Although the statistical methods of downscaling climate data have progressed significantly, the development of high-resolution precipitation products continues to be a challenge. This is especially true when interest centres on downscaling value over several study sites. In this paper , we report a new downscaling method termed the multi-site Climate Generative Adversarial Network (MSCliGAN), which can simulate annual maximum precipitation to the regional scale during the 1950-2010 period in different cities in Canada by using different AOGCM's from the Coupled Model Inter-Comparison Project 6 (CMIP6) as input. Auxiliary information provided to the downscaling model included topography and land-cover. The downscaling framework uses a convolution encoder-decoder U-net network to create a generative network and a convolution encoder network to create a critic network. An adversarial training strategy is used to train the model. The critic/discriminator used Wasserstein distance as a loss measure and on the other hand the generator is optimized using a summation of content loss on Nash-Shutcliff Model Efficiency (NS), structural loss on structural similarity index (SSIM), and adversarial loss Wasserstein distance. Downscaling results show that downscaling AOGCMs by incorporating topography and land-use/land-cover can produce spatially coherent fields close to observation over multiple-sites. We believe the model has sufficient downscaling potential in data sparse regions where climate change information is often urgently needed.

Despite numerous studies in statistical downscaling methodology, there remains a lack of methods that can downscale from precipitation modeled in global climate models to regional level high resolution gridded precipitation. This paper reports a novel downscaling method using a Generative Adversarial Network (GAN), CliGAN, which can downscale large-scale annual maximum precipitation given by simulation of multiple atmosphere-ocean global climate models (AOGCM) from Coupled Model Inter-comparison Project 6 (CMIP6) to regional-level gridded annual maximum precipitation data. This framework utilizes a convolution encoder-dense decoder network to create a generative network and a similar network to create a critic network. The model is trained using an adversarial training approach. The critic uses the Wasserstein distance loss function and the generator is trained using a combination of adversarial loss Wasserstein distance, structural loss with the multi-scale structural similarity index (MSSIM), and content loss with the Nash-Sutcliff Model Efficiency (NS). The MSSIM index allowed us to gain insight into the model’s regional characteristics and shows that relying exclusively on point-based error functions, widely used in statistical downscaling, may not be enough to reliably simulate regional precipitation characteristics. Further use of structural loss functions within CNN-based downscaling methods may lead to higher quality downscaled climate model products.

The widespread availability of tools to collect and share spatial data enables us to produce a large amount of geographic information on a daily basis. This enormous production of spatial data requires scalable data management systems. Geospatial architectures have changed from clusters to cloud architectures and more parallel and distributed processing platforms to be able to tackle these challenges. Peer-to-peer (P2P) systems as a backbone of distributed systems have been established in several application areas such as web3, blockchains, and crypto-currencies. Unlike centralized systems, data storage in P2P networks is distributed across network nodes, providing scalability and no single point of failure. However, managing and processing queries on these networks has always been challenging. In this work, we propose a spatio-temporal indexing data structure, DSTree. DSTree does not require additional Distributed Hash Trees (DHT) to perform multi-dimensional range queries. Inserting a piece of new geographic information updates only a portion of the tree structure and does not impact the entire graph of the data. For example, for time-series data, such as storing sensor data, the DSTree performs better. Despite the advantages of our proposed framework, challenges remain. We conclude that more significant research effort from GIScience and related fields in developing decentralized applications is needed. The need for the standardization of different geographic information when sharing data on the IPFS network is one of the requirements.

We derive an uncertainty principle for Lipschitz maps acting on subsets of Banach spaces. We show that this nonlinear uncertainty principle reduces to the Heisenberg-Robertson-Schrodinger uncertainty principle for linear operators acting on Hilbert spaces.

We study C*-algebraic versions of following conjectures/theorems: (1) Bieberbach conjecture (de Branges theorem) (2) Robertson conjecture (3) Lebedev-Milin conjecture (4) Zalcman conjecture (5) Krzyz conjecture (6) Corona conjecture (Carleson theorem). We prove that the C*-algebraic Bieberbach Conjecture for invertible coefficients is true for second degree C*-algebraic polynomials.

In recent years, it has become common for individuals to juggle employment and unpaid care work. This is just as true for the England-based academic workforce, our focus in this article. We discuss how, in the context of English HE, support for carers is enacted and negotiated through policies and practices of care. Our focus on academics with a diverse range of caring responsibilities is unusual insofar as the literature on care in academia is overwhelmingly concerned with parents, usually mothers. The article is informed primarily by critical and post-structuralist feminist perspectives. We draw on a corpus of 47 interviews conducted with academics representing a broad range of caring responsibilities, subjects, and positions. A thematic analysis reveals how carers’ relationship with the provision and policies of care support at institutional level is characterised by ambiguity. On the one hand, participants approve of societal and institutional policy support for carers. On the other hand, they are often reluctant to position themselves as the beneficiary of such policies, expressing instead a general preference for support from outside the workplace or for workplace-based inter-individual and informal care arrangements. This resistance is particularly noticeable in the case of participants with caring responsibilities other than the parenting of healthy, able-bodied children and of those whose gender, class, racial, or sexual identity do not conform with the figure of the ‘ideal academic’, contributing to their othering in the academic realm. These findings have significant implications for policies supporting carers, pointing to the need for greater visibility and recognition of caring responsibilities in academia, especially in terms of their diverse identities.

There is increasing interdisciplinary interest in phytoplankton community dynamics as the growing environmental problems of water quality (particularly eutrophication) and climate change demand attention. This has led to a pressing need for improved biophysical and causal understanding of Phytoplankton Functional Type (PFT) optical signals, in order that satellite radiometry may be used to detect ecologically relevant phytoplankton assemblage changes. This understanding can best be achieved with biophysically and biogeochemically consistent phytoplankton Inherent Optical Property (IOP) models, as it is only via modelling that phytoplankton assemblage characteristics can be examined systematically in relation to the bulk optical waterleaving signal. The Equivalent Algal Populations (EAP) model is used here to investigate the source and magnitude of size- and pigment- driven PFT signals in the water-leaving reflectance, as well as the potential to detect these using satellite radiometry. This model places emphasis on explicit biophysical modelling of the phytoplankton population as a holistic determinant of IOPs, and a distinctive attribute is its comprehensive handling of the spectral and angular character of phytoplankton scattering. Selected case studies and sensitivity analyses reveal that phytoplankton spectral scattering is the primary driver of the PFT-related signal. Key findings are that the backscattering-driven signal in the 520 to 600 nm region is the critical PFT identifier at marginal biomass, and that while PFT information does appear at blue and red wavelengths, it is compromised by biomass/gelbstoff ambiguity in the blue and low signal in the red, due primarily to absorption by water. These findings are hoped to provide considerable insight into the next generation of PFT algorithms.

Bacillus thuringiensis (Bt) is a spore-forming bacterium that produces insecticidal proteins and other virulence factors and is considered one of the most successful bioinsecticides available to control pests in agriculture. Bt strains have been reported as endophyte or rhizospheric bacteria, but little is known about the implications of this property of Bt in crop protection. Here, we review if Bt can establish as an endophyte/rhizobacterium and evaluate if Bt as an endophyte/rhizobacterium can simultaneously act against different phytopathogens (fungi, bacteria, insects and viruses) plus promote plant growth. The implications of the proposed review will broaden our understanding of Bt as a versatile entomopathogen by exhibiting differential behavior depending on context.

Most quantum gravity theories endow space-time with a discreet nature by space quantization on the order of Planck length (lp ). This discreetness could be demonstrated by confirmation of Lorentz invariance violations (LIV) manifested at length scales proportional to lp. In this paper, space-time line elements compatible with the uncertainty principle are calculated for a homogeneous, isotropic expanding Universe represented by the Friedmann-Lemaitre-Robertson-Walker solution to General Relativity (FLRW or FRW metric). To achieve this, the covariant geometric uncertainty principle (GeUP) is applied as a constraint over geodesics in FRW geometries. A generic expression for the quadratic proper space-time line element is derived, proportional to Planck length-squared and dependent on two contributions. The first is associated to the energy-time uncertainty, and the second depends on the Hubble function. The results are in agreement with space-time quantization on the expected length orders, according to quantum gravity theories and experimental constraints on LIV.

We propose a methodology for the quantification of model risk in the context of credit derivatives pricing and CVA, where the uncertain or unmodelled parameter is often the correlation between rates and credit. We take the rates model to be Hull-White (normal) and the credit model to be Black-Karasinski (lognormal). We show how highly accurate analytic pricing formulae, hitherto unpublished, can be derived for CDS and extended to address instruments with defaultable Libor flows which may in addition be capped and/or floored. We also consider the pricing of a contingent CDS with an interest rate swap underlying. We derive explicit expressions showing how to good accuracy the dependence of model prices on the uncertain parameter(s) can be captured in analytic formulae which are readily amenable to computation without recourse to Monte Carlo or lattice-based computation. In so doing, we take into account the impact on model calibration of the uncertain (or unmodelled) parameter.

Chimeric antigen receptor and T-cell receptor (CAR-T/TCR) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1,007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR industry may be a robust response to success and failure of competitor products.

Peer-to-peer (P2P) energy trading is a new data-driven business model currently being trialed within the energy sector. Introducing P2P transactions to an essential service such as energy could have far-reaching implications for individuals and the grid. This paper raises considerations and questions from social, economic/markets and regulatory points of view, that should be understood and addressed by societies and policymakers. It does this by considering under what circumstances it is reasonable to conceptualize P2P energy trading as part of the sharing economy, and drawing parallels to the sharing economy experience in other sectors. In order to reap the full societal benefits, while avoiding considerable risks to infrastructure and individuals, a policy approach promoting dialogue and innovation is necessary. We suggest the regulatory sandbox is the most appropriate tool to achieve this and would help avoid the breakdown of trust between policymakers and platform companies observed in other sectors.

A novel compressible real gas 1D finite volume thermofluid network modelling methodology is proposed that can be applied in the analysis of supercritical CO₂ (sCO2) power cycles. It is applied to simulate centrifugal compressor performance via a mean line approach that directly solves the mass, energy, and momentum balance equations for the discretized flow channels within the machine along with the associated loss models, component characteristics, and applicable compressible real gas equation of state. This can be integrated seamlessly with the rest of the power cycle components like pipes, valves, heat exchangers, etc., thereby eliminating the need for static performance maps and the associated difficulties to ensure similarity over the whole range of operation. This direct simulation of the internal flows also makes it possible to do integrated cycle design optimization that includes the geometry of the compressors, and to simulate fast transients for dynamic analysis. The methodology was applied to simulate well-documented air and sCO2 centrifugal compressors and compared the generated results with that of conventional thermofluid network incompressible and compressible ideal gas approaches. The results indicate that the proposed compressible real gas approach can capture the stagnation pressure changes and isentropic efficiencies with good accuracy for both cases over the whole range of mass flow rates and shaft rotational speeds. In contrast, the conventional thermofluid network incompressible and compressible ideal gas approaches are only applicable in selected regions of the fluid property regime and suffer from discretization errors and inappropriate treatment of the relationship between stagnation and static pressures. Furthermore, comparative analyses between the newly proposed approach and the traditional mechanical energy balance method are performed, showing that the latter approach needs to be discretized more finely through the compression process to correctly capture the polytropic compression path shape, whereas the former more accurately captures the stagnation pressure changes through the analyzed compressors with only a single increment per compressor component.

It has been proposed that upregulation of the noradrenergic (NA) system through exposure to novelty might be one of the key components for building cognitive reserve and resilience to neurodegeneration. A personality trait that promotes greater interest in novel experiences is Openness to Experience (OE). Individuals who are high in OE exhibit strong curiosity towards novelty and are more likely to be exposed to novel stimuli throughout the lifespan.Performing voxel-based morphometry analyses, we examined whether OE in 135 healthy young adults was associated with Locus Coeruleus (LC) - the main core of the noradrenergic system. We also investigated whether LC mediates the relationship between OE and a key measure of reserve, I.Q. In comparison with other neuromodulators’ seeds (Dorsal and Median Raphe [DR-MR] -5-HT, Ventral Tegmental Area [VTA] -DA- and Nucleus Basalis of Meynert [NBM] -Ach-), results show that greater LC integrity was related to greater OE and IQ. Additionally, mediation analyses revealed that only LC mediated the relationship between OE and IQ. Furthermore, a Bayesian multiple regression was conducted to model the contribution of both isolated and combined neuromodulator seeds to OE trait express. This approach found that the LC + VTA could account for more variance in OE expression compared to the LC alone. Other weaker but significant associations were observed between DR and OE, between LC + NBM and Conscientiousness and between DR + NBM and Extraversion. These results are together suggestive that OE is primarily underpinned by monoaminergic functioning, and that the LC-NA system plays a central role mediating the interdependence between OE expression and cognition (IQ level). While offering further understanding of the neurobiology of human personality, these findings indicate a pivotal role of LC-NA system integrity in novelty seeking in daily life. This provides a psychobiological account for how OE expression may be beneficial for maintaining the noradrenergic system to facilitate cognitive reserve and resilience to neurodegenerative conditions.

Non-targeted effects (NTE) such as bystander effects or genomic instability have been known for many years but their significance for radiotherapy or medical diagnostic radiology are far from clear. Central to the issue are reported differences in response of normal and tumour tissues to signals from directly irradiated cells. This review will discuss possible mechanisms and implications of these different responses and will then discuss possible new therapeutic avenues suggested by the analysis. Finally, the importance of NTE for diagnostic radiology and nuclear medicine which stems from the dominance of NTE in the low dose region of the dose response curve will be presented. Areas such as second cancer induction and microenvironment plasticity will be discussed.

