bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide Linkage and Association Analyses to Identify Genes Influencing Adiponectin Levels: The GEMS Stud
Authors: Ling Hua , Waterworth Dawn M. , Stirnadel Heide A. , Pollin Toni I. , Barter Philip J. , Kesäniemi Y. Antero , Mahley Robert W. , McPherson Ruth , Waeber Gérard , Bersot Thomas P. , Cohen Jonathan C. , Grundy Scott M. , Mooser Vincent E. , Mitchell Braxton D.
Published: January 2009

Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome‐wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome‐wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single‐nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10−7). These two SNPs were in high linkage disequilibrium (r2 = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 × 10−5) was to an SNP within CDH13, whose protein product is a newly identified receptor for high‐molecular‐weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.
Altering PPARγ Ligand Selectivity Impairs Adipogenesis by Thiazolidinediones But Not Hormonal Inducers
Authors: Samarasinghe Shanika P. , Sutanto Maria M. , Danos Arpad M. , Johnson Daniel N. , Brady Matthew J. , Cohen Ronald N.
Published: January 2009

Peroxisome proliferator‐activated receptor γ (PPARγ) acts as a ligand‐dependent transcription factor with a key role in mediating adipocyte differentiation and insulin sensitivity. Recently, we and others have shown that PPARγ recruits the nuclear corepressors NCoR and silencing mediator for retinoid and thyroid hormone receptors (SMRT) to modulate adipogenesis. While the synthetic ligands for PPARγ, the thiazolidinediones (TZD), are widely used in the treatment of type 2 diabetes mellitus, the biologically relevant endogenous PPARγ ligand involved in adipogenesis remains unidentified. To further understand the role of ligand binding and corepressor interaction in PPARγ‐mediated adipogenesis, a mutation was introduced in the ligand‐binding domain (LBD) of murine PPARγ. PPARγmut was created via two amino acid substitutions known to be major determinants of ligand selectivity among PPAR isotypes, H323Y and R288M. These mutations alter PPARγ to the corresponding residues of the PPARα. Characterizing the in vitro functional properties of this mutant, we show that PPARγmut preferentially responds to the PPARα agonist, WY‐14643, over the TZD, pioglitazone. When expressed in 3T3‐L1 preadipocytes using recombinant adenovirus, wild‐type PPARγ leads to adipocyte formation with both hormonal and TZD treatment. PPARγmut blocks the upregulation of adipocyte‐specific proteins by TZD, but surprisingly, not by standard hormonal inducers. Our data suggest that TZDs and the purported endogenous ligand do not interact in the same way with the PPARγ LBD. We propose that the endogenous ligand has distinct properties that allow for promiscuity within the hydrophobic PPAR ligand‐binding pocket, yet fosters appropriate cofactor recruitment and release to allow adipogenesis to proceed.
Adipogenic Cascade Can Be Induced Without Adipogenic Media by a Human Adenovirus
Authors: Rathod Miloni A. , Rogers Pamela M. , Vangipuram Sharada D. , McAllister Emily J. , Dhurandhar Nikhil V.
Published: January 2009

Several metabolic abnormalities are associated with relative excess or deficiency of adipose tissue. Identifying the regulators of adipogenic differentiation is critical for its successful manipulation. Ad36, a human adenovirus, is a novel factor that promotes adipogenesis. We exploited the adipogenic potential of Ad36 to reveal exogenous modifiers of adipogenesis in rodent preadipocyte cell line in the presence or absence of differentiation inducers methyl‐isobutyl‐xanthine, dexamethasone, and insulin (M, D, and I; MDI). A nonadipogenic human adenovirus Ad2 was used as a negative control for viral infection. First, we confirmed that, Ad36, but not Ad2, increases lipid accumulation in the presence or absence of MDI. Time‐course studies for expression of key genes of adipogenic cascade showed that it is Ad36, but not Ad2, which downregulated preadipocyte marker gene Wnt10b, and upregulated expression of early (C/EBPΔ and C/EBPβ), intermediate (PPARγ2), and late genes (aP2 and G3PDH) of adipogenic cascade even in the absence of MDI. In the presence of MDI, onset of expression of adipogenic genes coincided for Ad36 and control groups, but the expressions were significantly greater for the Ad36 group. Next, we observed that attenuation of Ad36 mRNA expression by an antiadenoviral agent reduced 3T3‐L1 differentiation, indicating that viral mRNA expression is required for the process. Furthermore, with or without MDI or its components, Ad36 significantly increased lipid accumulation in 3T3‐L1 cells. Cell confluency at the time of Ad36 infection positively influenced lipid accumulation. The results reveal that Ad36 is an MDI‐independent exogenous regulator of the adipogenic process. Elucidating the molecular pathways involved may reveal novel regulatory controls of adipogenesis.
The function of ROCO proteins in health and disease
Authors: Lewis Patrick A.
Published: January 2009

