (P= .29;I2= 18%). Results were observed to be heterogeneous due to study design, quality of studies, and definition of mortality.

Conclusions.

MRSA invasive infection with USA300 does not appear to be associated with higher mortality compared with infections due to non-USA300 strains. Nevertheless, larger well-designed studies are warranted to further evaluate this association.
Structure and DNA-binding properties of the Bacillus subtilis SpoIIIE DNA translocase revealed by single-molecule and electron microscopies
Authors: Cattoni Diego I. , Thakur Shreyasi , Godefroy Cedric , Le Gall Antoine , Lai-Kee-Him Josephine , Milhiet Pierre-Emmanuel , Bron Patrick , Nöllmann Marcelo
Published: December 2013

SpoIIIE/FtsK are a family of ring-shaped, membrane-anchored, ATP-fuelled motors required to segregate DNA across bacterial membranes. This process is directional and requires that SpoIIIE/FtsK recognize highly skewed octameric sequences (SRS/KOPS for SpoIIIE/FtsK) distributed along the chromosome. Two models have been proposed to explain the mechanism by which SpoIIIE/FtsK interact with DNA. The loading model proposes that SpoIIIE/FtsK oligomerize exclusively on SpoIIIE recognition sequence/orienting polar sequences (SRS/KOPS) to accomplish directional DNA translocation, whereas the target search and activation mechanism proposes that pre-assembled SpoIIIE/FtsK hexamers bind to non-specific DNA, reach SRS/KOPS by diffusion/3d hopping and activate at SRS/KOPS. Here, we employ single-molecule total internal reflection imaging, atomic force and electron microscopies and ensemble biochemical methods to test these predictions and obtain further insight into the SpoIIIE–DNA mechanism of interaction. First, we find that SpoIIIE binds DNA as a homo-hexamer with neither ATP binding nor hydrolysis affecting the binding mechanism or affinity. Second, we show that hexameric SpoIIIE directly binds to double-stranded DNA without requiring the presence of SRS or free DNA ends. Finally, we find that SpoIIIE hexamers can show open and closed conformations in solution, with open-ring conformations most likely resembling a state poised to load to non-specific, double-stranded DNA. These results suggest how SpoIIIE and related ring-shaped motors may be split open to bind topologically closed DNA.
Amplatzer Septal Occluder Migration into the Pulmonary Trunk
Authors: Cresce Giovanni Domenico , Favaro Alessandro , Auriemma Stefano , Salvador Loris
Published: December 2013

The Amplatzer Septal Occluder for transcatheter closure of interatrial communications is a standard procedure and a widely accepted alternative to surgery in most patients with atrial septal defect (ASD). Device dislocation or embolization has been reported as one of the commonest complications of ASD percutaneous closure. In this case, if a transcatheter removal is not possible, it requires a surgical therapy, usually through a median sternotomy. We report on a case of a 30-year-old woman, who underwent percutaneous closure of an ostium secundum ASD. After a late embolization of the Amplatzer Septal Occluder into the pulmonary trunk 10 months later, the implant was successfully obtained via a surgical removal through a video-guided minimally invasive port-access approach. This case shows that, in experienced hands, the port-access technique for surgical procedures on the pulmonary trunk is feasible, and therefore, it might be a good alternative option to the traditional surgery, mainly in young patients.
Hydrocarbon liquefaction: viability as a peak oil mitigation strategy
Authors: Höök Mikael , Fantazzini Dean , Angelantoni André , Snowden Simon
Published: December 2013

Current world capacity of hydrocarbon liquefaction is around 400 000 barrels per day, providing a marginal share of the global liquid fuel supply. This study performs a broad review of technical, economic, environmental and supply chain issues related to coal-to-liquids (CTL) and gas-to-liquids (GTL). We find three issues predominate. First, significant amounts of coal and gas would be required to obtain anything more than a marginal production of liquids. Second, the economics of CTL plants are clearly prohibitive, but are better for GTL. Nevertheless, large-scale GTL plants still require very high upfront costs, and for three real-world GTL plants out of four, the final cost has been so far approximately three times that initially budgeted. Small-scale GTL holds potential for associated gas. Third, both CTL and GTL incur significant environmental impacts, ranging from increased greenhouse gas emissions (in the case of CTL) to water contamination. Environmental concerns may significantly affect growth of these projects until adequate solutions are found.
Biofuels in the long-run global energy supply mix for transportation
Authors: Timilsina Govinda R.
Published: December 2013

