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OaPAC is a recently discovered blue-light-using flavin adenosine dinucleotide (BLUF) photoactivated adenylate cyclase from the cyanobacterium Oscillatoria acuminata that uses adenosine triphosphate and translates the light signal into the production of cyclic adenosine monophosphate. Here, we report crystal structures of the enzyme in the absence of its natural substrate determined from room-temperature serial crystallography data collected at both an X-ray free-electron laser and a synchrotron, and we compare these structures with cryo-macromolecular crystallography structures obtained at a synchrotron by us and others. These results reveal slight differences in the structure of the enzyme due to data collection at different temperatures and X-ray sources. We further investigate the effect of the Y6W mutation in the BLUF domain, a mutation which results in a rearrangement of the hydrogen-bond network around the flavin and a notable rotation of the side chain of the critical Gln48 residue. These studies pave the way for picosecond–millisecond time-resolved serial crystallography experiments at X-ray free-electron lasers and synchrotrons in order to determine the early structural intermediates and correlate them with the well studied picosecond–millisecond spectroscopic intermediates.

Mutations in the Budding uninhibited by benzimidazoles (BUB1) gene were recently associated with neurodevelopmental disorders (Carvalhal et al., 2022). Here, we describe the generation and characterization of two induced pluripotent stem cells (iPSC) clones from a young female with microcephaly. The patient carried two variants in the BUBfibroblast gene (OMIM # 602452), one (c.[2197dupG]; p.[D732fs*11]) paternally inherited and one (c.[2625+1G>A]; p.[V822_L875del] maternally inherited. The generated clones exhibit a normal karyotype (UALGi003-A) and trisomy 8 (UALGi003-B), express pluripotency markers, and differentiate into trilineage cells in vitro. These cell lines can be used to study neurodevelopment and the processes of chromosome segregation.

BACKGROUND: Treatment of deep chronic wounds with the bone tissue involvement against the background of lower limb atherosclerosis and diabetic foot syndrome does not fit any reasonable hospital stay duration and at the same time has no effective outpatient methods. Therapy with conditioned medium derived from human mesenchymal stem cells (CM-MSC) may be a solution for this problem. CLINICAL CASE DESCRIPTION: Patient F., 77-year-old, arrived for an outpatient treatment of local necrosis in the area of the 1st toe of the left foot in April, 2022. The main diagnosis: Peripheral arterial disease of the lower extremities. Multifocal atherosclerosis. Occlusion of the superficial femoral and popliteal arteries, diffuse lesions of the lower leg arteries on the left. Chronic arterial insufficiency of the 4th degree. Attempts of revascularisation of the left lower limb. Limited gangrene (Wagner IV) of the 1st toe of the left foot. Associated diseases: insulin-dependent type 2 diabetes mellitus (for more than 30 years). Diabetic polyneuropathy. Diabetic foot syndrome, neurotrophic form. Local treatment was performed by the microsurgical debridement of the affected surface in combination with the method of multilayered dressings, according to the previously patented technology. The microsurgical treatment of the bone surface in the wound area was carried out with the use of CM-MSC. Positive dynamics in the form of a partial closure of the bone fragment with soft tissue was observed on the sixth month of therapy. The complete closure of the open bone fragment was observed in 12 months from the beginning of the outpatient treatment. CONCLUSION: The developed method of treatment using CM-MSC can be effective for chronic wounds with open bone surfaces.

Introduction. Persistent left superior vena cava is the most common congenital venous abnormality of the thorax and has a prevalence of 0,3-0,5% among the general population. In most cases, the presence of a persistent left superior vena cava is asymptomatic and is usually a finding during surgery. Most often additional left superior vena cava coexists with superior vena cava in 80-90% cases. This feature is extremely important for choosing the optimal surgical tactics. Case Presentation. Patient Sh., 44 years old, was urgently hospitalized for orthotopic heart transplantation. From the anamnesis it is known that in 2017 the patient was diagnosed congenital heart disease: critical stenosis of the bicuspid aortic valve. However, the patient refused surgery at that moment. Conservative treatment was carried out. In 2022, the patient`s condition progressively worsened: severe exertional dyspnea, increased shortness of breath at rest, pitting edema in the lower extremities, interruptions in the work of the heart. The patient is diagnosed: dilated cardiomyopathy. The patient was included in the waiting list on the heart transplantation. In March 2023, patient underwent orthotopic heart transplantation with reconstruction a persistent left superior vena cava. A tubular conduit from the autopericardium with a diameter of 20 mm and a length of 5 cm was used for reconstruction. An anastomosis was formed between the distal part of the accessory left superior vena cava and the right atrial auricle. The patient was discharged without any complications and no signs of venous congestion in the upper body were detected during the follow-up examination after three months of observation. Conclusions. Our clinical observation demonstrates the feasibility of successful orthotopic heart transplantation using an autologous autopericardium graft in patients with a persistent left superior vena cava and shows encouraging immediate follow-up results.

Epilepsy is a worldwide public health issue, given its biological, social, and economic impacts. Considering several open questions about synchronization and desynchronization mechanisms underlying epileptic phenomena, the development of algorithms and computational toolboxes for such analysis is highly relevant to their research. Moreover, given the recent developments of neurotechnology for epilepsy, it is essential to understand that proposals like computational tools may provide consistent data for closed-loop control systems, necessary in neuromodulation treatment alternatives, and for real-time monitoring systems to predict the occurrence of epileptic seizures. In the present work, SynchroLINNce, a freely distributable MATLAB toolbox designed to be used by epilepsy neuroscientists, including software-untrained), is proposed. Among its features, several functionalities such as recording visualization, digital filtering, and correlation analysis, as well as more specific methodologies, such as mechanisms for the automatic detection of epileptiform spikes, morphology analysis of these spikes, and their coincidence between channels are presented.

The use of autonomous recording units (ARUs) has become an increasingly popular and powerful method of data collection for biological monitoring in recent years. However, the large-scale recordings collected using these devices are often nearly impossible for human analysts to parse through, as they require copious amounts of time and resources. Automated recognition techniques have allowed for quick and efficient analysis of these recordings, and machine learning (ML) approaches, such as deep learning, have greatly improved recognition robustness and accuracy. We evaluated the performance of two deep-learning algorithms: 1. our own custom convolutional neural network (CNN) detector (specialist approach) and 2. BirdNET, a publicly available detector capable of identifying over 6,000 bird species (generalist approach). We used audio recordings of mountain chickadees (Poecile gambeli) collected from ARUs and directional microphones in the field as our test stimulus set, with our custom detector trained to identify mountain chickadee songs. Using confidence thresholds of 0.6 for both detectors, we found that our custom CNN detector yielded higher detection compared to BirdNET. Given both ML approaches are significantly faster than a human detector and the custom CNN detector is highly accurate, we hope that our findings encourage bioacoustics practitioners to develop custom solutions for targeted species identification, especially given the availability of open-source toolboxes such as Koogu.

