Dual-Locked Fluorescent Probes Activated by Aminopeptidase N and the Tumor Redox Environment for High-Precision Imaging of Tumor Boundaries.

Clear delineation of tumor margins is essential for accurate resection and decreased recurrence rate in the clinic. Fluorescence imaging is emerging as a promising alternative to traditional visual inspection by surgeons for intraoperative imaging. However, traditional probes lack accuracy in tumor diagnosis, making it difficult to depict tumor boundaries accurately. Herein, we proposed an offensive and defensive integration (ODI) strategy based on the "attack systems (invasive peptidase) and defense systems (reductive microenvironment)" of multi-dimensional tumor characteristics to design activatable fluorescent probes for imaging tumor boundaries precisely. Screened out from a series of ODI strategy-based probes, ANQ performed better than traditional probes based on tumor unilateral correlation by distinguishing between tumor cells and normal cells and minimizing false-positive signals from living metabolic organs. To further improve the signal-to-background ratio in vivo, derivatized FANQ, was prepared and successfully applied to distinguish orthotopic hepatocellular carcinoma tissues from adjacent tissues in mice models and clinical samples. This work highlights an innovative strategy to develop activatable probes for rapid diagnosis of tumors and high-precision imaging of tumor boundaries, providing more efficient tools for future clinical applications in intraoperative assisted resection.

Research on Dynamic Pig Counting Method Based on Improved YOLOv7 Combined with DeepSORT.

A pig inventory is a crucial component of achieving precise and large-scale farming. In complex pigsty environments, due to pigs' stress reactions and frequent obstructions, it is challenging to count them accurately and automatically. This difficulty contrasts with most current deep learning studies, which rely on overhead views or static images for counting. This research proposes a video-based dynamic counting method, combining YOLOv7 with DeepSORT. By utilizing the YOLOv7 network structure and optimizing the second and third 3 × 3 convolution operations in the head network ELAN-W with PConv, the model reduces the computational demand and improves the inference speed without sacrificing accuracy. To ensure that the network acquires accurate position perception information at oblique angles and extracts rich semantic information, we introduce the coordinate attention (CA) mechanism before the three re-referentialization paths (REPConv) in the head network, enhancing robustness in complex scenarios. Experimental results show that, compared to the original model, the improved model increases the mAP by 3.24, 0.05, and 1.00 percentage points for oblique, overhead, and all pig counting datasets, respectively, while reducing the computational cost by 3.6 GFLOPS. The enhanced YOLOv7 outperforms YOLOv5, YOLOv4, YOLOv3, Faster RCNN, and SSD in target detection with mAP improvements of 2.07, 5.20, 2.16, 7.05, and 19.73 percentage points, respectively. In dynamic counting experiments, the improved YOLOv7 combined with DeepSORT was tested on videos with total pig counts of 144, 201, 285, and 295, yielding errors of -3, -3, -4, and -26, respectively, with an average accuracy of 96.58% and an FPS of 22. This demonstrates the model's capability of performing the real-time counting of pigs in various scenes, providing valuable data and references for automated pig counting research.

Supramolecular Assembly in Live Cells Mapped by Real-Time Phasor-Fluorescence Lifetime Imaging.

The complex dynamics and transience of assembly pathways in living systems complicate the understanding of these molecular to nanoscale processes. Current technologies are unable to track the molecular events leading to the onset of assembly, where real-time information is imperative to correlate their rich biology. Using a chemically designed pro-assembling molecule, we map its transformation into nanofibers and their fusion with endosomes to form hollow fiber clusters. Tracked by phasor-fluorescence lifetime imaging (phasor-FLIM) in epithelial cells (L929, A549, MDA-MB 231) and correlative light-electron microscopy and tomography (CLEM), spatiotemporal splicing of the assembly events shows time-correlated metabolic dysfunction. The biological impact begins with assembly-induced endosomal disruption that reduces glucose transport into the cells, which, in turn, stymies mitochondrial respiration.