The ROCO family of multidomain proteins extends across the eukaryotes, and has been implicated in numerous cellular processes. Following the description of mutations causing PD (Parkinson's disease) in a human representative of the ROCO family, LRRK2 (leucine‐rich repeat kinase 2), a great deal of research has been carried out into these proteins. This review examines the published data regarding the roles the ROCO proteins are thought to play in cell processes, and how the structure and domain organization of these proteins relates to their function.
Identification of a cluster of residues in transmembrane segment 6 of domain III of the cockroach sodium channel essential for the action of pyrethroid insecticides
Authors: Du Yuzhe , Lee Jung-Eun , Nomura Yoshiko , Zhang Tianxiang , Zhorov Boris S. , Dong Ke
Published: January 2009

A phenylalanine residue (Phe1519) in the sixth transmembrane segment of domain III (IIIS6) of the cockroach BgNav sodium channel is required for the binding and action of pyrethroids. However, whether or not other residues in IIIS6 participate in the action of pyrethroids remains to be determined. In the present study, we conducted a systematic analysis of 20 residues in IIIS6 of the BgNav channel using alanine-scanning mutagenesis. Our results show that alanine substitutions of four residues, Ile1514, Gly1516, Phe1518 and Asn1522, altered sodium channel sensitivity to pyrethroid insecticides. Whereas the G1516A, F1518A and N1522A substitutions diminished sodium channel sensitivity to all seven pyrethroids examined, including four type I (lacking the α-cyano group at the phenoxybenzyl alcohol) and three type II (containing the α-cyano group) pyrethroids, the I1514A substitution enhanced sodium channel sensitivity to four type I and type II pyrethroids that contain the phenoxybenzyl alcohol only. We also show that alanine/lysine substitutions of Leu1521 and Ser1517 affected the action of BTX (batrachotoxin), but not pyrethroids. In the Kv1.2-based homology model of the open sodium channel, side chains of Ile1514, Phe1518 and Asn1522 are exposed towards helix IIS5 and linker IIS4–IIS5, which contain previously identified pyrethroid-interacting residues, whereas Ser1517 and Leu1521 face the inner pore where the BTX receptor is located. Thus the present study provides further evidence for structural models in which pyrethroids bind to the lipid-exposed interface formed by helices IIIS6, IIS5 and linker helix IIS4–IIS5, whereas BTX binds to the pore-exposed side of the IIIS6 helix.
How is the archaeal MCM helicase assembled at the origin? Possible mechanisms
Authors: Sakakibara Nozomi , Kelman Lori M. , Kelman Zvi
Published: January 2009

In order for any organism to replicate its DNA, a helicase must unwind the duplex DNA in front of the replication fork. In archaea, the replicative helicase is the MCM (minichromosome maintenance) helicase. Although much is known about the biochemical properties of the MCM helicase, the mechanism of assembly at the origin of replication is unknown. In the present paper, several possible mechanisms for the loading process are described.
Mutational studies of archaeal RNA polymerase and analysis of hybrid RNA polymerases
Authors: Thomm Michael , Reich Christoph , Grünberg Sebastian , Naji Souad
Published: January 2009

The recent success in reconstitution of RNAPs (RNA polymerases) from hyperthermophilic archaea from bacterially expressed purified subunits opens the way for detailed structure–function analyses of multisubunit RNAPs. The archaeal enzyme shows close structural similarity to eukaryotic RNAP, particularly to polymerase II, and can therefore be used as model for analyses of the eukaryotic transcriptional machinery. The cleft loops in the active centre of RNAP were deleted and modified to unravel their function in interaction with nucleic acids during transcription. The rudder, lid and fork 2 cleft loops were required for promoter-directed initiation and elongation, the rudder was essential for open complex formation. Analyses of transcripts from heteroduplex templates containing stable open complexes revealed that bubble reclosure is required for RNA displacement during elongation. Archaeal transcription systems contain, besides the orthologues of the eukaryotic transcription factors TBP (TATA-box-binding protein) and TF (transcription factor) IIB, an orthologue of the N-terminal part of the α subunit of eukaryotic TFIIE, called TFE, whose function is poorly understood. Recent analyses revealed that TFE is involved in open complex formation and, in striking contrast with eukaryotic TFIIE, is also present in elongation complexes. Recombinant archaeal RNAPs lacking specific subunits were used to investigate the functions of smaller subunits. These studies revealed that the subunits P and H, the orthologues of eukaryotic Rpb12 and Rpb5, were not required for RNAP assembly. Subunit P was essential for open complex formation, and the ΔH enzyme was greatly impaired in all assays, with the exception of promoter recruitment. Recent reconstitution studies indicate that Rpb12 and Rpb5 can be incorporated into archaeal RNAP and can complement for the function of the corresponding archaeal subunit in in vitro transcription assays.
Reactions to UV damage in the model archaeon Sulfolobus solfataricus
Authors: Fröls Sabrina , White Malcolm F. , Schleper Christa
Published: January 2009

