Functional Significance Research Articles

Evaluation of left atrial function and the relationship between left atrial stiffness index and exercise capacity in hypertension-related heart failure with preserved ejection fraction

ObjectiveThe left atrial stiffness index (LASI) holds significance in the atrioventricular coupling function and heart failure progression. To assess left atrial function and evaluate the relationship between LASI and exercise capacity in hypertension-related heart failure with preserved ejection fraction (HT-HFpEF).MethodsThe study involved 62 healthy subjects and 163 patients with HT (112 patients in simple HT group and 51 patients in HT-HFpEF group). Each patient performed exercise stress test and standard ultrasonic images were evaluated. A comprehensive evaluation of atrioventricular function, along with investigation into the correlation between these functional parameters and exercise capacity. And further to investigate the feasibility of predicting exercise intolerance using three-dimensional derived left atrial strain index (LASI) (E/e'/LASr and E/e'/LASr-c).ResultsCompared to healthy subjects, HT group demonstrated the elevation in left atrial volume accompanied by decrease in strain value (P < 0.05). In HT-HFpEF group, further significant reductions were observed in both longitudinal (LASr) and circumferential strain (LASr-c, LASct-c) (P < 0.05). Univariate regression demonstrated that both E/e'/LASr and E/e'/LASr-c were significantly correlated with metabolic equivalents (METs) (r = −0.462, P < 0.001; r = −0.381, P < 0.001). The E/e'/LASr demonstrates comparable diagnostic efficacy to exercise-E/e' in assessing exercise intolerance in HT-HFpEF patients (AUC: 0.836 vs. 0.867, P = 0.239).ConclusionProgressive LA remodeling contributes to decreased atrioventricular compliance in HT and HT-HFpEF patients.E/e'/LASr serves as an independent indicator of exercise intolerance in patients with HT-HFpEF.

Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review

Objective: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients. Method: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus. Results: We included seven prospective studies, published in 2010–2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation. Conclusions: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.

Association of Neurokinin-1 Receptor Signaling Pathways with Cancer.

Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity. This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed. NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.

Onconephrology: The Significance of Renal Function for the Development, Diagnosis, and Treatment of Cancer.

Modern treatment strategies have markedly improved the chances of survival for patients with cancer. As the population ages, cancer is becoming more common, as is chronic kidney disease (CKD). CKD increases the risk of cancer; conversely, cancer treatments can cause CKD. This review is based on publications retrieved by a selective literature search concerning the epidemiology and comorbidities of cancer and kidney diseases, the renal side effects of new anticancer drugs, and the need to consider renal function in cancer treatment. The prevalence of severe CKD in Germany is 2.3%. Persons who have CKD, are on dialysis, or have undergone kidney transplantation are 1.2 to 3.5 times more likely to develop cancer than the general population. For patients who have CKD or are dialysis-dependent, the doses of approximately 67% of anticancer drugs need to be adjusted on the basis of their glomerular filtration rate and the renally excreted fraction of the drug. The optimal efficacy of therapeutic drugs, as well as of those used for diagnostic purposes, and the minimization of side effects, depend critically on adapted dosing and on proper timing of administration before or after dialysis. Modern anticancer drugs can also cause acute kidney damage (incidence with checkpoint inhibitors: 2-16%). Patients who have CKD, are on dialysis, or have undergone kidney transplantation make up a considerable fraction of persons being treated for cancer, and they need interdisciplinary treatment.

Evolution and Significance of Sine Function in Ancient Indian Mathematics

This research article delves into the historical and mathematical intricacies of the construction of sine functions, particularly focusing on ancient Indian mathematical concepts and their evolution. It begins by highlighting the significance of sine (jya) as a fundamental trigonometric function in Indian mathematics, alongside its synonyms in Sanskrit. The historical journey of the term “sine” is traced back to ancient Indian mathematical texts, which were later translated into Arabic and then into Latin, ultimately leading to the adoption of the term “sine” in modern mathematics. The article elaborates on the definitions and interpretations of sine (ज्या), cosine (कोटिज्या), versed sine (उत्क्रमज्या), and co-versed sine (कोट्युत्क्रमज्या) in Indian mathematical traditions. It explains how these functions were conceptualized and utilized in astronomical calculations, emphasizing their geometric and trigonometric significance. Furthermore, the article discusses the division of a circle into quadrants (Vṛttapādas) and the concept of Trijyā (radius), highlighting the mathematical sophistication and terminology used by ancient Indian mathematicians. Several mathematical formulas related to the construction and calculation of sine functions are presented, including formulas for finding sine values at specific angles such as 45 degrees, 18 degrees and 72 degrees. These formulas showcase the mathematical ingenuity and problem-solving skills of ancient Indian mathematicians. Overall, this research article provides a comprehensive overview of the historical development and mathematical foundations of sine functions in ancient Indian mathematics, shedding light on their enduring legacy and contributions to modern trigonometry.

