Early Phase Research Articles

Dengue viremia kinetics and effects on platelet count and clinical outcomes: An analysis of 2340 patients from Vietnam.

Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage. We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models. Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5-6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes. This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials. Wellcome Trust and European Union Seventh Framework Programme.

An Exploration of Organoid Technology: Present Advancements, Applications, and Obstacles.

Organoids are in vitro models that exhibit a three-dimensional structure and effectively replicate the structural and physiological features of human organs. The capacity to research complex biological processes and disorders in a controlled setting is laid out by these miniature organ-like structures. This work examines the potential applications of organoid technology, as well as the challenges and future directions associated with its implementation. It aims to emphasize the pivotal role of organoids in disease modeling, drug discovery, developmental biology, precision medicine, and fundamental research. The manuscript was put together by conducting a comprehensive literature review, which involved an in-depth evaluation of globally renowned scientific research databases. The field of organoids has generated significant attention due to its potential applications in tissue development and disease modelling, as well as its implications for personalised medicine, drug screening, and cell-based therapies. The utilisation of organoids has proven to be effective in the examination of various conditions, encompassing genetic disorders, cancer, neurodevelopmental disorders, and infectious diseases. The exploration of the wider uses of organoids is still in its early phases. Research shall be conducted to integrate 3D organoid systems as alternatives for current models, potentially improving both fundamental and clinical studies in the future.

Staging of psychiatric disorders in patients with limited and advanced/metastatic solid cancer: A pilot study.

e22545 Background: 38% of cancer patients (pts) receive diagnosis of major depressive disorder. According with the clinimetric approach of the staging of psychiatric disease, the 5-step model of unipolar depression allows for the evaluation of the extent of the disorder, its severity, and characteristics at a specific time in the course of the disease. This study was aimed: a) to assess mental health and quality of life of cancer patients with limited (LS) and advanced/metastatic (AS) solid cancer through the join evaluation of the staging of psychiatric disorders; b) to explore the potential role of severity of oncological disease in anxious/depressive disease development. Methods: A cross-sectional study was conducted at the Oncology Unit of Luigi Sacco Hospital of Milan during the first session of a psychological support path. Patients’ cancer diagnosis and stage, as well as regular engagement in work, leisure and social activities were explored. Hospital and Depression Anxiety Scale (HADS), the Revised Illness Perception Questionnaire (IPQ-R) and Mental Health Continuum Short-Form (MHC-SF) were also administered. Results: 104 pts were included: F 86, M 18, median age 57,5 (27-84), 30% AS, and 70% LS. Pts’ anxious/depressive symptoms were assessed by HADS scoring and they were divided into 3 groups according to the model of unipolar depression: Group 1a (prodromal phase – no symptoms), Group 1b (prodromal phase – mood symptoms) and Group 2 (anxious/depressive disorder). Pts in group 2 were significantly more frequently AS pts, while in group 1a pts in LS stage (χ² = 7.78, p < .05). Based on MHC-SF scores, flourishing and languishing were significantly more frequently reported by pts in group 1a (55,5% and 46% of pts, respectively), and moderate mental health in group 2 (45,9% of pts, χ² = 18.1, p < .001). Regression analysis highlighted non-hobbyist vs. hobbyists, AS vs. LS cancer pts, asthenic vs. non asthenic pts, and moderate vs flourishing metal health were more likely to receive a provisional anxious depressive disorder diagnosis (Stage 2). No association emerged for other physical symptoms, work, and socialization. Conclusions: AS pts with asthenia, no engagement in structured activities and moderate mental health had a higher risk of developing anxious/depressive disorders. Screening psychiatric disorders in cancer pts may improve the physician's ability to recognize earlier phase of psychopathological disease and guide pts to tailored treatment. These may prevent progression of psychiatric disease and promote mental health and positive quality of life.

Intratumor transforming growth factor-β signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer

Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-β (TGF-β) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-β1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-β receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-β-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-β1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.

Correlating Aggregation Ability of Polymer Donors with Film Formation Kinetics for Organic Solar Cells with Improved Efficiency and Processability.