Reservoir computing is a machine learning method that uses the response of a dynamical system to a certain input in order to solve a task. As the training scheme only involves optimising the weights of the responses of the dynamical system, this method is particularly suited for hardware implementation. Furthermore, the inherent memory of dynamical systems which are suitable for use as reservoirs mean that this method has the potential to perform well on time series prediction tasks, as well as other tasks with time dependence. However, reservoir computing still requires extensive task dependent parameter optimisation in order to achieve good performance. We demonstrate that by including a time-delayed version of the input for various time series prediction tasks, good performance can be achieved with an unoptimised reservoir. Furthermore, we show that by including the appropriate time-delayed input, one unaltered reservoir can perform well on six different time series prediction tasks at a very low computational expense. Our approach is of particular relevance to hardware implemented reservoirs, as one does not necessarily have access to pertinent optimisation parameters in physical systems but the inclusion of an additional input is generally possible.

Yogic and meditative traditions have long held that the fluctuations of the breath and the mind are intimately related. While respiratory modulation of cortical activity and attentional switching are established, the extent to which electrophysiological markers of attention exhibit synchronization with respiration is unknown. To this end, we examined 1) frontal midline theta-beta ratio, an indicator of attentional control state known to correlate with mind wandering episodes and functional connectivity of the executive control network; 2) pupil diameter (PD), a known proxy measure of locus coeruleus (LC) noradrenergic activity; and 3) respiration for evidence of phase synchronization and information transfer (multivariate Granger causality) during quiet restful breathing. Our results indicate that both TBR and PD are simultaneously synchronized with the breath, suggesting an underlying oscillation of an attentionally relevant electrophysiological index that is phase-locked to the respiratory cycle which could have the potential to bias the attentional system into switching states. We highlight the LC’s pivotal role as a coupling mechanism between respiration and TBR, and elaborate on its dual functions as both a chemosensitive respiratory nucleus and a pacemaker of the attentional system. We further suggest that an appreciation of the dynamics of this weakly coupled oscillatory system could help deepen our understanding of the traditional claim of a relationship between breathing and attention.

Abstract: This paper summarises an early and successful piece of citizen science, performed within The University of Queensland Seismograph Stations (UQSS) observatory, in cooperation with colleagues at CSIRO. It was designed to en-courage young STEM students from Brisbane high schools to engage in “real” re-search, back in 1995. Having completed the project report, their (analog) results sat in a cupboard until the report was dusted off and the project was re-analysed in 2022 by an honors student, considering timely climate change applications for the study. This is a time when science is changing considerably from analog to digital medium and operational methods. The original project was called Earthquake generated T phases on BRS Seismograph (Brisbane, Q’ld)- a predictor for Tasman Sea Tsunamis? [1] Fortunately, seismology is a very collaborative field. The research question has since changed. There is a lot of data analysis involved in the science of recording earthquake signals, with auxiliary definitive catalogues, observers logbooks, housing of the recordings themselves (analog and digital) and the software mediums that change over time. In other words, a lot of headaches can be encountered in longitudinal data collection study such as this. The citizen science students used a pre-prepared decadal collection (1980-90) derived from the BRS observatory data catalogue. BRS is part of the global World-Wide Seismograph Station Network (WWSSN). Currently in Australia, university earth science observatories have diminished, and in their place, public seismic networks (PSN) have evolved, either in back-yard sheds or school science labs. The level of expertise required fits the role of advancing citizen science for a real science advantage. This is a topical citizen disaster preparedness action area for today’s climate emergency, which is threatening the globe and all lifeforms. Citizen engagement or mobilisation is an essential preparedness strategy. Keywords: citizen science 1; seismology 2; earth observation 3; climate change 4; education for sustainable development 5; disaster preparedness 6; disaster alerts 7

Abstract: The contribution of breakfast to diet quality (DQ) can inform future dietary guidelines. This study examined breakfasts that were associated with highest-quality diets. Dietary data came from the first reported day of the National Health and Examination Survey (NHANES) 2011-2014 (n=14,488). DQ measures were the Nutrient Rich Foods Index (NRF9.3) and the USDA Healthy Eating Index 2015 (HEI 2015). Analyses of breakfast intakes were conducted by NRF9.3 tertiles and by age and socioeconomic groups. Four out of 5 NHANES participants ate breakfast. Breakfast provided 19-22% of dietary energy depending on age. Breakfast intakes of complex carbohydrates and total sugars were higher and intakes of protein and fats were lower relative to energy intakes. Breakfast provided more that 20% of daily intakes of B vitamins, vitamins A and D, folate, calcium, iron, potassium and magnesium. Eating breakfast was associated with higher NRF9.3d scores. Breakfasts associated with top tertile of NRF9.3d had more carbohydrates and less added sugars and fats. Such breakfasts had more fruit and juices, more whole grains, more milk and yogurt and less meat and eggs. Breakfast patterns that favored fruit, whole grains, and dairy were associated with healthiest diets.

The interplay between Diffuse Idiopathic Skeletal Hyperostosis (DISH) and the gut microbiota represents a compelling area of research, offering insights into the relationship between spinal degenerative diseases and the gut's microbial inhabitants. This comprehensive review seeks to unravel the complex connection, shedding light on its implications for human health and potential therapeutic avenues. A crucial section dives into the world of gut microbiota (GM), exploring its impact on human health, featuring its defining characteristics, and highlighting its role in metabolism, immunomodulation, host interaction, and how its composition changes over time. The subsequent portion delves into the relationship between microbiome composition and pathological bone development, including the link between Intervertebral Disc Degeneration (IDD) and gut inflammation, emphasizing how gut inflammation and GM dysbiosis play pivotal roles. Further dissecting the interconnections, various axes of influence, including the gut-spine axis, gut-bone axis, gut-joint axis, gut-disc axis (specific to DISH), gut-ligament axis, and gut-muscle axis, are discussed. Of particular interest is the section on the impact of GM on DISH-derived pain, addressing a critical aspect of the condition's manifestation. The review discusses the potential of GM modulation as a treatment for DISH, providing hope for therapeutic advancements. Additionally, it highlights the positive impact of lifestyle interventions, such as dietary modifications, sleep optimization, and exercise regimens, in mitigating GM dysbiosis and potentially improving DISH outcomes. Lastly, the intriguing prospect of fecal microbiome transplant and its implications for DISH management is examined, opening new avenues for research and therapeutic interventions. In conclusion, this comprehensive review underscores the intricate interplay between DISH and the gut microbiota, offering a fresh perspective on the impact of GM on spinal degenerative diseases. It emphasizes the potential for innovative treatments, such as GM modulation and lifestyle interventions, and presents fecal microbiome transplant as an exciting area for future exploration.

The aim of this work was to investigate the microstructure and the mechanical properties of la-ser-welded joints combined of DP800 and DP1000 high strength thin steel sheets. The welded joints (WJ) comprised of similar/dissimilar steels with similar/dissimilar thickness were consisted of different zones and exhibited similar microstructural characteristics. The trend of microhard-ness for all WJs was consistent, characterized of the highest value at hardening zone (HZ) and lowest at softening zone (SZ). The degree of softening was more severe and the size of SZ was wider in the WJ combinations of DP1000 than DP800. The tensile test fractures were located at the base material (BM) for all DP800 weldments, while the fractures occurred at the fusion zone (FZ) for the weldments with DP1000 and those with dissimilar sheet thicknesses. The DP800-DP1000 weldment presented similar yield strength (YS) and ultimate tensile strength (UTS) values but lower elongation (EI) in comparison with the DP800-DP800 weldment, which showed similar strength properties as the BM of DP800. However, the EI of DP1000-DP1000 weldment was much lower in comparison with the BM of DP1000. The DP800-DP1000 weldment with dissimilar thicknesses showed the highest YS and UTS values compared with the other weldments, but with the lowest EI. The fatigue fractures occurred at the WJ for all types of weldments. The DP800-DP800 weldment had the highest fatigue limit and DP800-DP1000 with dissimilar thick-nesses had the lowest fatigue limit. The fatigue crack initiated from the weld surface.

The dynamic interaction between carbon nanodots (CNDs) and cannabidiol (CBD) has captured significant attention as an innovative avenue for redefining drug delivery and amplifying therapeutic effectiveness. This in-depth review delves into the intricate synergy between these two elements, unveiling their profound potential in medicine. Commencing with an examination of the unique characteristics of CNDs and the techniques governing their synthesis, we discuss their versatility as drug carriers, highlighting their invaluable role in advancing CBD delivery. Cannabidiol, a non-psychoactive compound sourced from cannabis, has emerged as a focal point for its diverse therapeutic attributes. Nevertheless, the limitations posed by its restricted bioavailability and susceptibility to degradation pose substantial hindrances to realizing its full potential. Here, we elucidate how the amalgamation of CBD with CNDs transcends these challenges. We delve into the mechanisms that underlie this synergy, such as the augmentation of solubility and the safeguarding of CBD against premature breakdown, providing an intricate analysis. We will also journey you through a comprehensive exploration of diverse CBD loading techniques onto CNDs, dissecting the realms of physical encapsulation, covalent bonding, and adsorption processes. In summation, the combination of CNDs and CBD presents an extraordinary opportunity to elevate therapeutic outcomes. This synergetic paradigm masterfully tackles pivotal challenges in drug delivery, thereby paving the path for pioneering medical solutions.

Drowning is a serious public health concern. Low middle income countries are mostly affected, as they carry 90% of the global drowning burden. The purpose of this epidemiological study is to provide a comprehensive overview of fatal drownings in South Africa between 2016 and 2021. The data used for the study was obtained from the South African Police Service. Descriptive statistics were used to summarise data. Statistical analysis included a t-test and chi-square test. The results indicate that the average fatal drownings per annum is 1477 in South Africa, with a drowning rate of 2.54 per 100 000 population from 2016 - 2021. The KwaZulu-Natal province had the highest incidence of drowning. The 0 – 4-year category has a high prevalence of drowning amongst all the age categories. More males drowned in South Africa compared to females. The study highlights key areas of concern these include age, sex, race, province, type of water body and time of day. This information is crucial to inform drowning prevention initiatives in South Africa.

The spillover of a virus from an animal reservoir to humans requires both molecular and ecological risk factors to align. While extensive research both before and after the emergence of SARS-CoV-2 in 2019 implicates horseshoe bats as the significant animal reservoir for the new human coronavirus, it remains unclear why it emerged at this time. One massive disruption to animal-human contacts in 2019 is linked to the on-going African swine fever virus (ASFV) pandemic. Pork is the major meat source in the Chinese diet. We hypothesize that the dramatic shortage of pork following large-scale culling and restrictions of pig movement (resulting in marked price increases) led to alternative sources of meat and unusual animal and meat movements nationwide, e.g., involving wildlife, and thus greatly increased opportunities for human-sarbecovirus contacts. Pork prices were particularly high in southern provinces (Guangdong, Guangxi, Fujian, Jiangxi, Hunan, and Hubei), where wildlife is farmed and more frequently consumed. Major wildlife farming provinces are spread from Northern to Southern China, which overlaps with horseshoe bat host ranges, potential hosts of the proximal SARS-CoV-2 ancestor, and wildlife sourcing provinces of Wuhan Huanan market and possibly other markets. Trading of SARS-CoV-2 susceptible wildlife in these markets, such as minks, raccoon dogs, foxes and palm civets in Wuhan markets, could have increased the risk of SARS-CoV-2 from an intermediary host. Moreover, large quantities of animals raised for fur could have entered the human food chain undetected and significantly increased risks of animal-human contact. Performing retrospective testing of stored susceptible animals and their meat sold before December 2019 may be helpful in the next stage of tracing the animal origin of SARS-CoV-2 as spillover events are more likely to have taken place in 2019 when China was experiencing the worst effects of the ASFV pandemic.

Summary CoV-GLUE is an online web application for the interpretation and analysis of SARS-CoV-2 virus genome sequences, with a focus on amino acid sequence variation. It is based on the GLUE data-centric bioinformatics environment and provides a browsable database of amino acid replacements and coding region indels that have been observed in sequences from the pandemic. Users may also analyse their own SARS-CoV-2 sequences by submitting them to the web application to receive an interactive report containing visualisations of phylogenetic classification and highlighting genomic variation of potentially high impact, for example linked to primer mismatches.Availability and implementation Available at http://cov-glue.cvr.gla.ac.uk. Implemented using GLUE, an open source framework for the development of virus sequence data resources. Contact [email protected]

The concept of a Social License to Operate (SLO) has become increasingly important in the sustainability literature in recent years. Having its origins in the business discourse of the mining industry with respect to limiting opposition to mining projects, the notion of a social contract above and beyond legal requirements has since become applied across a number of different industries. Despite the concepts adoption confusion exists over the practices and outcomes of SLO, and particularly the nature of engagement. Given this situation it is surprising that not more attention to the role of marketing, and social marketing in particular, in operationalizing the concept. The paper discusses the potential of social marketing to contribute to SLO. Economic, political and social relations are complex in SLO and exchange is intricate in such relational environments. A community-based social marketing orientation is proposed as a means to improve exchange relations and enhance engagement. Seven models of SLO related social marketing models are discussed with community-based social marketing and adaptive co-marketing models being regarded as the most positive for the achievement of an SLO. Potential barriers to adoption of these approaches are noted.

We present a summary of our protocol for employment of small-molecule circadian rhythm modulators. The abilities of compounds to affect oscillations have received significant attention. We outline assessments of circadian changes using indirubin-3’-oxime (IO), 5-iodo-indirubin-3’-oxime (5I-IO), and 5-sulfonic acid-indirubin-3’-oxime (5SA-IO), analyzing effects on Bmal1 and Per2 oscillations and oncogenic features.

