Gestational diabetes mellitus is associated with greater incidence of dementia during long-term post-partum follow-up.

BACKGROUND: The impact of gestational diabetes mellitus (GDM) on incident dementia is unknown. Our aim was to evaluate the relationship between GDM and all-cause dementia and the mediating effects of chronic diseases on this relationship. METHODS: This prospective cohort study included women from the UK Biobank who were grouped based on GDM history. Multivariate Cox proportional hazard models were used to explore the associations between GDM and dementia. We further analysed the mediating effects of chronic diseases on this relationship and the interactions of covariates. RESULTS: A total of 1292 women with and 204,171 women without a history of GDM were included. During a median follow-up period of 45 years after first birth, 2921 women were diagnosed with dementia. Women with a GDM history had a 67% increased risk of incident dementia (hazard ratio 1.67, 95% confidence interval: 1.03-2.69) compared with those without a GDM history. According to mediation analyses, type 2 diabetes, coronary heart disease, chronic kidney disease and comorbidities (diagnosed with any two of the three diseases) explained 34.5%, 8.4%, 5.2% and 18.8% of the mediating effect on the relationship. Subgroup analyses revealed that physical activity modified the association between GDM history and dementia (p for interaction = 0.030). Among physically inactive women, GDM was significantly associated with incident dementia; however, this association was not observed among physically active women. CONCLUSIONS: A history of GDM was associated with a greater risk of incident dementia. Type 2 diabetes partially mediated this relationship. Strategies for dementia prevention might be considered for women with a history of GDM.

CDHu40: a novel marker gene set of neuroendocrine prostate cancer (NEPC).

Prostate cancer (PCa) is the most prevalent cancer affecting American men. Castration-resistant prostate cancer (CRPC) can emerge during hormone therapy for PCa, manifesting with elevated serum prostate-specific antigen (PSA) levels, continued disease progression, and/or metastasis to the new sites, resulting in a poor prognosis. A subset of CRPC patients shows a neuroendocrine (NE) phenotype, signifying reduced or no reliance on androgen receptor (AR) signaling and a particularly unfavorable prognosis. In this study, we incorporated computational approaches based on both gene expression profiles and protein-protein interaction (PPI) networks. We identified 500 potential marker genes, which are significantly enriched in cell cycle and neuronal processes. The top 40 candidates, collectively named as CDHu40, demonstrated superior performance in distinguishing NE prostate cancer (NEPC) and non-NEPC samples based on gene expression profiles compared to other published marker sets. Notably, some novel marker genes in CDHu40, absent in the other marker sets, have been reported to be associated with NEPC in the literature, such as DDC, FOLH1, BEX1, MAST1, and CACNA1A. Importantly, elevated CDHu40 scores derived from our predictive model showed a robust correlation with unfavorable survival outcomes in patients, indicating the potential of the CDHu40 score as a promising indicator for predicting the survival prognosis of those patients with the NE phenotype. Motif enrichment analysis on the top candidates suggests that REST and E2F6 may serve as key regulators in the NEPC progression. Significance: our study integrates gene expression variances in multiple NEPC studies and protein-protein interaction network to pinpoint a specific set of NEPC maker genes namely CDHu40. These genes and scores based on their gene expression levels effectively distinguish NEPC samples and underscore the clinical prognostic significance and potential mechanism.

Profiling of immune infiltration landscape of ruptured intracranial aneurysm.

BACKGROUND: Previous research has indicated that the rupture of intracranial aneurysm (IA) is a significant contributor to mortality from stroke. The objective of this present study was to examine the infiltration patterns in ruptured intracranial aneurysm (RIA), with the aim of generating insights that could inform the development of effective immunotherapeutic approaches. METHODS: To achieve this, we obtained Gene Expression Omnibus datasets pertaining to ruptured aneurysms, encompassing a total of 19 unruptured intracranial aneurysms (UIA) and 27 RIA. Subsequently, we conducted differential gene analysis and immune cell analysis specifically for the RIA. RESULTS: According to the conducted studies, the analysis has identified 10 hub genes within key modules. Through the utilization of Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology terms analyses, it has been established that genes exhibiting differential expression are associated with immune cell infiltration in the aneurysm wall. Furthermore, the implementation of the CIBERSORT algorithm has revealed that there are 22 distinct immune cells between RIA and tissues of UIA. IA samples contained a higher proportion of macrophages M1, mast cells resting, and CD4 naive T cells, while macrophages M0 and neutrophils were relatively lower in RIA compared with those in UIA. CONCLUSION: The current study initially identified highly conservative hub genes and immune cell infiltration patterns in IA. Data presented in the current study improved understanding of immune genes that drive IA which can be exploited in development of effective immunotherapies.

