A novel doxorubicin/CTLA-4 blocker co-loaded drug delivery system improves efficacy and safety in antitumor therapy.

Doxorubicin's antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of immune checkpoint inhibitors and doxorubicin into liposomes can produce synergistic benefits and address problems, including quick drug clearance, toxicity, and low drug penetration efficiency. In our previous study, we modified a nanobody targeting CTLA-4 onto liposomes (LPS-Nb36) to be an extremely potent CTLA-4 signal blocker which improve the CD8+ T-cell activity against tumors under physiological conditions. In this study, we designed a drug delivery system (LPS-RGD-Nb36-DOX) based on LPS-Nb36 that realized the doxorubicin and anti-CTLA-4 Nb co-loaded and RGD modification, and was applied to antitumor therapy. We tested whether LPS-RGD-Nb36-DOX could targets the tumor by in vivo animal photography, and more importantly, promote cytotoxic T cells proliferation, pro-inflammatory cytokine production, and cytotoxicity. Our findings demonstrated that the combination of activated CD8+ T cells with doxorubicin/anti-CTLA-4 Nb co-loaded liposomes can effectively eradicate tumor cells both in vivo and in vitro. This combination therapy is anticipated to have synergistic antitumor effects. More importantly, it has the potential to reduce the dose of chemotherapeutic drugs and improve safety.

Dynamic Metallosupramolecular Cages Containing 12 Adaptable Pockets for High-Order Guest Binding Beyond Biomimicry.

Molecular recognition lies at the heart of biological functions, which inspires lasting research in artificial host syntheses to mimic biomolecules that can recognize, process, and transport molecules with the highest level of complexity; nonetheless, the design principle and quantifying methodology of artificial hosts for multiple guests (≥4) remain a formidable task. Herein, we report two rhombic dodecahedral cages [(Zn/Fe)8Pd6-MOC-16], which embrace 12 adaptive pockets for multiguest binding with distinct conformational dynamics inherent in metal-center lability and are able to capture 4-24 guests to manifest a surprising complexity of binding scenarios. The exceptional high-order and hierarchical encapsulation phenomena suggest a wide host-guest dynamic-fit, enabling conformational adjustment and adaptation beyond the duality of induced-fit and conformational selection in protein interactions. A critical inspection of the host-guest binding events in solution has been performed by NMR and ESI-MS spectra, highlighting the importance of acquiring a reliable binding repertoire from different techniques and the uncertainty of quantifying the binding affinities of multiplying guests by an oversimplified method.

Association of Complement C3 with Clinical Deterioration Among Hospitalized Patients with COVID-19.

BACKGROUND: The role of the complement system in coronavirus disease 2019 (COVID-19) remains controversial. This study aimed to evaluate the relationship between serum complement C3 levels, clinical worsening, and risk of death in hospitalized patients with COVID-19. METHODS: Data were collected from 216 adults with COVID-19 admitted to a designated clinical center in Wuhan Union Hospital (China) between February 13, 2020, and February 29, 2020. Their complement C3 levels were measured within 24 h of admission. The primary outcome was a clinical worsening of 2 points on a 6-point ordinal scale. The secondary outcome was all-causes of death. Inverse probability of treatment weighting (IPTW) analysis was conducted to adjust for the baseline confounders. RESULTS: The median value of C3 was 0.89 (interquartile range, 0.78-1.01) g/L. Clinical worsening occurred in 12.3% (7/57) and 2.5% (4/159) of patients with baseline C3 levels < and ≥0.79 g/L, respectively (hazard ratio [HR], 5.22; 95% confidence interval [CI], 1.53-17.86). After IPTW adjustment, the risk for clinical worsening was 4-fold greater (weighted HR, 4.61; 95% CI, 1.16-18.4) in patients with C3 levels less than 0.79 g/L comparatively. The sensitivity analyses revealed the robustness of the results. No significant associations between C3 levels and death were observed on unadjusted (HR, 2.92; 95% CI, 0.73-11.69) and IPTW analyses (weighted HR, 3.78; 95% CI, 0.84-17.04). CONCLUSION: Low complement C3 levels are associated with a higher risk for clinical worsening among inpatients with COVID-19. The serum C3 levels may contribute to the identification of patient populations that could benefit from therapeutic complement inhibition.

Single-cell transcriptomic analysis reveals a novel cell state and switching genes during hepatic stellate cell activation in vitro.