Mechanisms involved in DNA repair and genome maintenance are essential for all organisms on Earth and have been studied intensively in bacteria and eukaryotes. Their analysis in extremely thermophilic archaea offers the opportunity to discover strategies for maintaining genome integrity of the relatively little explored third domain of life, thereby shedding light on the diversity and evolution of these central and important systems. These studies might also reveal special adaptations that are essential for life at high temperature. A number of investigations of the hyperthermophilic and acidophilic crenarchaeote Sulfolobus solfataricus have been performed in recent years. Mostly, the reactions to DNA damage caused by UV light have been analysed. Whole-genome transcriptomics have demonstrated that a UV-specific response in S. solfataricus does not involve the transcriptional induction of DNA-repair genes and it is therefore different from the well-known SOS response in bacteria. Nevertheless, the UV response in S. solfataricus is impressively complex and involves many different levels of action, some of which have been elucidated and shed light on novel strategies for DNA repair, while others involve proteins of unknown function whose actions in the cell remain to be elucidated. The present review summarizes and discusses recent investigations on the UV response of S. solfataricus on both the molecular biological and the cellular levels.
Molecular biology of the pRN1 plasmid from Sulfolobus islandicus
Authors: Lipps Georg
Published: January 2009

The pRN1 plasmid is a rather small multicopy plasmid which was isolated from a Sulfolobus islandicus strain in 1993 by Wolfram Zillig and co-workers. Sequence analysis of the genome sequence suggested that three conserved genes are important for plasmid replication. These genes code for two sequence-specific DNA-binding proteins (ORF56 and ORF80) and for a large multifunctional replication protein (ORF904). The protein ORF904 has primase, DNA polymerase and helicase activity. Remarkably, the primase activity is highly sequence specific, and primers are only efficiently synthesized on templates with the motif GTG. This protein could initiate the plasmid replication by melting the double-stranded DNA at the origin of replication and by synthesizing the first primers at the replication bubble. The protein ORF56 is a repressor, and combined biochemical and genetic evidence shows that this protein is involved in regulating the copy number of the plasmid. The function of the third conserved protein, ORF80, is still mysterious. Although this protein is highly conserved, it is not essential for replication, since shuttle vectors with a deleted orf80 gene are still able to replicate in Sulfolobus. Interestingly, plasmids lacking the orf80 gene display reduced plasmid retention under non-selective conditions, raising the possibility that ORF80 is involved in plasmid partitioning or has an accessory role in plasmid replication.
Role of multiprotein bridging factor 1 in archaea: bridging the domains?
Authors: de Koning Bart , Blombach Fabian , Wu Hao , Brouns Stan J.J. , van der Oost John
Published: January 2009

MBF1 (multiprotein bridging factor 1) is a highly conserved protein in archaea and eukaryotes. It was originally identified as a mediator of the eukaryotic transcription regulator BmFTZ-F1 (Bombyx mori regulator of fushi tarazu). MBF1 was demonstrated to enhance transcription by forming a bridge between distinct regulatory DNA-binding proteins and the TATA-box-binding protein. MBF1 consists of two parts: a C-terminal part that contains a highly conserved helix–turn–helix, and an N-terminal part that shows a clear divergence: in eukaryotes, it is a weakly conserved flexible domain, whereas, in archaea, it is a conserved zinc-ribbon domain. Although its function in archaea remains elusive, its function as a transcriptional co-activator has been deduced from thorough studies of several eukaryotic proteins, often indicating a role in stress response. In addition, MBF1 was found to influence translation fidelity in yeast. Genome context analysis of mbf1 in archaea revealed conserved clustering in the crenarchaeal branch together with genes generally involved in gene expression. It points to a role of MBF1 in transcription and/or translation. Experimental data are required to allow comparison of the archaeal MBF1 with its eukaryotic counterpart.
Piecing together the ESCRTs
Authors: Hurley James H. , Im Young Jun , Lee Hyung Ho , Ren Xuefeng , Wollert Thomas , Yang Dong
Published: January 2009

High-resolution structural analysis has characterized nearly all of the individual domains of ESCRT (endosomal sorting complex required for transport) subunits, all of the core structures of the soluble complexes and many of the interactions involving domains. Recent emphasis in structural studies has shifted towards efforts to integrate these structures into a larger-scale model. Molecular simulations, hydrodynamic analysis, small-angle X-ray scattering and cryo-EM (electron microscopy) techniques have all been brought to bear on the ESCRT system over the last year.
The ESCRT pathway and HIV-1 budding
Authors: Usami Yoshiko , Popov Sergei , Popova Elena , Inoue Michio , Weissenhorn Winfried , G. Göttlinger Heinrich
Published: January 2009

HIV-1 Gag engages components of the ESCRT (endosomal sorting complex required for transport) pathway via so-called L (late-assembly) domains to promote virus budding. Specifically, the PTAP (Pro-Thr-Ala-Pro)-type primary L domain of HIV-1 recruits ESCRT-I by binding to Tsg101 (tumour susceptibility gene 101), and an auxiliary LYPXnL (Leu-Tyr-Pro-Xaan-Leu)-type L domain recruits the ESCRT-III-binding partner Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X]. The structurally related CHMPs (charged multivesicular body proteins), which form ESCRT-III, are kept in an inactive state through intramolecular interactions, and become potent inhibitors of HIV-1 budding upon removal of an autoinhibitory region. In the absence of the primary L domain, HIV-1 budding is strongly impaired, but can be efficiently rescued through the overexpression of Alix. This effect of Alix depends on its ability to interact with CHMP4, suggesting that it is the recruitment of CHMPs that ultimately drives virus release. Surprisingly, HIV-1 budding defects can also be efficiently corrected by overexpressing Nedd (neural-precursor-cell-expressed developmentally down-regulated) 4-2s, a member of a family of ubiquitin ligases previously implicated in the function of PPXY (Pro-Pro-Xaa-Tyr)-type L domains, which are absent from HIV-1. At least under certain circumstances, Nedd4-2s stimulates the activity of PTAP-type L domains, raising the possibility that the ubiquitin ligase regulates the activity of ESCRT-I.
Genetic analysis of ESCRT function in Drosophila: a tumour model for human Tsg101
Authors: Herz Hans-Martin , Bergmann Andreas
Published: January 2009

Class E Vps (vacuolar protein sorting) proteins are components of the ESCRTs (endosomal sorting complexes required for transport) which are required for protein sorting at the early endosome. Most of these genes have been identified and genetically characterized in yeast. Recent genetic studies in Drosophila have revealed the phenotypic consequences of loss of vps function in multicellular organisms. In the present paper, we review these studies and discuss a mechanism which may explain how loss of the human Tsg101 (tumour susceptibility gene 101), a vps23 orthologue, causes tumours.
A complex interplay between Akt, TSC2 and the two mTOR complexes
Authors: Huang Jingxiang , Manning Brendan D.
Published: January 2009

Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1–TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1–TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1–TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR–rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1–TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1–TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.
mTORC1 signalling and mRNA translation
Authors: Proud Christopher G.
Published: January 2009

Signalling through mTORC1 (mammalian target of rapamycin complex 1) is important in controlling many cell functions, including protein synthesis, which it activates. mTORC1 signalling is activated by stimuli which promote protein accumulation such as anabolic hormones, growth factors and hypertrophic stimuli. mTORC1 signalling regulates several components of the protein synthetic machinery, including initiation and elongation factors, protein kinases which phosphorylate the ribosome and/or translation factors, and the translation of specific mRNAs. However, there are still important gaps in our understanding of the actions of mTORC1 and the relative contributions that different targets of mTORC1 make to the activation of protein synthesis remain to be established.
Nutrient-dependent regulation of autophagy through the target of rapamycin pathway
Authors: Chang Yu-Yun , Juhász Gábor , Goraksha-Hicks Pankuri , Arsham Andrew M. , Mallin Daniel R. , Muller Laura K. , Neufeld Thomas P.
Published: January 2009