Film formation kinetics significantly impact molecular processability and power conversion efficiency (PCE) of organic solar cells. Here, two ternary random copolymerization polymers are reported, D18─N-p and D18─N-m, to modulate the aggregation ability of D18 by introducing trifluoromethyl-substituted pyridine unit at para- and meta-positions, respectively. The introduction of pyridine unit significantly reduces material aggregation ability and adjusts the interactions with acceptor L8-BO, thereby leading to largely changed film formation kinetics with earlier phase separation and longer film formation times, which enlarge fiber sizes in blend films and improve carrier generation and transport. As a result, D18─N-p with moderate aggregation ability delivers a high PCE of 18.82% with L8-BO, which is further improved to 19.45% via interface engineering. Despite the slightly inferior small area device performances, D18─N-m shows improved solubility, which inspires to adjust the ratio of meta-trifluoromethyl pyridine carefully and obtain a polymer donor D18─N-m-10 with good solubility in nonhalogenated solvent o-xylene. High PCEs of 13.07% and 12.43% in 1 cm2 device and 43 cm2 module fabricated with slot-die coating method are achieved based on D18─N-m-10:L8-BO blends. This work emphasizes film formation kinetics optimization in device fabrication via aggregation ability modulation of polymer donors for efficient devices.

Breast cancer diagnosis using support vector machine optimized by improved quantum inspired grey wolf optimization

A prompt diagnosis of breast cancer in its earliest phases is necessary for effective treatment. While Computer-Aided Diagnosis systems play a crucial role in automated mammography image processing, interpretation, grading, and early detection of breast cancer, existing approaches face limitations in achieving optimal accuracy. This study addresses these limitations by hybridizing the improved quantum-inspired binary Grey Wolf Optimizer with the Support Vector Machines Radial Basis Function Kernel. This hybrid approach aims to enhance the accuracy of breast cancer classification by determining the optimal Support Vector Machine parameters. The motivation for this hybridization lies in the need for improved classification performance compared to existing optimizers such as Particle Swarm Optimization and Genetic Algorithm. Evaluate the efficacy of the proposed IQI-BGWO-SVM approach on the MIAS dataset, considering various metric parameters, including accuracy, sensitivity, and specificity. Furthermore, the application of IQI-BGWO-SVM for feature selection will be explored, and the results will be compared. Experimental findings demonstrate that the suggested IQI-BGWO-SVM technique outperforms state-of-the-art classification methods on the MIAS dataset, with a resulting mean accuracy, sensitivity, and specificity of 99.25%, 98.96%, and 100%, respectively, using a tenfold cross-validation datasets partition.

Psychological Trust Dynamics in Climate Change Adaptation Decision-Making Processes: A Literature Review

There has been a growth in interest among academics and professionals in psychological trust dynamics during climate change adaptation. This literature review aimed to examine the research concerning trust dynamics in climate change adaptation from different levels of analysis, encompassing the different phases of adaptation and considering the importance of trust in climate change decision-making. The method consisted of systematically reviewing researches on this topic published in scientific articles, by using appropriate and relevant search keywords (e.g., trust, community, natural hazard, climate change adaptation, decision-making) in academic databases. A total of 25 studies met inclusion criteria. All the articles focused on the latter phases of the climate change adaptation cycle, specifically implementation and monitoring/evaluation, with limited attention devoted to decision-making related to earlier phases of preparation, assessment of risks, and identification and selection of adaptation options. The reviews also indicates that psychological trust is related to different adaptive actions (e.g., adoption of renewable energy technologies), and low- and high-impact mitigation behaviors (e.g., acceptance of paying taxes for actions that mitigate climate change). Therefore, this review underscores the significant role of psychological trust dynamics in shaping individuals’ decision-making processes concerning climate change adaptation, thereby yielding immediate and direct implications for climate systems. Therefore, it is essential to actively promote the culture of trust within the context of climate change adaptation.

Health-related quality of life and impact of socioeconomic status among primary and secondary school students after the third COVID-19 wave in Berlin, Germany.

