julilili42/papers huggingface dataset:
Gene therapy restores vision and delays degeneration in the CNGB1-/- mouse model of retinitis pigmentosa
2012-07-16

Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1(-/-)) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1(-/-) mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1(-/-) retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1(-/-) mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.
Senescence‐specific Alteration of Hydrogen Peroxide Levels in Arabidopsis thaliana and Oilseed Rape Spring Variety Brassica napus L. cv. MozartF
2012-07-16

Abstract In order to analyze the signaling function of hydrogen peroxide (H 2 O 2 ) production in senescence in more detail, we manipulated intracellular H 2 O 2 levels in Arabidopsis thaliala (L.) Heynh by using the hydrogen‐peroxide‐sensitive part of the Escherichia coli transcription regulator OxyR, which was directed to the cytoplasm as well as into the peroxisomes. H 2 O 2 levels were lowered and senescence was delayed in both transgenic lines, but OxyR was found to be more effective in the cytoplasm. To transfer this knowledge to crop plants, we analyzed oilseed rape plants Brassica napus L. cv. Mozart for H 2 O 2 and its scavenging enzymes catalase (CAT) and ascorbate peroxidase (APX) during leaf and plant development. H 2 O 2 levels were found to increase during bolting and flowering time, but no increase could be observed in the very late stages of senescence. With increasing H 2 O 2 levels, CAT and APX activities declined, so it is likely that similar mechanisms are used in oilseed rape and Arabidopsis to control H 2 O 2 levels. Under elevated CO 2 conditions, oilseed rape senescence was accelerated and coincided with an earlier increase in H 2 O 2 levels, indicating that H 2 O 2 may be one of the signals to inducing senescence in a broader range of Brassicaceae .
Selective Attention Increases Choice Certainty in Human Decision Making
2012-07-16

Choice certainty is a probabilistic estimate of past performance and expected outcome. In perceptual decisions the degree of confidence correlates closely with choice accuracy and reaction times, suggesting an intimate relationship to objective performance. Here we show that spatial and feature-based attention increase human subjects' certainty more than accuracy in visual motion discrimination tasks. Our findings demonstrate for the first time a dissociation of choice accuracy and certainty with a significantly stronger influence of voluntary top-down attention on subjective performance measures than on objective performance. These results reveal a so far unknown mechanism of the selection process implemented by attention and suggest a unique biological valence of choice certainty beyond a faithful reflection of the decision process.
Effects of a health‐promotion programme in sixth grade German students' physical education
2012-07-16

Abstract The aim of the study was to assess the effects of a school‐based health‐promotion programme in physical education (PE) on sixth grade German students' motor performance, BMI and health‐related quality of life (HRQOL). In a quasi‐experimental design, 516 students (54.7% girls) were assigned to either the intervention group (IG) that received eight 90‐minute health‐promoting PE lessons or the control group (CG), which continued regular PE. Outcome variables were assessed at baseline, immediately after, and three months after the intervention in order to explore significant short‐ and middle‐term intervention effects, respectively. The intervention programme had gender specific effects in motor performance with girls reaching higher levels. Positive short‐term intervention effects were found in girls' sideways jumps ( η 2 =0.17) and negative effects were measured in the 20‐meter sprints ( η 2 =0.05) and the standing long jump ( η 2 =0.04). Positive middle‐term effects were measured on the motor performance score ( η 2 =0.05), sideways jumps ( η 2 =0.08) and stand‐and‐reach flexibility ( η 2 =0.04). In boys, short‐term positive intervention effects were found in 20‐meter sprints ( η 2 =0.04). In the middle‐term, differences in favour of the CG were found in press‐ups ( η 2 =0.03) and sideways jumps ( η 2 =0.06). Concerning BMI the IG had significantly lower levels compared to the CG in the short‐term ( η 2 =0.04) and in the middle‐term ( η 2 =0.03), respectively. There were no significant differences between the groups in HRQOL. In conclusion, the results demonstrate the feasibility of promoting health related parameters in PE, but also raise the question whether gender‐specific tailored interventions would result in higher intervention effects concerning motor performance especially in boys.
Bacterial Cell Wall Recycling
2012-07-16

