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Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRASmutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8expression (termed KRT8+alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRASmutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Krasmutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

The kidney is an essential organ that ensures bodily fluid homeostasis and removes soluble waste products from the organism. Nephrons, the functional units of the kidney, comprise a blood filter, the glomerulus or glomus, and an epithelial tubule that processes the filtrate from the blood or coelom and selectively reabsorbs solutes, such as sugars, proteins, ions, and water, leaving waste products to be eliminated in the urine. Genes coding for transporters are segmentally expressed, enabling the nephron to sequentially process the filtrate. The Xenopusembryonic kidney, the pronephros, which consists of a single large nephron, has served as a valuable model to identify genes involved in nephron formation and patterning. Therefore, the developmental patterning program that generates these segments is of great interest. Prior work has defined the gene expression profiles of Xenopusnephron segments via in situhybridization strategies, but a comprehensive understanding of the cellular makeup of the pronephric kidney remains incomplete. Here, we carried out single-cell mRNA sequencing of the functional Xenopuspronephric nephron and evaluated its cellular composition through comparative analyses with previous Xenopusstudies and single-cell mRNA sequencing of the adult mouse kidney. This study reconstructs the cellular makeup of the pronephric kidney and identifies conserved cells, segments, and associated gene expression profiles. Thus, our data highlight significant conservation in podocytes, proximal and distal tubule cells, and divergence in cellular composition underlying the capacity of each nephron to remove wastes in the form of urine, while emphasizing the Xenopuspronephros as a model for physiology and disease.

The enantioselective synthesis of 6′-boryl-anti-1,2-oxaborinan-3-enes is reported. A Cu-catalyzed highly stereoselective 1,4-protoboration of 1,1-bisboryl-1,3-butadiene is developed to generate (E)-α,δ-bisboryl-crotylboronate. The chiral phosphoric-acid-catalyzed asymmetric allylboration of aldehydes with the boron reagent produces 6′-boryl-anti-1,2-oxaborinan-3-enes with excellent Z-selectivities and enantioselectivities. The product contains a vinyl and alkyl boronate unit that can directly participate in a variety of subsequent transformations.

Investigations of the ground and excited states absorption are very important for the development of advanced optical limiters. Linear response time-dependent density-functional theory (LR-TDDFT) has become popular for calculating absorption spectra of molecules in their ground state. However, calculation for the excited state turns out to be much more complicated. In the present paper, it is shown that the transition dipole moments between two excited states can be well-estimated based on auxiliary excited-state wavefunctions extracted from the LR-TDDFT calculation. For application, the absorption spectra in zinc phthalocyanine (ZnPc), distyrylbenzene (DSB), and 3-methylthiophenes heptamer (3MT heptamer) are investigated in detail along with different density functional models, and results are compared with experimental data and other theoretical methods. The computational cost of the present method is much cheaper than other theoretical methods, such as quadratic response TDDFT.

Stereoselective synthesis of γ,δ-bifunctionalized homoallylic alcohols and ethers via chemoselective allylation is reported. Pd-catalyzed 1,2-diboration of allenylsilane provided a novel 1,1,2-trifunctional allylation reagent. Allylboration of aldehydes with the reagent followed by in situprotection gave TES-protected homoallylic alcohols with excellent Z-selectivities. Chemoselective allylsilation with the same reagent delivered γ,δ-bifunctionalized homoallylic ethers with high E-selectivities. The bifunctionalized alkene group in the products underwent various transformations without erosion of the olefin geometry.

A Cu-catalyzed addition of silicon or boron nucleophiles to vinylidene cyclopropanes is reported. The reactions generated propargylic silane or boron products by forming a C–Si or C–B bond at the terminal carbon of the allene moiety of vinylidene cyclopropanes. The obtained silicon and boron reagents are versatile intermediates that can undergo a variety of transformations to give synthetically useful products. Preliminary mechanistic studies indicated a copper enolate was involved in the reaction process.

A synthetic method to prepare dispiroheterocycles containing two all-carbon quaternary centers efficiently that relies on the gold(I)-catalyzed double spirocyclization of 3-ene-1,7-diyne esters is described. The suggested mechanism delineates a rare example of a dispirocyclization featuring two 1,n-acyloxy shifts comprising a 1,3-acyloxy migration and an interrupted 1,5-acyl migration that was achieved with the assistance of residual water in the reaction media.

A synthetic method for the efficient preparation of partially hydrogenated benzo[f]cyclobuta[cd]cyclopenta[h]benzofurans and cyclopropa[c]chromen-3a(1H)-ols that relies on the gold(I)-catalyzed cascade cycloisomerization of 3-allyloxy-1,6-diynes is described.

Complex microbial ecosystems in both gastrointestinal and respiratory systems have been found to have a significant impact on human health. Growing evidence has demonstrated that intestinal dysbiosis can increase vulnerability to pulmonary infections. However, changes in the composition and activity of the intestinal flora after probiotic supplementation may alter the disease state of the host. The effects of probiotics on the improvement of diseases, such as severe pneumonia (SP), in intensive care units (ICUs) remain controversial. We retrospectively included 88 patients diagnosed with severe pneumonia between April 2021 and June 2022. The patients were divided into 2 groups: a probiotic group (n = 40) and a control group (n = 48). In addition, changes in CRP, PCT, WBC, IL-6, Clostridium difficile toxin, and PSI pneumonia scores were assessed. Changes in the gut microbiome of the patients were assessed using amplicon sequencing. Compared to the control group, a significant reduction in the incidence of length of hospital stay was observed in the probiotic group, but there were no significant differences in the mortality rate, duration of fever, diarrhea, and constipation. After probiotic treatment, CRP, PCT, WBC, and PSI score were significantly lower than before, and better clinical efficacy was achieved in the probiotic group for the duration of antibiotic therapy. Gut microbiota analysis revealed that the abundance of opportunistic pathogens (e.g., Massilia) increased remarkably at the genus level in the control group, and a significant increase in Erysipelotrichaceae_gewas observed after probiotic intervention. The control group showed an increase in opportunistic pathogens (Citrobacter, Massilia) during the antibiotic treatment. Probiotics interventions inhibit the growth of opportunistic pathogens. In addition, we found that the population of butyrate-producing bacteria (e.g., Ruminococcaceae UCG-005) increased following probiotic treatment.

Diastereoselective synthesis of γ-boryl substituted syn-β-alkoxy- or syn-β-amino-homoallylic alcohols is developed. Pt-catalyzed regioselective diboration of alkoxyallene or aminoallene with B2pin2occurred at the terminal alkene unit of the allene to give (Z)-γ-alkoxy- or (Z)-γ-amino-β-boryl substituted allylboronates with high selectivities. Addition of the allylboronates to aldehydes followed by protection of the resulting secondary hydroxyl group gave TES-protected syn-1,2-diols and syn-1,2-amino alcohols with high diastereoselectivities. The vinyl-Bpin group in the products is a useful handle for further transformations.

Background: Natural products have been an exemplary source of new drugs as they have served as direct or indirect precursors for many currently available medicines. The natural product β -elemene has been used clinically in the treatment of various cancers; however, its efficacy is hampered by its poor solubility and bioavailability. Methods: An aldehyde metabolite of β-elemene, 13-β-elemenal, was further identified and proved to exhibit significantly better anti-proliferative activity than β -elemene. A series of prodrug-like 13- and 14-substituted ester derivatives, as well as their alcohol and aldehyde intermediates, were rational designed, synthesized and biologically evaluated. Results: The intermediates and ester derivatives of β-elemene displayed comparable to better antiproliferative activity on human cancer cell lines (A549, HepG-2 and U87). Notably, ester compounds 10d, 10m-o, 10s, 10t, 13d, 13h and 13m-o were superior over β-elemene in their antiproliferation effects, while the predicted in vivo metabolites of the designed ester compounds, 13- β-elemental (8) and 14-β-elemental (11), demonstrated the most potent anti-proliferative effect. Conclusion: Most of the esters displayed better antitumor effects than β -elemene, which were predicted to play more significant roles in the in vivo treatment by being metabolized continuously to β -elemental. More importantly, these compounds showed better drug-like properties, such as decreased LogP values and improved solubility.

Inspired by a remarkably high-temperature superconductivity (Tc∼ 473 K) obtained from ternary lithium magnesium hydride and considering the relatively close electronegativity of the elements magnesium and beryllium, similar superconductivity could also appear in ternary lithium beryllium hydride. Here, we investigate the structural stabilities and superconducting properties of Li2BeH6at 50–400 GPa based on the first-principles calculation and the CALYPSO structure prediction method. The calculated results show that the ground state of Li2BeH6is maintained as the Pbamphase at 50–400 GPa. In addition, a phase transition from semiconductor to metal occurs at about 300 GPa, and the superconducting transition temperature of 19 K at 350 GPa is predicted. More importantly, two highly symmetric metastable phases I4/mmmand Fm3̅mare found in Li2BeH6, which can be synthesized in an experiment by analyzing their decomposition routes. Electron–phonon coupling analysis reveals that I4/mmmand Fm3̅mmight be potential high temperature superconductors with a Tcof 134 and 149 K at 150 and 100 GPa respectively, which slightly higher than 98 K at 100 GPa in Li2BH6. This excellent superconductivity may be attributed to the BeH6octahedral structure with a laminar distribution in I4/mmmand Fm3̅m. Our studies will provide some new thoughts for further in-depth exploration of ternary hydrogen-rich compounds with superior superconducting properties.

We investigate the structural phase transition and optical properties of RbSnX3(X = Cl, Br, I) at pressures of 0 and 160 GPa by means of the first-principles theory. Our calculated results indicate that two reconstructive phase transitions of P21/c(I) → ppPv-Pnma(IV) → P21/c(II) for RbSnCl3, ppPv-Pnma→ I4mm→ P21/c(III) for RbSnBr3, and ppPv-Pnma→ Pmn21→ ppPv-Pnma(IV) for RbSnI3are predicted. New ppPv-Pnma(IV) differed from other ppPv-Pnmaphases in previous reports [Phys. Rev. B2018, 97, 020103(R)], and diversified P21/cphases are obtained. More importantly, RbSnBr3and RbSnI3systems present an obvious piezochromic effect and a semiconductor-to-metal phase transition. Furthermore, the pressure-induced optical and mechanical properties of these stable phases are investigated and analyzed comprehensively. Meanwhile, a superconducting critical temperature Tcof 1.2 K at a pressure of 140 GPa of the metal phase ppPv-Pnma(IV) in RbSnI3is also estimated. These results provide comprehensive theoretical guidance and support for enriching the high-pressure phase diagram and diversified properties of halide perovskites under high pressure.

By coupling nitric oxide (NO)-donating moieties with ATPT, an orally active AT1 receptor antagonist, a series of novel NO-releasing derivatives with N-phenylpyrrolyl-2-tetrazole moiety were designed and synthesized. The NOreleasing assay indicated that compound 4c had good maximum amount of NO release. Moreover the target compounds were evaluated for their antagonism of AT1 receptor with induced contraction in the rat thoracic aortic ring, and the results showed that compound 4c exhibited potent antagonistic activity of AT1 receptor, which was obviously superior to that of the control drug losartan. These results suggested that NO-donor ATPT hybrids may provide a promising approach for the search for novel antihypertensive agents.

The daunting task of lung epithelium development is to transform a cluster of foregut progenitors into a three‐dimensional (3D) tubular network with distinct cell types distributed at their appropriate locations. A complete understanding of lung development needs to address not only how, but also where, different cell types form. We propose that the lung epithelium forms through regulated deployment of three developmental programs: branching morphogenesis to expand progenitors and build a tree‐like tubular network, airway differentiation to specify cells for the proximal conducting airways, and alveolar differentiation to specify cells for the peripheral gas exchange region. Each developmental program has its unique morphological features and molecular control mechanisms; their spatiotemporal coordination can be accounted for in a balanced progenitor model where progenitors balance between alternative developmental programs in response to spatiotemporal cues. This model integrates progenitor morphogenesis and differentiation, and provides new insights to lung immaturity in preterm birth and lung evolution. Advanced gene targeting and 3D imaging tools are needed to achieve a comprehensive understanding of lung epithelial progenitors on molecular, cellular, and morphological levels. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular DifferentiationSignaling Pathways > Cell Fate SignalingVertebrate Organogenesis > From a Tubular Primordium: Branched

An unprecedented Sc(OTf)3-catalyzed C2-selective cyanation/defluorination cascade of perfluoroalkylated 3-indolylmethanols with TMSCN is described, which provides a novel and practical strategy for the synthesis of structurally diverse 3-(2-cyano)-indolyl substituted gem-difluoroalkenes and β-fluoro-β-perfluoroalkylalkenes. The reaction features excellent regio- and stereoselectivity and broad substrate scope. Notably, the obtained gem-difluoroalkenes and β-fluoro-β-perfluoroalkylalkenes could be easily transformed into 3-fluoro(perfluoroalkyl)-β-carbolines with excellent efficiency simply by treating them with Grignard reagents or DIBAL-H under mild reaction conditions.

