In partnership with the Medicines for Malaria Venture (MMV), we screened a collection ('Stasis Box') of 400 compounds (which have been in clinical development but have not been approved for illnesses ...other than neglected infectious diseases) for inhibitory activity against Haemonchus contortus, in order to attempt to repurpose some of the compounds to parasitic nematodes.
We assessed the inhibition of compounds on the motility and/or development of exsheathed third-stage (xL3s) and fourth-stage (L4) larvae of H. contortus using a whole-organism screening assay.
In the primary screen, we identified compound MMV690767 (also known as SNS-032) that inhibited xL3 motility by ~70% at a concentration of 20 μM after 72 h as well as compound MMV079840 (also known as AG-1295), which induced a coiled xL3 phenotype, with ~50% inhibition on xL3 motility. Subsequently, we showed that SNS-032 (IC
= 12.4 μM) and AG-1295 (IC
= 9.92 ± 1.86 μM) had a similar potency to inhibit xL3 motility. Although neither SNS-032 nor AG-1295 had a detectable inhibitory activity on L4 motility, both compounds inhibited L4 development (IC
values = 41.24 μM and 7.75 ± 0.94 μM for SNS-032 and AG-1295, respectively). The assessment of the two compounds for toxic effects on normal human breast epithelial (MCF10A) cells revealed that AG-1295 had limited cytotoxicity (IC
> 100 μM), whereas SNS-032 was quite toxic to the epithelial cells (IC
= 1.27 μM).
Although the two kinase inhibitors, SNS-032 and AG-1295, had moderate inhibitory activity on the motility or development of xL3s or L4s of H. contortus in vitro, further work needs to be undertaken to chemically alter these entities to achieve the potency and selectivity required for them to become nematocidal or nematostatic candidates.
There is increased recognition that people with lived-experience of mental ill-health ought to be centred in research design, implementation and translation, and quality improvement and program ...evaluation of services. There is also an increased focus on ways to ensure that co-design processes can be led by people with lived-experience of mental ill-health. Despite this, there remains limited explanation of the physical, social, human, and economic infrastructure needed to create and sustain such models in research and service settings. This is particularly pertinent for all health service sectors (across mental and physical health and social services) but more so across tertiary education settings where research generation occurs for implementation and translation activities with policy and services. The Co-Design Living Labs program was established in 2017 as an example of a community-based embedded approach to bring people living with trauma and mental ill-health and carers/family and kinship group members together with university-based researchers to drive end-to-end research design to translation in mental healthcare and research sectors. The program's current membership is near to 2000 people. This study traces the evolution of the program in the context of the living labs tradition of open innovation. It overviews the philosophy of practice for working with people with lived-experience and carer/family and kinship group members-togetherness by design. Togetherness by design centres on an ethical relation of
that moves beyond unethical and transactional approaches of
and
, as articulated by sociologist Zygmunt Bauman. The retrospective outlines how an initial researcher-driven model can evolve and transform to become one where people with lived-experience of mental ill-health and carer/family kinship group members hold clear decision-making roles, share in power to enact change, and move into co-researcher roles within research teams. Eight mechanisms are presented in the context of an explanatory theoretical model of change for co-design and coproduction, which are used to frame research co-design activities and provide space for continuous learning and evolution of the Co-Design Living Labs program.
Horizontal gene transfer-the exchange of genes across mating barriers-is recognized as a major force in bacterial evolution. However, in eukaryotes it is prevalent only in certain phagotrophic ...protists and limited largely to the ancient acquisition of bacterial genes. Although the human genome was initially reported to contain over 100 genes acquired during vertebrate evolution from bacteria, this claim was immediately and repeatedly rebutted. Moreover, horizontal transfer is unknown within the evolution of animals, plants and fungi except in the special context of mobile genetic elements. Here we show, however, that standard mitochondrial genes, encoding ribosomal and respiratory proteins, are subject to evolutionarily frequent horizontal transfer between distantly related flowering plants. These transfers have created a variety of genomic outcomes, including gene duplication, recapture of genes lost through transfer to the nucleus, and chimaeric, half-monocot, half-dicot genes. These results imply the existence of mechanisms for the delivery of DNA between unrelated plants, indicate that horizontal transfer is also a force in plant nuclear genomes, and are discussed in the contexts of plant molecular phylogeny and genetically modified plants.
