Duchenne muscular dystrophy (DMD) is a debilitating and fatal genetic disease affecting 1/3500 boys globally, characterized by progressive muscle breakdown and eventual death with an average lifespan in the mid-late twenties. While no cure yet exists for DMD, gene and antisense therapies have been heavily explored in recent years to better treat this disease. Four antisense therapies have received conditional FDA approval, and many more exist in varying stages of clinical trials. These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease within the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development, and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.

The objective of the present work is to investigate the performance of flat-plate solar panels in Greece that continuously follow the daily motion of the Sun. To that end, the annual energy sums are estimated on such surfaces from hourly solar horizontal radiation values at 43 locations covering all of Greece. The solar horizontal radiation values are embedded in the typical meteorological years of the sites obtained from the PV-GIS tool. All calculations use a near-real surface albedo; an isotropic and an anisotropic model are used to estimate the diffuse-inclined radiation. The analysis provides regression equations for the energy sums as a function of time (month, season). The annual energy sums are found to vary between 2247 kWhm−2 and 2878 kWhm−2 under all-sky conditions with the anisotropic transposition model. Finally, maps of Greece showing the distribution of the annual and seasonal solar energy sums under all- and clear-sky conditions are derived for the first time.

This paper draws an earlier book (with Evans and Higgins) entitled Bad Call: Technology’s Attack on Referees and Umpires and How to Fix It (hereafter Bad Call) and its various precursor papers. These show why it is that current match officiating aids are unable to provide the kind of accuracy that is often claimed for them and that sports aficianados have been led to expect from them. Accuracy is improving all the time but the notion of perfect accuracy is a myth because, for example, lines drawn on sports fields and the edges of balls are not perfectly defined. The devices meant to report the exact position of a ball – for instance ‘in’ or ‘out’ at tennis – work with the mathematically perfect world of virtual reality, not the actuality of an imperfect physical world. Even if ball-trackers could overcome the sort of inaccuracies related to fast ball speeds and slow camera frame-rates the goal of complete accuracy will always be beyond reach. Here it is suggested that the purpose of technological aids to umpires and referees be looked at in a new way that takes the viewers into account.

Delivering nucleic acid therapeutics across cell membranes is a significant challenge. Cell-penetrating peptides (CPPs) containing arginine (R), tryptophan (W), and histidine (H) show promise for siRNA delivery. To improve siRNA delivery and silencing a model STAT3 gene, we hypothesized that oleyl acylation to CPPs, specifically (WRH)n, would enhance STAT3 silencing efficiency in breast and ovarian cancer cells. Using Fmoc/tBu solid-phase peptide chemistry, we synthesized, purified, and characterized the oleyl-conjugated (WRH)n (n = 1-4) peptides. The peptide:siRNA complexes were non-cytotoxic at N/P 40 (~20 μM) against MDA-MB-231, MCF-7, SK-OV-3, and HEK-293 cells after 72 h incubation. All peptide:siRNA complexes showed serum stability at N/P ≥40. The synthesized conjugates, with a diameter of <100 nm, formed nano complexes with siRNA and exhibited stable range of zeta potential values (13-18 mV at N/P 40). Confocal microscopy and flow cytometry analysis provided qualitative and quantitative evidence of successful cellular internalization of siRNA. Peptides oleyl-(WRH)3 and oleyl-(WRH)4 showed ~60% and ~75% cellular uptake of siRNA, respectively, in both MDA-MB-231 and SK-OV-3 cells. Western blot analysis of oleyl-(WRH)4 demonstrated effective silencing of the STAT-3 gene, with ~75% silencing in MDA-MB-231 cells and ~45% in SK-OV-3 cells.

This work investigates the influence of ground albedo on the solar radiation obtained by surfaces mounted on fixed-tilt to south, one-axis, and two-axis systems. To do this, estimation of the solar radiation difference is performed by applying real albedo and zero albedo. This is done within Saudi Arabia, at 82 selected sites. Annual, seasonal, and monthly mean solar energy differences are computed as function of the site’s number, latitude, and local near-real ground albedo. The great variation in the ground-albedo values at the 82 sites (0.1 - 0.46) could be thought as having a significant effect on the solar radiation levels received on the 3 tracking modes. The analysis shows quite the opposite; a zero-albedo ground diminishes solar radiation levels by 1.43%, 3.50%, and 3.20%, respectively for the 3 modes. Therefore, in most solar engineering applications a ground albedo of 0.2 (considered as reference) can be used without losing accuracy. This is the main conclusion of the study, which must, however, be applied with caution in areas with snow cover, especially for mode-III tracking systems. In such situations the increase in solar radiation levels may be up to 15% (but ≈3.5% for mode-I and -II systems instead).

Urbanization and climate change have increased the need for stormwater management and nature-based solutions. Decisions made at project level impact the emergence of systemic traits of the stormwater network and the functionality of the catchment areas in urban planning. To that end, it is vital to introduce the decision-making tools for analyzing both the utilities and amenities of nature-based solutions (NBS) to increase their adoption to reduce the peak loads in the stormwater system, and to that end, mitigate the impacts of climate change. This paper demonstrates a workflow using drone-based photogrammetry, 3D modeling, and simulation software to generate visual and functional models assisting in informed decision-making in the design of stormwater systems as functional landscape architecture. Using aerial data from drones and modeled design solutions, the proposed workflow simulates rain events, infiltration, evaporation, water flow, and accumulation of stormwater in a way that allows the visual and quantified analysis of detailed landscape architecture designs. The paper provides an example of a rooftop site simulation demonstrating the infiltration and flow of water to the drainage. The visual decision-making method provided can aid in investment decisions for functional landscape design in support of stormwater management.

Knowledge of a lasers beam’s profile throughout a laser system and experiment can help immensely in diagnosing laser problems and assisting in beam alignment and focusing at a sample. Obtaining such profiles is a trivial task in the ultraviolet-visible wavelength range but more challenging with near-infrared to infrared beams. Scientific grade bolometer arrays, suitable for such a task, do exist but are extremely costly, relatively large and have a large pixel size, of the order of 80 μm, which is adequate for profiling larger beams but poses an issue when trying to profile sub 100 μm beams for example at a focal point. This communication identifies a micro-bolometer array for near- to mid-infrared laser beam profiling, which is extremely low cost. In addition, the device is very compact, enabling use in confined spaces, and has a small, 12 μm, pixel size permitting the profiling of focused laser beams. The best scientific grade device identified has a pixel size of 17 μm. This device is a powerful tool for infrared laser spectroscopists, reducing the time required to measure the spot size of beams and to achieve spatial overlap of multiple infrared beams as used in two-dimensional infrared spectroscopy, saving many hours of setup time. The use of the bolometer array as a spectrographic detector and probe of long-term beam drifts is also demonstrated.

High-performance insulation and airtight building envelopes are the two most important factors to optimize the building energy efficiency and thermal performance. However, thermal performance of building envelopes can be significantly affected by thermal bridging. Thermal bridges can take place at different locations of the building envelope, causing added transmission losses, increasing heat flow, lower inner surface temperatures. Thermal bridges are regarded in all national regulations for new buildings of all states of European Union (EU) but there are no specifications assessing balconies to wall junctions and the impact on the building thermal performance is not well regulated. In this paper, balcony to wall thermal bridge assessment using infrared thermography is highlighted. The originality is that, infrared thermography, has been applied to a real living latest building in the north east of France showing that there is noncompliance in the national regulations as some exigencies are not met. Thermography of thermal break windows and window doors has also revealed air leakage. The goal, is to illustrate that thermal imaging is a means of quality assurance to new building specifications and should include a clause specifying quality assurance procedure for balconies junction in national building regulations for all states if the EU.

Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.

Considering the health benefits of the kombucha, already widely studied, the objective of the study was to development of the beverage with the addition of infusion of special arabica coffee from the first fermentation varying the proportion of special coffee (2% a 13%) and evaluate the pH, volatile acidity, degree of alcohol, centesimal composition, sodium contents, colour parameters as like acceptability of the beverages. With respect to the pH, all the formulations conformed with the kombucha identity standard, but K3 and K4 were below the established minimum for volatile acidity. Except for K4, all the other formulations were classified as alcoholic kombuchas, although the values were very close to the limit for non-alcoholic. The formulations presented low sugar and sodium content, which corroborated the low caloric value. Therefore, coffee-flavored kombucha fermented for 18 days becomes an option for consumers looking for low-calorie, refreshing and healthy drinks. The luminosity of the beverages decreased as the proportion of coffee increased, and consequently the values for a* and b* increased, indicating a strong tendency for a yellowish red colour. Sensorially, the formulations K4 and K3 were the most well accepted in all respects and can therefore be considered formulations with high commercialization potential.

Colon cancer (CRC) is a prevalent malignancy that exhibits distinct differences in incidence, prognosis, and treatment responses between males and females. These disparities have long been attributed to hormonal differences, particularly the influence of estrogen signaling. This review aims to provide a comprehensive analysis of recent advances in our understanding of the molecular mechanisms underlying sex differences in colon cancer and the protective role of membrane and nuclear estrogen signaling in CRC development, progression, and therapeutic interventions. We discuss the epidemiological and molecular evidence supporting sex differences in colon cancer, followed by an exploration of the impact of estrogen in CRC through various genomic and non-genomic signaling pathways involving membrane and nuclear estrogen receptors. Furthermore, we examine the interplay between estrogen receptors and other signaling pathways, in particular the Wnt/-catenin proliferative pathway and hypoxia in shaping biological sex differences and estrogen protective actions in colon cancer. Lastly, we highlight the potential therapeutic implications of targeting estrogen signaling in the management of colon cancer and propose future research directions to address the current gaps in our understanding of this complex phenomenon.

This paper explores the views of a group of young men aged 16–18, studying towards a Level 1 diploma in music in the North East area of England. It uses the conceptualization of “social haunting” to focus our discussions about how Level 1 learners articulated their experiences in the context of their learning journeys and perceived marginalization. The research took place at a large Further Education (FE) college and included a series of five “research encounters” with the group of Level 1 learners. These encounters included a range of activities, resulting in a variety of data being collected, including several activity worksheets, structured and unstructured focus group interviews, and questionnaires. This paper focusses on the outcomes of a single research activity that focused on exploring the topic of marginalization. We present a discussion on social haunting as one of the emerging findings from this research encounter, outlining how the reality of the social and cultural legacy of the UK’s industrial past can shape today’s youth and their futures. We will talk about the young men’s views of marginalization, their school-to-work transitions, the formation of masculinity in post-industrial communities and the role of Further Education in it. The paper concludes by discussing some insights for practice and future research.

We investigated preschool-aged children’s understanding of early fractional tasks and how that performance correlates with fine motor skills and use of gestures while counting. Participants were 33 preschoolers aged 4 to 5 in two Southeastern public elementary schools. Children were tested individually in an interview-like setting. Mathematics tasks were presented in a paper and pencil format and the Grooved Pegboard test assessed fine motor skills. Finally, utilization of gestures was evaluated by taking a behavioral rating of the child’s hand morphology, accuracy of gestures, and synchrony of gestures and spoken word while performing a counting task. Results indicate performance on fractional reasoning tasks significantly predicts both fine motor ability and accuracy of gestures.

The issue of when and how to return to business following COVID-19 lockdown is occupying the minds of policymakers, C-Suite executives and managers the world over. We are concerned by the extent to which it appears that these decisions are being taken on a wing and a prayer, while being pitched to the public as though they shouldn’t be questioned. In this paper, we compare the likely impact of COVID-19 infections from travellers coming from the main countries that visit Greece, to the revenues they generate for the Greek economy. We find that arrivals from some countries should be excluded but aren't, while arrivals from other countries that are excluded perhaps shouldn't be. We show that a rational choice around limitations on the reopening of tourist markets depends on the demand for travel to Greece. We conclude that the current policy is largely economically rational, with some exceptions, but also speculate that Greece may not be ready to handle the resulting infection load.

We examine the mass balance of the glaciers in the Novaya Zemlya Archipelago, located in the Russian High Arctic using time series of time-variable gravity from the NASA/DLR Gravity Recovery and Climate Experiment (GRACE) mission, laser altimetry data from the NASA Ice Cloud and land Elevation Satellite (ICESat) mission, and radar altimetry data from the ESA CryoSat-2 mission. We present a new algorithm for detecting changes in glacier elevation from these satellite altimetry data and evaluate its performance in the case Novaya Zemlya by comparing the results with GRACE. We find that the mass loss of Novaya Zemlya increased from 10±5 Gt/yr over 2003-2009 to 14±4 Gt/yr over 2010-2016, with a brief period of near mass balance between 2009 and 2011. The results are consistent across the gravimetric and altimetric methods. Furthermore, the analysis of elevation change from CryoSat-2 indicates that 60\% of the mass loss occurs at low elevation, where thinning rates are highest. We also find that marine-terminating glaciers in Novaya Zemlya are thinning significantly faster than land-terminating glaciers, which indicates an important role of ice dynamics of marine-terminating glaciers. We posit that the glacier changes have been caused by changes in atmospheric and ocean temperatures. We find that the increase in mass loss after 2010 is associated with a warming in air temperatures, which increased the surface melt rates. There is no enough information on the ocean temperature at the front of the glaciers to conclude on the role of the ocean, but we posit that the temperature of subsurface ocean waters must have increased during the observation period.

