Gene conversion in human rearranged immunoglobulin genes

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V<sub>H</sub> segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V<sub>H</sub> replacements with no addition of untemplated nucleotides at the V<sub>H</sub>–V<sub>H</sub> joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V<sub>H</sub> replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion

Enteric Neurospheres Are Not Specific to Neural Crest Cultures: Implications for Neural Stem Cell Therapies

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

Neurocognitive Changes among Elderly Exposed to PCBs/PCDFs in Taiwan

BACKGROUND: In 1979 approximately 2,000 people were exposed to polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) due to ingestion of contaminated cooking oil in Taiwan. Although a previous study has shown delayed developmental milestones and poorer neurocognitive functioning in children born to exposed mothers, it is unclear whether neurocognitive functioning was impaired in people who were directly exposed to the PCBs and PDCFs. OBJECTIVE: The objective of this study was to compare neurocognitive functioning in people exposed to PCBs and PCDFs with that of unexposed sex- and age-matched neighbors. METHODS: We conducted a retrospective cohort study among exposed and unexposed subjects >= 60 years of age using prospective outcome measurements. We evaluated neurocognitive tests including cognition, memory modalities, learning, motor and sensory function, mood, and daily activity. RESULTS: In total, 162 (59%) exposed and 151 (55%) reference subjects completed this study. In exposed men, all test results were similar to the reference group; however, exposed women had reduced functioning in attention and digit span (ADS), visual memory span (VMS), and verbal memory recalls (VMR ), especially learning ability. We also found a borderline reduction in the Mini-Mental State Examination. The digit symbol, motor, sensory, depression ( determined by the Geriatric Depression Scale-Short Form), and activity of daily life were not different between the exposed and reference groups. A significant dose-response relationship was found for VMR, ADS, and VMS. CONCLUSION: Our study showed dose-dependent neurocognitive deficits in certain aspects of attention, visual memory, and learning ability in women previously exposed to PCBs and PCDFs, but not in exposed men

Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor

Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium

Holographic rho mesons in an external magnetic field

We study the rho meson in a uniform magnetic field eB using a holographic QCD-model, more specifically a D4/D8/Dbar8 brane setup in the confinement phase at zero temperature with two quenched flavours. The parameters of the model are fixed by matching to corresponding dual field theory parameters at zero magnetic field. We show that the up- and down-flavour branes respond differently to the presence of the magnetic field in the dual QCD-like theory, as expected because of the different electromagnetic charge carried by up- and down-quark. We discuss how to recover the Landau levels, indicating an instability of the QCD vacuum at eB = m_rho^2 towards a phase where charged rho mesons are condensed, as predicted by Chernodub using effective QCD-models. We improve on these existing effective QCD-model analyses by also taking into account the chiral magnetic catalysis effect, which tells us that the constituent quark masses rise with eB. This turns out to increase the value of the critical magnetic field for the onset of rho meson condensation to eB = 1.1 m_rho^2 = 0.67 GeV^2. We briefly discuss the influence of pions, which turn out to be irrelevant for the condensation in the approximation made.Comment: 26 pages, 10 .pdf figures, v2: version accepted for publication in JHE

HypertenGene: extracting key hypertension genes from biomedical literature with position and automatically-generated template features

<p>Abstract</p> <p>Background</p> <p>The genetic factors leading to hypertension have been extensively studied, and large numbers of research papers have been published on the subject. One of hypertension researchers' primary research tasks is to locate key hypertension-related genes in abstracts. However, gathering such information with existing tools is not easy: (1) Searching for articles often returns far too many hits to browse through. (2) The search results do not highlight the hypertension-related genes discovered in the abstract. (3) Even though some text mining services mark up gene names in the abstract, the key genes investigated in a paper are still not distinguished from other genes. To facilitate the information gathering process for hypertension researchers, one solution would be to extract the key hypertension-related genes in each abstract. Three major tasks are involved in the construction of this system: (1) gene and hypertension named entity recognition, (2) section categorization, and (3) gene-hypertension relation extraction.</p> <p>Results</p> <p>We first compare the retrieval performance achieved by individually adding template features and position features to the baseline system. Then, the combination of both is examined. We found that using position features can almost double the original AUC score (0.8140vs.0.4936) of the baseline system. However, adding template features only results in marginal improvement (0.0197). Including both improves AUC to 0.8184, indicating that these two sets of features are complementary, and do not have overlapping effects. We then examine the performance in a different domain--diabetes, and the result shows a satisfactory AUC of 0.83.</p> <p>Conclusion</p> <p>Our approach successfully exploits template features to recognize true hypertension-related gene mentions and position features to distinguish key genes from other related genes. Templates are automatically generated and checked by biologists to minimize labor costs. Our approach integrates the advantages of machine learning models and pattern matching. To the best of our knowledge, this the first systematic study of extracting hypertension-related genes and the first attempt to create a hypertension-gene relation corpus based on the GAD database. Furthermore, our paper proposes and tests novel features for extracting key hypertension genes, such as relative position, section, and template features, which could also be applied to key-gene extraction for other diseases.</p

