Limitations of conventional approaches to identify photochemically produced reactive intermediates involved in contaminant indirect photodegradation.

Dissolved organic matter (DOM) mediated indirect photodegradation can play an important role in the degradation of aquatic contaminants. Predicting the rate of this process requires knowledge of the photochemically produced reactive intermediates (PPRI) that react with the compound of interest, as well as the ability of individual DOM samples to produce PPRI. Key PPRI are typically identified using quencher studies, yet this approach often leads to results that are difficult to interpret. In this work, we analyze the indirect photodegradation of atorvastatin, carbamazepine, sulfadiazine, and benzotriazole using a diverse set of 48 waters from natural and engineered aquatic systems. We use this large data set to evaluate relationships between PPRI formation and indirect photodegradation rate constants, which are directly compared to results using standard quenching experiments. These data demonstrate that triplet state DOM (3DOM) and singlet oxygen (1O2) are critical PPRI for atorvastatin, carbamazepine, and sulfadiazine, while hydroxyl radical (˙OH) contributes to the indirect photodegradation of benzotriazole. We caution against relying on quenching studies because quenching of 3DOM limits the formation of 1O2 and all studied quenchers react with ˙OH. Furthermore, we show that DOM composition directly influences indirect photodegradation and that low molecular weight, microbial-like DOM is positively correlated with the indirect photodegradation rates of carbamazepine, sulfadiazine, and benzotriazole.

Dissolved Organic Matter Composition Determines Its Susceptibility to Complete and Partial Photooxidation within Lakes.

Dissolved organic matter (DOM) plays an important role in carbon cycling within inland surface waters. Under sunlight irradiation, DOM undergoes complete photooxidation to produce carbon dioxide (CO2) and partial photooxidation that alters the molecular composition of DOM. However, a mechanistic understanding of the relationship between DOM composition and its susceptibility to partial and complete photooxidation in surface waters is currently lacking. This work combines light exposure experiments with high-resolution mass spectrometry to investigate DOM photooxidation using two DOM isolates and DOM from 16 lakes that vary in trophic status and size. High ratios of oxygen consumption to dissolved inorganic carbon (DIC) production demonstrate that all samples undergo extensive partial photooxidation. At the molecular level, more oxidized, aromatic DOM formulas are associated with oxygen consumption and DIC production. Bulk level measurements indicate that DOM becomes less aromatic and lower in apparent molecular weight following partial photooxidation, and there is molecular level evidence of oxygen addition and loss of CO2 in all samples. However, formulas most susceptible to photooxidation vary depending on the initial DOM composition. Collectively, this work provides insights into the relationship between DOM composition and photooxidation, which has important implications for carbon cycling in diverse surface waters.

Formation of Targeted and Novel Disinfection Byproducts during Chlorine Photolysis in the Presence of Bromide.

Chlorine photolysis is an advanced oxidation process that relies on the combination of direct chlorination by free available chlorine, direct photolysis, and reactive oxidants to transform contaminants. In waters that contain bromide, free available bromine and reactive bromine species can also form. However, little is known about the underlying mechanisms or formation potential of disinfection byproducts (DBPs) under these conditions. We investigated reactive oxidant generation and DBP formation under dark conditions, chlorine photolysis, and radical-quenched chorine photolysis with variable chlorine (0-10 mg-Cl2/L) and bromide (0-2,000 µg/L) concentrations, as well as with free available bromine. Probe loss rates and ozone concentrations increase with chlorine concentration and are minimally impacted by bromide. Radical-mediated processes partially contribute to the formation targeted DBPs (i.e., trihalomethanes, haloacetic acids, haloacetonitriles, chlorate, and bromate), which increase with increasing chlorine concentration. Chlorinated novel DBPs detected by high-resolution mass spectrometry are attributable to a combination of dark chlorination, direct halogenation by reactive chlorine species, and transformation of precursors, whereas novel brominated DBPs are primarily attributable to dark bromination of electron-rich formulas. The formation of targeted and novel DBPs during chlorine photolysis in waters with elevated bromide may limit treatment applications.

Impact of ozone-biologically active filtration on the breakthrough of Perfluoroalkyl acids during granular activated carbon treatment of municipal wastewater effluent.

