Nature Communications

Published by Springer Nature
Online ISSN: 2041-1723
Discipline: Multidisciplinary
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Nature Communications is an open access, multidisciplinary journal dedicated to publishing high-quality research in all areas of the biological, health, physical, chemical and Earth sciences. Papers published by the journal aim to represent important advances of significance to specialists within each field. We are committed to providing an efficient service for both authors and readers. Our team of independent editors make rapid and fair publication decisions. Prompt dissemination of accepted papers to a wide readership and beyond is achieved through a programme of continuous online publication.



Recent publications
Detection of antibody binding to ring-infected erythrocytes (rIEs). Malaria-immune plasma shows modest to low levels of binding to rIEs in comparison to mIEs in immunofluorescence assays. No binding detected with malaria-naive serum or with the secondary antibody in the absence of malaria-immune plasma. Representative data from 3 independent experiments with similar results. Source data are provided as a Source Data file.
Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/μl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and −140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria.
Structures of RML, aRML, and 263 K prions from cryo-EM. Core sequences of PrP subunits in a RML filaments and b aRML filaments. c Comparison of PrP conformations in RML and the 263 K prion fibrils. d Lateral views of aRML and 263 K fibrils showing stacks of three rungs. a and c are adapted from Manka et al.; b and d are adapted from Hoyt et al.
The prion hypothesis embodies the radical concept that prion proteins contain the necessary information for infectious replication within their shape, thus obviating the requirement for genomic material. Two elegant papers by Hoyt et al. and Manka et al. describing high-resolution structures of infectious prions bring us closer to answering the long-standing question of how different prion conformations produce heritably distinct diseases.
New microfluidic systems for whole organism analysis and experimentation are catalyzing biological breakthroughs across many fields, from human health to fundamental biology principles. This perspective discusses recent microfluidic tools to study intact model organisms to demonstrate the tremendous potential for these integrated approaches now and into the future. We describe these microsystems' technical features and highlight the unique advantages for precise manipulation in areas including immobilization, automated alignment, sorting, sensory, mechanical and chemical stimulation, and genetic and thermal perturbation. Our aim is to familiarize technologically focused researchers with microfluidics applications in biology research, while providing biologists an entrée to advanced microengineering techniques for model organisms.
Examples of the ambiguities embedded in the calculation of global irrigation water withdrawals 4 . a Uncertainties in the estimation of the crop evapotranspiration (ET c ). PM and PT stand for the Penman-Monteith and the Priestley-Taylor equation, respectively. Data is retrieved from Nichols et al. 11 . We describe the uncertainty in k c with the values reported for salt cedar for May 4 . b Distribution of the irrigation efficiency of China after propagating uncertainties. The red, dashed line marks the efficiency value used by some large-scale models 12 . c Distribution of the water withdrawn to irrigate wheat in a specific grid cell of the Uvalde County, TX, USA (lon = −99.7083, lat = 29.4583), January 6-7, 2007. All uncertainties in the calculation of IWW are considered 4 . The red, vertical line is the estimate produced when the uncertain parameters used in the calculation of IWW are characterized with point estimates (e.g., mean values).
Miscalculating the volumes of water withdrawn for irrigation, the largest consumer of freshwater in the world, jeopardizes sustainable water management. Hydrological models quantify water withdrawals, but their estimates are unduly precise. Model imperfections need to be appreciated to avoid policy misjudgements.
Polygenic scores can identify individuals with high disease risk based on inborn DNA variation. We explore their potential to enrich clinical trials by identifying individuals based on higher risk of disease (‘prognostic enrichment’), or increased probability of benefit (‘predictive enrichment’).
Practical guidelines to introduce an equity lens into the computational modeling of infectious diseases and related challenges. The figure illustrates and summarizes key recommendations and associated challenges, grouped by area of relevance in the data-model framework of computational epidemiology: surveillance data, behavioral data, and epidemic models. SES socioeconomic status.
The COVID-19 pandemic has highlighted how structural social inequities fundamentally shape disease dynamics, yet these concepts are often at the margins of the computational modeling community. Building on recent research studies in the area of digital and computational epidemiology, we provide a set of practical and methodological recommendations to address socioeconomic vulnerabilities in epidemic models. The COVID-19 pandemic has highlighted how structural social inequities fundamentally shape disease dynamics. Here, the authors provide a set of practical and methodological recommendations to address socioeconomic vulnerabilities in epidemic models.
AMP-activated protein kinase (AMPK) mediates the glucose-lowering effect of the antidiabetic agent metformin, but the sites of action remain unclear. In the March issue of Nature Communications, Zhang and colleagues reported that intestinal epithelium-specific AMPKα1 knockout mice fail to respond to metformin and exhibit disruption in metabolic homeostasis secondary to changes in the gut microbiome. This highlights a therapeutic potential of targeting intestinal AMPK for diabetes.
Malaria cases and deaths remain unacceptably high and are resurgent in several settings, though recent developments inspire optimism. This includes the approval of the world’s first malaria vaccine and results from novel vaccine candidates and trials testing innovative combinatorial interventions.
Studying malaria transmission biology using scRNA-sequencing provides information on within-host strain diversity and transcriptional states. Here, we comment on our collaborative efforts at establishing single-cell capacities in sub-Saharan Africa and the challenges encountered in Mali’s endemic setting.
Economic evaluations of public health interventions to prevent malaria should consider the adoption of wider perspectives and the inclusion of non-health impacts, particularly economic development outcomes, such as education. This is especially relevant in malaria elimination settings and in the context of the current SARS-CoV-2 pandemic.
On the cusp of Plasmodium falciparum (Pf) elimination, Thailand is accelerating towards zero malaria by 2024. This commentary reviews the heart of its success—effective surveillance—and what else may be needed to reach zero on time.
Exciton-specific vibrational structure and IR assignments. Slices of 2DEV spectrum at ω exc. = 14,690 cm −1 and ω exc. = 14,940 cm −1 , corresponding to the energies of exciton 2 and 8 at early (pink, 180 fs) and later (blue, 89 ps) waiting times. The difference absorption spectra of P + /P (dotted line) and Phe/Phe (solid line) are shown above for comparison (where the signs have been reversed to match the convention of the 2DEV data). Vertical dotted (solid) lines indicate band assignments corresponding P + /P (Phe/Phe) while dash-dotted lines distinguish more ambiguous assignments. The black arrow in exciton 2 marks the Chl D1 + mode at 1716 cm −1 and in exciton 8 marks the Chlz D1 ground state bleach. The P + /P and Phe/Phe spectra are reproduced from Refs. 30 and 29 with permission.
Dynamics of the PSII-RC. The time-dependent evolution of 2DEV spectra corresponding to excitons a 1, b 2, c 5, and d 8. The energy ranges for ω exc. are identical to those in Fig. 3. The waiting times are 60 fs (red), 850 fs (pink), 1.3 ps (yellow), 6.1 ps (light green), 39 ps (light blue), and 89 ps (blue). Bottom left and right panels show the range of ω det. = 1665-1695 cm −1 and 1705-1725 cm −1 , highlighting the shifting behavior of the GSB band of Chl and red-shifting behavior of the Chl + band.
2DEV spectral evolution and ZNLS dynamics of the PSII-RC. a 2DEV spectra of the PSII-RC at different waiting times. Zero node line slope (ZNLS), obtained by a linear fit of the zero signal intensity distribution along the excitation axis, is depicted in the spectra as a dotted line. Contour levels are drawn in 5% intervals. b ZNLS dynamics of the PSII-RC. Red dots indicate the ZNLS value at each waiting time and the black curve shows the fit result of double exponential functions (and an offset) with time constants of 3.8 ± 0.9 and 33 ± 9 ps.
IR frequency assignments of the PSII-RC.
Photosystem II is crucial for life on Earth as it provides oxygen as a result of photoinduced electron transfer and water splitting reactions. The excited state dynamics of the photosystem II-reaction center (PSII-RC) has been a matter of vivid debate because the absorption spectra of the embedded chromophores significantly overlap and hence it is extremely difficult to distinguish transients. Here, we report the two-dimensional electronic-vibrational spectroscopic study of the PSII-RC. The simultaneous resolution along both the visible excitation and infrared detection axis is crucial in allowing for the character of the excitonic states and interplay between them to be clearly distinguished. In particular, this work demonstrates that the mixed exciton-charge transfer state, previously proposed to be responsible for the far-red light operation of photosynthesis, is characterized by the Chl D1 ⁺ Phe radical pair and can be directly prepared upon photoexcitation. Further, we find that the initial electron acceptor in the PSII-RC is Phe, rather than P D1 , regardless of excitation wavelength.
Mechanism. a FTIR spectrum of PEGA, MEG2, MEG2-Li. b The vibration changes of C-O-C on MMA side chains under stretching. c Typical forceextension curves during force spectroscopy measurements of the stretching of a single chain of MEG2-Li: the breakage of PMMA interactions, the breakage of Li + -O interactions and slippage of PEGA side chains. d Typical force-extension curves of MEG2-Li from stretching-releasing cycles showing reversible unfolding and refolding.
Ligaments are flexible and stiff tissues around joints to support body movements, showing superior toughness and fatigue-resistance. Such a combination of mechanical properties is rarely seen in synthetic elastomers because stretchability, stiffness, toughness, and fatigue resistance are seemingly incompatible in materials design. Here we resolve this long-standing mismatch through a hierarchical crosslinking design. The obtained elastomer can endure 30,000% stretch and exhibit a Young’s modulus of 18 MPa and toughness of 228 MJ m ⁻³ , outperforming all the reported synthetic elastomers. Furthermore, the fatigue threshold is as high as 2,682 J m ⁻² , the same order of magnitude as the ligaments (~1,000 J m ⁻² ). We reveal that the dynamic double-crosslinking network composed of Li ⁺ -O interactions and PMMA nanoaggregates allows for a hierarchical energy dissipation, enabling the elastomers as artificial ligaments in soft robotics.
