Central Hypothesis Research Articles

Combination antiretroviral therapy prevents SIV- induced aging in the hippocampus and neurodegeneration throughout the brain.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated neurocognitive disorders (HAND) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining acute infection, and cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and altered expression of SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions, and treatment with cART reduced GFAP expression in SIV-infected animals and thus likely decreases inflammation in the brain. Importantly, cART reversed SIV-induced accelerated aging (p16 and SIRT1) and neurodegeneration in the frontal lobe and hippocampus. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HAND.

Abstract We037: GPC3-mediated metabolic rewiring of diabetic mesenchymal stromal enhances their cardioprotective functions via pyruvate kinase M2 activation

Background: Mesenchymal stromal cells (MSC) represent promising stem cell therapy for treating cardiovascular diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. However, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction is still poorly understood. Therefore, our study aimed to understand the molecular basis of diabetes-induced MSC functions and their metabolic mechanism, and potential metabolic reprogramming of diabetic MSC to reverse these dysfunctions may represent a strategy to enhance cell-based therapeutics for myocardial repair in diabetic patients. Hypothesis: Our central hypothesis is that increased Glypican-3 (GPC3) mediates diabetic MSC dysfunction and diminishes energy metabolism; metabolic reprogramming of diabetic MSC with GPC3 knockdown restored diabetic MSC reparative and therapeutic activities in post-MI cardiac repair. Methods: MSCs were isolated from the bone marrow of mice from db/+ non-diabetic (WT-MSC) and diabetic mice (db/db-MSC) to compare the MSC metabolic profiles and consequent reparative function. We investigated the effect of GPC3 knockdown on db/db-MSC energy metabolism, immunosuppression, angiogenic potential in vitro, and therapeutic potential for ischemic cardiac tissue repair. Results: Intra-myocardial transplantation of db/db-MSC into the ischemic myocardium of mice does not confer cardiac benefit post-MI. The seahorse metabolic flux assays and 13 C glucose tracing studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that GPC3, a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC. GPC3 knockdown-db/db-MSC restored their energy metabolism, immunomodulation, and angiogenesis. Intramyocardial injection of GPC3 metabolically reprogrammed-db/db-MSC confers cardiac benefit post-MI. Conclusion: Our findings indicate that metabolic rewiring using GPC3 may be used to restore the metabolic state and functions of db/db-MSC for cell therapy applications.

ANÁLISES DA EXECUÇÃO ORÇAMENTÁRIA DO ESTADO DO AMAZONAS (2016 – 2023) SOB A ÓTICA DA TEORIA DO EQUILÍBRIO PONTUADO

This study aims to examine budget execution in the State of Amazonas between 2016 and 2023, using the Punctuated Equilibrium Theory as a basis to identify periods of stability and abrupt changes. The methodology used was quantitative, with analyzes conducted based on data updated until December 31, 2023. To assess the normality of the distributions, the Kolmogorov-Smirnov and Shapiro-Wilk tests were applied, with a confidence level of 5%. The results indicated that budget decisions, both in expenses by nature groups and by government functions, showed atypical behavior. The presence of periods of stability with interruptions was observed, which validates the central hypothesis that the Punctuated Equilibrium Theory is applicable to the analysis of budget variations in Amazonas. It was found that, although budgets are prepared incrementally, their execution reveals an interrupted pattern of stability. This research advances the literature on the execution of budgetary policies by including the analysis of total revenue and expenses paid by personnel group.Theoretical contributions cover discussions on budget preparation in Brazil, the impacts of party changes on budget execution and financial imbalance.

