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Microstructural design of the stalk in the crinoid Seirocrinus supports its pseudoplanktonic lifestyle
Abstract During geological history, some crinoids convergently deviated from a benthic lifestyle. Seirocrinus is an iconic example of a crinoid that adapted to a pseudoplanktonic mode of life by living attached to drift logs. While significant effort has been devoted to exploring its functional morphology and palaeoecology, little attention has been given to the microstructural design of its stalk. Here, we describe the stereom microstructure and internal architecture of the Seirocrinus stalk. We demonstrate that its stereom organization closely resembles that observed in extant benthic crinoids (isocrinids): coarse, irregular labyrinthic-like stereom is found in the interpetaloid zones, while the aligned, galleried stereom is extensively developed in the petaloid zones. We show that this galleried stereom displays a distinct Voronoi-like geometrical pattern, enabling strength-to-weight optimization and minimization of calcification costs. In contrast to the stalks of extant isocrinids, however, the seirocrinid stalk exhibits certain skeletal adaptations that reduce the crinoid’s weight, such as large intercolumnar cavities. Consequently, the overall weight of these pseudoplanktonic crinoids might have been lower than previously thought, and thus they may not have significantly contributed to the sinking of the raft system, which would have allowed for multi-generational colonization of the log. These results support the hypothesis that the life of the Seirocrinus-bearing raft “colony” was more dependent on the wood structure itself and did not rely heavily on the seirocrinid “colonies” causing overloading.
Introduction of new quinolone-2-thio-acetamide-propane hydrazide-benzimidazole derivatives as new α-glucosidase and α-amylase inhibitors
Inactivation of RhoA for Hypertension Treatment Through the TRPV4–RhoA–RhoGDI1 Axis
BACKGROUND: The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges. METHODS: Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models, Trpv4 -/- and Arhgdia f/f Myh11-CRE ERT2 (smooth muscle–specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)–RhoA–RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension. RESULTS: AH001 (( R )-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4–RhoA–RhoGDI1 axis to effectively sequester inactive RhoA–GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4 AH001 –RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4–RhoA binding and facilitating RhoGDI1–RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure and prevented vascular remodeling in Ang II–induced hypertensive mice and spontaneously hypertensive rats. However, these antihypertensive effects were weakened in Trpv4 -/- and Arhgdia f/f Myh11-CRE ERT2 mice. Additionally, AH001 effectively inhibited VSMC contraction via the RhoA/ROCK (Rho-associated protein kinase)/MYPT1 (myosin phosphatase target subunit 1)/MLC (myosin light chain 2) signaling pathway and suppressed VSMC phenotype switching to myofibroblasts through the RhoA/ROCK/LIMK1 (LIM domain kinase)/cofilin/MRTF-A (myocardin-related transcription factor A)/SRF (serum response factor) signaling cascade. TRPV4 and RhoGDI1 knockdown attenuated AH001’s inhibition of VSMC contraction and phenotypic switching to myofibroblasts. CONCLUSIONS: This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4–RhoA–RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing innovative strategies for targeting challenging Rho GTPases.
A real-world safety signal detection study of ondansetron based on FAERS reports from 2014 to 2024
Deceptive Clues: When the Obvious Isn’t the Answer
A cross-cultural study to identify social behaviours of pedestrians in urban public spaces: evidence from Iran, Spain, Italy, and Australia
Abstract Despite the growing emphasis on social sustainability in urban design, limited research has examined how spatial configurations influence socio-behavioural patterns across culturally distinct urban squares. This study addresses this gap by investigating how the spatial configuration of public squares interacts with pedestrian social behaviours in four cities in Iran, Spain, Italy, and Australia. Guided by theories of space syntax and social behaviour frameworks, a unique mixed-method approach was adopted, combining spatial configuration analysis, behavioural mapping, and people-tracing, coupled with agent-based simulations. The findings revealed that the accessibility of urban squares is not necessarily determinative of their social vibrancy. Rather, stimulating sustained social life in these environments is governed by an intricate nexus of factors, including culturally specific behaviours, the purposeful allocation of functional amenities, and the critical amelioration of socio-economic challenges inherent to their shared public domain. Notably, this cross-cultural analysis highlights how socio-spatial dynamics differ across contexts, offering a richer lens for inclusive design. The originality of this study lies in its multi-scalar, comparative, and culture-sensitive approach to analysing public squares, advancing urban design strategies that are adaptable, equitable, and responsive to both spatial logic and cultural diversity.
