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Photodynamic therapy (PDT), is a rising star for suppression of in situand metastatic tumors, yet it is impeded by low ROS production and off-target phototoxicity. Herein, an aggregation degree editing strategy, inspired by gene editing, was accomplished by the coordination of an aggregation degree editor, p(MEO2MA160-co-OEGMA40)-b-pSS30[POEGS; MEO2MA = 2-(2-methoxyethoxy)ethyl methacrylate, OEGMA = oligo(ethylene glycol) methacrylate; pSS = poly(styrene sulfonate)] and indocyanine green (ICG) to nontoxic Mg2+, forming an ICG discretely loaded nanoaggregate (ICG-DNA). Optimization of the ICG aggregation degree [POEGS/ICG (P/I) = 6.55] was achieved by tuning the P/I ratio, alleviating aggregation-caused-quenching (ACQ) and photobleaching concurrently. The process boosts the PDT efficacy, spurring robust immunogenic cell death (ICD) and systemic antitumor immunity against primary and metastatic immunogenic “cold” 4T1 tumors viaintratumoral administration. Moreover, the temperature-sensitive phase-transition property facilitates intratumoral long-term retention of ICG-DNA, reducing undesired phototoxicity to normal tissues; meanwhile, the photothermal-induced tumor oxygenation further leads to an augmented PDT outcome. Thus, this simple strategy improves PDT efficacy, boosting the singlet oxygen quantum yield (ΦΔ)-dependent ICD effect and systemic antitumor responses vialocal treatment.

Accurate and rapid identification of infectious bacteria is important in medicine. Raman microspectroscopy holds great promise in performing label-free identification at the single-cell level. However, due to the naturally weak Raman signal, it is a challenge to build extensive databases and achieve both accurate and fast identification. Here, we used signal-to-noise ratio (SNR) as a standard indicator for Raman data quality and performed bacterial identification using 11, 141 single-cell Raman spectra from nine bacterial strains. Subsequently, using two machine learning methods, a simple filter, and a neural network-based denoising autoencoder (DAE), we demonstrated 92% (simple filter using 1 s/cell spectra) and 84% (DAE using 0.1 s/cell spectra) identification accuracy. Our machine learning-aided Raman analysis paves the way for high-speed Raman microspectroscopic clinical diagnostics.

Archaea can produce special cellular components such as polyhydroxyalkanoates, carotenoids, rhodopsin, and ether lipids, which have valuable applications in medicine and green energy production. Most of the archaeal species are uncultivated, posing challenges to investigating their biomarker components and biochemical properties. In this study, we applied Raman spectroscopy to examine the biological characteristics of nine archaeal isolates, including halophilic archaea (Haloferax larsenii, Haloarcula argentinensis, Haloferax mediterranei, Halomicrobium mukohataei, Halomicrobium salinus, Halorussus sp., Natrinema gari), thermophilic archaea (Sulfolobus acidocaldarius), and marine group I (MGI) archaea (Nitrosopumilus maritimus). Linear discriminant analysis of the Raman spectra allowed visualization of significant separations among the nine archaeal isolates. Machine-learning classification models based on support vector machine achieved accuracies of 88–100% when classifying the nine archaeal species. The predicted results were validated by DNA sequencing analysis of cells isolated from the mixture by Raman-activated cell sorting. Raman spectra of uncultured archaea (MGII) were also obtained based on Raman spectroscopy and fluorescence in situhybridization. The results combining multiple Raman-based techniques indicated that MGII may have the ability to produce lipids distinct from other archaeal species. Our study provides a valuable approach for investigating and classifying archaea, especially uncultured species, at the single-cell level.

Sorghum is a drought-tolerant staple crop for half a billion people in Africa and Asia, an important source of animal feed throughout the world and a biofuel feedstock of growing importance. Cultivated sorghum and its inter-fertile wild relatives constitute the primary gene pool for sorghum. Understanding and characterizing the diversity within this valuable resource is fundamental for its effective utilization in crop improvement. Here, we report analysis of a sorghum pan-genome to explore genetic diversity within the sorghum primary gene pool. We assembled 13 genomes representing cultivated sorghum and its wild relatives, and integrated them with 3 other published genomes to generate a pan-genome of 44,079 gene families with 222.6 Mb of new sequence identified. The pan-genome displays substantial gene-content variation, with 64% of gene families showing presence/absence variation among genomes. Comparisons between core genes and dispensable genes suggest that dispensable genes are important for sorghum adaptation. Extensive genetic variation was uncovered within the pan-genome, and the distribution of these variations was influenced by variation of recombination rate and transposable element content across the genome. We identified presence/absence variants that were under selection during sorghum domestication and improvement, and demonstrated that such variation had important phenotypic outcomes that could contribute to crop improvement. The constructed sorghum pan-genome represents an important resource for sorghum improvement and gene discovery.