In the earlier phases of the COVID-19 pandemic, studies in Germany and elsewhere found an overall reduction in health-related quality of life (HRQoL) among students. However, there is little evidence on later pandemic stages as well as socioeconomic influencing factors. We aimed to (1) describe HRQoL in a Berlin student cohort at two time points in mid-2021, and to (2) analyze the effects of household income and education. We assessed HRQoL of students from 24 randomly selected primary and secondary schools in Berlin, Germany, with the KIDSCREEN-10 index in June and September 2021. To adjust for non-response bias, inverse probability weighting was applied. The potential effects of both household income and education (lower vs. higher) were estimated in generalized linear mixed models, based on prior assumptions presented in directed acyclic graphs. Our cohort comprised 660 students aged 7-19 years. In June 2021, 11.3% [95% CI = 9.0% - 14.0%] reported low HRQoL, whereas in September 2021, this increased to 13.7% [95% CI = 11.1% - 16.5%], with adolescent girls more frequently reporting low HRQoL at both time points (20% [95% CI = 17.1% - 23.3%] and 29% [95% CI = 25.5% - 32.5%]) compared to boys and younger children. While there was no statistically significant total effect of lower household income on HRQoL, a negative effect of lower household education was statistically significant (β = -2.15, SE 0.95, 95% CI = -4.01 to -0.29, p = 0.024). In summary, students' HRQoL in mid-2021 was better than that documented in other studies conducted at pandemic onset using KIDSCREEN-10. Female adolescents reported low HRQoL more often, and lower household education significantly reduced children's HRQoL. Support strategies for psychosocial wellbeing should consider socioeconomically disadvantaged children as important target groups.

Intravenous angiotensin II as an add-on to standard of care vasopressors in patients with refractory shock on mechanical circulatory support: a single centre retrospective case series

Abstract Funding Acknowledgements None. Background Refractory shock is life-threatening condition characterized by hypotension with mean arterial pressure (MAP) less than 65 mmHg and end-organ dysfunction, despite volume resuscitation and high doses of vasopressors. Mortality rates in refractory shock exceeds 90%. Angiotensin II (Ang II) is a non-catecholamine vasopressor that targets the renin-angiotensin-aldosterone system by agonism of the angiotensin type 1 receptors. Ang II has been studied in settings of vasodilatory shock, however there is paucity of data regarding the usage of Ang II in patients with preexisting heart failure or in patients requiring mechanical circulatory support (MCS), either short term such as venoarterial extracorporeal membrane oxygenation (VA-ECMO) or long term such as left ventricular assist device (LVAD) (1,2). Purpose This report is aimed to analyse baseline characteristics of patients who have received Ang II from the moment it became available in our institution (January 2023). Methods Five patients were included in this retrospective analyses. Demographic, clinical and laboratory parameters as well as hourly changes of vasopressors doses, MAP, lactates, and diuresis were collected and analysed. Results Median age of 5 included patients, 4 of whom were male, was 53 years old (range 18-57). The most common comorbidities were chronic kidney disease (n=3), diabetes mellitus (n=3) and arterial hypertension (n=3), treated with valsartan as chronic therapy. All patients presented with severe shock. 4 patients were on VA-ECMO support, 1 had additionally implanted Impella for left ventricular unloading and 2 had implanted LVAD. All patients had severely reduced left ventricular ejection fraction (median 15%, range 10-25%). In 4 cases vasopressors were initiated due to sepsis and in 1 case during cardiopulmonary resuscitation. Median values prior to administration of Ang II were as following: MAP 51 mmHg (range 41-56 mmHg), lactates 6.7 mmol/L (range 2.4-10.7 mmol/L) and Sequential Organ Failure Assessment (SOFA) score 9 (range 5-11). Four hours following administration of Ang II median MAP was 61 mmHg (range 54-77 mmHg). Patient who ultimately survived had better response to Ang II, with median rise of MAP of 22 mmHg (range 12-22 mmHg). In contrast, patients who ultimately died didn’t respond to Ang II, with rise of MAP of only 2.5 mmHg. Median duration of Ang II administration was 52 h (range 20-96 h). 60% of patients are alive up to the present day. Complete patient data are shown in Table 1. Hourly changes of vasopressor doses and MAP are shown in Figure 1. Conclusion Ang II is an effective vasopressor with rapid effect. This case series suggests that it may be considered as salvage treatment option in patients on MCS with refractory shock. Patients who responded to Ang II had better survival, similar to previous findings. Therefore, Ang II should be considered in earlier phases of shock when maximum doses of vasopressors have not yet been reached.