The presence of perfluoroalkyl acids (PFAAs) in municipal wastewater has highlighted the need to develop PFAA treatment approaches for wastewater effluent and potable reuse applications. Ozone (O3) and biologically active filtration (BAF) were investigated as standalone and combined pretreatment processes to improve the performance of granular activated carbon (GAC) for PFAA removal from wastewater effluent. As individual processes, ozonation at all three investigated doses (0.35, 0.75, 1.0 mg O3/mg DOC) and BAF at both tested empty bed contact times (EBCT; 15 and 20 min) led to significant improvement in PFAA removal by subsequent GAC treatment. With respect to standalone ozonation, the specific O3 dose of 0.75 mg O3/mg DOC was proven to be the optimum operating condition as further increase of the specific ozone dose to 1.0 mg O3/mg DOC did not provide considerable additional improvement. Extending the EBCT during standalone BAF from 15 to 20 minutes significantly improved the efficacy of GAC for the removal of tested PFAAs. Pretreatment with O3-BAF (0.75 mg O3/mg DOC; 20 min EBCT) in tandem outperformed both standalone ozonation and BAF for the removal of PFAA by GAC. Characterization of effluent organic matter (EfOM) by size exclusion chromatography (SEC) and Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR-MS) before and after pretreatments suggest that among multiple co-occurring phenomena, the shift towards smaller and more polar EfOM may have predominantly alleviated pore constriction/blockage without having adverse impact on direct site competition. This observation is supported by SEC and FT-ICR-MS results indicating reduced EfOM molecular size through O3 and BAF pretreatment as well as transition to more hydrophilic byproducts.

Change and variability in Antarctic coastal exposure, 1979-2020.

Increased exposure of Antarctica's coastal environment to open ocean and waves due to loss of a protective sea-ice "buffer" has important ramifications for ice-shelf stability, coastal erosion, important ice-ocean-atmosphere interactions and shallow benthic ecosystems. Here, we introduce a climate and environmental metric based on the ongoing long-term satellite sea-ice concentration record, namely Coastal Exposure Length. This is a daily measure of change and variability in the length and incidence of Antarctic coastline lacking any protective sea-ice buffer offshore. For 1979-2020, ~50% of Antarctica's ~17,850-km coastline had no sea ice offshore each summer, with minimal exposure in winter. Regional summer/maximum contributions vary from 45% (Amundsen-Bellingshausen seas) to 58% (Indian Ocean and Ross Sea), with circumpolar annual exposure ranging from 38% (2019) to 63% (1993). The annual maximum length of Antarctic coastal exposure decreased by ~30 km (~0.32%) per year for 1979-2020, composed of distinct regional and seasonal contributions.

Episodic Plate Tectonics on Europa: Evidence for Widespread Patches of Mobile-Lid Behavior in the Antijovian Hemisphere.

A nearly pole-to-pole survey near 140°E longitude on Europa revealed many areas that exhibit past lateral surface motions, and these areas were examined to determine whether the motions can be described by systems of rigid plates moving across Europa's surface. Three areas showing plate-like behavior were examined in detail to determine the sequence of events that deformed the surface. All three areas were reconstructed to reveal the original pre-plate motion surfaces by performing multi-stage rotations of plates in spherical coordinates. Several motions observed along single plate boundaries were also noted in previous works, but this work links together isolated observations of lateral offsets into integrated systems of moving plates. Not all of the surveyed surface could be described by systems of rigid plates. There is evidence that the plate motions did not all happen at the same time, and that they are not happening today. We conclude that plate tectonic-like behavior on Europa occurs episodically, in limited regions, with less than 100 km of lateral motion accommodated along any particular boundary before plate motions cease. Europa may represent a world perched on the theoretical boundary between stagnant and mobile lid convective behavior, or it may represent an additional example of the wide variations in possible planetary convective regimes. Differences in observed strike-slip sense and plate rotation directions between the northern and southern hemispheres raise the question of whether tidal forces may influence plate motions.

The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis is effective against many cancer types. However, due in part to unresponsiveness or acquired resistance, not all patients experience a durable response to ICIs. HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor that directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. We hypothesized that HBI-8000 functions as an epigenetic immunomodulator to reprogram the tumor microenvironment from immunologically cold (nonresponsive) to hot (responsive). METHOD: Mice bearing syngeneic tumors (MC38 and CT26 murine colon carcinoma and A20 B-cell lymphoma were treated daily with HBI-8000 (orally), alone or in combination with PD-1, PD-1 L, or CTLA-4 antibodies. MC38 tumors were also analyzed in nanoString gene expression analysis. RESULTS: HBI-8000 augmented the activity of ICI antibodies targeting either PD-1, PD-L1 or CTLA-4, and significantly increased tumor regression (p < 0.05) in the above models. Gene expression analysis of the treated MC38 tumors revealed significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell and antigen-presenting cell functions, and modulation of MHC class I and II molecules. CONCLUSIONS: These findings suggest that HBI-8000 mediates epigenetic modifications in the tumor microenvironment, leading to improved efficacy of ICIs, and provide strong rationale for combination therapies with ICIs and HBI-8000 in the clinical setting. PRECIS: As an HDACi, HBI-8000 plays an important role in priming the immune system in the tumor microenvironment. The current preclinical data further justifies testing combination of HBI-8000 and ICIs in the clinic.

