The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH.OBJECTIVE To evaluate clinical characteristics, outcomes, and treatment response to vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. DESIGN, SETTING, AND PARTICIPANTSAnalysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020.INTERVENTION Vericiguat titrated to 10 mg daily vs placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. RESULTS Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms.CONCLUSIONS AND RELEVANCE Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of vericiguat did not differ significantly across the spectrum of risk in worsening HF.

The primary principle for new molecular evolution is from nature, mimicking nature, and beyond nature, since it is extremely important for the artificial molecules to keep their structure and function in the natural system. It is especially true for the self-assembled supramolecular construction in situ in complicated living bodies. Herein, we put forward a directed evolution strategy consisting of high-content screening from the living system and artificial modification in order to find "totipotential peptides" in a precise way. Progressive dimension reduction of the capability and precise anchoring of the target were realized. Through the living system evolution, we obtain a glioma-targeting and living system-induced self-assembled leading compound CCP. Through the artificial evolution, CCP was further stapled and was hydrophobically modified as N SCCP 2 , which demonstrated stability and NIR-II emission characteristics. N SCCP 2 could realize highresolution molecular imaging and therapy simultaneously. We envision that the strategy and its applications provide a new method for molecular discovery and improve the performance of peptide nano-self-assemblies for diagnostics and therapy.

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β‐sheets have the ability to hierarchically stack into assemblies, and much effort has been spent on designing different peptides to regulate their assembly behaviors. Although the progress is remarkable, it remains challenging to manipulate them in a controllable way for achieving both tailored structures and specific functions. In this study, we obtained bola‐like peptides using de novo design and combinatorial chemical screening. By regulating the solvent‐accessible surface area of the peptide chain, a series of assemblies with different tilt angles and active sites of the β‐sheet were obtained, resembling collapsed dominos. The structure‐activity relationship of the optimized peptide NQ40 system was established and its ability to target the PD‐L1 was demonstrated. This study successfully established the structure‐function relationship of β‐sheets assemblies and has positive implications on the rational design of peptide assemblies that possess recognition abilities.

Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.

A β-amyloid (Aβ) aggregation process is a spontaneous process where the original random coil or helical structure changes into a regularly arranged β-sheet structure. The development of inhibitors with the features of low cost, high efficiency, and biosafety by targeting Aβ self-aggregation is significant for Alzheimer’s disease treatment. However, the issues of low inhibition efficiency under low concentrations of inhibitors and biological toxicity are currently to be addressed. To resolve the above problems, a DNA nanoassembly (HCR-Apt) based on spatially ordered recognition elements was constructed by targeted disruption of Aβ ordered arrangement. It was discovered that HCR-Apt could inhibit effectively the fibrillation of Aβ40 monomers and oligomers at substoichiometric ratios. This may be due to orderly arrangement of aptamers in rigid nanoskeletons for enhancing the recognition interaction between aptamers and Aβ40. The strong interaction between HCR-Apt and Aβ40 limited the flexible conformational conversion of Aβ40 molecules, thereby inhibiting their self-assembly. Computational simulations and experimental analysis revealed the interactions of Apt42 with Aβ40, which explained different inhibition effects on the fibrillation of Aβ40 monomers and oligomers. Furthermore, the analysis of tyrosine intrinsic fluorescence spectra and surface plasmon resonance imaging showed that the interaction of HCR-Apt and Aβ40 was stronger than that of Apt42 and Aβ40. These findings contributed to establishing a promising method of boosting the recognition interaction by orderly arrangement of recognition elements. Taken together, this work is expected to provide a simple and efficient strategy for inhibiting Aβ aggregation, expanding aptamer’s application potential in neurodegenerative diseases.

β-sheets have the ability to hierarchically stack into assemblies, and much effort has been spent on designing different peptides to regulate their assembly behaviors. Although the progress is remarkable, it remains challenging to manipulate them in a controllable way for achieving both tailored structures and specific functions. In this study, we obtained bola-like peptides using de novo design and combinatorial chemical screening. By regulating the solvent-accessible surface area of the peptide chain, a series of assemblies with different tilt angles and active sites of the β-sheet were obtained, resembling collapsed dominos. The structure-activity relationship of the optimized peptide NQ40 system was established and its ability to target the PD-L1 was demonstrated. This study successfully established the structure-function relationship of β-sheets assemblies and has positive implications on the rational design of peptide assemblies that possess recognition abilities.