Molecular editing of NSC-666719 enabling discovery of benzodithiazinedioxide-guanidines as anticancer agents.

DNA polymerase ß (Polß) is crucial for the base excision repair (BER) pathway of DNA damage repair and is an attractive target for suppressing tumorigenesis as well as chemotherapeutic intervention of cancer. In this study, a unique strategy of scaffold-hopping-based molecular editing of a bioactive agent NSC-666719 was investigated, which led to the development of new molecular motifs with Polß inhibitory activity. NSC compound and its analogs (two series) were prepared, focusing on pharmacophore-based molecular diversity. Most compounds showed higher activities than the parent NSC-666719 and exhibited effects on apoptosis. The inhibitory activity of Polß was evaluated in both in vitro reconstituted and in vivo intact cell systems. Compound 10e demonstrated significant Polß interaction and inhibition characteristics, including direct, non-covalent, reversible, and comparable binding affinity. The investigated approach is useful, and the discovered novel analogs have a high potential for developing as anticancer therapeutics.

Association between Age at Diagnosis of Hyperlipidemia and Subsequent Risk of Dementia.

OBJECTIVES: The relationship between age at diagnosis of hyperlipidemia and dementia remains unclear. We examined whether younger age at diagnosis of hyperlipidemia is associated with higher risk of subsequent dementia. DESIGN: A longitudinal population-based study with a median follow-up of 12.8 years. SETTING AND PARTICIPANTS: We analyzed data on a sample of 489,642 participants in the United Kingdom. METHODS: This study was based on the UK Biobank. Information on hyperlipidemia and dementia diagnoses was collected at baseline (2006-2010) and follow-up [median = 12.8 years, interquartile range (IQR): 12.1-13.6 years]. Propensity score matching method and Cox proportional hazards models were used to assess the association between age at diagnosis of hyperlipidemia and dementia. RESULTS: Among 489,642 participants (mean age: 56.9 ± 8.1 years; female: 54.7%), 114,112 (23.3%) were diagnosed with hyperlipidemia. Younger age at diagnosis of hyperlipidemia (per 10-year decrease) was significantly associated with higher risks of all-cause dementia [hazard ratio (HR), 1.12; 95% CI, 1.07-1.18; P < .001], Alzheimer's disease (AD) (HR, 1.22; 95% CI, 1.14-1.31; P < .001), and vascular dementia (VD) (HR, 1.16; 95% CI, 1.05-1.27; P < .001). After propensity score matching, patients with hyperlipidemia diagnosed before 50 years had the highest HR for all-cause dementia (HR, 1.46; 95% CI, 1.15-1.86; P = .002), followed by patients diagnosed between 50 and 69 years (HR, 1.21; 95% CI, 1.12-1.31; P < .001) and then patients diagnosed aged 70 years and older (HR, 0.94; 95% CI, 0.84-1.06; P = .302). Similar results were observed for AD and VD. CONCLUSIONS AND IMPLICATIONS: A dose-response relationship between age at hyperlipidemia diagnosis and risk of dementia was found in the longitudinal cohort study, with younger age at diagnosis of hyperlipidemia being associated with higher subsequent risk.

Hepatocellular carcinoma cells downregulate NADH:Ubiquinone Oxidoreductase Subunit B3 to maintain reactive oxygen species homeostasis.

BACKGROUND: HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis. METHODS: NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers. RESULTS: HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells' growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase. CONCLUSIONS: Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.

RGBT Tracking via Challenge-Based Appearance Disentanglement and Interaction.

RGB and thermal source data suffer from both shared and specific challenges, and how to explore and exploit them plays a critical role in representing the target appearance in RGBT tracking. In this paper, we propose a novel approach, which performs target appearance representation disentanglement and interaction via both modality-shared and modality-specific challenge attributes, for robust RGBT tracking. In particular, we disentangle the target appearance representations via five challenge-based branches with different structures according to their properties, including three parameter-shared branches to model modality-shared challenges and two parameter-independent branches to model modality-specific challenges. Considering the complementary advantages between modality-specific cues, we propose a guidance interaction module to transfer discriminative features from one modality to another one to enhance the discriminative ability of weak modality. Moreover, we design an aggregation interaction module to combine all challenge-based target representations, which could form more discriminative target representations and fit the challenge-agnostic tracking process. These challenge-based branches are able to model the target appearance under certain challenges so that the target representations can be learned by a few parameters even in the situation of insufficient training data. In addition, to relieve labor costs and avoid label ambiguity, we design a generation strategy to generate training data with different challenge attributes. Comprehensive experiments demonstrate the superiority of the proposed tracker against the state-of-the-art methods on four benchmark datasets.