Lack of Risk Management at Insolvency Consulting Companies: An Empirical Study in Germany 2024

In the wake of the COVID-19 pandemic, the Russian war of aggression against Ukraine and the resurgence of the Middle East conflict, government measures to support the economy have intervened massively in economic activity and thus influenced the real insolvency situation. This situation creates disruptive conditions in insolvency counselling and requires comprehensive risk management for the strategic safeguarding of internal processes in insolvency counselling companies. Despite a number of academic articles that address a lack of risk awareness in insolvency counselling, there have been no valid statistical surveys on this topic to date. The topic has also been largely ignored in practice. This article presents a study that examines risk management in insolvency advisory companies in the context of government intervention in the global economy from 2020 to 2023. The aim of the research is to assess the necessity and existence of risk management in these companies. A survey of 350 insolvency advisors was conducted between March and April 2024, from which 113 complete data sets could be analysed. The central hypothesis of the research study is that a significant majority of insolvency advisory companies have insufficient risk awareness and do not implement comprehensive risk management strategies. The survey results confirm that risk management is rarely practised and that a well-founded risk awareness is lacking in most consulting companies. It is noteworthy that two-thirds of those surveyed consider the benefits of risk management to be low, although more than half of those surveyed recognise increased risks due to government crisis measures. Ultimately, this study concludes with a recommendation that a standardised EU insolvency regulation could offer the greatest benefits for the insolvency sector, as it would simplify risk management for consultants in all member states.

The influence of threat and right-wing authoritarianism on the selection of online (dis)information—a conceptual replication and extension of Lavine et al. (2005)

Abstract Over the decades, communication research has investigated the situational and personal conditions under which people particularly prefer attitude-consistent over attitude-inconsistent content (confirmation bias). In a central study, Lavine et al. (2005) [Lavine, H., Lodge, M., & Freitas, K. (2005). Authoritarianism, threat, and motivated reasoning. Political Psychology, 26(2), 219–244.] examined how right-wing authoritarianism (RWA) and threat cause bias when processing political information. Their laboratory experiment suggested that right-wing authoritarians prefer attitude-consistent information in the presence of a threat. Given new crisis environments accompanied by various threats, we re-examined this interaction effect and conceptually replicated Lavine et al.'s central hypothesis in a contemporary media environment. In an online experiment (N = 1,118), we focused on selective exposure to verified news and disinformation and tracked participants’ selection unobtrusively. Contrary to expectations, the interaction between different threats and RWA did not increase selective exposure to attitude-consistent (dis)information. The results challenge the hypothesis’ underlying framework and make it necessary to consider new ways of advancing the theoretical model.

Sulphonated graphene oxide as functionalized filler for polymer electrolyte membrane with enhanced anti-biofouling in microbial fuel cells

This research focuses on the development of a polymer electrolyte membrane (PEM) which is intended to increase power generation while addressing the persistent issue of biofouling in microbial fuel cells (MFC). The central hypothesis of this research work is that a novel PEM made from sulphonated polyether ether ketone (SPEEK) grafted with styrene sulphonic acid (SSA) integrated with sulphonated graphene oxide (SGO) will improve the membrane properties as well as enhance the anti-biofouling effect. The optimal percentage of SSA grafting has been determined based on physicochemical properties of the membrane. Various weight percentages of SGO (2.5, 5, 7.5, & 10 wt%) were introduced to the SPEEK/SSA base polymer to augment the physicochemical properties and also to defend against biofouling. Among the tested membranes, the SPEEK/SSA+5 % SGO composite membrane demonstrates the highest water uptake (106.2±1.9 %) and ion exchange capacity (1.55±0.2 meq g−1). Due to these superior properties, it achieves the maximum power density of 203 mW m−2 and an open circuit voltage (OCV) surpassing 700 mV. The crystal violet assay performed post-MFC operation affirms that the nanocomposite membrane effectively inhibits bacterial fouling. This study positions itself as a solution for long-term, high-performance MFC operations, all while significantly increasing power output and reducing biofouling concerns.