BACKGROUND: The transformation of hepatic stellate cell (HSC) to myofibroblast is a key event during liver fibrogenesis. However, the differentiation trajectory of HSC-to-myofibroblast transition and the switching genes during this process remains not well understood. METHODS: We applied single-cell sequencing data to reconstruct a single-lineage pseudotime trajectory of HSC transdifferentiation in vitro and analyzed the gene expression patterns along the trajectory. GeneSwitches was used to identify the order of critical gene expression and functional events during HSC activation. RESULTS: A novel cell state during HSC activation was revealed and the HSCs belonging to this state may be an important origin of cancer-associated fibroblasts (CAFs). Combining single-cell transcriptomics with GeneSwitches analyses, we identified some distinct switching genes and the order at which these switches take place for the new state of HSC and the classic culture-activated HSC, respectively. Based on the top switching genes, we established a four-gene combination which exhibited highly diagnostic accuracy in predicting advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis B (HBV). CONCLUSION: Our study revealed a novel cell state during HSC activation which may be relevant to CAFs, and identified switching genes that may play key roles in HSC transdifferentiation and serve as predictive markers of advanced fibrosis in patients with chronic liver diseases.

No significant benefit of moderate-dose vitamin C on severe COVID-19 cases.

There is no specific drug for coronavirus disease 2019 (COVID-19). We aimed to investigate the possible clinical efficacy of moderate-dose vitamin C infusion among inpatients with severe COVID-19. Data of 397 adult patients with severe COVID-19 admitted to a designated clinical center of Wuhan Union Hospital (China) between February 13 and February 29, 2020, were collected. Besides standard therapies, patients were treated with vitamin C (2-4 g/day) or not. The primary outcome was all-cause death. Secondary outcome was clinical improvement of 2 points on a 6-point ordinal scale. About 70 participants were treated with intravenous vitamin C, and 327 did not receive it. No significant association was found between vitamin C use and death on inverse probability treatment weighting (IPTW) analysis (weighted hazard ratio [HR], 2.69; 95% confidence interval [CI], 0.91-7.89). Clinical improvement occurred in 74.3% (52/70) of patients in the vitamin C group and 95.1% (311/327) in the no vitamin C group. No significant difference was observed between the two groups on IPTW analysis (weighted HR, 0.76; 95% CI, 0.55-1.07). Our findings revealed that in patients with severe COVID-19, treatment with moderate dose of intravenous vitamin C had no significant benefit on reducing the risk of death and obtaining clinical improvement.

Light-Driven Molecular Motors Boost the Selective Transport of Alkali Metal Ions through Phospholipid Bilayers.

A hydrophobic light-driven rotary motor is functionalized with two 18-crown-6 macrocycles and incorporated into phospholipid bilayers. In the presence of this molecular construct, fluorescence assays and patch clamp experiments show the formation of selective alkali ion channels through the membrane. Further, they reveal a strongly accelerated ion transport mechanism under light irradiation. This increase of the fractional ion transport activity (up to 400%) is attributed to the out-of-equilibrium actuation dynamics of the light-driven rotary motors, which help to overcome the activation energy necessary to achieve translocation of alkali ions between macrocycles along the artificial channels.

Self-Assembled Artificial Ion-Channels toward Natural Selection of Functions.

Owing to their significant physiological functions, especially as selective relays for translocation of physiological relevant species through cellular membranes, natural ion channels play important role in the living organisms. During the last decades, the field of self-assembled ion channels has been continuously developed. Convergent multidimensional self-assembly strategies have been used for the synthesis of unimolecular channels or non-covalent self-organized channels, designed to mimic natural ion channel proteins and for which a rich array of interconverting or adaptive channel conductance states can be observed. In this review, we give an overview on the development of various self-assembled artificial channels in a bottom-up approach, especially their design, self-assembly behaviour, transport activity in lipid bilayer membranes, mechanism of transport and comparison with natural ion channels. Finally, we discuss their applications, the potential challenges facing in this field as well as future development and perspectives.

ANDC: an early warning score to predict mortality risk for patients with Coronavirus Disease 2019.