Tertiary lymphoid structures and immune cell crosstalk in the breast cancer immune microenvironment. Breast tumor tissue sections from surgical resections (formalin-fixed and paraffin-embedded; FFPE) analyzed using multiplex immunohistochemistry. A Upper left image: region of an untreated primary breast tumor showing multiplex IHCstained tumor cells (pan CK, cyan) with immune cells in stromal localized TLS. TIL include CD4 (green) and CD8 (white) T cells, B cells (CD20, red), Tfr/Treg [Foxp3 (orange nucleus) plus CD4 (green membrane)] and macrophage lineage (CD68, magenta); upper right image: consecutive section of the same tumor region showing CD4 T cells (green), B cells (CD20, red), ICOS+ cells (yellow), Tfh [their pink/white color is a combination of three surface markers: PD-1 (magenta), ICOS (yellow) and CD4 (green)], Tfr/Treg [Foxp3 (orange nucleus) plus CD4 (green membrane)] and proliferating cells (Ki-67+, cyan; both B cells and tumor cells). B Enlarged region of TIL surrounding tumor islets in a residual tumor surgically resected following pre-surgical treatment. Multiplex IHC-stained tumor cells (pan CK, cyan) and TIL including CD4 (green), CD8 (white), B cells (CD20, red), Treg [Foxp3 (orange nucleus) plus CD4 (green membrane)] and macrophage lineage (CD68, magenta) are shown with examples of the crosstalk between these cells shown in circles (white). mIHC slides were scanned at ×20 magnification.
Tumor-infiltrating lymphocytes (TILs) are critical in the elimination of cancer cells, a concept highlighted by recent advances in cancer immunotherapy. Significant evidence reveals that their organization in tertiary lymphoid structures together with specific subpopulation composition/balances stimulates cellular crosstalk and anti-tumor immunity in patients.
Annual-to-decadal variability in northern midlatitude temperature is dominated by the cold season. However, climate field reconstructions are often based on tree rings that represent the growing season. Here we present cold-season (October-to-May average) temperature field reconstructions for the northern midlatitudes, 1701-1905, based on extensive phenological data (freezing and thawing dates of rivers, plant observations). Northern midlatitude land temperatures exceeded the variability range of the 18th and 19th centuries by the 1940s, to which recent warming has added another 1.5 °C. A sequences of cold winters 1808/9-1815/6 can be explained by two volcanic eruptions and unusual atmospheric flow. Weak southwesterlies over Western Europe in early winter caused low Eurasian temperatures, which persisted into spring even though the flow pattern did not. Twentieth century data and model simulations confirm this persistence and point to increased snow cover as a cause, consistent with sparse information on Eurasian snow in the early 19th century.
Honeybees are highly social insects with a rich behavioral repertoire and are a versatile model for neurobiological research. Their gut microbiota comprises a limited number of host-restricted bacterial phylotypes that are important for honeybee health. However, it remains unclear how specific gut members affect honeybee behaviors. Here, we find that antibiotic exposure disturbs the gut community and influences honeybee phenotypes under field conditions. Using laboratory-generated gnotobiotic bees, we show that a normal gut microbiota is required for olfactory learning and memory abilities. Brain transcriptomic profiling reveals distinct brain gene expression patterns between microbiota-free and conventional bees. Subsequent metabolomic analyses of both hemolymph and gut samples show that the microbiota mainly regulates tryptophan metabolism. Our results indicate that host-specific Lactobacillus strains promote memory behavior by transforming tryptophan to indole derivatives that activate the host aryl hydrocarbon receptor. Our findings highlight the contributions of specific gut members to honeybee neurological processes, thus providing a promising model to understand host-microbe interactions.
Methods to produce H 2 O 2 Schematic of the anthraquinone process. Schematic of the anthraquinone process (a) direct synthesis (b), and electrocatalytic method (c) to produce H 2 O 2 at the cathode while hydrogen is being oxidized (d) Scheme of the mechanism for direct synthesis of H 2 O 2 on Pd proposed by Abate et al. Figures adapted with permission from reference 28 , Springer Nature (2006). e Scheme of the non-Langmuirian proposed mechanism for direct synthesis of H 2 O 2 . f H 2 O 2 concentrations as functions of time during direct synthesis in protic (methanol-black and water-red) or aprotic (dimethyl sulfoxide-green, acetonitrile-blue, and propylene carbonate-magenta) media. g Scheme of the Langmuir mechanism for direct synthesis of H 2 O 2 . Figures adapted with permission from reference 51 , American Chemical Society (2016).
Current-voltage curves and complied Evans diagram for HOR and ORR. a Evans diagrams compiled from a variety of catalysts which have been reported as HOR and ORR catalysts. An exhaustive overview of all parameters can be found in Table S1. Independent current-voltage curves of both halfcell reactions with low (b) and high (c) HOR and ORR rates as well as one reaction being diffusion limited (d) in the framework of the mixed-potential theory.
Catalysis is inherently driven by the interaction of reactants, intermediates and formed products with the catalyst’s surface. In order to reach the desired transition state and to overcome the kinetic barrier, elevated temperatures or electrical potentials are employed to increase the rate of reaction. Despite immense efforts in the last decades, research in thermo- and electrocatalysis has often preceded in isolation, even for similar reactions. Conceptually, any heterogeneous surface process that involves changes in oxidation states, redox processes, adsorption of charged species (even as spectators) or heterolytic cleavage of small molecules should be thought of as having parallels with electrochemical processes occurring at electrified interfaces. Herein, we compare current trends in thermo- and electrocatalysis and elaborate on the commonalities and differences between both research fields, with a specific focus on the production of hydrogen peroxide as case study. We hope that interlinking both fields will be inspiring and thought-provoking, eventually creating synergies and leverage towards more efficient decentralized chemical conversion processes. Research in thermo- and electrocatalysis have often preceded in isolation, even for similar reactions. Here, the authors compare current trends in both fields and elaborate on the commonalities and differences with a specific focus on the production of hydrogen peroxide.
Cryo-EM structure of the Csy-AcrIF24 complex. a Binding kinetics of AcrIF24 with the Csy complex, measured by surface plasmon resonance (SPR) method. SPR curves (colored curves) were fit kinetically using a 1:1 Langmuir binding model (black lines). The data shown are representative of three independent experiments. b Static light scattering (SLS) studies of the mix of AcrIF24 and the Csy complex under different molar ratios. The predicted composition of each peak based on the calculated molecular weight is shown above the peaks. The calculated molecular weights of the peaks are shown in Supplementary Table 2. c Cryo-EM map of the Csy-AcrIF24 complex with each subunit color-coded. Two views are shown. d Atomic structure of CsyAcrIF24 in cartoon representation with each subunit colored as in c. Two views are shown. e The AcrIF24 dimer in the Csy-AcrIF24 structure. Cryo-EM density is shown in a slate mesh. The MD of AcrIF24 is marked in a box. f Close-up view of the MD of AcrIF24. Cryo-EM density is shown in slate mesh.
Detailed interactions between AcrIF24 and the Csy complex, which is essential to the inhibition capacity. a Overall structure of the Csy-AcrIF24 complex with one AcrIF24 bound to one Csy complex. The Csy complex is shown in the surface model with each subunit colored as in Fig. 3d. AcrIF24 is shown in cartoon model colored in yellow, hot pink, and cyan for its NTD, MD, and CTD, respectively. b-e Close-up view of the interfaces between AcrIF24 and the Csy complex. The interfaces of AcrIF24 NTD -Cas7.6f (b), AcrIF24 NTD -Cas7.5f (c), AcrIF24 MD -Cas7.4f (d), and AcrIF24 MD -Cas7.2f (e) are shown. AcrIF24 is colored as in a, and interacting residues are shown as sticks with cryo-EM density map shown in mesh. f Native gel was used to test the binding between the Csy complex and AcrIF24 or its mutants. Reactions were performed with 0.32 μM Csy complex and AcrIF24 concentrations of 0.16, 0.32, and 0.64 μM following the order indicated by the black triangle. DDRF/AAAA represents the D104A/D105A/R106A/F107A mutant. The gel was stained with Coomassie blue staining. g Mutations of the interface residues of AcrIF24 decreased its inhibition capacity of the in vitro cleavage activity of the type I-F CRISPR system. Reactions are performed as in Fig. 1a. DDRF/AAAA represents the D104A/D105A/R106A/F107A mutant.
CRISPR-Cas systems are prokaryotic adaptive immune systems and phages use anti-CRISPR proteins (Acrs) to counteract these systems. Here, we report the structures of AcrIF24 and its complex with the crRNA-guided surveillance (Csy) complex. The HTH motif of AcrIF24 can bind the Acr promoter region and repress its transcription, suggesting its role as an Aca gene in self-regulation. AcrIF24 forms a homodimer and further induces dimerization of the Csy complex. Apart from blocking the hybridization of target DNA to the crRNA, AcrIF24 also induces the binding of non-sequence-specific dsDNA to the Csy complex, similar to AcrIF9, although this binding seems to play a minor role in AcrIF24 inhibitory capacity. Further structural and biochemical studies of the Csy-AcrIF24-dsDNA complexes and of AcrIF24 mutants reveal that the HTH motif of AcrIF24 and the PAM recognition loop of the Csy complex are structural elements essential for this non-specific dsDNA binding. Moreover, AcrIF24 and AcrIF9 display distinct characteristics in inducing non-specific DNA binding. Together, our findings highlight a multifunctional Acr and suggest potential wide distribution of Acr-induced non-specific DNA binding.
Two cell-type CRISPR/Cas9 screen using NK cell-mediated killing of GSCs. a Schematic of screen design. Screening hits in GSC/NK cell co-culture (n = 2 samples per cell line) were compared with GSC monoculture to identify genes that induce resistance or sensitivity to NK cell killing (created with b Heatmap of individual and averaged scores of top 25 genes that increase sensitivity or resistance across four GSC models. c GO gene set enrichment analysis of hits. Y axis indicates −log10 FDR of gene set enrichment. d Scatter plot showing the stratification of genes identified by the GSC CRISPR/Cas9 two cell-type screen ordered by score. Highlighted in red are known genes known that typically activate NK cells (MICA, MICB, ULBP1, ULBP2, ULBP3, FAS, TNFRSF10A [TRAIL-R1], TNFRSF10B [TRAIL-R2], and ICAM1; and highlighted in blue are genes are known to inhibit NK cell-mediated activity (HLA-A, HLA-B, HLA-C, HLA-E, TAP1, and TAP2).
