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Abstract Bacteria-derived H2S plays multifunctional protective roles against antibiotics insult, and the H2S biogenesis pathway is emerging as a viable target for the antibacterial adjuvant design. However, the development of a pan-inhibitor against H2S-synthesizing enzymes is challenging and underdeveloped. Herein, we propose an alternative strategy to downregulate the H2S levels in H2S-producing bacteria, which depletes the bacteria-derived H2S chemically by H2S scavengers without acting on the synthesizing enzymes. After the screening of chemically diversified scaffolds and a structural optimization campaign, a potent and specific H2S scavenger is successfully identified, which displays efficient H2S depletion in several H2S-producing bacteria, potentiates both bactericidal agents and photodynamic therapy, enhances the bacterial clearance of macrophages and polymorphonuclear neutrophils, disrupts the formation of bacterial biofilm and increases the sensitivity of bacterial persister cells to antibiotics. Most importantly, such an H2S scavenger exhibits sensitizing effects with gentamicin in Pseudomonas aeruginosa -infected pneumonia and skin wound female mouse models. In aggregate, our results not only provide an effective strategy to deplete bacteria-derived H2S and establish the H2S biogenesis pathway as a viable target for persisters and drug-resistant bacteria, but also deliver a promising antibacterial adjuvant for potential clinical translation.

Abstract The translocation and assembly module (TAM) has been proposed to play a crucial role in the assembly of a small subset of outer membrane proteins (OMPs) in Proteobacteria based on experiments conducted in vivo using tamA and tamB mutant strains and in vitro using biophysical methods. TAM consists of an OMP (TamA) and a periplasmic protein that is anchored to the inner membrane by a single α helix (TamB). Here we examine the function of the purified E. coli complex in vitro after reconstituting it into proteoliposomes. We find that TAM catalyzes the assembly of four model OMPs nearly as well as the β-barrel assembly machine (BAM), a universal heterooligomer that contains a TamA homolog (BamA) and that catalyzes the assembly of almost all E. coli OMPs. Consistent with previous results, both TamA and TamB are required for significant TAM activity. Our study provides direct evidence that TAM can function as an independent OMP insertase and describes a new method to gain insights into TAM function.

Abstract The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

Abstract Constructing nanolaminate membranes made of two-dimensional graphene oxide nanosheets has gained enormous interest in recent decades. However, a key challenge facing current graphene-based membranes is their poor rejection for monovalent salts due to the swelling-induced weak nanoconfinement and the transmembrane co-transport of anions and cations. Herein, we propose a strategy of electrostatic-induced ion-confined partitioning in a reduced graphene oxide membrane for breaking the correlation of anions and cations to suppress anion-cation co-transport, substantially improving the desalination performance. The membrane demonstrates a rejection of 95.5% for NaCl with a water permeance of 48.6 L m−2 h−1 bar−1 in pressure-driven process, and it also exhibits a salt rejection of 99.7% and a water flux of 47.0 L m−2 h−1 under osmosis-driven condition, outperforming the performance of reported graphene-based membranes. The simulation and calculation results unveil that the strong electrostatic attraction of membrane forces the hydrated Na+ to undergo dehydration and be exclusively confined in the nanochannels, strengthening the intra-nanochannel anion/cation partitioning, which refrains from the dynamical anion-cation correlations and thereby prevents anions and cations from co-transporting through the membrane. This study provides guidance for designing advanced desalination membranes and inspires the future development of membrane-based separation technologies.

Abstract Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Abstract Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.

Abstract Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Abstract Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

Abstract Three-dimensional (3D) covalent organic frameworks (COFs) possess higher surface areas, more abundant pore channels, and lower density compared to their two-dimensional counterparts which makes the development of 3D COFs interesting from a fundamental and practical point of view. However, the construction of highly crystalline 3D COF remains challenging. At the same time, the choice of topologies in 3D COFs is limited by the crystallization problem, the lack of availability of suitable building blocks with appropriate reactivity and symmetries, and the difficulties in crystalline structure determination. Herein, we report two highly crystalline 3D COFs with pto and mhq-z topologies designed by rationally selecting rectangular-planar and trigonal-planar building blocks with appropriate conformational strains. The pto 3D COFs show a large pore size of 46 Å with an extremely low calculated density. The mhq-z net topology is solely constructed from totally face-enclosed organic polyhedra displaying a precise uniform micropore size of 1.0 nm. The 3D COFs show a high CO2 adsorption capacity at room temperature and can potentially serve as promising carbon capture adsorbents. This work expands the choice of accessible 3D COF topologies, enriching the structural versatility of COFs.

Although the role of FGFs in cardiovascular disease has attracted extensive attention, the potential role of FGF18 in pathological cardiac hypertrophy remains unknown. Here, the authors show the cardioprotective effect of FGF18 is mediated by maintaining redox homeostasis through FYN/Nox4 signaling.

Pancreatic ductal adenocarcinoma (PDAC) cells can utilise the tumour microenvironment to metastasise to the liver. Here the authors show that hepatoctyes overexpress SLIT2 to enable premetastatic niche formation for ROBO1-positive PDAC cells to support the survival of these tumour cells in the liver.

The structure of subpellicular microtubules (SPMTs) nucleated from the apical polar ring (APR) is essential for Plasmodium parasite morphogenesis, gliding motility, and invasion. Here, Qian et al. characterize the function of APR2 protein in P. yoelii ookinetes. Using co-localization analysis, proximity labeling, CoIP, expansion microscopy and FRAP, they show that APR2 binds to SMPTs and has a fixed position in APR. Deletion mutants fail to traverse the mosquito midgut as they fail to anchor SPMTs on APR, which affects invasive morphology and gliding motility.

