The field of domain adaptation, particularly in cross-domain sentiment classification, leverages labeled data from a source domain alongside unlabeled or sparsely labeled data from a target domain. The objective is to enhance performance in the target domain by mitigating the discrepancies in data distributions. Traditional methods in this area have focused on identifying and differentiating between pivotal sentiment words (shared across domains) and domain-specific sentiment words. In our work, we introduce a novel framework called Sentiment Domain Adapter (SDA), which incorporates a Category Attention Network (CAN) alongside a Convolutional Neural Network (CNN). This approach treats pivotal and domain-specific words as part of a collective category of attributes, which SDA learns to discern automatically, thereby enhancing domain adaptation. Additionally, SDA seeks to provide interpretative insights by learning these category attributes. Our model's optimization targets three main goals: (1) supervised classification accuracy, (2) minimizing the disparity in category feature distribution, and (3) maintaining domain invariance. Evaluations on three benchmark datasets for sentiment analysis affirm that SDA surpasses several established baselines.

The exploration and understanding of sentiments and emotions through textual analysis are foundational to advancements in natural language processing (NLP). While sentiment analysis, which involves discerning the polarity of text, has been extensively explored, the nuanced detection of complex emotions within textual content is still an emerging area of study. In this paper, we introduce EmoLeverage, a model leveraging Transformer architecture and enhanced with a novel Fusion Adapter module. This model aims to deepen emotion detection capabilities by drawing insights from fundamental sentiment analysis tasks, focusing exclusively on textual data. EmoLeverage sets a new standard in the field by demonstrating that deep, nuanced understanding of emotions is achievable through text alone, challenging and surpassing existing methodologies in emotion identification on key datasets. This is a significant step forward, considering the complexity of human emotions and the subtleties involved in their expression through language. By concentrating on textual input, EmoLeverage offers a promising avenue for applications where audio or visual data is not available, highlighting the versatility and potential of text-based emotional analysis. Our approach illustrates the untapped potential of leveraging sophisticated NLP techniques to enhance the detection and comprehension of a wide array of emotions from text. The success of EmoLeverage in outperforming conventional models in emotion recognition tasks underscores the model's effectiveness in parsing and understanding the intricate expressions of human emotions through linguistic cues alone. This achievement paves the way for more accurate, efficient, and nuanced emotion detection tools, potentially transforming various sectors by providing deeper insights into human emotional states through text.

The flux of opinions in newsletters and social media platforms significantly influences market perceptions regarding corporate entities and their financial instruments. This paper introduces an advanced model, the Sentiment Dynamics Analyzer (SDA), which leverages a refined hierarchical architecture of Transformers to effectively discern the sentiment embedded within financial texts, ranging from news headlines to microblogs. We have enhanced a RoBERTa model with specialized sentiment lexicons and an augmented layer of Transformer models tailored for nuanced sentence-level sentiment detection, aiming to assign a sentiment score from -1 to +1. Our evaluations demonstrate that SDA not only surpasses the previous best methods but also exhibits superior performance over robust baseline models. This success underscores the utility of integrating tailored contextual analyses with sector-specific sentiment insights in improving predictive accuracy.

The biosynthesis of DNA inherently competes with RNA synthesis because it depends on the reduction of ribonucleotides (RNA precursors) to 2’-deoxyribonucleotides by ribonucleotide reductase (RNR). Hence, RNA viruses can increase viral RNA production in cells by partially blocking the synthesis of DNA, e.g. by downregulating the mammalian selenoprotein thioredoxin reductase (TR), which normally acts to sustain DNA synthesis by regenerating reduced thioredoxin, a hydrogen donor for RNR. Computational and preliminary experimental evidence supports the hypothesis that a number of pathogenic RNA viruses, including HIV-1, Ebola, Zika, some flu viruses, and SARS-CoV-2, target TR isoforms by antisense. TR knockdown would create a host antioxidant defect that could be partially rectified by increased selenium intake, or be exacerbated by selenium deficiency, contributing to viral pathogenesis. There are several non-selenium-dependent means that viruses might also exploit to slow DNA synthesis, such as targeting RNR itself, or components of the glutaredoxin system, which serves as a backup redox system for RNR. HIV-1 substantially downregulates glutathione synthesis, so it interferes with both the thioredoxin and glutaredoxin systems. Computational results suggest that, like Ebola, SARS-CoV-2 targets TR3 by antisense. TR3 is the only TR isoform that includes an N-terminal glutaredoxin domain, so antisense knockdown of TR3 may also affect both redox systems, favoring RNA synthesis. In contrast, some DNA viruses encode their own glutaredoxins, thioredoxin-like proteins and even RNR homologues – so they are doing just the opposite, favoring DNA synthesis. This is clear evidence that viruses can benefit from shifting the RNA:DNA balance to their advantage.

Foot pain related to the plantar fascia is common in adults regardless of athletic background. Many pathologies can lead to the diagnosis of plantar enthesopathy, but the most relevant to this case study is related to structural defects within the plantar fascia. Due to the variety and sometimes unclear etiology of plantar fasciosis, no single standard of care treatment protocol is recognized. Often, patients receive NSAIDs, night splints, taping, physical therapy, foot orthosis, and extracorporeal shock wave therapies. This study presents Wharton Jelly (WJ) tissue allografts as an additional intervention for patients who fail standard-care treatments. WJ allografts are applied to supplement connective tissue defects directly, unlike other therapies, which aim to reduce swelling and symptomatic pain. This retrospective study includes seven patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. Patient progress was tracked using a visual analog scale, 0-10 scoring, reported by the patient at the initial visit and approximately thirteen weeks following, reporting an average improvement of 50%. The study's limitations include a small cohort size and a non-blinded retrospective design. These promising results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Chromatin structure plays a fundamental role in regulating gene expression, with histone modifiers shaping the structure of chromatin by adding or removing chemical changes to his-tone proteins. The p53 transcription factor controls gene expression, binds target genes, and regulates their activity. While p53 has been extensively investigated in the context of cancer research, its association with histone modifiers has received limited attention. This review ex-plores the interplay between histone modifiers and p53 in regulating gene expression. We discussed how histone modifications can influence how p53 binds to target genes and how this interplay can be disrupted in cancer cells. This study provides insights into the complex mechanisms underlying gene regulation and their implications for potential cancer therapy.

Dirac's Large Number Hypothesis (LNH), proposed in 1937, has captivated the scientific community with its exploration of profound correlations between cosmic and atomic scales. This hypothesis delves into the intricate interplay between the infinitesimally small and the vastly large, offering potential insights into the fundamental nature of the universe. As we continue to uncover the mysteries of the cosmos, the LNH oscillates on the precipice of scientific acceptance—neither fully validated nor entirely dismissed. In this review paper, we embark on a comprehensive journey through Dirac's LNH, shedding light on its theoretical underpinnings, its implications for universe models, and its resonance with the Anthropic Principle. We delve into the possibilities of variable gravitational constants and continuous mass creation, inviting further exploration into the intricacies of our cosmic symphony. By embracing the ongoing quest for understanding, we endeavor to unravel the profound harmonies that connect the infinitesimal with the infinite, contributing to the symphony of knowledge in theoretical physics and cosmology.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

The virtually complete loss of intestinal worms, known as helminths, from Western society has resulted in elimination of a range of helminth-induced morbidities. Unfortunately, that loss has also led to inflammation-associated deficiencies in immune function, ultimately contributing to widespread pandemics of allergies, autoimmunity, and neuropsychiatric disorders. Several socio-medical studies have examined the effects of intentional reworming, or self-treatment with helminths, on a variety of inflammation-related disorders. In this study, the latest results from ongoing socio-medical studies are described. The results point toward two important factors that appear to be overlooked in some if not most clinical trials. Specifically, (a) the method of preparation of the helminth can have a profound effect on its therapeutic efficacy, and (b) variation between individuals in the effective therapeutic dosage apparently covers a 10-fold range, regardless of the helminth used. These results highlight current limits in our understanding of the biology of both hosts and helminths, and suggest that information from self-treatment may be critical for clinical evaluation of the benefits and limits of helminth therapy.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care and shown remarkable efficacy clinically. This efficacy is, however, limited to subsets of patients with significant infiltration of lymphocytes into the tumor microenvironment. To extend their efficacy to patients who fail to respond or achieve durable responses, it is now becoming evident that complex combinations of immunomodulatory agents may be required to extend efficacy to patients with immunologically “cold” tumours. Oncolytic viruses (OVs) have the capacity to selectively replicate within and kill tumour cells resulting in the induction of immunogenic cell death and the augmentation of anti-tumour immunity and have emerged as a promising modality for combination therapy to overcome the limitations seen with ICIs. Pre-clinical and clinical data has demonstrated that OVs can increase immune cell infiltration into the tumour and induce anti-tumour immunity, thus changing a “cold” tumour microenvironment that is commonly associated with poor response to ICIs, to a “hot” microenvironment which can render patients more susceptible to ICIs. Here, we review the major viral vector platforms used in OV clinical trials, their success when used as a monotherapy and when combined with adjuvant ICIs, as well as pre-clinical studies looking at the effectiveness of encoding OVs to deliver ICIs locally to the tumour microenvironment through transgene expression.

Background: The Davidson Airway Function & Nasal Evaluation (DAFNE) Scoring System was developed as an intuitive and research-based scoring system that could be validated through beta testing and easily introduced to healthcare providers of several subspecialties who treat nasal obstruction and breathing disorders (MDs, PAs, PTs, APRNs, DDSs, and DCs). This scoring system was shown to increase the knowledge of airway function, nasal measurement parameters, and identification of proper treatment options for sleep and breathing disorders. The basis for the DAFNE score was developed from a systematic review of nasal measurement data. Methods: Electronic searches of PubMed, MEDLINE, EMBASE Cochrane Library, and Scopus of publications between 1988-2022 were used to identify studies validating nasal function measurement parameters to create the algorithm for the DAFNE Score™. The systematic review was accomplished using the 2020 ‘Preferred Reporting Items for Systematic Reviews’ (PRISMA) guidelines. Results: Twenty studies met the inclusion criteria for systematic review. Primary outcomes measurements demonstrated reliability, repeatability and validity of the DAFNE measurement technologies, data and output. Conclusions: The data analysis and systematic review uncovered a need and framework to develop and validate a web-based software algorithm for global access to improve the understanding of data interpretation of nasal measurements from three nasal measurement technologies. DAFNE Scoring should be used as an adjunct tool in routine clinical practice and research to further understand the technology data output and how to collaborate with other healthcare providers to improve patient outcomes.

