bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunoglobulin-like transcript receptors on human dermal CD14+dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming
Authors: Banchereau Jacques , Zurawski Sandra , Thompson-Snipes LuAnn , Blanck Jean-Philippe , Clayton Sandra , Munk Adiel , Cao Yanying , Wang Zhiqing , Khandelwal Sunaina , Hu Jiancheng , McCoy William H. , Palucka Karolina A. , Reiter Yoram , Fremont Daved H. , Zurawski Gerard , Colonna Marco , Shaw Andrey S. , Klechevsky Eynav
Published: October 2012

Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8+T cells compared with dermal CD14+dendritic cells (DCs). Here we show that dermal CD14+DCs instead prime a fraction of naïve CD8+T cells into cells sharing the properties of type 2 cytokine-secreting CD8+T cells (TC2). Differential expression of the CD8-antagonist receptors on dermal CD14+DCs, the Ig-like transcript (ILT) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LCs inhibited cytotoxic T lymphocytes (CTLs) and enhanced TC2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14+DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and ILT4 receptors inhibited CTL priming by LCs. Thus, ILT receptor expression explains the polarization of CD8+T-cell responses by LCs vs. dermal CD14+DCs.
CDX2is an amplified lineage-survival oncogene in colorectal cancer
Authors: Salari Keyan , Spulak Mary E. , Cuff Justin , Forster Andrew D. , Giacomini Craig P. , Huang Stephanie , Ko Melissa E. , Lin Albert Y. , van de Rijn Matt , Pollack Jonathan R.
Published: October 2012

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such asMYCandRAS, are active across many different cancer types. In contrast, “lineage-survival” oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor,CDX2when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterizeCDX2as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view thatCDX2is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.
Astronomically calibrated
40
Ar/
39
Ar age for the Toba supereruption and global synchronization of late Quaternary records
Authors: Storey Michael , Roberts Richard G. , Saidin Mokhtar
Published: October 2012

The Toba supereruption in Sumatra, ∼74 thousand years (ka) ago, was the largest terrestrial volcanic event of the Quaternary. Ash and sulfate aerosols were deposited in both hemispheres, forming a time-marker horizon that can be used to synchronize late Quaternary records globally. A precise numerical age for this event has proved elusive, with dating uncertainties larger than the millennial-scale climate cycles that characterized this period. We report an astronomically calibrated
40
Ar/
39
Ar age of 73.88 ± 0.32 ka (1σ, full external errors) for sanidine crystals extracted from Toba deposits in the Lenggong Valley, Malaysia, 350 km from the eruption source and 6 km from an archaeological site with stone artifacts buried by ash. If these artifacts were made by
Homo sapiens
, as has been suggested, then our age indicates that modern humans had reached Southeast Asia by ∼74 ka ago. Our
40
Ar/
39
Ar age is an order-of-magnitude more precise than previous estimates, resolving the timing of the eruption to the middle of the cold interval between Dansgaard–Oeschger events 20 and 19, when a peak in sulfate concentration occurred as registered by Greenland ice cores. This peak is followed by a ∼10 °C drop in the Greenland surface temperature over ∼150 y, revealing the possible climatic impact of the eruption. Our
40
Ar/
39
Ar age also provides a high-precision calibration point for other ice, marine, and terrestrial archives containing Toba sulfates and ash, facilitating their global synchronization at unprecedented resolution for a critical period in Earth and human history beyond the range of
14
C dating.
Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis
Authors: Harel Itamar , Maezawa Yoshiro , Avraham Roi , Rinon Ariel , Ma Hsiao-Yen , Cross Joe W. , Leviatan Noam , Hegesh Julius , Roy Achira , Jacob-Hirsch Jasmine , Rechavi Gideon , Carvajal Jaime , Tole Shubha , Kioussi Chrissa , Quaggin Susan , Tzahor Eldad
Published: October 2012

The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.
Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation–π interactions
Authors: Wilkinson Oliver J. , Latypov Vitaly , Tubbs Julie L. , Millington Christopher L. , Morita Rihito , Blackburn Hannah , Marriott Andrew , McGown Gail , Thorncroft Mary , Watson Amanda J. , Connolly Bernard A. , Grasby Jane A. , Masui Ryoji , Hunter Christopher A. , Tainer John A. , Margison Geoffrey P. , Williams David M.
Published: October 2012