In response to nutrient deficiency, eukaryotic cells activate macroautophagy, a degradative process in which proteins, organelles and cytoplasm are engulfed within unique vesicles called autophagosomes. Fusion of these vesicles with the endolysosomal compartment leads to breakdown of the sequestered material into amino acids and other simple molecules, which can be used as nutrient sources during periods of starvation. This process is driven by a group of autophagy-related (Atg) proteins, and is suppressed by TOR (target of rapamycin) signalling under favourable conditions. Several distinct kinase complexes have been implicated in autophagic signalling downstream of TOR. In yeast, TOR is known to control autophagosome formation in part through a multiprotein complex containing the serine/threonine protein kinase Atg1. Recent work in Drosophila and mammalian systems suggests that this complex and its regulation by TOR are conserved in higher eukaryotes, and that Atg1 has accrued additional functions including feedback regulation of TOR itself. TOR and Atg1 also control the activity of a second kinase complex containing Atg6/Beclin 1, Vps (vacuolar protein sorting) 15 and the class III PI3K (phosphoinositide 3-kinase) Vps34. During autophagy induction, Vps34 activity is mobilized from an early endosomal compartment to nascent autophagic membranes, in a TOR- and Atg1-responsive manner. Finally, the well-known TOR substrate S6K (p70 ribosomal protein S6 kinase) has been shown to play a positive role in autophagy, which may serve to limit levels of autophagy under conditions of continuously low TOR activity. Further insight into these TOR-dependent control mechanisms may support development of autophagy-based therapies for a number of pathological conditions.
Starvation in the midst of plenty: making sense of ceramide-induced autophagy by analysing nutrient transporter expression
Authors: Edinger Aimee L.
Published: January 2009

Ceramide induces differentiation, proliferative arrest, senescence and death in mammalian cells. The mechanism by which ceramide produces these outcomes has proved difficult to define. Building on observations that ceramide stimulates autophagy, we have identified a novel mechanism of action for this sphingolipid: ceramide starves cells to death subsequent to profound nutrient transporter down-regulation. In yeast, ceramide generated in response to heat stress adaptively slows cell growth by down-regulating nutrient permeases. In mammalian cells, a lethal dose of ceramide triggers a bioenergetic crisis by so severely limiting cellular access to extracellular nutrients that autophagy is insufficient to meet the metabolic demands of the cell. In keeping with this bioenergetic explanation for ceramide toxicity, methyl pyruvate, a membrane-permeable nutrient, protects cells from ceramide-induced starvation. Also consistent with this model, we have found that the metabolic state of the cell determines its sensitivity to ceramide. Thus the increased sensitivity of cancer cells to ceramide may relate to their inflexible biosynthetic metabolic programme. These studies highlight the value of assessing nutrient transporter expression in autophagic cells and the important role that culture conditions play in determining the cellular response to ceramide.
Prolyl hydroxylases as regulators of cell metabolism
Authors: Boulahbel Houda , Durán Raúl V. , Gottlieb Eyal
Published: January 2009

Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.
Mutant models for genes associated with schizophrenia
Authors: Desbonnet Lieve , Waddington John L. , O'Tuathaigh Colm M.P.
Published: January 2009

Schizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene–gene and gene–environment interactions in relation to schizophrenia.
When pain after surgery doesn't go away…
Authors: Burke Siún , Shorten George D.
Published: January 2009

Chronic post-surgical pain is a common, under-recognized and important clinical problem which affects millions of patients worldwide. It results from a series of neuroplastic changes associated most commonly with peripheral nerve injury at the time of surgery. Predisposing factors include the type of surgery, pre-operative and acute post-operative pain intensity, and probably psychological (e.g. pain-catastrophizing) and genetic factors [e.g. GCH1 (GTP cyclohydrolase 1) haplotype]. Preventive measures which are currently available include selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. Very promising therapeutic agents which target the sensitization process are currently in development.
Medium spiny neurons for transplantation in Huntington's disease
Authors: Kelly Claire M. , Dunnett Stephen B. , Rosser Anne E.
Published: January 2009

Cell-replacement therapy for Huntington's disease is one of very few therapies that has reported positive outcomes in clinical trials. However, for cell transplantation to be made more readily available, logistical, standardization and ethical issues associated with the current methodology need to be resolved. To achieve these goals, it is imperative that an alternative cell source be identified. One of the key requirements of the cells is that they are capable of acquiring an MSN (medium spiny neuron) morphology, express MSN markers such as DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa), and function in vivo in a manner that replicates those that have been lost to the disease. Developmental biology has progressed in recent years to provide a vast array of information with regard to the key signalling events involved in the proliferation, specification and differentiation of striatal-specific neurons. In the present paper, we review the rationale for cell-replacement therapy in Huntington's disease, discuss some potential donor sources and consider the value of developmental markers in the identification of cells with the potential to develop an MSN phenotype.
The effects of blood–brain barrier disruption on glial cell function in multiple sclerosis
Authors: McQuaid Stephen , Cunnea Paula , McMahon Jill , Fitzgerald Una
Published: January 2009

Dysfunction of the BBB (blood–brain barrier) is a major hallmark of MS (multiple sclerosis). Studies in our laboratories over the last decade have shown that increased BBB permeability is associated with decreased expression of TJ (tight junction) proteins in brain capillary endothelial cells. Results have revealed that TJ abnormalities were most common in active lesions (42% of vessels affected), but were also present in inactive lesions (23%) and in MS normal-appearing white matter (13%). Importantly, TJ abnormality was also positively associated with leakage of the serum protein fibrinogen which has recently been shown to be an activator of microglia. TJ abnormality and the resultant vascular permeability in both lesional and non-lesional white matter may impair tissue homoeostasis, which may have effects on disease progression, repair mechanisms and drug delivery.
Relativistic cosmology
Authors: Rindler Wolfgang
Published: January 2009