Evolving the narrative for protecting a rapidly changing ocean, post-COVID-19.

The ocean is the linchpin supporting life on Earth, but it is in declining health due to an increasing footprint of human use and climate change. Despite notable successes in helping to protect the ocean, the scale of actions is simply not now meeting the overriding scale and nature of the ocean's problems that confront us.Moving into a post-COVID-19 world, new policy decisions will need to be made. Some, especially those developed prior to the pandemic, will require changes to their trajectories; others will emerge as a response to this global event. Reconnecting with nature, and specifically with the ocean, will take more than good intent and wishful thinking. Words, and how we express our connection to the ocean, clearly matter now more than ever before.The evolution of the ocean narrative, aimed at preserving and expanding options and opportunities for future generations and a healthier planet, is articulated around six themes: (1) all life is dependent on the ocean; (2) by harming the ocean, we harm ourselves; (3) by protecting the ocean, we protect ourselves; (4) humans, the ocean, biodiversity, and climate are inextricably linked; (5) ocean and climate action must be undertaken together; and (6) reversing ocean change needs action now.This narrative adopts a 'One Health' approach to protecting the ocean, addressing the whole Earth ocean system for better and more equitable social, cultural, economic, and environmental outcomes at its core. Speaking with one voice through a narrative that captures the latest science, concerns, and linkages to humanity is a precondition to action, by elevating humankind's understanding of our relationship with 'planet Ocean' and why it needs to become a central theme to everyone's lives. We have only one ocean, we must protect it, now. There is no 'Ocean B'.

Citizens' juries give verdict on whether private practice veterinarians should attend unvaccinated Hendra virus suspect horses.

BACKGROUND: Hendra virus (HeV) is endemic in Australian flying foxes, posing a threat to equine and human health. Equine vaccination remains the most effective risk mitigation strategy. Many horses remain unvaccinated - even in higher-risk regions. Debate surrounding the vaccine's use is characterised by conflicting perspectives, misunderstanding and mistrust. Private veterinary practitioners are critical to early identification of public health risk through recognition, sampling and management of suspect-equine-HeV-cases. However, managing such cases can be burdensome, with some veterinarians opting not to attend unvaccinated horses or to abandon equine practice because of risk posed by HeV disease and liability. OBJECTIVE: Ascertain the perspectives of informed citizens on what obligations (if any) private veterinarians have to attend unvaccinated horses with HeV or HeV-like disease. METHODS: Three citizens' juries were tasked with considering approaches to managing HeV risk in Australia, including (reported here) roles and obligations of private veterinarians in responding to HeV-suspect-cases. RESULTS: Jurors acknowledged that HeV management posed an important challenge for private veterinarians. A clear majority (27 of 31 jurors) voted that veterinarians should not be obliged to attend unvaccinated horses. All recognised that greater support for veterinarians should be a priority. CONCLUSIONS: When informed of HeV risks and strategies for control and management, citizens appreciated the need to support veterinarians performing this critical 'One Health' role for public benefit. The current governance framework within which zoonotic disease recognition and response operates limits the contingency and scope for increasing support and efficacy of these important veterinary public health practices.

Colonial histories, racism and health-The experience of Maori and Indigenous peoples.