Abstract: Background: The diagnosis of nasal airway disorders relies on questionnaires, subjective data, and objective data. Interpretation of objective data obtained from measurement technology is not well understood by providers and researchers who use the equipment to test nasal airway function, justifying the need to cre-ate a new clinical tool. The Davidson Airway Function & Nasal Evaluation (DAFNE) Scoring System is a web-based scoring system that allows healthcare providers (MDs, PAs, PTs, APRNs, DMDs, DDSs, SLPs, and DCs) and researchers who treat nasal obstruction and breathing disorders to make more accurate diagnostic decisions, select the appropriate treatment for individualized patient care, monitor treatment progression and outcomes, and show how to approach a collaborative care model with other healthcare professionals. The current technologies, such as 4-phase rhinomanometry, use a simple approach that relies on a measurement tracing intersecting a color-coded y-axis on a four-quadrant graph with diagnostic numeric data output de-scribing nasal airflow and resistance. This is a good source of biofeedback demonstrating abnormal nasal breathing patterns but lacks interpretation guidelines to describe the severity of disease. The more sophisti-cated proprietary DAFNE approach uses multiple parameters which include airflow restriction, speed, vol-ume, and patient characteristics to identify patients’ disease progression much more accurately. Additionally, it explains how to segregate patients into appropriate treatment options which minimizes risks and compli-cations associated with sleep and breathing disorders while improving patient outcomes. Methods: Electronic searches of PubMed, MEDLINE, EMBASE Cochrane Library, and Scopus of publications between 1988-2022 were necessary to identify studies which determined the ranges of nasal function measurement parameters among three airway measurement technologies used in writing the DAFNE Score algorithm. The performance of DAFNE was evaluated compared to the research data and patient demographics used in previous studies. Results: By using primary outcome measurements from the literature, we were able to create a reliable, re-peatable, and validated tool to facilitate patient identification, treatment stratification, and collaboration for sleep and nasal breathing dysfunction. Subsequently, we found DAFNE could be used to identify the appro-priateness of a sleep study. Conclusions: DAFNE Scoring System has demonstrated the ability to detect high risk patients in the pediatric and adult populations susceptible of sleep apnea and breathing dysfunction needing a sleep study and treatment to improve nasal airway function and sleep. DAFNE Scoring System should be used as an adjunct tool in routine clinical practice and research to further understand the technol-ogy data output, identify patients at risk, stratify treatment options, progress, and stabilization after treatment, and how to collaborate with other healthcare providers to improve patient outcomes.

Damaged connective tissues between the bone and tendons or ligaments are common among adults regardless of activity level. Achilles tendinosis is one of the most common tissue defects and enthesopathies. The patient in this study is a 54-year-old female with chronic Achilles tendinosis from chronic enthesopathy at the Achilles tendon insertion with a retrocalcaneal exostosis for three years who has failed standard-of-care practices for over two years. The patient received extracorporeal pulsed-activated therapy (EPAT) before applying 2ml of CryoText, a Wharton’s jelly tissue allograft. The patient then received class IV laser therapy treatments twice weekly for three weeks. The patient started with a 10/10 VAS at the initial visit. At five weeks post-application, the patient’s score had improved by 80% at 2/10 VAS. By week 13, the patient rated her pain as 0/10 VAS. The improvement in patient-reported pain and functionality reported in this study after the application of Wharton’s Jelly, EPAT, and class IV laser therapy warrants future research studying the safety and efficacy of these patient care modalities together.

The cohesive energy of transition metal nanoparticles is crucial to understanding their stability and fundamental properties, which are essential for developing new technologies and applications in fields such as catalysis, electronics, energy storage, and biomedical engineering. In this study, we systematically investigate the size-dependent cohesive energies of all the 3d, 4d, and 5d transition-metal nanoparticles using first-principles density functional theory calculations. Our results show that the cohesive energies of nanoparticles decrease with decreasing size due to the increased surface-to-volume ratio and quantum confinement effects. We also find that the size-dependent cohesive energy trends are different for different transition metals, with some metals exhibiting stronger size effects than others. Our findings provide insights into the fundamental properties of transition-metal nanoparticles and have potential implications for their applications in various fields such as catalysis, electronics, and biomedical engineering.

Many studies in the current literature annotate patterns in stock prices and use computer vision models to learn and recognize these patterns from stock price-action chart images. Additionally, current literature also use Long Short-Term Memory Networks to predict prices from continuous dollar amount data. In this study, we combine the two techniques. We annotate the consolidation breakouts for a given stock price data, and we use continuous stock price data to predict consolidation breakouts. Unlike computer vision models that look at the image of a stock price action, we explore using the convolution operation on raw dollar values to predict consolidation breakouts under a supervised learning problem setting. Unlike LSTMs that predict stock prices given continuous stock data, we use the continuous stock data to classify a given price window as breakout or not. Finally, we do a regularization study to see the effect of L₁, L₂, and Elastic Net regularization. We hope that combining regression and classification shed more light on stock market prediction studies.

Clean water is now very rare due to the increased water pollution causing many diseases. Heavy metals mainly lead from industrial waste i.e. batteries, cable sheaths, machinery manufacturing, shipbuilding, lead oxide and radiation protection is accountable & largely contributed lead in river and canal waters. Presence of lead in water is hazardous to life due to many reasons. It can cause cancer, weakness, anemia, kidneys, high blood pressure and nerve diseases. Inorganic lead is reported to me more dangerous than organic one. Industries including batteries, cable sheaths, machinery manufacturing etc. drains water that has soluble lead ranging from 200 – 500 mg/L. The safe limit of lead in water is about 0.015 mg/L. Pakistan is a country rich in minerals. It has about 3.5 MT of Kaolin (Clay) deposits situated at Nagar Parker region of Sindh, Pakistan. This indigenous material is being used to produce ceramic products and in paper making. Now we use this mineral source to remove lead from water by adsorption. Kaolin clay can be used as an adsorbent due to its unique structure. XRF technique is employed for clay characterization. Resultants will be analyzed by UV – Vis Spectrophotometry.

Malignant melanoma (MM) is the most fatal form of skin cancer, accounting for 90% of all skin cancer deaths. Multiple dysregulated cellular pathways are involved in MM, including the MAPK/ERK and PI3K/PTEN/AKT pathways, which can be targeted with novel targeted inhibitors. However, these blockades can be overcome through the activation of alternative pathways, leading to treatment resistance. The high immunogenicity of MM has been exploited using checkpoint inhibitors resulting in improved survival outcomes of patients with advanced MM. However, their side effect profile and prohibitive cost remain a challenge and the survival outcomes for patients with metastatic MM remain poor. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, metastasis, and treatment resistance. CSCs reside within the MM tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system (RAS), expressed in many cancer types, including MM. This article reviews the current treatment of advanced MM with targeted therapy and immune checkpoint blockers, highlights the emergence of mRNA vaccine. It also discusses the MM TME and its relationship with CSCs, and the local immune system and the paracrine RAS. It highlights the regulation of the MAPK/ERK and PI3K/AKT/mTOR pathways by the RAS via prorenin receptor and angiotensin II receptor 1, and how this relates to the CSCs and treatment resistance. This underscores the potential multi-modal therapeutic strategy by concurrent targeting of multiple components of the TME.

Globally, anthropogenic sound and artificial light pollution have increased to alarming levels. Evidence suggests that these can disrupt critical processes that impact ecosystems and human health. However, limited focus has been given to the potential effects of sound and artificial light pollution on microbiomes. Microbial communities are the foundations of our ecosystems. They are essential for human health and provide myriad ecosystem services. Therefore, disruption to microbiomes by anthropogenic sound and artificial light could have important ecological and human health implications. In this mini-review, we provide a critical appraisal of available scientific literature on the effects of anthropogenic sound and light exposure on microorganisms and discuss the potential ecological and human health implications. Our mini-review shows that a limited number of studies have been carried out to investigate the effects of anthropogenic sound and light pollution on microbiomes. However, based on these studies, it is evident that anthropogenic sound and light pollution have the potential to significantly influence ecosystems and human health via microbial interactions. Many of the studies suffered from modest sample sizes, suboptimal experiments designs, and some of the bioinformatics approaches used are now outdated. These factors should be improved in future studies. This is an emerging and severely underexplored area of research that could have important implications for global ecosystems and public health. Finally, we also propose the photo-sonic restoration hypothesis: does restoring natural levels of light and sound help to restore microbiomes and ecosystem stability?

In the century and a half since Maxwell first conjured his “finite being” which Lord Kelvin subsequently dubbed a “daemon”, researchers have explored the connections between non-equilibrium thermodynamics, entropy, and information theory. In recent years various Thermodynamic Uncertainty Relations (TURs) have been derived to inform upon the relationship between the entropy production and the precision possible in thermodynamic machines and processes. In this paper the recently derived TURs are applied to the hypothetical thermodynamic economy as described by Parker [1]. The TURs define the lower bound on the total entropy production of the economy. Changes in this entropy production rate has consequences on the stability of the economic system and plays a central role in the business cycle. This new perspective has important implications for policy makers, researchers, and other economic actors.

Thermal interface material (TIM) that can exist as liquid at the service temperature enables efficient heat transfer across two adjacent surfaces in electronic applications. In this work, the thermal conductivities of different phase regions in the Ga-In system at various compositions and temperatures are measured for the first time. A modified comparative cut bar technique is used for the measurement of the thermal conductivities of In_xGa_1-x (x=0, 0.1, 0.214, 0.3, and 0.9) alloys at 40, 60, 80, and 100^oC that are the temperatures commonly encountered in consumer electronics. The thermal conductivity values for the liquid and semi-liquid (liquid+β) Ga-In alloys are higher than the TIM currently used in consumer electronics. These measured quantities, along with the available experimental data from the literature, served as input for the thermal conductivity parameter optimization using the CALPHAD (CALculation of PHase Diagram) method for the pure elements, solution phase, and two-phase region. A set of self-consistent parameters for the description of the thermal conductivity of the Ga-In system is obtained. There is good agreement between the measured and calculated thermal conductivity values for all the phases. Hence, it can be envisaged that liquid/semi-liquid Ga-In alloys can be considered as a potential TIM in consumer electronics due to its high thermal conductivity.

More than half of the states in the U.S. report that over 30% of adults are obese. Obesity increases the risk of many chronic diseases, including type 2 diabetes, hypertension, cardiovascular disease, and can even reduce one’s lifespan. Similarly, the prevalence of type 2 diabetes follows a comparable trend. As a result, researchers are striving to find solutions to reduce obesity rates, with a particular focus on gut health, which has been previously linked to both obesity and type 2 diabetes. Recent studies suggest that Akkermansia muciniphila(AKK) may have a positive probiotic effect on preventing the onset of type 2 diabetes and obesity. We conducted a quantitative meta-analysis of 15 qualified animal studies investigating the effects of AKK administration as a probiotic. The statistical analyses showed that AKK administration significantly reduced body weight gain by 10.4% and fasting blood glucose by 21.2%, while also significantly improving glucose tolerance by 22.1% and increasing blood insulin levels by 26.9%. However, our analysis revealed substantial heterogeneity between the control and experimental groups across all subgroups. Overall, AKK appears to be effective at reducing the onset of type 2 diabetes and diet-induced obesity. Long-term studies with larger sample sizes are needed to confirm these beneficial effects, as the current animal studies were of short duration (less than 20 weeks).

We exploit the properties of complex time to obtain an analytical relationship based on considerations of causality between the two conserved quantities of a system’s Hamiltonian and its Entropy Production. In natural units, when complexified, the one is simply the Wick-rotated complex-conjugate of the other. A Hilbert transform relation is constructed in the formalism of Quantitative Geometrical Thermodynamics which enables system irreversibility to be handled analytically within a framework that unifies both the microscopic and macroscopic scales, and which also unifies the treatment of both reversibility and irreversibility as complementary parts of a single physical description. In particular the thermodynamics of two unitary entities are considered: the alpha particle which is absolutely stable (that is, trivially reversible with zero entropy production), and a black hole whose absolute disequilibrium (unconditional irreversibility) is characterized by a non-zero entropy production for which we show an alternate derivation confirming our previous one (Universe 7, 2021, 325). The thermodynamics of a canonical decaying harmonic oscillator are also considered. In this treatment the complexification of time also enables a meaningful physical interpretation of both “imaginary time” and “imaginary energy”.