The Ballynoe barite deposit is a conformable, mineralized horizon of Lower Carboniferous age overlying a diastem and mass faunal extinction demarking the transition from a quiet water environment to one of dynamic sedimentation. The geometry of the barite orebody correlates with the palaeo-topography of the footwall, which acted as an important control over the lateral extent, thickness and nature of the mineralization. Sedimentary features within the barite horizon suggest that it was precipitated in the form of a cryptocrystalline mud which underwent major diagenetic modification resulting in extensive stylolitisation, recrystallisation and remobilization. There is abundant and compelling geological and isotopic evidence for early local exhalation from the presence of a hydrothermal vent fauna consisting of a delicately pyritized worm tubes hosted and haematized filaments of apparent microbial origin. The worm tubes are remarkably similar to examples from modern and ancient volcanic-hosted massive sulphide deposits, and the filamentous microfossils have similarities to modern Fe-oxidizing bacteria. Strontium in the barite has a 87Sr/86Sr ratio indistinguishable from sea-water between 350 and 344Ma whilst oxygen isotopes from barite and chert suggest a diagenetic origin in equilibrium such sea-water around 60-70°C. Fluid inclusion studies have shown that, in general, low temperature inclusions are very saline (20-25%) whilst at higher homogenization temperatures they are more dilute (9-12%).

The field of human microbiome and gut microbial diversity research has witnessed a profound transformation, driven by advances in omics technologies. These advancements have unveiled essential connections between microbiome alterations and severe conditions, spurring the development of new frameworks through epidemiological studies. Traditionally, each individual was thought to harbor unique microbial communities acquired early in life, but recent research challenges this belief. The neonatal microbiome's onset, influenced by factors like delivery mode and maternal health, remains a subject of intense debate, hinting at potential intrauterine microbial processes. In-depth research reveals associations between microbiome profiles and specific health outcomes, ranging from obesity to neurodevelopmental disorders. Understanding these diverse microbiome profiles is essential for unraveling the intricate relationships between the microbiome and health outcomes.

Recent times have witnessed an increasing number of countries and private firms pledging carbon neutrality by mid-century. Whilst representing a significant improvement in intentions to tackle climate change, such pledges lack substance and structure. For instance, individual pledges lack coordination and aggregation among peers, while strategies and measures to achieve ambitious targets are largely absent. Moreover, current disagreements obstructing progress in international climate change negotiations further undermine the reliability of carbon neutrality objectives. Effective international policies are needed to foster aggregate mitigation ambitions and the creation of adequate supporting mechanisms. This theoretical paper describes a governance innovation aimed at overcoming such shortfalls and disagreements through a unifying yet customizable pathway towards carbon neutrality. It does so by first outlining a political governance framework based on a climate club interpretation of Article 6 of the Paris Agreement. Secondly, it proposes carbon emission mitigation effort sharing on a per capita basis to ensure efficiency, equity and political feasibility. Thirdly, this paper describes how the supply of certified mitigations of carbon emissions required to satisfy effort sharing-based demand can be assetized as carbon credits by operationalizing Article 6 as a joint certification mechanism. The resulting governance architecture for managing demand and supply of mitigations shifts efforts to tackle climate change from a ‘problem-driven’ cost approach to ‘opportunity-driven’ value creation pathways towards carbon neutrality.

Recently, the properties of bouncing oil droplets, also known as `walkers', have attracted much attention because they are thought to offer a gateway to a better understanding of quantum behaviour. They indeed constitute a macroscopic realization of wave-particle duality, in the sense that their trajectories are guided by a self-generated surrounding wave. The aim of this paper is to try to describe walker phenomenology in terms of de Broglie-Bohm dynamics and of a stochastic version thereof. In particular, we first study how a stochastic modification of the de Broglie pilot-wave theory, à la Nelson, affects the process of relaxation to quantum equilibrium, and we prove an H-theorem for the relaxation to quantum equilibrium under Nelson-type dynamics. We then compare the onset of equilibrium in the stochastic and the de Broglie-Bohm approaches and we propose some simple experiments by which one can test the applicability of our theory to the context of bouncing oil droplets. Finally, we compare our theory to actual observations of walker behavior in a 2D harmonic potential well.

The aim of this paper is to examine the beneficial impact of feedback information in the dynamics of production-inventory control systems. Two production-inventory control system models are analyzed: APIOBPCS and 2APIOBPCS models. The simulation-based experiment designs were conducted by using the state-space equations of the two models. The bullwhip effect as measured by the variance ratio between the order rate and the consumption rate, and inventory responsiveness as measured by the Integral of Absolute Error between the actual and the target levels of inventory, are two metrics used to evaluate the performance of the production-inventory control system in response to a random customer demand. To ensure that both models work under optimal performance, multi-objective particle swarm optimization (MOPSO) is employed to address the problem of tuning the controller’s parameters. The simulation results show the 2APIOBPCS model outperforms the APIOBPCS model at achieving the desired bullwhip effect and being able to provide better inventory responsiveness. The improvement in the inventory responsiveness becomes more significant when the system operates under mismatched lead time and/or an initial condition.

Asymmetric reduction of enoates, imines and ketones are among the most important reactions in biocatalysis. These reactions are routinely conducted using enzymes that use nicotinamide cofactors as reductants. The deazaflavin cofactor F₄₂₀ also has electrochemical properties that make it suitable as an alternative to nicotinamide cofactors for use in asymmetric reduction reactions. However, cofactor F₄₂₀-dependent enzymes remain under-explored as a resource for biocatalysis. In this review, we consider the cofactor F₄₂₀-dependent enzyme families with greatest potential for the discovery of new biocatalysts: the flavin/deazaflavin-dependent oxidoreductases (FDORs) and the luciferase-like hydride transferases (LLHTs). We discuss characterized F₄₂₀-dependent reductions that have potential for adaptation for biocatalysis, and we consider the enzymes best suited for use in the reduction of oxidized cofactor F₄₂₀ to allow cofactor recycling in situ. We also discuss recent advances in the production of cofactor F₄₂₀ and its functional analog F_O-5’- phosphate, which remains an impediment to the adoption of this family of enzymes for industrial biocatalytic processes. Finally, we discuss the prospects for the use of this cofactor and dependent enzymes as a resource for industrial biocatalysis.

The selection of biomaterials for biomedical application is a significant challenge. In the last few decades, various bioabsorbable and stable biopolymers have been applied for use as biomedical devices in orthopedic applications. Ultra-high molecular weight polyethylene (UHMWPE) has been extensively used in medical implants, notably in the bearings of hip, knee, and other joint prostheses, owing to its biocompatibility and high wear resistance. For the ACL graft, synthetic UHMWPE is an ideal candidate due to its biocompatibility and its extremely high tensile strength. Despite the appeal of new advanced materials such as carbon fiber, poly-ether-ether ketone, and other load-bearing materials, UHMWPE remains a primary load-bearing candidate material for ACL reconstructions because of its extremely high strength, the simplicity of the fabrication process, its biocompatibility, and low friction. However, some significant problems are observed in UHMWPE based implants, such as wear debris, and oxidative degradation due to the generation of free radicals when exposed to irradiation with gamma rays for grafting or sterilization. Various innovative methodologies have been developed to resolve those problems and enhance the properties of UHMWPE. In this review, we will explore in detail the methods for surface functionalization of UHMWPE and will apply these findings to the case study of UHMWPE for Anterior Cruciate Ligament repair.

Apoptosis is associated with numerous phenotypical characteristics, and is thus studied with many tools. In this study, we compared two broadly used apoptotic assays: TUNEL and staining with an antibody targeting the activated form of an effector caspase. To compare them, we developed a protocol based on commonly used tools such as filters, zprojection and thresholding. Even though it is commonly used in imageprocessing protocols, thresholding remains a recurring problem. Here we analyzed the impact of processing parameters and readout choice on the accuracy of apoptotic signal quantification. Our results show that TUNEL is quite robust, even if image processing parameters can allow or not to detect subtle differences of the apoptotic rate. On the contrary, images from anticleaved caspase staining are more sensitive to handle and proved to necessitate to be processed more carefully. We then developed an open source Fiji macro automatizing most steps of the image processing and quantification protocol. It is noteworthy that the field of application of this macro is wider than apoptosis as it can perfectly be used to treat and quantify other kind of images.

Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal cancers, often before the age of 50 years. In LS, mutations in DNA repair genes lead to a dysfunctional post-replication repair system. As a result, the unrepaired errors in coding regions of the genome produce novel proteins, called neoantigens. Neoantigens are recognised by the immune system as foreign and trigger an immune response. Due to the invasive nature of cancer screening tests, universal cancer screening guidelines unique for LS (including colonoscopy) are poorly adhered to by LS variant heterozygotes (LSVH). Currently, it is unclear whether immunogenomic components produced as a result of neoantigen formation can be used as novel biomarkers in LS. We hypothesize that: (i) LSVH produce measurable and dynamic immunogenomic components in blood, and (ii) these quantifiable immunogenomic components correlate with cancer onset and stage. Here, we discuss feasibility and propose the potential to: (a) identify personalised novel immunogenomic biomarkers, (b) reduce invasive cancer screening tests and thus increase non-invasive cancer surveillance, (c) improve compliance and adherence to recommended cancer screening guidelines in LSVH.

Advances in DNA sequencing technology are facilitating genomic analyses of unprecedented scope and scale, widening the gap between our abilities to generate and fully exploit biological sequence data. Comparable analytical challenges are encountered in other data-intensive fields involving sequential data, such as signal processing, in which dimensionality reduction (i.e., compression) methods are routinely used to lessen the computational burden of analyses. In this work we explore the application of dimensionality reduction methods to numerically represent high-throughput sequence data for three important biological applications of virus sequence data: reference-based mapping, short sequence classification and de novo assembly. Despite using highly compressed sequence transformations to accelerate the processes, our sequence processing approach yielded comparable accuracy to existing approaches, and are ideally suited for sequences originating from highly diverse virus populations. We demonstrate the application of our methodology to both synthetic and real viral pathogen sequence data. Our results show that the use of highly compressed sequence approximations can provide accurate results and that useful analytical performance can be retained and even enhanced through appropriate dimensionality reduction of sequence data.

The quality of dietary patterns can be optimized using a mathematical technique known as linear programming (LP). LP methods have rarely been applied to individual meals. The present LP models optimized the breakfast meal for those participants in the nationally representative National Health and Nutrition Examination Survey 2011-2014 who ate breakfast (n=11,565). The Nutrient Rich Food Index (NRF9.3) was a measure of diet quality. Breakfasts in the bottom tertile of NRF9.3 scores (T1) were LP-modeled to meet nutrient requirements without deviating too much from current eating habits. Separate LP models were run for children and for adults. The LP-modeled breakfasts resembled the existing ones in the top tertile of NRF9.3 scores (T3), but were more nutrient-rich. Favoring fruit, cereals, and dairy, the LP-modeled breakfasts had less meat, added sugars and fats but more whole fruit and 100% juices, more whole grains, and more milk and yogurt. LP modeling methods can build on existing dietary patterns to construct food-based dietary guidelines and identify individual meals and/or snacks that need improvement.

Concentration and preservation of lactic acid bacteria (LAB) starter cultures for food production guarantee the long-term delivery of stable cultures in terms of viability and functional activity. One method that has commonly been used to prepare dried starter cultures for food applications is freeze-drying. During freeze-drying, the bacterial cells are exposed to stresses such as freezing, drying, and long-term exposure to low-water activity. Additionally, another added stress is introduced during the rehydration process. The purpose of this study was to evaluate the survival rates and fermentation performance of three (3) freeze-dried lactic acid bacterial cultures previously isolated from Ghanaian traditional fermented milk. LAB cultures, i.e., Lactobacillus delbrueckii, Lactococcus lactis and Leuconostoc mesenteroides were frozen in the chamber of a Telstar (Lyoquest) laboratory freeze dryer for 10 hrs at -55 °C (as single and combined cultures) using skimmed milk and cassava flour as cryoprotectants held in plastic or glass cryovial. For viability during storage, freeze-dried LAB cultures were stored in a refrigerator (4 °C) and at room temperature (25 °C) for 4-weeks. The survival of freeze-dried cultures was determined by growth kinetics at 600nm (OD₆₀₀). The performance of freeze-dried LAB cultures after 4-weeks storage was determined by their growth and acidification of milk during yogurt fermentation and consumer sensory evaluation of fermented milk using a 9-point hedonic scale. The survival rates for LAB ranged between 60.11% and 70.91% following freeze-drying. For single cultures, the highest survival was recorded for Lactobacillus delbrueckii (L12), whereas for combined cultures, the highest survival was observed for Lactococcus lactis (L3) combined with Lactobacillus delbrueckii (L12). During the fermentation process all the freeze-dried LAB cultures were able to acidify yogurt to a pH below 4, while yogurt produce from the spontaneous fermentation was characterized by low acidification. Yogurt fermented with freeze-dried lactic acid bacteria cultures, either single or combined strains, showed improved acceptability as compared to the spontaneously fermented yogurt. The consumer acceptability results showed that yogurts produced with combined starter culture of Lactoccus lactis and Lactobacillus delbrueckii or single culture of Lactococcus lactis were the most preferred products with Lactococcus lactis and Lactobacillus delbrueckii possessing high survival rates and high consumer acceptability in yogurt production. These findings are crucial and can be adopted for large-scale production and commercialization of yogurt production, however, in-depth investigation on the effects of freeze-drying and long-term storage on survival and performance of selected LAB cultures are needed.

Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930-2023 was conducted. This is the first review for this plant genus and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.

