Novel Distances for Dollo Data

We investigate distances on binary (presence/absence) data in the context of a Dollo process, where a trait can only arise once on a phylogenetic tree but may be lost many times. We introduce a novel distance, the Additive Dollo Distance (ADD), which is consistent for data generated under a Dollo model, and show that it has some useful theoretical properties including an intriguing link to the LogDet distance. Simulations of Dollo data are used to compare a number of binary distances including ADD, LogDet, Nei Li and some simple, but to our knowledge previously unstudied, variations on common binary distances. The simulations suggest that ADD outperforms other distances on Dollo data. Interestingly, we found that the LogDet distance performs poorly in the context of a Dollo process, which may have implications for its use in connection with conditioned genome reconstruction. We apply the ADD to two Diversity Arrays Technology (DArT) datasets, one that broadly covers Eucalyptus species and one that focuses on the Eucalyptus series Adnataria. We also reanalyse gene family presence/absence data on bacteria from the COG database and compare the results to previous phylogenies estimated using the conditioned genome reconstruction approach

The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing

Kinetoplastid parasites—trypanosomes and leishmanias—infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition

Repeat prostate biopsy strategies after initial negative biopsy: meta-regression comparing cancer detection of transperineal, transrectal saturation and MRI guided biopsy.

INTRODUCTION: There is no consensus on how to investigate men with negative transrectal ultrasound guided prostate biopsy (TRUS-B) but ongoing suspicion of cancer. Three strategies used are transperineal (TP-B), transrectal saturation (TS-B) and MRI-guided biopsy (MRI-B). We compared cancer yields of these strategies. METHODS: Papers were identified by search of Pubmed, Embase and Ovid Medline. Included studies investigated biopsy diagnostic yield in men with at least one negative TRUS-B and ongoing suspicion of prostate cancer. Data including age, PSA, number of previous biopsy episodes, number of cores at re-biopsy, cancer yield, and Gleason score of detected cancers were extracted. Meta-regression analyses were used to analyse the data. RESULTS: Forty-six studies were included; 12 of TS-B, 14 of TP-B, and 20 of MRI-B, representing 4,657 patients. Mean patient age, PSA and number of previous biopsy episodes were similar between the strategies. The mean number of biopsy cores obtained by TP-B and TS-B were greater than MRI-B. Cancer detection rates were 30·0%, 36·8%, and 37·6% for TS-B, TP-B, and MRI-B respectively. Meta-regression analysis showed that MRI-B had significantly higher cancer detection than TS-B. There were no significant differences however between MRI-B and TP-B, or TP-B and TS-B. In a sensitivity analysis incorporating number of previous biopsy episodes (36 studies) the difference between MRI-B and TP-B was not maintained resulting in no significant difference in cancer detection between the groups. There were no significant differences in median Gleason scores detected comparing the three strategies. CONCLUSIONS: In the re-biopsy setting, it is unclear which strategy offers the highest cancer detection rate. MRI-B may potentially detect more prostate cancers than other modalities and can achieve this with fewer biopsy cores. However, well-designed prospective studies with standardised outcome measures are needed to accurately compare modalities and define an optimum re-biopsy approach

Transcriptional down-regulation of ccr5 in a subset of HIV+ controllers and their family members.

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5, despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable

A cluster randomized controlled trial of a modified vaccination clinical reminder for primary care providers

Objective: Adult vaccination rates in the United States fall short of national goals, and rates are particularly low for Black Americans. We tested a provider-focused vaccination uptake intervention: a modified electronic health record clinical reminder that bundled together three adult vaccination reminders, presented patient vaccination history, and included talking points for providers to address vaccine hesitancy. Method: Primary care teams at the Atlanta Veterans Affairs Medical Center, who saw 28,941 patients during this period, were randomly assigned to receive either the modified clinical reminder (N = 44 teams) or the status quo (N = 40 teams). Results: Uptake of influenza and other adult vaccinations was 1.6 percentage points higher in the intervention group, which was not statistically significant (CI = [-1.3, 4.4], p = 0.28). The intervention had similar effects on Black and White patients and did not reduce the disparity in vaccination rates between these groups. Conclusion: Provider-focused interventions are a promising way to address vaccine hesitancy, but they may need to be more intensive than a modified clinical reminder to have appreciable effects on vaccination uptake

Combination Therapy of Brain Natriuretic Peptide and Sildenafil Attenuates Pulmonary Hypertension in Rats [abstract]

Abstract only availableFaculty Mentor: Dr. Vincent DeMarco, Child HealthBackground: Pulmonary arterial hypertension (PAH) is a lethal disease characterized by changes in pulmonary vascular structure and function. We tested the hypothesis that Sildenafil, a phosphodiesterase 5 inhibitor, and brain natriuretic peptide (BNP), a guanosine cyclase stimulator, in combination synergistically attenuates PAH when compared to individual therapy in rats through different mechanisms to increase cGMP while minimizing systemic side effects. Methods: Adult male Sprague-Dawley rats were subcutaneously injected with monocrotaline (n=30, 50 mg/kg). After approximately 5 weeks, rats were anesthetized and instrumented to measure systemic pressure (MAP) and right ventricular systolic pressure (RVSP) during infusions of vehicle solution (n=5), intravenous Sildenafil (84 mg/kg/min; n=8), and intravenous BNP (100 ng/kg/min; n=7) alone and a combination of Sildenafil and BNP (n=10). Results: Sildenafil alone decreased RVSP (-17 ±13.2 mmHg) and had a relatively minimal effect on MAP (-4±9.9 mmHg). BNP decreased RVSP (-19±14 mmHg) but also significantly effected MAP (-11±15.3mmHg). Combination therapy with Sildenafil and BNP lowered RVSP (-20±18.7 mmHg), however it also induced the greatest systemic hypotensive effect (MAP = -19±9.9 mmHg). Conclusion: The combination of Sildenafil and BNP, at these doses, significantly attenuates monocrotaline-induced pulmonary hypertension. However, compared with individual treatment, there is no significant difference in effect on RVSP. Furthermore, additive systemic side effects are too significant to consider combination therapy safe. With a different dosing regime, this combination is a potentially viable option in the treatment of patients with PAH

Parsing Arabic Dialects

The Arabic language is a collection of spoken dialects with important phonological, morphological, lexical, and syntactic differences, along with a standard written language, Modern Standard Arabic (MSA). Since the spoken dialects are not officially written, it is very costly to obtain adequate corpora to use for training dialect NLP tools such as parsers. In this paper, we address the problem of parsing transcribed spoken Levantine Arabic (LA). We do not assume the existence of any annotated LA corpus (except for development and testing), nor of a parallel corpus LA-MSA. Instead, we use explicit knowledge about the relation between LA and MSA

Hydrologic landscape regionalisation using deductive classification and random forests

Landscape classification and hydrological regionalisation studies are being increasingly used in ecohydrology to aid in the management and research of aquatic resources. We present a methodology for classifying hydrologic landscapes based on spatial environmental variables by employing non-parametric statistics and hybrid image classification. Our approach differed from previous classifications which have required the use of an a priori spatial unit (e.g. a catchment) which necessarily results in the loss of variability that is known to exist within those units. The use of a simple statistical approach to identify an appropriate number of classes eliminated the need for large amounts of post-hoc testing with different number of groups, or the selection and justification of an arbitrary number. Using statistical clustering, we identified 23 distinct groups within our training dataset. The use of a hybrid classification employing random forests extended this statistical clustering to an area of approximately 228,000 km2 of south-eastern Australia without the need to rely on catchments, landscape units or stream sections. This extension resulted in a highly accurate regionalisation at both 30-m and 2.5-km resolution, and a less-accurate 10-km classification that would be more appropriate for use at a continental scale. A smaller case study, of an area covering 27,000 km2, demonstrated that the method preserved the intra- and inter-catchment variability that is known to exist in local hydrology, based on previous research. Preliminary analysis linking the regionalisation to streamflow indices is promising suggesting that the method could be used to predict streamflow behaviour in ungauged catchments. Our work therefore simplifies current classification frameworks that are becoming more popular in ecohydrology, while better retaining small-scale variability in hydrology, thus enabling future attempts to explain and visualise broad-scale hydrologic trends at the scale of catchments and continents

A lifestyle intervention improves sexual function of women with obesity and infertility : A 5 year follow-up of a RCT

Acknowledgments We thank all the women who participated in this study. We thank all participating hospitals and their staff for their contribution to this study, and the lifestyle coaches, research nurses, research midwives and office members of the Dutch Consortium (www.studies-obsgyn.nl) for their hard work and dedication. Furthermore, we thank all members of the WOMB-project who contributed to the follow-up study; with special thanks to our colleague PhD students, post-docs, research assistants and students.Peer reviewe