We point out an inconsistency in Newton's equations of celestial mechanics. A set of differential equations implied by Newton's equations are shown to be free of this inconsistency. We then investigate the integrals of motion associated with this relative difference system.

Abstract: The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRa and GRb), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e. GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have lower expression of GRb, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. Increased expression of GRb can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. Endogenous expression of GRb in the TM may relate to differences in the development of GC-OHT among the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease modifying therapies to better treat these two sight threatening forms of glaucoma.

Relativistic atomic and molecular structure calculations start from very different premises to quantum electrodynamics (QED). QED predicts radiative corrections that can nly be approximated crudely in today's atomic structure programs. This paper describes rigorous simple algorithms for including accurate vacuum polarization and self-energy corrections in the GRASP programs.

Despite the Hebrides and Cleveland basins being geographically close, research has not previously been carried out to determine faunal similarities and assess the possibility of links between the dinosaur populations. The palaeogeography of both areas during the Middle Jurassic shows that there were no elevated landmasses being eroded to produce conglomeratic material in the basins at that time. The low-lying landscape and connected shorelines may have provided connectivity between the two dinosaur populations. The dinosaur fauna of the Hebrides and Cleveland basins has been assessed based primarily on the abundant ichnites found in both areas as well as their skeletal remains. In the two basins the dinosaur faunas are very similar, consisting of non-neosauropod eusauropods, a possible basal titanosauriform, large and small theropods and ornithopods and europodan thyreophorans. The main difference in the faunas is in the sizes. In the Cleveland Basin the ichnites suggest that there were medium and large theropods alongside small to medium sized ornithopods whereas in the Hebrides Basin the theropods were from small to large and the ornithopods were medium to large. It is suggested that migrations could have taken place between the two areas during the Middle Jurassic. A tentative food chain from the herbivorous dinosaurs to the top predators can be inferred from the footprints.

sustainability reporting, critical paradigm, upstream oil, and gasThe operating activities of the upstream oil and gas industry directly impact the environment. This industry faces significant social challenges and directly impacts the environment. Many Reputable international sustainability institutions organize sustainability awards. However, community conditions do not have a positive impact on sustainability practices. There are vari-ous serious violations related to sustainability, environmental pollution, multiple cases of cor-ruption, human rights, and other violations. In contrast, the companies receiving this award also received inspection findings of violations committed by The Audit Board of the Republic of In-donesia. This study uses critical discourse analysis that begins with phenomena related to viola-tions of sustainability reporting from scientific journals and other references using a systematic literature review approach over the last ten years. It produces a critical paradigm that is not val-ue-free, which is the basis for framing thought utilizing the theory of hegemony. The results of this study indicate that the upstream oil and gas industries are obliged to implement Corporate Social Responsibility (CSR) practices and Sustainability Reports (SR), has biased factors that are contrary to the sustainability concept and are not under the sustainability award based on evi-dence obtained from the stages of manuscript analysis with systematic literature review

In the global fight against malaria, standard vector control methods such as indoor residual spraying (IRS) and insecticide-treated nets (ITNs) are intended to protect inside residential structures and sleeping spaces. However, these methods can still leave individuals vulnerable to residual transmission from vectors that they may be exposed to outdoors. Nchelenge District in northern Zambia experiences high persistent malaria transmission even with ITNs and IRS in place. However, very few studies have examined outdoor vector activity. To assess diversity and abundance of outdoor foraging female anopheline mosquitoes, CDC light traps were used as proxy measures for mosquito host-seeking, set in three outdoor trapping schemes randomly assigned on different nights: 1) locations where people congregate at night outside of the house within the peri-domestic space, 2) animal pens or shelters, and 3) high human-trafficked areas, such as paths to latrines, where traps were baited with BG-Lure®. 1,087 total female anophelines were collected over a total of 74 trap nights. Anopheles funestus s.s. comprised the majority of the collection (86%), with An. gambiae s.s. (2%) and a highly diverse sampling of other anophelines (12%) making up the remainder. Plasmodium falciparum parasites were only detected in An. funestus (1%). No significant difference in species diversity or female anopheline abundance was detected between trapping schemes. Outdoor foraging anopheline mosquitoes, including a number of infectious An. funestus, may partially explain the difficulty of controlling malaria transmission in Nchelenge District where vector control is only targeted indoors. BG-Lure® shows some promise as an alternative to human-baited landing catch collections in this resource-poor setting.

Here we investigate how the local properties of particles in a thermal bath may influence the thermodynamics of the bath, and consequently alter the statistical mechanics of subsystems that comprise the bath. We are guided by the theory of small-system thermodynamics, which is based on two primary postulates: that small systems can be treated self-consistently by coupling them to an ensemble of similarly small systems, and that a large ensemble of small systems forms its own thermodynamic bath. We adapt this “nanothermodynamics” to investigate how a large system may subdivide into an ensemble of smaller subsystems, causing internal heterogeneity across multiple size scales. For the semi-classical ideal gas, maximum entropy favors subdividing a large system of “atoms” into an ensemble of “regions” of variable size. The mechanism of region formation could come from quantum exchange symmetry that makes atoms in each region indistinguishable, while decoherence between regions allows atoms in separate regions to be distinguishable by their distinct locations. Combining regions reduces the total entropy, as expected when distinguishable particles become indistinguishable, and as required by a theorem in quantum mechanics for sub-additive entropy. Combining large volumes of small regions gives the usual entropy of mixing for a semi-classical ideal gas, resolving Gibbs paradox without invoking quantum symmetry for atoms that may be meters apart. Other models presented here are based on Ising-like spins, which are solved analytically in one dimension. Focusing on the bonds between the Ising-like spins we find similarity in the equilibrium properties of a two-state model in the nanocanonical ensemble and a three-state model in the canonical ensemble. Thus, emergent phenomena may alter the thermal behavior of microscopic models, and the correct ensemble is necessary for fully-accurate predictions. Another result using Ising-like spins involves simulations that include a nonlinear correction to Boltzmann’s factor, which mimics the statistics of indistinguishable states by imitating the dynamics of spin exchange on intermediate lengths. These simulations exhibit 1/f-like noise at low frequencies (f), and white noise at higher f, similar to equilibrium thermal fluctuations found in many materials.

Spironucleosis is considered one of the most significant enteric infectious diseases in young and growing game birds. Despite its importance diagnosing spironucleosis in game birds remains a continuing problem as no 'gold standard' test exists and there is no consensus for the use of the available methods for the diagnosis of spironucleosis in game birds. In this study we describe veterinarians’ perceptions of the adoption of existing methods for the diagnosis of spironucleosis in game birds and identify implications for the development of diagnostic guidelines. A questionnaire was used to evaluate participants’ familiarity with and use of existing diagnostic methods for spironucleosis, and to assess their perceptions of the adoption of these methods in their geographic regions. We surveyed veterinarians in practices in East Anglia (EA) and Northern Ireland (NI), UK with expertise or involvement in the treatment and/or diagnosis of spironucleosis in game birds. Of the 261 participants surveyed, 15 EA and 13 NI veterinarians (10.7%) responded to the questions on existing diagnostic methods. The study results indicate an overall insufficient knowledge and skills in the diagnosis and treatment of spironucleosis among veterinarians surveyed. These findings highlight the need for improved training of veterinarians in the diagnosis of spironucleosis.

This research investigates the economic resilience of small and medium enterprises (SMEs) during financial crises, focusing on the factors that enable these businesses to survive and recover from economic downturns. Employing a qualitative methodology, the study examines various aspects of SME operations, including financial management, innovation, leadership, government support, geographical location, social capital, and contingency planning. The findings reveal that effective financial management—encompassing cash flow management, debt restructuring, and diversified funding sources—is crucial for maintaining stability during financial crises. Innovation and adaptability also play significant roles, with SMEs that embraced new technologies and market strategies demonstrating greater resilience. Leadership emerged as a critical factor, with leaders who communicated effectively and managed stress contributing to their organization's ability to navigate crises. Government support provided essential relief, although its impact varied depending on accessibility and timeliness. Geographical location influenced resilience, with urban SMEs having better access to resources, while rural SMEs benefited from strong community networks. Social capital, including relationships with suppliers and customers, was vital for providing stability and support. Contingency planning and risk management were identified as essential for preparing for and responding to disruptions. The research highlights that resilience is a multifaceted attribute resulting from the interplay of financial prudence, adaptability, effective leadership, supportive policies, geographic factors, and strong social networks. These insights offer valuable lessons for SME owners, policymakers, and support organizations, emphasizing the need for a comprehensive approach to building and sustaining resilience in the face of economic challenges.

B chromosomes (Bs) were discovered a century ago, and since then most studies have focused on describing their distribution and abundance using traditional cytogenetics. Only recently have attempts been made to understand their structure and evolution at the level of DNA sequence. Many questions regarding the origin, structure, function and evolution of B chromosomes remain unanswered. Here we identify B chromosome sequences from several species of cichlid fish from Lake Malawi by examining the ratios of DNA sequence coverage in individuals with and without B chromosomes. We examine the efficiency of this method, and compare results using both Illumina and PacBio sequence data. The B chromosome sequences detected in 13 individuals from 7 species were compared to assess the rates of sequence replacement. B-specific sequence common to at least 12 of the 13 datasets are identified as the “Core” B chromosome. The location of B sequence homologs throughout the genome provides further support for theories of B chromosome evolution. Finally, we identified candidate genes located on the B chromosome which may regulate the segregation and maintenance of the B chromosome.

This article presents raw data of biaxial tensile measurements of rat heart passive myocardium conducted in lab scale environment. The passive myocardium of the rat was divided into three regions, namely: left ventricle, mid-wall and right ventricle. The biaxial dataset of passive rat myocardia is presented as stress vs strain of the passive rat myocardium in various regions. The determination of valid material properties of the heart plays an important role in the development computational models. These computational models are useful in studying various scenarios and mechanisms of heart diseases. In addition, valid and accurate materials are critical in the development of new therapies. The dataset presented here is useful in the area of soft tissue mechanics including studying the mechanisms of heart diseases such as myocardial infarction. Accordingly, the evaluation of stress and strain in left ventricle, mid-wall and right ventricle was performed.

Fatigue analysis plays a vital role in determining the structural integrity and life of a dental implant. With the use of such implants on the rise, there is a corresponding increase in the number of implant failures. As such, the aim of this research paper is to investigate the life of 3D-printed dental implants. The dental implants considered in this study were 3D printed according to the direct metal laser sintering (DMLS) method. Additionally, a finite element model was developed to study their performance, while fatigue life was predicted using Fe-Safe software®. The model was validated experimentally by performing fatigue tests. The life of the dental implants was analysed based on Normal strain and the Brown-Miller with Morrow mean correction factor algorithm. The model revealed that there was a strong correlation between the FEA and the experimental results. The clinical success of 3D-printed dental implant experimentally is 20.51 years and computationally under Normal strain is 19.89 years and Brown-Miller with Morrow mean correction factor is 26.82 years.

In this paper, we have proposed an effective metasurface design to accomplish cloaking of equilateral patch antennas and their array configuration. As such, we have exploited the concept of electromagnetic invisibility, employing the mantle cloaking technique with the intention to eliminate the destructive interference ensuing between two distinct triangular patches situated in a very congested arrangement (sub-wavelength separation is maintained between the patch elements). Basically, we demonstrate that implementation of the planar coated metasurface cloaks onto the patch antenna surfaces compels them to become invisible to each other, at the intended frequencies. In effect, an individual antenna element does not sense the presence of the other, in spite of being in a rather close vicinity. We also exhibit that the cloaks successfully reinstate the radiation attributes of each antenna in such a way that it emulates their respective performance in an isolated environment. Moreover, we have extended the cloak design to an interleaved one dimensional array of the two patch antennas and it is shown that the coated metasurfaces assure efficient performance of each array in terms of their matching as well as radiation characteristics, in turn, enabling them to radiate independently for various beam-scanning angles.

Image synthesis poses a challenging problem that researchers in computer vision and machine learning have been grappling with for several decades. Numerous machine learning techniques have emerged and proven effective in generating high-fidelity artificial images. This study breaks new ground by exploring image synthesis through generative learning using the D-Wave 2000Q quantum annealer, marking the first attempt to address the issue of generative image synthesis on a Quantum Processing Unit (QPU). Alongside executing image synthesis on the quantum annealer, this research also compares its performance with existing classical models and delves into resolving the Generative Learning Trilemma.

Abstract : This paper presents the investigation of biomechanical behaviour of sheep heart fibre using uniaxial tests in various samples. Non-linear Finite Element models (FEA) that are utilised in understanding mechanisms of different diseases may not be developed without the accurate material properties. This paper presents uniaxial mechanical testing data of the sheep heart fibre. The mechanical uniaxial data of the heart fibre was then used in fitting four constitutive models including the Fung model, Polynomial (Anisotropic), Holzapfel (2005) model, Holzapfel (2000) model and the Four-fibre Family model. Even though the constitutive models for soft tissues including heart myocardium have been presented over several decades, there is still a need for accurate material parameters from reliable hyperelastic constitutive models. Therefore, the aim of this research paper is to select five hyperelastic constitutive models and fit experimental data in the uniaxial experimental data of the sheep heart fibre. A fitting algorithm was made used to optimally fitting and determination of the material parameters based on selected hyperelastic constitutive model. In this study, the evaluation index (EI) was used to measure the performance and capability of each selected anisotropic hyperelatic model. It was observed that the best predictive capability of the mechanical behaviour of sheep heart fibre the Polynomial (anisotropic) model has the EI of 100 and this means that it is the best performance when compared to all the other models.