Alkyltransferase-like (ATL) proteins in
Schizosaccharomyces pombe
(Atl1) and
Thermus thermophilus
(TTHA1564) protect against the adverse effects of DNA alkylation damage by flagging
O
6
-alkylguanine lesions for nucleotide excision repair (NER). We show that both ATL proteins bind with high affinity to oligodeoxyribonucleotides containing
O
6
-alkylguanines differing in size, polarity, and charge of the alkyl group. However, Atl1 shows a greater ability than TTHA1564 to distinguish between
O
6
-alkylguanine and guanine and in an unprecedented mechanism uses Arg69 to probe the electrostatic potential surface of
O
6
-alkylguanine, as determined using molecular mechanics calculations. An unexpected consequence of this feature is the recognition of 2,6-diaminopurine and 2-aminopurine, as confirmed in crystal structures of respective Atl1-DNA complexes.
O
6
-Alkylguanine and guanine discrimination is diminished for Atl1 R69A and R69F mutants, and
S. pombe
R69A and R69F mutants are more sensitive toward alkylating agent toxicity, revealing the key role of Arg69 in identifying
O
6
-alkylguanines critical for NER recognition.
Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release
Authors: Park Seongjoon , Jiang Hong , Zhang Hongjie , Smith Roy G.
Published: October 2012

Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)–G-protein coupling to Gα
i/o
instead of Gα
q11
and dependence on energy balance. Here we present evidence for an equilibrium model of receptor heteromerization that fulfills these criteria. We show that GHS-R1a coupling to Gα
i/o
rather than Gα
q11
requires interactions between GHS-R1a and SST receptor subtype 5 (SST5) and that in the absence of SST5 ghrelin enhances GSIS. At concentrations of GHS-R1a and SST5 expressed in islets, time-resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, suppresses GSIS and cAMP accumulation. GHS-R1a–G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghrelin to SST. A high ratio enhances heteromer formation and Gα
i/o
coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a–Gα
q11
coupling. The [ghrelin]/[SST] ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet SST concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than SST establishes inhibitory tone on the β-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential regulation of islet function by ghrelin and SST. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context.
Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells
Authors: Zhang Weijia , Kai Kazuharu , Choi Dong Soon , Iwamoto Takayuki , Nguyen Yen H. , Wong Helen , Landis Melissa D. , Ueno Naoto T. , Chang Jenny , Qin Lidong
Published: October 2012

Here we report a microfluidics method to enrich physically deformable cells by mechanical manipulation through artificial microbarriers. Driven by hydrodynamic forces, flexible cells or cells with high metastatic propensity change shape to pass through the microbarriers and exit the separation device, whereas stiff cells remain trapped. We demonstrate the separation of (
i
) a mixture of two breast cancer cell types (MDA-MB-436 and MCF-7) with distinct deformabilities and metastatic potentials, and (
ii
) a heterogeneous breast cancer cell line (SUM149), into enriched flexible and stiff subpopulations. We show that the flexible phenotype is associated with overexpression of multiple genes involved in cancer cell motility and metastasis, and greater mammosphere formation efficiency. Our observations support the relationship between tumor-initiating capacity and cell deformability, and demonstrate that tumor-initiating cells are less differentiated in terms of cell biomechanics.
Vitamin D receptor as a master regulator of the c-MYC/MXD1 network
Authors: Salehi-Tabar Reyhaneh , Nguyen-Yamamoto Loan , Tavera-Mendoza Luz E. , Quail Thomas , Dimitrov Vassil , An Beum-Soo , Glass Leon , Goltzman David , White John H.
Published: October 2012

Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell- and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC–regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target
setd8
in mouse skin, whereas MXD1 levels increased. 1,25D inhibited
MYC
gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push–pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon
VDR
knockdown, an effect abrogated by ablation of
MYC
regulator β-catenin. c-MYC levels were widely elevated in
vdr

−/−

mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.
Anatomical evidence for the involvement of medial cerebellar output from the interpositus nuclei in cognitive functions
Authors: Lu Xiaofeng , Miyachi Shigehiro , Takada Masahiko
Published: October 2012