Various policy instruments along with increasing oil prices have contributed to a sixfold increase in global biofuels production over the last decade (2000–2010). This rapid growth has proved controversial, however, and has raised concerns over potential conflicts with global food security and climate change mitigation. To address these concerns, policy support is now focused on advanced or second-generation biofuels instead of crop-based first-generation biofuels. This policy shift, together with the global financial crisis, has slowed the growth of biofuels production, which has remained stagnant since 2010. Based upon a review of the literature, this paper examines the potential long-run contribution of biofuels to the global energy mix, particularly for transportation. We find that the contribution of biofuels to global transportation fuel demand is likely to be limited to around 5% over the next 10–15 years. However, a number of studies suggest that biofuels could contribute up to a quarter of global transportation fuel demand by 2050, provided technological breakthroughs reduce the costs of sustainably produced advanced biofuels to a level where they can compete with petroleum fuels.
The future of oil: unconventional fossil fuels
Authors: Chew Kenneth J.
Published: December 2013

Unconventional fossil hydrocarbons fall into two categories: resource plays and conversion-sourced hydrocarbons. Resource plays involve the production of accumulations of solid, liquid or gaseous hydro-carbons that have been generated over geological time from organic matter in source rocks. The character of these hydrocarbons may have been modified subsequently, especially in the case of solids and extra-heavy liquids. These unconventional hydrocarbons therefore comprise accumulations of hydrocarbons that are trapped in an unconventional manner and/or whose economic exploitation requires complex and technically advanced production methods. This review focuses primarily on unconventional liquid hydro-carbons. The future potential of unconventional gas, especially shale gas, is also discussed, as it is revolutionizing the energy outlook in North America and elsewhere.
An assessment of electric vehicles: technology, infrastructure requirements, greenhouse-gas emissions, petroleum use, material use, lifetime cost, consumer acceptance and policy initiatives
Authors: Delucchi M. A. , Yang C. , Burke A. F. , Ogden J. M. , Kurani K. , Kessler J. , Sperling D.
Published: December 2013

Concerns about climate change, urban air pollution and dependence on unstable and expensive supplies of foreign oil have led policy-makers and researchers to investigate alternatives to conventional petroleum-fuelled internal-combustion-engine vehicles in transportation. Because vehicles that get some or all of their power from an electric drivetrain can have low or even zero emissions of greenhouse gases (GHGs) and urban air pollutants, and can consume little or no petroleum, there is considerable interest in developing and evaluating advanced electric vehicles (EVs), including pure battery-electric vehicles, plug-in hybrid electric vehicles and hydrogen fuel-cell electric vehicles. To help researchers and policy-makers assess the potential of EVs to mitigate climate change and reduce petroleum use, this paper discusses the technology of EVs, the infrastructure needed for their development, impacts on emissions of GHGs, petroleum use, materials use, lifetime costs, consumer acceptance and policy considerations.
Exploring the undulating plateau: the future of global oil supply
Authors: Jackson Peter M. , Smith Leta K.
Published: December 2013

