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In real-world situations, marine fish farms accommodate multiple fish species and cohorts within the farm, leading to diverse farm layouts influenced by cage dimensions, configurations, and intricate arrangements. These cage management practices are essential to meet production demands, however, farm-level complexities can impact model predictions of waste deposition and benthic impact near fish cages. This is of particular importance when the cages are used for integrated multi-trophic aquaculture (IMTA) with benthic feeders, where this waste not only affects environmental conditions but also provides a potential food source. The Cage Aquaculture Particulate Output and Transport (CAPOT) model incorporated multiple species, cohorts, and cage arrangements to estimate waste distribution from a commercial fish farm in the Mediterranean between October 2018 and July 2019. This spreadsheet model estimated dispersion for individual fish cages using a grid resolution of 5 m x 5 m. The study categorized discrete production periods for each fish cage every month, aligning with intermittent changes in biomass and food inputs due to different cage management practices throughout production. This approach facilitated the use of detailed input data and enhanced model representativeness by considering variations in cage biomass, food types, settling velocities, and configurations. Model outputs, represented in contour plots, indicated higher deposition directly below fish cages that varied monthly throughout fish production cycles. Deposition footprints reflected changes in cage biomass, food inputs, and farm-level practices reflecting this real-world scenario where aquaculture does not follow a production continuum. Moreover, cohort dynamics and cage movements associated with the cage management practices of the fish farm influenced the quantity and fate of wastes distributed around fish cages, revealing variability in deposition footprints. Clearly, these findings have important implications for the design of benthic IMTA systems, with species such as sea cucumber and polychaetes. Variability in waste deposition creates challenges in identifying where the benthic organisms should be placed to allow optimal uptake of waste to meet their food requirements and increase survivability. Evidently, models have an important role to play and this study emphasizes the need for representative input data to describe actual food inputs, cage biomass changes, and management practices for more representative farm-scale modelling and essentially to improve particulate waste management. To effectively mitigate benthic impacts through IMTA, models must quantify and resolve particulate waste distribution and impact around fish farms to maintain a balanced system with net removal of wastes. Resolving farm-level complexities provides vital information about the variability of food availability and quality for extractive organisms that helps improve recycling of organic wastes in integrated systems, demanding a more representative modelling approach.

Rowing ergometers are popular tools for general fitness and competitive crew teams. The effect of the equipment set up on the rowing stroke has received limited attention. This study aimed to determine the effects of altering the foot-stretcher position on rowing kinematics across different stroke rates. Eleven college-level rowers took part in this study. A rowing ergometer was modified to allow the height and angle of the foot-stretcher to be adjusted. Seven foot-stretcher positions were tested, each at rates of 22, 26, and 32 strokes per minute. Sagittal plane kinematic waveforms were compared between conditions for all major joints using statistical parametric mapping, and temporal variables were assessed (p < 0.05). Stroke rate was found to affect kinematic patterns for all joints. The effect of the foot-stretcher position was limited to the ankle and hip. Similarly, the timing of events during the rowing stroke was affected by the stroke rate, but not foot position. These results indicate that while some limited changes to the stroke technique can be caused by altering the foot-stretcher position, the changes were largely compensated for by the rowers and are generally smaller than differences between stroke rates.

Development of genome-wide resources for application in genomic selection or genome-wide association studies, in the absence of full reference genomes, present a challenge to the forestry industry, where longer breeding cycles could benefit from the accelerated selection possible through marker-based breeding value predictions. In particular, large conifer megagenomes require a strategy to reduce complexity, whilst ensuring genome-wide coverage is achieved. Using a transcriptome-based reference template, we have successfully developed a high density exome capture genotype-by-sequencing panel for radiata pine (Pinus radiata D.Don), capable of capturing in excess of 80,000 single nucleotide polymorphism (SNP) markers with a minor allele frequency above 0.03 in the population tested. This represents approximately 29,000 gene models from a core set of 48,914 probes. A set of 704 SNP markers capable of pedigree reconstruction and differentiating individual genotypes were tested within two full-sib mapping populations. While as few as 70 markers could reconstruct parentage in almost all cases, the impact of missing genotypes was noticeable in several offspring. Therefore, 60 sets of 110 randomly selected SNP markers were compared for both parentage reconstruction and clone differentiation. The performance in parentage reconstruction showed little variation over 60 iterations. However, there was notable variation in discriminatory power between closely related individuals, indicating a higher density SNP marker panel may be required to elucidate hidden relationships in complex pedigrees.