Gene expression analysis of CHMP2A-KO in GSCs. a Differential gene expression comparing CHMP2A-KO vs shCONT (n = 2 samples per cell line). Genes in red are upregulated with a knockout at log2 FC>1 and FDR<0.05, whereas genes in blue are downregulated with a knockout at log2 FC < −1 and FDR < 0.05. Top altered genes are labeled in the panel. b Reactome and KEGG gene set enrichment analysis of genes upregulated with CHMP2A KO. Y axis indicates −log10 FDR of the gene set enrichment.
Secretion of CXCL10 and CXCL12 from CHMP2A-KO tumor cells increases NK cell migration. a ELISA comparing CXCL10 concentration WT and KO in CW468 and Cal27 cells. The error bars represent ±SEM across n = 3 independent experiments two-tailed Student's t test was performed to determine statistical significance. b ELISA comparing CXCL10 concentration in WT and KO in CW468 and Cal27 cells. Error bars represent ±SEM from the mean across n = 3 independent experiments two-tailed Student's t test was performed to determine statistical significance. c charts representing the number of NK cells migrating towards CW468-WT and KO (top chart) and Cal27-WT and KO (lower chart) cells analyzed by flow cytometry. Error bars represent ±SEM across n = 3 independent experiments. Two-tailed Student's t test was performed to determine statistical significance. d Immunoblot analysis of NF-κB P65 in Cal27 CHMP2A-WT or KO. GAPDH has been used as a loading control. e Dual-luciferase reporter assay showing NF-κB activity in Cal27 CHMP2A-WT and KO cells. Error bars represent ±SEM from the mean across n = 3 replicates, two-tailed Student's t test was performed to determine statistical significance. d, e Representative of n = 3 independent experiments.
Cal27-derived EVs secretion is reduced in CHMP2A-KO cells and in tipifarnib treated WT Cal27 cells. a, b Charts showing the size distribution and number of EVs secreted from Cal27-WT (a) and KO (b) cells. Samples were loaded on a Nanosight LM10 and analyzed for 1 min for each of n = 5 technical replicates and the error bars represent ±SEM across n = 5. c comparison of EV number in Cal27-WT and KO calculated on 10 μl of EV suspension diluted in 1 ml of DPBS. d average EVs size analyzed during nanoparticle tracking of Cal27-WT and KO derived EVs. e comparison of EVs number in Cal27-WT treated with tipifarnib (Tip) and the corresponding DMSO control (CTRL) calculated on 10 μl of EVs suspension diluted in 1 ml of DPBS. c-e error bars represent ±SEM across n = 5 technical replicates and unpaired two-tailed Student's t test was performed to determine statistically. f 4 hour cytotoxicity assay using NK cells as effectors against Cal27-WT, KO treated with tipifarnib or DMSO (CTRL). Error bars represent ±SEM, n = 3 replicates. Statistical analysis was performed by two-way ANOVA and Bonferroni's post hoc multiple comparison test (comparing Cal27-WT vs Cal27-WT + Tip E:T, 10:1 p < 0.0001; 5:1 p < 0.0001; 2:1 and 1:1 ns). Data are shown in a-f, representative of n = 3 independent experiments.
CHMP2A-KO HNSCC xenograft model shows increased sensitivity to NK cells. a Schematic of in vivo treatment. Non-obese diabetic/severe combined immunodeficiency/γc −/− (NSG) mice were inoculated subcutaneously with 6 × 10 6 cells (Cal27-WT or KO) and injected i.v. with 1 × 10 7 NK cells. NK cells were supported by injections IL-15 daily and IL-2 every other day for 1 week. Tumor volume was monitored every 2-3 days. b Tumor volume progression over 21 days shown as mean ±SEM of n = 5 mice per treatment. Statistical analysis was performed by two-way ANOVA and Bonferroni's post hoc multiple comparison test (ns, not significant). c Representative flow cytometry dot plots showing increased NK cell infiltration in Cal27 CHMP2A KO tumors. The gating strategy has been defined by combining NK cells and a cell suspension from the untreated tumor. Tumor samples without NK cell treatment were mixed with 2 × 10 4 human NK cells, stained with anti-human CD45 and anti-human CD56 antibodies or isotype controls, and analyzed. Cells double positive for (human) hCD45 and hCD56 were gated and the gate was used to quantify the number of infiltrating NK cells in Cal27-WT and CHMP2A KO tumors. The graph shows the average NK cell infiltration for all mice in each group (n = 4 mice per group). Error bars represent ±SEM across n = 4 technical replicates and an unpaired one-tailed Student's t test was performed to determine statistical significance. d Cartoon describing the proposed mechanism of CHMP2A KO in tumor cells. Tumor cells secrete EVs-bearing ligands like MICA/B and TRAIL, which suppress the antitumor effect of NK cells by binding to NKG2D and TRAIL-R to induce apoptosis on NK cells. By CHMP2A KO we reduce EVs secretion from tumor cells decreasing their inhibitory function. Tumor cells CHMP2A KO also secrete CXCL10 and CXCL12, chemokines that increase NK cell migration culminating in enhanced NK cell-mediated cytotoxicity (the cartoon has been created with
Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
Current limitations and a new approach for open-channel electrofluidics. a Schematic of common fluidic microsystems, comparing operating voltage and characteristic fluidic dimensions. This work offers digital fluidic actuation with micron-scale channel confinement and user-friendly, open-drop loading for either ionic or dielectric solutions. b Schematic of an open-micro-electrofluidic (OMEF) channel that travels a distance, dz, with a circular-sector cross section of radius R and sector angle α. Two electrodes comprise the legs of the sector separated by a gap, g, beneath a passivation layer with thickness t, dielectric permittivity ε t , and contact angle θ 0 . The liquid channel has a dielectric permittivity of ε L , surrounded by an environment with a permittivity of ε 0 and surface tension, γ. c Theoretical threshold voltage necessary to pull a channel of deionized (DI) water using coplanar electrodes (α = π) for various g values as a function of R. Literature values are plotted and in good agreement with our work 38,39,43 . A few of our results using a nonplanar geometry are plotted for comparison. d Reducing α simultaneously reduces the surface-energy cost to extrude OMEF channels (black curve) until spontaneous capillary action occurs and it also confines E-fields more efficiently within the channel volume (red curve, normalized to the coplanar geometry with the same radius). The inset shows simulation of the E-field distribution for a nanogap-stacked electrode whose sidewall forms the OMEF circular-sector channel. Symbols match the definitions of Fig. 1b. Source data are provided as a Source Data file for Fig. 1c, d.
Fluidic applications demonstrating high channel-density parallelization and low-loss viral biosensing. a A spiral-top electrode is patterned out of aluminum, with the bottom gold electrode colored yellow. A drop of PBS is positioned out of view. b Using the device shown in (a), spontaneous capillary flow is observed using a fluorescent dye due to a sidewall exceeding the capillary limit. The liquid channel travels ~684 µm from the drop. c After 3.5 V RMS voltage is applied, the liquid channel wraps around the outer edge of the top electrode and travels an additional ~566 µm in 5 min., for a total length of ~1.25 mm from the drop and 5 µm in width. d An image of a sample chip with five droplets placed for actuation. The inset shows an SEM image of a dense line-array used for channel parallelization (scale bar = 5 µm). e, f Fluorescent image of parallel fluidic channels used to extrude FITC-labeled norovirus-like particles, before (e) and after (f) voltage is applied. Images were artificially colored magenta to distinguish from other experiments. g Infrared spectroscopy was used to confirm the presence of viral material within the channels compared with fluorescent background. Dips unique to the virus samples are circled in black. Source data are provided as a Source Data file. h Three parallel top electrodes with larger separation were used for particle filtration. i After applying 3.5 V RMS , parallel microchannels formed along the edges of the top electrodes, as confirmed using fluorescent Alexa Fluor-594 molecules (red). Larger 190-nm polystyrene beads (green) spiked into the solution are filtered from entering the microchannels due to low-voltage dielectrophoresis.
Open-channel microfluidics enables precise positioning and confinement of liquid volume to interface with tightly integrated optics, sensors, and circuit elements. Active actuation via electric fields can offer a reduced footprint compared to passive microfluidic ensembles and removes the burden of intricate mechanical assembly of enclosed systems. Typical systems actuate via manipulating surface wettability ( i.e ., electrowetting), which can render low-voltage but forfeits open-microchannel confinement. The dielectric polarization force is an alternative which can generate open liquid microchannels (sub-100 µm) but requires large operating voltages (50–200 V RMS ) and low conductivity solutions. Here we show actuation of microchannels as narrow as 1 µm using voltages as low as 0.5 V RMS for both deionized water and physiological buffer. This was achieved using resonant, nanoscale focusing of radio frequency power and an electrode geometry designed to abate surface tension. We demonstrate practical fluidic applications including open mixing, lateral-flow protein labeling, filtration, and viral transport for infrared biosensing—known to suffer strong absorption losses from enclosed channel material and water. This tube-free system is coupled with resonant wireless power transfer to remove all obstructing hardware — ideal for high-numerical-aperture microscopy. Wireless, smartphone-driven fluidics is presented to fully showcase the practical application of this technology.
MTAP deficiency leads increased sensitivity to folate-based therapy in lung adenocarcinoma. a Retrospective analysis schema for the BATTLE-2 trial. b Scatterplot of CDKN2A and MTAP RNA expression divided into four distinct groups with CDKN2A lo /MTAP lo and CDKN2A hi /MTAP hi having no overlap. MTAP cutoff value was 5.44 and CDKN2A cutoff value was 4.6 c Response rates to pemetrexed-based therapy in CDKN2A lo /MTAP lo vs all other groups. Difference is statistically significant by two-sided Fisher's exact test (p = 0.0115). d Generalized linear regression model evaluating the correlation of 10 most altered genes in lung cancer beside MTAP to estimate the odds ratio and p value for each gene independently. Genes with an odds ratio >1 (log (odds ratio) >0) and a p value <0.05 are considered to be positively correlated with response. Genes with an odds ratio <1 (log (odds ratio) <0) and a p value <0.05 are considered to be negatively correlated with response. Adjustments were made for multiple gene comparisons and q value are presented in supplementary table S5. e Example of a patient with metastatic CDKN2A lo /MTAP lo lung adenocarcinoma who partially responded to pemetrexed-based therapy compared to a patient with CDKN2A hi /MTAP hi lung adenocarcimoma who progressed after pemetrexed-based therapy.
Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP def ) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAP def urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP def patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP def patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAP def associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP def and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.
Overall structures and ligand-binding pockets in peptide agonist-FPR-G i complexes. a Overall structures of fMLF-FPR1-G i1 , fM5-FPR2-G i2 , fM9-FPR2-G i2 , fHN-FPR2-G i2 , and Aβ 42 -FPR2-G i2 complexes. The cryo-EM maps and structures are colored according to chains. The peptide ligands are shown as spheres. b Cut-away view of ligand-binding pockets in the peptide agonist-FPR-G i structures. The receptors are shown as surface and cartoon representations. The ligands are shown as sticks. c, d Interactions between the FPRs and the N termini of the peptide agonists. The N-terminal residue fM1 of the peptides in the structures of fMLF-FPR1-G i1 , fM5-FPR2-G i2 , fM9-FPR2-G i2 , and fHN-FPR2-G i2 , and the N-terminal peptide residues D1 and A2 in the Aβ 42 -FPR2-G i2 structure are shown as sticks. The receptor residues that interact with the peptide N termini are also shown as sticks. Only the receptor in the fM5-FPR2-G i2 structure is shown in blue cartoon representation for clarity. c Interactions between the FPRs and the side chains of the peptide N termini. d Interactions between the FPRs and the N-formyl groups at the N termini of the peptides. The N-formyl groups are highlighted by a red dashed circle. e-h Peptide agonist-induced IP accumulation of FPR1 and FPR2 mutants. Bars represent differences in calculated peptide agonist potency (pEC 50 ) for each mutant relative to the wild-type receptor (WT). Data are shown as mean ± SEM (bars) from at least three independent experiments performed in triplicate with individual data points shown (dots). *P < 0.05, **P < 0.001, ***P < 0.0001 by one-way analysis of variance followed by Dunnett's post-test compared with the response of the wild-type receptor. Supplementary Table 3 provides detailed statistical evaluation, P-values, numbers of independent experiments (n), and expression levels. Source data are provided as a Source Data file.
Recognition of Aβ 42 at FPR2. a Binding pocket for Aβ 42 in FPR2. The Aβ 42 -FPR2-G i2 structure is shown in both side (left) and extracellular (right) views. Aβ 42 is shown as sticks and colored magenta (N-terminal part) and pink (C-terminal part). b Inhibition of WK(FITC)YMVm binding to wild-type FPR2 by Aβ 42 , Aβ 40 , or Aβ 1-12 . Data are displayed as mean ± SEM from at least three independent experiments (n) performed in triplicate (Aβ 42 , n = 18; Aβ 40 and Aβ 1-12 , n = 3). Source data are provided as a Source Data file. c-e, Interactions between FPR2 and Aβ 42 . Aβ 42 residues and the receptor residues that are involved in interactions are shown as sticks. Polar interactions are shown as red dashed lines. c Interactions between FPR2 and the Aβ 42 residues D1-E3. d Interactions between FPR2 and the Aβ 42 residues E3-R5. e Interactions between FPR2 and the Aβ 42 residues R5-Y10.
Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ 42 and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ 42 , implying its involvement in the pathogenesis of Alzheimer’s disease (AD). However, the interaction pattern between FPR2 and Aβ 42 or humanin remains unknown. Here we report the structures of FPR2 bound to G i and Aβ 42 or N -formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ 42 and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.
Single-cell Atlas of paired human normal mucosa and CRC tissues. a Graphic overview of this study design. Normal mucosa and tumor tissue from CRC patients were processed into single-cell suspension and unsorted cells were used for scRNA-seq with 10x Genomics. Tumor slides were processed to obtain spatial transcriptomics by 10x Genomics Visium. The following integrated analysis of single-cell transcriptome data is described in squares. b UMAP plots of 29,481 cells from normal mucosa and 24,622 cells from tumor tissue of 5 CRC patients, showing 9 clusters in each plot. Each cluster was shown in different color. R package harmony was used to correct batch effects and constructed one UMAP based on all cells from adjacent tissue and tumor, and then split cells by these two tissues. c Dot plots showing average expression of known markers in indicated cell clusters. The dot size represents percent of cells expressing the genes in each cluster. The expression intensity of markers is shown. d Expression levels of selected known marker genes across 54,103 unsorted cells illustrated in UMAP plots from both normal and tumor tissue in CRC patients. e Proportion of 9 major cell types showing in bar plots in different donors (left panel), tissues (middle panel), and total cell number of each cell type (right panel) are shown. CRC, colorectal cancer. Source data are provided as a Source data Fig. 1b-e.
Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP ⁺ fibroblasts and SPP1 ⁺ macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP ⁺ fibroblasts and SPP1 ⁺ macrophages interaction to improve immunotherapy.
Mechanism investigation. a Reaction orders with respect to H 2 and AP on Pd/Py-COF and Pd/Be-COF. b Potential energy profiles for carbonyl hydrogenation of AP with different sequences (O1st C2nd and C1st O2nd). c Arrhenius plots showing apparent activation barriers for Pd/Py-COF and Pd/ Be-COF. d FT-IR spectra of AP, Pd/Py-COF and AP absorbed on Pd/Py-COF and Pd/Be-COF. e The interaction energies between COFs and AP/CHO. f TOFs of AP and CHO hydrogenation on Pd/Py-COF and Pd/Be-COF. g Schematic diagram of Pd NPs confined in Py-COF and proposed reaction mechanism of AP hydrogenation on Pd/Py-COF. (Reaction conditions for a: 40 °C, 2 mL of EtOH, H 2 pressure varies from 1 to 20 bar, AP concentration varies from ∼7 to ∼28 mg/mL. The TOF values for Arrhenius plots in c were recorded at 30, 40, 50 and 60 °C. Reaction conditions for f: 130 °C, 20 bar of H 2 , 0.07 mmol of CHO, Pd catalysts 4 mmol%, 2 mL of H 2 O).
The utilization of weak interactions to improve the catalytic performance of supported metal catalysts is an important strategy for catalysts design, but still remains a big challenge. In this work, the weak interactions nearby the Pd nanoparticles (NPs) are finely tuned by using a series of imine-linked covalent organic frameworks (COFs) with different conjugation skeletons. The Pd NPs embedded in pyrene-COF are ca. 3 to 10-fold more active than those in COFs without pyrene in the hydrogenation of aromatic ketones/aldehydes, quinolines and nitrobenzene, though Pd have similar size and surface structure. With acetophenone (AP) hydrogenation as a model reaction, systematic studies imply that the π-π interaction of AP and pyrene rings in the vicinity of Pd NPs could significantly reduce the activation barrier in the rate-determining step. This work highlights the important role of non-covalent interactions beyond the active sites in modulating the catalytic performance of supported metal NPs.
Cancer cells within a tumour have heterogeneous phenotypes and exhibit dynamic plasticity. How to evaluate such heterogeneity and its impact on outcome and drug response is still unclear. Here, we transcriptionally profile 35,276 individual cells from 32 breast cancer cell lines to yield a single cell atlas. We find high degree of heterogeneity in the expression of biomarkers. We then train a deconvolution algorithm on the atlas to determine cell line composition from bulk gene expression profiles of tumour biopsies, thus enabling cell line-based patient stratification. Finally, we link results from large-scale in vitro drug screening in cell lines to the single cell data to computationally predict drug responses starting from single-cell profiles. We find that transcriptional heterogeneity enables cells with differential drug sensitivity to co-exist in the same population. Our work provides a framework to determine tumour heterogeneity in terms of cell line composition and drug response.
Artificial intelligence can enhance our ability to manage natural disasters. However, understanding and addressing its limitations is required to realize its benefits. Here, we argue that interdisciplinary, multistakeholder, and international collaboration is needed for developing standards that facilitate its implementation.
DoF augmentation concepts and natural augmentation. a Extra hand for assembly tasks. b Polydactyly hand with six fingers providing superior manipulation abilities 4 . c Third arm to facilitate activities of daily living in hemiplegics. d Centaur robot for stability and walking assistance. e Surgery with three tools controlled by the hands and a neural interface. f Augmented interaction with a mobile device can free one hand to e.g. operate a map. Panel a by Tobias Pistohl; b modified from ref. 4 . Panels c, e, and f by Nathanael Jarrassé. Panel d by Camille Blondin.
Interfaces for DoF augmentation (figure by Tobias Pistohl). An individual is augmented using a body, muscle or neural interface to control the supernumerary effector. Sensory information may be provided through feedback devices. The interfaces, supernumerary effector and feedback devices are shown at representative locations. While muscle interfaces are generally noninvasive, neural interfaces can be both invasive or noninvasive.
Augmenting the body with artificial limbs controlled concurrently to one’s natural limbs has long appeared in science fiction, but recent technological and neuroscientific advances have begun to make this possible. By allowing individuals to achieve otherwise impossible actions, movement augmentation could revolutionize medical and industrial applications and profoundly change the way humans interact with the environment. Here, we construct a movement augmentation taxonomy through what is augmented and how it is achieved. With this framework, we analyze augmentation that extends the number of degrees-of-freedom, discuss critical features of effective augmentation such as physiological control signals, sensory feedback and learning as well as application scenarios, and propose a vision for the field.
Marine mixotrophic protists that use both heterotrophic and phototrophic metabolisms may impact the carbon cycle in unexpected ways. A recently characterized mixotroph can craft three-dimensional mucilage feeding structures that trap nutrient-rich plankton prey and contribute to the sinking of carbon from the surface ocean.