"Zero" Intrinsic Fluorescence Sensing-Platforms Enable Ultrasensitive Whole Blood Diagnosis and In Vivo Imaging.

Abnormal physiological processes and diseases can lead to content or activity fluctuations of biocomponents in organelles and whole blood. However, precise monitoring of these abnormalities remains extremely challenging due to the insufficient sensitivity and accuracy of available fluorescence probes, which can be attributed to the background fluorescence arising from two sources, 1) biocomponent autofluorescence (BCAF) and 2) probe intrinsic fluorescence (PIF). To overcome these obstacles, we have re-engineered far-red to NIR II rhodol derivatives that possess weak BCAF interference. And a series of "zero" PIF sensing-platforms were created by systematically regulating the open-loop/spirocyclic forms. Leveraging these advancements, we devised various ultra-sensitive NIR indicators, achieving substantial fluorescence boosts (190 to 1300-fold). Among these indicators, 8-LAP demonstrated accurate tracking and quantifying of leucine aminopeptidase (LAP) in whole blood at various stages of tumor metastasis. Furthermore, coupling 8-LAP with an endoplasmic reticulum-targeting element enabled the detection of ERAP1 activity in HCT116 cells with p53 abnormalities. This delicate design of eliminating PIF provides insights into enhancing the sensitivity and accuracy of existing fluorescence probes toward the detection and imaging of biocomponents in abnormal physiological processes and diseases.

Hypertension as a prominent manifestation secondary to renal artery lesions in pediatric Behcet's disease.

OBJECTIVE: Hypertension caused by vascular Behcet's disease (BD) is an important prognostic factor of paediatric BD. However, much less is known about its clinical features. The objective of this study was to investigate the clinical characteristics of paediatric vascular BD complicated by hypertension. METHODS: A retrospective study was carried out in paediatric BD patients complicated by hypertension treated in the Children's Hospital Capital Institute of Paediatrics from Jan 2009 to Dec 2022. RESULTS: Of 65 BD patients, 6 (9.2%) were complicated by hypertension, 5 patients were female, and the median ages of onset and diagnosis were 9.8 years and 11.3 years, respectively. Three patients were found to have cardiac involvement and hypertensive retinopathy secondary to hypertension. Five of the 6 patients with hypertension had right renal artery involvement, and all of them were treated with glucocorticoids and immunosuppressants. Four patients were treated with biological agents. One patient with severe renal artery stenosis underwent unsuccessful vascular interventional therapy. After 3-6 years of follow-up, five patients were found to have renal atrophy, and one patient was at stable condition. CONCLUSION: Hypertension in paediatric BD is mainly caused by renal artery involvement. Early recognition and treatment of vascular involvement in BD is important to prevent poor prognosis.

[Association of Serine/Threonine Phosphoprotein Phosphatase 4C Expression With Prognosis of Gastric Cancer].