The health of Maori, the Indigenous peoples of Aotearoa, New Zealand, like that of almost all Indigenous peoples worldwide, is characterised by systematic inequities in health outcomes, differential exposure to the determinants of health, inequitable access to and through health and social systems, disproportionate marginalisation and inadequate representation in the health workforce. As health providers, we are often taught that 'taking a history' is a critical component of a patient consultation to ensure that the underlying conditions are treated rather than the often superficial presenting symptoms. In the same way, attempts to make sense of the health and well-being of Indigenous peoples is inadequate unless health providers engage critically with the history of their respective nations and any subsequent patterns of privilege or disadvantage. Understanding this history, within the framework of western imperialism and other similar colonial projects, allows us to make sense of international patterns of Indigenous health status. While health commentators acknowledge the unequal health outcomes of Indigenous people, and an increasing number also link these inequities to Indigenous marginalisation resulting from historic events, very few go further and expose the deep relationship between racism and coloniality and how these continue to be the basic determinants of Indigenous health today. This work includes honest examination of the role that science and the health disciplines have played historically in colonisation through the subjugation of Indigenous ways of knowing and knowledge production, as well as being complicit in the creation and maintenance of a fabricated hierarchy of humankind. Despite the 'science' of this racial hierarchy being discredited, it retains a false validity in our societies. As long as oppressive systems that continue to re-inscribe racism and white privilege remain in communities, including our academic communities, coloniality continues its discrimination. Indigenous voices on migration, ethnicity, racisma and health will always demand the elimination of inequities in health but to do so will require a parallel commitment to critically interrogating all of our histories and our disciplines, as well as examining how our practice, including research, disrupts or maintains global systems of racism and coloniality.

Indigenous data and health: critical approaches to 'race'/ethnicity and Indigenous data governance.

'Race'/ethnicity data have become increasingly institutionalised within research on Indigenous health. While these data are important to monitoring the differential distribution of health risks and benefits in racialised societies, their uncritical and undertheorised use can perpetuate harmful biologically deterministic and essentialist approaches to Indigenous health. In addition, narratives of Indigenous health are often still shaped by colonial logics, with Indigenous data rights, priorities and governance overlooked or ignored. Researchers need to critique the use of 'race'/ethnicity concepts and data in Indigenous health research. This requires an explicit shift away from describing 'race'/ethnicity as 'risk factors' to examining processes by which 'race'/ethnicity become meaningful in relation to health outcomes for Indigenous communities. In addition, researchers need to consider how Indigenous rights to health data are recognised, including the application of frameworks or principles of Indigenous data sovereignty.

Photochemical degradation of halogenated estrogens under natural solar irradiance.

Halogenated estrogens are thought to be moderately potent endocrine-disrupting compounds that are formed during chlorine-based wastewater disinfection processes and may represent a significant fraction of the total amount of estrogen delivered from wastewater treatment plants to receiving waters. Yet we lack key information about the photochemical degradation of halogenated estrogens, a process that has important implications for UV-based wastewater treatment and environmental fate modeling. To better understand halogenated estrogen degradation in aquatic environments, we studied the direct photolysis of 17ß-estradiol (E2), 2-bromo-17ß-estradiol (monoBrE2), 2,4-dibromo-17ß-estradiol (diBrE2), and 2,4-dichloro-17ß-estradiol (diClE2) as well as the indirect photolysis of diBrE2 under natural solar irradiance. We found that direct photolysis rate constants increased with halogenation as pKa values decreased and molar absorptivity spectra shifted toward higher wavelengths. Compared to E2, quantum yields were threefold larger for monoBrE2, but 15-32% smaller for the dihalogenated forms. The rate of diBrE2 (pKa ∼ 7.5) photolysis was strongly influenced by pH. At pH 7, diBrE2 degraded on minute time scales due to the large red-shifted molar absorptivity values and greater quantum yields of the phenolate form. Degradation rates were only slightly different in the presence of Suwannee River Humic Acid (5 mg L-1), and quenching experiments pointed to excited triplet state dissolved organic matter (3DOM*) as the dominant reactive intermediate responsible for the indirect photolysis of diBrE2. Overall, our data suggest that halogenated estrogens are particularly susceptible to photochemical degradation at environmentally relevant pH values.

Investigation of the effect of Equivac® HeV Hendra virus vaccination on Thoroughbred racing performance.

OBJECTIVE: To evaluate the effect of Equivac® HeV Hendra virus vaccine on Thoroughbred racing performance. DESIGN: Retrospective pre-post intervention study. METHODS: Thoroughbreds with at least one start at one of six major south-eastern Queensland race tracks between 1 July 2012 and 31 December 2016 and with starts in the 3-month periods before and after Hendra virus vaccinations were identified. Piecewise linear mixed models compared the trends in 'Timeform rating' and 'margin to winner' before and after initial Hendra virus vaccination. Generalised linear mixed models similarly compared the odds of 'winning', 'placing' (1st-3rd) and 'winning any prize money'. Timeform rating trends were also compared before and after the second and subsequent vaccinations. RESULTS: Analysis of data from 4208 race starts by 755 horses revealed no significant difference in performance in the 3 months before versus 3 months after initial Hendra vaccination for Timeform rating (P = 0.32), 'Margin to winner' (P = 0.45), prize money won (P = 0.25), wins (P = 0.64) or placings (P = 0.77). Further analysis for Timeform rating for 7844 race starts by 928 horses failed to identify any significant change in Timeform rating trends before versus after the second and subsequent vaccinations (P = 0.16) or any evidence of a cumulative effect for the number of vaccines received (P = 0.22). CONCLUSION: No evidence of an effect of Hendra virus vaccination on racing performance was found. The findings allow owners, trainers, industry regulators and animal health authorities to make informed decisions about vaccination.