Although the cerebellar interpositus nuclei are known to be involved in cognitive functions, such as associative motor learning, no anatomical evidence has been available for this issue. Here we used retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to area 46 of the prefrontal cortex of macaques in comparison with the projections to the primary motor cortex (M1). After rabies injections into area 46, many neurons in the restricted region of the posterior interpositus nucleus (PIN) were labeled disynaptically via the thalamus, whereas no neuron labeling was found in the anterior interpositus nucleus (AIN). The distribution of the labeled neurons was dorsoventrally different from that of PIN neurons labeled from the M1. This defines an anatomical substrate for the contribution of medial cerebellar output to cognitive functions. Like the dentate nucleus, the PIN has dual motor and cognitive channels, whereas the AIN has a motor channel only.
MyD88-deficient
Hydra
reveal an ancient function of TLR signaling in sensing bacterial colonizers
Authors: Franzenburg Sören , Fraune Sebastian , Künzel Sven , Baines John F. , Domazet-Lošo Tomislav , Bosch Thomas C. G.
Published: October 2012

Toll-like receptor (TLR) signaling is one of the most important signaling cascades of the innate immune system of vertebrates. Studies in invertebrates have focused on the fruit fly
Drosophila melanogaster
and the nematode
Caenorhabditis elegans
, and there is little information regarding the evolutionary origin and ancestral function of TLR signaling. In
Drosophila
, members of the Toll-like receptor family are involved in both embryonic development and innate immunity. In
C. elegans
, a clear immune function of the TLR homolog TOL-1 is controversial and central components of vertebrate TLR signaling including the key adapter protein myeloid differentiation primary response gene 88 (MyD88) and the transcription factor NF-κB are not present. In basal metazoans such as the cnidarians
Hydra magnipapillata
and
Nematostella vectensis
, all components of the vertebrate TLR signaling cascade are present, but their role in immunity is unknown. Here, we use a MyD88 loss-of-function approach in
Hydra
to demonstrate that recognition of bacteria is an ancestral function of TLR signaling and that this process contributes to both host-mediated recolonization by commensal bacteria as well as to defense against bacterial pathogens.
Mutational robustness of 16S ribosomal RNA, shown by experimental horizontal gene transfer in
Escherichia coli
Authors: Kitahara Kei , Yasutake Yoshiaki , Miyazaki Kentaro
Published: October 2012

The bacterial ribosome consists of three rRNA molecules and 57 proteins and plays a crucial role in translating mRNA-encoded information into proteins. Because of the ribosome’s structural and mechanistic complexity, it is believed that each ribosomal component coevolves to maintain its function. Unlike 5S rRNA, 16S and 23S rRNAs appear to lack mutational robustness, because they form the structural core of the ribosome. However, using
Escherichia coli
Δ7 (null mutant of operons) as a host, we have recently shown that an active hybrid ribosome whose 16S rRNA has been specifically substituted with that from non–
E. coli
bacteria can be reconstituted in vivo. To investigate the mutational robustness of 16S rRNA and the structural basis for its functionality, we used a metagenomic approach to screen for 16S rRNA genes that complement the growth of
E. coli
Δ7. Various functional genes were obtained from the Gammaproteobacteria and Betaproteobacteria lineages. Despite the large sequence diversity (80.9–99.0% identity with
E. coli
16S rRNA) of the functional 16S rRNA molecules, the doubling times (DTs) of each mutant increased only modestly with decreasing sequence identity (average increase in DT, 4.6 s per mutation). The three-dimensional structure of the 30S ribosome showed that at least 40.7% (628/1,542) of the nucleotides were variable, even at ribosomal protein-binding sites, provided that the secondary structures were properly conserved. Our results clearly demonstrate that 16S rRNA functionality largely depends on the secondary structure but not on the sequence itself.
MscS-Like10 is a stretch-activated ion channel from
Arabidopsis thaliana
with a preference for anions
Authors: Maksaev Grigory , Haswell Elizabeth S.
Published: October 2012

Like many other organisms, plants are capable of sensing and responding to mechanical stimuli such as touch, osmotic pressure, and gravity. One mechanism for the perception of force is the activation of mechanosensitive (or stretch-activated) ion channels, and a number of mechanosensitive channel activities have been described in plant membranes. Based on their homology to the bacterial mechanosensitive channel MscS, the 10 MscS-Like (MSL) proteins of
Arabidopsis thaliana
have been hypothesized to form mechanosensitive channels in plant cell and organelle membranes. However, definitive proof that MSLs form mechanosensitive channels has been lacking. Here we used single-channel patch clamp electrophysiology to show that MSL10 is capable of providing a MS channel activity when heterologously expressed in
Xenopus laevis
oocytes. This channel had a conductance of ∼100 pS, consistent with the hypothesis that it underlies an activity previously observed in the plasma membrane of plant root cells. We found that MSL10 formed a channel with a moderate preference for anions, which was modulated by strongly positive and negative membrane potentials, and was reversibly inhibited by gadolinium, a known inhibitor of mechanosensitive channels. MSL10 demonstrated asymmetric activation/inactivation kinetics, with the channel closing at substantially lower tensions than channel opening. The electrophysiological characterization of MSL10 reported here provides insight into the evolution of structure and function of this important family of proteins.
Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A
Authors: Chaturvedi Chandra-Prakash , Somasundaram Brinda , Singh Kulwant , Carpenedo Richard L. , Stanford William L. , Dilworth F. Jeffrey , Brand Marjorie
Published: October 2012