Objective To investigate the expression level of serine/threonine phosphoprotein phosphatase 4C(PPP4C)in gastric cancer,and analyze its relationship with prognosis and the underlying regulatory mechanism.Methods The clinical data of 104 gastric cancer patients admitted to the First Affiliated Hospital of Bengbu Medical College between January 2012 and August 2016 were collected.Immunohistochemical staining was employed to determine the expression levels of PPP4C and Ki-67 in the gastric cancer tissue.The gastric cancer cell lines BGC823 and HGC27 were cultured and transfected with the vector for PPP4C knockdown,the vector for PPP4C overexpression,and the lentiviral vector(control),respectively.The effects of PPP4C on the cell cycle and proliferation were analyzed and the possible regulatory mechanisms were explored.Results PPP4C was highly expressed in gastric cancer(P<0.001),and its expression promoted malignant progression of the tumor(all P<0.01).Univariate and Cox multivariate analysis clarified that high expression of PPP4C was an independent risk factor affecting the 5-year survival rate of gastric cancer patients(P=0.003).Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis suggested that PPP4C may be involved in the cell cycle.The correlation analysis showed that the expression of PPP4C was positively correlated with that of Ki-67 in gastric cancer(P<0.001).The up-regulation of PPP4C expression increased the proportion of tumor cells in the S phase,alleviated the G2/M phase arrest,and promoted the proliferation of gastric cancer cells and the expression of cyclin D1 and cyclin-dependent kinase 6(CDK6)(all P<0.05).The down-regulation of PPP4C decreased the proportion of gastric cancer cells in the S phase,promoted G2/M phase arrest,and inhibited cell proliferation and the expression of cyclin D1,CDK6,and p53(all P<0.05).p53 inhibitors promoted the proliferation of BGC823 and HGC27 cells in the PPP4C knockdown group(P<0.001,P<0.001),while p53 activators inhibited the proliferation of BGC823 and HGC27 cells in the PPP4C overexpression group(P<0.001,P=0.002).Conclusions PPP4C is highly expressed in gastric cancer and affects the prognosis of the patients.It may increase the proportion of gastric cancer cells in the S phase and alleviate the G2/M phase arrest by inhibiting p53 signaling,thereby promoting cell proliferation.

CBX7 Rejuvenates Late Passage Dental Pulp Stem Cells by Maintaining Stemness and Pro-angiogenic Ability.

BACKGROUND: Ever-growing tissue regeneration causes pressing need for large population of stem cells. However, extensive cell expansion eventually leads to impaired regenerative potentials. In this study, chromobox protein homolog 7 (CBX7) was overexpressed to rejuvenate late passage dental pulp stem cells (DPSCs-P9). METHODS: The recruitment of copper ions (Cu2+)-activated hypoxia-inducible factor-1α (HIF-1α) to the CBX7 gene promoter was confirmed by chromatin immunoprecipitation assay. Functions subsequent to Cu2+-induced or recombinant overexpression of CBX7 on proliferation, multipotency, odontoblastic differentiation and angiogenesis were investigated in vitro, while murine subcutaneous transplantation model was used to further detect the effects of Cu2+-induced CBX7 overexpression in vivo. RESULTS: Our data displayed that CBX7 overexpression maintain proliferation and multipotency of DPSCs-P9 almost as strong as those of DPSCs-P3. Both gene level of odontoblast-lineage markers and calcium precipitation were nearly the same between CBX7 overexpressed DPSCs-P9 and normal DPSCs-P3. Moreover, we also found upregulated expression of vascular endothelial growth factor in DPSCs-P9 with CBX7 overexpression, which increased the number of capillary-like structures and migrating co-cultured human umbilical vein endothelial cells as well. These findings indicate CBX7 as an effective factor to rejuvenate late passage stem cells insusceptible to cell expansion. Cu2+ has been proved to achieve CBX7 overexpression in DPSCs through the initiation of HIF-1α-CBX7 cascade. Under Cu2+ stimulation since P3, DPSCs-P9 exhibited ameliorated regenerative potential both in vitro and in vivo. CONCLUSION: Long-term stimulation of Cu2+ to overexpress CBX7 could be a new strategy to manufacture large population of self-renewing stem cells.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Long-term follow-up of Janus-kinase inhibitor and novel active disease biomarker in juvenile dermatomyositis.

OBJECTIVE: To evaluate the use of Janus kinase inhibitor (JAKi) in treating JDM and develop cytokine biomarkers of active disease. METHODS: This study involved a retrospective cohort study that evaluated JAKi in 101 JDM patients as well as a cross-sectional study of cytokines in 128 JDM patients and 30 controls between November 2017 and December 2021 in the Affiliated Children's Hospital of Capital Institute of Pediatrics (China). RESULTS: During the median follow-up period of 19 months, 65.5% of the patients had improved rashes, and CAT-BM scores decreased. Overall, 39.6% of JDM patients eliminated glucocorticoids. Muscle strength was improved in all patients who had abnormal muscle strength before JAKi use. Patients and parents provided positive subjective reviews of JAKi, and no serious adverse events were reported. Potential side effects of JAKi included abnormal leukopoenia (14/95) and cough (16/83), which affected over 10% of the JDM patients. In the cytokine analysis, 12/34 cytokines were significantly elevated in active JDM patients. Compared with active JDM patients with multiple phenotypes, active JDM patients with only rashes demonstrated lower cytokine levels. Anti-NXP2-positive active patients had lower cytokine levels compared with those without positive anti-NXP2 antibodies. Among all increased cytokines, IL-1RA changed most dramatically, reaching over 793 times the mean of normal values. We developed a panel composed of six cytokines to differentiate active or stable status in our cohort (area under the curve = 0.8486, P < 0.05). CONCLUSION: The preliminary evidence suggested that JAKi is a relatively safe and effective alternative for JDM patients. Cytokine profiles could well reflect the inflammatory status of JDM patients.

Polymer Chemistry in Living Cells.

The polymerization of biomolecules is a central operation in biology that connects molecular signals with proliferative and information-rich events in cells. As molecules arrange precisely across 3-D space, they create new functional capabilities such as catalysis and transport highways and exhibit new phase separation phenomena that fuel nonequilibrium dynamics in cells. Hence, the observed polymer chemistry manifests itself as a molecular basis leading to cellular phenotypes, expressed as a multitude of hierarchical structures found in cell biology. Although many milestone discoveries had accompanied the rise of the synthetic polymer era, fundamental studies were realized within a closed, pristine environment and that their behavior in a complex multicomponent system remains challenging and thus unexplored. From this perspective, there is a rich trove of undiscovered knowledge that awaits the polymer science community that can revolutionize understanding in the interactive nanoscale world of the living cell.In this Account, we discuss the strategies that have enabled synthetic polymer chemistry to be conducted within the cells (membrane inclusive) and to establish monomer design principles that offer spatiotemporal control of the polymerization. As reaction considerations such as monomer concentration, polymer growth dynamics, and reactivities are intertwined with the subcellular environment and transport processes, we first provide a chemical narrative of each major cellular compartment. The conditions within each compartment will therefore set the boundaries on the type of polymer chemistry that can be conducted. Both covalent and supramolecular polymerization concepts are explored separately in the context of scaffold design, polymerization mechanism, and activation. To facilitate transport into a localized subcellular space, we show that monomers can be reversibly modified by targeting groups or stimulus-responsive motifs that react within the specific compartment. Upon polymerization, we discuss the characterization of the resultant polymeric structures and how these phase-separated structures would impact biological processes such as cell cycle, metabolism, and apoptosis. As we begin to integrate cellular biochemistry with in situ polymer science, we identify landmark challenges and technological hurdles that, when overcome, would lead to invaluable discoveries in macromolecular therapeutics and biology.

In Situ Assembly of Platinum(II)-Metallopeptide Nanostructures Disrupts Energy Homeostasis and Cellular Metabolism.

Nanostructure-based functions are omnipresent in nature and essential for the diversity of life. Unlike small molecules, which are often inhibitors of enzymes or biomimetics with established methods of elucidation, we show that functions of nanoscale structures in cells are complex and can implicate system-level effects such as the regulation of energy and redox homeostasis. Herein, we design a platinum(II)-containing tripeptide that assembles into intracellular fibrillar nanostructures upon molecular rearrangement in the presence of endogenous H2O2. The formed nanostructures blocked metabolic functions, including aerobic glycolysis and oxidative phosphorylation, thereby shutting down ATP production. As a consequence, ATP-dependent actin formation and glucose metabolite-dependent histone deacetylase activity are downregulated. We demonstrate that assembly-driven nanomaterials offer a rich avenue to achieve broad-spectrum bioactivities that could provide new opportunities in drug discovery.

Stevens-Johnson Syndrome Following Non-steroidal Anti-inflammatory Drugs: A Real-World Analysis of Post-marketing Surveillance Data.

Background: The Stevens-Johnson syndrome (SJS) is a severe skin reaction to non-steroidal anti-inflammatory drugs (NSAIDs), and can even be life-threatening. However, there are still few real-world studies to compare the specific differences in the adverse effects of skin and mucosal invasion. Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected SJS after using NSAIDs based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of antipyretic analgesic-associated SJS were also investigated. Results: A total of 1,868 reports of SJS adverse events were identified with NSAIDs. Among 5 NSAIDs monotherapies we studied (acetaminophen, ibuprofen, aspirin, diclofenac and celecoxib), ibuprofen had the highest association with SJS based on the highest reporting odds ratio (ROR = 7.06, 95% two-sided CI = 6.59-7.56), proportional reporting ratio (PRR = 6.98, χ2 = 4201.14) and empirical Bayes geometric mean (EBGM = 6.78, 95% one-sided CI = 6.40). However, ibuprofen-associated SJS had the lowest fatality rate (6.87%, p < 0.0001) and the highest hospitalization rate (79.27%, p < 0.0001). Celecoxib-associated SJS had the latest time to onset (317.56 days, p < 0.0001). Diclofenac-associated SJS cases appeared to be associated with the highest risk of death (25.00%, p < 0.0001). Conclusions: The analysis of FAERS data provides a more accurate profile of the incidence and prognosis of SJS after NSAIDs treatment, enabling continued surveillance and timely intervention in patients at risk of SJS following these NSAIDs.

Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database.

Aims: We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. Methods: We performed disproportionality and Bayesian analyses based on data from the first quarter in 2004 to the third quarter in 2021 in the Food and Drug Administration Adverse Event Reporting System to characterize the signal differences of antifungal drugs-related DILI. We also compared the onset time and mortality differences of different antifungal agents. Results: A total of 2943 antifungal drugs-related DILI were identified. Affected patients tended to be aged >45 years (51.38%), with more males than females (49.03% vs. 38.09%). Antifungal drug-induced liver injury is most commonly reported with voriconazole (32.45%), fluconazole (19.37%), and itraconazole (14.51%). Almost all antifungal drugs were shown to be associated with DILI under disproportionality and Bayesian analyses. The intraclass analysis of correlation between different antifungal agents and DILI showed the following ranking: caspofungin (ROR = 6.12; 95%CI: 5.36-6.98) > anidulafungin (5.15; 3.69-7.18) > itraconazole (5.06; 4.58-5.60) > voriconazole (4.58; 4.29-4.90) > micafungin (4.53; 3.89-5.27) > posaconazole (3.99; 3.47-4.59) > fluconazole (3.19; 2.93-3.47) > ketoconazole (2.28; 1.96-2.64). The onset time of DILI was significantly different among different antifungal drugs (p < 0.0001), and anidulafungin result in the highest mortality rate (50.00%), while ketoconazole has the lowest mortality rate (9.60%). Conclusion: Based on the Food and Drug Administration Adverse Event Reporting System database, antifungal drugs are significantly associated with DILI, and itraconazole and voriconazole had the greatest risk of liver injury. Due to indication bias, more clinical studies are needed to confirm the safety of echinocandins.

Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid­functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

Light-emitting self-assembled metallacages.

Coordination-driven self-assembly of metallacages has garnered significant interest because of their 3D layout and cavity-cored nature. The well-defined, highly tunable metallacage structures render them particularly attractive for investigating the properties of luminophores, as well as for inducing novel photophysical characters that enable widespread applications. In this review, we summarize the recent advances in synthetic methodologies for light-emitting metallacages, and highlight some representative applications of these metallacages. In particular, we focus on the favorable photophysical properties-including high luminescence efficiency in various physical states, good modularity in photophysical properties and stimulus responsiveness-that have resulted from incorporating ligands displaying aggregation-induced emission (AIE) into metallacages. These features show that the synergy between carrying out coordination-driven self-assembly and using luminophores with novel photophysical characteristics like AIE could stimulate the development of supramolecular luminophores for applications in fields as diverse as sensing, biomedicine and catalysis.