Decoding the Significance of Alpha Cell Function in the Pathophysiology of Type 1 Diabetes.

Alpha cells in the pancreas, traditionally known for their role in secreting glucagon to regulate blood glucose levels, are gaining recognition for their involvement in the pathophysiology of type 1 diabetes (T1D). In T1D, autoimmune destruction of beta cells results in insulin deficiency, which in turn may dysregulate alpha cell function, leading to elevated glucagon levels and impaired glucose homeostasis. This dysfunction is characterized by inappropriate glucagon secretion, augmenting the risk of life-threatening hypoglycemia. Moreover, insulin deficiency and autoimmunity alter alpha cell physiological responses, further exacerbating T1D pathophysiology. Recent studies suggest that alpha cells undergo transdifferentiation and interact with beta cells through mechanisms involving gamma-aminobutyric acid (GABA) signaling. Despite these advances, the exact pathways and interactions remain poorly understood and are often debated. Understanding the precise role of alpha cells in T1D is crucial, as it opens up avenues for developing new therapeutic strategies for T1D. Potential strategies include targeting alpha cells to normalize glucagon secretion, utilizing glucagon receptor antagonists, enhancing GABA signaling, and employing glucagon-like peptide-1 (GLP-1) receptor agonists. These approaches aim to improve glycemic control and reduce the risk of hypoglycemic events in individuals with T1D. This review provides an overview of alpha cell function in T1D, highlighting the emerging focus on alpha cell dysfunction in the context of historically well-developed beta cell research.

Circumstantial and tactic augmentation

Abstract The present study attempts to unveil patterns in interactive information structure of clause enhancement that conventionalize the actual representation of circumstantial elements which add information about time, place, manner, means, and reason/cause through circumstantial augmentation, tactic augmentation, or connectives in method sections of research articles (RAs). The dataset consisted of 120 method sections of randomly selected empirical RAs from ISI-indexed Q1-ranked applied linguistic journals published between 2020 and 2022. The results of the study point to a significant distinction in hypotactic augmentation to register circumstantial information in comparison to other choices available to authors. Moreover, the most striking observation to emerge from the data is that a logical information structure of circumstantial meaning is mostly facilitated through hypotactic non-finite enhancement rather than its finite counterpart. This viable preference lies in elliptical, evincing, and expressive functions of hypotactic clauses that make comprehension more attainable to the readers and assist authors in fulfilling the generic conventions and communicative purposes of academic writing and managing interactive information structures. A major theoretical implication of the current research entails the significance of the interactive functions of the options available to authors which can impose priorities on the system of choices within the context of information.

Shaking Table Test Studies on Adaptive-Passive Variable Frequency Gas-Spring DVA for Structural Seismic Response Mitigation

The control performance of a passive dynamic vibration absorber (DVA) is known to be sensitive to its frequency deviation. This study upgrades the conventional device and proposes an adaptive-passive variable frequency gas-spring DVA (APVF-GSDVA) for controlling the structural seismic response, while an adaptive control algorithm is developed that requires only a single input signal. The DVA’s vibration frequency is precisely modulated by adjusting the gas pressure in the gas-spring, aligning it with the inherent frequency of the multi-degree-of-freedom (MDOF) structure. The working principle and control algorithm of the APVF system is introduced and derived in detail, the corresponding gas-spring DVA and implementation are designed, and the configuration of the entire control system is realized. An adaptive variable frequency test scheme is designed and the frequency retuning function of the prototype APVF-GSDVA device installed on an MDOF structure is experimentally validated. The seismic response control effectiveness of the retuned DVA is demonstrated by comparing the detuned DVA, highlighting the necessity of implementing adaptive frequency adjustment of the gas-spring DVA. Experimental findings demonstrate that APVF-GSDVA accurately identifies the inherent frequency of the MDOF structure in ambient excitation, it then adjusts the pressure of the gas-spring according to the frequency-pressure relationship, optimally retuning the DVA. A retuned GSDVA can effectively suppress the structural seismic responses, compared to a detuned DVA, its control effectiveness on peak and RMS responses can be improved by a maximum of nearly 13.5% and 53.3% at a frequency deviation of 10%. Furthermore, results from two “detuning-retuning” test paths with distinct seismic excitations indicate that the retuned DVA exhibits superior control effectiveness, underscoring the significance of the adaptive frequency adjustment function in passive DVAs.