Seafloor geomorphology of the Wrigley Gulf shelf, Amundsen Sea, West Antarctica, reveals two different phases of glaciation

AbstractKnowledge of the behaviour of marine‐based ice sheets during times of climatic warming, such as the last deglaciation, provides important information to understand how ice sheets respond to external forcing. We analysed swath bathymetric and acoustic sub‐bottom profiler data from Wrigley Gulf on the western Amundsen Sea shelf, West Antarctica, to identify glacial features and reconstruct past changes in the extent of the West Antarctic Ice Sheet (WAIS) and ice flow directions. Glacial bedforms mapped within a bathymetric cross‐shelf trough include features showing cross‐cutting and overprinting relationship and indicate changes in ice‐flow orientation. Here, we distinguish at least two phases of different ice‐flow patterns on the Wrigley Gulf shelf. During the earlier phase, seaward ice stream flow on the inner shelf was deflected towards the east due to the existence of an ice dome on the middle‐outer continental shelf. Retreat of grounded ice towards the centre of this dome is indicated by the asymmetric cross profile of recessional moraines mapped on the middle shelf. The later glaciation phase was characterized by fast, NNW‐directed ice flow across the shelf along a broad front and subsequent stepwise landward retreat, which is evident from the common occurrence and orientation of mega‐scale glaciation lineations and grounding zone wedges on the middle‐inner shelf. It is uncertain whether the two phases of glaciation recorded on the seafloor occurred during the last and penultimate glacial periods or at different times of the last glaciation. Reliable chronological constraints from sediment cores and additional geomorphological information are needed to understand the cause of the changes in WAIS dynamics reflected by the two ice‐flow phases.

The Importance of Context-Relevance: Entrepreneurial Personality Relates to Entrepreneurial Outcomes Beyond the HEXACO and Dark Triad

Entrepreneurial Personality (EP) is a collection of traits that causes someone to be entrepreneurial, including both an attraction to and success in entrepreneurial activities. Although EP and its inclusion criteria is defined by its relevance to entrepreneurship, research has yet to support that it relates to entrepreneurial outcomes more strongly than extant frameworks of personality, causing uncertainty regarding its theoretical rationale and conceptual foundation. Applying the bandwidth-fidelity dilemma as our theoretical lens, the current article reports two studies to test whether EP relates to entrepreneurial outcomes beyond the HEXACO and Dark Triad dimensions. Using a sample of non-business owners, Study 1 supports that EP explains both more variance than and variance beyond the HEXACO and Dark Triad in outcomes associated with the earlier phases of the entrepreneurial process, such as entrepreneurial goal setting, goal striving, and goal achievement. Using a sample of business owners, Study 2 supports that EP explains both more variance than and variance beyond the HEXACO and Dark Triad in outcomes associated with the later phases of the entrepreneurial process, including entrepreneurial performance and well-being. These results encourage future research on EP by supporting the validity of the personality framework, and we suggest several directions for future research, such as broader applications of the bandwidth-fidelity dilemma.

Chronic Kidney Disease in Light of Ayurveda: A Literary Review on Vataj Pandu

In recent years, chronic kidney disease (CKD) has become a centre of attraction for researchers all over the world, due to increasing incidence. However, delayed diagnosis and lack of proper management has made it one of the leading causes of death worldwide. In the earlier phase of the disease, relief to the patients can be provided based on chief complaints. But as the disease progresses, only dialysis and kidney transplants remain the line of treatment according to the mainstream system of medicine, thus leading to a large number of side effects and ultimately decreasing the life expectancy. In Ayurveda, CKD is not mentioned in the Samhita directly, but it can be correlated with Vataj pandu according to similarities in some of the symptoms and causes of these two diseases as mentioned in ancient literature. We can also look out for the Nidaan and Samprapti according to the history given by the patient and evaluate the Dosh, Dushya, and the Srotas involved, and then devise a line of treatment according to the patient's Bala, Prakriti, Agni and Oja. In this article, we're going to talk about an aspect of CKD that can be used as a part of management to improve the quality of life and give hope to all the patients suffering from this disease.

Comparison of Surgical and Colonoscopy Tissue to Establish Colorectal Patient-derived Organoids.