To Loop or Not to Loop? Why and How Cardiac Invasive Pressure-Volume Relations Remain Important
Ferrimagnetism in ionic liquid cation intercalated $$\hbox {NiPS}_3$$
Response by Ho et al to Letter Regarding Article, “A Proteomics-Based Approach for Prediction of Different Cardiovascular Diseases and Dementia”
Antimicrobial and anti-biofilm activity of Hypericum brasiliense extract and its fractions on Staphylococcus of canine origin
Abstract The growing resistance to antimicrobials, partly due to the ability to form biofilms, poses a challenge for developing new antimicrobial agents. This study assessed the antimicrobial and antibiofilm activity of Hypericum brasiliense extract, Japonicin, and Uliginosin-B against clinical isolates of S. pseudintermedius and S. coagulans from dogs. The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) were determined. In vitro antibiofilm activity was evaluated and showed promising results in young (6 h) and mature (24 h) biofilms. S. pseudintermedius and S. coagulans were highly sensitive to all tested substances. All tested isolates exhibited low MIC and MBC values, particularly for Uliginosin-B. Japonicin demonstrated higher MIC and MBC values. The analysis of antibiofilm activity revealed inhibition of biofilm formation and even disruption of pre-formed biofilms at various concentrations, including sub-inhibitory ones. H. brasiliense and its fractions exhibited antimicrobial and antibiofilm activity, offering promising prospects for treating infections caused by biofilm-forming bacteria.
The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20-Center Retrospective Cohort Study
BACKGROUND: Fontan circulatory failure (FCF) is a chronic state in palliated single ventricle heart disease with high morbidity and mortality rates, including heart failure, multisystem end-organ disease, and need for heart transplant. Specific FCF morbidities have not been rigorously defined, limiting study of how FCF morbidities affect pre–heart transplant and post–heart transplant outcomes. We hypothesized that FCF-related morbidities affect survival from heart transplant waitlisting through 1 year after heart transplant. METHODS: This 20-center, retrospective cohort study collected demographic, medical/surgical history, waitlist, and peri- and post–heart transplant data, and a priori defined FCF-specific morbidities, in Fontan patients who were listed for heart transplant from 2008 through 2022. Univariate 2-group statistics compared surviving individuals with those who died anytime from waitlisting to 1 year after heart transplant, died on the waitlist, or underwent transplant and died within 1 year after transplant. Using covariates from both univariate analyses, multivariable logistic regression determined the primary study outcome of independent FCF risk factors for death between waitlist and 1 year after heart transplant. RESULTS: Of 409 waitlisted patients, 24 (5.9%) died on the waitlist. Of the 341 (83.4%) who underwent transplant, 27 (8.5%) did not survive to 1 year. Univariate risk factors for waitlist death included higher aortopulmonary collateral burden, >1 hospitalization in the previous year, younger age, sleep apnea, higher New York Heart Association class, nonenrollment in school or work, and single-parent home. Risk factors for 1-year post–heart transplant mortality included hypoplastic left heart syndrome diagnosis, patent fenestration, anatomic Fontan obstruction, clinical cyanosis (pulse oximetry <90%), polycythemia, portal variceal disease, mental health condition requiring treatment, and higher human leukocyte antigen class II panel reactive antibody. Of the patients not surviving from waitlisting to 1 year after heart transplant, independent risk factors for death included >1 hospitalization in the year before waitlisting (adjusted odds ratio, 2.0 [95% CI, 1.0–4.1]; P =0.05) and clinical cyanosis (adjusted odds ratio, 5.0 [95% CI, 1.8–13.4]; P =0.002). CONCLUSIONS: Patients with Fontan palliation selected for heart transplant have substantial mortality rates from waitlisting through transplant. Among FCF-specific morbidities, cyanosis is associated with worsened survival and necessitates further study. Clinical morbidity of any type requiring repeated hospital admission also should prompt consideration of heart transplant.