Schematic design and characterization of bacteria eating gold nanoparticles for aggregation-enhanced imaging and killing bacteria. a Schematic showing bacteria eating gold nanoparticles for aggregation-enhanced imaging and killing bacteria. The imaging models include fluorescence imaging (FI) and photoacoustic imaging (PAI). The therapeutic methods include photothermal therapy (PTT) and photodynamic therapy (PDT). b Structure of ABC transporter in E. coli (Left: side view; Right: top view). The sequences of ABC transporter in E. coli were obtained from and the structure was simulated by PyMOL software. c TEM images of M. luteus (ML) or E. coli (EC) treated by 1.0 mg mL −1 of diazirine and chlorin e6 (Ce6)-modified gold nanoparticles (AuNPs) (dAuNPs@Ce6) or GP (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose]), diazirine and Ce6-modified gold nanoparticles (AuNPs) (GP-dAuNPs@Ce6) at 37 °C for 2 h. After incubation, the treated bacteria were rinsed with PBS buffer for several times. GPdAuNPs@Ce6-treated bacteria were subjected with or without laser irradiation (405 nm, 1.0 W cm −2 , 25 min). The bacterial cell concentration is ~1.0 × 10 7 CFU. Scale bars, 200 nm. All imaging experiments were repeated three times with similar results. The cartoons are created by Dr. Houyu Wang.
Schematic and characterization of nanoprobes of GP-dAuNPs@Ce6. a Irradiation time-dependent TEM images of GP-dAuNPs@Ce6 (405 nm, 1.0 W cm −2 ). Scale bars, 200 nm. b Corresponding irradiation time-dependent hydrodynamic size profiles of GP-dAuNPs@Ce6 (405 nm, 1.0 W cm −2 ). c Corresponding irradiation time-dependent absorption spectra of GP-dAuNPs@Ce6 (405 nm, 1.0 W cm −2 ). d Fluorescence intensity of 0.5 mg mL −1 GPdAuNPs@Ce6 with (+) and without laser irradiation (−). e The photothermal heating curves of PBS, non-aggregated GP-dAuNPs@Ce6 and aggregated GP-dAuNPs@Ce6 under the irradiation of 808-nm laser. f Evaluation of 1O 2 generation by PBS, free Ce6, non-aggregated GP-dAuNPs@Ce6 and aggregated GP-dAuNPs@Ce6 by using the SOSG assay. The concentration of Ce6 in each group is 25 µg mL −1 . g Chicken breast tissue thicknessdependent photoacoustic signals of 1.0 mg mL −1 GP-dAuNPs@Ce6 or GP-dAuNPs@Ce6 with (+) and without laser irradiation (−), h Corresponding plots of photoacoustic intensity versus chicken breast tissue thickness (p = 0.0007). All imaging experiments were repeated three times with similar results. Statistical analysis was performed using a one-way ANOVA analysis. Error bars represent the standard deviation obtained from three independent measurements (*** means p < 0.001, n = 3). Data are presented as mean values ± SD. Source data are provided as a Source Data file.
In vitro imaging of Gram-negative and Gram-positive bacteria based on the proposed strategy. a-d CLSM images of four different kinds of bacteria (S. aureus (SA), E. coli (EC), M. luteus (ML), P. aeruginosa (PA)) incubated with 1.0 mg mL −1 GP-AuNPs@Ce6 without (a) or with (b) 405-nm laser irradiation, or GP-dAuNPs@Ce6 without (c) or with (d) 405-nm laser irradiation. After incubation, the treated bacteria were rinsed with PBS buffer for several times. The bacterial cell concentration is ~1.0 × 10 7 CFU. Laser power:1.0 W cm −2 , irradiation time: 25 min. Scale bars, 10 μm. e Confocal fluorescence images of pure human blood, the mixture of human blood and EC or SA after incubation with GP-dAuNPs@Ce6. Arrows indicate red blood cells (RBCs). Scale bars: 25 μm. All imaging experiments were repeated three times with similar results.
Aggregation-enhanced in vivo antibacterial activity based on the developed strategy. a Representative photographs of SA-infected mice injected with GP-dAuNPs@Ce6 with different irradiations of 405, 660, and 808 nm laser. b Corresponding time-dependent relative wound area (S/S 0 ) SA-infected mice. c Bacterial counts (CFU mL −1 ) excised from the SA-infected tissues of mice at 8-day post-injection. d Corresponding histological images of SAinfected skin tissues of mice at 8-day post-injection. Scale bars, 50 μm. e Representative photographs of PA-infected mice injected with GP-dAuNPs@Ce6 with different treatments of 405, 660, and 808 nm laser irradiation. f Corresponding time-dependent relative wound area (S/S 0 ) PA-infected mice after different treatments. g Bacterial counts (CFU mL −1 ) excised from the PA-infected tissues of mice at 11-day post-injection. h Corresponding histological images of PA-infected skin tissues of mice at the 11-day post-injection. Scale bars, 50 μm. i Division of the mice into six therapy groups. The mice in group 1 (G1) are treated with GP-dAuNPs@Ce6 + 660-nm laser (12 mW cm −2 , 5 min); The mice in group 2 (G2) are treated with GP-dAuNPs@Ce6 + 808-nm laser (1.0 W cm −2 , 5 min); the mice in group 3 (G3) are treated by GP-dAuNPs@Ce6 + 660-nm laser (12 mW cm −2 , 5 min)+ 808-nm laser (1.0 W cm −2 , 5 min); the mice in group 4 (G4) are treated by GP-dAuNPs@Ce6 + 405-nm laser (1.0 W cm −2 , 25 min)+ 660-nm laser (12 mW cm −2 , 5 min); the mice in group 5 (G5) are treated by GPdAuNPs@Ce6 + 405-nm laser (1.0 W cm −2 , 25 min)+ 808-nm laser (1.0 W cm −2 , 5 min); the mice in group 6 (G6) are treated by the GP-dAuNPs@Ce6 + 405-nm laser (1.0 W cm −2 , 25 min)+ 660-nm laser (12 mW cm −2 , 5 min)+ 808-nm laser (1.0 W cm −2 , 5 min). All imaging experiments were repeated three times with similar results. Statistical analysis was performed using a one-way ANOVA analysis. Error bars represent the standard deviation obtained from three independent measurements. Data are presented as mean values ± SD (*** means p < 0.001, **** means p < 0.0001, n = 3). Source data are provided as a Source Data file.
Currently optical-based techniques for in vivo microbial population imaging are limited by low imaging depth and highly light-scattering tissue; and moreover, are generally effective against only one specific group of bacteria. Here, we introduce an imaging and therapy strategy, in which different bacteria actively eat the glucose polymer (GP)-modified gold nanoparticles through ATP-binding cassette (ABC) transporter pathway, followed by laser irradiation-mediated aggregation in the bacterial cells. As a result, the aggregates display ~15.2-fold enhancement in photoacoustic signals and ~3.0-fold enhancement in antibacterial rate compared with non-aggregated counterparts. Significantly, the developed strategy allows ultrasensitive imaging of bacteria in vivo as low ~10 ⁵ colony-forming unit (CFU), which is around two orders of magnitude lower than most optical contrast agents. We further demonstrate the developed strategy enables the detection of ~10 ⁷ CFU bacteria residing within tumour or gut. This technique enables visualization and treatment of diverse bacteria, setting the crucial step forward the study of microbial ecosystem.
Analytical pipeline and description of glycan compositions and fermentation dynamics. a Schematic representation of the analytical pipeline. b-f Monosaccharide compositions and fermentation dynamics of 653 SGs and 110 reference glycans. b Percentages of SGs (yellow) and reference glycans (indigo) containing various monosaccharide types. c Number of monosaccharide types composing each SG or reference glycan. d Distribution of weight average molecular weights of SGs measured by SEC. e-g Growth (OD 600 ) and pH dynamics of triplicate fecal cultures fermenting 5 g l −1 of a single SG or reference glycan in MM29 medium. e Hierarchical clustering of glycans into five fermentation groups based on twelve growth and pH parameters. Bars below the dendrogram show compound class: SG (yellow), reference glycan (indigo), or no glycan (magenta). Mean (f) growth and (g) pH curves (±SD) for each glycan fermentation group shown in e. Source data are provided as a Source Data file. SGs Synthetic Glycans, SEC size exclusion chromatography, OD 600 optical density at 600 nm, SD standard deviation, kDa kilodalton.
Effects of glycans on fecal community metabolic output and taxonomic composition. a Yields of two SCFAs, butyrate and propionate, from fecal cultures fermenting either an SG (yellow circles, n = 653), reference glycan (indigo triangles, n = 110), or no glycan (magenta square). b Maximum gas production rate (psi h −1 ) during fecal culture fermentation of glycans from each of the five fermentation groups in Fig. 1e-g. c Shannon diversity and d species richness of fecal cultures fermenting SGs (yellow, n = 190) versus reference glycans (indigo, n = 40). e Shannon diversity of fecal cultures fermenting BRF or BQM (yellow) is higher than reference glycans (indigo) for all comparisons except BQM versus XOS (Kruskal-Wallis followed by Dunn's comparison test, p < 0.05). f NMDS of metagenomic data calculated based on a matrix of Bray-Curtis dissimilarities using species-level mapping of sequencing reads from fecal cultures grown on either an SG (yellow circles, n = 190), reference glycan (indigo triangles, n = 40), or no glycan (magenta square). g NMDS as in f colored by differences in taxonomic composition defined by eight K-means clusters based on species-level mapping of sequencing reads. Data for each glycan is the mean of (a-d, f, g) three or (e) six replicate fecal cultures grown on 5 g l −1 of each SG or reference glycan for 45 h in MM29 medium. a, f, g BRF and BQM highlighted in red. b-e Box plots show median and interquartile ranges. Asterisks show significance (*p < 0.05, **p < 0.01) by b Tukey's test or c, d two-sided Wilcoxon rank-sum test. Source data are provided as a Source Data file. SG Synthetic Glycan, SCFA shortchain fatty acid, XOS xylo-oligosaccharides, FOS fructo-oligosaccharides, GOS galacto-oligosaccharides, NMDS non-metric multidimensional scaling.