The gut microbiome is a collection of microorganisms and parasites that reside in the gastrointestinal tract. There are many factors that can affect the composition of this community, such as age, sex, medications, and environmental triggers. The relationship between the human host and the gut microbiota is very important for both the survival and development of the organism. The disruption of this relationship can lead to the development of various inflammatory diseases. CBD and THC are used to treat muscle spasticity associated with multiple sclerosis. It is now clear these compounds also benefit patients with neuroinflammation. A study that investigated the role of gut microbiota in treating the inflammation and paralysis in a mouse model demonstrated that treatment with CBD and THC produced significant decrease in the inflammation levels. They also exhibited a significant increase in the number of anti-inflammatory cytokines. The presence of certain cannabinoids can suppress neuroinflammation and prevent microbial dysbiosis. Several studies have revealed the role of the gut microbiota in the development and maintenance of skeletal integrity and bone mineral density. The gut is a major source of nutrients, including vitamins B and K. It can also influence the development and maintenance of bone matrix. The presence of the gut microbiota can influence the actions of certain T regulatory cells, which can lead to the development of bone formation and proliferation. In addition, its metabolites can prevent bone loss. The gut microbiota can help maintain the bone's equilibrium and prevent the development of metabolic diseases, such as osteoporosis. In this review, the dual functions gut microbiota plays in the regulation of gut-bone axis and gut-brain axis and the impact of CBD on these roles are discussed in detail.

The ability to predict physical characteristics from DNA presents significant opportunities for forensic science. Giving scientists an ability to make predictions about the donor of genetic material at a crime scene can then give investigators new intelligence leads for cold cases where DNA evidence has not identified any person of interest. However, the interpretation of this new form of intelligence requires careful analysis. The responses to an online survey, conducted in 2018-19, were used to examine how actors in the criminal justice system assess and interpret different types of DNA evidence and intelligence. The groups of focus for the survey were investigators, legal practitioners and the general public (as potential jurors). Several statistically significant effects were identified based on occupation and whether an individual had prior exposure to new DNA technology. Monitoring how those involved in interpreting reports from different types of DNA evidence and intelligence interpret them helps to ensure that decisions are made based on a sound understanding of their capabilities and limitations and may inform broader training and awareness strategies.

Despite constituting the western-most edge of the population distributions for several native European flora, Ireland has largely been left out of key Europe-wide phylogeographic studies. This is true for birch (Betula pubescens Ehrh. and Betula pendula Roth.), for which the genetic diversity has yet to be mapped for Ireland. Here, we used eight cpDNA (two RFLP and six SSR) markers to map the genetic diversity of B. pubescens, B. pendula and putative hybrid individuals sampled from 19 populations spread cross most of the island of Ireland. Within Ireland, 11 distinct haplotypes were detected, the most common of which (H1) was also detected in England, Scotland, France and Norway. A moderate level of population structuring (GST = 0.282) was found across Ireland and the genetic diversity of its northern populations was twice that of its southern populations. This indicates that, unlike other native Irish trees, such as oak and alder, post-glacial recolonisation by birch did not begin in the south (i.e., from Iberia). Rather, and in agreement with palynological data, birch most likely migrated in from eastern populations in Britain. Finally, we highlight Irish populations with comparatively unique genetic structure which may be included as part of European genetic conservation networks.

Variability in traits forming the Leaf Economics Spectrum (LES) among and within crop species play a key role in governing agroecosystem processes. However, studies evaluating the extent, causes, and consequences of within-species variation in LES traits for some of the world’s most common crops remain limited. We quantified variation in nine leaf traits measured across 90 vines of five wine grape (Vitis vinifera) varieties at two ontogenetic stages. Grape traits covary along an intraspecific LES, in patterns similar to those documented in wild plants. Across varieties, high rates of photosynthesis (A), and leaf nitrogen (N) concentrations, are coupled with low leaf mass per area (LMA), while the opposite suite of traits defines the “resource conserving end” of this intraspecific LES in grape. Variety identity predicted of leaf physiological (A) and morphological traits (i.e., leaf area and leaf mass), while leaf chemical traits and LMA were best explained by ontogenetic stage. All varieties expressed greater resource conserving trait syndromes (i.e., higher LMA, lower N, lower Amass) later in the growing season. Traits related to leaf hydraulics, including instantaneous water-use efficiency (WUE), were unrelated to LES and other resource capture traits, and were better explained by spatial location. Our results highlight the relative contributions of genetic vs. phenotypic factors in structuring this variation and point to a key role of domestication in governing trait relationships in the world’s crops.

We report on ground-based measurements of the atmospheric electric field (Ez= -Potential Gradient (PG)) and current density (Jz) that were conducted at two locations in Israel. One is the Emilio Segre cosmic ray station located on Mt. Hermon (34.45 N, 2020 m AMSL) located in northern Israel near the Syrian-Lebanon border and at the other at the Wise astronomical observatory in the Negev desert highland plateau of southern Israel (31.18 N, 870 m AMSL). We searched for possible effects of strong, short-term solar events on the potential gradient and the vertical current density, as disruption to the Global Electric Circuit are often observed following strong solar events. The first case study (St. Patrick Day, 17 March 2015) was classified as the strongest event of 2015. The second case study (8 Sep 2017) was categorized as the strongest event of 2017 and one of the twenty strongest events on record to date. The results show that the electrical parameters measured at ground level at both stations were not affected during the two massive proton events and the ensuing geomagnetic storms. The magnetospheric shielding in lower latitudes is strong enough to shield against flux of energetic particles from solar events, obscuring any impact that may be noticeable above the local daily variations induced by local meteorological conditions (aerosol concentrations, clouds, high humidity, and wind speed) which were investigated as well.

High pressure crystallization technique has been successfully used to prepare an elusive form II of a non-steroidal anti-inflammatory drug, Mefenamic acid. Single crystal of form II was grown at 0.3 GPa from an 4:1 methanol/ ethanol mixture as a solvent using Diamond Anvil Cell. Comparison of crystal structures show that the efficient packing of MA molecules in Form II results from the structural flexibility of MA acid molecules. Compression studies performed on the single crystal of form I resulted in 14 % decrease of unit cell volume up to 2.5 GPa. No phase transition was observed up to this pressure. A reconstructive phase transition is required to induce conformational changes in the structure, which is confirmed by crystallization at high pressure results.

As a result of the cancer immunotherapy revolution hundreds of clinical trials of the newly approved immunotherapies are now under way to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by blockade of co-inhibitory signals. While success stories of terminal cancer patients achieving complete remissions are accumulating, not enough research has been done into the risks of the new therapies. Since the use of immunotherapy is becoming more common, and is expected to develop into first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the nemesis of immunotherapy. Immune-related adverse events (IrAEs) could affect any tissue, their incidence may reach up to 90% of patients and toxicity is dose-dependent. While the combination of two immune checkpoint inhibitors (ICIs) increased efficacy, the incidence of severe adverse events was also increased. Apparently, ICIs cannot be restricted to the targeted anti-tumor T cell population. The long lasting objective of cancer regression can only be achieved by paying a price: tolerance to healthy self tissues is compromised. In the face of an ipilimumab induced pan-lymphocytic activation, a therapeutic paradigm shift is required. The task is not desperately trying to put the genie back in the bottle by immune suppressive treatments, but instead harnessing the autoimmune forces by an off label low-dose combined anti-CTLA-4 and anti-PD1 antibody blockade, which is supplemented with conventional interleukin-2 stimulation and hyperthermia. The proof-of-principle of the low-dose-combination therapy was demonstrated in a heavily pre-treated triple negative breast cancer (TNBC) patient with far advanced pulmonary metastases and severe shortness of breath, who had exhausted all conventional treatment. Her pulmonary metastases went into complete remission with transient WHO I-II diarrhea and skin rash. She lived for 27 months after starting the low-dose-combination therapy. She had recurrence as a sternal mass and pleural metastases up to 3 cm. Since the low-dose-combination protocol consists only of approved drugs and treatments, this exceptional response should instigate further research efforts.

Incorrect sitting posture, characterized by asymmetrical or uneven positioning of the body, often leads to spinal misalignment and muscle tone imbalance. Prolonged maintenance of such postures can adversely impact well-being and contribute to the development of spinal deformities and musculoskeletal disorders. In response, smart-sensing chairs equipped with cutting-edge sensor technologies have been introduced as a viable solution for real-time detection, classification, and monitoring of sitting postures, aiming to mitigate the risk of musculoskeletal disorders and promote overall health. This comprehensive literature review evaluates the current body of research on smart-sensing chairs, with a specific focus on the strategies used for posture detection and classification, as well as the effectiveness of different sensor technologies. A meticulous search across MDPI, IEEE, and Google Scholar databases yielded 34 pertinent studies that utilize non-invasive methods for posture monitoring. The analysis reveals that Force Sensing Resistors (FSR) are the predominant sensors utilized for posture detection, whereas Convolutional Neural Networks (CNN) and Artificial Neural Networks (ANN) are the leading machine learning models for posture classification. However, it was observed that CNNs and ANNs do not outperform traditional statistical models in terms of classification accuracy, due to constrained size and lack of diversity within training datasets. These datasets often fail to comprehensively represent the array of human body shapes and musculoskeletal configurations. Moreover, this review identifies a significant gap in the evaluation of user feedback mechanisms, essential for alerting users to their sitting posture and facilitating corrective adjustments.

Tailed phages are the most abundant and diverse group of viruses on the planet. Yet, the smallest tailed phages display relatively complex capsids and large genomes compared to other viruses. The lack of tailed phages forming the common icosahedral capsid architectures T = 1 and T = 3 is puzzling. Here, we extracted geometrical features from high-resolution tailed phage capsid reconstructions and built a statistical model based on physical principles to predict the capsid diameter and genome length of the missing small tailed phage capsids. We applied the model to 3,348 isolated tailed phage genomes and 1,496 gut metagenome-assembled tailed phage genomes. Four isolated tailed phages were predicted to form T = 3 icosahedral capsids, and twenty-one metagenome-assembled tailed phages were predicted to form T < 3 capsids. The smallest capsid predicted was a T = 4/3 ≈ 1.33 architecture. No tailed phages were predicted to form the smallest icosahedral architecture, T = 1. We discuss the feasibility of the missing T = 1 tailed phage capsids and the implications of isolating and characterizing small tailed phages for viral evolution and phage therapy.

The female pelvis is often evolutionarily described as a compromise to accommodate the birthing process and bipedalism. This compromise puts a mother and baby at risk for fetopelvic disproportion, the mismatch between the size of the fetus and the mother's pelvis, impacting the ease at which the vaginal birthing process occurs. Obstructed labor, commonly caused by fetopelvic disproportion, is a leading cause of maternal mortality and morbidity and has serious medical sequelae for the fetus. In this review, this evolutionary aspect of fetopelvic disproportion is being reconsidered within a broader sociocultural and environmental approach related to a change of paradigm from a more reductionist Neo-Darwinist to a more encompassing Extended Evolutionary Synthesis view. The review explores a more comprehensive understanding of several factors related to fetopelvic disproportion, including socioeconomic factors and ethnic disparities amongst individuals that might lead to a higher likelihood of obstructed labor and maternal and fetal morbidity and mortality.

The frequent occurrence of rib fractures in slaughtered lambs results in significant economic loss to producers and processors in South Australia and raises concerns about the welfare of the animals. The prevalence of rib fractures became evident through the Enhanced Abattoir Surveillance (EAS) program introduced in 2007. The present study aimed to investigate the association between rib fracture prevalence in lambs at slaughter and their nutrition and management on the farm of origin. The slaughter of 30,055 lambs from 60 farms was monitored at a South Australian abattoir in November 2016. Rib fracture prevalence was 4% (range 0 - 18% per consignment), with all consignments of more than 240 lambs having at least one with fractured ribs. Traceback investigation on 56 of the 60 farms suggests that rib fractures most probably occur during routine husbandry procedures and, based on soil mineral analysis, are associated with calcium inadequacy. There was substantial variation between lines of lambs from different farms, and factors contributing to the differences included line size, region, and soil characteristics, including available calcium. There is a need to modify sheep husbandry and management practices to improve sheep welfare and reduce the cost of rib fractures to the sheep industry.

New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections. The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species it is important to examine potential interaction between CBD and common therapeutics such as broad-spectrum antibiotics. Here, we show that CBD-antibiotic co-therapy can effectively fight S. typhimurium via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics for potential antibiotic-CBD co-therapy. In this study, we reveal that Salmonella typhimurium (S. typhimurium) growth is inhibited at very low dosages of CBD-antibiotic. This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating Salmonella typhimurium.

Background: Physical activity is recommended to mitigate the incidence of obesity, but delivery of community wide initiatives is cumbersome. The challenges met by such programs are magnified when implementation transpires in the remote villages of Alaska. To overcome the difficulty of this challenge in the Arctic, the Skiku/AK Nordic cross-country skiing program was developed. The objective of this study was to evaluate whether access to Skiku/AK Nordic program would promote physical activity levels that met the daily recommendations for physical activity in Alaska Native children. Methods: Eight children (4 females and 4 males; 10±2 years/age) were recruited from Kaktovik, Alaska for participation in this study. Expert coaches and staff provided one week of cross-country ski instruction and access to ski equipment. Physical activity was monitored using ActiGraph GT3X+ accelerometers. Data collected from the devices was then downloaded and analyzed using ActiLife software. Results: The participants expended ~586 calories/day devoted to physical activity. Light and moderate physical activity was 68±38 minutes/day and 447±248 minutes/day, respectively. Conclusions: Delivery of the Skiku/AK Nordic program promoted favorable levels of physical activity in Alaska Native children. Further research is needed to assess the longitudinal and seasonal effectiveness of the Skiku/AK Nordic program.