In this paper, we analyse the factors that will influence long-term oil supply and describe the future form of the global oil supply profile as an ‘undulating plateau’ rather than an irreversible, short-term peak or an ever upward trend of increasing production. The ultimate transition from a world of relatively plentiful and cheap oil to one of tight supply and high cost will be slow and challenging. An understanding of the signposts for the future path of supply and the drivers of that profile will be critical to managing the transition. The ultimate form of the global supply curve may well be dictated by demand evolution rather than a limited resource endowment in the longer term. Several factors will probably control future global oil supply. We believe that the scale of global oil resource will not constitute a physical supply limit for at least the next two or three decades. However, all categories of oil resources are already more expensive to develop than in the past, requiring high oil prices to stimulate supply growth. Lower rates of oil demand growth relative to economic growth, combined with more challenging supply growth, will probably lead to an undulating plateau sometime after 2040, with demand from non-Organization for Economic Cooperation and Development states continuing to dominate. Upstream investment requirements and oil price volatility will increase towards and beyond the undulating production plateau. In this new world, high oil prices will induce demand destruction, fuel substitution and ever increasing energy efficiency. As we discuss below, the fundamental differences between the IHS Cambridge Energy Research Associates' (IHS CERA) view of the future of oil supply and many peak oil supply models are the timing of the onset of a dramatic slowdown in the rate of growth of supply and the existence or otherwise of a production plateau. We do not dispute that supply will plateau and eventually fall; the question is when, how and at what price? As the plateau approaches, oil prices are likely to increase strongly, with some very severe spikes along the way.
The future of oil supply
Authors: Miller Richard G. , Sorrell Steven R.
Published: December 2013

Abundant supplies of oil form the foundation of modern industrial economies, but the capacity to maintain and grow global supply is attracting increasing concern. Some commentators forecast a peak in the near future and a subsequent terminal decline in global oil production, while others highlight the recent growth in ‘tight oil’ production and the scope for developing unconventional resources. There are disagreements over the size, cost and recoverability of different resources, the technical and economic potential of different technologies, the contribution of different factors to market trends and the economic implications of reduced supply. Few debates are more important, more contentious, more wide-ranging or more confused. This paper summarizes the main concepts, terms, issues and evidence that are necessary to understand the ‘peak oil’ debate. These include: the origin, nature and classification of oil resources; the trends in oil production and discoveries; the typical production profiles of oil fields, basins and producing regions; the mechanisms underlying those profiles; the extent of depletion of conventional oil; the risk of an approaching peak in global production; and the potential of various mitigation options. The aim is to introduce the subject to non-specialist readers and provide a basis for the subsequent papers in this Theme Issue.
Spike-timing-dependent BDNF secretion and synaptic plasticity
Authors: Lu Hui , Park Hyungju , Poo Mu-Ming
Published: December 2013

In acute hippocampal slices, we found that the presence of extracellular brain-derived neurotrophic factor (BDNF) is essential for the induction of spike-timing-dependent long-term potentiation (tLTP). To determine whether BDNF could be secreted from postsynaptic dendrites in a spike-timing-dependent manner, we used a reduced system of dissociated hippocampal neurons in culture. Repetitive pairing of iontophoretically applied glutamate pulses at the dendrite with neuronal spikes could induce persistent alterations of glutamate-induced responses at the same dendritic site in a manner that mimics spike-timing-dependent plasticity (STDP)—the glutamate-induced responses were potentiated and depressed when the glutamate pulses were applied 20 ms before and after neuronal spiking, respectively. By monitoring changes in the green fluorescent protein (GFP) fluorescence at the dendrite of hippocampal neurons expressing GFP-tagged BDNF, we found that pairing of iontophoretic glutamate pulses with neuronal spiking resulted in BDNF secretion from the dendrite at the iontophoretic site only when the glutamate pulses were applied within a time window of approximately 40 ms prior to neuronal spiking, consistent with the timing requirement of synaptic potentiation via STDP. Thus, BDNF is required for tLTP and BDNF secretion could be triggered in a spike-timing-dependent manner from the postsynaptic dendrite.
PSD-95 promotes the stabilization of young synaptic contacts
Authors: Taft Christine E. , Turrigiano Gina G.
Published: December 2013