Family Resources and Parental Problem-Solving Skills Mediate Family Functioning and Family Adaptation in Families of Children With Cancer.

To explore the mediating roles of family resources (at the individual [parental self-efficacy], family [family resilience] and social level [social support]) and parental problem-solving skills in the association between family functioning and family adaptation in families of children with cancer. A cross-sectional study. This study recruited 318 parents of children with cancer from three tertiary hospitals in mainland China. Self-report questionnaires were used to collect data on key variables, including family functioning, parental self-efficacy, family resilience, social support, parental problem-solving skills and family adaptation. Data analyses were carried out using descriptive analysis, univariate analysis, Pearson correlation analysis, hierarchical linear regression and bootstrapping. Family functioning was significantly and positively correlated with family adaptation. Family resources (parental self-efficacy at the individual level, family resilience at the family level or social support at the social level) and parental problem-solving skills both independently mediated the relationship between family functioning and family adaptation. Additionally, family resources at all three levels mediated the relationship through their effects on cumulatively parental problem-solving skills, constructing a chain mediating model. The study underscores the significance of family functioning, family resources at the individual, family and social levels and parental problem-solving skills in promoting adaptation in families of children with cancer. It highlights the need for family-centred interventions targeted at these factors to improve family adaptation. This study extended related theories and previous studies to confirm the mediating role of family resources and parental problem-solving skills, both independently and sequentially. Moreover, parental problem-solving skills were confirmed as key elements that can be incorporated into future interventions, suggesting that problem-solving skills training may serve as a highly promising program for families of children with cancer. This study was reported according to the STROBE checklist. No Patient or Public Contribution.

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription. Second, ARF targets the RUNX family transcription factor 1 (RUNX1) to selectively tune gene transcription. Consistently, ARF loss triggers RUNX1- and PAF1c-dependent transcriptional activation of pro-growth ligands (growth differentiation factor/bone morphogenetic protein [GDF/BMP]), promoting a cell-intrinsic GDF/BMP-Smad1/5 axis that aberrantly induce cell growth. Notably, pharmacologic inactivation of GDF/BMP signaling and genetic perturbation of RUNX1 significantly attenuate cell proliferation mediated by dual p53 and ARF loss, offering therapeutic utility. Our data underscore the significance of selective ARF-mediated tumor-suppressive functions through a universal transcriptional regulator.

Significance of left atrial function in predicting early recurrence of atrial fibrillation following electrical cardioversion

Significance of left atrial function in predicting early recurrence of atrial fibrillation following electrical cardioversion

Beyond anosmia: olfactory dysfunction as a common denominator in neurodegenerative and neurodevelopmental disorders.

Olfactory dysfunction has emerged as a hallmark feature shared among several neurological conditions, including both neurodevelopmental and neurodegenerative disorders. While diseases of both categories have been extensively studied for decades, their association with olfaction has only recently gained attention. Olfactory deficits often manifest already during prodromal stages of these diseases, yet it remains unclear whether common pathophysiological changes along olfactory pathways cause such impairments. Here we probe into the intricate relationship between olfactory dysfunction and neurodegenerative and neurodevelopmental disorders, shedding light on their commonalities and underlying mechanisms. We begin by providing a brief overview of the olfactory circuit and its connections to higher-associated brain areas. Additionally, we discuss olfactory deficits in these disorders, focusing on potential common mechanisms that may contribute to olfactory dysfunction across both types of disorders. We further debate whether olfactory deficits contribute to the disease propagation or are simply an epiphenomenon. We conclude by emphasizing the significance of olfactory function as a potential pre-clinical diagnostic tool to identify individuals with neurological disorders that offers the opportunity for preventive intervention before other symptoms manifest.