Nephrolithiasis affects around 10% of the population and is frequently associated with impaired dietary factors. The first one is insufficient fluid intake inducing reduced urine volume, urine supersaturation, and subsequently urinary lithiasis. Kidneys regulate 24-hour urine volume, which, under physiological conditions, approximately reflect daily fluid intake. Increasing fluid intake has a preventive effect on the risk of developing a first kidney stone (primary prevention) but also decreases the risk of stone recurrence (secondary prevention). Current guidelines recommend increasing fluid intake at least at 2.5L /day to prevent stone formation, and even at 3.5-4L in some severe forms of nephrolithiasis (primary or enteric hyperoxaluria or cystinuria). Fluid intake must also be balanced between day and night, to avoid urinary supersaturation during the night. Patients should be informed and supported in this difficult process of increasing urine dilution, with practical ways and daily routines to increase their fluid intake. The liquid of choice is water, which should be chosen depending on its composition (such as calcium, bicarbonate or magnesium content). Finally, some additional advices have to be given to avoid some beverages such as those containing fructose or phosphoric acid, which are susceptible to increase the risk of nephrolithiasis.

This paper presents a multi-year research study conducted at the University of Toledo, aimed at improving human-machine teaming (HMT) methods and technologies. With the incorporation of artificial intelligence (AI) into 21st-century machines, collaboration between humans and machines has become highly complicated for real-time applications. The penetration of intelligent and synthetic assistants (IA/SA) in virtually every field has opened a path for the new area of HMT. When it comes to crucial tasks such as patient treatment and care, defense, and industrial production, the use of non-standardized HMT technologies may pose a risk to human lives as well as up to billions of taxpayer dollars. A thorough literature survey revealed that there are not many established standards or benchmarks for HMT. In this paper, we aim to address the lack of HMT design and development standards. We propose a method to design an HMT based on a generalized architecture. This design includes the development of an intelligent collaborative system and human team. Followed by processes and metrics to test and validate the proposed model, we present a novel human-in-the-loop (HIL) simulation method using two controlled HMT scenarios; first, emergency care provider (ECP) training, and second, patient treatment by an experienced medic. Both scenarios include humans processing visual data and performing actions that represent real-world applications while responding to a Voice-Based Synthetic Assistant (VBSA) as a collaborator that keeps track of actions. As part of these HMT simulation studies, the impact of each parameter related to machines, humans, and HMT (such as errors made by humans and by the VBSA) is presented from the perspective of performance, rules, roles, and operation limitations. In addition, based on the analysis of results from two case studies, we presented guidelines for designing future HMT. Our conclusions indicate that the proposed HIL can be used to perform standardization studies in the pursuit of developing techniques for benchmarking HMT that can be used in critical situations.

Abstract: Infectious bronchitis virus (IBV) induces respiratory and urogenital disease in chickens. Although IBV replicates in the gastrointestinal tract, enteric lesions are uncommon. We have reported a case of runting-stunting syndrome in commercial broilers from which an IBV variant was isolated from the intestines. The isolate, CalEnt, demonstrated an enteric tissue tropism in chicken embryos and SPF chickens experimentally. Here, we determined the full genome of CalEnt and compared it to other IBV strains, in addition to comparing the pathobiology of CalEnt and M41 in commercial broilers. Despite the high whole-genome identity to other IBV strains, CalEnt is rather unique in nucleotide composition. The S gene phylogenetic analyses showed great similarity between CalEnt and Cal 99. Clinically, vent staining was slightly more frequent in CalEnt-infected birds than those challenged with M41. Furthermore, IBV IHC detection was more evident and the viral shedding in feces was overall higher with the CalEnt challenge compared with M41. Despite underlying intestinal lesions caused by coccidiosis and salmonellosis vaccination, microscopic lesions in CalEnt-infected chickens were more severe than in M41-infected chickens or controls, supporting the enteric tropism of CalEnt. Further studies in SPF chickens are needed to determine the pathogenesis of the virus, its molecular mechanisms for the enteric tropism, and its influence in intestinal health.

The human virome is an area of increasing interest with relation to human health and disease. It has been demonstrated to alter in concert with the bacterial microbiome in early life and was also found to be different in patients with certain diseases such as inflammatory bowel disease. However, all virome analyses are hampered by a lack of annotated representative database sequences, often referred to as the ‘viral dark matter’. Here we provide the first description of the gut DNA virome in elderly individuals (>65 years old) as well as the description of novel bacteriophages not present in current reference databases. Diversity analysis comparing elderly persons from different residence locations (community living vs long term care facilities) did not reveal any difference in their virome diversity profiles despite the reported differences at the bacteriome level. An abundance of Microviridae of the subfamily Gokushovirinae were present in the faeces of elderly individuals. Several novel members of the order Caudovirales were also characterized and annotated. Assignment of host bacteria to detected viral genomes was attempted using a combination of CRISPR spacers, tRNA genes and a probabilistic approach. Further characterization of the viral dark matter is necessary for developing tools and expanding databases to study the human virome. This study focused on the virome of an aging human cohort with the goal of illuminating part of the viral dark matter.

The endocannabinoid system (ECS) is a complex neuromodulatory network in the human body that have enormous impact in developing the central nervous system, as well as modulates various physiological processes. The ECS is made up of anandamide, 2-arachidonoylglycerol (2-AG), which are responsible for the synthesis and degradation of endocannabinoids, and enzymes such as FAAH and MAGL ensures the precise control over endocannabinoid levels. The ECS relies on CB1 receptors found in the central nervous system (CNS), and CB2 receptors found in the peripheral nervous system and immune cells. Dysregulation of the ECS has been associated with several health conditions, prompting investigations into its association with phytocannabinoids to harness their therapeutic potential. The ECS is intricately linked with the nervous system, and it is known to modulate neuronal activities in the CNS, influencing pain and mood modulation. The ECS is also associated with neuropathies-peripheral nerve damage leading to symptoms such as weakness, numbness and pain as evidenced in diabetic neuropathy, Guillain-Barré Syndrome, carpal tunnel syndrome, peripheral neuropathy, and postherpetic neuralgia. The focus of this review is on the interplay between 2-arachidonoylglycerol and anandamide amidohydrolase in neuropathy, elucidating their roles in pain regulation, inflammation, and specific neuropathies. The knowledge generated is expected to have broad implications, providing comprehensive insights into neuropathic conditions and how to improve on them. Ultimately, this understanding may lead to more effective treatments and improved quality of life for individuals affected by these conditions.

(1) Background: Artificial Intelligence (AI) models have shown potential in various educational contexts. However, their utility in explaining complex biological phenomena, such as Intrinsically Disordered Proteins (IDPs), requires further exploration. This study empirically evaluated the performance of various Large Language Models (LLMs) in the educational domain of IDPs. (2) Methods: Four LLMs, GPT-3.5, GPT-4, GPT-4 with Browsing, and Google Bard (PaLM 2), were assessed using a set of IDP-related questions. An expert evaluated their responses across five categories: accuracy, relevance, depth of understanding, clarity, and overall quality. Descriptive statistics, ANOVA, and Tukey's honesty significant difference tests were utilized for analysis. (3) Results: The GPT-4 model consistently outperformed the others across all evaluation categories. Although GPT-4 and GPT-3.5 were not statistically significantly different in performance (p&gt;0.05), GPT-4 was preferred as the best response in 13 out of 15 instances. The AI models with browsing capabilities, GPT-4 with Browsing and Google Bard (PaLM 2) displayed lower performance metrics across the board with statistically significant differences (p&lt;0.0001). (4) Conclusion: Our findings underscore the potential of AI models, particularly LLMs such as GPT-4, in enhancing scientific education, especially in complex domains such as IDPs. Continued innovation and collaboration among AI developers, educators, and researchers are essential to fully harness the potential of AI for enriching scientific education.

Perinatal mortality is a major issue in laboratory mouse breeding. We compared a counting method using daily checks (DAILY_CHECK) with a method combining daily checks with detailed video analyses to detect cannibalisms (VIDEO_TRACK) for estimating the number of C57BL/6 pups born, died and weaned in 193 litters from trios with (TRIO-OVERLAP) or without (TRIO-NO_OVERLAP) the presence of another litter. Linear mixed models were used at litter level. To understand if cannibalism was associated with active killing (infanticide), we analysed VIDEO_TRACK recordings of 109 litters from TRIO-OVERLAP, TRIO-NO_OVERLAP or SOLO (single dams). We used Kaplan-Meier method and logistic regression at pup level. For DAILY_CHECK, the mean litter size was 35% smaller than for VIDEO_TRACK (P&lt;0.0001) and the number of dead pups was twice lower (P&lt;0.0001). The risk of pup loss was higher for TRIO-OVERLAP than TRIO-NO_OVERLAP (P&lt;0.0001). A high number of pup losses occurred between birth and the first cage checking. Analyses of VIDEO_TRACK data indicated that pups were clearly dead at the start of most of the cannibalism events and infanticide was rare. As most pups die and disappear before the first cage check, many breeding facilities are likely to be unaware of their real rates of mouse pup mortality.

The human virome is an area of increasing interest with relation to human health and disease. It has been demonstrated to alter in concert with the bacterial microbiome in early life and was also found to be different in patients with certain diseases such as inflammatory bowel disease. However, all virome analyses are hampered by a lack of annotated representative database sequences, often referred to as the ‘viral dark matter’. Here we provide the first description of the gut DNA virome in elderly individuals (>65 years old) as well as the description of novel bacteriophages not present in current reference databases. Diversity analysis comparing elderly persons from different residence locations (community living vs long term care facilities) did not reveal any difference in their virome diversity profiles despite the reported differences at the bacteriome level. An abundance of Microviridae of the subfamily Gokushovirinae were present in the faeces of elderly individuals. Several novel members of the order Caudovirales were also characterized and annotated. Assignment of host bacteria to detected viral genomes was attempted using a combination of CRISPR spacers, tRNA genes and a probabilistic approach. Further characterization of the viral dark matter is necessary for developing tools and expanding databases to study the human virome. This study focused on the virome of an aging human cohort with the goal of illuminating part of the viral dark matter.

The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the Locus Coeruleus - Noradrenergic System (LC-NA) originating in the Brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to Reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 Mild Cognitive Impairment, 135 Alzheimer’s Disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD – an objective measure which compares an individual’s structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual’s age). Further analyses were carried out on Reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the Serotoninergic (5-HT), Dopaminergic (DA) and Cholinergic (Ach) systems were contrasted with the Noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems.Results supported by bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of Reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g. cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.

Considering the increasing interest in understanding the biotic component of methane removal from our atmosphere, it becomes essential to study the physiological characteristics and genomic potential of methanotroph isolates, especially their traits allowing them to adapt to elevated growth temperatures. The genetic signatures of Methylocaldum species have been detected in many terrestrial and aquatic ecosystems. A small set of representatives of this genus has been isolated and maintained in culture. The genus is commonly described as moderately thermophilic, with the growth optimum reaching 50oC for some strains. Here, we present a comparative analysis of genomes of three Methylocaldum strains—two terrestrial M. szegediense strains (O-12 and Norfolk) and one marine strain Methylocaldum marinum (S8). The examination of the core genome inventory of this genus uncovers significant redundancy in primary metabolic pathways, including the machinery for methane oxidation (numerous copies of pmo genes) and methanol oxidation (duplications of mxaF, xoxF1-5 genes), three pathways for one-carbon (C1) assimilation, and two methods of carbon storage (glycogen and polyhydroxyalkanoates). We also investigate the genetics of melanin production pathways, as a key feature of the genus.

Tailings generated by mining account for the largest proportion of global waste from industrial activities. Copper is relatively uncommon world-wide, with low concentrations in sediments and waters, yet is very elevated around mining sites. On the Keweenaw Peninsula of Michigan, USA, jutting out into Lake Superior, 140 mines extracted native copper from the Portage Lake Volcanic Series, part of an intercontinental rift system. Between 1901-1932, two mills at Gay (Mohawk, Wolverine) sluiced 22.7 million metric tonnes (MMT) of copper-rich tailings (stamp sands) into Grand (Big) Traverse Bay. Here we examine: 1) 3D coastal elevation and reef bathymetry, 2) particle dispersal, 3) copper concentrations and leaching, plus 4) shoreline toxicity. About 10 MMT of tailings created a migrating coastal beach that stretches 7 km from the Gay pile to the Traverse River Seawall. Another 10 MMT are moving underwater on the coastal shelf, threatening Buffalo Reef, an important lake trout and whitefish breeding ground. Aerial photos, ALS (plane) LiDAR, and relatively inexpensive UAS (drone) surveys characterize shoreline structure and aid initial remediation. Because sands (natural beach quartz, stamp sand basalt) are silicates of similar density, particle dispersal is similar and challenging. However, stamp sand beaches contrast greatly with natural sand beaches in both physical profile and chemistry. Dispersing particles retain copper, and release toxic concentrations. Leaching is elevated by exposure to high DOC and low pH waters. Field experiments, shoreline seining, and benthic sampling confirm serious impacts on aquatic biota, supporting tailings removal.