Metabolomics can indicate the physiological and biochemical responses of mosquitoes to different stimulants, including insecticides, which allow them to adapt to different inhospitable environments. Though metabolic differences between insecticide-resistant and -susceptible strains have been established for other mosquito species, such as Anophelesand Culex, it is yet to be done for Aedes albopictus(Skuse). In this study, nuclear magnetic resonance (NMR) spectroscopy–based metabolomic analysis performed on Ae. albopictusdeltamethrin-resistant and -susceptible strains showed significant differences in amino acid, organic acid, and sugar metabolism. Concentrations of neutral amino acids and sugars tended to be lower in the deltamethrin-resistant strain than in the deltamethrin-suceptible strain, but the concentration of basic and acidic amino acids and organic acids increased. All these changes might accommodate biochemical and physiological needs in deltamethrin-resistant mosquitoes, such as enzyme synthesis and detoxification. This was further confirmed by the predictable draft metabolic map. This is the first report using NMR spectroscopy to investigate the metabolic differences between deltamethrin-resistant and -susceptible strains of Ae. albopictus. To a certain degree, this demonstrates how Ae. albopictusdevelop insecticide resistance by metabolic reprograming to survive under the insecticide pressure.

We report rapid and sensitive phenotyping of bacterial response to antibiotic treatment at single-cell resolution by a Raman-integrated optical mid-infrared photothermal (MIP) microscope. The MIP microscope successfully detected biochemical changes of bacteria in specific to the acting mechanism of erythromycin with 1 h incubation. Compared to Raman spectroscopy, MIP spectroscopy showed a much larger signal-to-noise ratio at the fingerprint region at an acquisition speed as fast as 1 s per spectrum. The high sensitivity of MIP enabled detection of metabolic changes at antibiotic concentrations below minimum inhibitory concentration (MIC). Meanwhile, the single-cell resolution of the technique allowed observation of heteroresistance within one bacterial population, which is of great clinical relevance. This study showcases characterizing antibiotic response as one of the many possibilities of applying MIP microscopy to single-cell biology.

Although bivalent palladium [Pd(II)] compounds exhibit favorable antitumor efficacy against platinum-resistant cancers, the mechanism remains unclear. Moreover, some drawbacks, such as structural lability, rapid elimination in vivo, and poor intratumoral retention, heavily limit their application in systemic tumor chemotherapy. Here, thermosensitive Pd-PNS nanogels are rationally designed by cross-linking coordination of Pd(II) ions with poly(styrenesulfonate-b-N-isopropylacrylamide-b-styrenesulfonate) (PNS), achieving high drug-loading ability (ca. 80% of entrapment efficiency and 40% of drug-loading efficiency), sustained release, and long-term retention of highly water-soluble K2PdCl4in intratumoral administration. Cytotoxicity on sensitive/resistant MCF-7 cells and cancer stem cell (CSC) spheroids indicates that Pd-PNS nanogels could inhibit the palladium efflux of P-glycoprotein and multidrug resistance-associated protein-1 and thus enhance the DNA damage and toxicity of platinum-resistant MCF-7/Pt cells and their CSCs. Based on their temperature-sensitive sol–gel transition, Pd-PNS nanogels show sustained release profiles and long-term retention in tumors, further enhancing in vivo antitumor efficacy on MCF-7/Pt tumor-bearing BALB/c nude mice. Owing to these advantages of prolonged retention, efflux inhibition, and efficient CSCs killing ability, Pd-PNS nanogels are promising to be developed as a new temperature-sensitive delivery nanoplatform for injectable regional chemotherapy on platinum-resistant cancers.

Highly efficient nanoarchitectures are of great interest for achieving precise chemotherapy with minimized adverse side effects in cancer therapy. However, a major challenge remains in exploring a rational approach to synthesize spatiotemporally selective vehicles for precise cancer chemotherapy. Here, we demonstrate a rational design of bifunctional light-activatable platinum nanocomplexes (PtNCs) that produce dually cooperative cancer therapy through spatiotemporally selective thermo-chemotherapy. The Pt4+-coordinated polycarboxylic nanogel is explored as the nanoreactor template, which is exploited to synthesize bifunctional PtNCs consisting of a zero-valent Pt0core and a surrounding bivalent Pt2+shell with tunable ratios through a facile and controllable reduction. Without light exposure, chemotherapeutic Pt2+ions are tightly bound on the surface of PtNCs, efficiently reducing undesirable drug leakage and nonselective damage on normal tissues/cells. Upon light exposure, PtNCs generate much heat via photothermal conversion from the Pt0core and simultaneously trigger a rapid release of chemotherapeutic Pt2+ions, thereby leading to the spatiotemporally light-activatable synergistic effect of thermo-chemotherapy. Moreover, PtNCs show enhanced tumor accumulation through the heat-triggered hydrophilicity–hydrophobicity transition upon immediate light exposure after injection, dramatically facilitating in vivotumor regression through their cooperative anticancer efficiency. This rational design of spatiotemporally activatable nanoparticles provides an insightful tool for precise cancer therapy.