BACKGROUND: Patients with severe Coronavirus Disease 2019 (COVID-19) will progress rapidly to acute respiratory failure or death. We aimed to develop a quantitative tool for early predicting mortality risk of patients with COVID-19. METHODS: 301 patients with confirmed COVID-19 admitted to Main District and Tumor Center of the Union Hospital of Huazhong University of Science and Technology (Wuhan, China) between January 1, 2020 to February 15, 2020 were enrolled in this retrospective two-centers study. Data on patient demographic characteristics, laboratory findings and clinical outcomes was analyzed. A nomogram was constructed to predict the death probability of COVID-19 patients. RESULTS: Age, neutrophil-to-lymphocyte ratio, D-dimer and C-reactive protein obtained on admission were identified as predictors of mortality for COVID-19 patients by LASSO. The nomogram demonstrated good calibration and discrimination with the area under the curve (AUC) of 0.921 and 0.975 for the derivation and validation cohort, respectively. An integrated score (named ANDC) with its corresponding death probability was derived. Using ANDC cut-off values of 59 and 101, COVID-19 patients were classified into three subgroups. The death probability of low risk group (ANDC < 59) was less than 5%, moderate risk group (59 ≤ ANDC ≤ 101) was 5% to 50%, and high risk group (ANDC > 101) was more than 50%, respectively. CONCLUSION: The prognostic nomogram exhibited good discrimination power in early identification of COVID-19 patients with high mortality risk, and ANDC score may help physicians to optimize patient stratification management.

A Voltage-Responsive Synthetic Cl- -Channel Regulated by pH.

Transmembrane protein channels are an important inspiration for the design of artificial ion channels. Their dipolar structure helps overcome the high energy barrier to selectively translocate water and ions sharing one pathway, across the cell membrane. Herein, we report that the amino-imidazole (Imu) amphiphiles self-assemble via multiple H-bonding to form stable artificial Cl- -channels within lipid bilayers. The alignment of water/Cl- wires influences the conduction of ions, envisioned to diffuse along the hydrophilic pathways; at acidic pH, Cl- /H+ symport conducts along a partly protonated channel, while at basic pH, higher Cl- /OH- antiport translocate through a neutral channel configuration, which can be greatly activated by applying strong electric field. This voltage/pH regulated channel system represents an unexplored alternative for ion-pumping along artificial ion-channels, parallel to that of biology.

Progressive Folding and Adaptive Multivalent Recognition of Alkyl Amines and Amino Acids in p-Sulfonatocalix[4]arene Hosts: Solid-State and Solution Studies.

Invited for this month's cover is the group of Dr. Mihail Barboiu from the Institut Europeen des Membranes of Montpellier, France and the Lehn Institute of Functional Materials at Sun-yat Sen University in Guangzhou, China. The cover picture shows the molecular recognition of folded 1,ω-amino-acids guests within p-sulfonatocalix[4]arene host anions stabilized with alternating hydrated cations and water molecules. Read the full text of the article at 10.1002/cplu.202000232.

Progressive Folding and Adaptive Multivalent Recognition of Alkyl Amines and Amino Acids in p-Sulfonatocalix[4]arene Hosts: Solid-State and Solution Studies.

Calix[4]arenes have the ability to encapsulate biomimetic guests, offering interesting opportunities to explore their molecular recognition, very close to biological scenarios. In this study, p-sulfonatocalix[4]arene (C4 A) anions and hydrated alkali cations have been used for the in situ recognition of cationic 1,ω-diammonium-alkanes and 1,ω-amino-acids of variable lengths. NMR spectroscopy illustrates that these systems are stable in aqueous solution and the interaction process involves several binding states or stabilized conformations within the C4 A anion, depending of the nature of the guest. DOSY experiments showed that monomeric 1 : 1 host-guest species are present, while the cation does not influence their self-assembly in solution. The folded conformations observed in the solid-state X-ray single-crystal structures shed light on the constitutional adaptivity of flexible chains to environmental factors. Futhermore, a comprehensive screening of 30 single crystal structures helped to understand the in situ conformational fixation and accurate determination of the folded structures of the confined guest molecules, with a compression up to 40 % compared with their linear conformations.

Visible-Light Photocatalysis of Asymmetric [2+2] Cycloaddition in Cage-Confined Nanospace Merging Chirality with Triplet-State Photosensitization.