Tendons transmit forces from muscles to bones through joints. Typically, tendons and muscles work together to innovate a particular type of motion. Therefore, in order for the tendons to find attachment to the bones, they are naturally adapted as much thinner strands than the muscles that they serve. Thus, they are often subjected to much higher stresses than the muscles that they actually serve in any given action. As a result, tendons are susceptible to injuries that may lead to a permanent dysfunction in joint mobility due to the fact that the scar tissue that forms after healing does not often have the same mechanical properties of the original tissue. It is, therefore, very important to understand the mechanical response of tendons. This paper examines the performances of two viscoelastic standard nonlinear models in modelling the elastic and plastic behaviour of the tendon in the light of a well-known hyperelastic Yeoh model. The use of the Yeoh model is more for validating the performances of the viscoelastic models within the elastic region rather than for comparison purposes. Yeoh model’s selection was based on its superior performance in modelling the elastic phase of soft tissue as reported in previous studies combined with its simplicity. The results show that the two standard nonlinear solid models perform extremely well both in fitting accuracies and in correlating stress results. The most promising result is the fact that the two standard nonlinear models can model tendon behaviour in the nonlinear plastic region. It is also noted that the two standard nonlinear models are physically insightful since their optimisation parameters can be easily interpreted in terms of tendon elasticity and viscoelastic parameters.

The initial stability after implantology is paramount to the survival of the dental implant and the surface roughness of the implant plays a vital role in this regard. The characterisation of surface topography is a complicated branch of metrology, with a huge range of parameters available. Each parameter contributes significantly towards the survival and mechanical properties of 3D-printed specimens. The purpose of this paper is to experimentally investigate the effect of surface roughness of 3D-printed dental implants and 3D-printed dogbone tensile samples under areal height (Ra) parameters, amplitude parameters (average of ordinates), skewness (Rsk) parameters and mechanical properties. During the experiment, roughness values were analysed and the results showed that the skewness parameter demonstrated a minimum value of 0.596%. The 3D-printed dental implant recorded Ra with a 3.4 mm diameter at 43.23% and the 3D-printed dental implant with a 4.3 mm diameter at 26.18%. Samples with a complex geometry exhibited a higher roughness surface, which was the greatest difficulty of additive manufacturing when evaluating surface finish. The results show that when the ultimate tensile stress (UTS) decreases from 968.35 MPa to 955.25 MPa, Ra increases by 1.4% and when UTS increases to 961.18 MPa, Ra increases by 0.6%. When the cycle decreases from 262142 to 137433, Ra shows that less than a 90.74% increase in cycle is obtained. For 3D-printed dental implants, the higher the surface roughness, the lower the mechanical properties, ultimately leading to decreased implant life and poor performance.

Sheep (Ovis aries) provide a vital source of protein and fibre to human populations. In coming decades, as the pressures associated with rapidly changing climates increase, breeding sheep sustainably as well as producing enough protein to feed a growing human population will pose a considerable challenge for sheep production across the globe. High quality reference genomes and other genomic resources can help to meet these challenges by: 1) informing breeding programmes by adding a priori information about the genome, 2) providing tools such as pangenomes for characterising and conserving genetic diversity, and 3) improving our understanding of fundamental biology using the power of genomic information to link cell, tissue and whole animal scale knowledge. In this review we describe recent advances in the genomic resources available for sheep, discuss how these might help to meet future challenges for sheep production, and provide some insight into what the future might hold.

Electromagnetic cloaking approach is employed with the intention to curb the destructive effects of mutual interference for rectangular and circularly shaped patch antennas situated in a tight spacing (sub-wavelength separation is employed). Primarily, we show that by coating the top surface of each patch with an appropriately designed metasurface, it is possible to considerably reduce the mutual coupling between the said antennas. We also demonstrate that, despite the close proximity of these patches, the individual radiation characteristic of each antenna is reinstated to emulate their performance in an isolated scenario. Furthermore, the cloak construct is extended to a tightly spaced, interleaved linear patch antenna array configuration and it is shown that the coated metasurfaces successfully enhance the performance of each array in terms of their matching characteristics, total efficiencies as well as their far-field realized gain patterns for a broad range of beam-scan angles. The decoupling and cloaking action of these metasurfaces are demonstrated by various full-wave numerical simulation results. We believe that the simple planar structure of our metasurface design (according to simulation models) makes it feasible for fabrication and the fact that it is used to accomplish cloaking of an electrically large antenna surface, makes it unique in itself.

In 2023, residential and commercial sectors together consumed approximately 27.6% of total U.S. energy, equivalent to about 20.6 quadrillion Btu. Factoring in the electrical system energy losses, the residential sector represented approximately 19.7% of total U.S. energy consumption during that time. There were approximately 144 million housing units in the United States in 2023, which is increasing yearly. In this study, information on energy usage in the United States (U.S.) residential sector has been analyzed and then represented as energy intensities to establish benchmark data and to compare energy consumption of varying sizes and locations. First, public sources were identified, and data from these previously published sources were aggregated to determine the energy use of the residential sector within the US. Next, as part of this study, the energy data for seven houses/apartments from five different United States climate zones were collected firsthand. That data was analyzed, and the energy intensity of each home was calculated and then compared with the energy intensities of the other homes in the same states using RECS data. The energy intensity for each facility was calculated based on the actual energy bills. Finally, the study evaluated the carbon footprint associated with residential energy consumption in all 50 states to reinforce the importance of sustainable development initiatives.

Obesity is treatment-resistant, and is linked with a number of serious, chronic diseases. Adult obesity rates in the United States have tripled since the early 1960s. Recent reviews show that an increased ratio of omega-6 to omega-3 fatty acids contributes to obesity rates by increasing levels of the endocannabinoid signals AEA and 2-AG, overstimulating CB₁R and leading to increased caloric intake, reduced metabolic rates, and weight gain. Cannabis, or THC, also stimulates CB₁R and increases caloric intake during acute exposures. The present meta-analysis reveals significantly reduced body mass index and rates of obesity in Cannabis users, in conjunction with increased caloric intake. We provide for the first time a causative explanation for this paradox, in which rapid and long-lasting downregulation of CB₁R following acute Cannabis consumption reduces energy intake and storage and increases metabolic rates, thus reversing the impact on body mass index of elevated dietary omega-6/omega-3 ratios.

The Centers for Disease Control and Prevention recommends everyone between 13-64 years be tested for HIV at least once as a routine procedure. HIV routine screening is reimbursable by Medicare, Medicaid, expanded Medicaid, and most commercial insurance plans. Yet, scaling-up HIV routine screening remains a challenge. We conducted a scoping review for studies on financial benefits and barriers associated with HIV screening in clinical settings in the U.S. to inform an evidence-based strategy to scale-up HIV routine screening. We searched Ovid MEDLINE®, Cochrane, and Scopus for studies published between 2006 - 2020 in English. The search identified 383 Citations; we screened 220 and excluded 163 (outside the time limit, irrelevant, or outside the U.S.). Of the 220 screened articles, we included 35 and disqualified 155 (did not meet the eligibility criteria). We organized eligible articles under two themes: financial benefits/barriers in healthcare settings (9 articles); and Cost-effectiveness in healthcare settings (26 articles). The review concluded recommendations in three areas: (1) Finance: Incentivize healthcare providers/systems for implementing HIV routine screening and/or separate its reimbursement from bundle payments; (2) Personnel: Encourage nurse-initiated HIV screening programs in primary care settings and educate providers on CDC recommendations; and (3) Approach: Use opt-out approach.

The log interpretation and evaluation of Chang 8 tight sandstone reservoir in Longdong West area, Ordos Basin, is facing great challenges due to the existence of low resistivity contrast oil pays. To better guide the exploration of oil resources in this area, the characteristics and control mechanism of low resistivity contrast oil pays were studied in this research. Firstly, according to the relative value of apparent resistivity increase rate of the target formation, the reservoir was divided into two types: low resistivity contrast oil pay (LRCP) and high resistivity oil pay (HRP). Then, the reservoir characteristics were studied by comparing and analyzing the experimental data, formation water data and logging data collected from the two reservoir types. On this basis, the control mechanism of LRCP was studied and summarized into reservoir micro factors and regional macro factors, respectively. It is found that the reservoir rock composition between LRCP and HRP is basically the same. Compared with HRP reservoir, the average porosity and permeability of LRCP reservoir are relatively better, but the pore structure is relatively poorer because of the high content of micro pores. When the filling pressure of crude oil is sufficient enough, the high oil saturation can be formed in LRCP reservoir. The high irreducible water saturation and high formation water salinity are the main micro factors reduced the reservoir resistivity. Besides, the difference of hydrocarbon expulsion capacity of source rock and the regional difference of formation water salinity are the macro factors influenced the distribution of LRCP and HRP from vertical and horizontal of the region. The formation of LRCP is controlled by the comprehensive influence of reservoir micro factors and regional macro factors. And the comprehensive consideration of the influence of micro factors and macro factors on LRCP is suggested during the log interpretation and evaluation.

Epigenetic reprogramming using cyclic expression of Yamanaka factors has been demonstrated to rejuvenate on a systemic level in animal models with no obvious deleterious effects. Here we discuss a strategy for cyclic and systemic expression of Yamanaka factors in wild-type animals amenable for adaptation as a human therapy. This is based on the use of the little- known Amsacta moorei Entomopoxvirus vector in combination with microbubble mediated focused ultrasound-driven blood vessel permeabilization to facilitate the system-wide distribution of the virus.

There is a major clinical need for accurate biomarkers for prostate cancer prognosis, to better inform treatment strategies and disease monitoring. Current clinically recognised prognostic factors, including prostate-specific antigen (PSA) levels, lack sensitivity and specificity in distinguishing aggressive from indolent disease, particularly in patients with localised intermediate grade prostate cancer. There has therefore been a major focus on identifying molecular biomarkers that can add prognostic value to existing markers, including investigation of DNA methylation, which has a known role in tumorigenesis. In this review, we will provide a comprehensive overview of the current state of DNA methylation biomarker studies in prostate cancer prognosis, and highlight the advances that have been made in this field. We cover the numerous studies into well-established candidate genes, and explore the technological transition that has enabled hypothesis-free genome-wide studies and the subsequent discovery of novel prognostic genes.

Digital dentistry, including CAD/CAM dentistry, is perhaps the most disruptive innovation in dentistry to date. The rapid development of digital dentistry technologies over the past several decades has enabled clinicians to improve patient care by significantly reducing the time necessary for the restorative phase of treatment. Advancements in intra-oral scanning and computer-aided design and manufacturing (CAD/CAM), in conjunction with new dental CAD/CAM ceramic materials, have simplified patient care and made same-day dentistry a reality. This review aims to present the most recent advancements described in current literature as well as to document the successful implementation of digital dentistry into a predoctoral program. The overall process of CAD/CAM same-day dentistry and the accompanying advancements in software and materials were presented and discussed. Implementation of technology and personnel requirements were reviewed. CAD/CAM dentistry has been influential in shaping and improving dental practice and education, and this influence will only continue with time.

A better understanding of diseases progress in tissues vest on the accurate understanding of tissues under mechanical loading. Also, development of therapies for injuries may depend on the available mechanical data for soft tissues. In this study, the raw data of biaxial tensile testing of sclera soft tissue is presented in this paper. Biaxial mechanical testing of soft tissues presents details understanding of how soft tissues behave when compared to uniaxial testing. Biomechanical properties of soft tissues are vital in the development of accurate computational models. Reliable computational models of studying mechanisms of diseases depends mainly on the accurate and more details mechanical behavior of soft tissues. These accurate and detailed computational models may be utilized to further develop the understanding and therapies of various diseases. The mechanical tensile testing was conducted on the passive sheep sclera. Engineering stress vs strain of several samples of the sheep sclera are further presented determined from force and displacement experimental data. The goal of this paper is to make available biaxial data of sheep sclera soft tissue that can be further utilized.

The financial performance of local governments is closely related to the economic growth of a region. Strong financial performance provides a solid foundation for sustainable economic development. This study analyses the relationship between local government financial performance, capital expenditure, and sustainable economic growth in Banten Province. A quantitative approach was employed, using secondary data from Regional Revenue and Expenditure Budgets and economic growth statistics. Purposive sampling was utilised, and data analysis was conducted using Path Analysis. The findings reveal that several financial ratio variables significantly impact economic growth directly and indirectly through capital expenditure as a mediating variable. Directly, the independence ratio, effectiveness ratio, efficiency ratio, fiscal decentralisation ratio, dependency ratio, and capital expenditure significantly influence economic growth. The independence and effectiveness ratios have a positive impact, indicating that improvements in these variables directly foster economic growth. However, the efficiency and fiscal decentralisation ratios have a negative impact, suggesting that increases in these variables may reduce economic growth. Indirectly, through capital expenditure, the independence, effectiveness, dependency, and compatibility ratios significantly affect economic growth, with the independence ratio being the most dominant. Conversely, the fiscal decentralisation and efficiency ratios do not show significant indirect effects, indicating that capital expenditure is not an effective mediator for these variables.

Specific nutrients including n-3 long chain polyunsaturated fatty acids (LCPUFAs), flavonoids, vitamin A, D and E are considered to possess protective properties on human health by impacting on immunological reactions. An ‘inflammation-suppressive’ effect appears to be the common denominator of the beneficial effects of most of these dietary components which may protect against the development of chronic immune disorders such as allergy. However, the majority of these promising data are from preclinical studies such as animal disease models, as the majority of clinical studies only indicate associations. PUFAs, especially n-3 LCPUFAs, have been shown to interact with both the sensitization as well as the effector phase in food allergy. However, it should be noted and realised that PUFAs are highly susceptible to lipid oxidation. Flavonoids and fat-soluble vitamins both contain anti-inflammatory properties and are able to act as anti-oxidants as well. Here, we explore the anti-allergic properties of PUFAs, flavonoids and fat-soluble vitamins in order to create an overview and, more importantly, suggest a strategy to target food allergies using these components and combinations thereof. Dietary n-3 LCPUFAs and the above mentioned micronutrients are promising anti‐allergy agents capable of influencing the allergic immune response through multiple and different biological pathways.

Abstract: Cardiovascular Disease (CVD) is the most prevalent disease worldwide, which has been linked to work stress because of poor job design as explained by the Job Demand-Control (JDC) and the Effort-Reward Imbalance (ERI) models. In this paper we explore for the first time relative impact of a specific aspect of organisational climate, Psychosocial Safety Climate (PSC), on any CVD including angina, myocardial infarction, hypertension, and stroke. We used two waves of interview data from Australia, with an average lag of 5 years (excluding baseline CVD, final n = 1223). Logistic regression was conducted to estimate the prospective associations between PSC at baseline on incident CVD at follow-up. It was found that participants in low PSC environments were 59% more likely to develop new CVD than those in high PSC environments. Logistic regression showed that PSC at baseline predicts lower CVD risk at follow-up (OR = 0.98, 95% CI 0.96-1.00), and this risk remained unchanged even after joint adjustment for measures of ERI and JDC. These results suggest that PSC is an independent risk factor for CVD in Australia. Beyond job design this study implicates organisational climate and prevailing management values regarding worker psychological health as the genesis of CVD.

The effect of land use on sandy soils of southern Botswana was carried out by comparing the composition and properties of soil organic matter. Virgin and disturbed soils were sampled from savanna ecosystems (Central District and Kweneng District). The biodegradability of organic matter was evaluated by incubation in the laboratory. Humic fractions were quantified and humic acids were analyzed by visible and infrared spectroscopy. The results indicate that continued disturbance, whether due to grazing or subsistence farming, has resulted in small significant changes in the concentration of available nutrients and organic matter in the soil. Nevertheless, substantial changes could be established in soil C/N ratio, humic acid/fulvic acid ratio and in the biodegradability of soil organic matter and the structural characteristics of humic acids. The increased aromaticity of humic acid (visible and IR spectroscopies) following disturbance, suggests increased biogeochemical activity and/or the impact of abiotic processes (such as periodic fires) selectively removing aliphatic constituents. The overall results indicate a low potential soil fertility, the sustainable preservation of which depending more on features related to quality than to the total amount of the soil organic matter, which shows considerable aromatization parallel to its degree of association with the mineral fraction.

Our understanding of Alzheimer’s disease (AD) pathogenesis has developed with several hypotheses over the last 40 years, including the Amyloid and Tau hypotheses, respectively. More recently, the p53 protein, well-known as ‘the guardian of the genome,’ has gained attention for its role in the early evolution of AD. This is due to p53’s central role in the control of oxidative stress and potential involvement in both Amyloid and Tau pathways. p53 is commonly regulated by post-translational modifications (PTMs), which affect its conformation, increasing its capacity to adopt multiple structural and functional states, including those that can influence several processes in AD. The following review will explore the impact of p53 post-translational modifications (PTMs) on its function and consequential involvement in AD pathogenesis.

DNA Topoisomerase IIa (Top2A) is a nuclear enzyme that is a cancer drug target, and there is interest in identifying novel sites on the enzyme to inhibit cancer cells more selectively and to reduce off-target toxicity. The C-terminal domain (CTD) is one potential target, but it is an intrinsically disordered domain, which prevents structural analysis. Therefore, we set out to analyze the sequence of Top2A from 105 species using bioinformatic analysis including the PSICalc algorithm, entropy analysis, and other approaches. Our results demonstrate that large (10th-order) interdependent clusters are found including non-proximal positions across the major domains of Top2A. Further, CTD-specific clusters of 3rd, 4th, and 5th-order were identified that included positions that had been previously analyzed via mutation and biochemical assays. Some of these clusters coincided with positions that when mutated either increased or decreased relaxation activity. Finally, sites of low entropy (i.e., high information content) were identified and mapped as key positions in the CTD. Included in the low entropy sites are phosphorylation sites and charged positions. Together, these results help to build a clearer picture of the critical positions in the CTD and provide potential sites/regions for further analysis.

Oxytocin is well known for its role in relationships and social cognition and has more recently been implicated in pain relief and pain perception. Connections between prosocial feelings and pain relief are also well documented, however, effects of exogenous oxytocin on social cognition and pain have not been explored. The current study tested whether intranasally-delivered oxytocin affects pain perception through prosocial behaviors. Additionally, moderation of the effects of oxytocin by life history or genetic polymorphisms are examined. Young adults (n=43; 65% female) were administered intranasal oxytocin (24 IU) or placebo in a crossover design on two visits separated by a one-week washout period. Pain was delivered via cold-pressor. Baseline measures for decision-making and social cognition were collected, as well as pain sensitivity and medication history. Saliva samples were collected for analysis of genetic markers, and urine samples were collected to assess oxytocin saturation. Following oxytocin administration, participants reported increased prosocial cognition and decision-making. Pain perception appeared to be adaptive, with procedural order and expectation affecting perception. Finally, behavioral trust and cooperation responses were significantly predicted by genetic markers. Oxytocin may increase a patient’s trust and cooperation and reduce pain sensitivity while having fewer physiological side effects than current pharmaceutical options.

The breast holds significant importance in women's lactation process. The breast has diverse tissues such as glandular, Cooper’s ligament, lactiferous ducts, adipose, muscles, and skin with various mechanical properties. Most soft tissues exhibit nonlinear, viscoelastic, and anisotropic mechanical behaviour. Stiffness is one of the commonly used mechanical properties for measuring mechanical behaviour in soft tissues. However, this is typically used in simplifying cases where analysis is limited to within the linear elastic region. Young’s modulus is the prevailing measure for quantifying stiffness in tissues. This systematic review examines commonly used techniques for mechanically characterising breast soft tissues to close the gap in the literature. Additionally, this systematic review summarises the mechanical behaviour of the breast tissues available in the literature and highlights the uncovered areas to understand the mechanical behaviour of breast tissues fully. These include a) more mechanical behaviour studies, allowing more accurate modelling for other applications, b) Viscoelastic analysis studies, and c) mechanical analysis on other breast tissues, such as the lactiferous duct, also known as the milk duct. The data obtained in the review can be used as inputs in computational models to analyse the behaviour of the breast tissues.

Variant H3.3, along with H2A.Z, is notably enriched at promoter regions and is commonly associated with transcriptional activation. However, the specific molecular mechanisms through which H3.3 influences chromatin dynamics at transcription start sites, and its role in gene regulation, remain elusive. Using a combination of biochemistry and cryo-electron microscopy (cryo-EM), we show that the inclusion of H3.3 alone does not induce discernible changes in nucleosome DNA dynamics. Conversely, the presence of both H3.3 and H2A.Z enhances DNA flexibility similarly to H2A.Z alone. Interestingly, our findings suggest that the presence of H3.3 in the H2A.Z nucleosome provides slightly increased protection to DNA near the superhelical location (SHL) -5.5/5.5. These results imply that while H2A.Z at active promoters promotes the formation of more accessible nucleosomes with increased DNA accessibility to facilitate transcription, the simultaneous presence of H3.3 offers an additional mechanism to fine-tune nucleosome accessibility and the chromatin environment.

Ambulatory heart rate (HR) monitors that acquire electrocardiogram (ECG) or/and photoplethysmographm (PPG) signals from the torso, wrists, or ears are notably less accurate in tasks associated with high levels of movement compared to clinical measurements. However, reliable estimation of HR can be obtained through data fusion from different sensors. These methods are especially suitable for multimodal hearable devices, where heart rate can be tracked from different modalities, including electrical ECG, optical PPG, and sounds (heart tones). Combined information from different modalities can compensate for single source limitations. In this paper, we evaluate the possible application of data fusion methods in hearables. We assess data fusion for heart rate estimation from simultaneous in-ear ECG and in-ear PPG, recorded on eight subjects while performing 5-minute sitting and walking tasks. Our findings show that data fusion methods provide a similar level of mean absolute error as the best single-source heart rate estimation but with much lower intra-subject variability, especially during walking activities. We conclude that data fusion methods provide more robust HR estimation than a single cardiovascular signal. These methods can enhance the performance of wearable devices, especially multimodal hearables, in heart rate tracking during physical activity.

Heart myocardia are critical to the facilitation of heart pumping and blood circulating around the body. The biaxial mechanical testing of the Left Ventricle (RV) is utilised to build the computa-tional model of the whole heart with little importance given to the unique mechanical properties of Right Ventricle (RV) and Mid-wall (MDW). Most of those studies focussed on the LV of the heart, and then apply the obtained characteristics with a few modifications to the right side of the heart. However, that view has been contested over time with the realisation that the right side of the heart possesses its own unique mechanical properties that are widely distinct from that of the left side of the heart. This paper is aimed at reporting and evaluating the passive mechanical property dif-ferences in the three main walls of the rat heart based on biaxial tensile test data. Fifteen mature Wistar rats weighing 225 ± 25 g were euthanised by inhalation of 5 % halothane. The hearts were excised after which all the top chambers comprising the two atria, pulmonary and vena cava trunks, aorta and valves are all dissected out. Then 5 x 5 mm sections from the middle of each wall were carefully dissected with a surgical knife to avoid over-prestraining the specimens. The specimens were subjected tensile test. The elastic moduli, peak stresses in the toe region and stresses at 40 % strain, anisotropy indices as well as the stored strain energy in the toe and linear region up to 40 % strain are used for statistical significance tests. The following are the main findings of this study: (1) LV and MDW tissues have relatively shorter toe regions of 10 - 15 % strain as compared to RV tissue whose toe region extends up to twice as much as that (2) LV tissues have higher strain energy storage in the linear region despite being lower in stiffness than the RV (3) the MDW has the highest strain energy storage along both directions which might be directly related to its high level of anisotropy. These findings, though for a specific animal species at similar age and around the same body mass, emphasize the importance of application of wall specific material parameters to obtain accurate ventricular hyperelastic models. The findings further enhance our understanding of the desired mechanical behaviour of the different ventricle walls.

We assessed the association between cirrhosis and severe COVID-19-related outcomes among people with laboratory-diagnosed COVID-19 infection in British Columbia, Canada. We used data from the British Columbia (BC) COVID-19 Cohort, a population-based cohort that integrates data on all individuals tested for COVID-19 with data on hospitalizations, medical visits, emergency room visits, prescription drugs, chronic conditions, and deaths in the Canadian province of BC. We included all individuals, aged ≥ 18 who tested positive for SARS-CoV-2 by real-time reverse transcription-polymerase chain reaction, from January 01, 2021, to December 31, 2021. Multivariable logistic regression models were used to assess the associations between cirrhosis status and COVID-19-related hospitalization and ICU admission. Of the 162,509 individuals who tested positive for SARS-CoV-2 and were included in the analysis, 768 (0.5%) had cirrhosis. In the multivariable models, cirrhosis was associated with increased odds of hospitalization (aOR=1.97, 95% CI: 1.58 – 2.47) and ICU admission (aOR=3.33, 95% CI: 2.56 – 4.35). In the analyses stratified by age, we found that the increased odds of ICU admission among people with cirrhosis were present in all the assessed age-groups. Cirrhosis is associated with increased odds of hospitalization and ICU admission among COVID-19 patients.

Background: Whilst lack of concentration is a known symptom of anaemia, its association with post-stroke dementia is unclear. Methods: We used data from a UK regional stroke register. To be eligible, patient must have survived to discharge and had anaemia by WHO criteria. Dementia status and other prevalent co-morbidities were assessed using ICD-10 codes. Patients were followed till May 2015 (mean follow-up 3.7 years, total person years = 27,769). Hazard Ratio for incident dementia was calculated using Cox-proportional hazards model controlling for potential confounders. Fine and Gray model was additionally constructed using mortality as the competing risk. Results: A total of 7,454 stroke patients were included with mean age (SD) of 75.9(12.3) years (50.2% men). Those with anaemia were older, has higher disability and co-morbidity burden prior to stroke. We observed a large amount of variation in the dementia incidence rates over time and that the hazard ratio increased every year. The significant association between anaemia and dementia incidence was lost after controlling for pre-stroke Modified Rankin score (HR1.17(0.97,1.40)). With every 20g/dL increase in Hb was associated with a significant reduction in the risk of dementia after adjustment for age, sex, stroke factors and disability but lost significance after adjustment for vascular risk factors. Competing risk analyses showed similar results. Conclusion: Whilst we found no evidence of anaemia as a risk factor for post-stroke dementia, the findings may be limited by potential under recognition of post stroke dementia.

Background: Whilst lack of concentration is a known symptom of anaemia, its association with post-stroke dementia is unclear. Methods: We used data from a UK regional stroke register. To be eligible, patient must have survived to discharge and had anaemia by WHO criteria. Dementia status and other prevalent co-morbidities were assessed using ICD-10 codes. Patients were followed till May 2015 (mean follow-up 3.7 years, total person years = 27,769). Hazard Ratio for incident dementia was calculated using Cox-proportional hazards model controlling for potential confounders. Fine and Gray model was additionally constructed using mortality as the competing risk. Results: A total of 7,454 stroke patients were included with mean age (SD) of 75.9(12.3) years (50.2% men). Those with anaemia were older, has higher disability and co-morbidity burden prior to stroke. We observed a large amount of variation in the dementia incidence rates over time and that the hazard ratio increased every year. The significant association between anaemia and dementia incidence was lost after controlling for pre-stroke Modified Rankin score (HR1.17(0.97,1.40)). With every 20g/dL increase in Hb was associated with a significant reduction in the risk of dementia after adjustment for age, sex, stroke factors and disability but lost significance after adjustment for vascular risk factors. Competing risk analyses showed similar results. Conclusion: Whilst we found no evidence of anaemia as a risk factor for post-stroke dementia, the findings may be limited by potential under recognition of post stroke dementia.

Nerve hydrodissection (HD), a technique used when treating nerve entrapments, involves using an anesthetic or solution such as saline or 5% dextrose solution to separate the nerve from the surrounding tissue, fascia, or adjacent structures. This technique aims to treat neuropathic pain, or pain caused by the nerve. Ultrasound-guided HD of peripheral nerves has gained significant attention in the medical profession and pain management fields in recent years. This is due to a number of high impact publications of randomized control trials demonstrating the efficacy and safety of this technique for the treatment of carpal tunnel syndrome. Even the 20th edition of Harrison’s Principles of Internal Medicine textbook lists injection of 5% dextrose as an alternative local treatment that does not have the side effects of corticosteroids. At present, there is no review of the current literature on this technique. This manuscript will summarize and discuss the following: 1) the different approaches to doing ultrasound-guided HD of nervous structures, 2) its usages in different clinical situations, 3) its clinical pearls, 4) the solution used, and 5) the postulated mechanisms of action.

Humanity will soon define a new era for nature – one that seeks to correct decades of underwhelming responses to the global biodiversity crisis. Area-based conservation efforts, which include both protected areas and other effective area-based conservation measures, are likely to extend and diversify. But persistent shortfalls in ecological representation, management effectiveness and measurable biodiversity outcomes diminish the potential role of area-based conservation in stemming biodiversity loss. Here we show how protected area expansion by governments since 2010 has had limited success in increasing biodiversity coverage, and identify four emergent issues that –if addressed – will enhance the performance of area-based conservation post-2020. We close with recommendations for a broad biodiversity agenda that maximises the potential of area-based conservation. Parties to the Convention on Biological Diversity must recognise that area-based conservation primarily focuses on local threats to species and ecosystems, and needs enhanced emphasis on biodiversity outcomes to better track and fund its contribution to global conservation efforts.

The switching game Lights Out and its variants were studied extensively as recreational mathematics problems. The game board of the ordinary Lights Out is a rectangular grid of lights, where each light is either on or off. By clicking a light, the clicked light and its adjacent rectilinear neighbors are toggled. Given an arbitrary initial configuration of lights, the final mission is to “solve” this game by switching off all the lights. Most studies on Lights Out and its variants focused on the solvability of given games or the number of solvable games, but when the game is viewed in a coding-theoretical perspective, more interesting questions with special meanings in coding theory will naturally pop up, such as finding the minimal number of lit lights among all solvable games except the solved game, or finding the minimal number of lit lights that the player can achieve from a given unsolvable game, etc. However, these problems are usually hard to be solved in general in terms of algorithmic complexity. This study considers a natural extension of the Lights Out game, which enlarges the toggle pattern in a way that all the lights in the same row and those in the same column of the clicked light are toggled. This variant of Lights Out is a two-state version of a switching game called Alien Tiles. In this paper, we investigate the properties of the two-state Alien Tiles, and discuss several coding-theoretical problems about this game. Then, we apply this game as an error correction code and investigate its optimality. We also give a brief overview on algorithmic complexity and coding theory for readers who are not familiar with these topics. The purpose of this paper is to propose ways of playing switching games in a think-outside-the-box manner, which benefit the recreational mathematics community.

Little is understood about the impact of nebulisation on the viability of SARS-CoV-2. In this study, a range of nebulisers with differing methods of aerosol generation were evaluated to determine SARS-CoV-2 viability following aerosolisation. The aerosol particle size distribution was assessed using an aerosol particle sizer (APS) and SARS-CoV-2 viability was determined after collection into liquid media using All-Glass Impingers (AGI). Viable particles of SARS-CoV-2 were further characterised using the Collison 6-jet nebuliser in conjunction with novel sample techniques in an Andersen size-fractioning sampler to predict lung deposition profiles. Results demonstrate that all the tested nebulisers can generate stable, polydisperse aerosols (Geometric standard deviation (GSD) circa 1.8) in the respirable range (1.2 to 2.2µm). Viable fractions (PFU/particle, the virus viability as a function of total particles produced) were circa 5x10^-3 and were not significantly affected by relative humidity. The novel Andersen sample collection methods successfully captured viable virus particles across all sizes; with most particle sizes below 3.3µm. MMADs (Mass Median Aerodynamic Diameters) were calculated from linear regression of log10-log10 transformed cumulative PFU data, and calculated MMADs accorded well with APS measurements and did not differ across collection method types. This data will be vital in informing animal aerosol challenge models, and infection prevention and control policies.

Arborists commonly investigate the extent of stem decay to assess the likelihood of stem failure when conducting tree risk assessments. Studies have shown that (i) arborists can sometimes judge the extent of internal decay based on external signs; (ii) sophisticated tools can reliably illustrate the extent of internal decay; and (iii) assessing components of tree risk can be highly subjective. We recruited 18 experienced tree risk assessors who held the International Society of Arboriculture’s Tree Risk Assessment Qualification (TRAQ) to assess the likelihood of stem failure due to decay after each of 5 consecutive assessments on 30 individuals of 2 genera. Five assessment techniques, in stepwise order, were 1) visual, 2) sounding the trunk with a mallet, 3) viewing a scaled diagram of the cross-section that revealed sound and decayed wood ascertained from resistance drilling, 4) viewing sonic and electrical resistance tomograms, and 5) consulting with a peer. For each technique, assessors assigned two or more likelihood of failure ratings (LoFRs) for at least 83% of trees, which were proportionally greatest after assessors viewed tomograms; the proportions did not differ among the other four assessment techniques. Covariates that influenced the distribution of LoFRs included percent of the cross-section that was decayed, and assessors’ experience using resistance drilling devices and tomography in regular practice. Practitioners should be aware that disagreement on the likelihood of tree failure exists even among experienced arborists.

Coronary optical coherence tomography (OCT) is an intravascular, near-infrared light-based imaging modality capable of reaching axial resolutions of 10-20 µm. This resolution allows for accurate determination of high-risk plaque features, such as thin cap fibroatheroma; however, visualisation of morphological features alone still provides unreliable positive predictive capability for plaque progression or future major adverse cardiovascular events (MACE). Biomechanical simulation could assist in this prediction, but this requires extracting morphological features from intravascular imaging to construct accurate three-dimensional simulations of patients’ arteries. Extracting these features is a laborious process, often carried out manually by trained experts. To address this challenge, numerous techniques have emerged to automate these processes while simultaneously overcoming difficulties associated with OCT imaging, such as its limited penetration depth. This systematic review summarises advances in automated segmentation techniques from the past five years (2016-2021) with a focus on their application to the three-dimensional reconstruction of vessels and their subsequent simulation. We discuss four categories based on the feature being processed, namely: coronary lumen; plaque characteristics and subtypes; artery layers; and stents. Areas for future innovation are also discussed as well as their potential for future translation.

The efficacy of time-restricted feeding for weight loss has not been established as prior studies were limited by lack of controlled isocaloric designs. This study describes the design and implementation of a controlled feeding study evaluating time-restricted feeding. We designed a randomized, controlled, parallel-arm, feeding study comparing time restricted feeding (TRF) to a usual feeding pattern (UFP) for the primary outcome of weight change. Participants were aged 18-69 years with prediabetes and obesity. TRF consumed 80% of calories by 1300, and UFP consumed ≥50% of calories after 1700. Both arms consumed identical macro- and micro-nutrients, based on a healthy palatable diet. We calculated individual calorie requirements which were maintained throughout the intervention. We randomized 41 participants who all completed the study. The desired distribution of calories across feeding windows in both arms was achieved, as were weekly averages for macronutrients and micronutrients. All randomized participants completed the study. We actively monitored participants and adapted diets to facilitate adherence. We provide the first report, to our knowledge, on the design and implementation of a feeding study that isolated the effect of meal timing on weight, while maintaining constant caloric intake and identical diets during the study period.

Over a billion people live in slums, with poor sanitation, education, property rights and working conditions having direct impact on current residents and future generations. A key problem in relation to slums is slum mapping. Without delineations of where all slum settlements are, informed decisions cannot be made by policymakers in order to benefit the most in need. Satellite images have been used in combination with machine learning models to try and fill the gap in data availability of slum locations. Deep learning has been used on RGB images with some success but since labeled satellite images of slums are relatively low quality and the physical/visual manifestation of slums significantly varies within and across countries, it is important to quantify the uncertainty of predictions for reliable application in downstream tasks. Our solution is to train Monte Carlo dropout U-Net models on multispectral 13-band Sentinel-2 images from which we can calculate pixelwise epistemic (model) and aleatoric (data) uncertainty in our predictions. We trained our model on labelled images of Mumbai and verified our epistemic and aleatoric uncertainty quantification approach using altered models trained on modified datasets. We also used SHAP values to investigate how the different features contribute towards the model’s predictions and this showed that certain short-wave infrared and red-edge image bands are powerful features for determining the locations of slums within images. Having created our model with uncertainty quantification, in the future it can be applied to downstream tasks and decision-makers will know where predictions have been made with low uncertainty, giving them greater confidence in its deployment.

Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or with radial cytotomy including pedogamic exchanges) and release of secondary cells and/or formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle and meiotic SC checkpoints. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.

Abstract Introduction: The mHealth active participant centred (MAPC) adverse events following immunisation (AEFI) surveillance is a promising area for early AEFI detection resulting in risk minimisation. Passive (spontaneous) AEFI surveillance is the backbone for vaccine pharmacovigilance, but has inherent drawbacks of under reporting, and requires strengthening with active surveillance methods. The Zimbabwe stimulated telephone assisted rapid safety surveillance (Zm-STARSS) randomized controlled trial (RCT) sought to evaluate the efficacy and feasibility of AEFI detection using a short message service (SMS) and computer assisted telephone interview (CATI) approach. Method: A multicentre Zm-STARSS RCT enrolled consented adult vaccinees or parents or guardians of children receiving vaccines, including COVID-19 vaccines, at study vaccination clinics. At enrolment study participants were randomised to either SMS-CATI group or control group. SMS prompts were sent on days 0-2 and 14 post-vaccination to SMS-CATI group to ascertain if a medical event following immunisation (MEFI) had occurred. However, no SMSs were sent to the control group. SMS-CATI group who responded “Yes” to SMS prompts were interviewed by research healthcare workers (RHCWs) who completed a CATI to determine if an MEFI/AEFI had occurred whilst an AEFI in control group was determined from passive AEFI reporting channels. The primary study outcome was the AEFI detection rate in the SMS-CATI group compared to the control group. Results: A total of 704 (31%) participants responded to the SMS prompts, with 75% (528/704) indicating “No” and 25% (176/704) "Yes” to experiencing a MEFI. However, 31% (55/176) who responded “Yes” did not complete a CATI survey, but 69% (121/176) did; and 64% (77/121) of these indicated negative to AEFI experience whilst 36% (44/121) were affirmative. There were no AEFI reported in control group participants. Zm-STARSS showed promising results in that the AEFI detection rate using SMS-CATI was 2% (44/2280) on an intention to treat cohort. Conclusion: Despite the low SMS response and CATI completion rate, we demonstrated that Zm-STARSS SMS system improves AEFI detection compared to passive AEFI surveillance. We recommend cost-effective multi-channel digital approaches for holistic pharmacovigilance to improve AEFI detection in LMICs for all vaccines.

