Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714

Cholera Outbreaks in Nigeria are Associated with Multidrug Resistant Atypical El Tor and non-O1/non-O139 Vibrio cholerae.

Background The current millennium has seen a steep rise in the number, size and case-fatalities of cholera outbreaks in many African countries. Over 40,000 cases of cholera were reported from Nigeria in 2010. Variants of Vibrio cholerae O1 El Tor biotype have emerged but very little is known about strains causing cholera outbreaks in West Africa, which is crucial for the implementation of interventions to control epidemic cholera. Methodology/Principal Findings V. cholerae isolates from outbreaks of acute watery diarrhea in Nigeria from December, 2009 to October, 2010 were identified by standard culture methods. Fifteen O1 and five non-O1/non-O139 strains were analyzed; PCR and sequencing targeted regions associated with virulence, resistance and biotype were performed. We also studied genetic interrelatedness among the strains by multilocus sequence analysis and pulsed-field gel electrophoresis. The antibiotic susceptibility was tested by the disk diffusion method and E-test. We found that multidrug resistant atypical El Tor strains, with reduced susceptibility to ciprofloxacin and chloramphenicol, characterized by the presence of the SXT element, andgyrASer85Leu alleles as well CTX phage and TCP cluster characterized byrstRElTor, ctxB-7 and tcpACIRS alleles, respectively, were largely responsible for cholera outbreaks in 2009 and 2010. We also identified and characterized a V. cholerae non-O1/non-O139 lineage from cholera-like diarrhea cases in Nigeria. Conclusions/Significance The recent Nigeria outbreaks have been determined by multidrug resistant atypical El Tor and non-O1/non-O139 V. cholerae strains, and it seems that the typical El Tor, from the beginning of seventh cholera pandemic, is no longer epidemic/endemic in this country. This scenario is similar to the East Africa, Asia and Caribbean countries. The detection of a highly virulent, antimicrobial resistant lineage in Nigeria is worrisome and points to a need for vaccine-based control of the disease. This study has also revealed the putative importance of non-O1/non-O139 V. cholerae in diarrheal disease in Nigeria

Accretion Disks in Active Galactic Nuclei: Gas Supply Driven by Star Formation

Self-gravitating accretion disks collapse to star-forming(SF) regions extending to the inner edge of the dusty torus in active galactic nuclei (AGNs). A full set of equations including feedback of star formation is given to describe the dynamics of the regions. We explore the role of supernovae explosion (SNexp), acting to excite turbulent viscosity, in the transportation of angular momentum in the regions within 1pc scale. We find that accretion disks with typical rates in AGNs can be driven by SNexp in the regions and metals are produced spontaneously. The present model predicts a metallicity--luminosity relationship consistent with that observed in AGNs. As relics of SF regions, a ring (or belt) consisting of old stars remains for every episode of supermassive black hole activity. We suggest that multiple stellar rings with random directions interact and form a nuclear star cluster after episodes driven by star formation.Comment: emulateapj.sty, 5 page, 4 figures (in press

The promoter from SlREO, a highly-expressed, root-specific Solanum lycopersicum gene, directs expression to cortex of mature roots

Root-specific promoters are valuable tools for targeting transgene expression, but many of those already described have limitations to their general applicability. We present the expression characteristics of SlREO, a novel gene isolated from tomato (Solanum lycopersicum L.). This gene was highly expressed in roots but had a very low level of expression in aerial plant organs. A 2.4-kb region representing the SlREO promoter sequence was cloned upstream of the uidA GUS reporter gene and shown to direct expression in the root cortex. In mature, glasshouse-grown plants this strict root specificity was maintained. Furthermore, promoter activity was unaffected by dehydration or wounding stress but was somewhat suppressed by exposure to NaCl, salicylic acid and jasmonic acid. The predicted protein sequence of SlREO contains a domain found in enzymes of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. The novel SlREO promoter has properties ideal for applications requiring strong and specific gene expression in the bulk of tomato root tissue growing in soil, and is also likely to be useful in other Solanaceous crop

The r'-band luminosity function of Abell1367: a comparison with Coma

We made a large (approximately 1degr x 1degr) r'-band imaging survey of the central regions of the two nearby clusters of galaxies, Abell1367 and Coma. The data, presented as a catalog, are used to construct the r'-band luminosity function (LF) of galaxies in these two clusters, by subtracting the Yasuda et al. (2001) galaxy counts from our cluster counts. Our Coma luminosity function is consistent with previous determinations, i.e. providing a faint end slope alpha = -1.47_-0.09^+0.08, significantly steeper than the one we find for Abell1367 (alpha = -1.07_-0.16^+0.20). The counts in Abell1367 show a relative minimum at r' ~ 19, followed by a steep increase faintward. The difference between the two clusters appears significant, given the consistency of the experimental conditions in the two clusters. Whereas for Coma we find a significant increase of the slope of the LF outwards, no such effect is found for Abell1367.Comment: 12 pages, 8 figures, accepted for publication in A&