Dual Function of Hydrogen Bond and CEI to Enhanced Lithium-Ion Battery Performance.

The stability of the commercial electrolyte is linked to the internal solvent molecule, particularly in enhancing the stability of these molecules. Hereby, we introduce a dual function strategy involving hydrogen bond induced solvent molecules and the in situ fabrication cathode-electrolyte interphase (CEI) to address this issue. The additive N-(4-(2,5-dioxo-4-oxazolidinyl)butyl)-2,2,2-trifluoroacetamide (DOTFA), with its oxazolidinyl and trifluoroacetamide functional units, establishes hydrogen bonds with the solvent, forming CEI films on the cathode surface that enhance the antioxidation ability of the electrolyte. These hydrogen bonds contribute to enhancing the high-pressure structural stability of the solvent molecule. Additionally, the uniform and robust in situ constructed CEI films act as a shield, protecting the cathode from various side reactions and enhancing interface compatibility. By incorporation of the DOTFA additive in the electrolyte, lithium-ion batteries with NCM811 cathodes exhibit excellent cycling performance. The work highlights the significance of dual function in solvent molecules and provides an effective method for enhancing the antioxidation ability of the electrolyte.

Comprehensive analysis of lactylation-related gene sets and mitochondrial functions in gastric adenocarcinoma: implications for prognosis and therapeutic strategies.

Gastric adenocarcinoma (STAD) is characterized by high heterogeneity and aggressiveness, leading to poor prognostic outcomes worldwide. This study explored the prognostic significance of lactylation-related gene sets and mitochondrial functions in STAD by integrating large-scale genomic datasets, including TCGA and several GEO datasets. We utilized Spatial transcriptomics and single-cell RNA sequencing to delineate the tumor microenvironment and assess the heterogeneity of cellular responses within the tumor. Additionally, the study identified distinct molecular subtypes within STAD that correspond with unique survival outcomes and immune profiles, enhancing the molecular classification beyond current paradigms. Prognostic models incorporating these molecular markers demonstrated superior predictive capabilities over existing models across multiple validation datasets. Furthermore, our analysis of immune landscapes revealed that variations in lactylation could influence immune cell infiltration and responsiveness, pointing towards novel avenues for tailored immunotherapy approaches. These comprehensive insights provide a foundation for targeted therapeutic strategies and underscore the potential of metabolic and immune modulation in improving STAD treatment outcomes.

Opportunities and Constraints of the Adsorption of Rare Earth Elements onto Pyrolytic Carbon-Based Materials: A Mini-Review

Rare earth elements (REEs), comprising seventeen metallic elements, including lanthanides, scandium, and yttrium, are indispensable for modern technological industries due to their unique properties. However, their supply is critically risky for the European Union, with 95% of global production concentrated in China, Brazil, Vietnam, Russia, India, and Australia. This mini-review examines the adsorption of REEs onto pyrolytic carbon-based materials as a sustainable recovery method from secondary raw materials. The review covers different types of carbon-based adsorbents used in several research works, such as activated carbon, chars, and biochar, and discusses their adsorption mechanisms and influencing factors. Comparative analyses of adsorption capacities highlight the significance of surface area and functionalization in enhancing adsorption efficiency. Despite promising results, the variability in adsorption performance due to experimental conditions and the scarcity of real-world application studies are noticed. This review underscores the need for further research using real e-waste leachates to validate the practical applicability of pyrolytic carbon-based adsorbents for REEs’ recovery, aiming for an economically and environmentally sustainable solution.

Development of international guidelines by Tuina practitioners for specific acupoints of paediatrics Tuina (2022 version).