Research Progress of Pharmacogenomics in Drug-Induced Liver Injury.

Background: Drug-induced liver injury (DILI) is a common and serious adverse drug reaction with insufficient clinical diagnostic strategies and treatment methods. The only clinically well-received method is the Roussel UCLAF Causality Assessment Method scale, which can be applied to both individuals and prospective or retrospective studies. However, in severe cases, patients with DILI still would develop acute liver failure or even death. Pharmacogenomics, a powerful tool to achieve precision medicine, has been used to study the polymorphism of DILI related genes. Summary: We summarized the pathogenesis of DILI and findings on associated genes and variations with DILI, including but not limited to HLA genes, drug metabolizing enzymes, and transporters genes, and pointed out further fields for DILI related pharmacogenomics study to provide references for DILI clinical diagnosis and treatment. Key Messages: At present, most of the studies are mainly limited to CGS and GWAS, and there is still a long way to achieve clinical transformation. DNA methylation could be a new consideration, and ethnic differences and special populations also deserve attention.

Analysis of five cases of monogenic lupus related to primary immunodeficiency diseases.

OBJECTIVE AND DESIGN: We studied five cases of PID-related monogenic lupus to explore the characteristics. MATERIAL OR SUBJECTS: Among 42 cases of PID patients between 2017-2020, 5 patients were diagnosed as PID-related monogenic lupus, including 2 males and 3 females, with age range from 2 years 3 months to 13 years old. TREATMENTS: DMARDs, biological agents and stem cell transplantation were used to treat different patients. METHODS: We collected the clinical observation indicators, auxiliary examination and treatment of the five patients. RESULTS: Patient 1 was diagnosed with monogenic lupus secondary to severe combined immunodeficiency and received prednisone and methotrexate treatment. Patient 2 was diagnosed with monogenic lupus secondary to activated phosphoinositide 3-kinase δ syndrome. Allogeneic stem cell transplantation was conducted. Patient 3 was diagnosed with monogenic lupus secondary to RAS-associated lymphoproliferative disease. The child was treated with prednisone and rituximab. Patient 4 was diagnosed with monogenic lupus secondary to PSTPIP1-associated myeloid-related proteinaemia inflammatory syndrome. The child was given methylprednisolone, methotrexate, and infliximab. Patient 5 was diagnosed with monogenic lupus secondary to A20 haploinsufficiency. The child was treated with methylprednisolone and infliximab. CONCLUSIONS: Multiple PIDs can lead to monogenic lupus. Different PID-related monogenic lupus has different suitable targeted drugs.

Polymer cyclization for the emergence of hierarchical nanostructures.

The creation of synthetic polymer nanoobjects with well-defined hierarchical structures is important for a wide range of applications such as nanomaterial synthesis, catalysis, and therapeutics. Inspired by the programmability and precise three-dimensional architectures of biomolecules, here we demonstrate the strategy of fabricating controlled hierarchical structures through self-assembly of folded synthetic polymers. Linear poly(2-hydroxyethyl methacrylate) of different lengths are folded into cyclic polymers and their self-assembly into hierarchical structures is elucidated by various experimental techniques and molecular dynamics simulations. Based on their structural similarity, macrocyclic brush polymers with amphiphilic block side chains are synthesized, which can self-assemble into wormlike and higher-ordered structures. Our work points out the vital role of polymer folding in macromolecular self-assembly and establishes a versatile approach for constructing biomimetic hierarchical assemblies.

Clinical characteristics and genetic analysis of A20 haploinsufficiency.

PURPOSE: To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). METHODS: The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed. RESULT: Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sjögren's syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNFα antagonist, patient 2 was treated with TNF α antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses. CONCLUSION: HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene. It may present as Behçet-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Behçet-like syndrome to achieve early diagnosis and accurate treatment.