In recent years, there is a growing concern about the alarming spread of antimicrobial resistance (AMR) in different environments. Increasingly, many species of bacteria, fungi and viruses are becoming immune to the most commonly used pharmaceuticals. One of the causes of the development of the resistance is the persistence of these drugs, excreted by humans, in municipal and hospital wastewater (WW). Consequently, wastewater treatment plants (WWTPs) are a primary source of antimicrobial resistance genes as novel pollutants. This systematic review sought to examine the relevant literature on pharmaceutical residues (PRs) responsible for AMR in municipal and hospital WW in order to propose a classification of the PRs of greatest concern and provide an updated source for AMR management in WWTPs. Among 546 studies collected from four databases, 18 were included in the present review. The internal and external validity of each study was assessed, and the risk of bias was evaluated on a 20-parameter basis. Results were combined in a narrative synthesis discussing influents and effluents PR concentrations at 88 WWTPs, seasonal variations, differences between hospital and municipal WW, environmental risk assessment values of antimicrobial substances and treatment facilities removal efficiencies. Among the 45 PRs responsible for AMR evaluated in this study, the antibiotics ciprofloxacin, clarithromycin, erythromycin, metronidazole, ofloxacin, sulfamethoxazole and trimethoprim constitute a considerable risk in terms of ubiquitous distribution, worrying concentrations, risk quotients values, and resistance to removal treatments. Gaps in knowledge, data and information reported in this review provide a valuable source for managing AMR in WWTPs.

Environmental policy involving citizen science (CS) is of growing interest. In support of this open data stream, validation or quality assessment of the CS data and their appropriate usage for evidence-based policy making, needs a flexible and easily adaptable data curation process ensuring transparency. Addressing these needs, this paper describes an approach for automatic quality assurance as proposed by the Citizen OBservatory WEB (COBWEB) FP7 project. This approach is based upon a workflow composition that combines different quality controls, each belonging to seven categories or ‘pillars’. Each pillar focuses on a specific dimension in the types of reasoning algorithms for CS data qualification. These pillars attribute values to a range of quality elements belonging to three complementary quality models. Additional data from various sources, such as Earth Observation (EO) data, are often included as part of the inputs of quality controls within the pillars. However, qualified CS data can also contribute to the validation of EO data. Therefore, the question of validation can be considered as ‘two sides of the same coin’. Based on an invasive species CS study, concerning Fallopia japonica (Japanese knotweed), the paper discusses the flexibility and usefulness of qualifying CS data, either when using an EO data for the validation within the quality assurance process, or validating an EO data product that describes the risk of occurrence of the plant. Both validation paths are found to be improved by quality assurance of the CS data. Addressing the reliability of CS open data, issues and limitations of the role of quality assurance for validation, due to the quality of secondary data used within the automatic workflow, are described, e.g. error propagation, paving the route to improvements in the approach.

Using two independent speckle imaging systems based on the recently published LSOCI method operating in contact mode on the skin, we assess the reproducibility of in vivo measurements and conduct an inter-instrument comparison. To this aim, we propose a calibration method to handle each imaging system as a comprehensive unit, which includes the laser source, optics, and camera. Our experimental results demonstrate that the microcirculation images produced by both instruments exhibit high accuracy and stability, with microcirculation activity values in excellent agreement, thereby paving the way for clinical applications.

Water-soluble nonionic surfactant, pentaethylene glycol monododecyl ether, C12E5, spontaneously blooms to the surface of spin-cast hydrophobic polyiso-prenes, generating hydrophilic surfaces. This system represents a simple model for hydrophilic chemical modification of rubbery polymers yet demonstrates surprisingly rich, complex and unexpected behaviour. The ver-tical depth profiles were quantified using neutron reflectometry (NR) and deuterated surfactant, and the surface properties were characterized using con-tact angle analysis and atomic force microscopy (AFM). Despite the low surface tension of the toluene solvent used in film preparation and the low surface en-ergy of the PI matrix, NR depth profiles revealed clear evidence of surfactant segregation. This surface layer was typically thicker than a monolayer, but incomplete, yet was remarkably stable with respect to dissolution, even when exposed to hundreds of thousands of times the volume of water required to dissolve all the surfactant on the surface. Despite the apparent resistance to removal from the surface, water exposure does alter the subsequent wettabil-ity of the surface, with a hydrophilic-to-hydrophobic transition occurring after rinsing. Complementary AFM images of these C12E5 / cis-PI films showed unexpected strand-like features on the surface of the film, which we attribute to a non-uniform lateral distribution of some of the surfactant. This surface structure becomes more evident after rinsing, and it appears that there are two distinct populations of surfactant on the PI film surface. We conclude that some of the bloomed surfactant exists as layers, which are relatively inert with respect to rinsing or surface modification, and some is laterally inhomogene-ous. This latter population is primarily responsible for surface wetting be-havior, but is not detected by specular NR.

Using a randomized, double-blinded, placebo-controlled, parallel group design, this investigation determined if the combination of 2-weeks flavonoid supplementation (329 mg/day, quercetin, anthocyanins, flavan-3-ols mixture) and a 45-minute walking bout (62.2±0.9% VO_2max) enhanced the translocation of gut-derived phenolics into circulation in a group of walkers (N = 77). The walkers (flavonoid, placebo groups) were randomized to either sit or walk briskly on treadmills for 45 minutes (thus four groups: placebo-sit, placebo-walk, flavonoid-sit, flavonoid-walk). A comparator group of runners (N = 19) ingested a double flavonoid dose for 2 weeks (658 mg/day) and ran for 2.5 h (69.2±1.2% VO_2max). Four blood samples were collected (pre- and post-supplementation, immediately-post- and 24-h post-exercise/rest). Of the 76 metabolites detected in this targeted analysis, 15 increased after the 2.5-h run, and when grouped were also elevated post-exercise (versus placebo-sit) for the placebo- and flavonoid-walking groups (P < 0.05). A secondary analysis showed that pre-study plasma concentrations of gut-derived phenolics in the runners were 40% higher compared to walkers (P = 0.031). These data indicate that acute exercise bouts (brisk walking, intensive running) are linked to an increased translocation of gut-derived phenolics into circulation, an effect that is amplified when combined with a 2-week period of increased flavonoid intake or chronic training as a runner.

Fanconi anemia (FA) develops due to a mutation in one of the FANC genes that are involved in repair of interstrand crosslinks (ICLs). FANCG, a member of the FA core complex, is essential for ICL repair. Previous FANCG-deficient mouse models were generated with drug-based selection cassettes in mixed mice backgrounds, leading to a disparity in interpretation of genotype-related phenotype. To exclude these confounders, we created a Fancg-KO (KO) mouse model using CRISPR/Cas9. The entire Fancg locus was targeted and maintained on the immunological well-characterized C57BL/6J background. Intercrossing of heterozygous mice resulted in sub-Mendelian numbers of homozygous mice, suggesting loss of FANCG can be embryonic lethal. KO mice displayed infertility, hypogonadism but no other developmental problems. Bone marrow analysis revealed a defect in various hematopoietic stem and progenitor subsets with a bias towards myelopoiesis. Cell lines derived from Fancg-KO mice were hypersensitive to crosslinking agents-cisplatin and Mitomycin C, and Fancg-KO mouse embryonic fibroblasts (MEFs) displayed increased γ-H2AX upon cisplatin treatment. Reconstitution of these MEFs with Fancg cDNA corrected for the ICL hypersensitivity. Collectively, this project provides a new, genetically and immunologically well-defined Fancg-KO mouse model for further in vivo and in vitro studies on FANCG and ICL repair.

Sinonasal carcinomas are aggressive neoplasms that present a high morbidity and mortality rate with unfavorable prognosis. This group of tumors exhibits morphological and genetic diversity. Genetic and epigenetic alterations in these neoplasms are currently targets for diagnosis and treatment. The most common type of cancer originated in the sinonasal tract are sinonasal squa-mous cell carcinomas (SNSCC), which presents different histological patterns and variable his-tological aggressiveness. A significant number of alterations have been reported in sinonasal tu-mors, including deficiencies in the SwItch/Sucrose non-fermentable (SWI/SNF) chromatin remod-eling complex. In the sinonasal tract, deficiencies of the subunits SMARCB1/INI1, SMAR-CA4/BRG1 and SMARCA2 have been noted in carcinomas, adenocarcinomas, and soft tissue tu-mors with distinctive high-grade morphology and fatal prognosis. Objective: To identify the status of the SWI/SNF complex using immunohistochemistry in sinonasal squamous cell carci-nomas and its association with morphology and survival. Methods: A total of 1582 SNSCC cases were analyzed, selecting those with high-grade malignancy morphology, which were then evalu-ated immunohistochemically for SMARCB1 and SMARCA4 proteins. Their expression was compared with the biological behavior and survival of the patients. Results: Among the SNSCC, 47% corresponded to the non-keratinizing squamous cell carcinoma (NKSCC) type with high-grade characteristics, 40% were keratinizing squamous cell carcinomas (KSCC), 9% were SMARCB1-deficient carcinomas, and 4% were SMARCA4-deficient carcinomas. Mosaic expres-sion for SMARCB1 (NKSCC 33%, KSCC 21.9%) and SMARCA4 (NKSCC 14.6%, KSCC 12.2%) was identified, showing an impact on tumor size and progression. Conclusions: We identified that the mosaic expression of INI1 in NKSCC exhibited a worse prognosis compared to intact carcinomas and was similar to SMARCB1-deficent carcinoma.

Solar pasteurization, as a means of treating milk in remote rural areas without electrical power, is based on using solar energy to thermally inactivate pathogenic microorganisms at temperatures below the boiling point to maintain or improve milk quality. A solar milk pasteurizer of flat‐plate water‐heating glass acting as the solar collector, connected to a stainless-steel cylindrical milk vat, was constructed and evaluated in Navrongo, in the tropical savanna zone of Ghana, West Africa. The novel approach taken in this project is to integrate the solar collection and heat exchanger into a single unit using materials and fabrication techniques readily available in the developing world. The vat comprises a 1.5 mm thick stainless steel cylindrical tank, a 2.2 cm wide hot water jacket, and an outer layer of 5.0 mm thick aluminium foil insulation. Hot water produced by the collector was used for pasteurizing milk. The optimum quantity of milk that this device could pasteurize under the study conditions was 8 L. The device could pasteurize raw milk to a maximum temperature of 74 °C at 14:00 h GMT. The ambient temperature during the pasteurization ranged from 30 °C to 43 °C. The microbial analysis before and after the pasteurization was done, and the result shows that the total bacteria count before pasteurization was 6.6x10⁶ log CFU/mL per unit volume, and the total bacteria count after pasteurization was 1.0x10² log CFU/mL. By acceptable standards, the total bacteria count after pasteurization is within a safe range for consumption, and coliform counts were negative. The solar milk pasteurization system is cost-effective. Hence, it is appropriate for milk producers in arid pastoral areas without electricity to adopt the solar pasteurizer as an alternative to firewood as a fuel source for milk pasteurization. This approach can potentially create a cottage industry that may also play a crucial role as a water treatment technology that will improve the health of rural populations.

Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT, ob/ob) or with cocoa extract (ob/ob + c) for 10 weeks. Glucose and insulin tolerance tests (GTT/ITT) were conducted at weeks 1, 5 and 2, 6, respectively. Cocoa provided mild non-significant protection against weight gain vs. ob/ob control in males but not females. Male ob/ob + c had increasing fasting glucose at weeks 1 and 5 GTTs, with significantly higher levels of fasting glucose than ob/ob control at week 5. This was not seen in females. Cocoa protected against elevated 4-hour fasting glucose in week 2, but not week 6, ITTs. Cocoa partly suppressed hyperinsulinemia in males but significantly amplified it in females and protected against loss of beta cell area in females only. The mechanisms of these sex-specific effects remain to be elucidated. This study informs additional experiments with larger sample sizes and demonstrates that sex differences must be considered when designing dietary interventions for T2D.

Lipid-based drugs are emerging as an interesting class of novel anticancer drugs with the potential to target specific cancer cell metabolic pathway linked to their proliferation and invasiveness. In particular, ω−3 polyunsaturated fatty acids (PUFA) derivatives such as epoxides and their bioisosteres have demonstrated the potential to suppress growth and promote apoptosis in triple-negative human breast cancer cells MDA-MB-231. In this study 16-(4’-chloro-3’-trifluorophenyl)carbamoylamino]hexadecanoic acid (ClFPh-CHA), an anticancer lipid derived from ω−3,17,18-epoxyeicosanoic acid, was formulated as a stable nanoemulsion with size around 150 nm and narrow droplet size distribution (PDI<0.200) through phase-inversion emulsification process followed by high pressure homogenization in view of an oral administration. The ClFPh-CHA-loaded nanoemulsions were able to significantly decrease the relative tumor volume in mice bearing an intramammary tumor xenograft at all doses tested (2.5, 10 and 40 mg/kg) after 32 days of daily oral administration. Furthermore, absolute tumor weight was decreased to 50% of untreated control at 10 and 40 mg/kg, while intraperitoneal administration could achieve a significant reduction only at the highest dose of 40 mg/kg. Results suggest that oral administration of ClFPh-CHA formulated as a nanoemulsion has a sufficient bioavailability to provide an anticancer effect in mice and that the activity is at least equal if not superior to that obtained by a conventional parenteral administration of equivalent doses of the same drug.

Salmonella Typhimurium is a typical Gram-Negative bacterium associated with food-borne illness threatening public health. This pathogen is reported to have caused millions of infections and thousands of hospitalizations yearly in the United States alone. Salmonella Typhimurium has a sophisticated array of virulent factors, including its flagella, which contributes significantly to its pathogenicity. Cannabidiol (CBD), the non-psychoactive component of the cannabis plant, has attracted the interest of many researchers recently because of its antimicrobial properties. With the growing interest in exploring CBD’s antimicrobial properties, we, in this study, have delved into unravelling how prolonged exposure of Salmonella Typhimurium to CBD influences the expression of the flgA gene. We hypothesized that the exposure of Salmonella Typhimurium to CBD may result in flgA upregulation, causing the bacteria to withstand various stresses and potentially enhance its survival rates and pathogenicity. We have employed several assays, such as mRNA expression, motility assays, pH induction assays, nutrient starvation interventions, and biofilm analysis, to explore the influence of CBD on the pathophysiology of Salmonella Typhimurium. Our findings reveal that CBD-resistant strains exhibit enhanced resilience to extreme pH levels and motility and survive poorly under nutrient starvation, with more robust biofilm formation compared to the susceptible strains. The results contribute to the broader comprehension of CBD resistance mechanisms in bacteria. This work provides insight into the potential therapeutic interventions for controlling CBD-resistant bacterial infections. This study also underscores the essence of exploring novel alternative antimicrobial agents to tackle the ever-persistence of bacterial antibiotic resistance.