Comprehensive Nomograms Using Routine Biomarkers Beyond Eosinophil Levels: Enhancing Predictability of Corticosteroid Treatment Outcomes in AECOPD.

Purpose: Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) exhibit heterogeneous responses to corticosteroid treatment. We aimed to determine whether combining eosinophil levels with other routine clinical indicators can enhance the predictability of corticosteroid treatment outcomes and to come up with a scoring system. Patients and Methods: Consecutive patients admitted with AECOPD receiving corticosteroid treatment between July 2013 and March 2022 at Beijing Chao-Yang Hospital were retrospectively analyzed. Data on patients' demographics, smoking status, hospitalization for AECOPD in the previous year, comorbidities, blood laboratory tests, in-hospital treatment and clinical outcomes were collected. Least absolute shrinkage and selection operator (LASSO) regression and backward logistic regression were used for predictor selection, and predictive nomograms were developed. The discrimination and calibration of the nomograms were assessed using the area under the receiver operating curve (AUC) and calibration plots. Internal validation was performed using the 500-bootstrap method, and clinical utility was evaluated using decision curve analysis (DCA). Results: Among the 3254 patients included, 804 (24.7%) had treatment failure. A nomogram of eosinophils, platelets, C-reactive protein (CRP), low density lipoprotein cholesterol, prognostic nutritional index (PNI), hospitalization for AECOPD in the previous year, ischemic heart diseases and chronic hepatic disease was developed to predict treatment failure for patients with a smoking history. For patients without a smoking history, a nomogram of CRP, PNI, ischemic heart diseases and chronic hepatic disease was developed. Although the AUCs of these two nomograms were only 0.644 and 0.647 respectively, they were significantly superior to predictions based solely on blood eosinophil levels. Conclusion: We developed easy-to-use comprehensive nomograms utilizing readily available clinical biomarkers related to inflammation, nutrition and immunity, offering modestly enhanced predictive value for treatment outcomes in corticosteroid-treated patients with AECOPD. Further investigations into novel biomarkers and additional patient data are imperative to optimize the predictive performance.

Polycationic Open-Shell Cyclophanes: Synthesis of Electron-Rich Chiral Macrocycles, and Redox-Dependent Electronic States.

π-Conjugated chiral nanorings with intriguing electronic structures and chiroptical properties have attracted considerable interests in synthetic chemistry and materials science. We present the design principles to access new chiral macrocycles (1 and 2) that are essentially built on the key components of main-group electron-donating carbazolyl moieties or the π-expanded aza[7]helicenes. Both macrocycles show the unique molecular conformations with a (quasi) figure-of-eight topology as a result of the conjugation patterns of 2,2',7,7'-spirobifluorenyl in 1 and triarylamine-coupled aza[7]helicene-based building blocks in 2. This electronic nature of redox-active, carbazole-rich backbones enabled these macrocycles to be readily oxidized chemically and electrochemically, leading to the sequential production of a series of positively charged polycationic open-shell cyclophanes. Their redox-dependent electronic states of the resulting multispin polyradicals have been characterized by VT-ESR, UV-vis-NIR absorption and spectroelectrochemical measurements. The singlet (ΔES-T = -1.29 kcal mol-1) and a nearly degenerate singlet-triplet ground state (ΔES-T(calcd) = -0.15 kcal mol-1 and ΔES-T(exp) = 0.01 kcal mol-1) were proved for diradical dications 12+2• and 22+2•, respectively. Our work provides an experimental proof for the construction of electron-donating new chiral nanorings, and more importantly for highly charged polyradicals with potential applications in chirospintronics and organic conductors.

Effect of a Salt Substitute on Incidence of Hypertension and Hypotension Among Normotensive Adults.