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. Here, the authors show that also presynaptic NMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner.

Spin density waves are a spatial modulation of the spin, and can be either commensurate or incommensurate with the crystal lattice. Here, Hu et al. use spin-polarised scanning tunnelling microscopy to observe the incommensurate spin density wave on cleaned Chromium surface.

Hunting behavior typically contains a sequential motor program, including search, chase, attack, and consumption. Here, the authors show that periaqueductal gray neuronal ensembles encode the sequential hunting motor program, which might provide a framework for decoding complex instinctive behaviors.

Glucocorticoid receptor (GR) agonists - used in the treatment of solid malignant tumors to reduce inflammation - could potentially affect the anti-tumor activity of chemotherapy. Here, the authors identify a mechanism of cisplatin resistance observed with GR agonist treatment, and show the binding and activation of GR by cisplatin, which leads to MAST1 activation and subsequent MAPK re-activation.

The fate of proteins in cells is determined by not only synthesis but also degradation. Here Chen et al. show that degradation of the plant blue light receptor CRY2 is determined by two distinct E3 ubiquitin ligases, Cul4COP1/SPAs and Cul3LRBs, regulating the function of CRY2 under different light conditions.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease characterized by an immunosuppressive microenvironment. Here the authors show that a subset of P2RX1-negative neutrophils with immunosuppressive properties accumulate in PDAC metastatic liver tissues and promote tumor growth.

Stimuli-responsive nanomaterials offer the opportunity to exploit nanoscale cooperativity to improve the precision of diagnostic or therapeutic outcomes. Here, the authors report the design, synthesis and characterization of a series of degradable ultra-pH sensitive polymers that amplify small acidic pH changes to efficacious therapeutic outputs.

The mechanistic details of fatty acid uptake into cells remains poorly understood. Here, the authors identify CD36 internalization via cavaeolae and demonstrate dynamic palmitoylationof CD36 is required for endocytic uptake of fatty acids.

Designing efficient wearable bioelectronics for health monitoring, disease prevention, and treatment, remains a challenge. Here, the authors demonstrate an ultra-conformal, customizable and deformable drawn-on-skin electronics which is robust to motion artifacts and resistant to physical damage.

Mosquito-derived xanthurenic acid (XA) is a trigger for gametogenesis of Plasmodium parasites. Here the authors show that the putative amino acid transporter GEP1 is required for XA-stimulated gametogenesis in Plasmodium yoelii and that it interacts with guanylyl cyclase α (GCα), a cGMP synthesizing enzyme in gametocytes.

The genomic heterogeneity of clear cell renal cell carcinoma (ccRCC) across populations is poorly understood. Here, the authors analyse a cohort of Chinese ccRCC cases revealing a mutational signature associated with aristolochic acid exposure, and higher mutational burden and enrichment for BAP1 and SETD2 mutations in ccRCC cases associated with tumor thrombus.

Auxin promotes lateral root emergence from pericycle cells in the root vasculature. Here the authors show that induction of the plasmodesmal regulator PDLP5 during lateral root emergence restricts the spatial scope of auxin signaling to the cells overlying the primordia.

To realize electronic skins for emerging technologies that require multifunctional sensing capability, intelligent design strategies are needed. Here, the authors report electronic skins with a single sensory unit that simultaneously transduces both tactile and touchless stimulations.

There has been a drastic increase in detection of lung nodules, many of which are precancers, preinvasive, minimally invasive or sometimes invasive lung cancers. Here, Hu et al. perform multi-region exome sequencing to discern the evolutional trajectory from precancers to invasive lung cancers.

Temporal cloaks, which hide a temporal event within a signal, have been previously limited to very short and periodic event cloaking. Here the authors report a temporal cloak with a programmable-length cloaking window using a silicon microring and optical frequency comb.

The environmental impacts of increasing wastewater management are poorly understood. Here, the authors simulate impacts for 173 countries between 1990 and 2050; despite the development of wastewater infrastructure, they identify hotspots of unexpected detrimental effects which are shifting from Asia to Africa.

Platelet aggregates generate contractile forces that contribute to their cohesion and adhesion. Here, Ting et al. develop a microfluidic device to measure contractile forces generated by platelet aggregates, and find it can detect the response of platelets to pharmacological agents and predict bleeding risk in trauma patients.

Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.

Plant cryptochromes are regulated by blue-light dependent phosphorylation. Here the authors map thein vivo phosphorylation sites of Arabidopsiscryptochrome 2 and identify four closely related kinases that act to both activate and destabilize the receptor in response to blue light.

Despite the advantages of using heterogeneous catalysts, most successful rhodium hydrogenations are carried out with homogeneous catalysts. Here the authors report a supported single atom rhodium catalyst providing high activities and selectivities for propene hydroformylation.

Carbohydrates are common biological molecules, but display huge stereochemical complexity that often cannot be elucidated by mass spectrometry. Here the authors show that recognition tunnelling can distinguish individual stereoisomers, utilizing picomole quantities of analytes.

The protein PEP-19 increases the rates of calcium binding to calmodulin. Here, the authors report the structure of PEP-19 bound to the C-terminal domain of calmodulin, and are able to propose a mechanism for the observed increased calcium association rate.

Photonic-based instantaneous frequency measurement systems are usually bulky or require high optical power. Here, Burla et al. demonstrate an integrated measurement system that can identify frequency-varying signals in a dynamic fashion, without the need for fast measurement instrumentation.

This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

Here, Imamuraet al. conduct meta-analysis of genome-wide association studies to identify novel susceptibility loci for type 2 diabetes (T2D) in the Japanese population. By doing so, this study shows that both ethnicity-specific and ethnically-shared genetic loci can contribute to T2D risk.