Dos Perspectivas Teóricas para Explicar la Gran Historia: Fred Spier & Pedro Ortiz Cabanillas

The central hypothesis of this research is that there are currently two theoretical proposals within the Big Story: the better known proposal of Fred Spier (1952 - ) and the lesser known proposal of Pedro Ortiz Cabanillas (1933 – 2011) implicitly contained in his Sociobiological Informational Theory. We will proceed to present and synthesize the two theories of Big History made by Spier and Ortiz, comparing them and identifying points of contact and differences. Spier’s theoretical proposal presents the becoming of the universe in three moments: cosmological, biological and social. The epistemological basis being a qualitative theory of complexity. Ortiz’s proposal (based on a qualitative theory of information) presents the evolution of the universe in six levels of complexity. In parallel, we would have: level 0 (Spier’s cosmological moment); level one, two, three and four (Spier’s biological level); and level 5 (Spier’s social moment). There are occasional differences between the two approaches, but more are the articulations and points of contact. The hypothesis of this research is correct: Spier (explicitly) and Ortiz (implicitly) have explanatory theories of Big History. Even if Spier and Ortiz never had contact (neither personally nor academically), their theories are articulated in the same explanatory scheme and are epistemologically nourished simultaneously. Big History is strengthened by what is presented here

Medieval European Witchcraft and the Perception of Women in Select Philippine Short Stories

This study addresses the persistent narrative of witchcraft-related violence in the contemporary era by delving into its historical root – the medieval practice of witch-hunts. It investigates gendered motifs linked to women accused of witchcraft and sorcery, using Morgan le Fay in Thomas Malory’s Morte Darthur as a reference. By examining gender stereotypes, we aim to demonstrate how medieval European concepts of witchcraft and sorcery have become entrenched in modern perceptions of women. This investigation employs Philippine literary texts – The Witch by Edilberto Tiempo and May Day Eve by Nick Joaquin, characterising women exhibiting postcolonial dispositions. Our central hypothesis holds that these contemporary stories adapt the medieval classic. The findings point to the medieval traces in the characters of Minggay and Agueda, leading to their societal categorisation as metaphorical witches. Textual analysis exemplifies strategies such as “un/belonging” the self to demonstrate “herstory,” acknowledging one's beliefs to express innate tendencies, and challenging social structures to promote reclamation of oppressive structures. This study contributes to understanding the challenged “mythical” nature of women’s identity in the modern era. Hence, the adaptive platform of medieval European influence lends support to stabilising women’s positionality rather than their essentiality.

Understanding Cerebellar Input Stage through Computational and Plasticity Rules.

A central hypothesis concerning brain functioning is that plasticity regulates the signal transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, the granular layer has been shown to control the gain of signals transmitted through the mossy fiber pathway. Until now, the impact of plasticity on incoming activity patterns has been analyzed by combining electrophysiological recordings in acute cerebellar slices and computational modeling, unraveling a broad spectrum of different forms of synaptic plasticity in the granular layer, often accompanied by forms of intrinsic excitability changes. Here, we attempt to provide a brief overview of the most prominent forms of plasticity at the excitatory synapses formed by mossy fibers onto primary neuronal components (granule cells, Golgi cells and unipolar brush cells) in the granular layer. Specifically, we highlight the current understanding of the mechanisms and their functional implications for synaptic and intrinsic plasticity, providing valuable insights into how inputs are processed and reconfigured at the cerebellar input stage.

Exercise does not cause post-exertional malaise in Veterans with Gulf War Illness: A randomized, controlled, dose–response, crossover study

Chronic multisymptom illnesses (CMI) such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Long-COVID, and Gulf War Illness (GWI) are associated with an elevated risk of post-exertional malaise (PEM), an acute exacerbation of symptoms and other related outcomes following exercise. These individuals may benefit from personalized exercise prescriptions which prioritize risk minimization, necessitating a better understanding of dose–response effects of exercise intensity on PEM. MethodsVeterans with GWI (n = 40) completed a randomized controlled crossover experiment comparing 20 min of seated rest to light-, moderate-, and vigorous-intensity cycling conditions over four separate study visits. Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 h after exercise and seated rest. Physical activity behavior was measured ≥ 7 days following each study visit via actigraphy. Linear mixed effects regression models tested the central hypothesis that higher intensity exercise would elicit greater exacerbation of negative outcomes, as indicated by a significant condition-by-time interaction for symptom, pain sensitivity, cognitive performance, and inflammatory marker models and a significant main effect of condition for physical activity models. ResultsSignificant condition-by-time interactions were not observed for primary or secondary measures of symptoms, pain sensitivity, cognitive performance, and a majority of inflammatory markers. Similarly, a significant effect of condition was not observed for primary or secondary measures of physical activity. ConclusionsUndesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.