Asthma prevalence has increased worldwide; although less so in developed countries recently. This study assessed changes in the prevalence of asthma and related symptoms in the Busselton community ...since 1966. Cross-sectional respiratory health surveys of Busselton adults were conducted in 1966, 1969, 1972, 1975, 1981, 1990 and 2005-2007. Logistic regression models were used to estimate prevalence rates of asthma, respiratory symptoms, smoking, airway hyperresponsiveness (AHR) and atopy and to make comparisons in 2005-2007 and previous survey years. Asthma was defined as ever having doctor-diagnosed asthma (DDA). The prevalence of DDA was around 6% from 1966 to 1975, 8% in 1981 and rose to 19% in 2005-2007. From 1981 to 2005-2007, smoking prevalence declined and obesity and atopy increased but changes in these variables explained only a small part of the increase in DDA. Wheeze and cough/phlegm increased but AHR, breathlessness and doctor-diagnosed bronchitis remained relatively stable over the same period. These observations indicate that the increase in DDA is partly explained by increased symptoms and atopy. The lack of changes in AHR and doctor-diagnosed bronchitis suggests that factors such as diagnostic transfer and increased awareness of asthma have also contributed to the rise in prevalence of DDA.
Cardiovascular disease (CVD) is a major cause of disability and mortality globally. Premature fatal and non-fatal CVD is considered to be largely preventable through the control of risk factors by ...lifestyle modifications and preventive medication. Lipid-lowering and antihypertensive drug therapies for primary prevention are cost-effective in reducing CVD morbidity and mortality among high-risk people and are recommended by international guidelines. However, adherence to medication prescribed for the prevention of CVD can be poor. Approximately 9% of CVD cases in the EU are attributed to poor adherence to vascular medications. Low-cost, scalable interventions to improve adherence to medications for the primary prevention of CVD have potential to reduce morbidity, mortality and healthcare costs associated with CVD.
To establish the effectiveness of interventions delivered by mobile phone to improve adherence to medication prescribed for the primary prevention of CVD in adults.
We searched CENTRAL, MEDLINE, Embase, and two other databases on 7 January 2020. We also searched two clinical trials registers on 5 February 2020. We searched reference lists of relevant papers. We applied no language or date restrictions.
We included randomised controlled trials investigating interventions delivered wholly or partly by mobile phones to improve adherence to cardiovascular medications prescribed for the primary prevention of CVD. We only included trials with a minimum of one-year follow-up in order that the outcome measures related to longer-term, sustained medication adherence behaviours and outcomes. Eligible comparators were usual care or control groups receiving no mobile phone-delivered component of the intervention.
We used standard methodological procedures recommended by Cochrane. The main outcomes of interest were objective measures of medication adherence (blood pressure (BP) and cholesterol), CVD events, and adverse events. We contacted study authors for further information when this was not reported.