To establish a standardized framework encompassing the precise locations, manipulations, functions and indications of specific acupoints in the field of paediatric Tuina. The development of consensus involved three distinct stages. Initially, a list of paediatric Tuina specific acupoints was compiled based on an extensive literature review, which was subsequently supplemented through expert interviews. In the second stage, the Delphi method was employed to assess the significance of acupoint locations, manipulations, functions, and indications. In situations where the questionnaire survey failed to yield agreement or when the experts held reservations, the nominal group approach was utilized during the expert consensus meeting. The final version of the technical standardized material was ultimately determined during an expert consensus conference. After undergoing external peer review and evaluation, the completed draft was prepared for public dissemination RESULTS: The comprehensive list identified a total of 66 specific acupoints. The location and manipulation questionnaire consisted of 156 items based on the literature database, while the function and indication questionnaire contained 116 items. Two rounds of Delphi surveys were conducted for the location and manipulation category, and another two rounds of Delphi surveys were conducted for the function and indication category. During the experts consensus meeting The panel of experts conducted in-depth discussions on 61 questions, resulting in the formulation of technical guidelines for the locations, manipulations, functions, and indications of 64 paediatric Tuina acupoints. Subsequently, the research team compiled and edited the draft of the technical guidelines for acupoints of paediatric Tuina, which was finalized after external review and feedback. This study successfully established the recognized technical standards for practitioners of paediatric Tuina, thereby standardizing clinical practices and providing a foundation setting the framework for future research. The guidelines offer theoretical insights and recommendations for conducting clinical studies comparing different acupoint sites, as well as modifying or enhancing treatment regimens.

NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia-Complementing Prostacyclin.

Aim: The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H2O2 production. Therefore, we aimed to elucidate NOX4's significance in endothelial function under hypoxia. Methods: Human vessels, in addition to murine vessels from Nox4-/- mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results: In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase (PTGIS). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4-/- mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusions: Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS.

Septins: Structural Insights, Functional Dynamics, and Implications in Health and Disease.

Septins are a class of proteins with diverse and vital roles in cell biology. Structurally, they form hetero-oligomeric complexes and assemble into filaments, contributing to the organization of cells. These filaments act as scaffolds, aiding in processes like membrane remodeling, cytokinesis, and cell motility. Functionally, septins are essential to cell division, playing essential roles in cytokinetic furrow formation and maintaining the structural integrity of the contractile ring. They also regulate membrane trafficking and help organize intracellular organelles. In terms of physiology, septins facilitate cell migration, phagocytosis, and immune responses by maintaining membrane integrity and influencing cytoskeletal dynamics. Septin dysfunction is associated with pathophysiological conditions. Mutations in septin genes have been linked to neurodegenerative diseases, such as hereditary spastic paraplegias, underscoring their significance in neuronal function. Septins also play a role in cancer and infectious diseases, making them potential targets for therapeutic interventions. Septins serve as pivotal components of intracellular signaling networks, engaging with diverse proteins like kinases and phosphatases. By modulating the activity of these molecules, septins regulate vital cellular pathways. This integral role in signaling makes septins central to orchestrating cellular responses to environmental stimuli. This review mainly focuses on the human septins, their structural composition, regulatory functions, and implication in pathophysiological conditions underscores their importance in fundamental cellular biology. Moreover, their potential as therapeutic targets across various diseases further emphasizes their significance.

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification.

Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

On the function and origin of the avian renal portal shunt and its potential significance throughout evolution.

All birds possess a unique venous architecture surrounding the kidneys known as the renal portal system. In veterinary medicine, this system is well known for causing a first-pass effect when medication is administered parenterally via the leg veins, that is venous blood from the leg is filtered before entering general circulation, thus possibly compromising adequate dosage. Additionally, bilateral valves are present in these veins, and it has been hypothesized that they play a crucial role in regulating flow through the kidneys to protect them against increases in blood pressure. While this hypothesis has been acknowledged, it has not been thoroughly explored. We propose that the function of the renal portal valve extends beyond its significance for kidney function, potentially impacting general hemodynamics. Examining anatomical similarities with extant non-avian reptiles, which lack the renal portal shunt with valve, could reveal additional functionalities of this system in birds. Given the endothermic metabolism and the energetically expensive locomotor activity of birds, the resistance of the hepatic and renal portal system might constrain the blood flow from splanchnic to non-splanchnic blood vessels necessary for (sustained) peak performance. Therefore, diverting blood from the renal portal system using the renal portal valve as a regulatory structure might represent a key adaptation to facilitate sustained peak performance. In addition, we hypothesize that this shunt and valve represents a very early adaptation in amniotes, possibly lost in extant non-avian reptiles but enhanced in birds, with a pivotal role in maintaining hemodynamic homeostasis to support the high metabolic rates characteristic of birds.