Isolated mediastinal lymphadenopathy - performance of EBUS-TBNA in clinical practice.

Background Isolated mediastinal lymphadenopathy is an increasingly common finding as a result of the increasing use of cross-sectional thoracic imaging. We investigated the performance of endobronchial ultrasoundguided transbronchial needle-aspiration (EBUS-TBNA) in establishing a pathological diagnosis in patients with isolated mediastinal lymphadenopathy. Methods We retrospectively analysed all consecutive EBUS-TBNA examinations performed over a 4-year period at a single tertiary referral centre. Final diagnoses were made using pathology reports, correlated with clinical features and the results of any other investigations. Results In total, 126 EBUS-TBNA examinations were performed to investigate isolated mediastinal lymphadenopathy. A positive pathological diagnosis was made following EBUSTBNA in 54 cases (43%). When the results of further investigations and variable radiological follow up were included, the final sensitivity of EBUS-TBNA for making a diagnosis in isolated mediastinal lymphadenopathy was 80% (95% CI 69%-89%). Conclusions This study confirms that EBUS-TBNA has acceptable sensitivity for detecting both benign and malignant pathologies underlying isolated mediastinal lymphadenopathy.

Microstructural and Mechanical Properties of the Posterior Cruciate Ligament: A Comparison of the Anterolateral and Posteromedial Bundles.

BACKGROUND: The microstructural organization (collagen fiber alignment) of the posterior cruciate ligament (PCL), which likely corresponds with its functional properties, has only been described qualitatively in the literature, to our knowledge. The goal of this study was to quantify the tensile mechanical and microstructural properties of the PCL and compare these qualities between the anterolateral and posteromedial bundles. METHODS: Twenty-two knee specimens from 13 donors (8 male and 5 female; mean age [and standard deviation] at the time of death, 43.0 ± 4.1 years; mean body mass index, 30.0 ± 6.7 kg/m2) were dissected to isolate the PCL, and each bundle was split into 3 regions. Mechanical testing of each regional sample consisted of preconditioning followed by a ramp-and-hold stress-relaxation test and a quasi-static ramp-to-failure test. Microstructural analysis was performed with use of a high-resolution, division-of-focal-plane polarization camera to evaluate the average direction of collagen orientation and the degree to which the collagen fibers were aligned in that direction. Results were compared between the anterolateral and posteromedial bundles and across the regions of each bundle. RESULTS: The anterolateral and posteromedial bundles demonstrated largely equivalent mechanical and microstructural properties. Elastic moduli in the toe and linear regions were not different; however, the posteromedial bundle did show significantly more stress relaxation (p = 0.004). There were also few differences in microstructural properties between bundles, which again were seen only in stress relaxation. Comparing regions within each bundle, several mechanical and microstructural parameters showed significant relationships across the posteromedial bundle, following a gradient of decreasing strength and alignment from anterior to posterior. CONCLUSIONS: The PCL has relatively homogenous microstructural and mechanical properties, with few differences between the anterolateral and posteromedial bundles. This finding suggests that distinct functions of the PCL bundles result primarily from size and anatomical location rather than from differences in these properties. CLINICAL RELEVANCE: These properties of the PCL can be used to assess the utility of graft choices and operative techniques for PCL reconstruction and may partly explain limited differences in the outcomes of single-bundle compared with double-bundle reconstruction techniques for the PCL.

BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment.

Excess deaths from cardiovascular disease are a major contributor to the significant reduction in life expectancy experienced by people with schizophrenia. Important risk factors in this are smoking, alcohol misuse, excessive weight gain and diabetes. Weight gain also reinforces service users' negative views of themselves and is a factor in poor adherence with treatment. Monitoring of relevant physical health risk factors is frequently inadequate, as is provision of interventions to modify these. These guidelines review issues surrounding monitoring of physical health risk factors and make recommendations about an appropriate approach. Overweight and obesity, partly driven by antipsychotic drug treatment, are important factors contributing to the development of diabetes and cardiovascular disease in people with schizophrenia. There have been clinical trials of many interventions for people experiencing weight gain when taking antipsychotic medications but there is a lack of clear consensus regarding which may be appropriate in usual clinical practice. These guidelines review these trials and make recommendations regarding appropriate interventions. Interventions for smoking and alcohol misuse are reviewed, but more briefly as these are similar to those recommended for the general population. The management of impaired fasting glycaemia and impaired glucose tolerance ('pre-diabetes'), diabetes and other cardiovascular risks, such as dyslipidaemia, are also reviewed with respect to other currently available guidelines.These guidelines were compiled following a consensus meeting of experts involved in various aspects of these problems. They reviewed key areas of evidence and their clinical implications. Wider issues relating to primary care/secondary care interfaces are discussed but cannot be resolved within guidelines such as these.

Induction of apoptosis by HBI-8000 in adult T-cell leukemia/lymphoma is associated with activation of Bim and NLRP3.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell lymphotropic virus 1. Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti-chemokine (C-C motif) receptor 4 antibody, although most patients still have a poor prognosis and there is a clear need for additional options. HBI-8000 is a novel oral histone deacetylase inhibitor with proven efficacy for treatment of T-cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI-8000 on ATL-derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI-8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested Bim activation and, interestingly, the contribution of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome pathway in HBI-8000-induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI-8000-induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI-8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI-8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway.

Butanol production in S. cerevisiae via a synthetic ABE pathway is enhanced by specific metabolic engineering and butanol resistance.

BACKGROUND: The fermentation of sugars to alcohols by microbial systems underpins many biofuel initiatives. Short chain alcohols, like n-butanol, isobutanol and isopropanol, offer significant advantages over ethanol in terms of fuel attributes. However, production of ethanol from resistant Saccharomyces cerevisiae strains is significantly less complicated than for these alternative alcohols. RESULTS: In this study, we have transplanted an n-butanol synthesis pathway largely from Clostridial sp. to the genome of an S. cerevisiae strain. Production of n-butanol is only observed when additional genetic manipulations are made to restore any redox imbalance and to drive acetyl-CoA production. We have used this butanol production strain to address a key question regarding the sensitivity of cells to short chain alcohols. In the past, we have defined specific point mutations in the translation initiation factor eIF2B based upon phenotypic resistance/sensitivity to high concentrations of exogenously added n-butanol. Here, we show that even during endogenous butanol production, a butanol resistant strain generates more butanol than a butanol sensitive strain. CONCLUSION: These studies demonstrate that appreciable levels of n-butanol can be achieved in S. cerevisiae but that significant metabolic manipulation is required outside of the pathway converting acetyl-CoA to butanol. Furthermore, this work shows that the regulation of protein synthesis by short chain alcohols in yeast is a critical consideration if higher yields of these alcohols are to be attained.

Six cases of silicosis: implications for health surveillance of stonemasons.

BACKGROUND: Silicosis is one of the oldest occupational lung diseases, but it continues to cause significant morbidity and mortality worldwide. AIMS: To report cases of silicosis presenting to two specialist respiratory clinics. METHODS: A retrospective analysis of prospectively collected data of cases of silicosis in workers referred to specialist respiratory clinics. RESULTS: Over the course of 6 years, six cases were identified. The patients were all male with an age range between 24 and 39 years. The duration of silica exposure ranged between 7 and 20 years (mean 13 years). Four cases were entirely asymptomatic at presentation, and two cases described minimal shortness of breath on exertion. Pulmonary function tests were normal in three cases, and a mild restrictive ventilatory defect was documented in the other cases. All had a low apparent predicted probability of pneumoconiosis based on health questionnaires, spirometry and duration of silica exposure. The initial chest X-ray was abnormal in all six cases with radiological evidence of silicosis (International Labour Office profusion category ≥1/1) on imaging, and all had evidence of silicosis on high-resolution computed tomography (HRCT). Three patients had already progressed to progressive massive fibrosis on HRCT scanning at the time of referral to specialist respiratory services. CONCLUSIONS: The appearances of these six cases of silicosis in young, asymptomatic construction workers emphasizes the importance of enforcing effective exposure control and comprehensive surveillance programmes. Our observations highlight the importance of having a low threshold for early radiological screening to promote early and effective detection of this disease.