Abstract Cell wall recycling is a process whereby bacteria degrade their own wall during growth, recover released constituents by active transport and reutilise them either to rebuild the wall or to gain energy. Most knowledge about cell wall recycling comes from studies with the Gram‐negative bacterium Escherichia coli . Within one generation, this organism breaks down and efficiently recycles approximately 60% of the mature peptidoglycan of its side‐wall during cell elongation and approximately 30% of newly deposited septal peptidoglycan during cell division. The reason for the massive turnover of the peptidoglycan is still unclear, although many other bacteria, including Gram‐positives, have been reported to turnover their cell wall and release similar quantities of peptidoglycan fragments during growth and differentiation. Whether these fragments are also recycled is basically unknown. The presence of recycling genes on most bacterial genomes, however, suggests that cell wall recycling is a very common pathway of bacteria. Key Concepts: The peptidoglycan of the bacterial cell wall represents a single, giant, reticular macromolecule (i.e. the murein sacculus) that encases the entire bacterial cell. The peptidoglycan cell wall has to be cleaved continuously during growth to allow cell expansion by insertion of new wall material. Bacteria possess a huge and partially redundant set of cell wall lytic enzymes that potentially target every covalent bond connecting the amino acid and amino sugar building blocks within the peptidoglycan network (cell wall lytic complement). Many bacteria release a great amount of cell wall material during bacterial growth (cell elongation and division). The reason for the massive turnover of approximately 50% of the existing peptidoglycan in one generation is still unclear. Bacteria eventually recover cell wall turnover fragments. The pathways for the continuous recycling of peptidoglycan have been explored in great detail in Escherichia coli . Cell wall recycling in Gram‐positive bacteria has been appreciated just recently and apparently differs from the E. coli paradigm as well as between Gram‐positive species. Cell wall‐derived peptidoglycan fragments function as potent biological effectors. They are involved in sensing the cell wall and growth state, inducing expression of antibiotic resistance genes, and triggering cell differentiation and resuscitation of dormant cells.
Rescue of epithelial HCO3− secretion in murine intestine by apical membrane expression of the cystic fibrosis transmembrane conductance regulator mutant F508del
2012-07-17

Key points Cystic fibrosis (CF) is a lethal disease characterized by low rates of epithelial Cl − and HCO 3 − secretion and obstruction of the airways and gastrointestinal and reproductive organs by sticky mucus. HCO 3 − secretion has recently been demonstrated to be necessary for mucus hydration. The most frequent CF mutation is F508del. This mutant protein is usually degraded in the proteasome. New therapeutic strategies have been developed which deliver F508del to the plasma membrane. Utilizing transgenic F508del mutant and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice, apical membrane expression of F508del protein was found to be associated with enhanced stimulation of intestinal HCO 3 − secretion. The predominant molecular mechanism for enhanced F508del HCO 3 − stimulation appeared to be the activation of a Cl − recycling pathway, with Cl − exit via membrane‐resident F508del protein and Cl − entry in exchange for HCO 3 − by apical Cl − /HCO 3 − exchange. In contrast, the predominant molecular mechanism for cAMP‐activated HCO 3 − secretion in WT intestine appears to be HCO 3 − exit via CFTR itself. Abstract This study investigated whether expression of the common cystic fibrosis transmembrane conductance regulator (CFTR) mutant F508del in the apical membrane of enterocytes confers increased bicarbonate secretory capacity on the intestinal epithelium of F508del mutant mice compared to that of CFTR knockout (KO) mice. CFTR KO mice, F508del mutant mice (F508del) and wild‐type (WT) littermates were bred on the FVB/N background. F508del isolated brush border membrane (BBM) contained approximately 5–10% fully glycosylated band C protein compared to WT BBM. Similarly, the forskolin (FSK)‐induced, CFTR‐dependent short‐circuit current (Δ I sc ) of F508del mucosa was approximately 5–10% of WT, whereas the HCO 3 − secretory response ( ) was almost half that of WT in both duodenum and mid‐colon studied in vitro and in vivo. While WT intestine retained full FSK‐induced in the absence of luminal Cl − , the markedly higher than Δ I sc in F508del intestine was dependent on the presence of luminal Cl − , and was blocked by CFTR inhibitors. The Ste20‐related proline–alanine‐rich kinases (SPAK/OSR1), which are downstream of the with‐no‐lysine (K) protein kinases (WNK), were rapidly phosphorylated by FSK in WT and F508del, but significantly more slowly in CFTR KO intestine. In conclusion, the data demonstrate that low levels of F508del membrane expression in the intestine of F508del mice significantly increased FSK‐induced HCO 3 − secretion mediated by Cl − /HCO 3 − exchange. However, in WT mucosa FSK elicited strong SPAK/OSR1 phosphorylation and Cl − ‐independent HCO 3 − efflux. This suggests that therapeutic strategies which deliver F508del to the apical membrane have the potential to significantly enhance epithelial HCO 3 − secretion.
Exome Enrichment and SOLiD Sequencing of Formalin Fixed Paraffin Embedded (FFPE) Prostate Cancer Tissue
2012-07-17