BACKGROUND: Reports on the effects of salt substitution among individuals with normal blood pressure are scarce and controversial. OBJECTIVES: This study sought to assess the effects of a salt substitute (62.5% NaCl, 25% KCl, and 12.5% flavorings) on incidence of hypertension and hypotension among older adults with normal blood pressure. METHOD: A post hoc analysis was conducted among older adults with normal blood pressure participating in DECIDE-Salt, a large, multicenter, cluster-randomized trial in 48 elderly care facilities for 2 years. We used the frailty survival model to compare risk of incident hypertension and the generalized linear mixed model to compare risk of hypotension episodes. RESULTS: Compared with usual salt group (n = 298), the salt substitute group (n = 313) had a lower hypertension incidence (11.7 vs 24.3 per 100 person-years; adjusted HR: 0.60; 95% CI: 0.39 to 0.92; P = 0.02) but did not increase incidence of hypotension episodes (9.0 vs 9.7 per 100 person-years; P = 0.76). Mean systolic/diastolic blood pressure did not increase from the baseline to the end of intervention in the salt substitute group (mean changes: -0.3 ± 11.9/0.2 ± 7.1 mm Hg) but increased in the usual salt group (7.0 ± 14.3/2.1 ± 7.5 mm Hg), resulting in a net reduction of -8.0 mm Hg (95% CI: -12.4 to -3.7 mm Hg) in systolic and -2.0 mm Hg (95% CI: -4.1 to 0.1 mm Hg) in diastolic blood pressure between intervention groups. CONCLUSIONS: In Chinese older adults with normal blood pressure, replacing usual salt with a salt substitute may reduce the incidence of hypertension without increasing hypotension episodes. This suggests a desirable strategy for population-wide prevention and control of hypertension and cardiovascular disease, deserving further consideration in future studies. (Diet Exercise and Cardiovascular Health [DECIDE]-Salt Reduction Strategies for the Elderly in Nursing Homes in China [DECIDE-Salt]; NCT03290716).

Switchable Adhesive Based on Shape Memory Polymer with Micropillars of Different Heights for Laser-Driven Noncontact Transfer Printing.

Switchable adhesive is essential to develop transfer printing, which is an advanced heterogeneous material integration technique for developing electronic systems. Designing a switchable adhesive with strong adhesion strength that can also be easily eliminated to enable noncontact transfer printing still remains a challenge. Here, we report a simple yet robust design of switchable adhesive based on a thermally responsive shape memory polymer with micropillars of different heights. The adhesive takes advantage of the shape-fixing property of shape memory polymer to provide strong adhesion for a reliable pick-up and the various levels of shape recovery of micropillars under laser heating to eliminate the adhesion for robust printing in a noncontact way. Systematic experimental and numerical studies reveal the adhesion switch mechanism and provide insights into the design of switchable adhesives. This switchable adhesive design provides a good solution to develop laser-driven noncontact transfer printing with the capability of eliminating the influence of receivers on the performance of transfer printing. Demonstrations of transfer printing of silicon wafers, microscale Si platelets, and micro light emitting diode (µ-LED) chips onto various challenging nonadhesive receivers (e.g., sandpaper, stainless steel bead, leaf, or glass) to form desired two-dimensional or three-dimensional layouts illustrate its great potential in deterministic assembly.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

Differential perovskite hemispherical photodetector for intelligent imaging and location tracking.

Advanced photodetectors with intelligent functions are expected to take an important role in future technology. However, completing complex detection tasks within a limited number of pixels is still challenging. Here, we report a differential perovskite hemispherical photodetector serving as a smart locator for intelligent imaging and location tracking. The high external quantum efficiency (~1000%) and low noise (10-13 A Hz-0.5) of perovskite hemispherical photodetector enable stable and large variations in signal response. Analysing the differential light response of only 8 pixels with the computer algorithm can realize the capability of colorful imaging and a computational spectral resolution of 4.7 nm in a low-cost and lensless device geometry. Through machine learning to mimic the differential current signal under different applied biases, one more dimensional detection information can be recorded, for dynamically tracking the running trajectory of an object in a three-dimensional space or two-dimensional plane with a color classification function.

Real-world effectiveness of nirmatrelvir-ritonavir versus azvudine in hospitalized patients with COVID-19 during the omicron wave in Beijing: a multicenter retrospective cohort study.