SOME OF THE MOST exciting recent developments in physics have been in the realms of the very small and the very large. Chief among the latter was the discovery of “quasars,” which has quadrupled our depth penetration of the universe (if quasars are where most astronomers think they are), and which has also stimulated the possibly irrelevant but intrinsically fruitful investigations into gravitational collapse. Then came the discovery of the 3°K background radiation, which seems to have taken us back a long way in time to an apparent “big-bang” origin of the universe. Both bode ill for the steady-state theory to which many of us had been attracted. Most recently, Robert H. Dicke's speculations and observations on the oblate sun have battered at the edifice of general relativity, and thus at the very foundations of modern cosmology. Even advances in the realm of the very small affect our knowledge of the very large; for, after all, most of the phenomena we see in the sky are manifestations of either gravitational or nuclear activity.
Laser action in liquids
Authors: Heller Adam
Published: January 2009

LIQUID-LASER RESEARCH, as many other fields in science, has oscillated between periods of activity and semislumber. In the period immediately following the first papers suggesting the possibility of light amplification by stimulated emission, the search for liquid-laser materials was at least as active as the search for solids or gases. However, unlike research on solids and gases, research on liquids did not produce active materials. This initial failure led most of the industrial and academic laboratories to discontinue work on liquids and to concentrate on gaseous and solid-state systems, in which tremendous progress has been made over the last eight years.
Second harmonic generation in random nonlinear dielectrics: Effective medium approximations and dilute limit expressions
Authors: Xu C. , Hui P. M. , Kwong Y. R.
Published: January 2009

Based on a general expression previously derived for the effective coefficient for second harmonic generation (SHG) in a random composite of nonlinear dielectrics, we develop and compare several possible effective medium approximations (EMAs). The general expression involves the volume average of products of local field factors of the form ⟨EωEωE2ω⟩, and the three EMAs amount to different decoupling schemes, and they all invoke the EMA for a linear binary composite. The performance of these EMAs is assessed by comparing with numerical results obtained by simulations on random resistor networks. We also derived the corresponding dilute limit expressions for each of the EMAs. The expressions differ in the terms that are proportional to the SHG coefficient of the majority component, and the different decoupling schemes give different terms that are quadratic in the dielectric contrast between the linear dielectric constants of the two constituents at the fundamental and second harmonic frequencies.
Linear instability of compound jets with nonaxisymmetric disturbances
Authors: Ruo An-Cheng , Chen Falin , Chang Min-Hsing
Published: January 2009

A three-dimensional linear instability analysis is carried out for a double infinitely, incompressible, and viscous compound jet moving in an inviscid surrounding gas. An analytical form of dispersion relation is derived and then solved by a direct numerical procedure. A detailed parametric study is performed to explore the instability mechanisms that cause the growth of nonaxisymmetric disturbances in compound jets. The results show that the Weber number defined on the outer interface between the ambient gas and the shell-liquid layer and the gas-to-shell density ratio both have significant influences on the growth of nonaxisymmetric instability modes, whereas the other parameters including the radius ratio, the core-to-shell density ratio, the Reynolds numbers, and the Weber number defined on the inner interface are relatively less important to the onset of the nonaxisymmetric modes. Particularly, it is found that the nonaxisymmetric sinuous mode may prevail over the axisymmetric mode for a compound jet operating at high Weber number but with low Reynolds number. The instability characteristics exhibit that the aerodynamic drag is the dominant mechanism resulting in the onset of nonaxisymmetric instability in compound jets. The present results complement the existing axisymmetric investigations and give a more complete theoretical understanding for the instability behaviors of compound jets.
Science and the educated man
Authors: Stratton Julius A.
Published: January 2009

In the summer of 1900 the city of Paris celebrated the arrival of the 20th Century with a Great Exposition. That was a year of almost universal hope and confidence in the future, and accordingly the Exposition was directed towards a Golden Age of science and industry. Among the 39000000 visitors who passed by those exhibits was an American by the name of Henry Adams, and in a famous autobiography he has recorded his thoughts on this preview of things to come. Henry Adams was the product of a tradition of unity and stability. Under the conflicting forces of the 19th Century he had seen that unity breaking up, and he was searching for what he called a dynamics of history that would anticipate the changing course of mankind. In the Gallery of Machinery at Paris he thought that at last he had found a solution in science.
Dislocations and plastic deformation
Authors: Read W. T.
Published: January 2009