Maintaining a population of stable synaptic connections is probably of critical importance for the preservation of memories and functional circuitry, but the molecular dynamics that underlie synapse stabilization is poorly understood. Here, we use simultaneous time-lapse imaging of post synaptic density-95 (PSD-95) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) to investigate the dynamics of protein composition at axodendritic (AD) contacts. Our data reveal that this composition is highly dynamic, with both proteins moving into and out of the same synapse independently, so that synapses cycle rapidly between states in which they are enriched for none, one or both proteins. We assessed how PSD-95 and CaMKII interact at stable and transient AD sites and found that both phospho-CaMKII and PSD-95 are present more often at stable than labile contacts. Finally, we found that synaptic contacts are more stable in older neurons, and this process can be mimicked in younger neurons by overexpression of PSD-95. Taken together, these data show that synaptic protein composition is highly variable over a time-scale of hours, and that PSD-95 is probably a key synaptic protein that promotes synapse stability.
Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil
Authors: Epstein Irina , Tushev Georgi , Will Tristan J. , Vlatkovic Irena , Cajigas Iván J. , Schuman Erin M.
Published: December 2013

The stability and dynamics of synapses rely on tight regulation of the synaptic proteome. Shank proteins, encoded by the three genes Shank1, Shank2 and Shank3 are scaffold molecules in the postsynaptic density of excitatory neurons that contribute to activity-dependent neuronal signalling. Mutations in the Shank genes are associated with neurological diseases. Using state-of-the-art technologies, we investigated the levels of expression of the Shank family messenger RNAs (mRNAs) within the synaptic neuropil of the rat hippocampus. We detected all three Shank transcripts in the neuropil of CA1 pyramidal neurons. We found Shank1 to be the most abundantly expressed among the three Shank mRNA homologues. We also examined the turnover of Shank mRNAs and predict the half-lives of Shank1, Shank2 and Shank3 mRNAs to be 18–28 h. Using 3′-end sequencing, we identified novel 3′ ends for the Shank1 and Shank2 3′ untranslated regions (3′ UTRs) that may contribute to the diversity of alternative polyadenylation (APA) for the Shank transcripts. Our findings consolidate the view that the Shank molecules play a central role at the postsynaptic density. This study may shed light on synaptopathologies associated with disruption of local protein synthesis, perhaps linked to mutations in mRNA 3′ UTRs or inappropriate 3′ end processing.
Cellular and subcellular localization of PKMζ
Authors: Hernández A. Iván , Oxberry William C. , Crary John F. , Mirra Suzanne S. , Sacktor Todd Charlton
Published: December 2013

In contrast to protein kinases that participate in long-term potentiation (LTP) induction and memory consolidation, the autonomously active atypical protein kinase C isoform, protein kinase Mzeta (PKMζ), functions in the core molecular mechanism of LTP maintenance and long-term memory storage. Here, using multiple complementary techniques for light and electron microscopic immunolocalization, we present the first detailed characterization of the cellular and subcellular distribution of PKMζ in rat hippocampus and neocortex. We find that PKMζ is widely expressed in forebrain with prominent immunostaining in hippocampal and neocortical grey matter, and weak label in white matter. In hippocampal and cortical pyramidal cells, PKMζ expression is predominantly somatodendritic, and electron microscopy highlights the kinase at postsynaptic densities and in clusters within spines. In addition, nuclear label and striking punctate immunopositive structures in a paranuclear and dendritic distribution are seen by confocal microscopy, occasionally at dendritic bifurcations. PKMζ immunoreactive granules are observed by electron microscopy in cell bodies and dendrites, including endoplasmic reticulum. The widespread distribution of PKMζ in nuclei, nucleoli and endoplasmic reticulum suggests potential roles of this kinase in cell-wide mechanisms involving gene expression, biogenesis of ribosomes and new protein synthesis. The localization of PKMζ within postsynaptic densities and spines suggests sites where the kinase stores information during LTP maintenance and long-term memory.
Long-term potentiation in the anterior cingulate cortex and chronic pain
Authors: Zhuo Min
Published: December 2013

