Enhancement of Adeno-Associated Virus-Mediated Gene Therapy Using Hydroxychloroquine in Murine and Human Tissues.

The therapeutic effects of gene therapy using adeno-associated virus (AAV) vectors are dependent on the efficacy of viral transduction. Currently, we have reached the safe limits of AAV vector dose, beyond which damaging inflammatory responses are seen. To improve the efficacy of AAV transduction, we treated mouse embryonic fibroblasts, primate retinal pigment epithelial cells, and human retinal explants with hydroxychloroquine (HCQ) 1 h prior to transduction with an AAV2 vector encoding GFP driven by a ubiquitous CAG promoter. This led to a consistent increase in GFP expression, up to 3-fold, compared with vector alone. Comparing subretinal injections of AAV2.CAG.GFP vector alone versus co-injection with 18.75 μM HCQ in paired eyes in mice, mean GFP expression was 4.6-fold higher in retinae co-treated with HCQ without retinal toxicity. A comparative 5.9-fold effect was seen with an AAV8(Y733F).GRK1.GFP vector containing the photoreceptor-specific rhodopsin kinase promoter. While the mechanism of action remains to be fully elucidated, our data suggest that a single pulse of adjunctive HCQ could safely improve AAV transduction in vivo, thus providing a novel strategy for enhancing the clinical effects of gene therapy

The Effects of Short-Term Detraining and Subsequent Retraining on Body Composition and Muscle Performance in Males Consuming a Whey Protein or Carbohydrate Supplement

An acute bout of resistance exercise (RE) can up-regulate processes that stimulate muscle protein synthesis (MPS). Additionally, nutritional strategies involving carbohydrate (CHO) and whey protein (WP) supplementation can augment MPS. However, resistance training (RT) induced muscle anabolism during the early phases of training can attenuate over time. The use of a short-term cessation of training (detraining; DT) can potentially restore the attenuated muscular anabolic adaptive responses. Therefore, the purpose of this study was to explore the effects of a successive cycle of detraining and retraining (ReT) in humans on body composition and muscle performance. Resistance-trained males (age 20.95 ± 1.23 y; n=20) were recruited and randomized into one of two groups (WP or CHO; 25 grams) in a double-blind fashion. Both groups followed a standardized 4 days per week resistance-training program for 4 weeks, carried out 2 weeks of DT and continued the resistance-training program for another 4 weeks of ReT. Participants were instructed to consume their respective supplement only on workout days during RT, but every day during DT. Research visits were conducted at baseline, 4 weeks (post-RT), 6 weeks (post-2-week-DT), and after 10 weeks (post-ReT). Each visit consisted of body composition assessments and muscular strength and endurance testing using the bench press and angled leg press exercises. Four-day diet records, workout logs, and supplement compliance forms were utilized. Factorial 2x4 (group by time) ANOVAs with repeated measures were conducted using SPSS (version 20.0) with a probability level of ≤ .05. There were no significant group by time interactions for lean or fat mass changes throughout the study (p \u3e .05). However, both groups were able to retain lean mass following 2 weeks of DT. The WP group appeared to have an elevation in lean mass (+1.58kg on average) by the end of ReT in comparison to baseline, even though it was not statistically significant (p \u3e .05). Leg press strength (LPS) increased throughout the study (p=.003), and neither group showed a decrease in LPS following DT. There were no group-by-time interactions or group differences between WP and CHO for bench press strength (BPS), bench press endurance (BPE), leg press endurance (LPE), or any dietary variables (p \u3e .05). Interestingly, the WP group presented a non-significant overall increase in lean mass compared to the CHO group by the end of 10 weeks. LPS and BPS were also elevated and retained respectfully following DT. In summary, a short-term 2 week cycle of DT in resistance trained males maintained both muscle mass and muscular strength, which potentially reinforces the importance of recovery