BACKGROUND AND AIM: Two oral antivirals (Nirmatrelvir- ritonavir and Azvudine) are widely used in China practice during the Omicron wave of the pandemic. However, little evidence regarding the real-world effectiveness of these two oral antivirals in in-hospital patients. We aimed to evaluate the clinical effectiveness of nirmatrelvir-ritonavir versus azvudine among adult hospitalized patients with COVID-19. METHODS: This retrospective cohort study used data from three Chinese PLA General Hospital medical centres. Hospitalized patients with COVID-19 treated with azvudine or nirmatrelvir-ritonavir from Dec 10, 2022, to February 20, 2023, and did not require invasive ventilation support on admission were eligible for inclusion. RESULTS: After exclusions and propensity-score matching, the final analysis included 486 azvudine recipients and 486 nirmatrelvir-ritonavir recipients. By 28 days of initiation of the antivirus treatment, the crude incidence rate of all-cause death was similar in both types of antivirus treatment (nirmatrelvir-ritonavir group 2.8 events 1000 person-days [95% CI, 2.1-3.6] vs azvudine group 3.4 events/1000 person-days [95% CI, 2.6-4.3], P = 0.38). Landmark analysis showed that all-cause death was lower in the nirmatrelvir-ritonavir (3.5%) group than the azvudine (6.8%, P = 0.029) within the initial 10-day admission period, while no significant difference was observed for results between 10 and 28 days follow-up. There was no significant difference between the nirmatrelvir-ritonavir group and the azvudine group in cumulative incidence of the composite disease progression event (8.6% with nirmatrelvir-ritonavir vs. 10.1% with azvudine, HR, 1.22; 95% CI 0.80-1.86, P = 0.43). CONCLUSION: Among patients hospitalized with COVID-19 during the omicron wave in Beijing, similar in-hospital clinical outcomes on 28 days were observed between patients receiving nirmatrelvir-ritonavir and azvudine. However, it is worth noticing that nirmatrelvir-ritonavir appears to hold an advantage over azvudine in reducing early mortality. Further randomized controlled trials are needed to verify the efficacy of those two antivirus medications especially in early treatment.

Morphological Profiling for Drug Discovery in the Era of Deep Learning.

Morphological profiling is a valuable tool in phenotypic drug discovery. The advent of high-throughput automated imaging has enabled the capturing of a wide range of morphological features of cells or organisms in response to perturbations at the single-cell resolution. Concurrently, significant advances in machine learning and deep learning, especially in computer vision, have led to substantial improvements in analyzing large-scale high-content images at high-throughput. These efforts have facilitated understanding of compound mechanism-of-action (MOA), drug repurposing, characterization of cell morphodynamics under perturbation, and ultimately contributing to the development of novel therapeutics. In this review, we provide a comprehensive overview of the recent advances in the field of morphological profiling. We summarize the image profiling analysis workflow, survey a broad spectrum of analysis strategies encompassing feature engineering- and deep learning-based approaches, and introduce publicly available benchmark datasets. We place a particular emphasis on the application of deep learning in this pipeline, covering cell segmentation, image representation learning, and multimodal learning. Additionally, we illuminate the application of morphological profiling in phenotypic drug discovery and highlight potential challenges and opportunities in this field.

Laser-driven noncontact bubble transfer printing via a hydrogel composite stamp.

Transfer printing that enables heterogeneous integration of materials into spatially organized, functional arrangements is essential for developing unconventional electronic systems. Here, we report a laser-driven noncontact bubble transfer printing via a hydrogel composite stamp, which features a circular reservoir filled with hydrogel inside a stamp body and encapsulated by a laser absorption layer and an adhesion layer. This composite structure of stamp provides a reversible thermal controlled adhesion in a rapid manner through the liquid-gas phase transition of water in the hydrogel. The ultrasoft nature of hydrogel minimizes the influence of preload on the pick-up performance, which offers a strong interfacial adhesion under a small preload for a reliable damage-free pick-up. The strong light-matter interaction at the interface induces a liquid-gas phase transition to form a bulge on the stamp surface, which eliminates the interfacial adhesion for a successful noncontact printing. Demonstrations of noncontact transfer printing of microscale Si platelets onto various challenging nonadhesive surfaces (e.g., glass, key, wrench, steel sphere, dry petal, droplet) in two-dimensional or three-dimensional layouts illustrate the unusual capabilities for deterministic assembly to develop unconventional electronic systems such as flexible inorganic electronics, curved electronics, and micro-LED display.

Synthesis of π-Conjugated Chiral Aza/Boracyclophanes with a meta and para Substitution.