Next generation sequencing (NGS) technologies have revolutionized cancer research allowing the comprehensive study of cancer using high throughput deep sequencing methodologies. These methods detect genomic alterations, nucleotide substitutions, insertions, deletions and copy number alterations. SOLiD (Sequencing by Oligonucleotide Ligation and Detection, Life Technologies) is a promising technology generating billions of 50 bp sequencing reads. This robust technique, successfully applied in gene identification, might be helpful in detecting novel genes associated with cancer initiation and progression using formalin fixed paraffin embedded (FFPE) tissue. This study’s aim was to compare the validity of whole exome sequencing of fresh-frozen vs. FFPE tumor tissue by normalization to normal prostatic FFPE tissue, obtained from the same patient. One primary fresh-frozen sample, corresponding FFPE prostate cancer sample and matched adjacent normal prostatic tissue was subjected to exome sequencing. The sequenced reads were mapped and compared. Our study was the first to show comparable exome sequencing results between FFPE and corresponding fresh-frozen cancer tissues using SOLiD sequencing. A prior study has been conducted comparing the validity of sequencing of FFPE vs. fresh frozen samples using other NGS platforms. Our validation further proves that FFPE material is a reliable source of material for whole exome sequencing.
An engineered PII protein variant that senses a novel ligand: atomic resolution structure of the complex with citrate
2012-07-17

PII proteins are central signal processing units for the regulation of nitrogen metabolism in bacteria, archaea and plants. They act in response to cellular energy, carbon and nitrogen availability. The central metabolites ATP, ADP and 2-oxoglutarate, which indicate cellular energy and carbon/nitrogen abundance, bind in a highly organized manner to PII and induce effector-molecule-dependent conformational states of the T-loop. Depending on these states, PII proteins bind and modulate the activity of various regulatory targets. A mutant variant of the Synechococcus elongatus PII protein (PII-I86N) has been identified to have impaired 2-oxoglutarate binding. Here, the PII-I86N variant was cocrystallized in the presence of ATP, magnesium and citrate and its structure was solved at a resolution of 1.05 Å. The PII-I86N variant bound citrate in place of 2-oxoglutarate. Citrate binding is mediated primarily by interactions with the ATP-coordinated magnesium ion and the backbone atoms of the T-loop. Citrate binding rearranges the conformation of the T-loop and, consistent with this, citrate suppresses the binding of PII-I86N to an NAG kinase variant, which is similar to the suppression of PII-NAG kinase complex formation by 2-OG. Based on the structures of 2-OG and citrate, homocitrate was suggested as a third ligand and an efficient response towards this molecule with different functional properties was observed. Together, these data provide a first glimpse of a genetically engineered PII variant that senses a new effector molecule.
New Combinatorial Construction Techniques for Low-Density Parity-Check Codes and Systematic Repeat-Accumulate Codes
2012-07-17

This paper presents several new construction techniques for low-density parity-check (LDPC) and systematic repeat-accumulate (RA) codes. Based on specific classes of combinatorial designs, the improved code design focuses on high-rate structured codes with constant column weights 3 and higher. The proposed codes are efficiently encodable and exhibit good structural properties. Experimental results on decoding performance with the sum-product algorithm show that the novel codes offer substantial practical application potential, for instance, in high-speed applications in magnetic recording and optical communications channels.
Transcorneal Electrical Stimulation Shows Neuroprotective Effects in Retinas of Light-Exposed Rats
2012-07-18

This sham-controlled study shows that TES can protect retinal cells against mild light-induced degeneration in Sprague Dawley rats. These findings could help to establish TES as a treatment in human forms of retinal degenerative disease.
Evolution of the turtle bauplan: the topological relationship of the scapula relative to the ribcage
2012-07-18

The turtle shell and the relationship of the shoulder girdle inside or ‘deep’ to the ribcage have puzzled neontologists and developmental biologists for more than a century. Recent developmental and fossil data indicate that the shoulder girdle indeed lies inside the shell, but anterior to the ribcage. Developmental biologists compare this orientation to that found in the model organisms mice and chickens, whose scapula lies laterally on top of the ribcage. We analyse the topological relationship of the shoulder girdle relative to the ribcage within a broader phylogenetic context and determine that the condition found in turtles is also found in amphibians, monotreme mammals and lepidosaurs. A vertical scapula anterior to the thoracic ribcage is therefore inferred to be the basal amniote condition and indicates that the condition found in therian mammals and archosaurs (which includes both developmental model organisms: chickens and mice) is derived and not appropriate for studying the developmental origin of the turtle shell. Instead, among amniotes, either monotreme mammals or lepidosaurs should be used.
EU facing the crisis: social and employment policies in times of tight budgets
2012-07-19