Improving the acquisition and retention of a new motor skill is of great importance. The present study (i) investigated the effects of difficulty manipulation strategies (gradual difficulty), combined with different modalities of feedback (FB) frequency on performance accuracy and consistency when learning a novel fine motor coordination task, and (ii) examined relationships between novel fine motor task performance and executive function (EF), working memory (WM), and perceived difficulty (PD). Thirty-six, right-handed, novice physical education students volunteered to participate in this study. Participants were divided into three progressive difficulty groups (PDG), 100% visual FB (FB1), 50% FB (FB2), and 33% FB (FB3). Progressive difficulty was increased by the manipulation of the distance to the target; 2 m, 2.37 m, and 3.56 m. Three FB modalities were investigated (i.e.: 100% visual FB (100% FB), 50% reduced feedback condition (50% RFB), and 33% reduced feedback conditions (33% RFB)). Performance assessments were conducted following familiarization, acquisition, and retention learning phases. Two stress-conditions of dart throws were investigated (i.e.: free condition (FC) and time pressure condition (TPC)). After the learning intervention, data showed that, under the free condition, the 100% FB group had a significant improvement in accuracy during all learning phases. Under time pressure condition, for the 50% RFB and the 33% RFB group, the measured variable (accuracy and consistency) showed a significant linear improvement in performance. The association between the percentage of RFB frequencies and the task difficulty (50% group) may be a more appropriate and manageable cognitive load compared to the 33% RFB and the 100% FB group. The present findings could have practical implications for practitioners because, while strategies are clearly necessary for improving learning, the efficacy of the process appears to be essentially based on the characteristics of the learners.

Eco-agricultural technology is crucial to alleviating agricultural resource scarcity and environ-mental pressures. However, financial constraint affects its successful promotion. Digital finance has a significant impact on farmers, but existing research lacks an exploration of the impact of digital finance on farmers' adoption of eco-agricultural technology. This study focuses on Rice–Crayfish Co-cultivation Technology as an example. It utilizes survey data from 1,063 households in China. An Endogenous Switching Probit model is employed to solve self-selection bias. The results reveal several key findings. First, the average treatment effect on the treated is 51.5%. This indicates that if farmers who use digital finance were to stop using it, the probability of adopting rice–crayfish co-cultivation technology would decrease by 51.5%. Therefore, digital finance is beneficial for farmers in adopting this technology. Second, heterogeneity analysis reveals that digital finance has a greater promoting effect on older farmers, those with lower education levels, and higher proportions of agricultural income. This suggests a greater reliance on digital financial services among vulnerable groups. Third, digital finance promotes farmers' adoption of rice–crayfish co-cultivation technology by alleviating financial constraints, expanding information channels, and increasing social capital accumulation. Overall, the findings offer valuable insights for for-mulating supportive policies.

Schistosomiasis is a parasitic disease acquired through contact with contaminated freshwater. The definitive hosts are terrestrial mammals, including humans, with some Schistosoma species crossing the animal-human boundary through zoonotic transmission. An estimated 12 million people live at risk of zoonotic schistosomiasis caused by Schistosoma japonicum and Schistosoma mekongi, largely in the World Health Organization’s Western Pacific Region and in Indonesia. Mathematical models have played a vital role in our understanding of the biology, transmission, and impact of intervention strategies, however, these have mostly focused on non-zoonotic Schistosoma species. Whilst these non-zoonotic-based models capture some aspects of zoonotic schistosomiasis transmission dynamics, the commonly-used frameworks are yet to adequately capture the complex epi-ecology of multi-host zoonotic transmission. However, overcoming these knowledge gaps goes beyond transmission dynamics modelling. To improve model utility and enhance zoonotic schistosomiasis control programmes, we highlight three pillars that we believe are vital to sustainable interventions at the implementation (community) and policy-level, and discuss the pillars in the context of a One-Health approach, recognising the interconnection between humans, animals and their shared environment. These pillars are: (1) human and animal epi-ecological understanding; (2) economic considerations (such as treatment costs and animal losses); and (3) sociological understanding, including inter- and intra-human and animal interactions. These pillars must be built on a strong foundation of trust, support and commitment of stakeholders and involved institutions.

The polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy (PML) in patients infected with JC polyomavirus, but the molecular events mediating polyomavirus entry are poorly understood. Through genetic knockdown approaches, we identified phosphoinositide 3’ kinase γ (PI3Kγ) and its regulatory subunit PIK3R5 as cellular proteins that facilitate infection of human SVG-A glial cells by JCPyV, but not by adenovirus, an unrelated small, non-enveloped DNA tumor virus. PI3Kα appears less important for polyomavirus infection than PI3Kγ. CRISPR/Cas9-mediated knockout of PIK3R5 or PI3Kγ inhibited infection by authentic JCPyV and by JC pseudovirus. PI3Kγ knockout also inhibited infection by BK and Merkel Cell pseudoviruses, other pathogenic human polyomaviruses, and SV40, an important model polyomavirus. Reintroduction of the wild-type PI3Kγ gene into the PI3Kγ knock-out SVG-A cells rescued the JCPyV infection defect. Disruption of the PI3Kγ pathway did not block binding of JCPyV to cells or virus internalization, implying that PI3Kγ facilitates some intracellular step(s) of infection. These results imply that agents that inhibit PI3Kγ signaling may have a role in managing polyomavirus infections.

While researchers have made notable progress in bio-inspired swimming robot development, a persistent challenge lies in creating propulsive gaits tailored to these robotic systems. The California sea lion achieves its robust swimming abilities through a careful coordination of foreflippers and body segments. In this paper, reinforcement learning (RL) was used to develop a novel sea lion foreflipper gait for a bio-robotic swimmer using a numerically modelled computational representation of the robot. This model integration enabled reinforcement learning to develop desired swimming gaits in the challenging underwater domain. The novel RL gait outperformed the characteristic sea lion foreflipper gait in the simulated underwater domain. When applied to the real-world robot, the RL constructed novel gait performed as well or better than the characteristic sea lion gait in many factors. This work shows the potential for using complimentary bio-robotic and numerical models with reinforcement learning to enable the development of effective gaits and maneuvers for underwater swimming vehicles.

Urinary extracellular vesicles (uEV) hold non-invasive RNA biomarkers for genitourinary tract diseases. However, missing knowledge about reference genes and effects of pre-analytical choices hinder biomarker studies. We aimed to assess how pre-analytical variables (urine storage temperature, isolation workflow) affect diabetic kidney disease (DKD) -linked miRNAs or kidney -linked miRNAs and mRNAs (kidney-RNAs) in uEV isolates and to discover stable reference mRNAs across diverse uEV datasets. We studied nine raw and normalized sequencing datasets including healthy controls and individuals with prostate cancer or type 1 diabetes with or without albuminuria. We focused on kidney-RNAs reviewing literature for DKD-linked miRNAs from kidney tissue, cell culture and uEV/urine experiments. RNAs were analyzed by expression heatmaps, hierarchical clustering and selecting stable mRNAs with normalized counts (>200) and minimal coefficient of variation. Kidney-RNAs were decreased after urine storage at -20°C vs -80°C. Isolation workflows captured kidney-RNAs with different efficiencies. Ultracentrifugation captured DKD -linked miRNAs that separated healthy and diabetic macroalbuminuria groups. Eleven mRNAs were stably expressed across the datasets. Hence, preanalytical choices had variable effects on kidney-RNAs – analyzing kidney-RNAs complemented global correlation, which could fade differences in some relevant RNAs. Replicating prior DKD-marker results and discovery of candidate reference mRNAs encourages further uEV biomarker studies.

We propose a framework for the understanding of the pathophysiology and management of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) that considers wider determinants of health and long-term temporal variation in pathophysiological features and disease phenotype throughout the natural history of the disease. As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to an insult, or repeated insults, and the nature of the host response. In people who develop ME/CFS, normal homeostatic processes in response to adverse insults may be replaced by aberrant responses leading to dysfunctional states. Thus, the predominantly neuro-immune and autonomic manifestations, underlined by a hyper-metabolic state, that characterise early disease, may be followed by various processes leading to multi-systemic related symptoms. This abnormal metabolic state and the effects of a range of mediators such as products of oxidative and nitrosamine stress, may lead to progressive cell and metabolic dysfunction culminating in a hypometabolic state with low energy production. These processes do not seem to happen uniformly; although a spiralling of progressive inter-related and self-sustaining abnormalities may ensue, reversion to states of milder abnormalities is possible if the host is able to restate responses to improve homeostatic equilibrium. Disease management and research efforts should seek to identify and apply strategies targeted at the different pathophysiological dysfunctions that characterise different disease stages. As disease presentation varies over time, no single case description, set of diagnostic criteria, or molecular feature is currently diagnostic for all patients at all times. While acknowledging its limitations due to the incomplete research evidence, we suggest the proposed framework may improve research design and health care interventions for people with ME/CFS.

Diet influences, and is influenced by, a wide range of socioeconomic, cultural, geographic, and genetic variables. Here we survey a matrix of such interactions as well as their connection to a variety of health outcomes, in a cohort of 689 diverse adults employed at Emory University and enrolled in the Center for Health Discovery and Well-Being (CHDWB) study. Principal component analysis (PCA) of the Block Food Frequency Questionnaire revealed seven PC cumulatively explaining 25.8% and each individually at least 2% of the proportional consumption of 110 food items. PC1 is strongly correlated with the Healthy Eating Index-2015 measure, and accordingly healthier scores associate with multiple measures of physical and mental health. It, as well as PC2 (likely a measure of food expense) and PC3 (carbohydrate versus protein consumption) show significant geographic structure across the Atlanta metropolitan area, correlating with race and ethnicity, income level, age and sex. Notably, a polygenic score for body mass index (BMI) consisting of 281 SNPs explains 2.8% of the variance in PC5, which is as strong as its association with BMI itself. PC5 appears to differentiate participants with respect to conscious eating behavior related to the choice of diet or comfort foods. Our analysis adds to the growing literature on factor analysis of socio-demographic influences on nutrition and health.

There are limited research articles focusing on Smart City Assessment (SCA) applications since it is a relatively new field of research and practice. However, numerous studies have been conducted and published to date, particularly in developing countries, with the broad objective of building theoretical frameworks that are centered on smart city assessments. This scoping review systematically provides an examination on the available literature on SCA, with a goal of synthesizing smart city assessments in developing economies. In order to improve the quality and transparency of the reviews and meta-analysis, as well as to reduce the risk of bias, this paper adopted the PRISMA scoping review research design to analyze 25 journal articles. Results showed that conceptual modeling appears to be the most common method identified while industrial development emerged as the most common objective identified in the MFO Model. On the other hand, ISO 37122:2019 was the most prevalent framework used in the collected sample size with 6 journal articles followed by IoT-Enabled Smart City Framework with 5 journal articles while Smart Cities Index Framework obtained 3. Meanwhile, India emerged as a leader in the global Smart City movement followed by Malaysia and Africa. The Qualitative Research Design approach was the most common among the literatures while social science was the most common subject area among the 25 journals being studied. More so, sustainability and renewable energy are the two most important assessment categories in SCA tools. By collating and evaluating different criteria and metrics in existing SCA, cities can learn from their successes and failures, adjust their strategies, and share best practices with other cities. This can foster a culture of continuous improvement and innovation in urban governance, and ultimately lead to more livable, resilient, and prosperous cities for all.

Background: Microbiome-Inspired Green Infrastructure (MIGI) was recently proposed as an integrative system to promote healthy urban ecosystems, through multidisciplinary design. Specifically, MIGI is defined as nature-centric infrastructure restored and/or designed and managed to enhance health-promoting interactions between humans and environmental microbiomes, whilst sustaining microbially-mediated ecosystem functionality and resilience. MIGI also aims to stimulate a research agenda that focuses on considerations for the importance of urban environmental microbiomes. Objectives: In this paper we provide details of what MIGI entails from a bioscience and biodesign perspective, highlighting the potential dual benefits for human and ecosystem health. We present ‘what is known’ about the relationship between urban microbiomes, green infrastructure and environmental factors that may affect urban ecosystem health (ecosystem functionality and resilience as well as human health). We discuss how to start operationalising the MIGI concept based on current available knowledge, and present a horizon scan of emerging and future considerations in research and practice. We conclude by highlighting challenges to the implementation of MIGI and propose a series of workshops to discuss multi-stakeholder needs and opportunities. Discussion: This article will enable urban landscape managers to incorporate initial considerations for the microbiome in their development projects to promote human and ecosystem health. However, overcoming the challenges to operationalising MIGI will be essential to furthering its practical development. Although the research is in its infancy, there is considerable potential for MIGI to help deliver sustainable urban development driven by considerations for reciprocal relations between humans and the foundations of our ecosystems –– the microorganisms.