Chromatin remodeling is essential for controlling the expression of genes during development. The histone-modifying enzyme G9a/KMT1C can act both as a coactivator and a corepressor of transcription. Here, we show that the dual function of G9a as a coactivator vs. a corepressor entails its association within two distinct protein complexes, one containing the coactivator Mediator and one containing the corepressor Jarid1a/KDM5A. Functionally, G9a is important in stabilizing the Mediator complex for gene activation, whereas its repressive function entails a coordinate action with the histone H3 lysine 4 (H3K4) demethylase Jarid1a for the maintenance of gene repression. The essential nature of cross-talk between the histone methyltransferase G9a and the demethylase Jarid1a is demonstrated on the embryonic
E

y

-globin
gene, where the concurrent introduction of repressive histone marks (dimethylated H3K9 and dimethylated H3K27) and removal of activating histone mark (trimethylated H3K4) is required for maintenance of gene silencing. Taken together with our previous demonstration of cross-talk between UTX and MLL2 to mediate activation of the adult
β

maj

-globin
gene, these data suggest a model where “active” and “repressive” cross-talk between histone-modifying enzymes coexist on the same multigene locus and play a crucial role in the precise control of developmentally regulated gene expression.
Quick-release medical tape
Authors: Laulicht Bryan , Langer Robert , Karp Jeffrey M.
Published: October 2012

Medical tape that provides secure fixation of life-sustaining and -monitoring devices with quick, easy, damage-free removal represents a longstanding unmet medical need in neonatal care. During removal of current medical tapes, crack propagation occurs at the adhesive–skin interface, which is also the interface responsible for device fixation. By designing quick-release medical tape to undergo crack propagation between the backing and adhesive layers, we decouple removal and device fixation, enabling dual functionality. We created an ordered adhesive/antiadhesive composite intermediary layer between the medical tape backing and adhesive for which we achieve tunable peel removal force, while maintaining high shear adhesion to secure medical devices. We elucidate the relationship between the spatial ordering of adhesive and antiadhesive regions to create a fully tunable system that achieves strong device fixation and quick, easy, damage-free device removal. We also described ways of neutralizing the residual adhesive on the skin and have observed that thick continuous films of adhesive are easier to remove than the thin islands associated with residual adhesive left by current medical tapes.
Quantitative field theory of the glass transition
Authors: Franz Silvio , Jacquin Hugo , Parisi Giorgio , Urbani Pierfrancesco , Zamponi Francesco
Published: October 2012

We develop a full microscopic replica field theory of the dynamical transition in glasses. By studying the soft modes that appear at the dynamical temperature, we obtain an effective theory for the critical fluctuations. This analysis leads to several results: we give expressions for the mean field critical exponents, and we analytically study the critical behavior of a set of four-points correlation functions, from which we can extract the dynamical correlation length. Finally, we can obtain a Ginzburg criterion that states the range of validity of our analysis. We compute all these quantities within the hypernetted chain approximation for the Gibbs free energy, and we find results that are consistent with numerical simulations.
Viral MHC class I inhibition evades CD8
+
T-cell effector responses in vivo but not CD8
+
T-cell priming
Authors: Gainey Maria D. , Rivenbark Joshua G. , Cho Hyelim , Yang Liping , Yokoyama Wayne M.
Published: October 2012

Although viral MHC class I inhibition is considered a classic immune-evasion strategy, its in vivo role is largely unclear. Mutant cowpox virus lacking its MHC class I inhibitors is markedly attenuated during acute infection because of CD8
+
T-cell–dependent control, but it was not known how CD8
+
T-cell responses are affected. Interestingly, we found no major effect of MHC class I down-regulation on priming of functional cowpox virus-specific CD8
+
T cells. Instead, we demonstrate that, during acute infection in vivo, MHC class I down-regulation prevents primed virus-specific CD8
+
T cells from recognizing infected cells and exerting effector responses to control the infection.
Differentiating two- from three-dimensional mental rotation training effects
Authors: Moreau David
Published: October 2012