A global neuronal workspace model of functional neurological disorders.

We introduce here a general model of Functional Neurological Disorders based on the following hypothesis: a Functional Neurological Disorder could correspond to a consciously initiated voluntary top-down process causing involuntary lasting consequences that are consciously experienced and subjectively interpreted by the patient as involuntary. We develop this central hypothesis according to Global Neuronal Workspace theory of consciousness, that is particularly suited to describe interactions between conscious and non-conscious cognitive processes. We then present a list of predictions defining a research program aimed at empirically testing their validity. Finally, this general model leads us to reinterpret the long-debated links between hypnotic suggestion and functional neurological disorders. Driven by both scientific and therapeutic goals, this theoretical paper aims at bringing closer the psychiatric and neurological worlds of functional neurological disorders with the latest developments of cognitive neuroscience of consciousness.

Abstract IA007: Tumor HLA-E expression and cytomegalovirus infection modulate NK cell activity in human bladder cancer

Abstract The intersection of viral infections and cancer therapy presents a complex landscape for immunotherapy strategies, particularly in solid tumors, where treatments such as systemic chemotherapy and targeted radiation are standard. Largely unexplored in solid tumors are the effects of human herpes virus-5 (HHV-5) also known as HCMV that imprints both lifelong effects on natural killer (NK) cells as well progressive effects on T cells with aging. HCMV is an extremely successful virus as it rarely kills the host outside of settings of compromised immunity, e.g. transplantation and advanced HIV-1 infection. HCMV is not considered a comorbidity in patients with solid tumors. Our group has identified reactivated cytomegalovirus (HCMV), found in bladder tissues post treatment, including infection of monocytes, fibroblasts, and even tumor cells, suggesting a viral influence that extends beyond traditional perspectives on cancer treatment resistance and response. We have observed spread of infection in both settings of BCG-treated non-muscle-invasive bladder cancer (NMIBC) as well as MIBC treated with gemcitabine and cisplatin chemotherapy. HCMV infection leads to the development of “adaptive” NK cells that express the activating isoform of NKG2A: NKG2C, which are likely expanded in response to HCMV reactivation and have established functions for controlling virus reactivation. Our central hypothesis is that certain treatments may reactivate HCMV, potentially greatly altering the biology within the tumor microenvironment (TME) and providing a framework to exploit NK cells for immunotherapy strategies. In a cohort of NMIBC patients (N=90) receiving BCG therapy at Mount Sinai, we profiled patients’ serum for HCMV-IgG (N=47 HCMV seropositive; N=43 HCMV seronegative) and observed a significantly improved recurrence-free survival in HCMV seropositive patients (HR=0.58, p=0.03). Further, HCMV-seropositive patients with circulating NKG2C+ adaptive NK cells experienced a near perfect response to BCG therapy (p=0.0002). Strikingly, in situ imaging and RNAscope analyses of patient tumors before and after BCG therapy revealed strong presence of active viremia in tumors. Further, analysis of on-treatment bladder biopsies after tumor resection demonstrated the presence of adaptive NK cells in HCMV+ bladder tissues, but only after exposure to BCG therapy and tissue-derived adaptive NK cells expressed high levels of chemokine receptors, CXCR3 and CXCR4 as well as tissue-residency markers, suggesting a mechanisms for trafficking to the bladder and taking up residence for subsequent antitumor control against recurrence. Impact and Translation: Our findings suggest that adaptive NK cells mediate response to immunotherapies for solid tumors as well as provide preclinical models for adoptive transfer therapies targeting NK cells. Additionally, if HCMV reactivation is widespread across solid tissues in response to systemic therapies, it may prove a critical comorbidity to consider in design of treatment strategies and in clinical trials. Citation Format: Amir Horowitz. Tumor HLA-E expression and cytomegalovirus infection modulate NK cell activity in human bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA007.

Instructions for meaningful figures in radiological research publications.

In this paper, we explain the structure and function of different types of figures and provide guidance on how to create effective figures for radiological research publications.Based on scientific literature and our own experience, we have compiled a series of instructions to support the purposeful creation of effective figures for radiological research publications.Effective figures play a crucial role in radiological research publications by clearly visualizing complex content and thereby enhancing its comprehensibility. Different types of figures have distinct strengths that should be strategically employed for optimal impact. The interplay between figures weaves the "common thread" of a publication, facilitating reader comprehension and providing a straightforward path to the answer of the central research question. The systematic coordination (line of evidence) and effective design of individual figures are crucial to compellingly support the publication's central hypothesis.The deliberate creation and coordination of figures in radiological research publications are decisive factors for successful publishing. · Different types of figures have distinct strengths that should be strategically employed for optimal impact.. · The interplay between figures weaves the "common thread" of a publication, facilitating reader comprehension and providing a straightforward path to the answer of the central research question.. · The appropriate coordination of different types of figures enables an effective and precise presentation of the research findings.. · The systematic coordination (line of evidence) and effective design of individual figures are crucial to compellingly support the publication's central hypothesis.. · The deliberate creation and coordination of figures in radiological research publications are decisive factors for successful publishing.. · Pape LJ, Hambach J, Bannas P. Instructions for figures in radiological research publications. Fortschr Röntgenstr 2024; DOI 10.1055/a-2285-3223.

Machine Learning and Information Theory Concepts towards an AI Mathematician

The current state of the art in artificial intelligence is impressive, especially in terms of mastery of language, but not so much in terms of mathematical reasoning. What could be missing? Can we learn something useful about that gap from how the brains of mathematicians go about their craft? This essay builds on the idea that current deep learning mostly succeeds at system 1 abilities—which correspond to our intuition and habitual behaviors—but still lacks something important regarding system 2 abilities—which include reasoning and robust uncertainty estimation. It takes an information-theoretical posture to ask questions about what constitutes an interesting mathematical statement, which could guide future work in crafting an AI mathematician. The focus is not on proving a given theorem but on discovering new and interesting conjectures. The central hypothesis is that a desirable body of theorems better summarizes the set of all provable statements, for example, by having a small description length while at the same time being close (in terms of number of derivation steps) to many provable statements.

Eigenvector spatial filtering enhancing natural hazards vulnerability assessment in a susceptible urban environment: A case study of Izmir earthquake in Turkey

The increasing risk of earthquakes in urban areas has made it crucial to develop accurate vulnerability models for city infrastructure and systems. We aimed to assess and compare the effectiveness of different models and vulnerability analysis techniques in predicting earthquake vulnerability in the specific context of Izmir, Turkey. One central hypothesis in this research aimed to determine whether integrating Eigenvector Spatial Filtering (ESF) into both regression models and machine learning algorithms would yield a comparable enhancement in model performance. We performed earthquake vulnerability modeling (EVM) by considering (ⅰ) only seismic-related variables (SRV) and (ⅱ) integrating ESF by using Moran's eigenvector maps (MEMs). For each approach, we evaluated the predictive performance of two simple regression-based models; generalized linear model (GLM) and generalized additive model (GAM), and two complex machine learning ones; generalized boosting model (GBM), and random forest (RF). The study utilized five primary indicators encompassing geotechnical, physical, structural, social, and facilities data. The predictive performance of the models was assessed using evaluation metrics including Root Mean Square Error (RMSE), Mean Absolute Error (MAE), and adjusted R2. The results indicated that the optimal candidate model consisted of five key variables: altitude, building height, distance to safety gathering places, Peak Ground Acceleration (PGA), and population density. We found that decision-tree-based methods performed better than regression-based methods for both modeling schemes. RF exhibited the highest predictive performance for the training data (RMSE = 0.59, adjusted R2 = 0.71), while GBM outperformed other models for the test data (RMSE = 0.79, adjusted R2 = 0.78). However, incorporating ESF to the EVM analysis revealed that regression-based methods, particularly the GLM, obtained highest improvement in accuracy (RMSE 0.94 vs 0.76 and adjusted R2 0.56 vs 0.71 for the SRV and SRV + MEMs modeling approach). Significant differences were observed between GLM-GBM and GLM-RF comparisons, as well as GAM-GBM and GAM-RF comparisons. The findings of this research are expected to be helpful for informed decision-making, targeted risk reduction, and the development of effective policies and strategies to enhance preparedness and resilience in the face of seismic events in highly susceptible urban systems.

