The Biochemistry of VapBC Toxin-Antitoxins

The VapBC toxin-antitoxin (TA) systems were first identified in 2005 and little is known about their contemporary biological function, despite the fact that VapBC TAs are the largest TA family and are widespread in bacteria and archaea (Arcus, Rainey, & Turner, 2005; Gerdes, Christensen, & Lobner-Olsen, 2005). Mycobacterium tuberculosis has a surprisingly large repertoire of 45 VapBC TAs. In contrast Mycobacterium smegmatis, a model organism for M. tuberculosis, contains only one vapBC operon, thereby making it an ideal system to uncover the possible role(s) that VapBC proteins play in mycobacteria. This thesis describes the functional characterisation of VapC from M. smegmatis and two homologues from Pyrobaculum aerophilum, along with biophysical characterisation of the VapBC complex from M. smegmatis. The VapBC proteins from M. smegmatis form a tight complex in a 1:1 ratio and interactions between the proteins result in a tetramer of VapBC heterodimers. VapB is susceptible to proteolytic degradation when not bound to DNA thus hinting at a mechanism for VapC activation. VapC proteins from P. aerophilum (VapCPAE2754 and VapCPAE0151) and VapC from M. smegmatis display Mg²⁺/Mn²⁺ dependent, sequence specific ribonuclease activity. VapC from M. smegmatis targets the AU rich sequences AUAU and AUAA. Whereas VapCPAE2754 and VapCPAE0151 from P. aerophilum both target GGUG and GGGG sequences. These sequences are present in over half the mRNA transcripts encoded in the P. aerophilum genome, making them potent toxins. VapC ribonuclease activity is inhibited when VapC is bound to VapB. When VapC is released from the VapBC complex it cleaves cohorts of mRNA transcripts thereby reducing protein synthesis for this cohort of genes. Microarray analysis revealed that the majority of transcripts downregulated in response to VapC expression in M. smegmatis are involved in carbon utilisation and transport (Robson, 2010). Bioinformatics shows that the target sequence is overrepresented in the downregulated transcripts. The majority of the downregulated genes are in operons, which suggests a mechanism for destabilising mRNA transcripts to regulate specific metabolic processes

A descriptive spatial analysis of bovine tuberculosis in intensively controlled cattle farms in New Zealand

We describe the temporal and geographical distribution of confirmed cases of bovine tuberculosis (TB) in a population of cattle in the south-east of the North Island of New Zealand. Data were derived from routine TB testing conducted between 1980 and 2003 and included details for 69 farms. Four six-year periods were defined to coincide with changes in depopulation strategies against the wildlife TB reservoir, the brushtail possum Trichosurus vulpecula. For the periods 1980 to 1985 and 1986 to 1991 the median annual incidence rate of TB was 0.4 and 4.7 cases per 1000 cattle-years at risk, respectively. For the period 1992 to 2003 the median annual incidence rate of TB decreased to 1.8 cases per 1000 cattle-years at risk, coincident with the use of poisoning to control possums in the surrounding forest park (a major possum habitat area). We identified clusters of TB cases adjacent to the forest park and found no evidence of spatio-temporal interaction of TB risk among farms. Our findings support the hypothesis that possums living in the forest park are a source of bovine TB in this area and that farm-to-farm spread of disease was not an important infection mechanism

Behind Closed Doors: Abuse and Retaliation Against Hunger Strikers in U.S. Immigration Detention

The decision to begin a hunger strike in immigration detention is not taken lightly. A detained person's refusal to eat may be the last option available to voice complaint, after all other methods of petition have failed. Detained and imprisoned people worldwide have engaged in hunger strikes to plead for humane conditions of confinement or release from captivity and to bring attention to broader calls for justice.Each day, the United States government unnecessarily locks up thousands of people in civil immigration detention, including children, in over two hundred immigration detention centers around the country.People may be locked up for many months — even years — as they await final adjudication of their cases or deportation. Trapped in a system marked by mistreatment and abuse, medical neglect, and the denial of due process, hundreds of people in immigration detention engage in hunger strikes as a means of protest each year. ICE's failure to provide safe and humane conditions in detention during the COVID-19 pandemic has only raised the stakes for detained people. Although some detained people, on occasion, are able to bring outside attention to their hunger strikes, very little is known of ICE's systemic response to hunger striking detainees.This report provides for the first time an in-depth, nationwide examination of what happens to people who engage in hunger strikes while detained by ICE

Notes from the field: Lessons learned from using ecosystem service approaches to inform real-world decisions