Enteric pathogen growth in pure culture and relative abundances in fecal communities grown on glycans. Six strains of a Klebsiella pneumoniae, b Escherichia coli, or c Enterococcus faecium were cultured with 5 g l −1 of a single SG (n = 148) or reference glycan (n = 32) in CM3 medium. Data is the mean maximum growth (OD 600 ) of triplicate cultures; strain names are shown above each plot. Fecal communities from a healthy donor were OD 600 -normalized to contain 8% of d K. pneumoniae CDC 003, e E. coli CDC 001, or f E. faecium ATCC 700221 and cultured in triplicate with 5 g l −1 of an SG (n = 45) or reference glycan (n = 17) for 45 h in MM29 medium. The relative abundances of the pathogens were quantified by 16S rRNA gene sequencing. Data points show FOS (indigo circle), BRF (yellow circle), or BQM (orange triangle) cultures. Box plots show median and interquartile ranges. Asterisks show significance (*p < 0.05, **p < 0.01) by two-sided Wilcoxon rank-sum test. Source data are provided as a Source Data file. SGs Synthetic Glycans, OD 600 optical density at 600 nm, FOS fructo-oligosaccharides.
Glycan effects in mouse models of DSS colitis and C. difficile infection. a-d Mice were treated in drinking water with 2.5% DSS (days 0-5, dashed lines) and 1% (v/v) glycans (days 7-14), as appropriate. Treatment groups (eight animals per group): −DSS (gray), +DSS (red), +DSS, FOS (indigo), +DSS, BRF (yellow). Treatment group comparisons of (a) body weight, (b) stool score averaged over days 0-14, (c) day 14 endoscopy scores with representative images, and (d) day 14 histology scores with representative 100x magnified H&E stained distal colon micrographs. e-g Mice were treated with antibiotics (days -14-3), infected with C. difficile (day 0), and treated with 50 mg kg −1 vancomycin daily (days 0-4) or 1% (v/v) glycans in drinking water (days 1-6), as appropriate. Treatment groups (12 animals per group): no glycan (gray), vancomycin (green), FOS (indigo), BRF (yellow circles), and BQM (orange triangles). Treatment group comparisons of (e) body weight, (f) survival, and (g) clinical scores. Data in (a, b, e, g) show treatment group means ± SEM. Box plots in (c, d) show median and interquartile range. Data points in (b-d, g) show individual mice. a, e Statistics on body mass changes are based on area under the curve for all individual mice. Asterisks show significance (*p < 0.05, **p < 0.01) by (a-e, g) two-sided Wilcoxon rank-sum test or (f) log-rank test. Source data are provided as a Source Data file. DSS dextran sodium sulfate, FOS fructo-oligosaccharides, ABX antibiotics, CFU colony forming units, SEM standard error of the mean, NS non-significant.
Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.
Electronic skins (e-skins) are devices that can respond to mechanical stimuli and enable robots to perceive their surroundings. A great challenge for existing e-skins is that they may easily fail under extreme mechanical conditions due to their multilayered architecture with mechanical mismatch and weak adhesion between the interlayers. Here we report a flexible pressure sensor with tough interfaces enabled by two strategies: quasi-homogeneous composition that ensures mechanical match of interlayers, and interlinked microconed interface that results in a high interfacial toughness of 390 J·m ⁻² . The tough interface endows the sensor with exceptional signal stability determined by performing 100,000 cycles of rubbing, and fixing the sensor on a car tread and driving 2.6 km on an asphalt road. The topological interlinks can be further extended to soft robot-sensor integration, enabling a seamless interface between the sensor and robot for highly stable sensing performance during manipulation tasks under complicated mechanical conditions.
Pourbaix diagrams for Co-and Mn-OECs. Potential-pH diagrams for (A) Co-OECs and (B) Mn-OECs at fixed current densities of j = 30 and 1.3 μA cm −2 (based on geometric electrode surface area), respectively. The dependence of the rate of OER and the rate of catalyst deposition/regeneration on proton activity (a H+ ) are highlighted in blue and magenta, respectively, for each catalyst type. The different pH dependence for the two processes forms the foundation for the self-healing properties of Co-OECs and Mn-OECs above pH 5.2 and −0.5, respectively, in solutions devoid of component metals as indicated with the teal zones in the graphs. All potentials are referenced to the NHE scale.
Electrochemical and photoelectrochemical water splitting offers a scalable approach to producing hydrogen from renewable sources for sustainable energy storage. Depending on the applications, oxygen evolution catalysts (OECs) may perform water splitting under a variety of conditions. However, low stability and/or activity present challenges to the design of OECs, prompting the design of self-healing OECs composed of earth-abundant first-row transition metal oxides. The concept of self-healing catalysis offers a new tool to be employed in the design of stable and functionally active OECs under operating conditions ranging from acidic to basic solutions and from a variety of water sources.
Discriminant analysis of principal components (DAPC) differentiating colour measurements among Iso-Y lines. a Scatterplot of the first 2 Discriminant Functions: Discriminant Function 1 (DF1) and Discriminant Function 2 (DF2). Each point represents a male, and colour denotes the Iso-Y line. b Heatmaps for each colour channel depicting the correlation between colour at each sampling location for Discriminant Function 1 (DF1) or Discriminant Function 2 (DF2). c Images of the male closest to each Iso-Y line's centroid, constructed from the Red Green Blue (RGB; top) and ultraviolet (UV; bottom) colour measurements at each sampling location. UV images are false colour, with lighter grey indicating higher UV reflectance. Source data underlying Fig. 1a are provided as a Source data file.
Analysis of LG1 and LG12 in the natural source population (n females = 16, n males = 10). a LG1 heatmap of patterns of linkage disequilibrium (LD) measured as R 2 . Amount of LD is shown by colour intensity as depicted in the legend (yellow: low LD; indigo: high LD). High LD is observed at coordinates: 11,114,772-15,890,374). b LG1 local PCA in 10 bp windows, depicting three significant multidimensional scales (MDS): MDS1 (yellow, coordinates: 11,216,906-15,375,083 bp); MDS2 (pink, coordinates: 11,430,012-14,570,259 bp); MDS3 (purple, coordinates: 12,326,328-15,308,055 bp). c Intersex F ST calculated in 1 kb windows across LG1. Dashed line marks the 95% quantiles. d Intersex D a calculated in 1 kb windows across LG1. Dashed lines mark the 5% and 95% quantiles. e LG12 heatmap of patterns of linkage disequilibrium (LD) measured as R 2 . Amount of LD is shown by colour intensity as depicted in the legend (yellow: low LD; indigo: high LD). High LD is observed between ~4.6-6 Mb and at the terminal region between ~23.8-25.3 Mb. f LG12 local PCA in 10 bp windows, depicting two significant multidimensional scales (MDS): MDS1 (yellow, coordinates: 21,913,633-25,664,533 bp); MDS2 (pink, coordinates: 5,608,703-7,063,435 bp). g Intersex F ST calculated in 1 kb windows across LG12. Dashed line marks the 95% quantile. h Intersex D a calculated in 1 kb windows across LG12. Dashed lines mark the 5% and 95% quantiles. X ticks are displayed in Megabases (Mb). Source data underlying all components of are provided as Source data files.
LG1 Region 2 haplotype structure. a Genotype plot for Iso-Y lines and natural data combined showing the genotype of each SNP depicted as homozygous reference (HOM REF: yellow), heterozygous (HET: pink) or homozygous alternative (HOM ALT: purple); each individual is coloured by Iso-Y line, or by sex (females in purple, males in cyan). The bracket shows the heterozygous individuals used in the haplotype analysis in panel (b). b Haplotype plot of phased data for natural-derived heterozygous samples (n total = 9, n males = 3, n females = 6) polarised to the Iso-Y9 haplotype (purple) and alternative haplotype (yellow). Symbols next to each of the individuals represent sex (females in purple, males in cyan). Breakpoints (BP) in the haplotype are identified when phases switch between purple and yellow. Dashed lines mark conserved BPs (≥2 individuals): BP1: 11.6 Mb (n females = 2); BP2: 11.7 Mb (n females = 3); BP3: 12.2 Mb (n females = 3, n males = 1); BP4: 13.1 Mb (n females = 2, n males = 2); BP5: 14.4 Mb (n females = 2); BP6: 15.4 Mb (n females = 2). Arrows at the bottom highlight the location of gene annotations for the region. Source data underlying all components of are provided as Source data files.
Male colour patterns of the Trinidadian guppy ( Poecilia reticulata ) are typified by extreme variation governed by both natural and sexual selection. Since guppy colour patterns are often inherited faithfully from fathers to sons, it has been hypothesised that many of the colour trait genes must be physically linked to sex determining loci as a ‘supergene’ on the sex chromosome. Here, we phenotype and genotype four guppy ‘Iso-Y lines’, where colour was inherited along the patriline for 40 generations. Using an unbiased phenotyping method, we confirm the breeding design was successful in creating four distinct colour patterns. We find that genetic differentiation among the Iso-Y lines is repeatedly associated with a diverse haplotype on an autosome (LG1), not the sex chromosome (LG12). Moreover, the LG1 haplotype exhibits elevated linkage disequilibrium and evidence of sex-specific diversity in the natural source population. We hypothesise that colour pattern polymorphism is driven by Y-autosome epistasis.
RBV is required for the proper localization of HYL1 in D-bodies. a RBV is localized in the nucleoplasm. eYFP and mRuby3 signals were detected in root cells (n = 100) from pRBV:RBV-eYFP pSE:SE-mRuby3 transgenic plants. Bar = 10 μm. b HYL1 and SE protein localization in roots of pHYL1:HYL1-YFP pSE:SE-mRuby3 plants. Both proteins show nucleoplasmic localization while HYL1 also shows D-body localization. In total 100 cells were observed. Bar = 10 μm. c Representative images of pHYL1:HYL1-YFP signals in root cells from the meristematic zone in the two genotypes. Arrows indicate D-bodies. Bars = 5 μm. d The percentage of cells with 1-4 D-bodies per cell in wild type and rbv-1. The x-axis represents the number of D-bodies per cell, and the yaxis represents the percentage of cells with the corresponding number of D-bodies. "N" means the numbers of total root cells examined. Source data are provided as a Source Data file.
