Explore the vast range of titles available.

Deoxyribonucleic acid (DNA) has been widely used to construct homogeneous structures with increasing complexity for biological and biomedical applications due to their powerful functionalities. Especially, dynamic DNA assemblies (DDAs) have demonstrated the ability to simulate molecular motions and fluctuations in bionic systems. DDAs, including DNA robots, DNA probes, DNA nanochannels, DNA templates, etc., can perform structural transformations or predictable behaviors in response to corresponding stimuli and show potential in the fields of single molecule sensing, drug delivery, molecular assembly, etc. A wave of exploration of the principles in designing and usage of DDAs has occurred, however, knowledge on these concepts is still limited. Although some previous reviews have been reported, systematic and detailed reviews are rare. To achieve a better understanding of the mechanisms in DDAs, herein, the recent progress on the fundamental principles regarding DDAs and their applications are summarized. The relative assembly principles and computer‐aided software for their designing are introduced. The advantages and disadvantages of each software are discussed. The motional mechanisms of the DDAs are classified into exogenous and endogenous stimuli‐triggered responses. The special dynamic behaviors of DDAs in biomedical applications are also summarized. Moreover, the current challenges and future directions of DDAs are proposed. Recently, dynamic deoxyribonucleic acid (DNA) assemblies have emerged as promising platforms for diagnostics and therapeutics in biomedical applications. This work provides an overview of dynamic DNA assemblies, detailing their designing software, motional mechanisms, and dynamic behaviors in biomedical applications. The mechanisms are classified into exogenous and endogenous stimuli‐triggered responses. This work also summarizes this area of research and proposes future directions.

Background Though tamoxifen achieves success in treating estrogen receptor α (ERα)-positive breast cancer, the followed development of tamoxifen resistance is a common challenge in clinic. Signals downstream of prolactin receptor (PRLR) could synergize with ERα in breast cancer progression. However, the potential effect of targeting PRL-PRLR axis combined with tamoxifen has not been thoroughly investigated. Methods High-throughput RNA-seq data obtained from TCGA, Metabric and GEO datasets were analyzed to explore PRLR expression in breast cancer cell and the association of PRLR expression with tamoxifen treatment. Exogenous or PRL overexpression cell models were employed to investigate the role of activated PRLR pathway in mediating tamoxifen insensitivity. Immunotoxin targeting PRLR (N8-PE24) was constructed with splicing-intein technique, and the efficacy of N8-PE24 against breast cancer was evaluated using in vitro and in vivo methods, including analysis of cells growth or apoptosis, 3D spheroids culture, and animal xenografts. Results PRLR pathway activated by PRL could significantly decrease sensitivity of ERα-positive breast cancer cells to tamoxifen. Tamoxifen treatment upregulated transcription of PRLR and could induce significant accumulation of PRLR protein in breast cancer cells by alkalizing lysosomes. Meanwhile, tamoxifen-resistant MCF7 achieved by long-term tamoxifen pressure exhibited both upregulated transcription and protein level of PRLR. Immunotoxin N8-PE24 enhanced sensitivity of breast cancer cells to tamoxifen both in vitro and in vivo. In xenograft models, N8-PE24 significantly enhanced the efficacy of tamoxifen and paclitaxel when treating PRLR-positive triple-negative breast cancer. Conclusions PRL-PRLR axis potentially associates with tamoxifen insensitivity in ERα-positive breast cancer cells. N8-PE24 could inhibit cell growth of the breast cancers and promote drug sensitivity of PRLR-positive breast cancer cells to tamoxifen and paclitaxel. Our study provides a new perspective for targeting PRLR to treat breast cancer. Highlights Tamoxifen up-regulates PRLR protein level in breast cancer cells and activation of PRLR pathway by PRL could decrease drug-sensitivity of breast cancer cells to tamoxifen. The immunotoxin targeting PRLR could reverse drug-sensitivity to tamoxifen in tamoxifen-resistant breast cancer in vitro and in vivo. The immunotoxin targeting PRLR significantly improve the efficacy of chemotherapy in PRLR-positive TNBC and xenograft models.

Proteolysis Targeting Chimeras (PROTACs) are bifunctional compounds that have been extensively studied for their role in targeted protein degradation (TPD). The capacity to degrade validated or undruggable targets provides PROTACs with significant potency in cancer therapy. However, the clinical application of PROTACs is limited by their poor potency and unfavorable pharmacokinetic properties. In this study, a novel degrader-antibody conjugate (DAC) was developed by conjugating the BRD4-degrading PROTAC with the ROR1 (receptor tyrosine kinase-like orphan receptor 1) antibody. The affinity, internalization efficacy, degradation, and cytotoxic activity of the ROR1 DAC were assessed. The pharmacokinetics, antitumor activity, and acute toxicity of ROR1 DAC were evaluated in mouse models. RNA sequencing (RNA-seq) and immunohistochemistry were performed to analyze the therapeutic efficacy mediated by the combination of ROR1 DAC and anti-mouse programmed cell death protein 1 (αmPD1) mAb. The ROR1 DAC exhibited strong degradation activity and cytotoxicity following antigen binding and internalization. Compared to unconjugated PROTAC, the ROR1 DAC demonstrated improved pharmacokinetics and potent antitumor efficacy in PC3 and MDA-MB-231 xenograft mouse models. Furthermore, enhanced antitumor activity and immune cell infiltration within solid tumors were observed when combined with αmPD-1 mAb in C57BL/6J mice. RNA sequencing revealed that the enhanced immune response associated with the combination treatment is related to tumor microenvironment modulation, including the upregulation of Th1-biased cytokines. Moreover, the ROR1 DAC exhibited a favorable safety profile in an acute toxicity study. These results indicate that the degrader-antibody conjugate is a promising candidate for tumor-specific degradation and effective cancer therapy.

Abstract Background Graves’ disease (GD) is a typical organ-specific autoimmune disease. Intestinal flora plays a pivotal role in immune homeostasis and autoimmune disease development. However, the association and mechanism between intestinal flora and GD remain elusive. Objective To investigate the association and mechanism between intestinal flora and GD. Methods We recruited 58 initially untreated GD patients and 63 healthy individuals in the study. The composition and metabolic characteristics of the intestinal flora in GD patients and the causal relationship between intestinal flora and GD pathogenesis were assessed using 16S rRNA gene sequencing, targeted/untargeted metabolomics, and fecal microbiota transplantation. Results The composition, metabolism, and inter-relationships of the intestinal flora were also changed, particularly the significantly reduced short-chain fatty acid (SCFA)-producing bacteria and SCFAs. The YCH46 strain of Bacteroides fragilis could produce propionic acid and increase Treg cell numbers while decreasing Th17 cell numbers. Transplanting the intestinal flora of GD patients significantly increased GD incidence in the GD mouse model. Additionally, there were 3 intestinal bacteria genera (Bacteroides, Alistipes, Prevotella) could distinguish GD patients from healthy individuals with 85% accuracy. Conclusions Gut dysbiosis contributes to a Treg/Th17 imbalance through the pathway regulated by propionic acid and promotes the occurrence of GD, together with other pathogenic factors. Bacteroides, Alistipes, and Prevotella have great potential to serve as adjunct markers for GD diagnosis. This study provided valuable clues for improving immune dysfunction of GD patients using B. fragilis and illuminated the prospects of microecological therapy for GD as an adjunct treatment.

Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment. ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.

The Earth’s interior and surficial systems underwent dramatic changes during the Paleoproterozoic, but the interaction between them remains poorly understood. Rocks deposited in orogenic foreland basins retain a record of the near surface to deep crustal processes that operate during subduction to collision and provide information on the interaction between plate tectonics and surface responses through time. Here, we document the depositional-to-deformational life cycle of a Paleoproterozoic foreland succession from the North China Craton. The succession was deposited in a foreland basin following ca. 2.50–2.47 Ga Altaid-style arc–microcontinent collision, and then converted to a fold-and-thrust belt at ca. 2.0–1.8 Ga due to Himalayan-style continent–continent collision. These two periods correspond to the assembly of supercratons in the late Archean and of the Paleoproterozoic supercontinent Columbia, respectively, which suggests that similar basins may have been common at the periphery of other cratons. The multiple stages of orogenesis and accompanying tectonic denudation and silicate weathering, as recorded by orogenic foreland basins, likely contributed to substantial changes in the hydrosphere, atmosphere, and biosphere known to have occurred during the Paleoproterozoic. Two different styles of orogenesis during the Neoarchean and Paleoproterozoic are recorded in the depositional-to-deformational evolution of the orogenic foreland of the North China Craton, and would have differently changed the surface environment.

Response KCI Citation Count: 0

Key Points Angiotensin-converting enzyme (ACE) 2 and its product angiotensin 1–7 are thought to have effects that counteract the adverse actions of other, better-known renin–angiotensin system (RAS) components Numerous experimental studies have suggested that ACE2 and angiotensin 1–7 have notable protective effects in the heart and blood vessels ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the functional importance and signalling mechanisms of angiotensin-1–7-induced actions remain unclear New pharmacological interventions targeting ACE2 are expected to be useful in clinical treatment of cardiovascular disease, especially those associated with overactivation of the conventional RAS More studies, especially randomized controlled clinical trials, are needed to clearly delineate the benefits of therapies targeting angiotensin 1–7 actions Angiotensin-converting enzyme 2, and its product angiotensin 1–7, are thought to have counteracting effects against the adverse actions of the better-known members of the renin–angiotensin system and might, therefore, be useful therapeutic targets in patients with cardiovascular disease. Professor Jiang and colleagues review the evidence for the potential roles of these proteins in various cardiovascular conditions, including hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes. The renin–angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1–7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1–7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1–7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1–7 have not been conclusively determined. The ACE2–angiotensin 1–7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS.

Background: Metabolic dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), in which the abnormalities in brown adipose tissue (BAT) play important roles. However, the cellular composition and function of BAT as well as its pathological significance in diabetes remain incompletely understood. Our objective is to delineate the single-cell landscape of BAT-derived stromal vascular fraction (SVF) and their characteristic alterations in T2DM rats.Methods: T2DM was induced in rats by intraperitoneal injection of low-dose streptozotocin and high-fat diet feeding. Single-cell mRNA sequencing was then performed on BAT samples and compared to normal rats to characterize changes in T2DM rats. Subsequently, the importance of key cell subsets in T2DM was elucidated using various functional studies.Results: Almost all cell types in the BAT-derived SVF of T2DM rats exhibited enhanced inflammatory responses, increased angiogenesis, and disordered glucose and lipid metabolism. The multidirectional differentiation potential of adipose tissue-derived stem cells was also reduced. Moreover, macrophages played a pivotal role in intercellular crosstalk of BAT-derived SVF. A novel Rarres2+macrophage subset promoted the differentiation and metabolic function of brown adipocytes via adipose-immune crosstalk.Conclusion: BAT SVF exhibited strong heterogeneity in cellular composition and function and contributed to T2DM as a significant inflammation source, in which a novel macrophage subset was identified that can promote brown adipocyte function.