We included 14 trials with 25,633 randomised participants. Participants were recruited from community-based primary and tertiary care or outpatient clinics. The interventions varied widely from those delivered solely through short messaging service (SMS) to those involving a combination of modes of delivery, such as SMS in addition to healthcare worker training, face-to-face counselling, electronic pillboxes, written materials, and home blood pressure monitors. Some interventions only targeted medication adherence, while others additionally targeted lifestyle changes such as diet and exercise. Due to heterogeneity in the nature and delivery of the interventions and study populations, we reported most results narratively, with the exception of two trials which were similar enough to meaningfully pool in meta-analyses. The body of evidence for the effect of mobile phone-based interventions on objective outcomes of adherence (BP and cholesterol) was of low certainty, due to most trials being at high risk of bias, and inconsistency in outcome effects. Two trials were at low risk of bias. Among five trials (total study enrolment: 5441 participants) recording low-density lipoprotein cholesterol (LDL-C), two studies found evidence for a small beneficial intervention effect on reducing LDL-C (-5.30 mg/dL, 95% confidence interval (CI) -8.30 to -2.30; and -9.20 mg/dL, 95% CI -17.70 to -0.70). The other three studies found results varying from a small reduction (-7.7 mg/dL) to a small increase in LDL-C (0.77 mg/dL). All of which had wide confidence intervals that included no effect. Across 13 studies (25,166 participants) measuring systolic blood pressure, effect estimates ranged from a large reduction (MD -12.45 mmHg, 95% CI -15.02 to -9.88) to a small increase (MD 2.80 mmHg, 95% CI 0.30 to 5.30). We found a similar range of effect estimates for diastolic BP, ranging from -12.23 mmHg (95% CI 14.03 to -10.43) to 1.64 mmHg (95% CI -0.55 to 3.83) (11 trials, 19,716 participants). Four trials showed intervention benefits for systolic and diastolic BP with confidence intervals excluding no effect, and among these were all three of the trials evaluating self-monitoring of blood pressure with mobile phone-based telemedicine. The fourth trial included SMS and provider support (with additional varied features). Seven studies (19,185 participants) reported 'controlled' BP as an outcome, and intervention effect estimates varied from negligible effects (odds ratio (OR) 1.01, 95% CI 0.76 to 1.34) to large improvements in BP control (OR 2.41, 95% CI: 1.57 to 3.68). The three trials of clinician training or decision support combined with SMS (with additional varied features) had confidence intervals encompassing benefits and harms, with point estimates close to zero. Pooled analyses of the two trials of interventions solely delivered through SMS were indicative of little or no beneficial intervention effect on systolic BP (MD -1.55 mmHg, 95% CI -3.36 to 0.25; I
= 0%) and small increases in controlled BP (OR 1.32, 95% CI 1.06 to 1.65; I
= 0%). Based on four studies (12,439 participants), there was very low-certainty evidence (downgraded twice for imprecision and once for risk of bias) relating to the intervention effect on combined (fatal and non-fatal) CVD events. Two studies (2535 participants) provided low-certainty evidence for the effect of the intervention on cognitive outcomes, with little or no difference between trial arms for perceived quality of care and satisfaction with treatment. There was moderate-certainty evidence (downgraded due to risk of bias) that the interventions did not cause harm, based on six studies (8285 participants). Three studies reported no adverse events attributable to the intervention. One study reported no difference between groups in experience of adverse effects of statins, and that no participants reported intervention-related adverse events. One study stated that potential side effects were similar between groups. One study reported a similar number of deaths in each arm, but did not provide further information relating to potential adverse events.
There is low-certainty evidence on the effects of mobile phone-delivered interventions to increase adherence to medication prescribed for the primary prevention of CVD. Trials of BP self-monitoring with mobile-phone telemedicine support reported modest benefits. One trial at low risk of bias reported modest reductions in LDL cholesterol but no benefits for BP. There is moderate-certainty evidence that these interventions do not result in harm. Further trials of these interventions are warranted.
Background. In China, the use of traditional Chinese medicine (TCM) is very popular, but little is known about how it is integrated with conventional cancer care. We conducted parallel surveys of ...patients and physicians on TCM utilization. Methods. Two hundred forty-five patients and 72 allopathic physicians at the Fudan University Shanghai Cancer Center completed questions on their use of and attitude towards TCM. Results. Patient mean age was 51, with 60% female. Eighty-three percent of patients had used TCM. Use was greatest for Chinese herbal medicine (CHM; 55.8%). Only 1.3% of patients used acupuncture and 6.8% Qi Gong or Tai Qi. Sixty-three percent of patients notified their oncologist about TCM use. The most common reason for use was to improve immune function. CHM was often used with a goal of treating cancer (66.4%), a use that 57% of physicians agreed with. Physicians were most concerned with interference with treatment, lack of evidence, and safety. Ninety percent of physicians have prescribed herbs and 87.5% have used TCM themselves. Conclusion. The use of TCM by Chinese cancer patients is exceptionally high, and physicians are generally well informed and supportive of patients’ use. Botanical agents are much more commonly used than acupuncture or movement-based therapies.
Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in ...vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy.