We herein describe the synthesis of a new class of axially chiral aza/boracyclophanes (BDN1, BXN1, BDB1 and BXB1) using binaphthyls as chiral building blocks and the main-group (B/N) chemistry with tunable electronic effects. All macrocycles substituted with triarylamine donors or triarylborane acceptors are strongly luminescent. These macrocycles showed two distinct meta and para π-conjugation pathways, leading to the formation of quasi figure-of-eight and square-shaped conformations. Interestingly, comparison of such structural models revealed that the former type of macrocycles BXN1 and BXB1 gave higher racemization barriers relative to the other ones. The results reported here may provide a new approach to engineer the optical stability of π-conjugated chiral macrocycles by controlling π-substitution patterns. The ring constraints induced by macrocyclization were also demonstrated to contribute to the configurational persistence as compared with the open-chain analogues p-BTT and m-BTT.

Ceramides in peripheral arterial plaque lead to endothelial cell dysfunction.

Background: Peripheral arterial atheroprogression is increasingly prevalent, and is a risk factor for major limb amputations in individuals with risk factors such as diabetes. We previously demonstrated that bioactive lipids are significantly altered in arterial tissue of individuals with diabetes and advanced peripheral arterial disease. Methods: Here we evaluated whether sphingolipid ceramide 18:1/16:0 (C16) is a cellular regulator in endothelial cells and peripheral tibial arterial tissue in individuals with diabetes. Results: We observed that C16 is the single most elevated ceramide in peripheral arterial tissue from below the knee in individuals with diabetes (11% increase, P < .05). C16 content in tibial arterial tissue positively correlates with sphingomyelin (SPM) content in patients with and without diabetes (r2 = 0.5, P < .005; r2 = 0.17, P < .05; respectively). Tibial arteries of individuals with diabetes demonstrated no difference in CERS6 expression (encoding ceramide synthase 6; the predominate ceramide synthesis enzyme), but higher SMPD expression (encoding sphingomyelin phosphodiesterase that catalyzes ceramide synthesis from sphingomyelins; P < .05). SMPD4, but not SMPD2, was particularly elevated in maximally diseased (Max) tibial arterial segments (P < .05). In vitro, exogenous C16 caused endothelial cells (HUVECs) to have decreased proliferation (P < .03), increased apoptosis (P < .003), and decreased autophagy (P < .008). Selective knockdown of SMPD2 and SMPD4 decreased native production of C16 (P < .01 and P < .001, respectively), but only knockdown of SMPD4 rescued cellular proliferation (P < .005) following exogenous supplementation with C16. Conclusions: Our findings suggest that C16 is a tissue biomarker for peripheral arterial disease severity in the setting of diabetes, and can impact endothelial cell viability and function. Clinical relevance: Peripheral arterial disease and its end-stage manifestation known as chronic limb-threatening ischemia (CLTI) represent ongoing prevalent and intricate medical challenges. Individuals with diabetes have a heightened risk of developing CLTI and experiencing its complications, including wounds, ulcers, and major amputations. In the present study, we conducted a comprehensive examination of the molecular lipid composition within arterial segments from individuals with CLTI, and with and without diabetes. Our investigations unveiled a striking revelation: the sphingolipid ceramide 18:1/16:0 emerged as the predominant ceramide species that was significantly elevated in the peripheral arterial intima below the knee in patients with diabetes. Moreover, this heightened ceramide presence is associated with a marked impairment of endothelial cell function and viability. Additionally, our study revealed a concurrent elevation in the expression of sphingomyelin phosphodiesterases, enzymes responsible for catalyzing ceramide synthesis from sphingomyelins, within maximally diseased arterial segments. These findings underscore the pivotal role of ceramides and their biosynthesis enzymes in the context of CLTI, offering new insights into potential therapeutic avenues for managing this challenging disease process.

Neutrophil heterogeneity and aging: implications for COVID-19 and wound healing.

Neutrophils play a critical role in the immune response to infection and tissue injury. However, recent studies have shown that neutrophils are a heterogeneous population with distinct subtypes that differ in their functional properties. Moreover, aging can alter neutrophil function and exacerbate immune dysregulation. In this review, we discuss the concept of neutrophil heterogeneity and how it may be affected by aging. We then examine the implications of neutrophil heterogeneity and aging for COVID-19 pathogenesis and wound healing. Specifically, we summarize the evidence for neutrophil involvement in COVID-19 and the potential mechanisms underlying neutrophil recruitment and activation in this disease. We also review the literature on the role of neutrophils in the wound healing process and how aging and neutrophil heterogeneity may impact wound healing outcomes. Finally, we discuss the potential for neutrophil-targeted therapies to improve clinical outcomes in COVID-19 and wound healing.