Glutamate is the primary excitatory transmitter of sensory transmission and perception in the central nervous system. Painful or noxious stimuli from the periphery ‘teach’ humans and animals to avoid potentially dangerous objects or environments, whereas tissue injury itself causes unnecessary chronic pain that can even last for long periods of time. Conventional pain medicines often fail to control chronic pain. Recent neurobiological studies suggest that synaptic plasticity taking place in sensory pathways, from spinal dorsal horn to cortical areas, contributes to chronic pain. Injuries trigger long-term potentiation of synaptic transmission in the spinal cord dorsal horn and anterior cingulate cortex, and such persistent potentiation does not require continuous neuronal activity from the periphery. At the synaptic level, potentiation of excitatory transmission caused by injuries may be mediated by the enhancement of glutamate release from presynaptic terminals and potentiated postsynaptic responses of AMPA receptors. Preventing, ‘erasing’ or reducing such potentiation may serve as a new mechanism to inhibit chronic pain in patients in the future.
Hippocampal NMDA receptors are important for behavioural inhibition but not for encoding associative spatial memories
Authors: Taylor A. M. , Bus T. , Sprengel R. , Seeburg P. H. , Rawlins J. N. P. , Bannerman D. M.
Published: December 2013

The idea that an NMDA receptor (NMDAR)-dependent long-term potentiation-like process in the hippocampus is the neural substrate for associative spatial learning and memory has proved to be extremely popular and influential. However, we recently reported that mice lacking NMDARs in dentate gyrus and CA1 hippocampal subfields (GluN1ΔDGCA1mice) acquired the open field, spatial reference memory watermaze task as well as controls, a result that directly challenges this view. Here, we show thatGluN1ΔDGCA1mice were not impaired during acquisition of a spatial discrimination watermaze task, during which mice had to choose between two visually identical beacons, based on extramaze spatial cues, when all trials started at locations equidistant between the two beacons. They were subsequently impaired on test trials starting from close to the decoy beacon, conducted post-acquisition.GluN1ΔDGCA1mice were also impaired during reversal of this spatial discrimination. Thus, contrary to the widely held belief, hippocampal NMDARs are not required for encoding associative, long-term spatial memories. Instead, hippocampal NMDARs, particularly in CA1, act as part of a comparator system to detect and resolve conflicts arising when two competing, behavioural response options are evoked concurrently, through activation of a behavioural inhibition system. These results have important implications for current theories of hippocampal function.
Leptin regulation of hippocampal synaptic function in health and disease
Authors: Irving Andrew J. , Harvey Jenni
Published: December 2013

The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.
Long-term depression-inducing stimuli promote cleavage of the synaptic adhesion molecule NGL-3 through NMDA receptors, matrix metalloproteinases and presenilin/γ-secretase
Authors: Lee Hyejin , Lee Eun-Jae , Song Yoo Sung , Kim Eunjoon
Published: December 2013

Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low-frequency stimulation in brain slices and requires the activities of NMDA glutamate receptors, matrix metalloproteinases (MMPs) and presenilin/γ-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and γ-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.
The search for a hippocampal engram
Authors: Mayford Mark
Published: December 2013

Understanding the molecular and cellular changes that underlie memory, the engram, requires the identification, isolation and manipulation of the neurons involved. This presents a major difficulty for complex forms of memory, for example hippocampus-dependent declarative memory, where the participating neurons are likely to be sparse, anatomically distributed and unique to each individual brain and learning event. In this paper, I discuss several new approaches to this problem.
In vivo
calcium imaging techniques provide a means of assessing the activity patterns of large numbers of neurons over long periods of time with precise anatomical identification. This provides important insight into how the brain represents complex information and how this is altered with learning. The development of techniques for the genetic modification of neural ensembles based on their natural, sensory-evoked, activity along with optogenetics allows direct tests of the coding function of these ensembles. These approaches provide a new methodological framework in which to examine the mechanisms of complex forms of learning at the level of the neurons involved in a specific memory.
Synaptic plasticity in multiple sclerosis and in experimental autoimmune encephalomyelitis
Authors: Nisticò Robert , Mori Francesco , Feligioni Marco , Nicoletti Ferdinando , Centonze Diego
Published: December 2013