Abstract PO3-28-12: Targeting the KCa3.1 potassium channel arrests ER+ breast cancer growth and re-sensitizes to drug resistance

Abstract Standard of care for breast cancer (BC) treatment including Selective-Estrogen Receptor (ER)-modulators and/or degraders (SERM; tamoxifen, SERD;Fulvestrant) or cyclin-dependent kinases CDK4 and CDK6 (palbociclib) can be effective therapeutic strategies. However, drug toxicity and/or drug resistance severely limit these approaches and patients succumb to the disease. Therefore, there is an urge to develop new therapeutic strategies against ER+-BC. Ion channels are general pharmacological targets however, little is known about the role of this class of proteins in cancer biology. We discovered that expression of the KCa3.1 potassium ion channel is downregulated in ER+-BC. Also, patients expressing high level of KCa3.1 present a better overall survival (OS) and relapse free survival when compared with patients with low expression. Thus, these data indicate that KCa3.1 is a prognostic factor in ER+-BC and that high activity of this channel plays a fundamental role in an oncosuppressor signature. Our central hypothesis is that pharmacological targeting KCa3.1 with activator molecules arrests growth of ER+-BC. We discovered that ER+-BC patient-derived organoids (PDO) and cell lines treated with KCa3.1 agonists including the FDA approved Chlorzoxazone, (CZX) arrests significantly inhibit tumor growth. Activation of KCa3.1 arrested the cell cycle in the G0/G1 phase by activating a senescent-like phenotype. Furthermore, our studies on the biochemical signaling that underlines this event demonstrated that increased expression level of KCa3.1 protein associated with lower expression level of ERa in a cell cycle phase-dependent manner. Furthermore, use of KCa3.1activator produced a proteasomal-dependent ERa degradation. To better characterize the therapeutic benefit of targeting the KCa3.1, we assessed the effects of CZX on developed several tamoxifen and/or palbociclib resistant cell lines and PDO models. We found that the combination of CZX strongly potentiated the lethal effects of both tamoxifen and palbociclib in the relative resistant models. We conclude that pharmacological targeting KCa3.1 potassium channel in ER+-BC can be considered a novel, safe and efficacious therapeutic strategy. Citation Format: Davide Delisi, Metin Cetin, Ozge Saatci, Ozgur Sahin, Saverio Gentile. Targeting the KCa3.1 potassium channel arrests ER+ breast cancer growth and re-sensitizes to drug resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-12.

Modulation of WNT signalling by inflammatory factor TWEAK, and its consequences on fibroblast-epithelial communication