Retraction Note: Decoding intelligence via symmetry and asymmetry
Sit-Stand Transitions in Postmenopausal Women: Big Implications for a Small Change
Hypoxia suppressed the Siglec-5 signaling in TAMs via modulating the balance of SHP2/SYK activation in hepatocellular carcinoma
Abstract Objective To investigate the effects of Siglec-5 on hepatocellular carcinoma and the mechanism of action. The interactions and expression changes between Siglec-5 and Siglec-14 not only affect immune cell function, but may also influence tumor progression. A deeper understanding of the mechanisms regulating their balance could provide new insights and strategies for hepatocellular carcinoma treatment. Methods A cell co-culture model was established. Western blotting was used to detect protein expression in different groups. The CCK-8 assay was employed to observe the proliferation of HepG2 hepatocellular carcinoma cells, and the Transwell assay was used to examine their migration. Tumorigenic capacity of HepG2 cells detected by subcutaneous transplantation tumor assay in nude mice. Results Overexpression of Siglec-5 under hypoxic conditions resulted in increased levels of SHP2 and arginase-1 proteins and decreased levels of P-SYK, IL-1β, and TNFα proteins. Addition of SHP2 inhibitor under hypoxic conditions or Siglec-5 overexpression resulted in increased expression of P-SYK and NOX4 proteins and decreased levels of arginase-1. When Siglec-5 expression was inhibited under hypoxic conditions, the levels of P-SHP2 and arginase-1 were decreased, whereas the levels of P-SYK, IL-1β, and TNFα were increased. The expression of P-SYK, NOX4, IL-1β, and TNFα was decreased, whereas the levels of arginase-1 were increased after the use of SYK inhibitors under hypoxic conditions that inhibited Siglec-5 expression. The proliferation, migration and tumorigenicity of HepG2 cells were increased when Siglec-5 was overexpressed under hypoxic conditions, while the proliferation, migration and tumorigenicity of HepG2 cells were decreased when Siglec-5 was inhibited under hypoxic conditions. Conclusion Hypoxia suppressed the Siglec-5 signaling in TAMs via modulating the balance of SHP2/SYK activation in hepatocellular carcinoma.
Letter by Wu and Zheng Regarding Article, “A Proteomics-Based Approach for Prediction of Different Cardiovascular Diseases and Dementia”
Research on the synthesis of lithium iron phosphate using vivianite prepared from municipal sludge
Mitochondrial One-Carbon Metabolism Drives CD34-Lineage Cells to Differentiate Into T Follicular Helper Cells to Form Tertiary Lymphoid Organs in Transplant Arteriosclerosis
BACKGROUND: Allograft arteriosclerosis, a significant cause of graft failure, is linked to the formation of tertiary lymphoid organs. T follicular helper (Tfh) cells are a vital subset of helper T cells that control the formation of the germinal center in tertiary lymphoid organs. Thus, understanding the origins and regulatory mechanisms of Tfh cells in allograft arteriosclerosis is essential for developing targeted therapies. METHODS: We used a lineage-tracing strategy to track Tfh cell fate in mouse models. Single-cell RNA sequencing, flow cytometry, and immunofluorescence staining were employed to analyze cell populations in remodeled arteries 2 and 4 weeks after transplantation. Additionally, we used VEGFR-3 inhibitors and lymph node dissection to suppress lymphatic vessel formation. Metabolic signatures and flux in different cell types were investigated using ultrahigh-performance liquid chromatography and high-resolution mass spectrometry–based metabolomics. CD4 + T cell–specific MTHFD2 knockout mice were used to corroborate our hypothesis about the role of mitochondrial one-carbon metabolism in Tfh cell differentiation. Mechanisms discovered in vivo were also tested ex vivo. RESULTS: CD34-lineage cells were found to be the major source of cells differentiating into T cell populations in allograft