On the origins and timescales of geoeffective IMF

Southward Interplanetary Magnetic Field (IMF) in the Geocentric Solar Magnetospheric (GSM) reference frame is the key element that controls the level of space-weather disturbance in Earth’s magnetosphere, ionosphere and thermosphere. We discuss the relation of this geoeffective IMF component to the IMF in the Geocentric Solar Ecliptic (GSE) frame and, using the almost continuous interplanetary data for 1996-2015 (inclusive), we show that large geomagnetic storms are always associated with strong southward, out-of-ecliptic field in the GSE frame: dipole tilt effects, that cause the difference between the southward field in the GSM and GSE frames, generally make only a minor contribution to these strongest storms. The time-of-day/time-of-year response patterns of geomagnetic indices and the optimum solar wind coupling function are both influenced by the timescale of the index response. We also study the occurrence spectrum of large out-of-ecliptic field and show that for one-hour averages it is, surprisingly, almost identical in ICMEs (Interplanetary Coronal Mass Ejections), around CIRs/SIRs (Corotating and Stream Interaction Regions) and in the “quiet” solar wind (which is shown to be consistent with the effect of weak SIRs). However, differences emerge when the timescale over which the field remains southward is considered: for longer averaging timescales the spectrum is broader inside ICMEs, showing that these events generate longer intervals of strongly southward average IMF and consequently stronger geomagnetic storms. The behavior of out-of-ecliptic field with timescale is shown to be very similar to that of deviations from the predicted Parker spiral orientation, suggesting the two share common origins

The development of a space climatology: 3. Models of the evolution of distributions of space weather variables with timescale

We study how the probability distribution functions of power input to the magnetosphere Pα and of the geomagnetic ap and Dst indices vary with averaging timescale, , between 3 hours and 1 year. From this we develop and present algorithms to empirically model the distributions for a given and a given annual mean value. We show that lognormal distributions work well for ap, but because of the spread of Dst for low activity conditions, the optimum formulation for Dst leads to distributions better described by something like the Weibull formulation. Annual means can be estimated using telescope observations of sunspots and modelling, and so this allows the distributions to be estimated at any given between 3 hour and 1 year for any of the past 400 years, which is another important step towards a useful space weather climatology. The algorithms apply to the core of the distributions and can be used to predict the occurrence rate of “large” events (in the top 5% of activity levels): they may contain some, albeit limited, information relevant to characterizing the much rarer “superstorm” events with extreme value statistics. The algorithm for the Dst index is the more complex one because, unlike ap, Dst can take on either sign and future improvements to it are suggested

The development of a space climatology: 1. solar-wind magnetosphere coupling as a function of timescale and the effect of data gaps

Different terrestrial space weather indicators (such as geomagnetic indices, transpolar voltage, and ring current particle content) depend on different “coupling functions” (combinations of near-Earth solar wind parameters) and previous studies also reported a dependence on the averaging timescale, {\tau}. We study the relationships of the am and SME geomagnetic indices to the power input into the magnetosphere P_{\alpha}, estimated using the optimum coupling exponent {\alpha} for a range of {\tau} between 1 min and 1 year. The effect of missing data is investigated by introducing synthetic gaps into near-continuous data and the best method for dealing with them when deriving the coupling function, is formally defined. Using P_{\alpha}, we show that gaps in data recorded before 1995 have introduced considerable errors into coupling functions. From the near-continuous solar wind data for 1996-2016, we find {\alpha} = 0.44 plus/minus 0.02 and no significant evidence that {\alpha} depends on {\tau}, yielding P_{\alpha} = B^0.88 Vsw^1.90 (mswNsw)^0.23 sin4({\theta}/2), where B is the Interplanetary Magnetic Field (IMF), Nsw the solar wind number density, msw its mean ion mass, Vsw its velocity and {\theta} is the IMF clock angle in the Geocentric Solar Magnetospheric reference frame. Values of P_{\alpha} that are accurate to within plus/minus 5% for 1996-2016 have an availability of 83.8% and the correlation between P_{\alpha} and am for these data is shown to be 0.990 (between 0.972 and 0.997 at the 2{\sigma} uncertainty level), 0.897 plus/minus 0.004, and 0.790 plus/minus 0.03, for {\tau} of 1 year, 1 day and 3 hours, respectively, and that between P_{alpha} and SME at {\tau} of 1 min. is 0.7046 plus/minus 0.0004

Rapid Molecular Detection of Rifampicin Resistance Facilitates Early Diagnosis and Treatment of Multi-Drug Resistant Tuberculosis: Case Control Study

Multi-drug resistant tuberculosis (MDR-TB) is a major public health concern since diagnosis is often delayed, increasing the risk of spread to the community and health care workers. Treatment is prolonged, and the total cost of treating a single case is high. Diagnosis has traditionally relied upon clinical suspicion, based on risk factors and culture with sensitivity testing, a process that can take weeks or months. Rapid diagnostic molecular techniques have the potential to shorten the time to commencing appropriate therapy, but have not been put to the test under field conditions.This retrospective case-control study aimed to identify risk factors for MDR-TB, and analyse the impact of testing for rifampicin resistance using RNA polymerase B (rpoB) mutations as a surrogate for MDR-TB. Forty two MDR-TB cases and 84 fully sensitive TB controls were matched by date of diagnosis; and factors including demographics, clinical presentation, microbiology findings, management and outcome were analysed using their medical records. Conventionally recognised risk factors for MDR-TB were absent in almost half (43%) of the cases, and 15% of cases were asymptomatic. A significant number of MDR-TB cases were identified in new entrants to the country. Using rpoB mutation testing, the time to diagnosis of MDR-TB was dramatically shortened by a median of 6 weeks, allowing patients to be commenced on appropriate therapy a median of 51days earlier than those diagnosed by conventional culture and sensitivity testing.MDR-TB is frequently an unexpected finding, may be asymptomatic, and is particularly prevalent among TB infected new entrants to the country. Molecular resistance testing of all acid fast bacilli positive specimens has the potential to rapidly identify MDR-TB patients and commence them on appropriate therapy significantly earlier than by conventional methods

Implementing smartphone enabled collaborative travel: Routes to success in the tourism domain.

Smartphone technology can help identify current and anticipate future patterns of behaviour and, with its social networking capabilities, allow users to imagine and organise collaborative travel opportunities, such as lift share. This has led to the development of collaborative apps designed to enable activities like lift sharing. Such apps require new norms of behaviour to establish a user base and research has yet to address the socio-cultural barriers to both the use of this technology to organise travel and the sharing of personal space that collaborative travel entails. This paper reports the findings of a study which designed, built and tested a collaborative travel app in the tourism domain. Data derived from exploratory interviews, post-trial interviews and a questionnaire reveal that user age and extent of mobile engagement play a less significant role than expected, while other aspects of the social exchange, notably social tie strength, trust and obligations play a more marked role. A conceptual framework and discussion of strategies to address these barriers provides insight into appropriate contexts and routes for implementation of collaborative travel apps

The development of a space climatology: 2. The distribution of power input into the magnetosphere on a 3‐hourly timescale

Paper 1 in this series (Lockwood et al., 2018a, https://doi.org/10.1029/2018SW001856) showed that the power input into the magnetosphere Pα is an ideal coupling function for predicting geomagnetic “range” indices that are strongly dependent on the substorm current wedge and that the optimum coupling exponent α is 0.44 for all averaging timescales, τ, between 1 min and 1 year. The present paper explores the implications of these results. It is shown that the form of the distribution of Pα at all averaging timescales τ is set by the interplanetary magnetic field orientation factor via the nature of solar wind‐magnetosphere coupling (due to magnetic reconnection in the dayside magnetopause) and that at τ = 3 hr (the timescale of geomagnetic range indices) the normalized Pα (divided by its annual mean, that is, τ=3hr/τ=1yr) follows a Weibull distribution with k of 1.0625 and λ of 1.0240. This applies to all years to a useful degree of accuracy. It is shown that exploiting the constancy of this distribution and using annual means to predict the full distribution gives the probability of space weather events in the largest 10% and 5% to within uncertainties of magnitude 10% and 12%, respectively, at the one sigma level

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10−14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10−4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10−8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10−9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10−7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS–SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved