Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer.

BACKGROUND/OBJECTIVE: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. METHODS: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. RESULTS: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3ß, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3ß as a GSK3ß inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. CONCLUSION: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3ß.

Novel variant Hendra virus genotype 2 infection in a horse in the greater Newcastle region, New South Wales, Australia.

In October 2021, the first contemporary detection of Hendra virus genotype 2 (HeV-g2) was made by veterinary priority disease investigation in a horse near Newcastle, New South Wales, Australia, as part of routine veterinary priority disease surveillance. This discovery followed an update of Hendra virus diagnostic assays following retrospective identification of this variant from 2015 via sentinel emerging infectious disease research, enabling timely detection of this case. The sole infected horse was euthanized in moribund condition. As the southernmost recognised HeV spill-over detection to date, it extends the southern limit of known cases by approximately 95 km. The event occurred near a large urban centre, characterised by equine populations of diverse type, husbandry, and purpose, with low HeV vaccination rates. Urgent multi-agency outbreak response involved risk assessment and monitoring of 11 exposed people and biosecurity management of at-risk animals. No human or additional animal cases were recognised. This One Health investigation highlights need for research on risk perception and strategic engagement to support owners confronted with the death of companion animals and potential human exposure to a high consequence virus. The location and timing of this spill-over event diverging from that established for prototype HeV (HeV-g1), highlight benefit in proactive One Health surveillance and research activities that improve understanding of dynamic transmission and spill-over risks of both HeV genotypic lineages and related but divergent emerging pathogens.

Contributions of village animal health workers to foot-and-mouth disease control in Cambodia.

Local animal health services in rural communities in Cambodia are mainly provided by village animal health workers (VAHWs), although the participation and contribution of VAHWs to livestock disease prevention are uncertain. The participation of the VAHWs as identified by their 'dropout rate' was examined in a desktop review in December 2020 of the national data on VAHWs recorded between 2011 and 2020. The contribution and involvement of VAHWs in disease prevention programmes were examined in a survey conducted between February and March 2014, then analyzed in the context of other surveys of VAHW knowledge, attitudes and practices. The survey involved guided group discussion with VAHWs (n = 198) from the two Cambodian provinces of Kampong Cham and Pursat. This study identified that VAHWs generated less than 22% of their annual household incomes from animal health services. Less than one-third had vaccinated livestock against foot-and-mouth disease (FMD), with none having vaccinated cattle every 6 months during the study period, and nearly half of the VAHWs having never vaccinated their own cattle against FMD. As no privately provided FMD vaccination services occurred in these communities, with all vaccines delivered through the government-subsidized programme, the findings confirmed that VAHWs only vaccinated animals against FMD when vaccines were made available by the Government. The desktop review found that the number of VAHWs in 2020 declined by more than 24% since 2017, and the proportion of female VAHWs was consistently low, with a mean of 8.26 (±1.019). These findings confirm findings from previous studies that identified considerable weaknesses in the VAHW system in Cambodia, particularly in contributing to FMD control. Cambodian animal health authorities require more effective policies to strengthen the current VAHW system, improving their services delivery; their retention as 'active'; their development of more sustainable roles with lower 'dropout' rates and the prolonged gender inequity. With the limited availability of government-subsidized FMD vaccination currently, extension programmes that engage VAHWs and farmers in seeking privately funded and delivered FMD vaccination that incorporates appropriate multivalent FMD serotype vaccines of high quality, delivered in small dose vials from a robust cold chain, is suggested. This strategy would assist VAHWs to contribute to the provision of private livestock vaccination services that are likely essential for sustainable FMD prevention and control in Cambodia.

Influenza-associated myositis: a single-centre, 5-year retrospective study.

We aimed to describe the clinical epidemiology of influenza-associated myositis (IAM) over a 5-year period. We identified ICD-10-coded myositis cases retrospectively 2011-2015 and performed limited chart reviews. We excluded myositis with non-viral causes and cross-referenced with laboratory records of influenza tests to identify confirmed IAM. We defined probable IAM as viral myositis occurring during the influenza season without alternative cause. We described epidemiological and clinical features of IAM and compared IAM with all hospitalised influenza. We identified 283 cases of viral myositis with seasonal peaks (May to October, 85% of cases); 69 were tested for influenza, 52 (78%) were positive. Given the strong seasonality concurrent with the influenza season, we estimated that 80% (95% CI 76-85) of viral myositis is attributable to IAM annually. Of 226 cases of IAM, 21% (n = 49) were confirmed and the remaining probable. IAM was associated with being male (82%), aged 5-9 (73%), and influenza B (86%). The majority had bilateral calf pain; mean creatinine kinase (CK) value was 3579 U/L, and no cases had renal impairment.Conclusion: Childhood viral myositis shows strong association with the influenza season. IAM is clinically stereotyped, age restricted, and benign in most and strongly associated with influenza B. What is Known: • Childhood viral myositis has been reported in association with influenza for decades, more frequently with influenza B and in school-aged children. What is New: • Here, we show over a 5-year period that viral myositis is strongly seasonal with up to 80% of cases attributable to influenza. • Influenza-associated myositis (IAM) typically occurs in boys, aged 5-9 years, with influenza B and is most often benign. Early clinical recognition may avoid unnecessary treatment and testing.

Acute toxicity testing of TiO2-based vs. oxybenzone-based sunscreens on clownfish (Amphiprion ocellaris).

Given the prevalence of skin cancer, sunscreens are recommended by dermatologists including the American Academy of Dermatology to protect skin from harmful ultraviolet rays. Unfortunately, this leads to an estimated 14,000 tons of sunscreen entering waterways each year. Many of the chemicals in sunscreens, such as oxybenzone and benzophenone-2, are indicated to have adverse effects on corals and other aquatic life. As an eco-conscious alternative, physical barrier sunscreens, such as non-nano-titanium dioxide (TiO2), have been suggested as a replacement. This study examines the impact of a non-nano-TiO2-based sunscreen over a nationally sold brand of sunscreen containing oxybenzone, on clownfish (Amphiprion ocellaris). Animals were evaluated for mortality, swimming behavior, and feeding behavior. Our data indicate that at an exposure level of 100 mg/L oxybenzone-containing sunscreen had a negative impact on mortality, leading to 25% death by the end of the 97-h testing period. Negative impacts on behavior were even more dramatic for the 100 mg/L oxybenzone-containing sunscreen, with 100% of the animals failing to feed over the first 49 h of testing and 100% of animals demonstrating abnormal swimming behavior over the entire testing period. By comparison, the non-nano-(TiO2) sunscreen at 100 mg/L had little (6.7%) negative impact on mortality and feeding. While swimming behavior was disrupted during the first 25 h of testing (26.7% abnormal movement), animals recovered well over the remainder of the testing period (out to 97 h).

Masking a fish's detection of environmental stimuli: application to improving downstream migration at river infrastructure.

According to Signal Detection Theory, the ability to detect a stimulus (discriminability, d') is inversely related to the magnitude of internal and external noise. In this study, downstream moving brown trout Salmo trutta were used to investigate whether external hydrodynamic noise (in this case turbulence) could mask a signal that induced an unwanted response, such as rejecting accelerating velocity gradients commonly encountered at entrances to fish bypass channels. S. trutta behaviour was quantified in the absence (control) or presence of an accelerating velocity gradient created by an unconstricted or constricted channel, respectively, under two levels (low and high) of background turbulent kinetic energy (hydrodynamic noise). Experiments were conducted in an indoor recirculating flume in the dark and a range of passage metrics were quantified. Under the control condition, most (ca. 91%) S. trutta passed, usually oriented downstream (67%), with minimal delay (median 0.13 min). In comparison, fewer S. trutta (ca. 43%) passed under constricted conditions, they tended to orient facing into the flow (ca. 64%) and delay was greater (median > 20 min). When viewed from a coarse-scale perspective, discriminability of the velocity gradient was lower when turbulence was high suggesting masking of the signal occurred. However, the resulting increase in the percentage of fish that passed, decrease in time to pass and reduction in the distance at which S. trutta reacted (switched orientation) was subtle and non-significant. Despite the mixed results obtained, the use of masking to manipulate an animal's perception of environmental stimuli as a fisheries management tool is conceptually valid and the results of this experiment present a useful stepping stone for future research.

Effect of vaccine storage temperatures and dose rate on antibody responses to foot and mouth disease vaccination in Cambodia.

A field study investigated the effects of foot and mouth disease vaccine storage temperature for 7 days (frozen, refrigerated or held at ambient temperature) and dose (half or full dose) on the serological response to vaccination. It utilised a complete factorial design replicated on 18 smallholder cattle farms in three villages in Pursat province, Cambodia. Antibody responses from the 108 cattle involved were assessed by serological examination of blood samples collected at primary vaccination (day 0), at booster vaccination (day 30) and finally at 60 days post primary vaccination. Vaccination responses to the inactivated vaccine were assessed by testing for antibodies directed against FMD structural proteins in a liquid-phase blocking ELISA (LPBE test) and differentiated from responses to natural infection by examining antibody titres against non-structural viral proteins (NSPE test). LPBE results indicated that the mean log10 LPBE antibody titres of all experimental cattle increased from below protective levels at day 0 to protective levels at 30 days post primary vaccination, and increased further at 60 days post primary vaccination. Storage at ambient temperature for 1 week had no effect on antibody response to vaccination. However, freezing the vaccine for a week or use of a half dose resulted in significant reduction in titres at day 60 (P = 0.04 and P = 0.02, respectively). The results of this study reinforce the need to store FMD vaccines within the range recommended by the manufacturers and to adhere to the specified dosage instructions.

PARTICLE triplexes cluster in the tumor suppressor WWOX and may extend throughout the human genome.

The long non-coding RNA PARTICLE (Gene PARTICL- 'Promoter of MAT2A-Antisense RadiaTion Induced Circulating LncRNA) partakes in triple helix (triplex) formation, is transiently elevated following low dose irradiation and regulates transcription of its neighbouring gene - Methionine adenosyltransferase 2A. It now emerges that PARTICLE triplex sites are predicted in many different genes across all human chromosomes. In silico analysis identified additional regions for PARTICLE triplexes at >1600 genomic locations. Multiple PARTICLE triplexes are clustered predominantly within the human and mouse tumor suppressor WW Domain Containing Oxidoreductase (WWOX) gene. Surface plasmon resonance diffraction and electrophoretic mobility shift assays were consistent with PARTICLE triplex formation within human WWOX with high resolution imaging demonstrating its enrichment at this locus on chromosome 16. PARTICLE knockdown and over-expression resulted in inverse changes in WWOX transcripts levels with siRNA interference eliminating PARTICLEs elevated transcription to irradiation. The evidence for a second functional site of PARTICLE triplex formation at WWOX suggests that PARTICLE may form triplex-mediated interactions at multiple positions in the human genome including remote loci. These findings provide a mechanistic explanation for the ability of lncRNAs to regulate the expression of numerous genes distributed across the genome.

Choice of analysis pathway dramatically affects statistical outcomes in breaking continuous flash suppression.

Breaking Continuous Flash Suppression (bCFS) has been adopted as an appealing means to study human visual awareness, but the literature is beclouded by inconsistent and contradictory results. Although previous reviews have focused chiefly on design pitfalls and instances of false reasoning, we show in this study that the choice of analysis pathway can have severe effects on the statistical output when applied to bCFS data. Using a representative dataset designed to address a specific controversy in the realm of language processing under bCFS, namely whether psycholinguistic variables affect access to awareness, we present a range of analysis methods based on real instances in the published literature, and indicate how each approach affects the perceived outcome. We provide a summary of published bCFS studies indicating the use of data transformation and trimming, and highlight that more compelling analysis methods are sparsely used in this field. We discuss potential interpretations based on both classical and more complex analyses, to highlight how these differ. We conclude that an adherence to openly available data and analysis pathways could provide a great benefit to this field, so that conclusions can be tested against multiple analyses as standard practices are updated.

Assessing hydrodynamic space use of brown trout, Salmo trutta, in a complex flow environment: a return to first principles.

It is commonly assumed that stream-dwelling fish should select positions where they can reduce energetic costs relative to benefits gained and enhance fitness. However, the selection of appropriate hydrodynamic metrics that predict space use is the subject of recent debate and a cause of controversy. This is for three reasons: (1) flow characteristics are often oversimplified, (2) confounding variables are not always controlled and (3) there is limited understanding of the explanatory mechanisms that underpin the biophysical interactions between fish and their hydrodynamic environment. This study investigated the space use of brown trout, Salmo trutta, in a complex hydrodynamic flow field created using an array of different sized vertically oriented cylinders in a large open-channel flume in which confounding variables were controlled. A hydrodynamic drag function (D) based on single-point time-averaged velocity statistics that incorporates the influence of turbulent fluctuations was used to infer the energetic cost of steady swimming. Novel hydrodynamic preference curves were developed and used to assess the appropriateness of D as a descriptor of space use compared with other commonly used metrics. Zones in which performance-enhancing swimming behaviours (e.g. Kármán gaiting, entraining and bow riding) that enable fish to hold position while reducing energetic costs (termed 'specialised behaviours') were identified and occupancy was recorded. We demonstrate that energy conservation strategies play a key role in space use in an energetically taxing environment with the majority of trout groups choosing to frequently occupy areas in which specialised behaviours may be adopted or by selecting low-drag regions.

Blunt diaphragmatic rupture--a rare injury in blunt thoracoabdominal trauma.

INTRODUCTION: Blunt traumatic rupture of the diaphragm is rare. DISCUSSION: We provide a case report of rupture of the diaphragm with visceral herniation in blunt thoracoabdominal trauma.

The UV index: definition, distribution and factors affecting it.

The UV Index was introduced in Canada in 1992 in response to growing concerns about the potential increase of ultraviolet (UV) radiation due to ozone depletion. The index was adopted as a standard indicator of UV levels by the World Meteorological Organization and World Health Organization in 1994. This survey article gives an overview of the UV Index and the main features of its geographical distribution. UV index values are determined from measurements made by ground-based spectrometers, broad-band filter radiometers and multi-filter radiometers. Radiative transfer models are used to estimate UV Index values from other types of geophysical observations, primarily column ozone and cloud thickness. UV Index values can also be retrieved from satellite measurements of atmospheric ozone and cloud cover. Forecasts of UV Index values are now widely available and are intended to be used by the public as a guide to avoid excessive exposure to UV radiation. Over the US and Canada, mean noontime UV Index values in summer range from 1.5 in the Arctic to 11.5 over southern Texas and can be as high as 20 at high elevations in Hawaii. The UV Index is also often used to quantify UV levels in studies investigating the impact of UV on other biological and photochemical processes. Factors affecting the UV Index, such as the sun elevation, total amount of ozone in the atmosphere, cloud cover, reflection from snow and local pollution, are also discussed. Since its introduction in 1992, the UV Index has become a widely used parameter to characterize solar UV. Information about it can be useful for helping people avoid excessive levels of UV radiation.

Prevalence of gastric ulcers in endurance horses--a preliminary report.

Gastric endoscopy was performed at the end of a 50 or 80 km endurance ride. Gastric ulceration was evident in 67% of the horses with ulcers on the squamous region of the stomach found in 57% of the horses and active bleeding of the glandular mucosa in 27%. Three horses (10%) had lesions only on the glandular mucosa. Values of albumin, creatinine and glucose were higher in horses without gastric lesions. We conclude that horses from endurance competitions have a high prevalence of gastric ulceration that is similar to that observed in performance horses. However the severity of ulceration is less severe than has been reported in Thoroughbred race horses in active training. Owners should be aware of the high prevalence of gastric ulceration in horses that perform in endurance competitions. The high incidence of active bleeding from the glandular mucosa of the stomach in these horses requires further investigation.

The 1994 North American Interagency Intercomparison of Ultraviolet Monitoring Spectroradiometers.

Concern over stratospheric ozone depletion has prompted several government agencies in North America to establish networks of spectroradiometers for monitoring solar ultraviolet irradiance at the surface of the Earth. To assess the ability of spectroradiometers to accurately measure solar ultraviolet irradiance, and to compare the results between instruments of different monitoring networks, the first North American Intercomparison of Ultraviolet Monitoring Spectroradiometers was held September 19-29, 1994 at Table Mountain outside Boulder, Colorado, USA. This Intercomparison was coordinated by the National Institute of Standards and Technology and the National Oceanic and Atmospheric Administration (NOAA). Participating agencies were the Environmental Protection Agency, National Science Foundation, Smithsonian Environmental Research Center, and Atmospheric Environment Service, Canada. Instruments were characterized for wavelength accuracy, bandwidth, stray-light rejection, and spectral irradiance responsivity, the latter with a NIST standard lamp calibrated to operate in the horizontal position. The spectral irradiance responsivity was determined once indoors and twice outdoors, and demonstrated that, while the responsivities changed upon moving the instruments, they were relatively stable when the instruments remained outdoors. Synchronized spectral scans of the solar irradiance were performed over several days. Using the spectral irradiance responsivities determined with the NIST standard lamp, and a simple convolution technique to account for the different bandwidths of the instruments, the measured solar irradiances agreed within 5 %.

Mount St. Helen scientific worshop : Proceedings

The deliberations of a special workshop on the science and technology associated with the 1980 Mount St. Helens eruptions are reported, including recommendations for action programs. The origins and operations of the Federal Emergency Management Agency (FEMA) technical and scientific effort associated with the Mount St. Helens disaster field program are described. Selected documents, other references, and a bibliography are included. (AU)