Our understanding of the plastic behavior of solids has lagged well behind the knowledge gained in other branches of solid state physics. Electrical, thermal, elastic, magnetic, and optical properties are explained in terms of a few basic concepts such as the vibrations of atoms and the motion and spin of electrons. We understand fairly well what happens to the atoms and electrons when, for example, a metal absorbs heat or light or carries current in an electric or magnetic field. It is considerably more difficult, however, to discover what basic atomic mechanisms operate when a metal fractures or deforms plastically. Nevertheless the problems of strength and plasticity are highly important technologically and become more so with the increasing importance of jet engines, gas turbines, and other devices that require materials to withstand large forces at high temperatures.
Art and Form in Science
Authors: Smith Cyril Stanley
Published: January 2009

The Renaissance Society of the University of Chicago is planning, as one of its regular art exhibitions, a display illustrating artistic form in the scientific research laboratory. The exhibit will be composed of specimens, apparatus, photographs, models, records, and the like (including working demonstrations), all of which are to be indigenous to the laboratory though they will be selected by a group of artists solely on the basis of intrinsic form.
Free nuclear induction
Authors: Hahn E. L.
Published: January 2009

The study of nuclear magnetic resonance or nuclear induction, a recent field of research for which F. Bloch and E. M. Purcell have been awarded the Nobel Prize, has been carried out by a variety of techniques. The usual approach has been to observe the nuclear resonance of an ensemble of nuclear moments in a large static magnetic field as a function of a slow change in this field. Meanwhile, a small radio-frequency field is applied continuously to the nuclear sample in a direction perpendicular to the large field. An alternative method to this steady state or “slow passage” technique is one by which the radio-frequency energy is applied to the sample in the form of short, intense pulses, and nuclear signals are observed after the pulses are removed. The effects which result can be compared to the free vibration or “ringing” of a bell, a term often applied to the free harmonic oscillations of a shocked inductive-capacitive (LC) circuit. The circuit is first supplied with electrical energy from some source, and the supply of energy is suddenly removed. The LC circuit then remains for a time in the “excited state”, and the energy is gradually dissipated into heat, mostly in the circuit resistance. Similarly the atom or nucleus in the excited state can store energy for a time before it is completely dissipated, and in the case discussed here, the free oscillation or precession of an ensemble of nuclear spins in a large static field provides the ringing process.
Some personal experiences in the international coordination of crystal diffractometry
Authors: Ewald Paul P.
Published: January 2009

X-ray crystallography, like any good crystallization, grew from a few distinct nuclei. The first nucleus was the Laue-Friedrich-Knipping experiment in Munich. Hardly had the news of this new effect been given at the spring 1912 meeting of the Bavarian Academy of Science and found its way into the papers, before a second nucleation was induced in England. While Laud had explained the effect as one of diffraction of very short light waves by the regular lattice arrangement of scattering atoms, W. L. Bragg concluded from the shape of the Laud spots that they should be explained as an effect of reflection of waves on the internal atomic planes, an idea that led him at once to what is now known as Bragg's Law. Thus it was the focusing property which gave the first clue to the Bragg version of the phenomenon, as published in the Proceedings of the Cambridge Philosophical Society in November 1912.
The Kelly Committee Report… a summary
Authors: Kelly Mervin J. , Green John C. , DuBridge Lee A. , Everitt William L. , Parker James W. , Pitzer Kenneth S. , Rosser J. Barkley , Suits Guy , Williams Clyde , Wolman Abel
Published: January 2009

On October 15th, six months after the Secretary of Commerce called for the formation of the ad hoc Committee for “the evaluation of the functions and operations of the National Bureau of Standards in relation to the national needs”, the Committee submitted a comprehensive 109-page report which should stand as a positive and convincing answer to the Bureau's critics. The report makes some important points clear at the outset: in the first place, the Bureau's staff is competent and its work is not only of high caliber but is essential to the nation, thus meriting the fullest support of the Federal Government; secondly, the Bureau, severely handicapped by obsolete and inadequate space and facilities, has not been able to keep pace with the expanding needs of the nation's technology and its basic programs of testing and research are in urgent need of being strengthened; thirdly, in spite of the high standing of the present personnel of the Bureau in the scientific world, the Committee is concerned that NBS is not attracting its proper share of the talented young scientists.
A center of fundamental research
Authors: Bragg W. L.
Published: January 2009