Block videogame training has consistently demonstrated transfer effects to mental rotation tasks, yet how variations in training influence performance with different stimuli remains unclear. In this study, participants took mental rotation assessments before and after a 3-week training programme based on 2D or 3D block videogames. Assessments varied in terms of dimensionality (2D or 3D) and stimulus type (polygon or body). Increases in videogame scores throughout training were correlated with mental rotation improvements. In particular, 2D training led to improvements in 2D tasks, whereas 3D training led to improvements in both 2D and 3D tasks. This effect did not depend on stimulus type, demonstrating that training can transfer to different stimuli of identical dimensionality. Interestingly, traditional gender differences in 3D mental rotation tasks vanished after 3D videogame training, highlighting the malleability of mental rotation ability given adequate training. These findings emphasize the influence of dimensionality in transfer effects and offer promising perspectives to reduce differences in mental rotation via designed training programmes.
Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression
Authors: Powers Sarah E. , Mandal Malay , Matsuda Satoshi , Miletic Ana V. , Cato Matthew H. , Tanaka Azusa , Rickert Robert C. , Koyasu Shigeo , Clark Marcus R.
Published: October 2012

Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro–B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase–regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of >200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination.
Realization of an atomically flat surface of diamond using dressed photon–phonon etching
Authors: Yatsui Takashi , Nomura Wataru , Naruse Makoto , Ohtsu Motoichi
Published: October 2012

We obtained an atomically flat diamond surface following dressed photon–phonon (DPP) etching using 3.81 eV light and O2 gas. We obtained a surface roughness (R

a
) of 0.154 nm for Ib-type (1 1 1) diamond and 0.096 nm for Ib-type (1 0 0) diamond. To evaluate the surface roughness, we grouped the surface into bins of width l and introduced the standard deviation of the height difference function for a given separation l, which allowed us to determine the height variation of the surface. Based on the calculation of standard deviation, the conventional adiabatic photochemical reaction did not remove the small surface features, while DPP etching decreased the surface roughness for all length scales.
On the asymptotic behavior of Kac-Wakimoto characters
Authors: Bringmann Kathrin , Folsom Amanda
Published: October 2012

Recently, Kac and Wakimoto established specialized character formulas for irreducible highest weight

s
ℓ
(
m
,
1

)
∧

s\ell (m,1)^\wedge

modules and established a main exponential term in their asymptotic expansions. By different methods, we improve upon the Kac-Wakimoto asymptotics for these characters, obtaining an asymptotic expansion with an arbitrarily large number of terms beyond the main term. More specifically, it is well known that in the case of holomorphic modular forms, asymptotic information may be obtained using modular transformation properties. However, here this is not the case due to the analytic nature of the Kac-Wakimoto series as discovered recently by the first author and Ono. We first “complete” these series by adding to them certain integrals, obtaining functions that exhibit suitable modular transformation laws, at the expense of the completed objects being nonholomorphic. We then exploit this mock-modular behavior of the Kac-Wakimoto series to obtain our asymptotic expansion. In particular, we show that beyond the main term, the asymptotic behavior is dictated by the nonholomorphic part of the completed Kac-Wakimoto characters, which is a priori invisible. Euler numbers (equivalently, zeta-values) appear as coefficients.
A passion for the science of the human genome
Authors: Dunston Georgia M.
Published: October 2012

The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: “How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?” As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives.
Bringing the physical sciences into your cell biology research
Authors: Robinson Douglas N. , Iglesias Pablo A.
Published: October 2012

Historically, much of biology was studied by physicists and mathematicians. With the advent of modern molecular biology, a wave of researchers became trained in a new scientific discipline filled with the language of genes, mutants, and the central dogma. These new molecular approaches have provided volumes of information on biomolecules and molecular pathways from the cellular to the organismal level. The challenge now is to determine how this seemingly endless list of components works together to promote the healthy function of complex living systems. This effort requires an interdisciplinary approach by investigators from both the biological and the physical sciences.
Building a path in cell biology
Authors: Voeltz Gia , Cheeseman Iain
Published: October 2012

Setting up a new lab is an exciting but challenging prospect. We discuss our experiences in finding a path to tackle some of the key current questions in cell biology and the hurdles that we have encountered along the way.
The benefits of using a heart failure management programme in Swedish primary healthcare
Authors: Agvall Björn , Alehagen Urban , Dahlström Ulf
Published: October 2012

Aim

Heart failure (HF) is a common condition with which high mortality, morbidity, and poor quality of life are associated. It has previously been shown that use of HF management programmes (HFMPs) in HF clinics can be beneficial. The purpose of this study was to evaluate if the use of HFMPs also has beneficial effects on HF patients in primary healthcare (PHC).