BACKGROUND AND AIMS: A single layer of epithelial cells that are supported by resident mucosal fibroblasts, provides an intestinal barrier against pathogens. In Inflammatory Bowel Disease (IBD), this barrier is disrupted by mechanisms which are poorly understood. Intestinal fibroblasts produce WNT, BMP and Notch mediators that contribute to epithelial homeostasis and an impairment on these signals results in the loss of barrier integrity which has been observed in IBD. In fact, fibroblasts producing these signals may be lost during inflammation. Yet the mediators and mechanism that drive this loss of homeostatic stromal-derived signals are unknown. TWEAK is a member of the tumour necrosis factor superfamily (TNFSF) that was found to be upregulated in IBD biopsies and dysregulated tissue repair and promote chronic inflammation in in vivo murine models. However, whether TWEAK exerts its effects on fibroblasts and how these may contribute to barrier breakdown remains unknown. My central hypothesis is that TWEAK dysregulates the crosstalk between fibroblasts and epithelial cells in the intestinal tract by impairing a homeostatic signalling network. METHODS: To assess the effect of TWEAK on WNT signalling and wound healing in fibroblasts and epithelial cells, the expression of WNT ligands and receptors were assessed. Primary human colonic fibroblasts and human colonic epithelial cells were stimulated with TWEAK at various time points and analysed by qPCR, Western blot and Flow cytometry and scratch wound assay. RESULTS: Both Fibroblasts and epithelial cells displayed abundant Fn14 surface receptor, although epithelial cells at a level lower than that found on colonic fibroblasts. Transcriptional signatures at gene RSPO2 (0.5-fold ± decrease, *p<0.05, n=4), WNT5A (1 fold ± decrease, **p<0.01, n=4) and BMP6 (1 fold ± decrease, ***p<0.001, n=4) and protein level RSPO2 (50% ± decrease respectively, n=5) showed a TWEAK-mediated suppression after prolonged exposure (24-48h), but not in epithelial cells. Moreover, TWEAK delayed fibroblast healing capacity after 24h (50% ± decrease in wound closure, n=4) in a wound-scratch assay. CONCLUSION: TWEAK represses the expression of homeostatic factors in colonic fibroblasts but not on epithelial cells, suggesting this mechanism could be specific to the intestinal stroma. The effect that this impairment of WNT signals in stromal cells may have on their differentiation and communication with the epithelium will be subject for further study. UCD Ad Astra PhD Scholarship. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of neuroendothelial cells in aging-related vascular cognitive impairment

Vascular cognitive impairment (VCI) is a growing health problem in many developed countries due to aging of its population. Aging-induced impairment of neurovascular coupling (NVC) responses and brain microvascular rarefaction have been implicated as major driving mechanisms in age-related cognitive decline. One of the cellular hallmarks of NVC involve the release of vasodilator nitric oxide (NO) by endothelial cells in response to mediators released from activated neurons. Recent studies from our group identified and characterized a novel, minority subtype of scattered ECs with endothelial and neuronal characteristics, hence the name neuroendothelial cell (NECs). NECs present a well-defined arteriovenous zonal localization exclusively in small resistance arterioles with the highest density in the brain followed by the kidney. Intravital multiphoton microscopy (MPM) of intact brain arterioles in vivo suggest that NECs play an important role in regulating blood flow to the brain and able to detect changes in systemic blood pressure, hypoxia and perhaps other metabolic changes in the local microenvironment. Our central hypothesis is that NECs are novel key players in blood flow autoregulation, vascular control of organ functions in both short-term (hemodynamics) and long-term (angiogenesis, tissue regeneration). We further hypothesize that the decrease in NEC density and function in aged subjects is a major player in the development of age-related cerebral microvascular pathologies and that augmenting NEC number and function in aged animals will provide therapeutic benefit. This study used a NEC specific comprehensive research toolbox including NEC-GFP transgenic mouse models and high-resolution single-cell based transcriptome analysis to establish the NEC specific molecular atlas in young adult (3 month of age) and aged (2 years of age) animals. Furthermore, transgenic animal models combined with serial intravital imaging of the same tissue volume over consecutive days was used to study changes in vascular endothelial cell composition in response to NEC stimuli in young adult and aged mice. Cell fate tracking studies of the Nos1-lineage combined with Nos1 immunostaining revealed that NECs represent a permanent cell type with terminal neuronal differentiation. Importantly, NEC density is reduced with aging in all organs including the brain. High resolution single-cell based transcriptome analysis of 100K endothelial cells isolated from mouse brain demonstrated that, in contrast to other ECs, NECs highly express several traditional (e.g., Nos1, Angpt1, Egfl8) and novel (e.g., Cytl1, MGP, Gkn3) tissue trophic factors that are known to play important roles in acute hemodynamic responses including NO mediated functional hyperemia, and in chronic settings in angiogenesis, aging, vascular (dys)function, and chronic vascular diseases. Furthermore, the expression of many of these factors were significantly reduced in NECs isolated from aged animals. In conclusion, the newly discovered NEC-specific molecular and signaling mechanisms may play a role in the age-related decrease in NVC capacity and microvascular rarefaction and may be targeted for therapeutic benefits in age related VCI. American Society of Nephrology Carl W. Gottschalk Research Scholar Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