The first building of the Cavendish Laboratory at Cambridge University, England, was opened in 1874 and its first professors were James Clark Maxwell, Lord Rayleigh, and J. J. Thomson. It was in this Laboratory that C. T. R. Wilson constructed the cloud chamber, an apparatus which has perhaps had more influence on the development of atomic physics than any other single piece of equipment; it was here that F. W. Aston developed his mass spectrograph, Lord Rutherford confirmed the disintegration of nitrogen by alpha particles, Sir James Chadwick discovered the neutron, and Sir John Cockroft and E. T. S. Walton first achieved the disintegration of atomic nuclei by artificially accelerated particles.
Air Force geophysical research
Authors: staff Terrestrial Sciences Laboratory , staff Atmospheric Analysis Laboratory , staff Atmospheric Physics Laboratory
Published: January 2009

The operational and engineering problems encountered in acquiring and maintaining air supremacy are manifold. Not the least of these problems concerns the behavior, characteristics, and properties of the atmosphere and the related phenomena of the lithosphere and the hydrosphere which directly or indirectly influence the atmosphere, the medium in which the Air Force operates. As part of the Air Research and Development Command, the Geophysics Research Directorate of the Air Force Cambridge Research Center carries on a major portion of the investigation being conducted today to increase our knowledge of such geophysical phenomena as are pertinent to air operating techniques and procedures. The fruits of this research contribute not only to new concepts of air warfare and to the over-all effectiveness of the United States Air Force, but also to the national economy through application of results to civil aviation, agriculture, hydroelectricity, and flood control.
The new physicists
Authors: Shapiro Theresa R. , Wood Helen
Published: January 2009

The progress physics has recently made as a field of employment, as well as a field of inquiry, is well known to the readers of this journal. During the present century, the science has grown at an ever-increasing pace. Since World War II, its growth has been more rapid than that of any other major branch of the natural sciences.
Reflecting Microscopes
Authors: Weston R. Mc. V.
Published: January 2009

Discussed at Meeting in Britain
The crystal conduction counter
Authors: McKay Kenneth G.
Published: January 2009

Whenever a nuclear physicist observes a new effect caused by an atomic particle, he tries to make a counter out of it. After all, neutrons, protons, and their ilk are elusive little beasties and their detection and measurement form the life blood of experimental nuclear physics. The fact that charged particles can ionize gas molecules has been exploited to produce the ionization chamber, the proportional counter, and the Geiger counter. The fact that certain solids luminesce when bombarded with high-speed particles made possible many of the early studies in nuclear physics where the observer peered at a zinc sulphide screen through a microscope and laboriously counted the minute light flashes caused by alpha particles striking the screen. Recently, a photomultiplier tube has supplanted the eye-weary observer, resulting in the modern scintillation counter which plays an important role in all nuclear physics laboratories today. Thus it is only logical that attempts should be made to utilize the electrical effects produced in solids by ionizing particles—the solid state equivalent of an ionization chamber. Indeed, such effects have been sought for many years, yet it is only since World War II that new theory and new techniques have demonstrated that the crystal counter is actually a potentially useful measuring instrument. That its application is potential is an unfortunate consequence of the complexity of the solid state and the lack of an adequate understanding of the detailed electrical behavior of real crystals.
The National Bureau of Standards
Authors: Astin A. V.
Published: January 2009

Since the time I was first asked to speak at this meeting of the American Physical Society, events have occurred that are of appreciable importance to the National Bureau of Standards. These events have been sufficiently well publicized that there is no need for me to specify them. Furthermore, committees of specialists have been or are being set up to resolve the basic issues of the controversy involving the Bureau and its directorship. Hence, I believe it to be inappropriate for me on this occasion to discuss the case except to convey appreciation to the members of the American Physical Society, and others, for their expressions of confidence and support. For these we are sincerely grateful.
Brookhaven Conference
Authors: Goldberg Murrey D.
Published: January 2009

MEV Neutron Cross Sections
Integrity of science in government
Authors: Harnwell G. P.
Published: January 2009

Physicists have been greatly disturbed by the information that has reached them through the public press regarding the resignation of A. V. Astin from his position as Director of the National Bureau of Standards. The alleged grounds for the request of Dr. Astin's resignation by Secretary of Commerce Weeks were that the findings in certain tests on the prolongation of the life of storage batteries by a proprietary additive were incorrect. Though this conclusion is open to question and the performance of the tests antedated Dr. Astin's incumbency as Director of the Bureau, what is of still greater concern to scientists is that the Secretary of Commerce appears to believe that science and politics are miscible in the cauldron of the marketplace. Members of the Institute of Physics will welcome the views of a committee under the chairmanship of Dr. M. J. Kelly, upon which the Institute is represented by Dr. L. A. DuBridge, which has been appointed to evaluate the present functions and operations of the Bureau and which will furnish Secretary Weeks and the public with a report on its findings.