Within the first year of implementation, 43% of women who tested HIV positive at their first antenatal care visit were no longer retained and being followed in the free prevention of mother to child transmission (PMTCT) of HIV program offered by the Kenyan Ministry of Health and Médecins Sans Frontières in the informal settlement of Kibera, Nairobi. This study aimed to explore barriers to enrolling and remaining engaged in PMTCT services throughout the pregnancy and postpartum periods. Qualitative data from 31 focus group discussions and 35 in-depth interviews across six stakeholder groups that included women, men, and PMTCT service providers were analyzed. Using an inductive exploratory approach, four researchers coded the data and identified key themes. Five themes emerged from the data that may influence attrition from PMTCT service in this setting: 1) HIV in the context of Kibera, 2) knowledge of HIV status, 3) knowledge of PMTCT, 4) disclosure of HIV status, and 5) male partner support for PMTCT services. A new HIV diagnosis during pregnancy immediately triggered an ongoing risk assessment of perceived hazards in the home, community, and clinic environments that could occur as a result of female participation in PMTCT services. Male partners were a major influence in this risk assessment, but were generally unaware of PMTCT services. To preserve relationships with male partners, meet community expectations of womanhood, and maintain confidentiality while following recommendations of healthcare providers, women had to continuously weigh the risks and benefits of PMTCT services and interventions. Community-based HIV testing and PMTCT education, male involvement in antenatal care, and counseling customized to assist each woman in her own unique risk assessment, may improve uptake of and retention in care and optimize the HIV prevention benefit of PMTCT interventions.

Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation.Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis.Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. In vivo validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines.The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.

There is a wide diversity of bioinformatic tools available for the assembly of next generation sequence and subsequence variant calling to identify genetic markers at scale. Integration of genomics tools such as genomic selection, association studies, pedigree analysis and analysis of genetic diversity, into operational breeding is a goal for New Zealand's most widely planted exotic tree species, Pinus radiata. In the absence of full reference genomes for large megagenomes such as in conifers, RNA sequencing in a range of genotypes and tissue types, offers a rich source of genetic markers for downstream application. We compared nine different assembler and variant calling software combinations in a single transcriptomic library and found that Single Nucleotide Polymorphism (SNPs) discovery could vary by as much as an order of magnitude (8,061 SNPs up to 86,815 SNPs). The assembler with the best realignment of the packages trialled, Trinity, in combination with several variant callers was then applied to a much larger multi-genotype, multi-tissue transcriptome and identified 683,135 in silico SNPs across a predicted 449,951 exons when mapped to the Pinus taeda ver 1.01e reference.

Weather conditions are commonly believed to influence musculoskeletal pain, however the evidence for this is mixed. This study aimed to examine the relationship between local meteorological conditions and online search trends for terms related to knee pain, hip pain, and arthritis. Five years of relative online search volumes for these terms were obtained for the 50 most populous cities in the contiguous United States, along with corresponding local weather data for temperature, relative humidity, barometric pressure, and precipitation. Methods from the climate econometrics literature were used to assess the casual impact of these meteorological variables on the relative volumes of searches for pain. For temperatures between -5°C and 30°C, search volumes for hip pain increased by 12 index points, and knee pain increased by 18 index points. Precipitation had a negative effect on search volumes for these terms. At temperatures >30°C, search volumes for arthritis related pain decreased by 7 index points. These patterns were not seen for pain searches unrelated to the musculoskeletal system. In summary, selected local weather conditions are significantly associated with online search volumes for specific musculoskeletal pain symptoms. We believe the predominate driver for this to be the relative changes in physical activity levels associated with meteorological conditions.

Accurate inference of relatedness between individuals in breeding population contributes to the precision of genetic parameter estimates, effectiveness of inbreeding management and the amount of genetic progress delivered from breeding programs. Pedigree reconstruction has been proven to be an efficient tool to correct pedigree errors and recover hidden relatedness in open pollinated progeny tests but the method can be limited by the lack of parental genotypes and the high proportion of alien pollen from outside the breeding population. Our study investigates the efficiency of sib-ship reconstruction in an advanced breeding population of Eucalyptus nitens with only partially tracked pedigree. The sib-ship reconstruction allowed the identification of selfs (4% of the sample) and the exploration of their potential effect on inbreeding depression in the traits studied. We detected signs of inbreeding depression in diameter at breast height and growth strain while no indications were observed in wood density, wood stiffness and tangential air-dry shrinkage. After the application of a corrected sib-ship relationship matrix, additive genetic variance and heritability were observed to increase where signs of inbreeding depression were initially detected. Conversely, the same genetic parameters for traits that appeared to be free of inbreeding depression decreased in size. It therefore appeared that greater genetic variance may be due, at least in part, to contributions from inbreeding in these studied populations rather than a removal of inbreeding as is traditionally thought.

Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB-231, FaDu, HT29 -CAIX high and HT29 -CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 µM, p = 0.0003). Similar results were observed for HT29-CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 µM, p

Pedigree reconstruction using molecular markers enables efficient management of inbreeding in open-pollinated breeding strategies, replacing expensive and time-consuming controlled pollination. This is particularly useful in preferentially outcrossed, insect pollinated Eucalypts known to suffer considerable inbreeding depression from related matings. A single nucleotide polymorphism (SNP) marker panel consisting of 106 markers was selected for pedigree reconstruction from the recently developed high-density Eucalyptus Infinium SNP chip (EuCHIP60K). The performance of this SNP panel for pedigree reconstruction in open-pollinated progenies of two Eucalyptus nitens seed orchards was compared with that of two microsatellite panels with 13 and 16 markers respectively. The SNP marker panel out-performed one of the microsatellite panels in the resolution power to reconstruct pedigrees and out-performed both panels with respect to data quality. Parentage of all but one offspring in each clonal seed orchard was correctly matched to the expected seed parent using the SNP marker panel, whereas parentage assignment to less than a third of the expected seed parents were supported using the 13-microsatellite panel. The 16-microsatellite panel supported all but one of the recorded seed parents, one better than the SNP panel, although there was still a considerable level of missing and inconsistent data. SNP marker data was considerably superior to microsatellite data in accuracy, reproducibility and robustness. Although microsatellites and SNPs data provide equivalent resolution for pedigree reconstruction, microsatellite analysis requires more time and experience to deal with the uncertainties of allele calling and faces challenges for data transferability across labs and over time. While microsatellite analysis will continue to be useful for some breeding tasks due to the high information content, existing infrastructure and low operating costs, the multi-species SNP resource available with the EuCHIP60k, opens a whole new array of opportunities for high-throughput, genome-wide or targeted genotyping in species of Eucalyptus.

Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

BackgroundTo improve retention on ART, Médecins Sans Frontières, the Ministry of Health and patients piloted a community-based antiretroviral distribution and adherence monitoring model through Community ART Groups (CAG) in Tete, Mozambique. By December 2012, almost 6000 patients on ART had formed groups of whom 95.7% were retained in care. We conducted a qualitative study to evaluate the relevance, dynamic and impact of the CAG model on patients, their communities and the healthcare system.MethodsBetween October 2011 and May 2012, we conducted 16 focus group discussions and 24 in-depth interviews with the major stakeholders involved in the CAG model. Audio-recorded data were transcribed verbatim and analysed using a grounded theory approach.ResultsSix key themes emerged from the data: 1) Barriers to access HIV care, 2) CAG functioning and actors involved, 3) Benefits for CAG members, 4) Impacts of CAG beyond the group members, 5) Setbacks, and 6) Acceptance and future expectations of the CAG model. The model provides cost and time savings, certainty of ART access and mutual peer support resulting in better adherence to treatment. Through the active role of patients, HIV information could be conveyed to the broader community, leading to an increased uptake of services and positive transformation of the identity of people living with HIV. Potential pitfalls included limited access to CAG for those most vulnerable to defaulting, some inequity to patients in individual ART care and a high dependency on counsellors.ConclusionThe CAG model resulted in active patient involvement and empowerment, and the creation of a supportive environment improving the ART retention. It also sparked a reorientation of healthcare services towards the community and strengthened community actions. Successful implementation and scalability requires (a) the acceptance of patients as partners in health, (b) adequate resources, and (c) a well-functioning monitoring and management system.

Over the past two decades finite element (FE) analysis has become a popular tool for researchers seeking to simulate the biomechanics of the healthy and diabetic foot. The primary aims of these simulations have been to improve our understanding of the foot's complicated mechanical loading in health and disease and to inform interventions designed to prevent plantar ulceration, a major complication of diabetes. This article provides a systematic review and summary of the findings from FE analysis-based computational simulations of the diabetic foot.A systematic literature search was carried out and 31 relevant articles were identified covering three primary themes: methodological aspects relevant to modelling the diabetic foot; investigations of the pathomechanics of the diabetic foot; and simulation-based design of interventions to reduce ulceration risk.Methodological studies illustrated appropriate use of FE analysis for simulation of foot mechanics, incorporating nonlinear tissue mechanics, contact and rigid body movements. FE studies of pathomechanics have provided estimates of internal soft tissue stresses, and suggest that such stresses may often be considerably larger than those measured at the plantar surface and are proportionally greater in the diabetic foot compared to controls. FE analysis allowed evaluation of insole performance and development of new insole designs, footwear and corrective surgery to effectively provide intervention strategies. The technique also presents the opportunity to simulate the effect of changes associated with the diabetic foot on non-mechanical factors such as blood supply to local tissues.While significant advancement in diabetic foot research has been made possible by the use of FE analysis, translational utility of this powerful tool for routine clinical care at the patient level requires adoption of cost-effective (both in terms of labour and computation) and reliable approaches with clear clinical validity for decision making.