While there have been rapid advances in assessments of biodiversity and ecosystem services (BES), a critical remaining challenge is how to move from scientific knowledge to real-world decision making. We offer 6 lessons from our experiences applying new approaches and tools for quantifying BES in 20 pilot demonstrations: (1) Applying a BES approach is most effective in leading to policy change as part of an iterative science-policy process; (2) simple ecological production function models have been useful in a diverse set of decision contexts, across a broad range of biophysical, social, and governance systems. Key limitations of simple models arise at very small scales, and in predicting specific future BES values; (3) training local experts in the approaches and tools is important for building local capacity, ownership, trust, and long-term success; (4) decision makers and stakeholders prefer to use a variety of BES value metrics, not only monetary values; (5) an important science gap exists in linking changes in BES to changes in livelihoods, health, cultural values, and other metrics of human wellbeing; and (6) communicating uncertainty in useful and transparent ways remains challenging

One Health research and training and government support for One Health in South Asia

Introduction: Considerable advocacy, funding, training, and technical support have been provided to South Asian countries to strengthen One Health (OH) collaborative approaches for controlling diseases with global human pandemic potential since the early 2000s. It is essential that the OH approach continues to be strengthened given South Asia is a hot spot for emerging and endemic zoonotic diseases. The objectives of this article are to describe OH research and training and capacity building activities and the important developments in government support for OH in these countries to identify current achievements and gaps. Materials and methods: A landscape analysis of OH research, training, and government support in South Asia was generated by searching peer-reviewed and grey literature for OH research publications and reports, a questionnaire survey of people potentially engaged in OH research in South Asia and the authors’ professional networks. Results: Only a small proportion of zoonotic disease research conducted in South Asia can be described as truly OH, with a significant lack of OH policy-relevant research. A small number of multisectoral OH research and OH capacity building programmes were conducted in the region. The governments of Bangladesh and Bhutan have established operational OH strategies, with variable progress institutionalising OH in other countries. Identified gaps were a lack of useful scientific information and of a collaborative culture for formulating and implementing integrated zoonotic disease control policies and the need for ongoing support for transdisciplinary OH research and policy-relevant capacity building programmes. Discussion: Overall we found a very small number of truly OH research and capacity building programmes in South Asia. Even though significant progress has been made in institutionalising OH in some South Asian countries, further behavioural, attitudinal, and institutional changes are required to strengthen OH research and training and implementation of sustainably effective integrated zoonotic disease control policies

Predicting farm-level animal populations using environmental and socioeconomic variables

Accurate information on the geographic distribution of domestic animal populations helps biosecurity authorities to efficiently prepare for and rapidly eradicate exotic diseases, such as Foot and Mouth Disease (FMD). Developing and maintaining sufficiently high-quality data resources is expensive and time consuming. Statistical modelling of population density and distribution has only begun to be applied to farm animal populations, although it is commonly used in wildlife ecology. We developed zero-inflated Poisson regression models in a Bayesian framework using environmental and socioeconomic variables to predict the counts of livestock units (LSUs) and of cattle on spatially referenced farm polygons in a commercially available New Zealand farm database, Agribase. Farm-level counts of cattle and of LSUs varied considerably by region, because of the heterogeneous farming landscape in New Zealand. The amount of high quality pasture per farm was significantly associated with the presence of both cattle and LSUs. Internal model validation (predictive performance) showed that the models were able to predict the count of the animal population on groups of farms that were located in randomly selected 3 km zones with a high level of accuracy. Predicting cattle or LSU counts on individual farms was less accurate. Predicted counts were statistically significantly more variable for farms that were contract grazing dry stock, such as replacement dairy heifers and dairy cattle not currently producing milk, compared with other farm types. This analysis presents a way to predict numbers of LSUs and cattle for farms using environmental and socio-economic data. The technique has the potential to be extrapolated to predicting other pastoral based livestock species

Volumetric and correlational implications of brain parcellation method selection:a 3-way comparison in the frontal lobes.

OBJECTIVE: The aims of this study were to compare distinct brain frontal lobe parcellation methods across 90 brain magnetic resonance imaging scans and examine their associations with cognition in older age. METHODS: Three parcellation methods (Manual, FreeSurfer, and Stereology) were applied to T1-weighted magnetic resonance imaging of 90 older men, aged ∼73 years. A measure of general fluid intelligence (g(f)) associated with dorsolateral frontal regions was also derived from a contemporaneous psychological test battery. RESULTS: Despite highly discordant raw volumes for the same nominal regions, Manual and FreeSurfer (but not Stereology) left dorsolateral measures were significantly correlated with g(f) (r > 0.22), whereas orbital and inferior lateral volumes were not, consistent with the hypothesized frontal localization of g(f). CONCLUSIONS: Individual differences in specific frontal lobe brain volumes—variously measured—show consistent associations with cognitive ability in older age. Importantly, differences in parcellation protocol for some regions that may impact the outcome of brain-cognition analyses are discussed

COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol

Background The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. Methods/Design The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants’ views of the intervention and factors that acted as facilitators and barriers to participation. Discussion This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. Trial registration Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT0232554