Double-spiral galaxies are common in the Universe. It is known that the logarithmic double spiral is a Maximum Entropy geometry and represents spiral galaxies well. It is also known that the virial mass of such a galaxy can be approximately determined from the entropy of its central supermassive black hole. But over time the black hole must accrete mass, and therefore the overall galactic entropy must increase. From the associated entropic Euler-Lagrange equation (forming the basis of the Principle of Least Exertion, and also enabling the application of Nöther’s theorem) we show that the galactic entropy production is a conserved quantity, and we derive an appropriate expression for the relativistic entropic Hamiltonian of an idealised spiral galaxy. We generalise Onsager’s celebrated expression for entropy production and demonstrate that galactic entropy production has two parts, one many orders of magnitude larger than the other, and where the smaller is comparable to the Hawking radiation of the central supermassive black hole. We conclude that galaxies cannot be isolated, since even idealised spiral galaxies have non-zero entropy production.

Many reported sea level records are often not a single measurement. They are then a composition of different records from several tide gauges. Sometimes, they are from the same tide gauge, but the tide gauge stability has been affected by earthquakes. This is the case of Guam as discussed in the present manuscript. The claimed sea level acceleration of Guam is only the result of two earthquakes that have compromised the stability of the tide gauge.

This work presents the computation of reliable warming trends for central Australia around Alice Springs within a circle of radius 1,000 km. Between 1880 and 2011, the average warming for the centre of Australia is +0.166 ºC/century, slightly smaller than the warming of Alice Springs, that is +0.176 ºC/century. Over a shorter time between 1910 and 2011, the centre of Australia is warming +0.794 ºC/century, slightly more than the warming of Alice Springs, that is +0.719 ºC/century.

The HIV-1 nef gene terminates in a 3’-UGA stop codon, which is highly conserved in the main group of HIV-1 subtypes, along with a downstream potential coding region that could extend the nef protein by 33 amino acids, if readthrough of the stop codon occurs. Antisense tethering interactions (ATIs) between a viral mRNA and a host selenoprotein mRNA are a potential viral strategy for the capture of a host selenocysteine insertion sequence (SECIS) element (Taylor et al, 2016) [1]. This mRNA hijacking mechanism could enable the expression of virally encoded selenoprotein modules, via translation of in-frame UGA stop codons as selenocysteine (SeC). Here we show that readthrough of the 3’-terminal UGA codon of nef occurs during translation of HIV-1 nef expression constructs in transfected cells. This was accomplished via fluorescence microscopy image analysis and flow cytometry of HEK 293 cells, transfected with engineered GFP reporter gene plasmid constructs, in which GFP can only be expressed by translational recoding of the UGA codon. SiRNA knockdown of thioredoxin reductase 1 (TR1) mRNA resulted in a 67% decrease in GFP expression, presumably due to reduced availability of the components involved in selenocysteine incorporation for the stop codon readthrough, thus supporting the proposed ATI. Addition of 20 nM sodium selenite to the media significantly enhanced stop codon readthrough in the pNefATI1 plasmid construct, by >100%, supporting the hypothesis that selenium is involved in the UGA readthrough mechanism.

The Principle of Indifference (“PI”: the simplest non-informative prior in Bayesian probability) has been shown to lead to paradoxes since Bertrand (1889). Von Mises (1928) introduced the “Wine/Water Paradox” as a resonant example of a “Bertrand paradox”, and which has been presented as demonstrating that the PI must be rejected. We now resolve these paradoxes by a Maximum Entropy (MaxEnt) treatment of the PI that also includes information provided by Benford’s “Law of Anomalous Numbers” (1938). We show that the PI should be understood to represent a family of informationally-identical MaxEnt solutions; each solution being identified with its own explicitly justified boundary condition. In particular, our solution of the Wine/Water Paradox exploits Benford’s Law to construct a non-uniform distribution representing the universal constraint of scale invariance, which is a physical consequence of the Second Law of Thermodynamics.

The estuarine exchange flow increases longitudinal dispersion of passive tracers and traps sinking particles, potentially creating an estuarine turbidity maximum (ETM): a localized maximum of suspended particulate matter concentration in an estuary. The ETM can have many implications - dead zones due to increased turbidity or hypoxia from organic matter decomposition, naval navigation challenges, and other water quality problems. Using timescales, we investigate how the interaction between exchange flow and particle sinking leads to ETMs by modeling a sinking tracer in an idealized box model of the Total Exchange Flow (TEF) first developed by Parker MacCready. Results indicate that the balance of particle sinking and vertical mixing is critical to determining ETM size and location. We then focus on the role of ecology in ETM formation through the use of The Peter-Parker Model: a new biophysical model which combines the TEF box model with a Nutrient-Phytoplankton-Zooplankton-Detritus (NPZD) model, the likes of which were first developed by Peter J.S. Franks. Detritus sinking rates similarly influence detritus peak concentration and location (an ETM), but detritus ETMs occur in a different location than the sinking tracer due to the influence of the biological factors which create a time lag of about 1 day. Lastly, we characterize the flow of the models with a dimensionless parameter that compares timescales and summarizes the dynamics of the sinking tracer in ETM formation and can be used across systems.

Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex metabolic disorder that manifests in genetically susceptible women following a range of negative exposures to nutritional and environmental factors related to contemporary lifestyle. The hypothesis that PCOS phenotypes are derived from a mismatch between ancient genetic survival mechanisms and modern lifestyle practices is supported by a diversity of research findings. The proposed evolutionary model of the pathogenesis of PCOS incorporates evidence related to evolutionary theory, genetic studies, in-utero developmental epigenetic programming, transgenerational inheritance, metabolic features including insulin resistance, obesity and the apparent paradox of lean phenotypes, reproductive effects and subfertility, the impact of the microbiome and dysbiosis, endocrine disrupting chemical exposure, and the influence of lifestyle factors such as poor quality diet and physical inactivity. Based on these premises, the diverse lines of research are synthesized into a composite evolutionary model of the pathogenesis of PCOS. It is hoped that this model will assist clinicians and patients to understand the importance of lifestyle interventions in the prevention and management of PCOS and provide a conceptual framework for future research. It is appreciated that this theory represents a synthesis of the current evidence and that it is expected to evolve and change over time.

The Robotics Vision Lab of Northwest Nazarene University has developed Orchard Robot (OrBot), which was designed for harvesting fruits. OrBot is composed of a machine vision system to locate fruits on the tree, a robotic manipulator to approach the target fruit, and a gripper to remove the target fruit. Field trials conducted at commercial orchards for apples and peaches during the harvesting season of 2021 yielded a harvesting success rate of about 85% and had an average harvesting cycle time of 12 seconds. Building upon this success, the goal of this study is to evaluate the performance of OrBot during nighttime harvesting. The idea is to have OrBot harvest at night, and then human pickers continue the harvesting operation during the day. This human and robot collaboration will leverage the labor shortage issue with a relatively slower robot working at night. The specific objectives are to determine the artificial lighting parameters suitable for nighttime harvesting and to evaluate the harvesting viability of OrBot during the night. LED lighting was selected as the source for artificial illumination with a color temperature of 5600 K and 10% intensity. This combination resulted with the lowest noise in the images. OrBot was tested in a commercial orchard using twenty Pink Lady apple trees. Results showed an increased success rate during the night, with OrBot gaining 94%. compared to 88% during the daytime operations.

Binge drinking is associated with increased mortality and morbidity. Burkholderia pseudomallei, the causative agent of pneumonic melioidosis can occur in healthy humans; however, binge alcohol intoxication is a major risk factor. Previous findings indicate that a single binge alcohol episode increases Burkholderia spp. infection by reducing alveolar macrophage function. The aim of this study was to test the ability of the phytonutrient sulforaphane (SFN) to rescue the phagocytic function of alveolar macrophages when infected with Burkholderia spp. in vitro. B. thailandensis E264 was used as a useful BSL-1 model to determine the effects of SFN pre-treatment. The primary outcome was macrophage phagocytic killing, while the secondary outcome was the nuclear factor (erythroid-derived 2)-like (Nrf2) signaling response measured by western blot analysis. Results indicate that alveolar macrophages pre-treated with SFN (5 M) and challenged with 0.2% (v/v) alcohol for 3 or 8 h prior to live B. thailandensis infection improved intracellular killing of B. thailandensis ~2-fold compared to MH-S cells treated with alcohol alone. These data demonstrate that SFN may be an effective pre-treatment option to prevent alcohol mediated immune dysfunction and restore macrophage phagocytic killing of Burkholderia spp. and other similar opportunistic pathogens.

Polycystic ovary syndrome (PCOS) is increasingly being viewed as an evolutionary mismatch disorder that manifests in women after exposure to a range of lifestyle and environmental factors. Although there is ongoing debate regarding the pathogenesis, international guidelines recommend lifestyle treatment, with diet and exercise, as the first line of management in all women with PCOS. In addition, accumulating evidence suggests that environmental factors such as endocrine disrupting chemicals (EDC) may be involved in the pathogenesis of PCOS due to their known hormonal and metabolic effects. As a result, international professional bodies have recommended that all pregnant women be advised of the risks of EDC and that education programs be developed to inform health professionals. Microparticulate air pollution (MAP) is also a significant environmental exposure that has been associated with a variety of chronic diseases, including PCOS. We performed a systematic review of studies examining the relationship between MAP and PCOS using the PRISMA methodology. The review identified 214 records from PubMed, Cochrane, and Scopus databases, and 4 studies that met the inclusion criteria for qualitative assessment. Preliminary data suggest that MAP may contribute to the pathogenesis of PCOS via a number of mechanisms. This review highlights the need for greater awareness and further research on the effects of MAP in women with PCOS.

Dirac's Large Number Hypothesis (LNH), proposed in 1937, has captivated the scientific community with its exploration of profound correlations between cosmic and atomic scales. This hypothesis delves into the intricate interplay between the infinitesimally small and the vastly large, offering potential insights into the fundamental nature of the universe. As we continue to uncover the mysteries of the cosmos, the LNH oscillates on the precipice of scientific acceptance—neither fully validated nor entirely dismissed. In this review paper, we embark on a comprehensive journey through Dirac's LNH, shedding light on its theoretical underpinnings, its implications for universe models, and its resonance with the Anthropic Principle. We delve into the possibilities of variable gravitational constants and continuous mass creation, inviting further exploration into the intricacies of our cosmic symphony. By embracing the ongoing quest for understanding, we endeavor to unravel the profound harmonies that connect the infinitesimal with the infinite, contributing to the symphony of knowledge in theoretical physics and cosmology.

Science seeks to explicate truths about our reality. But what is truth? How do we know things? Given our ignorance, and our fallibility, why should scientists be trusted? A theory of knowledge that addresses these human questions is sketched, in conversation with recent advances in thermodynamics which underline the seminal importance of unity by demonstrating (i) a definite physical meaning of the idea of “unitary entity”, (ii) the commensurability of the local and the non-local (resolving the Loschmidt Paradox), and (iii) the applicability of this entropic physics to entities at all scales, whether small (“quantum mechanical”) or large (subject to “general relativity”). Similarly, integrity is indispensable to the scientific enterprise, whether at the level of the mathematico-physical, the practising scientist, the scientific community, or the public. As a human activity aimed at touching reality, it is fundamental that the scientific enterprise necessarily also has an irreducibly poetic component. Although in principle it cannot be completely specified, this enterprise is a cluster of procedures designed to increase our understanding of the natural world. Our apprehension of knowledge is irreducibly personal, depending both on our own individual integrity as well as on the integrity of the scientific community. Believing that “reality” exists and can be grasped (however incompletely), scientists look for coherence and value unified accounts. Strictly speaking, although reality can be known truly (if only in part) the idea of “objective” knowledge is an oxymoron, even if such an idea is often a useful approximation. Knowledge is necessarily personal.