Globular cluster systems in elliptical galaxies of Coma

Globular cluster systems of 17 elliptical galaxies have been studied in the Coma cluster of galaxies. Surface-brightness fluctuations have been used to determine total populations of globular clusters and specific frequency (S_N) has been evaluated for each individual galaxy. Enormous differences in S_N between similar galaxies are found. In particular, S_N results vary by an order of magnitude from galaxy to galaxy. Extreme cases are the following: a) at the lower end of the range, NGC 4673 has S_N = 1.0 +/- 0.4, a surprising value for an elliptical galaxy, but typical for spiral and irregular galaxies; b) at the upper extreme, MCG +5 -31 -063 has S_N = 13.0 +/- 4.2 and IC 4051 S_N = 12.7 +/- 3.2, and are more likely to belong to supergiant cD galaxies than to "normal" elliptical galaxies. Furthermore, NGC 4874, the central supergiant cD galaxy of the Coma cluster, also exhibits a relatively high specific frequency (S_N = 9.0 +/- 2.2). The other galaxies studied have S_N in the range [2, 7], the mean value being S_N = 5.1. No single scenario seems to account for the observed specific frequencies, so the history of each galaxy must be deduced individually by suitably combining the different models (in situ, mergers, and accretions). The possibility that Coma is formed by several subgroups is also considered. If only the galaxies of the main subgroup defined by Gurzadyan & Mazure (2001) are used, a trend in S_N arises in the sense of S_N being bigger in higher density regions. This result needs further confirmation.Comment: 43 pages including 12 .ps figures, accepted for publication in Ap

Factors Influencing Dietetic Interns\u27 Dietary Habits During Supervised Practice

Supervised practice is a prerequisite to becoming a registered dietitian. Research suggests that environmental and social factors may affect dietary choices. This focus group research aimed to gather opinions from dietetic interns to understand what factors related to supervised practice, if any, affected their dietary habits. Qualitative data were collected via seven recorded virtual focus groups in which trained moderators facilitated a discussion using a series of controlled questions. Participants, dietetic interns (n = 42) who were currently completing or had completed their supervised practice within the previous six months, attended one of seven virtual focus groups. Each focus group had five to eight participants. Transcripts were separately coded by two trained researchers using a grounded theory approach to identify themes and subthemes. Researchers discussed any disagreements in coding and established a consensus. Elements related to the dietetic internship were observed to influence participants’ dietary choices. Main themes included time, finances, food access and availability, physical and mental effects, non-supervised practice factors, and social factors. Dietetic programs and preceptors should explore ways to raise interns’ awareness and minimize the potential negative impacts of these factors on interns’ dietary habits to improve their overall internship experience

Overexpression of the AtLOS5 gene increased abscisic acid level and drought tolerance in transgenic cotton

Drought is the major environmental stress that limits cotton (Gossypium hirsutum L.) production worldwide. LOS5/ABA3 (LOS5) encodes a molybdenum co-factor and is essential for activating aldehyde oxidase, which is involved in abscisic acid (ABA) biosynthesis. In this study, a LOS5 cDNA of Arabidopsis thaliana was overexpressed in cotton cultivar Zhongmiansuo35 (Z35) by Agrobacterium tumefaciens-mediated transformation. The transformation and overexpression of AtLOS5 were assessed by PCR and RT-PCR analysis. Detached shoots of transgenic cotton showed slower transpirational water loss than those of Z35. When pot-grown 6-week-old seedlings were withheld from watering for 3 d, transgenic cotton accumulated 25% more endogenous ABA and about 20% more proline than Z35 plants. The transgenic plants also showed increased expression of some drought-responding genes such as P5CS and RD22, and enhanced activity of antioxidant enzymes such as superoxide dismutase, peroxidase, and ascorbate peroxidase. Their membrane integrity was considerably improved under water stress, as indicated by reduced malondialdehyde content and electrolyte leakage relative to control plants. When the pot-grown plants were subjected to deficit irrigation for 8 weeks (watering to 50% of field capacity), transgenic plants showed a 13% increase in fresh weight than the wild type under the same drought condition. These results suggest that the AtLOS5 transgenic cotton plants acquired a better drought tolerance through enhanced ABA production and ABA-induced physiological regulations