End-to-end automated speech recognition using a character based small scale transformer architecture

This study explores the feasibility of constructing a small-scale speech recognition system capable of competing with larger, modern automated speech recognition (ASR) systems in both performance and word error rate (WER). Our central hypothesis posits that a compact transformer-based ASR model can yield comparable results, specifically in terms of WER, to traditional ASR models while challenging contemporary ASR systems that boast significantly larger computational sizes. The aim is to extend ASR capabilities to under-resourced languages with limited corpora, catering to scenarios where practitioners face constraints in both data availability and computational resources. The model, comprising a compact convolutional neural network (CNN) and transformer architecture with 2.214 million parameters, challenges the conventional wisdom that large-scale transformer-based ASR systems are essential for achieving high accuracy. In comparison, contemporary ASR systems often deploy over 300 million parameters. Trained on a modest dataset of approximately 3000 h – significantly less than the 50,000 h used in larger systems – the proposed model leverages the Common Voice and LibriSpeech datasets. Evaluation on the LibriSpeech test-clean and test-other datasets produced character error rates (CERs) of 6.40% and 16.73% and WERs of 16.03% and 35.51% respectively. Comparisons with existing architectures showcase the efficiency of our model. A gated recurrent unit (GRU) architecture, albeit achieving lower error rates, incurred a computational cost 24 times larger than our proposed model. Large-scale transformer architectures, while achieving marginally lower WERs (2%–4% on LibriSpeech test-clean), require 200 times more parameters and 53,000 additional hours of training data. Modern large language models are used to improve the WERs, but require large computational resources. To further enhance performance, a small 4-g language model was integrated into our end-to-end ASR model, resulting in improved WERs. The overarching goal of this work is to provide a practical solution for practitioners dealing with limited datasets and computational resources, particularly in the context of under-resourced languages.

Novel, engineered fusogenic liposome-based anti-oxidant delivery system improves the blood-brain barrier integrity in aging

Vascular dysfunction plays a pivotal role in age-related cognitive decline and neurodegeneration. The aging process often leads to a loss of integrity in the blood-brain barrier (BBB), initiating neuroinflammation and contributing to a decline in cognitive function. In previous research, we demonstrated the potential of resveratrol (RSV), a natural polyphenol, to target cerebromicrovascular endothelial cells (CMVECs), effectively countering age-related oxidative stress and improving vascular function, both in vitro and in vivo. However, the limited bioavailability of resveratrol raised questions about its effectiveness concerning the BBB and neuroinflammation. Our study aimed to address this challenge by introducing a novel drug delivery system designed to enhance the effciency of polyphenol delivery. This innovative approach involved the use of fusogenic liposomes (FL) integrated with a bioengineered protein corona (PC) featuring specific apolipoprotein E (ApoE). Our central hypothesis posited that PC formation could be harnessed to directly target CMVECs and enhance liposomal uptake, with the ultimate objective of effectively delivering RSV to the brain's microvessels in aging subjects (ApoE-FL-RSV). Our investigation encompassed the characterization of ApoE-FL uptake by CMVECs, along with an analysis of its biodistribution and pharmacokinetics in vivo. Remarkably, our findings revealed a significant increase in ApoE-FL-RSV accumulation within CMVECs in vivo, compared to control FL uptake. We employed advanced in vivo multiphoton imaging to longitudinally monitor the effects of ApoE-FL-RSV on the BBB, which demonstrated a significant rejuvenation of the endothelial barrier function in aged mice treated with ApoE-FL-RSV. In light of these results, we concluded that the fusogenic liposomal delivery system holds promise as a viable pharmacological intervention for addressing age-related vascular cognitive impairment. AHA834339, RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, R01NS100782, R01CA255840, and Presbyterian Health Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.