Over the past years the centre of the economic crisis has repeatedly shifted. Starting as a subprime crisis in the US, it soon unfolded as a global economic and financial crisis in order then to become a sovereign debt crisis, euro crisis and, eventually, also a social and democratic crisis. Against the background of the general political and economic conditions within the EU, this article traces the shifts of the political terrain. It focuses above all on the transition from a rather costly crisis management (bank rescues, economic stimulus programmes and automatic stabilizers) towards a new agenda of austerity policies. Structurally, this agenda can be seen as the reaction to significant increases in public debt. In addition, it has been promoted politically and institutionalized through successive European economic governance reforms. These reforms have also had a serious impact on domestic social and employment policies. In some countries dependent on external credits this is already evident, while in other countries the deregulatory aspects of the radicalized reform agenda have only just started to unfold.
The nuclear factor κB inhibitor (E)-2-fluoro-4′-methoxystilbene inhibits firefly luciferase
2012-07-19

Photinus pyralis (firefly) luciferase is widely used as a reporter system to monitor alterations in gene promoter and/or signalling pathway activities in vitro. The enzyme catalyses the formation of oxyluciferin from D-luciferin in an ATP-consuming reaction involving photon emission. The purpose of the present study was to characterize the luciferase-inhibiting potential of (E)-2-fluoro-4′-methoxystilbene, which is known as a potent inhibitor of the NF-κB (nuclear factor κB) signalling pathway that is used to modulate the NF-κB signalling pathway in vitro. Results show that (E)-2-fluoro-4′-methoxystilbene effectively inhibits firefly luciferase activity in cell lysates and living cells in a non-competitive manner with respect to the luciferase substrates D-luciferin and ATP. By contrast, the compound has no effect on Renilla and Gaussia luciferases. The mechanism of firefly luciferase inhibition by (E)-2-fluoro-4′-methoxystilbene, as well as its potency is comparable to its structure analogue resveratrol. The in vitro use of trans-stilbenes such as (E)-2-fluoro-4′-methoxystilbene or resveratrol compromises firefly luciferase reporter assays as well as ATP/luciferase-based cell viability assays.
Optimum Length and Flexibility of Reovirus Attachment Protein σ1 Are Required for Efficient Viral Infection
2012-07-19

ABSTRACT Reovirus attachment protein σ1 is an elongated trimer with head-and-tail morphology that engages cell-surface carbohydrate and junctional adhesion molecule A (JAM-A). The σ1 protein is comprised of three domains partitioned by two flexible linkers termed interdomain regions (IDRs). To determine the importance of σ1 length and flexibility at different stages of reovirus infection, we generated viruses with mutant σ1 molecules of altered length and flexibility and tested these viruses for the capacity to bind the cell surface, internalize, uncoat, induce protein synthesis, assemble, and replicate. We reduced the length of the α-helical σ1 tail to engineer mutants L1 and L2 and deleted midpoint and head-proximal σ1 IDRs to generate ΔIDR1 and ΔIDR2 mutant viruses, respectively. Decreasing length or flexibility of σ1 resulted in delayed reovirus infection and reduced viral titers. L1, L2, and ΔIDR1 viruses but not ΔIDR2 virus displayed reduced cell attachment, but altering σ1 length or flexibility did not diminish the efficiency of virion internalization. Replication of ΔIDR2 virus was hindered at a postdisassembly step. Differences between wild-type and σ1 mutant viruses were not attributable to alterations in σ1 folding, as determined by experiments assessing engagement of cell-surface carbohydrate and JAM-A by the length and IDR mutant viruses. However, ΔIDR1 virus harbored substantially less σ1 on the outer capsid. Taken together, these data suggest that σ1 length is required for reovirus binding to cells. In contrast, IDR1 is required for stable σ1 encapsidation, and IDR2 is required for a postuncoating replication step. Thus, the structural architecture of σ1 is required for efficient reovirus infection of host cells.
Monitoring high-risk bladder cancer
2012-07-19

New serological and urine-based markers have been identified for monitoring high-risk bladder cancer, and demand incorporation into established clinicopathological risk models to tailor surveillance regimens and provide improved prognostication for the need of adjuvant treatment.
Review of Particle Physics
2012-07-20

This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2658 new measurements from 644 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 112 reviews are many that are new or heavily revised including those on Heavy-Quark and Soft-Collinear Effective Theory, Neutrino Cross Section Measurements, Monte Carlo Event Generators, Lattice QCD, Heavy Quarkonium Spectroscopy, Top Quark, Dark Matter, V-cb &amp; V-ub, Quantum Chromodynamics, High-Energy Collider Parameters, Astrophysical Constants, Cosmological Parameters, and Dark Matter. \\nA booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website: http://pdg.lbl.gov.
Novel Maneuver Facilitating Descemet Membrane Unfolding in the Anterior Chamber
2012-07-20

Simultaneous digital pressure with corneal tapping is a helpful maneuver to unfold the DM inside the anterior chamber. This technique may reduce the need for unnecessary instrumental and noninstrumental manipulation of the graft.