The transcription factors Runx1 and c-Myc have individually been shown to regulate important gene targets as well as to collaborate in oncogenesis. However, it is unknown whether there is a regulatory relationship between the two genes. In this study, we investigated the transcriptional regulation of endogenous c-Myc by Runx1 in the human T cell line Jurkat and murine primary hematopoietic cells. Endogenous Runx1 binds to multiple sites in the c-Myc locus upstream of the c-Myc transcriptional start site. Cells transduced with a C-terminally truncated Runx1 (Runx1.d190), which lacks important cofactor interaction sites and can block C-terminal-dependent functions of all Runx transcription factors, showed increased transcription of c-Myc. In order to monitor c-Myc expression in response to early and transiently-acting Runx1.d190, we generated a cell membrane-permeable TAT-Runx1.d190 fusion protein. Murine splenocytes treated with TAT-Runx1.d190 showed an increase in the transcription of c-Myc within 2 hours, peaking at 4 hours post-treatment and declining thereafter. This effect is dependent on the ability of Runx1.d190 to bind to DNA. The increase in c-Myc transcripts is correlated with increased c-Myc protein levels. Collectively, these data show that Runx1 directly regulates c-Myc transcription in a C-terminal- and DNA-binding-dependent manner.

Plague is endemic within the central highlands of Madagascar, where its main reservoir is the black rat, Rattus rattus. Typically this species is considered susceptible to plague, rapidly dying after infection inducing the spread of infected fleas and, therefore, dissemination of the disease to humans. However, persistence of transmission foci in the same area from year to year, supposes mechanisms of maintenance among which rat immune responses could play a major role. Immunity against plague and subsequent rat survival could play an important role in the stabilization of the foci. In this study, we aimed to investigate serological responses to plague in wild black rats from endemic areas of Madagascar. In addition, we evaluate the use of a recently developed rapid serological diagnostic test to investigate the immune response of potential reservoir hosts in plague foci.We experimentally infected wild rats with Yersinia pestis to investigate short and long-term antibody responses. Anti-F1 IgM and IgG were detected to evaluate this antibody response. High levels of anti-F1 IgM and IgG were found in rats one and three weeks respectively after challenge, with responses greatly differing between villages. Plateau in anti-F1 IgM and IgG responses were reached for as few as 500 and 1500 colony forming units (cfu) inoculated respectively. More than 10% of rats were able to maintain anti-F1 responses for more than one year. This anti-F1 response was conveniently followed using dipsticks.Inoculation of very few bacteria is sufficient to induce high immune response in wild rats, allowing their survival after infection. A great heterogeneity of rat immune responses was found within and between villages which could heavily impact on plague epidemiology. In addition, results indicate that, in the field, anti-F1 dipsticks are efficient to investigate plague outbreaks several months after transmission.

The gastrointestinal tract microbiota (GTM) of mammals is a complex microbial consortium, the composition and activities of which influences mucosal development, immunity, nutrition and drug metabolism. It remains unclear whether the composition of the dominant GTM is conserved within animals of the same strain and whether stable GTMs are selected for by host-specific factors or dictated by environmental variables.The GTM composition of six highly inbred, genetically distinct strains of mouse (C3H, C57, GFEC, CD1, CBA nu/nu and SCID) was profiled using eubacterial -specific PCR-DGGE and quantitative PCR of feces. Animals exhibited strain-specific fecal eubacterial profiles that were highly stable (c. >95% concordance over 26 months for C57). Analyses of mice that had been relocated before and after maturity indicated marked, reproducible changes in fecal consortia and that occurred only in young animals. Implantation of a female BDF1 mouse with genetically distinct (C57 and Agoutie) embryos produced highly similar GTM profiles (c. 95% concordance) between mother and offspring, regardless of offspring strain, which was also reflected in urinary metabolite profiles. Marked institution-specific GTM profiles were apparent in C3H mice raised in two different research institutions.Strain-specific data were suggestive of genetic determination of the composition and activities of intestinal symbiotic consortia. However, relocation studies and uterine implantation demonstrated the dominance of environmental influences on the GTM. This was manifested in large variations between isogenic adult mice reared in different research institutions.