arteries. CD34-lineage cells mainly originated from the thymus, with drainage through lymphatic vessels, and differentiated into effective T cells around grafting arteries. Using CD34 lineage-tracing mice and single-cell RNA sequencing, we identified a Tfh cell population derived from CD34-lineage CD4 + T cells. Untargeted and targeted metabolomics revealed distinct upregulation of one-carbon metabolism during CD4 + T-to-Tfh cell differentiation. Supplementation of amino acids essential for one-carbon metabolism, such as serine, methionine or glycine, facilitated differentiation from CD4 + T to Tfh cells. Using deuterium-labeled serine, we found that the mitochondrial one-carbon pathway is predominant. Inhibition of the mitochondrial one-carbon metabolic enzyme MTHFD2 by administration of DS18561882 or generating CD4 + T cell–specific MTHFD2 knockout mice, significantly inhibited the numbers of Tfh cells and tertiary lymphoid organ formation as well as vascular remodeling. CONCLUSIONS: This study provides insights into the critical role of mitochondrial one-carbon metabolism and MTHFD2 in governing the differentiation of CD34-lineage cells into Tfh cells, which contributes to tertiary lymphoid organ formation in transplant vasculopathy, offering potential therapeutic targets to enhance transplant outcomes.
Seasonal use of American beaver lodge areas by gray wolves in Isle Royale National Park
Impacts of Reducing Sitting Time or Increasing Sit-to-Stand Transitions on Blood Pressure and Glucose Regulation in Postmenopausal Women: Three-Arm Randomized Controlled Trial
BACKGROUND: Public health and clinical guidelines identify the importance of sedentary behaviors for cardiovascular diseases, particularly among postmenopausal women. The goal of this trial was to compare the behavioral and physiological impacts of 2 distinct approaches to changing sedentary behaviors. METHODS: Overweight or obese sedentary postmenopausal women (N=407) were randomly assigned to 1 of 3 study conditions for 3 months: (1) healthy living (control), (2) reduce sitting time (sit less), and (3) increase sit-to-stand transitions (STSTs; sit-to-stand). Each study arm received 7 individual health coach sessions across 12 weeks. At baseline and 3 months, participants had fasting blood drawn, had blood pressure measured, and wore thigh (activPAL) and hip (ActiGraph) accelerometers for 7 days. Linear mixed models evaluated each intervention arm compared with the control (healthy living) arm. RESULTS: A total of 388 women (95%) completed the 3-month trial. The sit less arm reduced total sitting time by 58 minutes per day more than the healthy living arm (95% CI, –82.9 to –33.6; P <0.001) but did not change STSTs (–1 STST/day [95% CI, –9.4 to 6.5]; P =0.72). Conversely, the sit-to-stand arm significantly increased STST by 26 STST per day more than the healthy living arm (95% CI, 17.71 to 33.64; P <0.001) but did not differ in change to sitting time (–10 min/day [95% CI, –34.6 to 14.9]; P =0.44). The sit-to-stand arm had significant decreases in diastolic blood pressure compared with the healthy living arm (–2.24 mm Hg [95% CI, –4.08 to –0.40]; P =0.02) and similar decreases in systolic blood pressure compared with the healthy living arm (–3.33 mm Hg [95% CI, –6.32 to –0.33]; P =0.03), although it did not reach the a priori significance threshold of P <0.025. There were no significant intervention effects on blood pressure for the sit less arm and no intervention effects for the glucoregulatory outcomes for either arm. CONCLUSIONS: This trial demonstrated the feasibility of changing sedentary behaviors as well as the distinct nature of sitting time and STST. Increasing STST improved blood pressure in overweight and obese postmenopausal women within 3 months. Focusing on increasing STST may be an achievable behavioral target to reduce cardiovascular disease risk in postmenopausal women. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03473145.