Methods and results

This is a randomized, prospective, open‐label study including 160 patients from five PHC centres with systolic HF and a mean age of 75 years (standard deviation 7.8). In the intervention group, an intensive follow‐up was performed by HF nurses and physicians providing information and education about HF and the optimization of HF treatment according to recognized guidelines. There was a significant improvement of composite endpoints in the intervention group. Significantly more patients with reduced N‐terminal pro brain natriuretic peptide (P = 0.012), improved cardiac function (P = 0.03), fewer healthcare contacts (P = 0.04), and fewer emergency room visits and admittances (P = 0.0002 and P = 0.03, respectively) could be seen in the intervention group when compared with the control group.

Conclusions

The use of a HFMP in a PHC setting was found to have beneficial effects in terms of reducing the number of healthcare contacts and hospital admissions, and improving cardiac function in patients with systolic HF, even if the result should be interpreted with caution. It can therefore be recommended that HFMPs should be used in PHC.
A carbon-rich Mira variable in a globular cluster: a stellar merger
Authors: Feast Michael W. , Menzies John W. , Whitelock Patricia A.
Published: October 2012

The membership of Matsunaga's variable 1, a carbon-rich, mass-losing, Mira variable, in the globular cluster Lynga 7 is discussed on the basis of radial velocities. We conclude that it is a member, the first known C-Mira in a globular cluster. Since such a variable is expected to have an age of ∼1–2 Gyr and an initial mass of ∼1.5 M⊙, we conclude that this star must be the product of a stellar merger.
Effects of epidermal growth factor receptor and phosphatase and tensin homologue gene expression on the inhibition of U87MG glioblastoma cell proliferation induced by protein kinase inhibitors
Authors: Xing Wen‐Jing , Zou Yan , Han Qing‐Lian , Dong Yu‐Cui , Deng Zhen‐Ling , Lv Xiao‐Hong , Jiang Tao , Ren Huan
Published: October 2012

The aim of the present study was to analyse the antiproliferative effects and mechanisms of action of protein kinase inhibitors (PKIs) in human glioblastoma multiforme (GBM) cells with different epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) status.

The GBM cell models were established by transfection of plasmids carrying wild‐type EGFR, mutated EGFRvIII or PTEN and clonal selection in U87MG cells. Phosphatidylinositol 3‐kinase (PI3‐K)/AKT pathway‐focused gene profiles were examined by real‐time polymerase chain reaction‐based assays, protein expression was evaluated by western blotting and the antiproliferative effects of PKI treatment were determined by the 3‐(4,5‐dimethyl‐2 thiazoyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay in GBM cells.

The cell model with intact PTEN and low EGFR levels was the most sensitive to treatment with the EGFR inhibitor erlotinib, whereas the model with EGFRvIII was the most resistant to treatment with the mitogen‐activated protein kinase kinase inhibitor U0126. The dual PI3‐K and mammalian target of rapamycin (mTOR) inhibitor PI103 had the most potent antiproliferative effects against all GBM cells tested. Following simultaneous stimulation of AKT and extracellular signal‐regulated kinase, rapamycin concentrations > 0.5 nmol/L failed to exhibit a further growth inhibitory effect. Concurrent inhibition of mTOR and ribosomal protein s6 activity may underlie the inhibition of GBM proliferation by PKI.

In conclusion, overexpression of EGFR or EGFRvIII, accompanied by a loss of PTEN, contributed to the activation of multiple intracellular signalling pathways in GBM cells. Rigorous examination of biomarkers in tumour tissues before and after treatment may be necessary to determine the efficacy of PKI therapy in patients with GBM.
Update in clinical allergy and immunology
Authors: von Gunten S. , Marsland B. J. , von Garnier C. , Simon D.
Published: October 2012

In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field.
Intensive playing leads to non‐monosymptomatic enuresis in children with low prepulse inhibition
Authors: Schulz‐Juergensen S , Bolte L , Gebhardt J , Eggert P
Published: October 2012

Aim

Parents of children suffering from non‐monosymptomatic enuresis (nmE) report their child wetting itself during intensive playing. As children with enuresis are characterized by reduced bladder control (measured as prepulse inhibition (PPI) of startle reflex), the hypothesis suggests that intensive playing leads to further decrease in control and consecutive wetting. Two questions are important: Does PPI change while concentrating? Is this difference more explicit in children with daytime incontinence?