Atherogenesis and dyslipidemia increase the risk of cardiovascular disease, which is the leading cause of death in developed countries. While blood lipid levels have been studied as disease predictors, their accuracy in predicting cardiovascular risk is limited due to its high interindividual and interpopulation variability. The lipid ratios: atherogenic index of plasma (AIP=log TG/HDL-C) and the Castelli risk index 2 (CI2=LDL-C/HDL-C) have been proposed as better predictors of cardiovascular risk, but the genetic variability associated to these ratios has not been investigated. This study aimed to identify genetic associations with these indexes. The study population (n=426) included males (40%) and females (60%) aged 18-52 years (mean 39 years), the Infinium GSA array was used for genotyping. Regression models were developed using R and PLINK. AIP was associated with variation on APOC3, KCND3, CYBA, CCDC141/TTN, and ARRB1 (p-value < 2.1E-6) the three former previously associated to blood lipids, while CI2 was associated with variants on DIPK2B, LIPC, and 10q21.3 rs11251177 (p-value 1.1E-7) the latter previously linked to coronary atherosclerosis and hypertension. KCND3 rs6703437 was associated with both indexes. This study is the first to characterize the potential link between genetic variation and atherogenic indexes, AIP and CI2, highlighting the relation between genetic variation and dyslipidemia predictors. These results also contribute to consolidating the genetics of blood lipid and lipid indexes.

RNA virus polymerases carry out multiple functions necessary for successful genome replication and transcription. A key tool for molecular studies of viral RNA-dependent RNA polymerases (RdRps) is a ‘minigenome’ or ‘minireplicon’ assay, in which viral RdRps are reconstituted in cells in the absence of full virus infection. Typically, plasmids expressing the viral polymerase protein(s) and other co-factors are co-transfected along with a plasmid expressing an RNA encoding a fluorescent or luminescent reporter gene flanked by viral untranslated regions containing cis-acting elements required for viral RdRp recognition. This reconstitutes the viral transcription/replication machinery and allows viral RdRp activity to be measured as a correlate of reporter protein signal. Here we report the first development of a plasmid-based minigenome assay for species A rotavirus, using a firefly luciferase reporter gene.

This retrospective study assesses the efficacy and tolerability of anti-CGRP therapy in adolescents and young adults (ages 12-21) with migraines and chronic daily headaches unresponsive to standard treatments. Migraines severely affect school performance, self-esteem, psychological well-being, and cognitive health in this demographic, who are also sensitive to the side effects of conventional medications often prescribed off-label and face high insurance denial rates. Medication overuse, including analgesics, triptans, and NSAIDs, is prevalent due to treatment failures. Elevated plasma CGRP levels during migraines suggest that anti-CGRP therapies, which have shown success in adults, might benefit this age group. Over three years, patients at a specialized headache center were evaluated for the impact of anti-CGRP treatments, including monoclonal antibodies (erenumab, fremanezumab, galcanezumab) and small molecule CGRP receptor antagonists (ubrogepant, rimegepant, atogepant), either alone or in combination with OnabotulinumtoxinA. The study found significant improvements in migraine management, especially among older adolescents, with reduced rescue medication use and emergency visits. Longer treatment courses and combination therapy with traditional medications were more effective than monotherapy, reducing migraine intensity and frequency. Adverse effects were minimal, and no significant medication interactions were noted. Anti-CGRP therapy demonstrates substantial potential in improving outcomes for this age group with chronic and episodic migraines.

Background: Self-harm (SH) refers to self-injury or intentional self-poisoning with varying degrees of suicidal intent and is a major public health issue for children and adolescents (C&A) worldwide. Given significant gaps exist in our understanding of the associated psychopathology in C&A, this paper outlines the protocol for a prospective clinical study examining risk factors of SH and additional candidate parameters (not routinely assessed) during an acute SH episode. Methods: The EXPAAND (EXploring Psychiatric and Attentional risk-factors in Adolescents Needing intervention for Deliberate self-harm) is a randomised control trial to assess additional novel candidate risk factors for SH in C&A and to evaluate the effectiveness of SH-targeted brief psychological intervention (Therapeutic Assessment (TA)), within a real-world acute clinical setting, as we include neurodiversity and gender diversity in this study. EXPAAND is conducted in 4 phases: (i) recruitment & randomisation; (ii) extended assessment; (iii) randomised intervention; and (iv) follow-up observational period to ascertain clinical outcomes for comparison. Expected Results: We envisage that by diagnosing and treating attentional disorders when detected will mitigate potential confounding effects of these conditions. We also expect that SH-focused TA will be effective in reducing subsequent SH and in improving engagement in follow-up and subsequent treatments.

Several epidemiological studies have demonstrated that particulate matter (PM) in air pollution can be involved in the genesis or aggravation of different cardiovascular, respiratory, perinatal, and cancer diseases. This study assessed the in vitro effects of PM &lt;10 μm in aerodynamic diameter (PM10) on the secretion of cytokines by a human monocytic cell line (THP-1). We compared the chemotactic, pro-inflammatory, and anti-inflammatory cytokines induced by PM10 collected for two years during three different seasons in five different Mexico City locations. MIP-1α, IP-10, MCP-1, TNF-α, and VEGF were the main secretion products after stimulation with 80 μg/mL of PM10 for 24 hours. The THP-1 cells showed a differential response to PM10 obtained in the different sites of Mexico City. The PM10 from the north and the central city areas induced a higher pro-inflammatory cytokine response than those from the south. Seasonal pro-inflammatory cytokine secretion always exceeded the anti-inflammatory one. The rainy season-derived particles caused the lowest pro-inflammatory effects. We concluded that toxicological assessment of airborne particles provides evidence supporting their potential role in chronic exacerbation of local or systemic inflammatory responses that may worsen the evolution of some chronic diseases.

(1) Background: It is unclear whether the reported presenting clinical features of coronavirus disease 2019 (COVID-19) are useful in identifying high-risk patients for early testing and isolation in the emergency department (ED). We aimed to compare the exposure history, clinical, laboratory, and radiographic features of ED patients who tested positive and negative for COVID-19; (2) Methods: We conducted a case-control study in seven EDs during the first five weeks of the COVID-19 outbreak in Hong Kong. Thirty-seven laboratory-confirmed COVID-19 patients were compared with 111 age- and gender-matched controls; (3) Results: There were no significant differences in patient characteristics and reported symptoms between the groups, except patient-reported fever. A positive travel history or contact history was the most significant predictor for COVID-19 infection. After adjustment for age and presumed location of acquiring the infection in Wuhan/Hubei, patient-reported fever (OR 2.6, 95% CI 1.1 to 6.3), delayed presentation (OR 5.0, 95% CI 2.0 to 12.5), having medical consultation before ED presentation (OR 7.4, 95% 2.9 to19.1), thrombocytopenia (OR 4.0, 95% CI 1.6 to 9.7), raised lactate dehydrogenase (OR 5.9, 95% CI 1.9 to 18.5), haziness, consolidation or ground-glass opacity on chest radiography (OR 5.6, 95% CI 2.0 to 16.0), and bilateral changes on chest radiography (OR 13.2, 95% CI 4.7 to 37.4) were associated with a higher odds of COVID-19 separately while neutrophilia was associated with a lower odds (OR 0.3, 95% CI 0.1-0.8); and (4) Conclusions: This study highlights several features that may be useful in identifying high-risk patients for early testing and isolation while waiting for test result. Further studies are warranted to verify the findings.

Cryptococcosis is a leading cause of death among people with HIV in sub-Saharan Africa. Limited diagnostic and therapeutic options significantly impair treatment options in Africa. We investigated the burden of cryptococcosis and related mortality among people with HIV and suspected sepsis in Ethiopia. We conducted a prospective cohort at 1) Adama Hospital Medical College and 2) Asella Referral and Teaching Hospital from September 2019 to November 2020. We enrolled adult HIV-infected patients presenting with suspected sepsis and assessed 28-day survival. We performed blood cultures and cryptococcal antigen (CrAg) testing. In total, 82 participants were enrolled with a median age of 35 years and 61% being female. Overall, 11(13%) had positive CrAg tests, of which 5 had Cryptococcus detected in blood cultures. Despite high-dose fluconazole (1200mg/d) monotherapy in patients with positive CrAg tests, the 28-day mortality was 64%(7/11), being significantly higher than in CrAg-negative patients (9%(6/71); p&lt;0.001). Cryptococcosis is the leading cause of mortality among HIV-infected sepsis patients. CrAg screening in HIV-infected patients attending emergency department can minimize the cryptococcosis missing case irrespective of CD4 count and viral load. These findings warrant the need of a bundle approach for diagnosis of HIV-infected persons presenting with sepsis in low- and middle-income countries.

Psyllids (Hemiptera: Psylloidea) can transmit the phloem restricted bacterium ‘Candidatus Liberibacter solanacearum’ (Lso). In Europe, Lso causes severe losses to carrot and represents a threat to the potato industry. A rising concern of Lso transmission from carrot to potato and within potato has driven the need for monitoring populations of psyllid species that could serve as vectors on both crops, which would provide a fundamental understanding of the epidemiology of this pathogen. Different sampling methods were used to survey populations of psyllid species in commercial carrot and potato fields in Central and Eastern mainland Spain from 2015 to 2017. Two psyllid species, Bactericera trigonica and Bactericera nigricornis were found to be mainly associated with carrot and potato crops. In carrot fields the most abundant species was B. trigonica occurring from crop emergence to harvest, whereas in potato crops the most abundant psyllid species was B. nigricornis. The maximum psyllid population occurred between June and October its timing depending on the field location. Since B. nigricornis was found on both carrot and potato and is the only psyllid species able to feed and breed on both these crops in Europe, there is the potential risk of Lso transmission from carrot to potato

The genus Chaetogaster belongs to the subfamily Naidinae (Naididae), includes mostly species of small size and is diverse and abundant in surface coarse sediments in streams. The aim of the present study is to initiate an inventory of lineages of Chaetogaster in Switzerland. We used 135 specimens collected at six sites in four streams of four cantons. We sequenced the cytochrome c oxidase (COI) gene from all specimens and ITS2 and rDNA 28S from all or several specimens of each lineage delimited using COI data and preserved a voucher of almost all sequenced specimens. We could delimit one lineage (=species) for Chaetogaster diaphanus (Gruithuisen, 1828), three within Chaetogaster diastrophus (Gruithuisen, 1828), one for Chaetogaster langi Brestcher, 1896, one for Chaetogaster setosus Svetlov, 1925 and three unidentified Chaetogaster spp. Two lineages of Chaetogaster spp. could correspond to a new morphological group, but this should be confirmed on more specimens. We described the three C. diastrophus lineages and two Chaetogaster spp. as new species for science. The prospects of the present work are to complete the data of the molecular diversity of this genus in Switzerland and to describe on a molecular/morphological basis the new Chaetogaster species that we will probably find.

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

The marine environment is the largest ecological habitat on Earth, albeit one of the least explored, particularly in terms of its microbial inhabitants. The marine fish gut is host to a diverse microbial community from which diverse bioactive molecules can be sourced. Due to the unique environmental pressures these microbial communities experience, the bioactive molecules they produce often evolve unique adaptations that give them diverse structures and activities, differentiating them from terrestrial homologues. Of particular interest, due to their structural and functional diversity, are the ribosomally-synthesized antimicrobial peptides (bacteriocins). With increasing pressure from emerging antibiotic-resistant disease and industrial demand for novel therapeutics, the marine fish gut microbiome represents a relatively untapped resource of novel bacteriocins that could prove beneficial to human health and aquaculture. This review presents an overview of the marine fish gut microbiome and explores its potential as a source of bacteriocins for human health with considerations for applications and future research in this area.

Iron oxide nanoparticles are widely used as contrast agent for MRI and may be used as therapeutic agent by magnetic hyperthermia if they display a high magnetic anisotropy. Considering the effect of the nanoparticles shape on anisotropy, the reproducible shape control of nanoparticles is currently a challenge of synthesis methods. By investigating reaction parameters which are the iron precursor structure, the water content and the amount of the surfactant, sodium oleate, reported to trigger the cubic shape, iron oxide nanoparticles with different shape and composition were observed to form. In particular, iron oxide nanoplates have been thus synthesized. The effect of the surfactant coming from precursor was taking into account by using in house iron stearates bearing either two or three stearate chains and the negative effect of water on shape was confirmed by considering these precursors after their dehydration. Nanocubes with straight faces and a FeO@Fe3-xO4 composition were obtained only with dehydrated precursors and 50% of sodium oleate in the oleic acid and sodium oleate surfactant mixtures. When iron stearates with three chains led mainly to nanocubes in presence of soduim oleate, Iron stearates with two chains led to the formation of nanoplates with 80% of sodium oleate. The original flat shape of the plates was confirmed with 3D TEM tomography. The investigation of the synthesis mechanisms confirmed the major role of deprotonated carboxylic acid and of the heating rate to drive the cubic shape of nanoparticles and showed that the nanoplate formation would depend mainly on the nucleation step and possibly on the presence of a given ratio of oleic acid and deprotonated carboxylic acid.