Physics has been thought to truly represent reality since at least Galileo, and the foundations of physics are always established using philosophical ideas. In particular, the elegant naming of physical entities is usually very influential in the acceptance of physical theories. We here demonstrate (using current developments in thermodynamics as an example) that both the epistemology and the ontology of physics ultimately rest on poetic language. What we understand depends essentially on the language we use. We wish to establish our knowledge securely, but strictly speaking this is impossible using only analytic language. Knowledge of the meanings of things must use a natural language designed to express meaning, that is, poetic language. Although the world is really there, and although we can indeed know it truly, this knowledge is never either complete or certain but ultimately must rest on intuition. Reading a recently discovered artefact with a palaeo-Hebrew inscription as from the first century, we demonstrate from it that this ontological understanding long predates the Hellenic period. Poetic language is primary, both logically and temporally.

We survey the main results emerging in the rapidly developing field that considers the geometry of thermodynamics and statistical mechanics. Our ideas of stability depend on variational principles – Maximum Entropy together with Least Action (and the isomorphic Least Exertion) – and this stability (invariance in time) indicates the centrality of the geometries of the systems. We explore a variety of examples of the application of thermodynamics in both macro- and micro-systems, and propose that irreversibility is an intrinsic and fundamental property of the physical realm (instead of being merely emergent). Using the concept of complex time, we examine the underlying mathematical unity of quantum mechanics, statistical mechanics, and geometrical thermodynamics. We show how the Planck and Boltzmann constants provide the fundamental quantum units for the phenomenological characteristics of the two Noether-conserved quantities controlling overall thermodynamic behaviour: respectively, energy and entropy production. We discuss the far-reaching isomorphisms (between all of complex time, temperature and the system symmetry) that always exist for Maximum Entropy systems, even as they exhibit either irreversible (dissipative, yet still dynamically stable) or reversible (including stable and static geometries) behaviours.

Vigorous early-season growth rate allows crops to compete more effectively against weeds and to conserve soil moisture in arid areas. Many crop species, including common bean, show genetic variation in growth rate between varieties. Despite this, the genetic basis of the early-season growth-related traits has not been well resolved in the species, in part due to historic phenotyping challenges. Using a range of UAV- and ground-based methods, we evaluated early-season growth vigor of two populations. These growth data were then used to find QTLs associated with several growth parameters. Our results suggest that early-season growth rate is the result of complex interactions between several genetic and environmental factors and highlight the need for the high-precision phenotyping provided by UAVs. The QTLs identified in this study are the first in common bean to be identified remotely using UAV technology and will be useful for developing crop varieties that compete with weeds more effectively. Ultimately, this will reduce crop losses and mitigate the need for herbicides and manual labor for weed control.

Recombinant laboratory plasmids (RLPs) are common in biological research and freely shared among academic research laboratories (ARLs), a practice required by many research funding agencies. However, the generation of accurate, reproducible results in experiments utilizing RLPs can be hampered by a lack of accompanying sequence information and metadata. This culture of RLP sharing without knowledge of sequence or etiology is accepted by publishers, not regulated by governments, and outside the realm of bio-industry. In addition, no centralized infrastructure currently exists to collate such data, which at the moment is fragmented across companies, non-profits, and governments and thus is not easily accessed or enacted toward threat assessment. The ubiquity, free exchange, and dual-use risk of RLPs exemplifies a biosecurity threat and elevates the need to characterize their composition to facilitate improved biorisk management by the academic community. A number of common sense solutions are available to create a culture that addresses the biosecurity gap posed by RLP sharing. Culture shift in RLP management will require new norms, effective data management for collation of RLP sequences and metadata, and an incentive structure that encourages sequencing by stakeholders. The next generation of researchers must initiate and champion this shift with support from funding agencies and endorsement from governments and international organizations. Coordination of efforts and stakeholders will require international public/private collaboration, a structure that will be critical to ensure widespread utility as well as the ability of lower-resourced partners to participate, contribute, and benefit.

Acetaminophen use during pregnancy and early childhood was accepted in the 1970s, but is now a subject of considerable concern. Careful analysis shows that initial acceptance of the drug was based on false assumptions and ignorance of the impact of the drug on brain development. Fourteen studies now indicate that prenatal exposure to acetaminophen is associated with neurodevelopmental problems. Based on corrections for confounding factors applied to the analyses of available data, it can be concluded that prenatal exposure to acetaminophen causes statistically significant risks of one subtype of autism spectrum disorder (ASD), developmental delays, and attention deficit hyperactivity disorder. In contrast, data regarding postnatal exposure to acetaminophen are limited, and several factors impede a classic multivariate analysis of data to resolve the issue. However, circumstantial evidence regarding postnatal exposure to the drug is abundant, and it can be concluded beyond a reasonable doubt that postnatal exposure to acetaminophen in susceptible children is responsible for many if not most cases of ASD. Circumstantial evidence includes at least three otherwise unexplained temporal relationships, data from laboratory animal studies, several miscellaneous and otherwise unexplained correlations, and the lack of alternative suspects that fit the evidence-derived profile.

Tissue engineered heart valves can grow, repair, and remodel after implantation, presenting a more favorable long-term solution compared to mechanical and porcine valves. Achieving functional engineered valve tissue requires the maturation of human cells seeded onto valve scaffolds under favorable growth conditions in bioreactors. The mechanical stress and strain on developing valve tissue caused by different pressure and flow conditions in bioreactors are currently unknown. The aim of this study is to quantify the wall shear stress (WSS) magnitude in heart valve prostheses under different valve geometries and bioreactor flow rates. To achieve this, the study used fluid-structure interaction simulations to obtain the valve's opening geometries during the systolic phase. These geometries were then used in computational fluid dynamics simulations with refined near-wall mesh elements and ranges of prescribed inlet flow rates. The data obtained included histograms and regression curves that characterized the distribution, peak, and median WSS for various flow rates and opening configurations. The study also found that the upper region of the valve near the commissures experienced higher WSS magnitudes than the rest of the valve.

The construction of optimized biological fuel cells requires a cathode which combines the longevity of a microbial catalyst with the power density of an enzymatic catalyst. Laccase secreting fungi were grown directly on the cathode of a biological fuel cell to facilitate the exchange of inactive enzymes with active enzymes with the goal of extending the lifetime of laccase cathodes. Additionally, a functionally graded coating was developed to increase enzyme loading at the cathode. Directly incorporating the laccase producing fungus at the cathode extends the operational lifetime of laccase cathodes while eliminating the need for frequent replenishment of the electrolyte. Additionally, the hybrid microbial-enzymatic cathode addresses the issue of enzyme inactivation by using the natural ability of fungi to exchange inactive laccases at the cathode with active laccases. Finally, enzyme adsorption was increased through the use of a functionally graded coating containing an optimized ratio of titanium dioxide nanoparticles and single walled carbon nanotubes. The hybrid microbial-enzymatic fuel cell combines the higher power density of enzymatic fuel cells with the longevity of microbial fuel cells and demonstrates the feasibility of a self-regenerating fuel cell in which inactive laccases are continuously exchanged with active laccases.

More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, though immunologically “cold” tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergize with immunotherapies by turning immunologically “cold” tumours “hot”. Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective “precision virotherapies” that are extensively engineered to prevent off-target up take via native routes of infection, and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.

Downwind odor characteristics can be very different depending upon the size of the upwind point-source, interim topography, and wind conditions. At one extreme, the downwind odor plume from a relatively large, confined animal feeding operation (CAFO), located on a flat open plain and under stable, near-straight-line wind conditions can be rather broad, sustained and predictable relative to a fixed receptor site downwind. In contrast, the plume from a small point-source (e.g., a roof vent stack) located on irregular topography and under rapidly shifting wind conditions can be intermittent and fleeting. These transient odor events can be surprisingly intense and offensive, in spite of their fleeting occurrence and perception. This work reports on efforts to optimize an environmental odor sampling strategy, which is optimized for the challenges of (1) sampling of such transient odor 'spikes' and (2) the prioritization of odors/odorants from multiple, closely co-located point-sources, under such transient event conditions. Protocol refinement has emerged by way of 2 environmental odor assessment projects which have been undertaken on behalf of the Missouri Department of Natural Resources. The challenge of transient odor events has been mitigated utilizing rapid, odor cued whole-air grab capture sampling into metalized-FEP gas sampling bags, followed by immediate adsorption transfer onto SPME fibers or sorbent tubes for stabilization during the shipment and storage interval between collection and final analysis. Initial results demonstrated approximately 11 fold increases in target odorant yields for 900 mL sorbent tube transfers from 2-3 second 'burst' odor event bag-captures, as compared to equivalent direct collections at the same downwind receptor location but during perceived (stable) odor 'lull' periods. Results-to-date targeting refinement and field trials of this integrated environmental odor assessment strategy are presented. Preliminary application targeting general odor sampling and point-source differentiation utilizing tracer gases is also presented.

Polycystic ovary syndrome (PCOS) is a multisystem disorder that presents with a variety of phenotypes involving metabolic, endocrine, reproductive, and psychological symptoms and signs. Women with PCOS are at increased risk of pregnancy complications including implantation failure, miscarriage, gestational diabetes, fetal growth restriction, preterm labour, and preeclampsia (PE). This may be attributed to the presence of specific susceptibility features associated with PCOS before and during pregnancy, such as chronic systemic inflammation, insulin resistance (IR), and hyperandrogenism, all of which have been associated with an increased risk of pregnancy complications. Many of the features of PCOS are reversible following lifestyle interventions such as diet and exercise, and pregnant women following a healthy lifestyle have been found to have a lower risk of complications, including PE. This review summarizes the evidence investigating the risk of PE and the role of nutritional factors in women with PCOS. The findings suggest that the beneficial aspects of lifestyle management of PCOS, as recommended in the evidenced-based international guidelines, extend to improved pregnancy outcomes. Identifying high-risk women with PCOS will allow targeted interventions, early pregnancy screening, and increased surveillance for PE. Women with PCOS should be included in risk assessment algorithms for PE.

The analysis of social media content plays a crucial role in uncovering intricate user behaviors and trends across diverse digital platforms. Social media is inherently multimodal, incorporating texts, images, audios, and videos, each offering unique insights into user engagement and preferences. Traditional classification methods often focus narrowly on the most prominent modality, typically neglecting the synergistic potential of integrating multiple data types. To address this gap, we introduce the Unified Multimodal Classifier (UMC), a suite of streamlined models that adeptly harness and integrate these varied modalities. UMC leverages a novel architecture that combines a pooling layer with auxiliary learning tasks, facilitating the formation of a robust and shared feature space. This integration allows UMC to not only accommodate but also capitalize on the inherent diversity of social media data. The models are designed to be inherently flexible, adjusting to the availability of data modalities and maintaining high classification accuracy under varied conditions. In emotion classification scenarios, UMC has shown exceptional performance, significantly outperforming traditional methods by effectively synthesizing information across modalities. Its robustness is highlighted in its ability to deliver consistent results, even in the absence of one or more modalities. The simplicity and efficiency of UMC make it a potent tool for social media analytics, enabling it to achieve higher accuracies and maintain effectiveness even with limited data inputs. This adaptive capability ensures that UMC can be deployed in real-world applications where data incompleteness is common, thus broadening the scope of its applicability in various analytical contexts.