Infant electrocardiograms (ECG) and heart rates (HR) are very useful biosignals for psychological research and clinical work, but can be hard to analyze properly, particularly long form (≥5 minutes) recordings taken in naturalistic environments. Infant HRs are typically much faster than adult HRs, and so some of the underlying frequency assumptions made about adult ECGs may not hold for infants. However, the bulk of publicly available ECG approaches focus on adult data. Here, existing open-source ECG approaches are tested on infant datasets. The best performing open-source method is then modified to maximize its performance on infant data (e.g., including a 15Hz high pass filter, adding local peak correction). The HR signal is then subsequently analyzed, developing an approach for cleaning data with separate sets of parameters for the analysis of cleaner and noisier HR. A Signal Quality Index (SQI) for HR is also developed, providing insight into where a signal is recoverable and where it is not, allowing for more confidence in analysis performed on naturalistic recordings. The tools developed and reported in this paper provide a base for future analysis of infant ECG and related biophysical characteristics. Of particular importance, the proposed solutions outlined here can be efficiently applied to real-world large datasets.

The use of recombinant bovine somatotropin (rbST) leads to an increase, in variable amounts, of milk production in buffalo, but there is a lack of information on the influence of rbST on their metabolism. This study looked at the effects of a single 500 mg dose of rbST on lipid profile, liver and kidney function and physical, chemical and cellular constitution of milk in 14 buffalo over 14 days, from the 100th day of lactation, and compared them with 14 animals in a control group. From the 1st day after rbST, there was a rise in beta hydroxybutyrate (β-HBO), possibly due to the higher dry matter intake or by biotransformation of NEFA into β-HBO. Treatment did not influence blood glucose, non-esterified fatty acids (NEFA), triglycerides, cholesterol, total protein, albumin, AST, GGT, bilirubin, urea or creatinine. In 71.3% of the buffalo there was a gradual increase in milk production with maximal response in the first week that was then followed by a gradual decrease, whilst in 21.4%, the increase in production occurred between 7 and 10 days, and only 7.1% of animals did not respond. On the 3rd, 5th, 7th and 10th days after treatment, an increase was found in milk production between the two groups equal to 1.04, 1.52, 1.42 and 1.06 liters, respectively. In relative terms this means an increase in milk production, respectively, of 15.1%; 21.0%; 19.8 % and 15.1 %. The constitution of the milk showed no difference in the amounts of fat, lactose, total solids or somatic cell count; however, on the 3rd day after rbST, there was a decrease in protein; notably, from the 5th day, protein values show no statistical difference. It can be concluded that the application of rbST in buffalo from the 100th day of lactation is metabolically safe, since the treatment neither caused imbalances in fat metabolism nor overloaded the liver or renal function, and the changes in milk composition were transient and limited to a decrease in milk protein.

Forest degradation is known to be widespread in the tropics, but is currently very poorly mapped, in part because there is little quantitative data on which satellite sensor characteristics and analysis methods are best at detecting it. To improve this, we used data from the Tropical Forest Degradation Experiment (FODEX) plots in the southern Peruvian Amazon, where different numbers of trees had been removed from four 1 ha forest plots, carefully inventoried by hand and Terrestrial Laser Scanning before and after the logging to give a range of biomass change (ΔAGB) values. We conducted a comparative study of six multispectral optical satellite sensors (WorldView-3, SkySat, SPOT-7, PlanetScope, Sentinel-2 and Landsat 8) at 0.3 – 30 m spatial resolution, to find the best combination of sensor and remote sensing indicator for change detection. Spectral reflectance, the Normalized Difference Vegetation Index (NDVI) and texture parameters were extracted after radiometric calibration and image preprocessing. The strength of the relationships between the change in these values and field-measured ΔAGB (computed in % ha−1) was analysed. The results demonstrate that: (a) texture measures correlates more with ΔAGB than simple spectral parameters; (b) the strongest correlations are achieved for those sensors with spatial resolutions in the intermediate range (1.5 - 10 m), with finer or coarser resolutions producing worse results, and (c) when texture is computed using a moving square window ranging between 9 - 14 m in length. Maps predicting ΔAGB showed very promising results using a NIR-derived texture parameter for 3 m resolution PlanetScope (R2 = 0.97 and RMSE = 1.80 % ha−1), followed by 1.5 m SPOT-7 (R2 = 0.74 and RMSE = 5.25 % ha−1) and 10 m Sentinel-2 (R2 = 0.71 and RMSE = 5.55 % ha−1). Texture models derived from 0.3 m WorldView-3 improved with increasing window size, with highest R2 of 0.62 and RMSE = 6.35 % ha−1 for a window of 14 m in length. The degradation in our field plots is invisible to the 30 m resolution Landsat data. Our findings imply that, at least for lowland Peru, low-medium intensity disturbance can be detected best in optical wavelengths using a texture measure derived from 3 m PlanetScope data. That such data are being collected daily, and currently released free as monthly mosaics over tropical forests as part of the Norway’s International Climate and Forest Initiative (NICFI), is excellent news for monitoring such degradation.

Differentiated thyroid cancer (DTC), comprising of papillary and follicular thyroid cancers, is the most prevalent type of thyroid malignancy. Accurate prediction of DTC is crucial for improving patient outcomes. Machine learning (ML) offers a promising approach to analyze risk factors and predict cancer recurrence. In this study, we aimed to develop predictive models to identify patients at an elevated risk of DTC recurrence based on 16 risk factors. We developed six ML models and applied them to a DTC dataset. We evaluated the ML models using Synthetic Minority Over-Sampling Technique (SMOTE) and with hyperparameter tuning. We measured the models’ performance using precision, recall, F1 score, and accuracy. Results showed that Random Forest consistently outperformed the other investigated models (KNN, SVM, Decision Tree, AdaBoost, and XGBoost) across all scenarios, demonstrating high accuracy and balanced precision and recall. The application of SMOTE improved model performance and hyperparameter tuning enhanced overall model effectiveness.

In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, Pgc1a, and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, we found that the elevated adiposity in the ApoA1 knock out mice is associated with a significant reduction of the hematopoietic stem cells and common myeloid, but not common lymphoid, progenitors. Moreover, the “beiging”-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1, and most probably HDL-C, regulate bone marrow microenvironment, favouring beige/brown adipocyte characteristics.

Embryonic development proceeds through a series of differentiation events. The mosaic version of this process (binary cell divisions) can be analyzed by comparing early development of Ciona intestinalis and Caenorhabditis elegans. To do this, we reorganize lineage trees into differentiation trees using the graph theory ordering of relative cell volume. Lineage and differentiation trees provide us with means to classify each cell using binary codes. Extracting data characterizing lineage tree position, cell volume, and nucleus position for each cell during early embryogenesis, we conduct several statistical analyses, both within and between taxa. We compare both cell volume distributions and cell volume across developmental time within and between single species and assess differences between lineage tree and differentiation tree orderings. This enhances our understanding of the differentiation events in a model of pure mosaic embryogenesis and its relationship to evolutionary conservation. We also contribute several new techniques for assessing both differences between lineage trees and differentiation trees, and differences between differentiation trees of different species. The results suggest that at the level of differentiation trees, there are broad similarities between distantly related mosaic embryos that might be essential to understanding evolutionary change and phylogeny reconstruction. Differentiation trees may therefore provide a basis for an Evo-Devo Postmodern Synthesis.

Chronic Chagas Cardiomyopathy (CCC) results from infection with the protozoan parasite Trypanosoma cruzi and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H/HeN mice chronically infected with T. cruzi JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC. We utilized electrocardiography (ECG) to monitor T. cruzi-infected mice and determine whether ECG markers could be correlated with cardiac function abnormalities. We found that the C3H/HeN:JR combination frequently displayed early onset CCC indicators, such as sinus bradycardia and right bundle branch block, as well as prolonged PQ, PR, RR, ST and QT intervals in the acute stage. Our model exhibited high levels of cardiac inflammation and enhanced iNOS expression in the acute stage, but denervation did not appear to have a role in pathology. These results demonstrate the potential of the C3H/HeN:JR host:parasite combination as a model for CCC that could be used for screening new compounds targeted at cardiac remodeling and for examining the potential of anti-parasitic drugs to prevent or alleviate CCC development and progression.

Community-level mass treatment with azithromycin has been associated with a mortality benefit in children. However, antibiotic exposures result in disruption of the gut microbiota and repeated exposures may reduce recovery of the gut flora. We conducted a nested cohort study to examine associations between mass drug administration (MDA) with azithromycin and the gut microbiota of rural Malawian children aged between 1-59 months. Fecal samples were collected from the children prior to treatment and 6 months after two or four biannual rounds of azithromycin treatment. DNA was extracted from fecal samples and V4-16S rRNA sequencing used to characterize the gut microbiota. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. There were no associations between azithromycin treatment and changes in alpha diversity, however, four biannual rounds of treatment were associated with increased abundance of Prevotella. The lack of significant changes in gut microbiota after four biannual treatments supports the use of mass azithromycin treatment to reduce mortality in children living in low- and middle-income settings.

The Galápagos Islands are one of the most emblematic protected areas on the planet, and also one of the most studied. Their main economic activity is tourism, which has grown rapidly in recent years. The increase in tourists is associated with the increase in population and the introduction of invasive species, which puts conservation at risk. This makes adequate management even more necessary and relevant on an international scale, since the economy of Galápagos depends on the good state of conservation of its ecosystems and species. Numerous studies have shown that social factors, rather than physical-natural ones, determine the success or failure of a marine protected area (MPA), so they must be urgently incorporated into all phases of MPA management. In this study we have analyzed the management of the protected areas of Galápagos: the National Park and the Marine Reserve. The methodology used presents five prescribed scenarios in which priority is given to one or other factors, each of which has an impact on biophysical and socio-economic systems that are influenced by the MPA. These scenarios have been called: proactive, interactive, centralized, learning, and formal management. The results show that the archipelago's protected areas follow a proactive management model, with a continuous feedback loop. This feedback is a key element in any adaptive management process, which also allows practitioners to anticipate future problems. Both public participation and strategic planning are essential.

Current satellite remote sensing methods struggle to detect and map forest degradation, a critical issue as it is likely a major and growing source of carbon emissions and biodiveristy loss. TanDEM-X InSAR phase height (hϕ) is a promising variable for measuring forest disturbances, as it is closely related to mean canopy height, and thus should decrease if canopy trees are removed. However, previous research has focused on relatively flat terrain, despite the fact that much of the worlds’ remaining tropical forests are found in hilly areas, and this inevitably introduces artifacts in sideways imaging systems. In this paper, we find a relationship between hϕ and aboveground biomass change in four selectively logged plots in a hilly region of central Gabon. We show that minimising the level of multilooking in the interferometric processing chain strengthens this relationship, and that degradation estimates across steep slopes in the surrounding region are improved by selecting data from the most appropriate pass directions on a pixel-by-pixel basis. This shows that TanDEM-X InSAR can measure the magnitude of degradation, and that topographic effects can be mitigated if data from multiple SAR viewing geometries are available.

BACKGROUNDRestrictive practices are defined by measures linked to physical and chemical restraints to reduce the movement or control behaviours during any emergency. Seclusion is an equal part of restrictive practices intended to isolate and reduce the sensory stimulation to safeguard the patient and those within the vicinity. Using interventions by way of virtual reality (VR) could assist with reducing the need for restrictive practices as it could help reduce anxiety or agitation by way of placing users into realistic and immersive environments. This could also aid staff to and change current restrictive practices.AIMTo assess the feasibility and effectiveness of using a VR platform to provide reduction in restrictive practice (RRP) training. METHODSThe study received ethics approval was obtained prior to starting the study from the Health Research Authority in United Kingdom (22/HRA/3030 REFERENCE). A randomised controlled feasibility study was conducted alongside of an evaluation at at 1 month and 6 within inpatient psychiatric wards at Southern Health NHS Foundation Trust, UK. Virti Virtual Reality scenarios will be used on VR headsets to provide training on reducing restrictive practices in 3 inpatient psychiatric wards. Outcome measures included General Self-Efficacy (GSE) scale, Generalised Anxiety Disorder Assessment 7 (GAD-7), Burnout Assessment Tool (BAT-12), The Everyday Discrimination (EDS) Scale, and the Compassionate Engagement and Action (CEA) Scale. RESULTSThe statistical significance of most variables is high, with the exception of the BAT12 score, compassionate engagement to others score, compassionate to others total score, compassionate engagement from others score, and compassionate from others total score, which exhibit lower statistical power in two-sample t-tests. To assess the acceptability, preference, and adherence of users to the Virti VR technology for RRP training, we calculated the System Usability Scale (SUS) scores and visualized the program's completion using pie charts. The majority of respondents reported SUS scores exceeding 70, with a mean SUS score of 71.79. In accordance with the insights provided by Bangor et al. (38), the VR platform demonstrated superior usability compared to approximately 62% of other products. we utilized the GAD7 score to assess the confidence levels within the two groups. We compared the data for the VR group and the control group after one month, as well as the baseline and one-month data for both the VR group and the control group. Given that the p-values are below 0.05 and the statistical power is high, it can be concluded that there are no statistically significant differences in confidence levels between the VR and control groups at baseline and day-30. CONCLUSIONSOur study has revealed the challenges associated with implementing such a program, even though the staff has given it high usability ratings. With the ongoing advancement of VR technology, we have the capability to create scenarios and simulations tailored to various healthcare environments. This empowers staff to receive more comprehensive and effective training for handling a wide range of situations.

Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC), implicated in tumorigenesis, invasion, and drug resistance, and characterized by elevated expression of stem cell markers, such as CD133. We previously showed that siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. The current study investigates underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockdown or Dox-inducible expression of CD133. To maintain stable expression of CD133, MACS-sorted CD133(+) positive cells were expanded by ROCK-mediated conditional reprogramming of BAKP melanoma cells (BAKR). BAKR showed increased survival via reduced apoptosis after exposure to trametinib or DTIC, compared to BAKP. CRISPR-Cas9- mediated CD133 knockdown in BAKR cells (BAKR-T3) re-sensitized the cells, while CRISPR-Cas9 knockdown of CD133 in parental BAKP and POT cells even further increased trametinib-induced apoptosis (cleaved PARP) by reducing levels of anti-apoptotic BCL-xL, p-AKT, and p-BAD, and increasing pro-apoptotic BAD and active BAX. Dox-induced CD133 overexpression had the opposite effect, and blocked trametinib-induced apoptosis in both cell lines, coincident with elevated p-AKT, p-BAD, BCL-2 and BCL-xL and decreased levels of the active form of BAX and caspases-3 and -9. The roles of CD133 in AKT and BAD phosphorylation, or in the upregulation of anti-apoptotic BCL-2 family members, was further investigated by AKT knockout with siRNA, or inhibition of BCL-2 family members with navitoclax (ABT-263). Similar to CD133 knockdown, AKT1/2 siRNA knockdown in BAKP cells also reduced p-BAD. CD133 knockdown (T3)-mediated reduction of pBAD levels was equivalent in AKT-knockdown or AKT control cells indicating that CD133 may be upstream of AKT signaling. In BAKP cells treated with trametinib and/or ABT-263, effects of ABT-263 mirrored CD133 knockdown, since levels of active BAX and cleaved-PARP in BAKP-SC (CD133-) cells increased to the same level as that exhibited by BAKP-T3 cells (CD133+). CD133 may therefore activate a survival pathway where 1) increased phosphorylation of AKT induces 2) phosphorylation and inactivation of BAD, 3) decrease in the active form of BAX, and 4) reduction in caspase-mediated PARP cleavage, indicating apoptosis suppression leading to drug resistance in melanomas. Targeting survival pathways by which CD133 may confer chemoresistance in MICs can contribute to development of more effective treatments for patients with high-risk melanoma.

As renewed interest in human space-exploration intensifies, a coherent and modernized strategy for mission-design and planning has become increasingly crucial. Biotechnology has emerged as a promising approach to increase mission resilience, flexibility, and efficiency by virtue of its ability to efficiently utilize in situ resources and reclaim resources from waste streams. Since its infancy during the Apollo years, biotechnology, and specifically biomanufacturing, have witnessed significant expansions of scope and scale. Here we outline four primary mission classes, on Luna and Mars, that drive a staged and accretive biomanufacturing strategy. Each class requires a unique approach to integrate biomanufacturing into the existing mission architecture and so faces unique challenges in technology development.These challenges stem directly from the resources available in a given mission class – the degree to which feedstocks are derived from cargo and in situ resources – and the degree to which loop-closure is necessary. We see that as mission duration and distance from Earth increase, the benefits of specialized sustainable biomanufacturing processes increases. Here we present a strategic approach, guided by technoeconomics, to development, testing, and deployment of these technologies serves to nucleate the larger effort of supporting a sustained human presence in space. The processes needed for each scenario spans the technical breadth of synthetic biology to design engineering, from sophisticated genetic tailoring of chassis-organisms to building scalable, automated, easily operable bioreactors and processing systems. As space-related technology development often does, these advancements are likely to have profound implications for the creation of a stable, resilient bioeconomy on Earth.

As variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, assessment of vaccine immunogenicity remains a critical factor to support continued vaccination. To this end, an in vitro microneutralization (MN50) assay was validated to quantitate SARS-CoV-2 neutralizing antibodies against ancestral and variant strains (Beta, Delta, Omicron BA.1, Omicron BA.5 and XBB.1.5) in human serum. For ancestral strain, the MN50 assay met acceptance criteria for inter-/intra-assay precision, specificity, linearity, and selectivity. The assay was robust against changes to virus/serum incubation time, cell seeding density, virus content per well, cell passage number, and serum interference. Analyte in serum samples was stable up to 5 freeze/thaw cycles and for up to 12 months of storage at –80 ± 10 °C. Similar results were observed for the variant-adapted MN50 assays. The conversion factor to convert assay result units to WHO international standard units (IU/mL) was determined to be 0.62 for the ancestral prototype strain. This MN50 assay will be useful for vaccine immunogenicity analyses in clinical trial samples, enabling assessment of vaccine immunogenicity for ancestral and variant strains as variant-adapted vaccines are developed.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role, and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Furunculosis, caused by Aeromonas salmonicida, poses a significant threat to both salmonid and non-salmonid fish in diverse aquatic environments. This study explores the genomic intricacies of re-emergent A. salmonicida outbreaks in Atlantic salmon (Salmo salar). Previous clinical cases have exhibited pathological characteristics, such as periorbital hemorrhages and gastrointestinal abnormalities. Genomic sequencing of three Chilean isolates (ASA04, ASA05, and CIBA_5017) and 25 previously described genomes determined the pan-genome, phylogenomics, insertion sequences, and restriction-modification systems. Unique gene families have contributed to an improved understanding of the psychrophilic and mesophilic clades, while phylogenomic analysis has been used to identify mesophilic and psychrophilic strains, thereby further differentiating between typical and atypical psychrophilic isolates. Diverse insertion sequences and restriction-modification patterns have highlighted genomic structural differences and virulence factor predictions can emphasize exotoxin disparities, especially between psychrophilic and mesophilic strains. Thus, a novel plasmid was characterized, which emphasized the role of plasmids in virulence and antibiotic resistance. The analysis of antibiotic resistance factors revealed resistance against various drug classes in Chilean strains. Overall, this study elucidates the genomic dynamics of re-emergent A. salmonicida and provides novel insights into their virulence, antibiotic resistance, and population structure. However, rigorous monitoring and control in aquaculture remain crucial to mitigate the spread of antibiotic resistance.

Headstarting is a conservation approach that suggests offering an advantage to a population by improving egg production, survival of embryos and/or juveniles. In this article, we are providing the quantitative data obtained during 10-years for different stages of headstarting (production of eggs per pair, hatching and fledging rates) and the resulting impact (survival to maturity, philopatry rate, sex ratio, apparent survival, growth/decline rate) on the local population of the critically endangered spoon-billed sandpiper. We have shown that headstarting gain is reduced over time from fledging to long-term recruitment to the local breeding population. The possible reasons for this reduction are suggested and discussed. The unexpected finding was a drastic difference in sex ratios of the new recruits which was about even for headstaring, but strongly male-biased for wild reared birds. We suggest that to happen due to increased mortality of female chicks in nature. We have also shown only headstarting could stop the global decline of the species, particularly once the suggested improvements are implemented and the number of pairs involved is scaled up. Headstarting also had a significant social effect due to involvement of in-creasing numbers of people both in the local communities in Chukotka and from many countries on the flyway into searching for marked birds and learning about waders, raising awareness about ecological problems on the East Asian-Australasian Flyway, thus, making the need for conservation actions on the flyway more obvious and sensible.

Background & Aims: Reports of a rise in childhood cancer incidence in Australia and globally prompted the investigation of cancer incidence and survival in South Australia (SA) and the Northern Territory (NT) over a 28-year period, with emphasis on Indigenous peoples. Methods: This cross-sectional analysis of two prospective longitudinal databases, the SA and NT Cancer Registries (1990-2017), included all reported cases of childhood cancers. Poisson regression provided estimates of incidence rate ratios and survival was modelled using Cox proportional hazard models for children aged 0.05). With reference to the 1990-1999 era, overall survival improved in subsequent eras in SA (2000-2009: HR 0.53 [0.38-0.73]; 2010-2017: 0.44 [0.28-0.68]); however, remained unchanged in the NT (2000-2009: 0.78 [0.40-1.51]; 2010-2017: 0.50 [0.24-1.05]). In the NT, overall survival of Indigenous patients was significantly lower compared with the non-Indigenous cohort (3.42 [1.92-6.10]). While the survival of Indigenous children with cancer significantly improved in the last two eras (p0.05). Conclusions: The incidence of childhood cancers has remained unchanged over 28-years in SA and the NT. Encouragingly, improved survival rates over time were observed in SA and amongst Indigenous children of the NT. Nevertheless, survival rates in Indigenous children remain lower than non-Indigenous children.

Introduction- The dynamics of SARS-CoV-2 shedding and replication in humans remain incompletely understood. Methods- We analyzed SARS-CoV-2 shedding from multiple sites in individuals with an acute COVID-19 infection by weekly sampling for five weeks in 98 immunocompetent and 25 immunosuppressed individuals. Samples and culture supernatants were tested by RT-PCR for SARS-CoV-2 to determine viral clearance rates and in vitro replication. Results- A total of 2447 clinical specimens were evaluated, including 557 nasopharyngeal swabs, 527 saliva samples, 464 urine specimens, 437 anal swabs and 462 blood samples. The SARS-CoV-2 genome sequences at each site were classified as belonging to the B.1.128 (ancestral strain) or Gamma lineage. SARS CoV-2 detection was highest in nasopharyngeal swabs regardless of the virus strain involved or the immune status of infected individuals. The duration of viral shedding varied between clinical specimens and individual patients. Prolonged shedding of potentially infectious virus varied from 10 days up to 191 days, and primarily occurred in immunosuppressed individuals. Virus was isolated in culture from 18 nasal swab or saliva samples collected 10 or more days after onset of disease. Conclusions-Our findings indicate that persistent SARS-CoV-2 shedding may occur in both competent or immunosuppressed individuals, at multiple clinical sites and in a minority of subjects is capable of in vitro replication.

The analysis reported here is unique in that it is the first study of the original data from the Pfizer/BioNTech BNT162b2 mRNA vaccine clinical trial (CA4591001) to be carried out by a group unaffiliated with the trial sponsor. Our study is a forensic analysis of the 38 trial subjects who died between July 27, 2020, the start of Phase 2/3 of the clinical trial, and March 13, 2021, the data end date of their 6-Month Interim Report. Phase 2/3 of the trial involved 44,060 subjects who were equally distributed into two groups and received Dose 1 of either the BNT162b2 mRNA vaccinated or the Placebo control (0.9% normal saline). At Week 20, when the BNT162b2 mRNA vaccine received Emergency Use Authorization from the U.S. FDA, subjects in the placebo arm were given the option to be BNT162b2 vaccinated. All but a few accepted. Surprisingly, a comparison of the number of subject deaths per week during the 33 Weeks of this study found no significant difference between the number of deaths in the vaccinated versus placebo arms for the first 20 weeks of the trial, the placebo-controlled portion of the trial. After Week 20, as subjects in the Placebo were unblinded and vaccinated, deaths among this still unvaccinated cohort of this group slowed and eventually plateaued. Deaths in the BNT162b2 vaccinated subjects continued at the same rate. Our analysis revealed inconsistencies between the subject data listed in the 6-Month Interim Report and publications authored by Pfizer/BioNTech trial site administrators. Most importantly, we found evidence of an over 3.7-fold increase in number of deaths due to cardiovascular events in BNT162b2 vaccinated subjects compared to Placebo controls. This significant adverse event signal was not reported by Pfizer/BioNTech. Potential sources of these data inconsistencies are identified.

Inducible genetically defined mouse models of cancer uniquely facilitate the investigation of early events in cancer progression, however there are valid concerns about the ability of such models to faithfully recapitulate human disease. We developed an inducible mouse model of progressive lung adenocarcinoma (LuAd) that combines sporadic activation of oncogenic KRas^G12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible transition from adenoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation. Laser-capture microdissection coupled with RNA-SEQ was employed to determine transcriptional changes associated with tumour progression. Upregulated genes were triaged for relevance to human LuAd using datasets from Oncomine and cBioportal. Selected genes were validated by RNAi screening in human lung cancer cell lines and examined for association with lung cancer patient overall survival using KMplot.com. Depletion of progression-associated genes resulted in pronounced viability and/or cell migration defects in human lung cancer cells. Progression-associated genes moreover exhibited strong associations with overall survival, specifically in human lung adenocarcinoma, but not in squamous cell carcinoma. The KM mouse model faithfully recapitulates key molecular events in human lung cancer and is a useful tool for mechanistic interrogation of LuAd progression.

Background: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between epithelial and mesenchymal stage is essential for tissue homeo-stasis. Many of the genes promoting mesenchymal transformation has been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify genes responsible for maintaining the epithelial phenotype and in-hibiting EMT. Methods: RNA seq was performed using an vitro model of EMT. CTGF expres-sion was determined by qPCR and Western blot analysis. Knockout of CTGF was done using the CTGF sgRNA CRISPR/CAS9. Tumorigenic potential was determined using NCG mice. Results: Knocked-out of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as Anoikis resistance, cytoskel-eton remodeling, increased cell stiffness, and acquisition of invasion and tumorigenic capacity. Conclusions: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for conserva-tion of epithelial structure and function. These findings provide a new window to understand the early stages on mesenchymal transformation