Approximately half of all patients with multiple sclerosis (MS) experience cognitive dysfunction, including learning and memory impairment. Recent studies suggest that hippocampal pathology is involved, although the mechanisms underlying these deficits remain poorly understood. Evidence obtained from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests that in the hippocampus of EAE mice long-term potentiation (LTP) is favoured over long-term depression in response to repetitive synaptic activation, through a mechanism dependent on enhanced IL-1β released from infiltrating lymphocytes or activated microglia. Facilitated LTP during an immune-mediated attack might underlie functional recovery, but also cognitive deficits and excitotoxic neurodegeneration. Having identified that pro-inflammatory cytokines such as IL-1β can influence synaptic function and integrity in early MS, it is hoped that new treatments targeted towards preventing synaptic pathology can be developed.
How the mechanisms of long-term synaptic potentiation and depression serve experience-dependent plasticity in primary visual cortex
Authors: Cooke Sam F. , Bear Mark F.
Published: December 2013

Donald Hebb chose visual learning in primary visual cortex (V1) of the rodent to exemplify his theories of how the brain stores information through long-lasting homosynaptic plasticity. Here, we revisit V1 to consider roles for bidirectional ‘Hebbian’ plasticity in the modification of vision through experience. First, we discuss the consequences of monocular deprivation (MD) in the mouse, which have been studied by many laboratories over many years, and the evidence that synaptic depression of excitatory input from the thalamus is a primary contributor to the loss of visual cortical responsiveness to stimuli viewed through the deprived eye. Second, we describe a less studied, but no less interesting form of plasticity in the visual cortex known as stimulus-selective response potentiation (SRP). SRP results in increases in the response of V1 to a visual stimulus through repeated viewing and bears all the hallmarks of perceptual learning. We describe evidence implicating an important role for potentiation of thalamo-cortical synapses in SRP. In addition, we present new data indicating that there are some features of this form of plasticity that cannot be fully accounted for by such feed-forward Hebbian plasticity, suggesting contributions from intra-cortical circuit components.
Molecular genetic analysis of vesicular transport in Aspergillus niger reveals partial conservation of the molecular mechanism of exocytosis in fungi
Authors: Kwon Min Jin , Arentshorst Mark , Fiedler Markus , de Groen Florence L. M. , Punt Peter J. , Meyer Vera , Ram Arthur F. J.
Published: December 2013

The filamentous fungusAspergillus nigeris an industrially exploited protein expression platform, well known for its capacity to secrete high levels of proteins. To study the process of protein secretion inA. niger, we established a GFP-v-SNARE reporter strain in which the trafficking and dynamics of secretory vesicles can be followedin vivo. The biological role of putativeA. nigerorthologues of seven secretion-specific genes, known to function in key aspects of the protein secretion machinery inSaccharomyces cerevisiae, was analysed by constructing respective gene deletion mutants in the GFP-v-SNARE reporter strain. Comparison of the deletion phenotype of conserved proteins functioning in the secretory pathway revealed common features but also interesting differences betweenS. cerevisiaeandA. niger. Deletion of theS. cerevisiaeSec2p orthologue inA. niger(SecB), encoding a guanine exchange factor for the GTPase Sec4p (SrgA inA. niger), did not have an obvious phenotype, whileSEC2deletion inS. cerevisiaeis lethal. Similarly, deletion of theA. nigerorthologue of theS. cerevisiaeexocyst subunit Sec3p (SecC) did not result in a lethal phenotype as inS. cerevisiae, although severe growth reduction ofA. nigerwas observed. Deletion ofsecA,secHandssoA(encoding SecA, SecH and SsoA theA. nigerorthologues ofS. cerevisiaeSec1p, Sec8p and Sso1/2p, respectively) showed that these genes are essential forA. niger, similar to the situation inS. cerevisiae.These data demonstrate that the orchestration of exocyst-mediated vesicle transport is only partially conserved inS. cerevisiaeandA. niger.