In this work, we introduce the TriFusion Network, an innovative deep learning framework designed for the simultaneous analysis of auditory, visual, and textual data to accurately assess emotional states. The architecture of the TriFusion Network is uniquely structured, featuring both independent processing pathways for each modality and integrated layers that harness the combined strengths of these modalities to enhance emotion recognition capabilities. Our approach addresses the complexities inherent in multimodal data integration, with a focus on optimizing the interplay between modality-specific features and their joint representation. Extensive experimental evaluations on the challenging AVEC Sentiment Analysis in the Wild dataset highlight the TriFusion Network's robust performance. It significantly outperforms traditional models that rely on simple feature-level concatenation or complex score-level fusion techniques. Notably, the TriFusion Network achieves Concordance Correlation Coefficients (CCC) of 0.606, 0.534, and 0.170 for the arousal, valence, and liking dimensions respectively, demonstrating substantial improvements over existing methods. These results not only confirm the effectiveness of the TriFusion Network in capturing and interpreting complex emotional cues but also underscore its potential as a versatile tool in real-world applications where accurate emotion recognition is critical.

This work considers the task of representation learning on the attributed relational graph (ARG). Both the nodes and edges in an ARG are associated with attributes/features allowing ARGs to encode rich structural information widely observed in real applications. Existing graph neural networks offer limited ability to capture complex interactions within local structural contexts, which hinders them from taking advantage of the expression power of ARGs. We propose Motif Convolution Module (MCM), a new motif-based graph representation learning technique to better utilize local structural information. The ability to handle continuous edge and node features is one of MCM’s advantages over existing motif-based models. MCM builds a motif vocabulary in an unsupervised way and deploys a novel motif convolution operation to extract the local structural context of individual nodes, which is then used to learn higher-level node representations via multilayer perceptron and/or message passing in graph neural networks. When compared with other graph learning approaches to classifying synthetic graphs, our approach is substantially better in capturing structural context. We also demonstrate the performance and explainability advantages of our approach by applying it to several molecular benchmarks.

The virtually complete loss of intestinal worms, known as helminths, from Western society has resulted in elimination of a range of helminth-induced morbidities. Unfortunately, that loss has also led to inflammation-associated deficiencies in immune function, ultimately contributing to widespread pandemics of allergies, autoimmunity, and neuropsychiatric disorders. Several socio-medical studies have examined the effects of intentional reworming, or self-treatment with helminths, on a variety of inflammation-related disorders. In this study, the latest results from ongoing socio-medical studies are described. The results point toward two important factors that appear to be overlooked in some if not most clinical trials. Specifically, (a) the method of preparation of the helminth can have a profound effect on its therapeutic efficacy, and (b) variation between individuals in the effective therapeutic dosage apparently covers a 10-fold range, regardless of the helminth used. These results highlight current limits in our understanding of the biology of both hosts and helminths, and suggest that information from self-treatment may be critical in moving the field forward into mainstream medicine.

Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine and oncology applications, Ad based platforms offer advantages including ease of genetic manipulation, scale of production and well established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that may need to be overcome for adenovirus based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects upon the downstream impact of an adenovirus-based therapeutic. This review focusses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, both in context of the innate and adaptive immune responses. We summarize different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

The feasibility of using full ion kinetics, instead of gyrokinetics, in simulating low-frequency Ion-Temperature-Gradient (ITG) instabilities in tokamaks has recently been demonstrated by Sturdevant et al. [Physics of Plasmas 24, 081207 (2017)]. In that work, a variational integrator was developed to integrate the full orbits of ions in toroidal geometry, which proved to be accurate in capturing both the short-time scale cyclotron motion and long time scale drift motion. The present work extends that work in three aspects. First, we implement a relatively simple full orbit integrator, the Boris integrator, and demonstrate that the accuracy of this integrator is also sufficient for simulation of ITG instabilities. Second, the equilibrium magnetic configuration is extended to general toroidal configuration specified numerically, enabling simulation of realistic equilibria reconstructed from tokamak experiments. Third, we extend that work to the nonlinear regime and investigate the nonlinear saturation of ITG instabilities. To verify the new numerical implementation of the orbit integrator and magnetic configuration, the linear electrostatic ITG frequency and growth rate are compared with those given in Sturdevant's work and good agreement is found.

The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

The reaction of 2-bromo-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (1) with 4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazole-3-thiol (2) in absolute ethanol in the presence of triethyl amine as catalyst gave 2-((4-amino-5-((2,4-dichlorophenoxy)methyl)-4H-1,2,4-triazol-3-yl)thio)-1-(5-methyl-1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (3) in 73% yield. The structure of the title heterocycle (3) was confirmed by X-ray single crystal diffraction and spectral analyses (NMR and IR).

Background: Exposure to environmental tobacco smoke (ETS) presents substantial health risks for pregnant women and newborn infants. Measurements of ETS include invasive and expensive biochemical tests as well as less invasive and lower-cost self-reported exposure and avoidance measures. Better understanding of self-report measures will help to select ETS assessments for evaluation. Methods: This analysis was conducted within the context of a tailored video intervention to reduce tobacco smoking and ETS exposure during pregnancy and after delivery, in the control group sample of 147 nonsmoking women. Measurements of salivary cotinine concentration, self-reported ETS exposure and avoidance behaviors were captured at 32 weeks gestation and 6 months postpartum. Results: Salivary cotinine concentration was significantly related to ETS avoidance among pregnant nonsmokers at 32 weeks gestation, but not ETS exposure. At 6 months postpartum, both the reported ETS exposure of the infant and maternal avoidance behaviors to reduce her infant’s exposure were associated with the infant’s salivary cotinine concentration. At 32 weeks gestation and 6 months postpartum, avoidance behaviors decreased as exposure increased. Discussion: This study suggests that for nonsmoking women during pregnancy, report of tobacco smoke avoidance is more valid than report of exposure. After delivery, self-reported ETS exposure or avoidance are associated with each other and biochemical measurement of salivary cotinine. These results provide researchers and clinicians with evidence to support inclusion of avoidance behaviors in the selection of ETS measure.

Although cancer care is often contextualized in terms of survival, there are other important cancer care outcomes, such as quality of life and cost of care. The ASCO Value Framework assesses the value of cancer therapies not only in terms of survival but with consideration of quality of life and financial cost. Early palliative care for patients with advanced cancer is associated with improved quality of life, mood, symptoms, overall survival, and cost savings. While palliative care has been shown to have numerous benefits, the impact of real-world implementation of outpatient embedded palliative care on value-based metrics is not fully understood. We sought to describe the association of outpatient embedded palliative care in a multidisciplinary thoracic oncology clinic on inpatient value-based metrics. We performed a retrospective cohort study of 215 patients being treated for advanced thoracic malignancies with non-curative intent. We evaluated the association of outpatient embedded palliative care with inpatient clinical outcomes including emergency room visits, hospitalizations, intensive care unit admissions, hospital charges, as well as hospital quality metrics including 30-day readmissions, admissions within 30 days of death, inpatient mortality, and inpatient hospital charges. Outpatient embedded palliative care was associated with lower hospital charges per day ($3,807 versus $4,695, p=0.024). Furthermore, patients who received outpatient embedded palliative care had decreased hospital admissions within 30 days of death (O.R. 0.50; 95% CI 0.34, 0.74; P<0.001) and decreased inpatient mortality (O.R. 0.46; 95%CI 0.23, 0.94; p=0.032). Our study further supports that outpatient palliative care is a high-value intervention and alternative models of palliative care, including one embedded into a multidisciplinary thoracic oncology clinic, is associated with improved value-based metrics.

We prove that the probability of “A OR B”, where A and B are events or hypotheses that are recursively dependent (OR is the logico-probabilistic operator) is given by a "Hyperbolic Sum Rule” (HSR) relation isomorphic to the hyperbolic-tangent double-angle formula, and that this HSR is Maximum Entropy (MaxEnt). The possibility of recursive probabilities is excluded by the “Conventional Sum Rule” (CSR) which we also prove MaxEnt (within its narrower domain of applicability). The concatenation property of the HSR is exploited to enable analytical, consistent and scalable calculations for multiple recursive hypotheses: such calculations are not conveniently available for the CSR, and are also intrinsic to current artificial intelligence and machine learning architectures presently considered intractable to analytical study and methodological validation. We also show that it is as reasonable to state that “probability is physical” (it is not merely a mathematical construct) as it is to state that “information is physical” (now recognised as a truism of communications network engineering). We relate this treatment to the physics of Quantitative Geometrical Thermodynamics which is defined in complex hyperbolic (Minkowski) spacetime, and show how the HSR is isomorphic to other physical quantities including certain components important for digital signal processing.

The atomic structures of Zn and Na borophosphate glasses were studied by X-ray and neutron diffraction. Peaks assigned to the B−O, P−O, and O−O distances confirm that only BO4 units co-exist with the PO4 tetrahedra. The Zn−O and Na−O coordination numbers are found to be a little larger than four. The narrowest peaks of the Zn−O first-neighbor distances exist for the glasses along a line connecting the Zn(PO3)2 and BPO4 compositions (50 mol% P2O5) which is explained by networks of ZnO4, BO4, and PO4 tetrahedra with twofold coordinated oxygens. Calculated amounts of the available oxygen support this interpretation. Broadened peaks occur for glasses with lower P2O5 contents, consistent with the presence of threefold coordinated oxygens. The two distinct P−O peak components of the Zn and Na borophosphate glasses differ in their relative abundances which is interpreted by Na+ cations that coordinate oxygens in some P−O−B bridges, something not seen for the Zn2+ ions.

Zero-day threats are a more severe and constantly developing menace to various participants including large companies, government offices, and educational establishments. These entities may contain valuable information and essential operations that attract cyber attackers. These exploits are especially devastating as they target weaknesses that an organization’s vendors are not even aware of, making them have no protection against them. This paper focuses on the background and use of zero-day exploitation and the structure and technologies of these complex malware attacks. We examine two notable real-life cases: the case of ‘HAFNIUM targeting Exchange Servers with zero-day exploits’ that was investigated by Microsoft 365 Security and Microsoft Threat Intelligence, and the ‘Log4j vulnerability’ case that was reported by the National Cyber Security Centre. These cases show the critical effects of zero-day vulnerabilities and measures taken to combat them. Additionally, this paper outlines different strategies that can be used to prevent zero-day attacks with the help of modern technologies. These are fast patch release, effective IDS/IPS, and a security model that involves constant vigilance and use of behavioral analytics. Thus, by studying the lifecycle of zero-day vulnerabilities and the structure of the exploits, one can enhance the protection of the organization against the threats that are invisible to traditional security systems. This extensive survey is designed to be useful in understanding the characteristics of zero-day vulnerabilities, the technologies for their mitigation, and the constant threat and development in the field of cybersecurity. Thus, it is possible to strengthen the protection against these threats that are constant and develop with time by analyzing the previous events and predicting potential problems.

Rising antimicrobial resistance (AMR) in Salmonella serotypes host-adapted to cattle is of increasing concern to the beef and dairy industry. The bulk of the existing literature focuses on AMR post-slaughter. In comparison, the understanding of AMR in Salmonella among pre-harvest cattle is still limited, particularly in Texas, which ranks top five in beef and dairy exports in the United States; inherently, the health of Texas cattle has nationwide implications for the health of the United States beef and dairy industry. In this study, long-read whole genome sequencing and bioinformatic methods were utilized to analyze antimicrobial resistance genes (ARGs) in 98 isolates from beef and dairy cattle in the Texas Panhandle. Fisher exact tests and elastic net models accounting for population structure were used to infer associations between ARGs and antimicrobial phenotypic profiles and metadata. Gene mapping was also performed to assess the role of mobile genetic elements in harboring ARGs. ARG were found to be statistically different between the type of cattle operation and Salmonella serotypes. Beef operations were statistically significantly associated with more resistance genes compared to dairy operations. Salmonella Heidelberg, followed by Salmonella Dublin isolates, were associated with the most ARGs. Additionally, specific classes of ARGs were only present within mobile genetic elements.