Abstract Peptides or proteins containing small biomolecular aggregates, such as micelles, bicelles, droplets and nanodiscs, are pivotal in many fields ranging from structural biology to pharmaceutics. Monitoring dynamics of such systems has been limited by the lack of experimental methods that could directly detect their fast (picosecond to nanosecond) timescale dynamics. Spin relaxation times from NMR experiments are sensitive to such motions, but their interpretation for biomolecular aggregates is not straightforward. Here we show that the dynamic landscape of peptide-containing molecular assemblies can be determined by a synergistic combination of solution state NMR experiments and molecular dynamics (MD) simulations. Solution state NMR experiments are straightforward to implement without an excessive amount of sample, while direct combination of spin relaxation data to MD simulations enables interpretation of dynamic landscapes of peptides and other aggregated molecules. To demonstrate this, we interpret NMR data from transmembrane, peripheral, and tail anchored peptides embedded in micelles. Our results indicate that peptides and detergent molecules do not rotate together as a rigid body, but peptides rotate in a viscous medium composed of detergent micelle. Spin relaxation times also provide indirect information on peptide conformational ensembles. This work gives new perspectives on peptide dynamics in complex biomolecular assemblies.

Electric and hybrid vehicles have become widespread in large cities due to the desire for environmentally friendly technologies, reduction of greenhouse gas emissions and fuel, and economic advantages over gasoline and diesel vehicles. In electric vehicles, overheating, vibration, or mechanical damage due to collision with an object or another vehicle can lead to the failure of lithium-ion batteries up to thermal runaway and fire. Therefore, the development of battery safety control systems is one of the most important factors contributing to the large-scale electrification of public and private transport. This review examines the design features of the location and management of the battery pack to achieve maximum safety and operational efficiency when using an electric vehicle. The power characteristics and life-cycles of various types of lithium-ion batteries depending on the chemical nature of their electrodes are considered, using the example of commercial vehicles’—Tesla, Nissan Leaf, Porsche Taycan, Zeekr, and Chevrolet Volt—strategic technologies for the placement and packaging of batteries, and battery cooling and monitoring systems (State of Health and State of Charge) are also discussed. In conclusion, the current challenges in the field are summarized and promising research directions are proposed.

Las ciencias de la actividad física, deporte y educación física (CADEF) son un campo interdisciplinar que estudia el movimiento humano y sus implicaciones para la salud, el bienestar y la sociedad. Este trabajo tiene como objetivo analizar las redes de colaboración (autores, instituciones y países) de las revistas de CADEF en Colombia. Se identificaron 11 revistas colombianas que cumplían con los criterios de inclusión, en las que se publicaron 675 manuscritos entre el 2018 y 2022. Los resultados muestran que la red de autores es pequeña y con baja densidad (0,003), lo que indica que la colaboración entre autores es relativamente baja, al igual que la red de instituciones (0,01). La red de países es la más grande y con mayor densidad (0,117), aunque la colaboración entre países sigue siendo relativamente moderada. Los autores colombianos son los más activos en la red de colaboración, seguidos de los autores brasileños, españoles y mexicanos. Las comunidades más activas en la red de colaboración son las de Colombia, Brasil, España, México y Ucrania. Finalmente, es importante promover la integridad y la relevancia de la investigación, impulsando así el avance del conocimiento científico. Palabras clave: Redes Científicas, Cienciometría, Investigadores, Indicador de Colaboración. Abstract. The sciences of physical activity, sport and physical education (CADEF) is an interdisciplinary field that studies human movement and its implications for health, well-being and society. This paper aims to analyze the collaborative networks (authors, institutions and countries) of CADEF journals in Colombia. Eleven Colombian journals were identified that met the inclusion criteria, in which 675 manuscripts were published between 2018 and 2022. The results show that the network of authors is small and with low density (0.003), indicating that collaboration between authors is relatively low, as is the network of institutions (0.01). The network of countries is the largest and with the highest density (0.117), although collaboration between countries remains relatively moderate. Colombian authors are the most active in the collaboration network, followed by Brazilian, Spanish and Mexican authors. The most active communities in the collaborative network are those of Colombia, Brazil, Spain, Mexico and Ukraine. Finally, it is important to promote the integrity and relevance of research, thus promoting the advancement of scientific knowledge. Keywords: Scientific Networks, Scientometrics, Researchers, Collaboration Indicator.

Abstract There is currently little information about the evolution of gene clusters, genome architectures and karyotypes in early branching animals. Slowly evolving anthozoan cnidarians can be particularly informative about the evolution of these genome features. Here we report chromosome-level genome assemblies of two related anthozoans, the sea anemones Nematostella vectensis and Scolanthus callimorphus. We find a robust set of 15 chromosomes with a clear one-to-one correspondence between the two species. Both genomes show chromosomal conservation, allowing us to reconstruct ancestral cnidarian and metazoan chromosomal blocks, consisting of at least 19 and 16 ancestral linkage groups, respectively. We show that, in contrast to Bilateria, the Hox and NK clusters of investigated cnidarians are largely disintegrated, despite the presence of staggered hox/gbx expression in Nematostella. This loss of microsynteny conservation may be facilitated by shorter distances between cis-regulatory sequences and their cognate transcriptional start sites. We find no clear evidence for topologically associated domains, suggesting fundamental differences in long-range gene regulation compared to vertebrates. These data suggest that large sets of ancestral metazoan genes have been retained in ancestral linkage groups of some extant lineages; yet, higher order gene regulation with associated 3D architecture may have evolved only after the cnidarian-bilaterian split.