Bacterial microcompartments (BMCs) represent proteinaceous macromolecular nanobioreactors that are found in a broad range of bacteria, and which are associated with either anabolic or catabolic ...processes. They consist of a semipermeable outer shell that packages a central metabolic enzyme or pathway, providing both enhanced flux and protection against toxic intermediates. Recombinant production of BMCs has led to their repurposing with the incorporation of altogether new pathways. Deconstructing BMCs into their component parts has shown that some individual shell proteins self-associate into filaments that can be further modified into a cytoplasmic scaffold, or cytoscaffold, to which enzymes/proteins can be targeted. BMCs therefore represent a modular system that is highly suited for engineering biological systems for useful purposes.
Bacterial microcompartments (BMCs) are widespread proteinaceous organelles consisting of a semipermeable protein shell and an encapsulated enzymatic pathway.
BMCs can be divided into the anabolic carboxysomes and the catabolic metabolosomes.
Targeting to organelles is facilitated by short, amphipathic, alpha helical encapsulation peptides.
Heterologous enzymatic pathways can be encapsulated within empty organelles, resulting in enhanced productivity.
A BMC-H-based cytoscaffold is able to significantly enhance biofuel production through enzyme colocation.
Metagenomic studies are leading to the discovery of a hidden diversity of RNA viruses. These new viruses are poorly characterized and new approaches are needed predict the host species these viruses ...pose a risk to. The rhabdoviruses are a diverse family of RNA viruses that includes important pathogens of humans, animals, and plants. We have discovered thirty-two new rhabdoviruses through a combination of our own RNA sequencing of insects and searching public sequence databases. Combining these with previously known sequences we reconstructed the phylogeny of 195 rhabdovirus sequences, and produced the most in depth analysis of the family to date. In most cases we know nothing about the biology of the viruses beyond the host they were identified from, but our dataset provides a powerful phylogenetic approach to predict which are vector-borne viruses and which are specific to vertebrates or arthropods. By reconstructing ancestral and present host states we found that switches between major groups of hosts have occurred rarely during rhabdovirus evolution. This allowed us to propose seventy-six new likely vector-borne vertebrate viruses among viruses identified from vertebrates or biting insects. Based on currently available data, our analysis suggests it is likely there was a single origin of the known plant viruses and arthropod-borne vertebrate viruses, while vertebrate- and arthropod-specific viruses arose at least twice. There are also few transitions between aquatic and terrestrial ecosystems. Viruses also cluster together at a finer scale, with closely related viruses tending to be found in closely related hosts. Our data therefore suggest that throughout their evolution, rhabdoviruses have occasionally jumped between distantly related host species before spreading through related hosts in the same environment. This approach offers a way to predict the most probable biology and key traits of newly discovered viruses.
Mitochondrial gene content is highly variable across extant eukaryotes. The number of mitochondrial protein genes varies from 3 to 67, while tRNA gene content varies from 0 to 27. Moreover, these ...numbers exclude the many diverse lineages of non-respiring eukaryotes that lack a mitochondrial genome yet still contain a mitochondrion, albeit one often highly derived in ultrastructure and metabolic function, such as the hydrogenosome. Diversity in tRNA gene content primarily reflects differential usage of imported tRNAs of nuclear origin. In the case of protein genes, most of this diversity reflects differential degrees of functional gene transfer to the nucleus, with more minor contributions resulting from gene loss from the cell as a consequence of either substitution via a functional nuclear homolog or the cell’s dispensation of the function of the gene product. The tempo and pattern of mitochondrial gene loss is highly episodic, both across the broad sweep of eukaryotes and within such well-studied groups as angiosperms. All animals, some plants, and certain other groups of eukaryotes are mired in profound stases in mitochondrial gene content, whereas other lineages have experienced relatively frequent gene loss. Loss and transfer to the nucleus of ribosomal protein and succinate dehydrogenase genes has been especially frequent, sporadic, and episodic during angiosperm evolution. Potential mechanisms for activation of transferred genes have been inferred, and intermediate stages in the process have been identified by comparative studies. Several hypotheses have been proposed for why mitochondrial genes are transferred to the nucleus, why mitochondria retain genomes, and why functional gene transfer is almost exclusively unidirectional.
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