The intracellular pathogen Salmonella entericahas evolved an array of traits for propagation and invasion of the intestinal layers. It remains largely elusive how Salmonellaadjusts its metabolic states to survive inside immune host cells. In this study, single-cell Raman biotechnology combined with deuterium isotope probing (Raman-DIP) have been applied to reveal metabolic changes of the typhoidal SalmonellaTyphi Ty2, the nontyphoidal SalmonellaTyphimurium LT2, and a clinical isolate Typhimurium D23580. By initially labeling the Salmonellastrains with deuterium, we employed reverse labeling to track their metabolic changes in the time-course infection of THP-1 cell line, human monocyte-derived dendritic cells (MoDCs) and macrophages (Mf). We found that, in comparison with a noninvasive serovar, the invasive Salmonellastrains Ty2 and D23580 have downregulated metabolic activity inside human macrophages and dendritic cells and used lipids as alternative carbon source, perhaps a strategy to escape from the host immune response. Proteomic analysis using high sensitivity mass spectrometry validated the findings of Raman-DIP analysis.

Pear (Pyrus) is a globally grown fruit, with thousands of cultivars in five domesticated species and dozens of wild species. However, little is known about the evolutionary history of these pear species and what has contributed to the distinct phenotypic traits between Asian pears and European pears. We report the genome resequencing of 113 pear accessions from worldwide collections, representing both cultivated and wild pear species. Based on 18,302,883 identified SNPs, we conduct phylogenetics, population structure, gene flow, and selective sweep analyses. Furthermore, we propose a model for the divergence, dissemination, and independent domestication of Asian and European pears in which pear, after originating in southwest China and then being disseminated throughout central Asia, has eventually spread to western Asia, and then on to Europe. We find evidence for rapid evolution and balancing selection for S-RNase genes that have contributed to the maintenance of self-incompatibility, thus promoting outcrossing and accounting for pear genome diversity across the Eurasian continent. In addition, separate selective sweep signatures between Asian pears and European pears, combined with co-localized QTLs and differentially expressed genes, underline distinct phenotypic fruit traits, including flesh texture, sugar, acidity, aroma, and stone cells. This study provides further clarification of the evolutionary history of pear along with independent domestication of Asian and European pears. Furthermore, it provides substantive and valuable genomic resources that will significantly advance pear improvement and molecular breeding efforts.

Here we analyse genetic variation, population structure and diversity among 3,010 diverse Asian cultivated rice (Oryza sativaL.) genomes from the 3,000 Rice Genomes Project. Our results are consistent with the five major groups previously recognized, but also suggest several unreported subpopulations that correlate with geographic location. We identified 29 million single nucleotide polymorphisms, 2.4 million small indels and over 90,000 structural variations that contribute to within- and between-population variation. Using pan-genome analyses, we identified more than 10,000 novel full-length protein-coding genes and a high number of presence–absence variations. The complex patterns of introgression observed in domestication genes are consistent with multiple independent rice domestication events. The public availability of data from the 3,000 Rice Genomes Project provides a resource for rice genomics research and breeding.

ABSTRACTIntroduction:In the three patent applications, the impact of changing the pyrimidine core of the rilpivirine (RPV) to a variety of alternative fused cores was explored, culminating in the identification of a series of conformationally restricted compounds with comparable potencies against WT and mutant HIV-1 strains with those of efavirenz (EFV) and RPV, and higher security in the Human Ether-a-go-go-Related Gene (hERG) assay.Areas covered:The present review provides a fused pyrimidine and isoquinoline derivatives as potent HIV-1 NNRTIs, and highlights the conformational restriction strategies in the development of NNRTIs.Expert opinion:The molecular docking analysis of the newly synthesized compounds maintain the classical horseshoe conformation and shares similar binding mode with RPV. The conformational restriction strategies have greatly accelerated the optimization of the DAPY NNRTIs and contribute to finding new chemical entities (NCEs) with favorable druggability.

Ginger (Zingiber officinale), the type species of Zingiberaceae, is one of the most widespread medicinal plants and spices. Here, we report a high-quality, chromosome-scale reference genome of ginger ‘Zhugen’, a traditionally cultivated ginger in Southwest China used as a fresh vegetable, assembled from PacBio long reads, Illumina short reads, and high-throughput chromosome conformation capture (Hi-C) reads. The ginger genome was phased into two haplotypes, haplotype 1 (1.53 Gb with a contig N50 of 4.68 M) and haplotype 0 (1.51 Gb with a contig N50 of 5.28 M). Homologous ginger chromosomes maintained excellent gene pair collinearity. In 17,226 pairs of allelic genes, 11.9% exhibited differential expression between alleles. Based on the results of ginger genome sequencing, transcriptome analysis, and metabolomic analysis, we proposed a backbone biosynthetic pathway of gingerol analogs, which consists of 12 enzymatic gene families, PAL, C4H, 4CL, CST, C3’H, C3OMT, CCOMT, CSE, PKS, AOR, DHN, and DHT. These analyses also identified the likely transcription factor networks that regulate the synthesis of gingerol analogs. Overall, this study serves as an excellent resource for further research on ginger biology and breeding, lays a foundation for a better understanding of ginger evolution, and presents an intact biosynthetic pathway for species-specific gingerol biosynthesis.