A new polymorph of anhydrous β-cyclodextrin (polymorph III) was obtained and characterized for the first time using powder X-ray diffraction, infrared spectroscopy, and thermal analysis. The solution enthalpy and time of dissolution in water were determined using solution calorimetry for this polymorph and compared with those of the dried commercial form of β-cyclodextrin (polymorph I), its amorphous form, and 2-hydroxypropyl-β-cyclodextrin. The specific heat capacities of polymorphs I and III were determined using differential scanning calorimetry across a wide range of temperatures, providing enthalpy and Gibbs energy values for the polymorphic transition at 298 K. The affinities of polymorph III and 2-hydroxypropyl-β-cyclodextrin for water were characterized by determining their hydration isotherms, which provided values of hydration Gibbs energy. Being energy-rich, the new-found polymorph of β-cyclodextrin has a significantly higher dissolution rate and an increased affinity for water compared with the dried commercial form of β-cyclodextrin. These properties render the new polymorph promising in industrial applications for guest inclusion in aqueous solutions and pastes, and may be a desirable alternative for water-soluble β-cyclodextrin derivatives.

Background: DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear. Objectives: The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation. Methods: A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation. Results: Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as “high risk” or “some concerns.” Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significant changes in DNA methylation when compared to placebo. Conclusion: Folic acid supplementation may change global DNA methylation levels in animals supplemented with high, as compared to low, doses. Heterogeneity in studies and supplementation protocols make it difficult to establish clinical recommendations. However, these effects, even if small, might be of clinical importance in the management of patients with diseases related to DNA hypomethylation.

Involved fatherhood in Russia is defined and evaluated using a time diary. In one-third of the surveyed households, fathers devote more (or the same) time to childcare than mothers on weekends. Additionally, in one-third of households, fathers spend more than two hours with their children on weekends. An important characteristic of involved fatherhood is care diversity – they provide almost all types of care. However, they continue to play a secondary role, not performing the accompanying routine household services necessary for the full and independent care of the child, such as cooking and subsequent cleaning, washing clothes, etc. In only 3-4% of households, fathers take care of the child and household, but even in this case, they remain in the position of helpers since household management remains primarily a female activity. Involved fatherhood is facilitated by urban living, a higher level of education, and a higher income level for both parents.

Abstract Background Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase whose activity propagates inflammatory signaling through its association with pattern recognition receptors (PRRs) and subsequent TAK1, NF-κB, and MAPK pathway activation. After stroke, dead and dying cells release a host of damage-associated molecular patterns (DAMPs) that activate PRRs and initiate a robust inflammatory response. We hypothesize that RIPK2 plays a damaging role in the progression of stroke injury by enhancing the neuroinflammatory response to stroke and that global genetic deletion or microglia-specific conditional deletion of Ripk2 will be protective following ischemic stroke. Methods Adult (3–6 months) male mice were subjected to 45 min of transient middle cerebral artery occlusion (tMCAO) followed by 24 h, 48 h, or 28 days of reperfusion. Aged male and female mice (18–24 months) were subjected to permanent ischemic stroke and sacrificed 48 h later. Infarct volumes were calculated using TTC staining (24–48 h) or Cresyl violet staining (28d). Sensorimotor tests (weight grip, vertical grid, and open field) were performed at indicated timepoints. Blood–brain barrier (BBB) damage, tight junction proteins, matrix metalloproteinase-9 (MMP-9), and neuroinflammatory markers were assessed via immunoblotting, ELISA, immunohistochemistry, and RT-qPCR. Differential gene expression profiles were generated through bulk RNA sequencing and nanoString®. Results Global genetic deletion of Ripk2 resulted in decreased infarct sizes and reduced neuroinflammatory markers 24 h after stroke compared to wild-type controls. Ripk2 global deletion also improved both acute and long-term behavioral outcomes with powerful effects on reducing infarct volume and mortality at 28d post-stroke. Conditional deletion of microglial Ripk2 (mKO) partially recapitulated our results in global Ripk2 deficient mice, showing reductive effects on infarct volume and improved behavioral outcomes within 48 h of injury. Finally, bulk transcriptomic profiling and nanoString data demonstrated that Ripk2 deficiency in microglia decreases genes associated with MAPK and NF-κB signaling, dampening the neuroinflammatory response after stroke injury by reducing immune cell activation and peripheral immune cell invasion. Conclusions These results reveal a hitherto unknown role for RIPK2 in the pathogenesis of ischemic stroke injury, with microglia playing a distinct role. This study identifies RIPK2 as a potent propagator of neuroinflammatory signaling, highlighting its potential as a therapeutic target for post-stroke intervention.

Abstract Over the last five decades, breast density has been associated with increased risk of developing breast cancer. Mammographically dense breasts are considered those belonging to the heterogeneously dense breasts, and extremely dense breasts subgroups according to the American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS). There is a statistically significant correlation between the increased mammographic density and the presence of more glandular tissue alone. However, the strength of this correlation is weak. Although the mechanisms driving breast density-related tumor initiation and progression are still unknown, there is evidence suggesting that certain molecular pathways participating in epithelial-stromal interactions may play a pivotal role in the deposition of fibrillar collagen, increased matrix stiffness, and cell migration that favor breast density and carcinogenesis. This article describes these molecular mechanisms as potential “landscapers” for breast density-related cancer. We also introduce the term “Breast Compactness” to reflect collagen density of breast tissue on chest CT scan and the use of breast stiffness measurements as imaging biomarkers for breast cancer screening and risk stratification.

Qualitative and quantitative risk–benefit assessments (RBA) can be used to support public health decisions in food safety. We conducted an evidence scan to understand the state of the science regarding RBA in seafood to help inform seafood dietary advice in the United States. We collected published RBA studies assessing seafood consumption, designed inclusion and exclusion criteria to screen these studies, and conducted systematic data extraction for the relevant studies published since 2019. Our findings indicate the selection of health risks and benefits does not generally follow a systematic approach. Uncertainty and variability in RBAs is often not addressed, and quantitative RBAs making use of a single health metric generally have not been leveraged to directly support published regulatory decisions or dietary guidance. To elevate the role of RBA in supporting regulatory decision-making, risk assessors and risk managers must work together to set expectations and goals. We identified the need for a prioritization phase (e.g., multicriteria decision analysis model) to determine the risks and benefits of greatest public health impact to inform the RBA design. This prioritization would consider not only the degree of public health impact of each risk and benefit, but also the potential for risks and benefits to converge on common health outcomes and their importance to subpopulations. Including a prioritization could improve the utility of the RBAs to better inform risk management decisions and advance public health. Our work serves to guide the United States Food and Drug Administration’s approaches to RBA in foods.

Abstract Background Adherens junctions (AJs) facilitate cell–cell contact and contribute to cellular communication as well as signaling under physiological and pathological conditions. Aberrant expression of AJ proteins is frequently observed in human cancers; however, how these factors contribute to tumorigenesis is poorly understood. In addition, for some factors such as α‐catenin contradicting data has been described. In this study we aim to decipher how the AJ constituent α‐catenin contributes to liver cancer formation. Methods TCGA data was used to detect transcript changes in 23 human tumor types. For the detection of proteins, liver cancer tissue microarrays were analyzed by immunohistochemistry. Liver cancer cell lines (HLF, Hep3B, HepG2) were used for viability, proliferation, and migration analyses after RNAinterference-mediated gene silencing. To investigate the tumor initiating potential, vectors coding for α‐catenin and myristoylated AKT were injected in mice by hydrodynamic gene delivery. A BioID assay combined with mass spectrometry was performed to identify α‐catenin binding partners. Results were confirmed by proximity ligation and co-immunoprecipitation assays. Binding of transcriptional regulators at gene promoters was investigated using chromatin-immunoprecipitation. Results α‐catenin mRNA was significantly reduced in many human malignancies (e.g., colon adenocarcinoma). In contrast, elevated α‐catenin expression in other cancer entities was associated with poor clinical outcome (e.g., for hepatocellular carcinoma; HCC). In HCC cells, α‐catenin was detectable at the membrane as well as cytoplasm where it supported tumor cell proliferation and migration. In vivo, α‐catenin facilitated moderate oncogenic properties in conjunction with AKT overexpression. Cytokinesis regulator centrosomal protein 55 (CEP55) was identified as a novel α‐catenin-binding protein in the cytoplasm of HCC cells. The physical interaction between α‐catenin and CEP55 was associated with CEP55 stabilization. CEP55 was highly expressed in human HCC tissues and its overexpression correlated with poor overall survival and cancer recurrence. Next to the α‐catenin-dependent protein stabilization, CEP55 was transcriptionally induced by a complex consisting of TEA domain transcription factors (TEADs), forkhead box M1 (FoxM1), and yes-associated protein (YAP). Surprisingly, CEP55 did not affect HCC cell proliferation but significantly supported migration in conjunction with α‐catenin. Conclusion Migration-supporting CEP55 is induced by two independent mechanisms in HCC cells: stabilization through interaction with the AJ protein α‐catenin and transcriptional activation via the FoxM1/TEAD/YAP complex.

Abstract Background Molluscum contagiosum virus (MCV) is a benign, common cutaneous infection predominantly affecting the younger pediatric population. Traditional treatments may be time consuming with variable efficacy. Time to spontaneous resolution is variable and treatment is often sought to shorten duration of infection, prevent further autoinoculation, prevent infectious spread to others and treat cosmetic intolerability. Case presentation We present the case of two patients with complete, simultaneous clearance of their molluscum contagiosum infections after receiving a routine 2018 quadrivalent influenza vaccination. Neither patient has had recurrence of molluscum contagiosum or permanent scarring. We review trials of intralesional immunotherapy in treatment of cutaneous infections to theorize the mechanism of MCV infection clearance post influenza vaccination. Conclusion We propose a delayed-type hypersensitivity reaction was induced as a heterologous effect of the influenza vaccination, similar to that seen in current immunotherapy treatments. This is the first reported case of MCV-directed immune reaction with infection clearance after influenza vaccination.

Objective: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain–SNS–adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. Methods: We examined the role of lipolysis, and the brain–SNS–adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1β (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with β3 adrenergic agonist or undergoing restraint stress. Results: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through β3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. Conclusions: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

This paper presents a parallel single-phase to three-phase drive system, using two single-phase rectifiers. The rectifiers are not isolated from the grid by low-frequency transformers, so the reduction of the circulation current is an important objective for the control strategy. Modulated Model Predictive Control regulates the grid current and minimizes the circulation current between the parallel rectifiers. Furthermore, the analyzed predictive control consists of two strategies, where the first has the application of two vectors in a sampling period while the second has three vectors. The addition of a vector allows the reduction of the computational cost due to the reduction of tests performed in the predictive control and reduces the harmonic distortion in the electrical grid due to the greater application of vectors in a sampling period. Simulation and experimental results are presented in order to validate the control strategy.

This research measures gender inequality in Russia in axial institutions: household and labor markets, education and science, state and corporate governance and relates it to agency, measured on the World Values Survey. Russian women are actively engaged in labor markets, including healthcare, science and other fields, which are widely viewed as male, as a legacy of the Soviet era. The gender income and the wage gap stem from the double burden and “maternity fee.” Demographic policy reinforces women’s role as prime caregivers, multiplies “maternity fee” and increases gender inequality, which consequently lowers the birth rate. Women are highly educated; however, education does not necessarily serve women’s career and success due to patriarchal values in the hidden curriculum. Many women are engaged in science, accounting for 43% of scientific workers, particularly in humanitarian sciences. However, the main reason is low wages. And ­science still functions within patriarchal traditions, while gender and women studies remain heterodox and have low impact on mainstream academic discussion. Governance remains a male field, while women account for deputies, and mostly languish in administrative­ jobs and are only entrusted with decision-making capabilities both in state and corporate governance.

The combination of the phonocardiogram (PCG) and the electrocardiogram (ECG) allows the simultaneous evaluation of the heart’s mechanical and electrical conditions and could significantly improve the accuracy of an initial cardiovascular disease diagnosis. Both signals can be acquired using non-invasive and low-complexity devices. However, the currently available devices do not have a suitable form factor for the established medical routines, restricting their usability in clinical practice. They are also bound to proprietary tools that limit collaboration, which are constraints for both clinicians and researchers. To tackle these problems, we propose a novel electronic stethoscope that combines PCG and ECG sensors which use polymer-based dry electrodes with a previously validated 3D-printed acoustic stethoscope. We performed an experimental evaluation of the sensors, and the temporal relation between the two signals and heartbeat morphology were assessed. The effect of the rotation of the stethoscope head at different angles was also studied, further extending the state-of-the-art in the field. It was verified that the ECG lead voltages at different angles follow Kirchhoff’s law, similar to the Einthoven leads. By comparing the ECG waveforms between a reference and the experimental device, the best case reached a Pearson’s correlation coefficient of 0.916±0.008. The results demonstrate the validity of the proposed electronic stethoscope, establishing a foundation for further development. The accessibility, low cost, and simplicity of the device should significantly facilitate its integration into healthcare facilities and telemedicine interventions, as well as into research and education.

The first study aims to examine cyberbullying roles and their relation to personal and normative beliefs. For this purpose, a total of 404 7th to 9th grade students answered the Inventory of Observed Cyberbullying Incidents. For the second study, semi-structured interviews to 34 9th grade students were analysed based on the Social Cognitive Theory of Moral Agency, to understand which moral disengagement mechanisms were more frequent regarding cyberbullying scenarios. Results revealed that bystanders were the most common role. Regarding beliefs, the All type of involvement group considered cyberbullying to be less severe than Bystanders, Bystanders-Victims and No Involvement group. Moreover, they perceived that their peer group believed cyberbullying was less unfair than Bystanders and No Involvement group. The most used moral disengagement mechanisms were blaming the victim and euphemistic labelling regarding seriousness. Personal, normative beliefs, as well as moral disengagement mechanisms operating in cyberbullying should be considered when designing interventions.

This research aims to identify major fields and structures of economics of gender research based on bibliometric analysis between 1960 and 2020. The analysis of the journals in economics of gender captures major development stages of gender economics. The study of economics of gender is growing rapidly as seen in the increasing number of journals, articles and citations from the 1970s onwards. It grew faster than the pace of economic publications during the 1980–1990s. The economics of gender research disciplines largely replicates economics and can be viewed as part of economics of inequality. But its feminist philosophy and methodology distinguish the economics of gender as a separate branch of economic sciences which furnishes new findings. According to the Scimago and Web of Science databases, more than 90% of articles in economics of gender are published in English (fewer than in the field of economics in general). The structure of the analyzed countries reflects not only the sophistication of national research in economics of gender, but also the degree of their integration into international scientific discourse, including the presence of a language barrier. Gender economists are primarily focused on the problems of developing countries. Advanced economies account for less than a third of all publications.

Abstract Background Diet has a large influence on gut microbiota diversity and function. Although previous studies have investigated the effect of dietary interventions on the gut microbiome, longitudinal changes in the gut microbiome, microbial functions, and metabolite profiles post dietary interventions have been underexplored. How long these outcomes require to reach a steady-state, how they relate to one another, and their impact on host physiological changes are largely unknown. To address these unknowns, we collected longitudinal fecal samples following an abrupt dietary change in healthy adult beagles (n = 12, age: 5.16 ± 0.87 year, BW: 13.37 ± 0.68 kg) using a crossover design. All dogs were fed a kibble diet (control) from d1-14, and then fed that same diet supplemented with fiber (HFD) or a protein-rich canned diet (CD) from d15-27. Fresh fecal samples were collected on d13, 16, 20, 24, and 27 for metabolite and microbiome assessment. Fecal microbial diversity and composition, metabolite profiles, and microbial functions dramatically diverged and stabilized within a few days (2 d for metabolites; 6 d for microbiota) after dietary interventions. Fecal acetate, propionate, and total short-chain fatty acids increased after change to HFD, while fecal isobutyrate, isovalerate, total branched-chain fatty acids, phenol, and indole increased after dogs consumed CD. Relative abundance of ~ 100 bacterial species mainly belonging to the Firmicutes, Proteobacteria, and Actinobacteria phyla increased in HFD. These shifts in gut microbiome diversity and composition were accompanied by functional changes. Transition to HFD led to increases in the relative abundance of KEGG orthology (KO) terms related to starch and sucrose metabolism, fatty acid biosynthesis, and amino sugar and nucleotide sugar metabolism, while transition to CD resulted in increased relative abundance of KO terms pertaining to inositol phosphate metabolism and sulfur metabolism. Significant associations among fecal microbial taxa, KO terms, and metabolites were observed, allowing for high-accuracy prediction of diet group by random forest analysis. Conclusions Longitudinal sampling and a multi-modal approach to characterizing the gastrointestinal environment allowed us to demonstrate how drastically and quickly dietary changes impact the fecal microbiome and metabolite profiles of dogs following an abrupt dietary change and identify key microbe-metabolite relationships that allowed for treatment prediction.

Abstract Local administration of attenuated mycobacterium has been used as a cancer treatment adjuvant to re-boost patient immune responses with variable clinical outcomes. We aimed to clarify the impact of attenuated heat-killed tuberculosis (HKTB) on tumor-associated macrophages which play critical roles in shaping immunological regulation in the tumor microenvironment. Upon HKTB stimulation, both primary macrophages derived from the peripheral blood of healthy subjects and from lung cancer patients as well as THP1-derived classically activated macrophages (Ms) and tumor-educated macrophages (TEMs) were polarized into the proinflammatory phenotype, as characterized by increased expression cluster of differentiation 86. A quantitative proteomic analysis revealed that stimulated TEMs were unable to activate the toll-like receptor 2, signal transducer and activator of transcription 1, or nuclear factor-κB signaling. Instead, they showed distinct intercellular adhesion molecule 1 signaling, impaired cell adhesion, and mitochondrial dysfunction. These molecular mechanisms might contribute to lower cytotoxicity of HKTB-stimulated TEMs against A549 cells via the release of distinct inflammatory cytokines compared to HKTB-stimulated Ms. Our study provides an unbiased and systematic interpretation of cellular and molecular alterations of HKTB-reeducated macrophages which should help illuminate potential strategies of HKTB-stimulated macrophage-based combination therapy for cancer treatment.

Known methods of a boron doped lithium niobate charge synthesis were analyzed. Such a charge is applied for the growth by Czochralski of single crystals with high optical quality. Homogeneous doping (the charge is obtained from precursor Nb2O5 : B and Li2CO3 ) was compared with solid phase doping (the charge is obtained from the mixture Li2CO3 : Nb2O5 : H3BO3). Homogeneous doping was determined to help produce LiNbO3 : B crystals with a more uniform distribution of a boron dopant, boron distributes more uniform in the melt volume; technological regimes established during crystal growth become easier. For the first time the paper considers liquidphase charge synthesis method; the method excludes the stage of annealing of homogenized mixture of niobium pentoxide and lithium carbonate. Results are crucial for the choice of technology at growing of boron doped lithium niobate crystals for exact areas of technics.

Abstract Introduction Like many helping professionals in emotional labor occupations, clergy experience high rates of mental and physical comorbidities. Regular stress management practices may reduce stress-related symptoms and morbidity, but more research is needed into what practices can be reliably included in busy lifestyles and practiced at a high enough level to meaningfully reduce stress symptoms. Methods and analysis The overall design is a preference-based randomized waitlist control trial. United Methodist clergy in North Carolina will be eligible to participate. The intervention and waitlist control groups will be recruited by email. The interventions offered are specifically targeted to clergy preference and include mindfulness-based stress reduction, Daily Examen, and stress inoculation training. Surveys will be conducted at 0, 12, and 24 weeks with heart rate data collected at 0 and 12 weeks. The primary outcomes for this study are self-reported symptoms of stress and heart rate at week 12 for each intervention compared to waitlist control; the secondary outcome is symptoms of anxiety comparing each intervention vs waitlist control. Ethics and dissemination Ethical approval was obtained from the Duke University Campus IRB (2019-0238). The results will be made available to researchers, funders, and members of the clergy community. Strengths and limitations of this study While evidence-based stress reduction practices such as mindfulness-based stress reduction (MBSR) exist, a wider variety of practices should be tested to appeal to different individuals. Clergy in particular may prefer, and consequently enact, spiritual practices like the Daily Examen, and individuals such as clergy who spend most of their time thinking and feeling may prefer experiential-based practices like stress inoculation training. If efficacious, the Daily Examen and stress inoculation training practices have high feasibility in that they require few minutes per day. This study is limited by the inclusion of Christian clergy of only one denomination. Trial registration ClinicalTrials.gov NCT04625777 . November 12, 2020.

The use of biobased polymers or natural inorganic materials in place of synthetic polymers or liquid crystals derived from petroleum to fabricate optical components establishes the concept of “sustainable optics”, at least for what concerns the environmental dimension of sustainability as these polymers are renewable and often biodegradable or compostable. To identify the main obstacles to be addressed prior to industrial uptake of these polymeric resins in the optics industry, we focus on two promising and widely studied biobased polymeric materials, namely nanocellulose and poly(limonene carbonate). The conclusions have implications also for the emerging bioeconomy and the undergoing reshaping of the chemical industry driven by sustainability megatrend.

A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B infection through vertical transmission, though several follow-up doses are required to induce long-lived protection. In addition to stimulating antibodies, a birth-dose of HepB might also induce polyfunctional CD4+ T-cells, which may contribute to initial protection. We investigated whether vaccination with HepB in the first week of life induced detectable antigen-specific CD4+ T-cells after only a single dose and following completion of the entire HepB vaccine schedule (3 doses). Using HBsAg- stimulated peripheral blood mononuclear cells from 344 infants, we detected increased populations of antigen-specific polyfunctional CD154+IL-2+TNFα+ CD4+ T-cells following a single birth-dose of HepB in a proportion of infants. Frequencies of polyfunctional T-cells increased following the completion of the HepB schedule but increases in the proportion of responders as compared to following only one dose was marginal. Polyfunctional T-cells correlated positively with serum antibody titres following the birth dose (day30) and completion of the 3-dose primary HepB vaccine series (day 128). These data indicate that a single birth dose of HepB provides immune priming for both antigen-specific B- and T cells

Mesothelial cells have been shown to have remarkable plasticity towards mesenchymal cell types during development and in disease situations. Here, we have characterized the potential of mesothelial cells to undergo changes toward perivascular cells using an in vitro angiogenesis assay. We demonstrate that GFP-labeled mesothelial cells (GFP-MCs) aligned closely and specifically with endothelial networks formed when human dermal microvascular endothelial cells (HDMECs) were cultured in the presence of VEGF-A165 on normal human dermal fibroblasts (NHDFs) for a 7-day period. The co-culture with GFP-MCs had a positive effect on branch point formation indicating that the cells supported endothelial tube formation. We interrogated the molecular response of the GFP-MCs to the angiogenic co-culture by qRT-PCR and found that the pericyte marker Ng2 was upregulated when the cells were co-cultured with HDMECs on NHDFs, indicating a change towards a perivascular phenotype. When GFP-MCs were cultured on the NHDF feeder layer, they upregulated the epithelial–mesenchymal transition marker Zeb1 and lost their circularity while increasing their size, indicating a change to a more migratory cell type. We analyzed the pericyte-like behavior of the GFP-MCs in a 3D cardiac microtissue (spheroid) with cardiomyocytes, cardiac fibroblasts and cardiac endothelial cells where the mesothelial cells showed alignment with the endothelial cells. These results indicate that mesothelial cells have the potential to adopt a perivascular phenotype and associate with endothelial cells to potentially support angiogenesis.

Abstract Background Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes. Methods Immunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed. Results Immunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis. Conclusions YAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies.

In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine Pandemrix (GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4+ T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a “two-hit” hypothesis. The collective in silico, in vitro, and preclinical in vivo data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.

Introduction. The development of modern Russia is characterized by a high degree of differentiation in the level of socio-economic development of the constituent entities of the Russian Federation. Interregional cooperation is one of the tools to overcome this differentiation. Although new forms of such cooperation have been emerging, its potential remains underestimated. The purpose of the study is to analyze the existing and prospective forms of cooperation between the regions of Russia. Materials and Methods. The study based on a structural and substantive analysis of regulatory legal acts of the federal and regional levels, as well as on strategic planning documents, various forms of budget reporting, bilateral and multilateral agreements between the constituent entities of the Russian Federation aimed at identifying various areas, tools and mechanisms for ensuring interregional cooperation. Results. The authors have considered the tools of interregional cooperation that involve direct financial participation of regional authorities or economic entities. The role and prospects of horizontal subsidies and budget loans provided by one region to another have been identified, their legal and regulatory justification has been given; a financial assessment has been made, and the identified practices have been analyzed. In terms of the implementation of public procurement from suppliers based in other regions, the authors have estimated the degree of how closed or open the constituent entities of the Russian Federation are. Discussion and Conclusion. The authors have confirmed the idea that interregional cooperation in Russia is still underdeveloped and lacks legislative and scientific-methodological justification. The authors also assess the prospects for further development of interregional cooperation in Russia and suggest a number of measures to promote it. The results of the study can be used in the interests of the authorities to improve the system of regulation of various mechanisms of regional cooperation, as well as to develop the scientific potential in this area.

Abstract Background There is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host. Results We examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes. Conclusion This study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy. Video abstract

Abstract Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory, and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is widely consumed worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of caffeine’s effects on cancer and cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel nanocarrier-based formulations, to enhance the bioavailability of caffeine and its beneficial effects will be discussed.

Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.

The world’s largest extant fish, the whale shark Rhincodon typus, is one of the most-studied species of sharks globally. The discovery of predictable aggregation sites where these animals gather seasonally or are sighted year-round – most of which are coastal and juvenile-dominated – has allowed for a rapid expansion of research on this species. The most common method for studying whale sharks at these sites is photographic identification (photo-ID). This technique allows for long-term individual-based data to be collected which can, in turn, be used to evaluate population structure, build population models, identify long-distance movements, and assess philopatry and other population dynamics. Lagged identification rate (LIR) models have fewer underlying assumptions than more traditional capture mark recapture approaches, making them more broadly applicable to marine taxa, especially far-ranging megafauna species like whale sharks. However, the increased flexibility comes at a cost. Parameter estimations based on LIR can be difficult to interpret and may not be comparable between areas with different sampling regimes. Using a unique data-set from the Philippines with ~8 years of nearly continuous survey effort, we were able to derive a metric for converting LIR residency estimates into more intuitive days-per-year units. We applied this metric to 25 different sites allowing for the first quantitatively-meaningful comparison of sightings-derived residence among the world’s whale shark aggregations. We validated these results against the only three published acoustic residence metrics (falling within the ranges established by these earlier works in all cases). The results were then used to understand residency behaviours exhibited by the sharks at each site. The adjusted residency metric is an improvement to LIR-based population modelling, already one of the most widely used tools for describing whale shark aggregations. The standardised methods presented here can serve as a valuable tool for assessing residency patterns of whale sharks, which is crucial for tailored conservation action, and can cautiously be tested in other taxa.

Abstract The architectural features of cellular life and its ecologies at larger scales are built upon foundational networks of reactions between molecules that avoid a collapse to equilibrium. The search for life’s origins is, in some respects, a search for biotic network attributes in abiotic chemical systems. Radiation chemistry has long been employed to model prebiotic reaction networks, and here we report network-level analyses carried out on a compiled database of radiolysis reactions, acquired by the scientific community over decades of research. The resulting network shows robust connections between abundant geochemical reservoirs and the production of carboxylic acids, amino acids, and ribonucleotide precursors—the chemistry of which is predominantly dependent on radicals. Moreover, the network exhibits the following measurable attributes associated with biological systems: (1) the species connectivity histogram exhibits a heterogeneous (heavy-tailed) distribution, (2) overlapping families of closed-loop cycles, and (3) a hierarchical arrangement of chemical species with a bottom-heavy energy-size spectrum. The latter attribute is implicated with stability and entropy production in complex systems, notably in ecology where it is known as a trophic pyramid. Radiolysis is implicated as a driver of abiotic chemical organization and could provide insights about the complex and perhaps radical-dependent mechanisms associated with life’s origins.

Abstract Background Overexpression and nuclear enrichment of the oncogene yes-associated protein (YAP) cause tumor initiation and support tumor progression in human hepatocellular carcinoma (HCC) via cell autonomous mechanisms. However, how YAP expression in tumor cells affects intercellular communication within the tumor microenvironment is not well understood. Methods To investigate how tumor cell-derived YAP is changing the paracrine communication network between tumor cells and non-neoplastic cells in hepatocarcinogenesis, the expression and secretion of cytokines, growth factors and chemokines were analyzed in transgenic mice with liver-specific and inducible expression of constitutively active YAP (YAPS127A). Transcriptomic and proteomic analyses were performed using primary isolated hepatocytes and blood plasma. In vitro, RNAinterference (RNAi), expression profiling, functional analyses and chromatin immunoprecipitation (ChIP) analyses of YAP and the transcription factor TEA domain transcription factor 4 (TEAD4) were performed using immortalized cell lines. Findings were confirmed in cohorts of HCC patients at the transcript and protein levels. Results YAP overexpression induced the expression and secretion of many paracrine-acting factors with potential impact on tumorous or non-neoplastic cells (e.g. plasminogen activator inhibitor-1 (PAI-1), C-X-C motif chemokine ligand 13 (CXCL13), CXCL16). Expression analyses of human HCC patients showed an overexpression of PAI-1 in human HCC tissues and a correlation with poor overall survival as well as early cancer recurrence. PAI-1 statistically correlated with genes typically induced by YAP, such as connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61) or YAP-dependent gene signatures (CIN4/25). In vitro, YAP inhibition diminished the expression and secretion of PAI-1 in murine and human liver cancer cell lines. PAI-1 affected the expression of genes involved in cellular senescence and oncogene-induced senescence was confirmed in YAPS127A transgenic mice. Silencing of TEAD4 as well as treatment with the YAP/TEAD interfering substance Verteporfin reduced PAI-1 expression. ChIP analyses confirmed the binding of YAP and TEAD4 to the gene promoter of PAI-1 (SERPINE1). Conclusions These results demonstrate that the oncogene YAP changes the secretome response of hepatocytes and hepatocyte-derived tumor cells. In this context, the secreted protein PAI-1 is transcriptionally regulated by YAP in hepatocarcinogenesis. Perturbation of these YAP-dependent communication hubs including PAI-1 may represent a promising pharmacological approach in tumors with YAP overexpression. Video abstract

Water absorption capacity is a key characteristic of cellulosic pulps used for different commodities. This property is influenced by the affinity of the pulp fiber surface with water, chemical composition of the pulp, morphology, and organization of fibers in the network. In this study, surface properties of six industrial Eucalyptus bleached kraft pulps (fluff pulps) dry-defiberized in a Hammermill, which were obtained by wood pulping and pulp bleaching under different production conditions, were studied while employing dynamic water vapor sorption and contact angles measurements. The absorption properties of air-laid pulp pads were analyzed following the absorbency testing procedure and the relationship between these properties and pulp’s chemical composition and fiber network structure were assessed by multivariate analysis. The results showed that the accessibility of the fiber surface is related to the reduction of the contact angles, but, at the same time, to the longer absorption time and less absorption capacity of the fiber network. Therefore, the absorption properties of the pulps are not necessarily directly related to their surface properties. Indeed, absorptivity is related to the surface chemical composition, fiber morphology, and fiber network structure. Thus, surface carboxylic groups promote total water uptake, resulting in better absorption capacity. Greater fiber coarseness and deformations (curl and kink) provide a less wettable surface, but a more porous network with higher specific volume, resulting in more absorbent air-laid formulations.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

The interest in the pharmacological applications of cannabinoids is largely increasing in a wide range of medical areas. Recently, research on its potential role in eye conditions, many of which are chronic and/or disabling and in need of new alternative treatments, has intensified. However, due to cannabinoids’ unfavorable physicochemical properties and adverse systemic effects, along with ocular biological barriers to local drug administration, drug delivery systems are needed. Hence, this review focused on the following: (i) identifying eye disease conditions potentially subject to treatment with cannabinoids and their pharmacological role, with emphasis on glaucoma, uveitis, diabetic retinopathy, keratitis and the prevention of Pseudomonas aeruginosa infections; (ii) reviewing the physicochemical properties of formulations that must be controlled and/or optimized for successful ocular administration; (iii) analyzing works evaluating cannabinoid-based formulations for ocular administration, with emphasis on results and limitations; and (iv) identifying alternative cannabinoid-based formulations that could potentially be useful for ocular administration strategies. Finally, an overview of the current advances and limitations in the field, the technological challenges to overcome and the prospective further developments, is provided.

Photo-Fenton-like oxidation of organic substances is one of the key advanced oxidation processes based on the reversible Fe2+↔Fe3+ transition and the generation of a strong oxidant ·OH in the presence of H2O2 and is currently considered as a promising method for the purification of polluted aqueous media. However, the absence of effective and stable photocatalysts of this process, operating under the action of visible light, necessitates the exploratory studies, mainly among iron oxides and ferrites of various compositions and structures. In this work, using the method of solution combustion followed by heat treatment in air the heterojunction nanocomposites based on ytterbium orthoferrite and cerium dioxide of the composition o-YbFeO3/h-YbFeO3/CeO2 (0–20 mol.%) with high absorption in the visible region and advanced photo-Fenton-like activity were obtained. The nanocomposites were studied by EDS, SEM, XRD, BET, and DRS methods. The photo-Fenton-like activity of the nanocomposites was investigated during the degradation of methyl violet under the action of visible (λmax = 410 nm) radiation. As a result, the formation of I-type heterojunction based on stable rhombic (55.4–79.0 nm) and metastable hexagonal (19.5–24.0 nm) modifications of ytterbium orthoferrite (o-YbFeO3 and h-YbFeO3, respectively) and cubic cerium dioxide CeO2 (13.2–19.2 nm) nanocrystals was established. It was shown that the obtained nanocomposites had foamy morphology and were characterized by a specific surface in the range of 9.1–25.0 m2/g, depending on the CeO2 content. It was found that nanocrystalline components were chemically and phase-pure, uniformly spatially distributed over the nanocomposite, and had multiple contacts with each other. Based on this fact and the established electronic structure of the nanocomposite components, the formation of I-type heterojunction with the participation of o-YbFeO3 (Eg = 2.15 eV), h-YbFeO3 (Eg = 2.08 eV), and CeO2 (Eg = 2.38 eV) was shown, the presence of which increased photocatalytic activity of the resulting nanocomposite. The optimal content of CeO2 in the nanocomposite was 5%, and the o-YbFeO3/h-YbFeO3/CeO2–5% sample was characterized by the highest rate constant of photo-Fenton-like degradation of methyl violet under the action of visible light equal to k = 0.138 min–1, which was 2.5 to 5 times higher than for nanocomposites based on ytterbium orthoferrite. The obtained results obtained indicate that the developed nanocomposites can be considered as a promising basis for the advanced oxidation processes for the purification of aqueous media from organic pollutants.

OBJECTIVE: To assess the possible factors that influence sleep quality in adolescents with and without chronic immunosuppressive conditions quarantined during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study included 305 adolescents with chronic immunocompromised conditions and 82 healthy adolescents. Online surveys were completed, which included questions on socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and the following validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0), and Pediatric Outcome Data Collection Instrument (PODCI). RESULTS: The median current age [14 (10-18) vs. 15 (10-18) years, p=0.847] and frequency of female sex (62% vs. 58%, p=0.571) were similar in adolescents with chronic conditions compared with healthy adolescents. The frequency of poor sleep quality was similar in both groups (38% vs. 48%, p=0.118). Logistic regression analysis, including both healthy adolescents and adolescents with chronic conditions (n=387), demonstrated that self-reported increase in screen time (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.3-6.8; p=0.008) and intrafamilial violence report (OR 2.1; 95% CI 1.2-3.5; p=0.008) were independently associated with poor sleep quality in these adolescents. However, the PODCI global function score was associated with a lower OR for poor sleep quality (OR 0.97; 95% CI 0.94-0.99; p=0.001). Further logistic regression, including only adolescents with chronic conditions (n=305), demonstrated that self-reported increase in screen time (OR 3.1; 95% CI 1.4-6.8; p=0.006) and intrafamilial violence report (OR 2.0; 95% CI 1.2-3.4; p=0.011) remained independently associated with poor quality of sleep, whereas a lower PODCI global function score was associated with a lower OR for sleep quality (OR 0.96; 95% CI 0.94-0.98; p

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Helichrysum italicum essential oil (H. italicum EO) is recognized for its anti-inflammatory, antimicrobial and wound-healing properties. The main goal of the present work was the development and characterization of a gel formulation comprising H. italicum EO loaded in chitosan nanoparticles (NPs) for dermatological applications. H. italicum EO-loaded chitosan NPs presented hydrodynamic diameter and PdI of about 300 nm and 0.28, respectively, and a surface charge of +19 mV. The H. italicum EO-loaded chitosan NPs were prepared by means of ionic gelation and then incorporated into a thermal water gel formulation. The organoleptic and physicochemical properties of the developed gel were studied. The gel remained stable under accelerated test conditions, maintaining pH, viscosity and organoleptic properties. In addition, the formulation presented pH, viscosity and spreadability properties suitable for topical application. Finally, the performance of the gel in topical application was evaluated on the skin of volunteers using non-invasive methods, particularly, by means of biometric evaluation. These assays showed that the properties of the developed thermal water-based gel formulation with H. italicum EO-loaded chitosan NPs can improve skin hydration and maintain healthy skin conditions, demonstrating its putative role for distinct dermatological applications.