Mammalian organs consist of diverse, intermixed cell types that signal to each other via ligand-receptor interactions – an interactome – to ensure development, homeostasis and injury-repair. Dissecting such intercellular interactions is facilitated by rapidly growing single-cell RNA sequencing (scRNA-seq) data; however, existing computational methods are often not readily adaptable by bench scientists without advanced programming skills. Here, we describe a quantitative intuitive algorithm, coupled with an optimized experimental protocol, to construct and compare interactomes in control and Sendai virus-infected mouse lungs. A minimum of 90 cells per cell type compensates for the known gene dropout issue in scRNA-seq and achieves comparable sensitivity to bulk RNA sequencing. Cell lineage normalization after cell sorting allows cost-efficient representation of cell types of interest. A numeric representation of ligand-receptor interactions identifies, as outliers, known and potentially new interactions as well as changes upon viral infection. Our experimental and computational approaches can be generalized to other organs and human samples.

The lung undergoes a striking repair process in response to severe injuries such as influenza infection. A study now demonstrates that associated stem/progenitor cells are heterogeneous in nature and comprise subpopulations dominated by hypoxia/Notch or Wnt signalling. Modulation of this heterogeneity in favour of functional repair may have therapeutic value.

ABSTRACTHeteroresistance refers to phenotypic heterogeneity of microbial clonal populations under antibiotic stress, and it has been thought to be an allocation of a subset of “resistant” cells for surviving in higher concentrations of antibiotic. The assumption fits the so-called bet-hedging strategy, where a bacterial population “hedges” its “bet” on different phenotypes to be selected by unpredicted environment stresses. To test this hypothesis, we constructed a heteroresistance model by introducing a blaCTX-M-14gene (coding for a cephalosporin hydrolase) into a sensitive Escherichia colistrain. We confirmed heteroresistance in this clone and that a subset of the cells expressed more hydrolase and formed more colonies in the presence of ceftriaxone (exhibited stronger “resistance”). However, subsequent single-cell-level investigation by using a microfluidic device showed that a subset of cells with a distinguishable phenotype of slowed growth and intensified hydrolase expression emerged, and they were not positively selected but increased their proportion in the population with ascending antibiotic concentrations. Therefore, heteroresistance—the gradually decreased colony-forming capability in the presence of antibiotic—was a result of a decreased growth rate rather than of selection for resistant cells. Using a mock strain without the resistance gene, we further demonstrated the existence of two nested growth-centric feedback loops that control the expression of the hydrolase and maximize population growth in various antibiotic concentrations. In conclusion, phenotypic heterogeneity is a population-based strategy beneficial for bacterial survival and propagation through task allocation and interphenotypic collaboration, and the growth rate provides a critical control for the expression of stress-related genes and an essential mechanism in responding to environmental stresses.IMPORTANCEHeteroresistance is essentially phenotypic heterogeneity, where a population-based strategy is thought to be at work, being assumed to be variable cell-to-cell resistance to be selected under antibiotic stress. Exact mechanisms of heteroresistance and its roles in adaptation to antibiotic stress have yet to be fully understood at the molecular and single-cell levels. In our study, we have not been able to detect any apparent subset of “resistant” cells selected by antibiotics; on the contrary, cell populations differentiate into phenotypic subsets with variable growth statuses and hydrolase expression. The growth rate appears to be sensitive to stress intensity and plays a key role in controlling hydrolase expression at both the bulk population and single-cell levels. We have shown here, for the first time, that phenotypic heterogeneity can be beneficial to a growing bacterial population through task allocation and interphenotypic collaboration other than partitioning cells into different categories of selective advantage.