ASCI 2010 appropriateness criteria for cardiac magnetic resonance imaging: a report of the Asian Society of Cardiovascular Imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group

There has been a growing need for standard Asian population guidelines for cardiac CT and cardiac MR due to differences in culture, healthcare system, ethnicity and disease prevalence. The Asian Society of Cardiovascular Imaging, as the only society dedicated to cardiovascular imaging in Asia, formed a cardiac CT and cardiac MR guideline working group in order to help Asian practitioners to establish cardiac CT and cardiac MR services. In this ASCI cardiac MR appropriateness criteria report, 23 Technical Panel members representing various Asian countries were invited to rate 50 indications that can frequently be encountered in clinical practice in Asia. Indications were rated on a scale of 1–9 to be categorized into ‘appropriate’ (7–9), ‘uncertain’ (4–6), or ‘inappropriate’ (1–3). According to median scores of the 23 members, the final ratings for indications were 24 appropriate, 18 uncertain and 8 inappropriate with 22 ‘highly-agreed’ (19 appropriate and 3 inappropriate) indications. This report is expected to have a significant impact on the cardiac MR practices in many Asian countries by promoting the appropriate use of cardiac MR

Measurements of knee rotation-reliability of an external device in vivo

<p>Abstract</p> <p>Background</p> <p>Knee rotation plays an important part in knee kinematics during weight-bearing activities. An external device for measuring knee rotation (the Rottometer) has previously been evaluated for validity by simultaneous measurements of skeletal movements with Roentgen Stereometric Analysis (RSA). The aim of this study was to investigate the reliability of the device.</p> <p>Method</p> <p>The within-day and test-retest reliability as well as intertester reliability of the device in vivo was calculated. Torques of 3, 6 and 9 Nm and the examiner's apprehension of end-feel were used at 90°, 60° and 30° of knee flexion. Intraclass Correlation Coefficient _2,1(ICC _2,1), 95% confidence interval (CI) of ICC and 95% CI between test trials and examiners were used as statistical tests.</p> <p>Result</p> <p>ICC_2,1ranged from 0.50 to 0.94 at all three flexion angles at 6 and 9 Nm as well as end-feel, and from 0.22 to 0.75 at 3 Nm applied torque.</p> <p>Conclusion</p> <p>The Rottometer was a reliable measurement instrument concerning knee rotation at the three different flexion angles (90°, 60° and 30°) with 6 and 9 Nm applied torques as well as the examiner's apprehension of end-feel. Three Nm was not a reliable torque. The most reliable measurements were made at 9 Nm applied torque.</p

Assessing Internet addiction using the parsimonious Internet addiction components model - a preliminary study [forthcoming]

Internet usage has grown exponentially over the last decade. Research indicates that excessive Internet use can lead to symptoms associated with addiction. To date, assessment of potential Internet addiction has varied regarding populations studied and instruments used, making reliable prevalence estimations difficult. To overcome the present problems a preliminary study was conducted testing a parsimonious Internet addiction components model based on Griffiths’ addiction components (2005), including salience, mood modification, tolerance, withdrawal, conflict, and relapse. Two validated measures of Internet addiction were used (Compulsive Internet Use Scale [CIUS], Meerkerk et al., 2009, and Assessment for Internet and Computer Game Addiction Scale [AICA-S], Beutel et al., 2010) in two independent samples (ns = 3,105 and 2,257). The fit of the model was analysed using Confirmatory Factor Analysis. Results indicate that the Internet addiction components model fits the data in both samples well. The two sample/two instrument approach provides converging evidence concerning the degree to which the components model can organize the self-reported behavioural components of Internet addiction. Recommendations for future research include a more detailed assessment of tolerance as addiction component

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizu- mab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approxi- mately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points (95% CI, –7.6 to 8.2; nominal P=0.94). CONCLUSIONS In this randomized trial involving hospitalized patients with severe Covid-19 pneu- monia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov num- ber, NCT04320615.