Understanding and preventing the “great obstetrical syndromes” has been the focus of pregnancy research for decades. The combined global impact from these syndromes on maternal and perinatal morbidity and mortality is compounded by increased long-term risk of adverse health effects following pregnancy. Accumulating evidence indicates that conditions such as pre-eclampsia, fetal growth restriction, spontaneous preterm labour, and stillbirth, are syndromes with etiologic heterogeneity that share common pathophysiologic pathways involving placental dysfunction. Recently, the importance of the interaction between fetal and maternal genomes has been extended to include the epigenetic impact of pre-existing maternal pathophysiology on placental development and highlights the importance of nutritional and environmental factors in altered placentation. Validated first-trimester screening algorithms for preeclampsia can identify high-risk women and prophylactic treatment with low-dose aspirin can be initiated. High-risk women can be monitored during the second trimester using clinical assessment, ultrasound, and biochemical markers, that are able to predict complications prior to the development of clinical signs and symptoms. The integration of lifestyle interventions, pregnancy screening, and medical management represents a conceptual advance in pregnancy care. This approach has the potential to significantly reduce pregnancy complications, maternal and perinatal morbidity and mortality, adverse health outcomes later in life, and health-care costs.

Heel pain in the “funnel-shaped” space between the calcaneus, talus, and talocalcaneonavicular and subtalar joints may be representative of Sinus Tarsi syndrome. The pain is often characterized by a burning, numbness, or tingling sensation that can stem from strains and tears on the ligaments in that area. Injury treatment typically includes balance training, muscle exercises, bracing, foot orthosis, and non-steroidal anti-inflammatory drugs (NSAIDs). This study presents Wharton Jelly (WJ) tissue allografts as an alternative intervention for patients who fail standard-care treatments. WJ targets tissue defects, unlike other therapies, which aim to reduce swelling and symptomatic pain. This study includes five female patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. After an average of 80 days, the cohort had an overall 85.29% improvement in pain. The study's limitations include a small cohort size and a non-blinded design. Given the significant improvement in pain, WJ tissue allograft, combined with other techniques, presents an optimal patient care plan for tissue defects associated with Sinus Tarsi syndrome when standard-of-care treatments fail. These results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Solving environmental odor issues can be confounded by many analytical, technological, and socioeconomic factors. Considerable know-how and technologies can fail to properly identify odorants responsible for the downwind nuisance odor and mitigate it for the affected citizenry. We propose enabling solutions to environmental odor issues by utilizing troubleshooting techniques developed for the food, beverage, and consumer products industries. We showed that the downwind odorant impact-priority ranking process can be definable and relatively simple. The initial challenge is the prioritization of environmental odor character from the perspective of the impacted citizenry downwind. In this research, we aim at summarizing three natural models of the rolling unmasking effect (RUE) and discuss them more systematically in the context of the proposed downwind environmental odor prioritization approach. Regardless of the size and reach of an odor source, a simplification of odor character and composition typically develops with downwind dilution. The extreme odor simplification-upon-dilution was demonstrated for two plant varieties, prairie verbena and Virginia pepperweed. Their downwind odor frontal boundaries were dominated by single, character-defining odorants; p-cresol-dominated ‘barnyard’ odor, and benzyl mercaptan-dominated ‘burnt match’ odor, respectively. The P.T. porcupine downwind odor frontal boundary was dominated by two potent, character-defining odorants: (1) ‘onion’/‘body odor’ odorant #1 and (2) ‘onion’/‘grilled’ odorant #2. In contrast with their downwind boundary simplicities, each odor source presented considerable compositional complexity and composite character difference near the source. The proposed RUE approach’s ultimate significance is the illustration of naturally occurring phenomena that explain why some environmental odors and their sources can be challenging to identify and mitigate using the analytical only approach (focused on compound identities and concentrations). These approaches rarely move beyond comprehensive lists of compounds being emitted by the source.

The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR`s actions but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter`s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.

Background: Although widely believed to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Further, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Methods: Publications on PubMed between 1974 and 2017 that contained the keywords “infant” and either “paracetamol” or “acetaminophen” were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. From these 218, a total of 103 papers were identified as sources of authority for the safety claim. Results and Conclusions: A total of 52 papers contained actual experiments designed to test safety, and had a median follow-up time of 48 hours. None monitored neurodevelopment. Further, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed.

Acne Vulgaris is a multifactorial skin disorder affecting many adolescents involving a complex array of factors. Previous extensive research has delved into the correlation between acne outbreaks and specific diet consumption, and while there have been a variety of treatment indications for decreasing acne in patients, many do not involve the significant impact a holistic approach can take. This case reports on the relationship between cystic acne and dietary habits, presenting a possible treatment approach for acne vulgaris by eliminating dairy consumption.

As the smallest member of the fullerene family, C20 is yet to be discovered in planetary nebulae. In this work, we present a quantum chemical study via density functional theory (DFT) on the ionization tolerance of this molecule in the space environment. Considering that the ionization and excitation phenomena play key roles in alerting the lifetime of a molecule, we examined both ground and excited electronic states potential energy surfaces (PES) of C20 and its cations C20q+. Our theoretical results indicate that the C20 cage tolerates a positive charge as high as 13+ via characterizing local minimum geometries on both mentioned electronic states. We also explored theoretically and systematically, scenarios in which the electronic structure of neutral C20 is excited to very high spin multiplicity (beyond triplet state) and local minimum molecular geometries with cage structure are well characterized. We anticipate that such structural resistance to excitation and ionization deliver a prolonged lifetime necessary for the spectroscopic detection of this interesting molecule and its cations in space and potentially in planetary nebulea (PN).

Evidence that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible children has mounted for more than a decade. Evidence is diverse, including extensive work with laboratory animals, otherwise unexplained associations, factors associated with the metabolism of acetaminophen, and some limited studies in humans. Although evidence has reached an overwhelming level and has been reviewed in detail recently, some controversy remains. In this narrative review, some of those controversies are evaluated. First, the associations through time between acetaminophen use and the prevalence of neurodevelopmental disorders are considered. A systematic review reveals that the use of acetaminophen in the pediatric population was never tracked carefully, but historical events that affected use of the drug were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. Second, problems with exclusive reliance on results from meta-analyses of large datasets and from studies involving small time frames of drug exposure are reviewed. Third, the potential bias in a study designed to separate the role of vaccines and acetaminophen in the induction of autism spectrum disorder (Autism 2008;12:293-307) is carefully evaluated. Finally, evidence demonstrating why some children are susceptible to acetaminophen-induced neurodevelopmental injury is examined. It is concluded that, at least among the factors considered, there is no valid rationale for controversy regarding the conclusion that early life exposure to acetaminophen causes neurodevelopmental injury in susceptible babies and small children.

Myocardial infarction is one of the main causes of death, and cardiovascular risk factors (CVRF) are always considered when studying it. However, although it is known that other social and psychological variables, and especially frailty, can increase the risk of infarction, their simultaneous effect has not been extensively studied. This study is based on data from the SHARE project (latest wave, 8), with a representative sample of 46498 participants, aged 50 or older (M = 70.40, SD = 9.33), 57.4% were females. Statistical analyses included a full structural equation model that predicts 27% of infarction occurrence and evidences the significant effect of well-being, depression, and social connectedness on frailty. Frailty in turn explains 15.5% of the variability of CVRF. This work supports the need to study these physical, social, and mental health factors together to intervene on frailty, and in turn improve cardiovascular outcomes.

In this study we mimic the unique, transparent protective carapace (shell) of myodocopid ostracods, through which their compound eyes see, to demonstrate that the carapace ultrastructure also provides functions of strength and protection for a relatively thin structure. The bulk ultrastructure of the transparent window in the carapace of the relatively large, pelagic cypridinid (Myodocopida) Macrocypridina castanea was mimicked using thin film deposition of dielectric materials to create a transparent, 15 bi-layer material. This biomimetic material was subjected to the natural forces withstood by the ostracod carapace in situ, including scratching by captured prey and strikes by water-borne particles. The biomimetic material was then tested in terms of its extrinsic (hardness value) and intrinsic (elastic modulus) response to indentation along with its scratch resistance. The performance of the biomimetic material was compared with that of a commonly used, anti-scratch resistant lens and polycarbonate that is typically used in the field of transparent armoury. The biomimetic material showed the best scratch resistant performance, and significantly greater hardness and elastic modulus values. The ability of biomimetic material to revert back to its original form (post loading), along with its scratch resistant qualities, offers potential for a biomimetic eye protection coating that could enhance material currently in use.

Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

Seed bank survival underpins plant population persistence but studies on seed bank trait-environment interactions are few. Changes in environmental conditions relevant to seed banks occur in desert ecosystems owing to solar energy development. We developed a conceptual model of seed bank survival to complement methodologies using in-situ seed bank packets. Using this framework, we quantified the seed bank survival of two closely related annual desert plant species, one rare (Eriophyllum mohavense) and one common (Eriophyllum wallacei) and the seed bank-environment interactions of these two species in the Mojave Desert within a system that emulates microhabitat variation associated with solar energy development. We tracked 4,860 seeds buried across 540 seed packets and found, averaged across both species, that seed bank survival was 21% and 6% for the first and second growing seasons, respectively. After two growing seasons, the rare annual had a significantly greater seed bank survival (10%) than the common annual (2%). Seed bank survival, across both species, was significantly greater in Shade (10%) microhabitats compared to Runoff (5%) microhabitats and Control microhabitats (3%). Our study confers insight into this early life-stage across rare and common congeners and their environmental interactions using a novel conceptual framework for seed bank survival.

This work presents emission line flux and kinematic structure mapping based on IFU data of the planetary nebulae Abell 30 (A30). The IFU has a field of view (FoV) of 16" x 12.3" and was used to partially cover knots J1 and J2, and completely cover knots J3 and J4 of A30. Our emission line flux map shows recombination species C II, C III, He I, O II as well as forbidden line species [O III], [Ne III] and [Ne IV] of high excitation level are all distributed in different parts of the knots. The kinematic structure shows considerable variation in both the velocities and spatial locations of these knots with positive and negative velocity excursions from the systematic value. Forbidden line species [O III], [Ne III] are distributed in both knots J3 and J4 but they are travelling at different speeds in opposite directions. Despite variation in distribution of the species, the velocities of [Ne IV] and [O III] are similar and travelling in the same direction while the other species [Ne III], He I, and O II share similar velocity of 200kms−1 up in the opposite direction. The complexity of distribution and kinematic structure of the knots revealed in this work indicates a strong tendency towards the hypothesis of multiple triggering events in the past history of A30.