RBV function is required in the splicing of short introns in certain pre-mRNAs. a Examples of two genes with intron retention defects in the rbv-1 mutant. RNA-seq reads are shown against the gene models below. In the gene models, rectangles and lines represent exons and introns, respectively. The black rectangles indicate retained introns in the rbv-1 mutant. b A scatter plot showing percent retained introns (PI) in wild type and the rbv-1 mutant. The green dots represent introns with statistically significant retention defects in the mutant (Wilcoxon test, P = 0). c Cumulative density plots of intron length for all introns and for retained introns in the rbv-1 mutant (Wilcoxon test, P = 1.984E−22). d Cumulative density plots of intron number in all genes and for genes with retained introns in the rbv-1 mutant. (Wilcoxon test, P = 2.823E−05). e Venn diagrams showing the numbers of retained introns in rbv-1, prl1 prl2 and mac3a mac3b mutants, and the overlaps among the introns retained in these mutants.
A model for the role of RBV in miRNA biogenesis. A pathway of miRNA biogenesis entailing MIR gene transcription, pri-miRNA processing, miRNA methylation, and miRISC formation is shown. Key protein players in each step are depicted as ovals. RBV promotes miRNA biogenesis at the MIR gene transcription and AGO1 loading steps and may also enhance pri-miRNA processing.
MicroRNAs (miRNAs) play crucial roles in gene expression regulation through RNA cleavage or translation repression. Here, we report the identification of an evolutionarily conserved WD40 domain protein as a player in miRNA biogenesis in Arabidopsis thaliana . A mutation in the REDUCTION IN BLEACHED VEIN AREA ( RBV ) gene encoding a WD40 domain protein led to the suppression of leaf bleaching caused by an artificial miRNA; the mutation also led to a global reduction in the accumulation of endogenous miRNAs. The nuclear protein RBV promotes the transcription of MIR genes into pri-miRNAs by enhancing the occupancy of RNA polymerase II (Pol II) at MIR gene promoters. RBV also promotes the loading of miRNAs into AGO1. In addition, RNA-seq revealed a global splicing defect in the mutant. Thus, this evolutionarily conserved, nuclear WD40 domain protein acts in miRNA biogenesis and RNA splicing.
Biaryl scaffolds are found in natural products and drug molecules and exhibit a wide range of biological activities. In past decade, the transition metal-catalyzed C–H arylation reaction came out as an effective tool for the construction of biaryl motifs. However, traditional transition metal-catalyzed C–H arylation reactions have limitations like harsh reaction conditions, narrow substrate scope, use of additives etc. and therefore encouraged synthetic chemists to look for alternate greener approaches. This review aims to draw a general overview on C–H bond arylation reactions for the formation of C–C bonds with the aid of different methodologies, majorly highlighting on greener and sustainable approaches.
A high-level workflow for autonomous data-driven organic synthesis. This process requires the close integration of synthesis planning and synthesis execution, linked by data that captures details of reaction and purification processes and their outcomes.
Achieving autonomous multi-step synthesis of novel molecular structures in chemical discovery processes is a goal shared by many researchers. In this Comment, we discuss key considerations of what an ideal platform may look like and the apparent state of the art. While most hardware challenges can be overcome with clever engineering, other challenges will require advances in both algorithms and data curation.
Synthetic biology has played a key role in responding to the current pandemic. Biofoundries are critical synthetic biology infrastructure which should be available to all nations as a part of their independent bioengineering, biosecurity, and countermeasure response systems.
The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity.
Synthetic DNA is a growing alternative to electronic-based technologies in fields such as data storage, product tagging, or signal processing. Its value lies in its characteristic attributes, namely Watson-Crick base pairing, array synthesis, sequencing, toehold displacement and polymerase chain reaction (PCR) capabilities. In this review, we provide an overview of the most prevalent applications of synthetic DNA that could shape the future of information technology. We emphasize the reasons why the biomolecule can be a valuable alternative for conventional electronic-based media, and give insights on where the DNA-analog technology stands with respect to its electronic counterparts.
Visualization of different machine learning architectures. Topology and training scheme for the three different concepts discussed in this comment. DNN deep neural networks; RC reservoir computing, NVAR nonlinear vector-auto-regression.
Deep neural networks via time delay and sequential sampling. Illustration of a delay-based RC scheme with a delay loop and one physical node (blue circle), b deep neural network (DNN) with three layers (each layer contains two physical nodes), and c corresponding folded-in-time deep neural network (Fit-DNN) realized via three feedback loops with time-varying feedback strengths and sequential sampling of the physical node (iteration 5 and 6 are shown).
Standfirst Among the existing machine learning frameworks, reservoir computing demonstrates fast and low-cost training, and its suitability for implementation in various physical systems. This Comment reports on how aspects of reservoir computing can be applied to classical forecasting methods to accelerate the learning process, and highlights a new approach that makes the hardware implementation of traditional machine learning algorithms practicable in electronic and photonic systems.
The protein corona is a key component controlling biological activity, that develops on foreign materials when introduced to biological environments. This comment discusses the risk of errors from poor methodology that can lead to misinterpretation and poor outcomes.
| Circum-Arctic patterns of terrestrial organic carbon (terrOC) release. The four maps show accumulation rates of released terrOC apportioned between a total terrOC in dark green shades; b specifically surface soil (SurfSoil) incl. permafrost active layer in light green shades; c Ice Complex Deposits (ICD) in orange shades 3 incl. costal erosion with >1 m yr −1 outlined in red 34 ; and d Peat OC in brown colors. Furthermore, the total flux (in Tg yr −1 ) is shown for each shelf sea as colored bar charts, together with red bars indicating the Integrated Carbon Release Index (I-CRI) for each source compartment. The I-CRI is a relative measure of terrOC recipient flux, relative to source region stock, from different compartments (see main text). Arctic Ocean base maps are based on IBCAOv4 58,59 .
| Possible drivers of terrestrial organic carbon (terrOC) release in the circum-Arctic. The map on the left (a) shows the change of the annual summer temperatures (May-Oct) for the period 1960-2015 37,38 , together with the Integrated Carbon Release Index (I-CRI) for total terrOC as red bars. On the bottom left (c), the correlation between the warming trend and the I-CRI terr is shown. The map on the right (b) shows the circum-Arctic drainage basins incl. its major river systems and the Arctic permafrost (PF) zones 49 , next to the I-CRI for surface soil OC as red bars and the ratio of watershed-internal CO 2 evasion to the lateral export of terrOC via the major Arctic rivers as blue bars 31,50-52 . On the bottom right, d the correlation between the southward extent of the basin and the I-CRI SurfSoil is shown. The seven shelf seas are abbreviated as CAA Canadian Arctic Archipelago, BFS Beaufort Sea, CS Chukchi Sea, ESS East Siberian Sea, LS Laptev Sea, KS Kara Sea; and BS Barents Sea. The maps of the Arctic Ocean in panels a and b are based on IBCAOv4 58,59 .
Arctic change is expected to destabilize terrestrial carbon (terrOC) in soils and permafrost, leading to fluvial release, greenhouse gas emission and climate feedback. However, landscape heterogeneity and location-specific observations complicate large-scale assessments of terrOC mobilization. Here we reveal differences in terrOC release, deduced from the Circum-Arctic Sediment Carbon Database (CASCADE) using source-diagnostic (δ13C-Δ14C) and carbon accumulation data. The results show five-times larger terrOC release from the Eurasian than from the American Arctic. Most of the circum-Arctic terrOC originates from near-surface soils (61%); 30% stems from Pleistocene age permafrost. TerrOC translocation, relative to land-based terrOC stocks, varies by a factor of five between circum-Arctic regions. Shelf seas with higher relative terrOC translocation follow the spatial pattern of recent Arctic warming, while such with lower translocation reflect long-distance lateral transport with efficient remineralization of terrOC. This study provides a receptor-based perspective for how terrOC release varies across the circum-Arctic.