Patient-derived organoids (PDOs) are ex vivo models that retain the functions and characteristics of individualized source tissues, including a simulated tumor microenvironment. However, the potential impact of undiscovered differences between tissue sources on PDO growth and progression remains unclear. This study aimed to compare the growth and condition of PDO models originating from surgical resection and colonoscopy and to provide practical insights for PDO studies. Tissue samples and relevant patient clinical information were collected to establish organoid models. PDOs were derived from both surgical and colonoscopy tissues. The growth of the organoids, including their state, size, and success rate of establishment, was recorded and analyzed. The activity of the organoids at the end stage of growth was detected using calcein-AM fluorescence staining. The results showed that the early growth phase of 2/3 colonoscopy-derived organoids was faster compared to surgical PDOs, with a growth difference observed within 11-13 days of establishment. However, colonoscopy-derived organoids exhibited a diminished growth trend after this time. There were no significant differences observed in the terminal area and quantity between the two types of tissue-derived organoids. Immunofluorescence assays of the PDOs revealed that the surgical PDOs possessed a denser cell mass with relatively higher viability than colonoscopy-derived PDOs. In the establishment of colorectal patient-derived organoids, surgically derived organoids require a slightly longer establishment period, while colonoscopy-derived organoids should be passaged prior to growth inhibition to preserve organoid viability.

Benthic pterobranchs from the Cambrian (Drumian) Marjum Konservat‐Lagerstätte of Utah

AbstractPterobranchs are rare in Cambrian strata of North America despite discoveries of more than 30 exceptionally preserved fossil biotas. Miaolingian pterobranchs from this continent typically form low‐diversity and low‐abundance assemblages. Here we describe an abundant pterobranch material from the Drumian Marjum Formation recently collected at the Gray Marjum Quarry in the House Range of Utah, USA. The faunule is composed of two new species: Sphenoecium marjumensis, an encrusting representative forming compact bushy colonies of more than 80 tubes with poorly developed rhizomes, and Tarnagraptus cupidus, an erect growing taxon characterized by intertwining stems and a monopodial colonial growth. Known in extant rhabdopleurids, this mode of colonial growth had hitherto never been observed in fossil pterobranchs. Its documentation in a c. 500‐myr‐old taxon attests to its deep origin in the evolutionary history of the group. Although the new species almost exclusively occur in the Marjum strata, this pterobranch faunule is broadly similar to those recovered from other Miaolingian Burgess Shale‐type deposits of North America in terms of genus‐level composition, species richness, and ecological structure. This may indicate that pterobranchs were poorly diverse components of animal communities at that time, or that they mostly thrived in more proximal shelf environments where conditions conducive to their preservation rarely developed. The common co‐occurrence of taxa with fundamentally different ecomorphotypes in the Miaolingian Series of North America strongly suggests an earlier phase of morphological diversification of benthic pterobranchs during the early Cambrian, which remains insufficiently documented by fossils.

Adapting the DIST-M Model for Designing Experimental Activities—A Theoretical Discussion from an Interdisciplinary Perspective

This study focuses on interdisciplinary approaches within mathematics and physics education. Secondary schools, particularly those specialized in scientific curricula, have opportunities to explore common topics between mathematics and physics; however, creating a coherent interdisciplinary educational experience is challenging. Adopting an interdisciplinary perspective when designing learning sequences becomes imperative. The proposed approach harnesses the power of storytelling to engage students, emphasizing the interconnectedness of subjects and humanizing the evolution of scientific ideas. This study investigates the adaptation of the Digital Interactive Storytelling in Mathematics (DIST-M) model for interdisciplinary storytelling learning sequences. It aims to explore how this model, initially developed for mathematics activities in a virtual environment, can be enriched with elements from inquiry-based learning models to integrate the experimental aspects of physics. The research presents a theoretical discussion grounded in the design of a learning sequence centered around the study of light, taking place in a non-virtual environment and approached from an interdisciplinary standpoint. It introduces hypotheses for adapting the DIST-M model to accommodate interdisciplinary storytelling sequences. One involves the incorporation of an additional phase within the DIST-M cycle, dedicated to consolidating, transferring to other contexts, and addressing variations in the concepts explored, proved, and refined in earlier phases.

Blood Flow Restriction Training in the Young Athlete

Blood flow restriction training (BFRT) is increasing in popularity in the rehabilitation setting due to its believed impact on mitigating muscle atrophy, maintaining muscle mass and improving muscle function after musculoskeletal injury. This intervention has shown to be an effective option for addressing muscle strength and atrophy during earlier phases of rehabilitation when higher loads are not tolerated after injury. Although this intervention appears to be a safe and effective approach in sports medicine environments, there is limited information on the young athlete population. The purpose of this study is to provide a detailed overview of mechanisms, safety considerations, and clinical applications specific to the young athlete after musculoskeletal injury.

Briquetage in early Hellenistic Etruscan Spina (Ferrara, Italy)

Excavations in the urban area of the Etruscan port city of Spina near Ferrara (Italy) have shown that the city had a roughly trapezoidal ground plan and covered an area of about 6 ha. In the east it was situated on the ancient course of the river Po (Padus Vetus) and in the west and south-west probably on a lagoon and another smaller river. The study project of the University of Zurich (2008–2017) had the goal of providing a clear stratigraphical sequence of the settlement phases as well as a geophysical investigation of the entire city area and indications of the natural environment. The excavation revealed several phases with wooden houses from the late sixth to the end of the fourth century BCE bordered by orthogonal water canals of different scales. After the violent destruction of the house, built between 375 and 350 B.C., in the third quarter of the fourth century the site changed its character. Not only was the level artificially raised, but the canals were abandoned and the area acquired a new function around 300 BCE. A series of very small, flat, round or oval impressions were found in the floor, in the vicinity of which lay a large quantity of thick, reddish terracotta fragments, coarsely tempered with organic material, very brittle, with cord impressions and finger marks. Fewer in number are accessory supports, round, or oval in section. Given their special technique, their large number, their distribution and the type of accumulation on the site, these fragments can be interpreted as briquetage deliberately smashed after use in order to remove the salt yielded by boiling. The fragments probably belonged to smaller, rectangular basins which stood on the round supports. The deeper channels from earlier phases had become in the last phase shallow gullies which served to supply fresh water.

HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that, during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A KO in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion and, ultimately, improving cardiomyocyte survival to attenuate MI/R injury.

Immersive virtual reality in experiential learning for architecture design education: an action research

PurposeChallenges of conducting site visit activities, a vital component of architecture learning during the recent pandemic have proved our unreadiness in facing the digital future. The lack of understanding of learning technology has affected the education experience. Thus, there is a need to investigate immersive learning technology such as immersive virtual reality (IVR) to replace students’ concrete experience in the current learning setting. This study aims to answer: (1) What is the influence of IVR in experiential learning (EL) in enhancing the personal spatial experience? (2) Does IVR in EL influence students' approach to learning during the architecture design process?Design/methodology/approachThe research was conducted as an action research design approach. Action research was employed in the first-year architecture design studio by the lecturer as a practitioner-researcher. The personal spatial experience survey was performed in the earlier phase to identify the students’ prior spatial experience. Architectural Spatial Experience Simulation (ASES) a learning tool was implemented and assessed with Architecture Design Learning Assessment (ADLA) rubric, which was developed to evaluate EL and student’s approach to learning during the architecture design learning process.FindingsThe outcomes revealed that ASES as a learning tool in EL could improve the participants’ spatial experience, particularly those with minimal prior personal spatial experience. ASES was recognized to enhance the participants’ EL experience and encourage changes in student’s approach to learning from surface to deep learning.Originality/valueThis research benefits the architecture design learning process by offering a learning tool and a framework to resolve challenges in performing site visit activities and digital learning. It also contributes by expanding the EL theory and students’ approach to learning knowledge in the architecture education field.

Anharmonic effects on the squeezing of axion perturbations

It is assumed in standard cosmology that the Universe underwent a period of inflation in its earliest phase, providing the seeds for structure formation through vacuum fluctuations of the inflaton scalar field. These fluctuations get stretched by the quasi-exponential expansion of the Universe and become squeezed. The aim of this paper is to deepen the understanding of the squeezing process, considering the effect of self-interactions. Axion-like particles can provide a useful setup to study this effect. Specifically we focus on the consequences that a non-trivial evolution of the background axion field has on the squeezing of the perturbations. We follow the evolution of the axion's fluctuation modes from the horizon exit during inflation to the radiation-dominated epoch. We compute Bogoliubov coefficients and squeezing parameters, which are linked to the axion particle number and isocurvature perturbation. We find that the quantum mechanical particle production and the squeezing of the perturbations are enhanced, if one accounts for anharmonic effects, i.e., the effect of higher order terms in the potential. This effect becomes particularly strong towards the hilltop of the potential.