Methods

Forty‐four healthy children, 40 children with nmE and 37 with monosymptomatic enuresis (mE) were examined. PPI was measured while watching DVD and while playing Nintendo's Wii®, and calculated as percentage of the native startle response.

Results

All probands showed a relevant decrease in PPI: in relaxed state, the PPI of the controls was 54%; when concentrating, it fell to 34.5% (p = 0.014). The decrease in PPI in mE was from 66% to 51% (p = 0.008), and the decrease in PPI in nmE was from 29% to 21% (p = 0.125).

Conclusion

While the decrease in PPI when playing was smallest in the group with nmE, overall PPI level was by far the lowest. The findings confirm the aetiology of enuresis through impaired ‘sensori‐motor gating’ in children with nmE and provide a neurophysiologic correlate for wetting while playing.
The Kid‐Short Marfan Score (Kid‐SMS) – an easy executable risk score for suspected paediatric patients with Marfan syndrome
Authors: Mueller Goetz C , Stark Veronika , Steiner Kristoffer , Weil Jochen , von Kodolitsch Yskert , Mir Thomas S
Published: October 2012

Aim

Due to age‐dependent manifestations, diagnosis of Marfan syndrome (MFS) in children and adolescents is sophisticated. Although revised Ghent criteria is a major step forward, its utility in children is still restricted due to expensive and technically advanced diagnostics. As early diagnosis submits long‐term benefits concerning prognosis, the need of an appropriate diagnostic tool for risk stratification of suspected paediatric patients with Marfan is justified.

Methods and results

Sixty paediatric patients with Marfan were subject to a standardized diagnostic programme. All clinical symptoms of the revised Ghent nosology were analysed concerning age at first clinical manifestation, prevalence and likelihood ratio for MFS. Symptoms with early onset, high prevalence and high positive likelihood ratio were identified and combined for a risk score called Kid‐Short Marfan Score (Kid‐SMS). Three risk categories for suspicion of Marfan syndrome were developed. Finally, the Kid‐SMS was operated in 130 paediatric patients with suspected MFS. Kid‐SMS identified significantly more suspected patients with Marfan compared with Ghent nosology, revised Ghent and genetics alone without oversensitivity.

Conclusion

Whereas diagnosis of MFS in childhood is sophisticated, Kid‐SMS is a useful tool for risk stratification of suspected paediatric patients with Marfan by easy executable diagnostics, especially for paediatricians and paediatric cardiologists.
Comparison of X‐chromosome inactivation in Duchenne muscle/myocardium‐manifesting carriers, non‐manifesting carriers and related daughters
Authors: Viggiano E , Picillo E , Cirillo A , Politano L
Published: October 2012

Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5–7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X‐chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non‐manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation‐based assay. The results showed that DMD‐manifesting carriers had a preferential inactivation of the X‐chromosome carrying the normal allele, while non‐manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother–daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non‐random patterns of X inactivation.
Influence of zirconia abutment preparation on the fracture strength of single implant lithium disilicate crowns after chewing simulation
Authors: Mitsias Miltiadis , Koutayas Spiridon‐Oumvertos , Wolfart Stefan , Kern Matthias
Published: October 2012

Objective

The use of all‐ceramic crowns over zirconia abutments is a well‐established esthetic treatment option in implant dentistry; however, the effect of the mechanical processing due to abutment preparation has not been investigated under functional loading. The purpose of the study was to evaluate the influence of the zirconia abutment preparation depth and preparation mode on the fracture strength and fracture mode of lithium disilicate crowns after chewing simulation.

Material and methods

Seventy single implant‐supported lithium disilicate glass‐ceramic crowns (IPS e.max Press, Ivoclar Vivadent) were adhesively cemented (Multilink Automix, Ivoclar Vivadent) onto zirconia abutments (ZirDesign, Astra Tech) using implants with a diameter of 4.5 mm and a length of 15.0 mm (Osseospeed, Astra Tech). Study design concerned the replacement of a maxillary central incisor (11.0 mm in height and 8.0 mm in width). Subgroups (n = 7) were subjected to dynamic loading (C) up to 1.2 × 106 loading cycles at 135° with 98N in a thermomechanical chewing simulator (Kausimulator, Willytech); followed by quasi‐static loading at a cross‐head speed of 0.5 mm/min until fracture in a universal testing machine (Z010/TN2S, Zwick). Additional subgroups were also subjected to quasi‐static loading (S) at 135°. Lithium disilicate implant crowns were divided into five study groups (n = 14) according to the abutment preparation depth [A (control): 0.5 mm, B: 0.7 mm, C: 0.9 mm, and preparation mode [(No label): milling by the manufacturer, (P): copy‐milling by the Celay System (Mikrona)].