| YTHDF3 depletion impairs autophagosome formation and lysosomal function. a, b mCherry-GFP-LC3 was transfected into shNS and shYTHDF3 MEFs, and autophagosome (yellow) and autolysosome (red) formation was examined. Scale bar, 20 μm. c, d Endogenous ULK1, ATG13, ATG14, and DFCP1 puncta in shNS and shYTHDF3 MEFs were immunostained after nutrient deficiency, visualized with confocal microscopy (c), and quantified (d). Scale bar, 20 μm. e Histograms of R/ GFIR of 3000 events analyzed by flow cytometry after AO staining in shYTHDF3 MEFs and shNS MEFs, with or without 20 nM Baf.A1 for 4 h. Values above the histogram indicate mean R/GFIR ± SEM of three experiments. f, g Representative images (f) and quantification (g) of total LysoTracker Red in shNS and shYTHDF3 MEFs. Scale bar, 20 μm. h, i Representative images (h) and quantification (i) of intracellular proteolysis by DQ-BSA in shYTHDF3 MEFs and shNS MEFs, with or without 20 nM Baf.A1 for 4 h. Scale bar, 20 μm. j, k Live imaging of Magic Red dye,
| YTHDF3 requires METTL3-mediated m 6 A modification to promote autophagy. a Representative confocal images of YTHDF3 and m 6 A fluorescence localization were obtained in MEFs following nutrient starvation for the indicated time periods. Nuclei were stained with DAPI. Scale bar, 20 μm. b Quantification of GFP-LC3 puncta per cell. c LC-MS/MS quantification of m 6 A levels in mRNA extracts from MEFs following nutrient starvation for the indicated time periods (n = 3 biological replicates). d Immunoblot analyses of nuclear fractions from MEFs following nutrient starvation for the indicated time periods. e LC-MS/MS quantification of m 6 A levels in mRNA extracts from shNS and shMETTL3 MEFs, with or without nutrient deprivation (n = 3 biological replicates). f The relative m 6 A methylation catalytic activities of purified METTL3 from the MEFs starved for the indicated time periods were determined using an RNA probe and d 3 -m 6 A. The methylation yields were calculated based on the molar ratio of newly formed d 3 -m 6 A to digested RNA probes (n = 4, 4, 4, 2 biological replicates). G was used as an internal control to calculate the amount of RNA probes. g Immunoblot analysis of METTL3 in MEFs following nutrient starvation for the indicated time periods. h Immunoblot analyses of LC3-II and p62 in YTHDF3-OE MEFs infected with shNS or two independent METTL3 shRNAs (shMETTL3 and shMETTL3-2) following nutrient starvation for the indicated time periods, with or without Baf.A1 treatment (20 nM). GAPDH was used
| Inhibited RPS27a-METTL3 interaction stabilizes METTL3 under starvation. a qRT-PCR analysis of METTL3 in MEFs following nutrient starvation for the indicated time periods (n = 4 biological replicates). b MEFs were treated with Act.D (5 μg/mL) for the indicated times with or without nutrient starvation, respectively. The expression of METTL3 was examined with qRT-PCR (n = 3 biological replicates). c Left, MEFs with and without nutrient deficiency were treated with 20 µM MG132 for the indicated time periods. Levels of METTL3 were examined by immunoblot analyses. GAPDH was used as a loading control. Right, relative METTL3 protein levels were quantitatively defined (n = 3 biological replicates). d Up, MEFs with and without nutrient deficiency were treated with 100 µg/ml cycloheximide (CHX) for the indicated time periods. Levels of METTL3 were examined by immunoblot analyses. GAPDH was used as a loading control. Down, protein half-life of METTL3 was quantitatively defined (n = 3 biological replicates). Simple linear regression
| YTHDF3 recognizes starvation-induced m 6 A hypermethylation of FOXO3 mRNA. a The scatter plot depicts fold changes (log2) of YTHDF3-RIP target peaks in MEFs after nutrient deprivation. Red dots indicate significantly upenriched and down-enriched peaks with a cutoff fold change of 1.8. b The consensus sequence motif identified within significant differentially enriched YTHDF3-binding sites, determined by the HOMER database. c Metagene profiles of the significant differentially enriched YTHDF3-binding sites along a normalized transcript, consisting of three rescaled non-overlapping segments: 5'UTR, CDS, and 3'UTR. Pie chart depicting the fraction of significant differentially enriched YTHDF3-binding sites in different transcript segments. d Scatter plot showing m 6 A peaks with increased (red) or decreased (blue) levels in response to nutrient deficiency. e Venn diagram showing the number of overlapping up-enriched YTHDF3-binding targets and hyper-m 6 A-methylated mRNAs upon nutrient deprivation. Then the resultant 86 peaks were annotated to GO term autophagy (0006914) and
| YTHDF3 interacts with eIF3a and eIF4B to promote FOXO3 translation. a YTHDF3 immunoprecipitation workflow in MEFs under normal and nutrient-free conditions. b YTHDF3-specific interactors were identified through quantitative mass spectrometry. eIFs are labeled in red. 40S and 60S ribosomal subunits are labeled in light blue. Diameters correlate with mean numbers of unique peptides (n = 2). c Immunoblot analyses for eIF3a and eIF4B proteins from polysome fractions in shNS and shYTHDF3 MEFs. d Surface view of docked YTHDF3-eIF3a and YTHDF3-eIF4B complexes. YTHDF3, eIF3a, and eIF4B are colored in blue, green, and red, respectively. Inset, magnified views of the interacting residues are drawn in stick representation and labeled (in pink for YTHDF3 and in yellow for eIF3a or
Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m6A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m6A reader YTHDF3 is essential for autophagy induction. m6A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m6A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m6A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
a Schematic of a spatially multiplexed analog Ising machine for noise-induced sampling. The system consists of a set of N bistable nonlinear systems that represent N spin states and are mutually coupled. Inset: Bifurcation diagram of the spin amplitude as a function of the feedback gain for a single bistable system. Below the bifurcation point at α = 1 (red dashed line), only the trivial solution exists (solid black line), while above the bifurcation point, the trivial solution becomes unstable (black dotted line) and two new bistable fixed points arise (orange and blue line). b Exemplary time evolution of the Ising energy (orange) and the spin amplitudes (blue) while solving a Maxcut optimization problem with N = 100 spins. c Experimental setup of the time-multiplexed opto-electronic Ising machine, where Gaussian white noise with a standard deviation of δ is injected. PC polarization controller, ADC analog-digital converter, DAC digital-analog converter, MZM Mach-Zehnder modulator, EA electronic amplifier, FPGA field programmable gated array.
Time evolution (a, c) and sampled distribution function (b, d) of the Ising energy for noise-induced sampling (a, b) and discontinuous sampling (c, d). In b, d The energy distributions obtained with the Ising machine (IM) are compared to those obtained with the Metropolis–Hastings algorithm (MCMC). e Boltzmann distribution obtained from noise-induced sampling as a function of the noise variance δ2 for the three degenerate energy levels of a 4-spin ring network (dots, squares, and triangles) at α = 1.2 and β = 0.5. The probabilities are compared to the analytical solutions (solid lines) obtained from equation (1) at different temperatures T. The overlap of the distributions is quantified by the Kullback–Leibler divergence DKL (dashed line). f Relation between temperature and the noise variance for the problem in e for different coupling strengths β.
a Activation probability of single neurons as a function of the neuron bias for different temperatures. The probabilities have been obtained from continuous sampling of 100 independent Ising spins at different noise levels (squares, dots, and triangles) and are compared to the analytical solution at different temperatures (solid lines). b Activation probabilities for an RBM with 16 hidden and 16 visible neurons with random weights and biases. Probabilities for the analog Ising machine (IM, orange bars) have been obtained by continuous sampling at a fixed noise strength and are compared against probabilities obtained with the Metropolis–Hastings algorithm (MCMC, blue bars). c Comparison of the pseudolikelihood L and the prediction accuracy η for Ising machine- and MCMC-based sampling during unsupervised training of handwritten digit recognition.
a Kullback–Leibler divergence as a function of the problem size for sampling the energy distributions for different random sparse graphs (dots). The solid line shows the average. The insets (i) and (ii) show exemplary sampled distributions in comparison to the Metropolis–Hastings algorithm (MCMC) for N = 64 (i) and N = 8192 (ii) spins. b, c Average energy (top panel) and Kullback–Leiber divergence (lower panel) as a function of the temperature and the noise variance δ2 for a sparse random graph with N = 64 b and N = 8192 c. The average energy and Kullback–Leiber divergence is compared against MCMC-based sampling (blue lines). For DKL for the MCMC-based sampling, repeated sampling runs are compared against the reference distribution. The shaded regions show the standard deviation.
a Estimation of the sampling rate of a spatially multiplexed analog Ising machine at different analog bandwidths for randomly generated sparse Maxcut problems at a temperature of T = 2 (dots). The lines indicate the average of the different graphs. The sampling rate is estimated from the autocorrelation function of the Ising energy as the point when samples become statistically independent. b Number of iterations z required z to create statistically independent samples with the Metropolis–Hastings algorithm (MCMC) and with simulations of analog Ising machines (IM,sim) using the forward Euler method. Also shown is the average runtime t to obtain independent samples when executing the Metropolis–Hastings algorithm and the forward Euler integration on the same CPU.
Ising machines are a promising non-von-Neumann computational concept for neural network training and combinatorial optimization. However, while various neural networks can be implemented with Ising machines, their inability to perform fast statistical sampling makes them inefficient for training neural networks compared to digital computers. Here, we introduce a universal concept to achieve ultrafast statistical sampling with analog Ising machines by injecting noise. With an opto-electronic Ising machine, we experimentally demonstrate that this can be used for accurate sampling of Boltzmann distributions and for unsupervised training of neural networks, with equal accuracy as software-based training. Through simulations, we find that Ising machines can perform statistical sampling orders-of-magnitudes faster than software-based methods. This enables the use of Ising machines beyond combinatorial optimization and makes them into efficient tools for machine learning and other applications.
  • Eliodoro ChiavazzoEliodoro Chiavazzo
Recent studies in passive solar-driven evaporative technologies have introduced a plethora of new materials and devices which promise higher economic and environmental sustainability in water treatment. However, many challenges remain for the effective adoption of such technologies. Here, we identify three main pillars and the corresponding issues which future research activities should focus on to bring the proposed solutions to the next maturity level. Specifically, our analysis focuses on standards for comparing productivity, strategies to overcome the single stage limit, scalability and robustness. While passive solar-driven evaporative systems promise higher economic and environmental sustainability in water treatment, many challenges remain for their effective adoption. Here, the author identifies three main pillars and corresponding issues which future research should focus on to bring these technologies to the next maturity level.
| Many-qubit protection-operation dilemma. With no frequency disorder in qubits, one can apply fast two-qubit gates but the idle qubits rapidly leak quantum information. On the other hand, in sufficiently disordered systems, the quantum states are quasi-localized, rendering the idle qubits well protected. A downside is that the two-qubit gates are less efficient. Crosses visualize superconducting qubits and their colors indicates transition frequencies. Gray bars denote qubit-qubit interactions.
| A schematic of the tension map between optimally protecting and efficiently operating. Utilizing the measures based on the many-body localization, we see that different quantum processor manufacturers have settled upon varying architectural design protocols with both benefits and downfalls with respect to control and protection. The schematic is based on results of ref. 7.
  • Matti SilveriMatti Silveri
  • Tuure OrellTuure Orell
What is an optimal parameter landscape and geometric layout for a quantum processor so that its qubits are sufficiently protected for idling and simultaneously responsive enough for fast entangling gates? Quantum engineers pondering the dilemma might want to take a look on tools developed for many-body localization.
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Top-cited authors
Yi Cui
  • Stanford University
Lin Gu
  • Chinese Academy of Sciences
Takashi Taniguchi
  • National Institute for Materials Science
Hsin tsang Lin
  • Chia-Yi Christian Hospital
M. Zahid Hasan
  • Princeton University