More than 20 lines of independent evidence from clinical observations, studies in laboratory animal models, pharmacokinetic considerations, and numerous temporal and spatial associations previously indicate that numerous genetic and environmental factors leading to inflammation and oxidative stress confer vulnerability to aberrant metabolism of acetaminophen during early development, leading to autism spectrum disorder (ASD). Contrary to this conclusion, multivariate analyses of cohort data adjusting for inflammation-associated factors have tended to show little to no risk of acetaminophen use for neurodevelopment. To resolve this discrepancy, here we use in-silico methods to create an ideal (virtual) population of 120000 individuals in which 50% of all cases of virtual ASD are induced by oxidative stress-associated cofactors and acetaminophen use. We demonstrate that Cox regression analysis of this ideal data set shows little to no risk of acetaminophen use if cofactors which create aberrant metabolism of acetaminophen are adjusted for in the analysis. Further, under-reporting of acetaminophen use is shown to be a considerable problem for this analysis, leading to large and erroneously low calculated risks of acetaminophen use. In addition, we argue that factors which impart susceptibility to acetaminophen-induced injury, and propensity for acetaminophen use itself, can be shared between the prepartum, peripartum, and postpartum periods, creating additional difficulty in analysis of existing datasets to determine risks of acetaminophen exposure for neurodevelopment during a specific time frame. It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.

Introduction: Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. Methods: In this study, VISTA, an immune checkpoint, was blocked either by genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine cancer models. Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. Results: When combined with a single 15 Gy radiation doses, both VISTA blockade techniques significantly enhanced anti-tumor immune signaling pathways at the mRNA, cellular infiltration level and tumor growth delay. The data suggests that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune mediated cytotoxicity. Conclusion: VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15 Gy radiation through increased expression and stimulation of cell mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

Introduction: The academic landscape is increasingly recognizing the complex interplay of personal and professional responsibilities on scholarly productivity. For women scholars, particularly those with significant parenting duties, this balance is even more precarious. This study aims to explore how family responsibilities, personal vulnerabilities, and motivational theories such as Imposter Syndrome and Self-Determination Theory (SDT) influence the motivation to publish scholarly work. Understanding these dynamics is crucial for developing supportive mechanisms that can enhance academic productivity and personal fulfilment. Methods: Utilizing a Qualitative Evidence Synthesis (QES) framework, this study will systematically review and synthesize qualitative research on women scholars' experiences in academia, focusing on the challenges and motivators related to publishing. Data sources will include academic databases, grey literature, and first-hand narratives. Thematic analysis will be employed to identify key themes and patterns across the collected data. Results/Findings: Preliminary findings suggest that the dual demands of parenting—especially in extreme cases such as assuming responsibility for seven children—and academic work significantly impact women scholars' publishing activities. Personal vulnerabilities, including imposter syndrome and low self-efficacy, further exacerbate these challenges. However, the data also highlight resilience strategies and the potential for intrinsic and extrinsic motivational factors to mitigate these effects. Discussion: The study underscores the nuanced impact of familial and personal factors on academic motivation. The preliminary findings suggest that addressing imposter syndrome and enhancing self-determination could be pivotal in supporting women scholars. The role of institutional policies and academic culture in either exacerbating or alleviating these challenges is also discussed. Significance: By elucidating the specific challenges and motivators for women scholars in publishing, this study will contribute to the development of targeted interventions and policies that support work-life integration and promote academic productivity. The insights that will be gained could inform mentorship programs, institutional support systems, and policy reforms aimed at fostering a more inclusive and supportive academic environment.

Curcumin, found in the rhizome of turmeric, has extensive therapeutic promises via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown curcumin to be an effective treatment for multiple cancers. These effects are drived by curcumin's ability to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptotic pathways, disruption of molecular signaling, inhibition of invasion and metastasis, and by increasing the efficacy of existing chemotherapeutics. Here we focused on the hormetic behaviour of curcumin. Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress whereas high dose activates acute responses like autophagy and cell death. This phenomenon is referred to as hormesis. Many molecules that cause cell death elicite an initial autophagic step that is a cytoprotective mechanism relying on elimination of dysfunctional structures intracellular, notably by mitophagy. This phenomenon is considered as a primarily protective mechanism against stressors. At higher doses, cells undergo mitochondrial outer membrane permeabilization due to calcium release from the endoplasmic reticulum and die. Herein, we address the complex crosstalk between the induced mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy and cell death that can also be at play.

Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction referred for surgical myectomy. Plasma was collected at the surgical preoperative visit approximately one month prior to surgery and then at the post surgical visit approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of the differentially expressed proteins such as interferon-, TGF-1 and TNF. Biological pathways affected by the surgery included organ inflammation, migration and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function.

Objective: To evaluate two different DECT postprocessing protocols for detection of MSU deposits in foot tendons of cadavers with verification by polarizing light microscopy as gold standard.Material and Methods: A total of 40 embalmed cadavers (15 male; 25 female; median age, 82 years; mean, 80 years; range, 52 - 99; SD ± 10.9) underwent DECT to assess MSU deposits in foot tendons.Two postprocessing DECT protocols with different Hounsfield unit (HU) thresholds 150/500 (=established) versus 120/500 (= modified) HU were applied to dual source acquisition with 80 kV for tube A and 140 kV for tube B.Six fresh cadavers (4 male; 2 female; median age, 78; mean, 78,5; range 61 - 95 ) were examined by DECT. Tendon dissection of 2/6 fresh cadavers with positive DECT 120 and negative DECT 150 studies were used to verify MSU deposits by polarizing light microscopy.Results: The tibialis anterior tendon was found positive in 57.5%/100% (DECT 150/120), peroneus tendon in 35%/100%, achilles tendon in 25%/90%, flexor halluces longus tendon in 10%/100%, and tibialis posterior tendon in 12.5%/97.5%. DECT 120 resulted in increased tendon MSU deposit detection, when DECT 150 was negative, with an overall agreement between DECT 150 and DECT 120 of 80 % (P = 0.013). Polarizing light microscope confirmed MSU deposits detected only by DECT 120 in tibialis anterior, achilles, flexor halluces longus and peroneal tendons.Conclusion: The DECT 120 protocol showed a higher sensitivity when compared to DECT 150.

A growing body of literature suggests a causative relationship between severe adverse neurological outcomes and early life exposure to paracetamol (acetaminophen) in the presence of oxidative stress. Review of the literature revealed that, although its use is not regularly monitored, paracetamol has achieved near universal acceptance, with exposure in some pediatric populations exceeding 90%. In addition, use of the drug as well as associated adverse outcomes may have risen as a result of pharmaceutical advertising rather than need, and inappropriate use of the drug, both in terms of dose and indication, is widespread. These findings indicate that many clinicians and patients do not, at the present time, evenly weigh the potential risks with the potential benefits of paracetamol exposure early in life. Although retrospective studies might be envisioned to further address the neurodevelopmental risks of paracetamol use during early development, in silico simulations demonstrated that such studies can be thwarted by very high rates of use of the drug combined with associations between paracetamol use and oxidative stressors that act as cofactors in the induction of neurodevelopmental injury. These findings suggest that, despite persistent uncertainty, clinicians and patients should be more aware of available information pointing toward the potential dangers for neurodevelopment of early life exposure to paracetamol. Most importantly, health care workers need to provide a more balanced view, weighing both risks and benefits, when providing advice for patients regarding paracetamol use during periods of brain development.

Cutaneous Squamous Cell Carcinoma (cSCC) is an increasingly common malignancy of the skin and the leading cause of death from skin cancer in adults over the age of 85. Fibroblast Growth Factor Receptor 2 (FGFR2) has been identified as an important effector of signaling pathways that lead to the growth and development of cSCC. In recent years, there have been numerous studies evaluating the role FGFR2 plays in multiple cancers, its contribution to resistance to anti-cancer therapy, and new drugs that may be used to inhibit FGFR2. This review will provide an overview of our current understanding of FGFR2 and potential mechanisms in which we can target FGFR2 in cSCC. The goals of this review are the following: 1) to highlight our current knowledge on the role of FGFR2 in healthy skin and contrast this with its role in the development of cancer; 2) to further explain the specific molecular mechanisms that FGFR2 uses to promote tumorigenesis; 3) to describe how FGFR2 contributes to more invasive disease, 4) to describe its immunosuppressive effects in skin, and 5) to evaluate its effect on current anticancer therapy and discuss therapies on the horizon to target FGFR2 related malignancy.

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

We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies for such investigations. PubMed was searched using specified search terms. One small prospective study on diet and anti-TNF treatment in 56 patients with CD found similar remission rates after 56 weeks among 32 patients with good compliance that received concomitant enteral nutrition and 24 with poor compliance that had no dietary restrictions (78% versus 67%, p = 0.51). A meta-analysis of 295 patients found higher odds of achieving clinical remission and remaining in clinical remission among patients on combination therapy with specialised enteral nutrition and Infliximab (IFX) compared with IFX monotherapy (OR 2.73; 95% CI: 1.73–4.31, p < 0.01, OR 2.93; 95% CI: 1.66–5.17, p < 0.01, respectively). In conclusion, evidence-based knowledge on impact of diet on anti-TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in observational, animal and interventional studies are warranted.

Industries are required to utilize treatment technologies to reduce contaminants in wastewater prior discharge and valorize by-products to increase sustainability and competitiveness. Most acid leaching gypsum purification studies have obviated the treatment of the highly acidic wastewater produced. In this work, acidic wastewater from acid leaching purification of post-consumer gypsum was treated to recover a valuable solid product and reusable water. The main aims of this work were to determine the impact of recirculating acidic and treated wastewaters on the efficiency of the acid leaching purification process and to valorize the impurities in the wastewater. Samples were characterized through X-ray fluorescence and X-ray diffraction. SimaPro 9.5 and ReCiPe 2016 midpoint method were used for the life cycle assessment of three wastewater management approaches. The reuse of the acidic wastewater did not improve the chemical purity of gypsum. Soluble impurities were precipitated at pH 10.5 as a magnesium-rich gypsum that could be commercialized as fertilizer or soil ameliorant. The alkaline treated water was reused for 6 acid leaching purification cycles without impacting the efficiency of the purification process. An acid leaching-neutralization-filtration-precipitation approach demonstrated superior overall environmental performance. Barriers and enabling measures for the implementation of an in-house wastewater treatment were identified.

The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of preexisting immunity detected across screened populations. However, many aspects of the basic virology of species D, such as their cellular tropism, receptor usage and in vivo biodistribution profile, remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49), a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen whilst avoiding liver interactions, such as intravascular vaccine applications.

Background: We previously developed a refined, tumor selective adenovirus, Ad5NULL-A20, har-boring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6 positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 hours post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6 selective manner, whilst cell killing me-diated by oncolytic Ad5NULL-A20 was αvβ6 selective. Biodistribution analysis following intrave-nous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor: liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20 based virotherapies efficiently target αvβ6 integrin positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic ap-plications, enabling tumor selective overexpression of virally encoded therapeutic transgenes.

Fatal motorcycle accidents on- and off-road continue to be overlooked in the literature. Research is scant on morbidity and mortality due to neck injury, which leaves patients and their families debilitated chronically. Great Lakes EMS Inc. conducted a 10-year retrospective case study, which highlighted that motocross riders who do not wear a neck brace are at an 89% higher risk of a critical cervical spine injury; highly unstable cervical spinal fractures have a sustainably higher risk of morbidity and mortality. Proposed mechanisms of motocross neck braces displace the forces on the neck onto the helmet of the rider to provide a smooth distribution of forces, whereas lack of neck brace use places riders at risk for upper cervical spine fractures such as Jefferson fractures, Hangman's fractures, and Odontoid fractures. Further, evidence suggests the use of back protectors may increase the risk of thoracic and upper spine injuries during a motorcycle crash. The limited data on this topic continues to be a challenge, as there is a lack of understanding of the nature of these injuries, which are likely preventable with proper neck protection.

In this article, we combine datasets from multiple research projects and remote sensing tech-nologies to evaluate the conservation conditions of La Fortaleza de Kuelap, a pre-Hispanic monument in Peru’s northeastern Andes that suffered significant damage during historically high seasonal rains in April 2022. Our analyses seek to identify the main causes of the collapse and locate places where the monument is likely at risk of further deterioration. To do so, we model surface hydrology using a digital elevation model (DEM) derived from drone LiDAR data, re-construct a history of previous collapses, and calculate the volume of the most recent by fusing terrestrial LiDAR and photogrammetric datasets. In addition, we examine subsurface water ac-cumulation through electrical resistivity data, reconstruct the stratification of the monument from seismic refraction data, and analyze vegetation loss and ground moisture accumulation using high resolution satellite imagery. Our results point to water accumulation as the most significant source of risk for La Fortaleza’s perimeter walls. Combined with adverse contemporary conser-vation interventions and natural conditions, this led to the collapse of April 2022. This integration of analytical results demonstrates how multi-scalar and multi-instrumental approaches provide comprehensive and timely assessments of conservation needs.

Whole-genome sequencing has advanced our understanding of the population structure of the pathogenic species complex Cryptococcus gattii, which has allowed for the phylogenomic specification of previously described major molecular type groupings and novel lineages. Recently, isolates collected in Mexico in the 1960s were determined to be genetically distant from other known molecular types and were classified as VGVI. We sequenced four clinical isolates and one veterinary isolate collected in the southwestern U.S. and Argentina during 2012-2021. Phylogenomic analysis groups these genomes with those of the Mexican VGVI isolates, expanding VGVI into a clade and establishing this molecular type as a clinically important population. These findings also potentially expand the known Cryptococcus ecological range with a previously unrecognized endemic area.

Long noncoding RNAs (lncRNAs) are known to play key roles in breast cancers; however, detailed mechanistic studies of lncRNA function have not been conducted in large cohorts of breast cancer tumors, nor have inter-donor and inter-subtype variabilities been taken into consideration. Here we provide the first identification and annotation of the human BORG lncRNA gene. Using multiple tumor cohorts of human breast cancers, we show that while BORG expression is strongly induced in breast tumors as compared to normal breast tissues, the extent of BORG induction varies widely between breast cancer subtypes and even between different tumors within the same subtype. Elevated levels of BORG in breast tumors are associated with the acquisition of core cancer aggression pathways, including those associated with basal tumor and pluripotency phenotypes, and with epithelial-mesenchymal transition (EMT) programs. While a subset of BORG-associated pathways was present in high BORG-expressing tumors across all breast cancer subtypes, many were specific to triple-negative breast cancer tumors. Finally, we show that genes induced by heterologous expression of BORG in murine models of TNBC both in vitro and in vivo strongly overlap with those associated with high BORG levels in human TNBC tumors, indicating that human BORG is a novel driver of the highly aggressive basal TNBC tumor phenotype.

Cardiac β₂-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β₂AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates generation of cyclic 3', 5'-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory cytokine, mediating also fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We have found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts, an effect prevented by endogenous β₂AR activation. Additionally, CRISPR-mediated OPN deletion enhances cAMP generation in response to both b₁AR and β₂AR activation in H9c2 cardiomyocytes, leading to upregulation of Epac1 protein levels. These effects render β₂AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacts constitutively with G_as subunits in H9c2 cardiac cells. Thus, we have uncovered a direct inhibitory role of OPN in cardiac β₂AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.

Ichthyosis is a genetic skin disorder marked by hyperkeratosis, pruritus, and scaling. This case study explores a potential association between ichthyosis and scalp paresthesia, a symptom not commonly linked with this dermatological condition. In a longstanding history of ichthyosis patients, we detail the therapeutic use of fluocinolone, a synthetic corticosteroid, in managing scalp paresthesia. The effectiveness of fluocinolone in reducing paresthesia episodes underscores its potential as a critical component in the symptomatic treatment of this complex interplay between skin and neurological symptoms. This case prompts a broader discussion on the need for increased awareness and education among healthcare providers regarding the diverse manifestations of ichthyosis. Enhanced understanding and recognition of these associations can lead to improved patient counseling, tailored management strategies, and, ultimately, better quality of life for individuals affected by ichthyosis.

Importance: The rapidly expanding 2019 novel coronavirus pandemic (COVID-19, caused by the SARS-CoV-2 virus) has challenged the medical community to an unprecedented degree. Physicians and healthcare workers are at added risk of exposure and infection during the course of the patient care. Due to the rapid spread of this disease through respiratory droplets, healthcare providers such as otolaryngologists-head & neck surgeons who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures are particularly at risk. Here we present a set of safety recommendations based on our review of literature and communications with physicians with first-hand knowledge of safety procedures during the 2019 COVID-19 pandemic.Observations: A high number of healthcare providers were infected during the first phase of the pandemic in Wuhan province. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for healthcare providers without jeopardizing the care of patients. We reviewed the most common procedures related to the examination and treatment of upper aerodigestive tract diseases. Each category was reviewed based on the potential risk imposed to healthcare workers. Specific recommendations were made, based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in COVID-19 patients. Conclusions and Relevance: Preserving highly skilled healthcare work force is a top priority for any community and healthcare system. Based on the experience of healthcare systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of healthcare providers could be significantly reduced, while providing high levels of care. The provided recommendations could be used as broad guidance for all healthcare workers who are involved with the care of COVID-19 patients.

Untargeted metabolomics is a powerful tool for measuring and understanding complex biological chemistries. However, employment, bioinformatics and downstream analysis of mass spectrometry (MS) data can be daunting for inexperienced users. Numerous open-source and free-to-use data processing and analysis tools exist for various untargeted MS approaches, including liquid chro-matography (LC), but choosing the ‘correct’ pipeline isn’t straight-forward. This tutorial, in con-junction with a user-friendly online guide presents a workflow for connecting these tools to process, analyse and annotate various untargeted MS datasets. The workflow is intended to guide explor-atory analysis in order to inform decision-making regarding costly and time-consuming down-stream targeted MS approaches. We provide practical advice concerning experimental design, organisation of data and downstream analysis, and offer details on sharing and storing valuable MS data for posterity. The workflow is editable and modular, allowing flexibility for updated/ changing methodologies and increased clarity and detail as user participation becomes more common. Hence, the authors welcome contributions and improvements to the workflow via the online repository. We believe that this workflow will streamline and condense complex mass-spectrometry approaches into easier, more manageable, analyses thereby generating opportunities for researchers previously discouraged by inaccessible and overly complicated software.

Recent research efforts in bone tissue engineering have been primarily directed towards manufacture-viable synthesis of biomaterials that can significantly enhance the biocompatibilities and osteogenic capabilities on the new biomaterials. This paper presents a straightforward, cost-effective, optimized, and well-controlled hydrothermal synthesis of Nb-doped potassium titanate nanofibers in high-purity. Characterization data revealed that the Nb-doping potassium titanate maintained the crystal structure, showing great promise for applications in bone tissue engineering.

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.

The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.

Global climate change and associated environmental extremes present a pressing need to understand and predict social-environmental impacts while identifying opportunities for mitigation and adaptation. In support of informing a more resilient future, emerging data analytics technologies can leverage the growing availability of Earth observations from diverse data sources ranging from satellites to sensors to social media. Yet, there remains a need to transition from research for knowledge gain to sustained operational deployment. In this paper, we use the Wisdom-Knowledge-Information-Data (WKID) Innovation framework to inform solutions-oriented science in an integrated Research to Commercialization (R2C) model that explores market viability for value-added analytics. We conduct a case study using this R2C model to address the wicked wildfire problem. By integrating WKID and human centered design (HCD), through an industry-university partnership called the Climate Innovation Collaboratory between the University of Colorado Boulder and Deloitte Consulting, we systematically evaluated 39 different user stories across 8 user personas and identified common gaps, how to define information technologies that add value, and how to develop a marketable product. This R2C model could enable transition of knowledge to operational implementation informing policy and decision makers, tasked with addressing some of our most challenging environmental problems.

Background: In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor (GPCR)-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). Results: GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone`s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally in NRVMs, GRK5 is necessary for the anti-apoptotic and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis and fibrosis. Conclusions: Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

This manuscript reviews two decades of projects funded by the Kirkhouse Trust (KT), a charity registered in the UK. KT was established to improve the productivity of legume crops important in African countries and in India. KT’s requirements for support are: 1) the research must be done by national scientists in their home institution, either a publicly funded agricultural research institute or a university; 2) the projects need to include a molecular biology component, which to date has mostly comprised the use of molecular markers for the selection of one or more target traits in a crop improvement programme; 3) the projects funded are included in consortia, to foster the creation of scientific communities and the sharing of knowledge and breeding resources. This account relates to the key achievements and challenges, reflects on the lessons learned and outlines future research priorities.

Background: Early diagnosis of postoperative complications is an urgent task, allowing timely prescribing of appropriate therapy and reducing the cost of patient treatment. Prognostic models based on various data could help in the early diagnosis of postoperative complications after cardiac surgery. Objectives: The purpose of the study was to determine whether an integrated approach based on clinical data along with metabolites and biomarkers had greater predictive value than the models built on less data. Methods: The study included patients (n=62) admitted for planned cardiac surgery (coronary artery bypass grafting with cardiopulmonary bypass), who were retrospectively divided into two groups depending on the presence (n=26) or absence (n=36) of postoperative complications of all types. Clinical and laboratory data on the first day after surgery were analyzed. Additionally, patients' blood samples were collected before and on the first day after surgery to determine biomarkers (interleukin-6, procalcitonin, NT-proBNP, high-sensitivity troponin T) and metabolites (8 aromatic and 2 dicarboxylic acids were detected using gas chromatography-mass spectrometry). Results: Patients before surgery, compared with healthy donors, differed in the concentration of metabolites (p &lt; 0.05), and had concentrations of a number of biomarkers exceeding the corresponding reference values. Multivariate PLS-DA models, predicting the presence or absence of postoperative complications, were built using clinical data (ROC-AUC=0.71), concentrations of metabolites and biomarkers (ROC-AUC=0.60), and the entire data set (ROC-AUC=0.75). For comparison we built univariate models using the EuroScore2 (ROC-AUC=0.59) and SOFA (ROC-AUC=0.76) scales; concentrations of lactate (ROC-AUC=0.71), the dynamic changes of 4-hydroxyphenyllactic acid (ROC-AUC=0.69), and the sum of three sepsis-associated metabolites (ROC-AUC=0.70). The proposed complex model using entire data set was comparable to the SOFA scale, which confirms the expediency of searching for new predictive models based on a variety of factors.

Introduction: Anterior Lumbar Interbody Fusion (ALIF) and Posterior Spinal Fusion (PSF) play pivotal roles in restoring lumbar lordosis in spinal surgery. Debates persist between combined single-position surgery and traditional prone-position PSF for optimizing segmental lumbar lordosis. Research Question: The study investigates the impact of performing ALIF in the supine position followed by PSF in the prone position on segmental lumbar lordosis. Material and Methods: A cohort of 59 patients underwent ALIF and PSF at a single institution. Preoperative, post-ALIF supine, and post-PSF prone Cobb angles were assessed using x-ray imaging. Statistical analyses, including one-way repeated measures ANOVA and Post-hoc analyses with Bonferroni adjustment, were employed for mean comparisons within subjects. Results: The mean Cobb angle for the entire cohort showed significant variations over different time points (p).