Results

All specimens survived dynamic loading and mean fracture strengths (N) after quasi‐static loading were as follows: Group SA: 384 ± 84; Group CA: 403 ± 67; Group SB: 294 ± 95; Group CB: 374 ± 75; Group SC: 332 ± 52; Group CC: 373 ± 105; Group SPB: 332 ± 80; Group CPB: 499 ± 91; Group SPC: 380 ± 101; and Group CPC: 358 ± 54.

Conclusions

Statistical analysis using multiple linear regression showed that both the preparation depth and mode had no influence on the fracture strength of the implant crowns (P > 0.05); however, fracture strength increased statistically significantly after 5 years chewing simulation (P = 0.01).
A focused educational program after religious services to improve organ donation in Hispanic Americans
Authors: Salim Ali , Bery Cherisse , Ley Eric J. , Schulman Danielle , Navarro Sonia , Zheng Ling , Chan Linda S.
Published: October 2012

Religion is an important determinant in Hispanic Americans (HA) becoming organ donors as HA often believe religion forbids donation. We investigated the effect of an educational program targeting HA organ donation in places of worship. A prospective observational study was conducted at four Catholic churches with a high percentage of HA. A 45‐min “culturally sensitive” educational program, conducted in Spanish, was implemented. Organ donation awareness, knowledge, perception, and beliefs, as well as the intent to become an organ donor, were measured before and after the intervention. Differences between before and after the intervention were analyzed. A total of 182 surveys were conducted before and 159 surveys were conducted after the educational program. A significant increase was observed in organ donation knowledge (54% vs. 70%, p < 0.0001), perception (43% vs. 58%, p < 0.0001), and beliefs (50% vs. 60%, p = 0.0001). However, no significant difference was found in the willingness to discuss donation with family, intent‐to‐donate, or registering to donate after the intervention. This study demonstrates that a focused educational program in places of worship can significantly improve HA knowledge, perceptions, and beliefs regarding organ donation. Further work is needed to understand why intent‐to‐donate does not increase despite the increase in organ donation awareness.
Patient Recruitment into a Multicenter Randomized Clinical Trial  for Kidney Disease: Report of the Focal Segmental Glomerulosclerosis Clinical Trial (FSGS CT)
Authors: Ferris Maria , Norwood Victoria , Radeva Milena , Gassman Jennifer J. , Al‐Uzri Amira , Askenazi David , Matoo Tej , Pinsk Maury , Sharma Amita , Smoyer William , Stults Jenna , Vyas Shefali , Weiss Robert , Gipson Debbie , Kaskel Frederick , Friedman Aaron , Moxey‐Mims Marva , Trachtman Howard
Published: October 2012

We describe the experience of the focal segmental glomerulosclerosis clinical trial (FSGS CT) in the identification and recruitment of participants into the study. This National Institutes of Health funded study, a multicenter, open‐label, randomized comparison of cyclosporine versus oral dexamethasone pulses plus mycophenolate mofetil, experienced difficulty and delays meeting enrollment goals. These problems occurred despite the support of patient advocacy groups and aggressive recruitment strategies. Multiple barriers were identified including: (1) inaccurate estimates of the number of potential incident FSGS patients at participating centers; (2) delays in securing one of the test agents; (3) prolonged time between IRB approval and execution of a subcontract (mean 7.5 ± 0.8 months); (4) prolonged time between IRB approval and enrollment of the first patient at participating sites (mean 19.6 ± 1.4 months); and (5) reorganization of clinical coordinating core infrastructure to align resources with enrollment. A Web‐based anonymous survey of site investigators revealed site‐related barriers to patient recruitment. The value of a variety of recruitment tools was of marginal utility in facilitating patient enrollment. We conclude that improvements in the logistics of study approval and regulatory start‐up and testing of promising novel agents are important factors in promoting enrollment into randomized clinical trials in nephrology. Clin Trans Sci 2013; Volume 6: 13–20
Head circumference needs to be measured
Authors: Essex Charles
Published: October 2012

Please also see the Letter on this paper by Murray and Jackson on page 194 of this issue.