Herpes simplex virus (HSV) infections can be treated with direct acting antivirals like acyclovir and foscarnet, but long-term use can lead to drug resistance, which motivates research into broadly-acting antivirals that can provide a greater genetic barrier to resistance. Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species that inactivate microorganisms. The botanical plant extract Orthoquin^TM is a powerful photosensitizer with antimicrobial properties. Here we report that Orthoquin also has antiviral properties. Photoactivated Orthoquin inhibited herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection of target cells in a dose-dependent manner, across a broad range of sub-cytotoxic concentrations. HSV inactivation required direct contact between Orthoquin and the inoculum, whereas pre-treatment of target cells had no effect. Orthoquin did not cause appreciable damage to viral capsids or pre-mature release of viral genomes as measured by qPCR for the HSV-1 genome. By contrast, immunoblotting for HSV-1 antigens in purified virion preparations suggested that higher doses of Orthoquin had a physical impact on certain HSV-1 proteins that altered protein mobility or antigen detection. Orthoquin PDI also inhibited the non-enveloped adenovirus (AdV) in a dose-dependent manner, whereas Orthoquin-mediated inhibition of the enveloped vesicular stomatitis virus (VSV) was light-independent. Together, these findings suggest that broad antiviral effects of Orthoquin-mediated PDI may stem from damage to viral attachment proteins.

We explored the hypothesis that progesterone direct effect on Trichinella spiralis might be mediated indeed by a new steroid-binding parasite protein. Our first results showed that Progesterone decreases the parasite molting rate. We amplify, isolated, cloned and sequenced the PGRMC2 sequence using specific primers from known species. Furthermore, we expressed the protein and developed an antibody to performance immunofluorescent confocal microscopy, where detected that parasite cells showed expression of a P4-binding protein exclusively located at the oocyte and the parasite´s cuticle. Presence of the PGRMC2 protein in these cells was also confirmed by western blot and flow cytometry. Molecular modeling studies accompanied by computer docking using the sequenced protein showed that PGRMC2 is potentially able to bind steroid hormones such as progesterone, estradiol, testosterone, and dihydrodrotestosterone with different affinities. Phylogenetic analysis and sequence alignment clearly demonstrated that Trichinella spiralis PGRMC2 is related to a steroid-binding protein of another platyhelminths. Progesterone may probably act upon Trichinella spiralis oocytes probably by binding to PGRMC2. This research has implications in the field of host-parasite co-evolution as well as the sex-associated susceptibility to this infection. In a more practical matter, present results may contribute to the molecular design of new drugs with anti-parasite actions.

Background: Although rarely indicated, antibiotics are commonly used for acute diarrhoea in China. We conducted a randomized, double blind exploratory clinical trial of loperamide, berberine and turmeric for treatment of acute diarrhoea. Methods: Adults with acute uncomplicated diarrhoea were randomized to 4 groups: (A) loperamide; (B) loperamide and berberine; (C) loperamide and turmeric; (D) loperamide, berberine and turmeric. All participants were given rescue ciprofloxacin for use after 48 hours if symptoms worsened or were unimproved. Primary endpoints were feasibility and ciprofloxacin use during the 2 week follow-up period. Semi-structured interviews were conducted following recruitment. Results: Only 21.5% (278/1295) of patients screened were deemed eligible, and 49% (136/278) of these consented and entered into the final analysis. Most participants had mild symptoms, because most patients with moderate or severe symptoms wanted to be given antibiotics. Follow-up was good (94% at 2 weeks). Only two participants used rescue antibiotics compared to 65% of acute diarrhoea patients in the hospital during the recruitment period. The median symptom duration was: 14 hours in group B (IQR 10-22), 16 hours in group D (IQR 10-22), 18 hours in group A (IQR 10-33), 20 hours in group C (IQR 16-54). Re-consultation rates were low. There were no serious treatment-related adverse events. Most interviewed participants said the treatment was effective. Conclusion: Although recruitment was challenging because of widespread expectations for antibiotics, patients with mild diarrhoea accepted to try an alternative. This therapy requires further evaluation in a fully powered, randomised controlled trial among a broader sample.

Background & aims It is documented that low protein and amino-acid dietary intake is related to poorer cognitive health and increased risk of dementia. Degradation of the neuromodulatory pathways, (comprising the cholinergic, dopaminergic, serotoninergic and noradrenergic systems) is observed in neurodegenerative diseases and impairs the proper biosynthesis of key neuromodulators from micro-nutrients and amino acids. How these micro-nutrients are linked to neuromodulatory pathways in healthy adults is less studied. The Locus Coeruleus–Noradrenergic System (LC-NA) is the earliest subcortical structure affected in Alzheimer’s disease, showing marked neurodegeneration, but is also sensitive for age-related changes. The LC-NA system is critical for supporting attention and cognitive control, functions that are enhanced both by tyrosine administration and chronic tyrosine intake. The purpose of this study was to 1) investigate whether the dietary intake of tyrosine, the key precursor for noradrenaline (NA), is related to LC integrity 2) whether LC integrity mediates the reported association between tyrosine intake and higher cognitive performance (measured with Trail Making Test – TMT), and 3) whether LC integrity relates to an objective measure of brain maintenance (BrainPAD). Methods The analyses included 398 3T MRIs of healthy participants from the Berlin Aging Study II to investigate the relationship between LC integrity and habitual dietary tyrosine intake-daily average (HD-Tyr-IDA). As a control procedure, the same analyses were repeated on other main seeds of the neuromdulatory subcortical system (Dorsal and Medial Raphe, Ventral Tegmental Area and Nucleus Basalis of Meynert). In the same way, the relationships between the five nuclei and BrainPAD were tested. Results Results show that HD-Tyr-IDA is positively associated with LC integrity. Similarly, LC integrity disproportionally relates to better brain maintenance (BrainPAD). Mediation analyses reveal that only LC, relative to the other nuclei tested, mediates the relationship between HD-Tyr-IDA I and performance in the TMT and between HD-Tyr-IDA and BrainPAD. Conclusions These findings provide the first evidence linking tyrosine intake with LC-NA system integrity and its correlation with neuropsychological performance. This study strengthens the role of diet for maintaining brain and cognitive health and supports the noradrenergic theory of cognitive reserve. Within this framework, adequate tyrosine intake might increase the resilience of LC-NA system functioning, by preventing degeneration and supporting noradrenergic metabolism required for LC function and neuropsychological performance.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites between A-56 and A-75, and (ii) major C-terminal cleavage sites between T-383 and Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78, R-79, D-266 and A-267, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression.

Necrotizing enterocolitis (NEC) is a major cause of neonatal morbidity and mortality. Although the specific etiology is unknown, previous research shows that maternal environment may be a contributing factor. Gestational stress may lead to the development of NEC by interfering with the barrier function of the intestinal epithelial barrier. The migration of cells from the crypts to the tips of the villi is crucial in maintaining the integrity of the epithelial barrier. Previously, the Martin lab found that pups from psychologically stressed pregnant dams were more susceptible to NEC-like injury. We have also shown that investigated how stress signaling and zinc impact intestinal epithelial wound healing. Through a scratch assay, human Caco-2 cell migration was studied over 24 hours, and the percent wound healing was calculated. We found that only hydrocortisone at the 30 ug/ml concentration led to an inhibition of wound healing, and that zinc was unable to rescue hydrocortisone mediated inhibition.

There are uncertainties associated with every phase of the stock assessment process, ranging from the collection of data, assessment model choice, model assumptions and interpretation of risk to the implementation of management advice. The dynamics of fish populations are complex, and our incomplete understanding of those dynamics (and limited observations of important mechanisms) necessitate that models are simpler than nature. The aim is for the model to capture enough of the dynamics to accurately estimate trends and abundance and to provide advice to managers about sustainable harvests. The \textit{status quo} approach to assessment modelling has been to identify the `best' model, based on diagnostics and model selection criteria, and to generate advice from that model, mostly ignoring advice from other model configurations regardless of how closely they performed relative to the chosen model. We review the suitability of the ensemble modelling paradigm to more fully capture uncertainty in stock assessment model building and the provision of advice. We recommend further research to evaluate potential gains in modelling performance and advice from the use of ensemble modelling, while also suggesting revisions to the formal process for reviewing models and providing advice to management bodies.

Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under under investigation. The dentate gyrus, a structure highly susceptible to injury, and has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by non-biased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-seq was performed to determine differential gene expression in PTE+ vs. PTE- that may comport with the epileptogenic process. Results: CCI injury resulted in 37% PTE+-incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

Volunteering has many social, emotional and health benefits and could be an option for people with younger/early onset dementia to engage in stage and age-appropriate, personally meaningful activities within their local communities. This study explored how people with young onset dementia volunteer in the UK, the benefits and barriers, and how we can improve access to volunteering opportunities. Audio data of people with young onset dementia discussing their experiences of volunteering were taken from the Dementia Diaries audio and video diary project (https://dementiadiaries.org/). The data were co-analysed by a co-production team, (X), made up of six researchers living with young onset dementia and two facilitators. The findings suggest that stigma is the overarching concept (or net) which influences people’s experiences of volunteering with dementia. Within the stigma net, three themes were developed that employed a lifespan approach to challenging said stigma: 1) Valuing the past, 2) Valuing the present and 3) Valuing the future, each with additional subthemes. This research contributes to the limited pool of literature that highlights the clear benefits of volunteering for people with young onset dementia, while also considering how dementia stigma can create practical and institutional barriers to accessing volunteering. Guidance is provided for how to deliver meaningful and accessible volunteering opportunities.

This paper introduces a systematic approach to the design of Direct Current-to-Digital Converter (DCDC) specifically engineered to overcome the limitations of traditional current measurement methodologies in System-on-Chip (SoC) designs. The proposed DCDC addresses critical challenges such as high power consumption, large area requirements, and the need for intermediate analog signals. By incorporating a current mirror in a cascode topology and managing the current across multiple binary-sized branches with the Successive Approximation Register (SAR) logic, the design achieves precise current measurement. A simple comparator, coupled with an isolation circuit, ensures accurate and reliable sensing. Fabricated using the TSMC 180 nm process, the DCDC achieves 8-bit precision without the need for nonlinearity calibration, showcasing remarkable energy efficiency with an energy per conversion of 1.52 pJ, power consumption of 117 µW, and a compact area of 0.016 mm². This innovative approach not only reduces power consumption and area, but also provides a scalable and efficient solution for next-generation semiconductor technologies. The ability to conduct online measurements during both standard operations and in-field conditions significantly enhances the performance and reliability of SoCs, making this DCDC a promising advancement in the field.

BK polyomavirus (BKPyV) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein do not propagate to wild-type levels and fail to release from host cells. Despite this, loss of agnoprotein does not impair virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-SNAP is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell.

Electrostatic endothelial cell seeding has evolved as an exceptional technique to improve the efficiency of cell seeding in terms of frequency of attached cells and the amount of cell adhesion for the treatment of vascular diseases. In the recent times, both untreated and superhydrophilic thin film nitinol (TFN) have exhibited strong prospect as substrates for creation of small-diameter endovascular grafts due to their hallmark properties of superelasticity, ultra low-profile character, grown hemocompatible oxide layer with the presence of a uniform endothelial layer on the surface. The purpose of the current study is to understand the effects of endothelial cell seeding parameters (i.e., applied voltage, incubation time, substrate chemistry and cell suspension solution) to investigate the cell seeding phenomenon and to improve the cell adhesion and growth on the TFN surface under electrostatic transplantation. Both parallel plate and cylindrical capacitor models were used along with the Taguchi Design of Experiment (DOE) methods to design in vitro test parameters. A novel in vitro system for cylindrical capacitor model was created using a micro flow pump, micro incubation system, and silicone tubings. The augmented endothelialization on thin film nitinol was developed to determine the effect of cell seeding and deployed in a 6 Fr intravascular catheter setup. Cell viability along with morphology and proliferation of adhered cells were evaluated using fluorescent and scanning electron microscopy. Our results demonstrated that the maximum number of cells attached on STFN in the catheter was observed in 5V with the 2 hr exposure of in the cell culture medium (CCM) solution. The condition showed 5V voltage with 0.68×10-6 µC electrostatic charge and 5.11 V·mm-1 electric field. Our findings have first demonstrated that the electrostatic endothelialization on the superhydrophilic thin film nitinol endograft within the catheter prior to the endovascular procedure could enhance the biocompatibility for low-profile endovascular applications.

Melanoma, one of the most aggressive forms of skin cancer, is also one of the most diagnosed cancer types. While surgical excision of the lesions is the primary treatment for melanoma, not all cases are candidates for surgical procedures. New treatments and complementary options are necessary, given the increasing diagnosis rate. In the present study, a norcantharidin-containing nanoemulsion was developed and evaluated in vivo using a syngeneic graft murine model. Our model contemplates an amputation surgery simulating the standard treatment and the role of the nanoemulsion as a potential adjuvant therapy. We observed a significant decrease in the growth rate of the melanoma lesion in the treated groups compared to the control group, both at the 20th and 30th days of treatment. Moreover, we evaluated the drug bioavailability in serum samples, and the results showed that norcantharidin was detectable in a range of 0.1 to 0.18 mg per mL in the treated groups. Furthermore, histopathological analysis was performed on the amputated tumors, where significant differences were found regarding size, mitosis rate, lymphocytic infiltration, and multispectral quantitative image analysis compared to the control group. The norcantharidin-containing nanoemulsion could be a potential alternative or adjuvant therapy if more clinical studies are conducted. Topical nanosystems can become or complement standard therapies, which is needed as melanoma affects not only in terms of mortality but also the patient's morbidity and life quality.