Although the photodimerization of acenaphthylene (ACE) has been known for 100 years, the asymmetric cycloaddition of its 1-substituted derivatives is unknown. Herein, we report a supramolecular photochirogenic approach in which a homochiral and photoactive Δ/Λ-[Pd6 (RuL3 )8 ]28+ metal-organic cage (Δ/Λ-MOC-16) is used as a supramolecular reactor for the enantioselective exited-state photocatalysis of 1-Br-ACE. Owing to preorganization of the substrates by the supramolecular cage, stereochemical control of the triplet state, and nanospace transfer of energy and chirality, the cycloaddition of ACE proceeded with high selectivity for the formation of anti over syn stereoisomers, whereas the regio-, stereo-, and enantioselective cycloaddition of unsymmetrical 1-Br-ACE showed effective enantiodifferentiation of a pair of anti head-to-head stereoisomers. The enzyme-mimicking photocatalysis was verified by catalytic turnover, rate enhancement, and competing-guest inhibition experiments.

Self-Assembled Columnar Triazole Quartets: An Example of Synergistic Hydrogen-Bonding/Anion-π Interactions.

The self-assembly of triazole amphiphiles was examined in solution, the solid state, and in bilayer membranes. Single-crystal X-ray diffraction experiments show that stacked protonated triazole quartets (T4 ) are stabilized by multiple strong interactions with two anions. Hydrogen bonding/ion pairing of the anions are combined with anion-π recognition to produce columnar architectures. In bilayer membranes, low transport activity is observed when the T4 channels are operated as H+ /X- translocators, but higher transport activity is observed for X- in the presence of the K+ -carrier valinomycin. These self-assembled superstructures, presenting intriguing structural behaviors such as directionality, and strong anion encapsulation by hydrogen bonding supported by vicinal anion-π interactions can serve as artificial supramolecular channels for transporting anions across lipid bilayer membranes.

"Calix[4]-box" cages promote the formation of amide bonds in water in the absence of coupling reagents.

The present work shows that encapsulation can be used to promote amide bond formation in water under mild conditions, in the absence of carbodiimide coupling agents.

Structure-Driven Selection of Adaptive Transmembrane Na+ Carriers or K+ Channels.

Self-assembled alkyl-ureido-benzo-15-crown-5-ethers are selective ionophores for K+ cations, which are preferred to Na+ cations. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between the crown ether hole and the cation diameter. Herein, we demonstrate that systematic changes of the structure lead to unexpected modifications in the cation-transport activity and suffice to produce adaptive selection. We show that the main contribution to performance arises from optimal constraints on the conformational freedom, which are determined by the binding macrocycles, the nature of the hydrogen-bonding groups, and the hydrophobic tails. Simple changes to the flexible 15-crown-5-ether lead to selective carriers for Na+ . Hydrophobic stabilization of the channels through mutual interactions between lipids and variable hydrophobic tails appears to be an important cause of increased activity. Oppositely, restricted translocation is achieved when constrained hydrogen-bonded macrocyclic relays are less dynamic in a pore superstructure.

Research and application of transnasal transesophageal echocardiography probe.

The intubation of conventional transesophageal echocardiography (TEE) probes into patients causes serious esophagus irritation, and thus the use of TEE probes in pediatric practice is limited. In this study, we aimed at the development of a special probe which could be inserted through the nasopharyngeal cavity into the esophagus to obtain the same high-quality echocardiography images as those obtained by conventional TEE and improve patients' experience. During the examination, the patients felt relaxed for a longer time and cooperated with the sonographers in the process of cardiac catheterization conducted in the surgery room or the intensive care unit (ICU), resulting in improved accuracy of the diagnosis and timely administration of appropriate treatment. Two years ago, Prof. Xin-fang WANG put theories into practice by inserting the probe through the nasal cavity and pharynx into the esophagus of volunteers to successfully detect the heart and great vessels at the retrocardiac space. Later, Prof. Ming-xing XIE performed the transnasal TEE examination in 12 atrial septal defect (ASD) patients and proved the safety and reliability of this method, which could become a new way for clinical diagnosis and treatment.

Dynamic Spacer Installation for Multirole Metal-Organic Frameworks: A New Direction toward Multifunctional MOFs Achieving Ultrahigh Methane Storage Working Capacity.

A robust Zr-MOF (LIFM-28) containing replaceable coordination sites for additional spacer installation has been employed to demonstrate a swing- or multirole strategy for multifunctional MOFs. Through reversible installation/uninstallation of two types of spacers with different lengths and variable functional groups, different tasks can be accomplished using the same parent MOF. An orthogonal optimizing method is applied with seven shorter (L1-7) and six longer (L8-13) spacers to tune the functionalities, achieving multipurpose switches among gas separation, catalysis, click reaction, luminescence, and particularly, ultrahigh methane storage working capacity at 5-80 bar and 298 K.

m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program.

The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma.