Browse Articles

Unveiling the regulatory role of GRP7 in ABA signal-mediated mRNA translation efficiency regulation

Investigations into cyanobacterial photoacclimation processes address longstanding proposals for improving crop yields

Perturbing local steroidogenesis to improve breast cancer immunity

Abstract Breast cancer, particularly triple-negative breast cancer (TNBC), evades the body’s immune defences, in part by cultivating an immunosuppressive tumour microenvironment. Here, we show that suppressing local steroidogenesis can augment anti-tumour immunity against TNBC. Through targeted metabolomics of steroids coupled with immunohistochemistry, we profiled the existence of immunosuppressive steroids in TNBC patient tumours and discerned the steroidogenic activity in immune-infiltrating regions. In mouse, genetic inhibition of immune cell steroidogenesis restricted TNBC tumour progression with a significant reduction in immunosuppressive components such as tumour associated macrophages. Steroidogenesis inhibition appears to bolster anti-tumour immune responses in dendritic and T cells by impeding glucocorticoid signalling. Undertaking metabolic modelling of the single-cell transcriptomics and targeted tumour-steroidomics, we pinpointed the predominant steroidogenic cells. Inhibiting steroidogenesis pharmacologically using a identified drug, posaconazole, curtailed tumour expansion in a humanised TNBC mouse model. This investigation paves the way for targeting steroidogenesis and its signalling pathways in breast cancer affected by immune-steroid maladaptation.

Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice

Abstract The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO2-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO2-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO2-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5’-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO2-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO2-OA may represent a promising therapeutic strategy for HFpEF.

Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division

Abstract Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.

p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer

Both phytochrome A and phyB interact with PHYTOCHROME-INTERACTING FACTORs through an evolutionary conserved phyOPM-APA interaction

Catalytic enantioselective synthesis of inherently chiral calix[4]arenes via organocatalyzed aromatic amination enabled desymmetrization

Quantifying the global climate feedback from energy-based adaptation

Abstract Many behavioral responses to climate change are carbon-intensive, raising concerns that adaptation may cause additional warming. The sign and magnitude of this feedback depend on how increased emissions from cooling balance against reduced emissions from heating across space and time. We present an empirical approach that forecasts the effect of future adaptive energy use on global average temperature over the 21st century. We estimate that energy-based adaptation will lower global mean surface temperature in 2099 by 0.07 to 0.12 °C relative to baseline projections under Representative Concentration Pathways 4.5 and 8.5. This cooling avoids 0.6 to 1.8 trillion U.S. Dollars ($2019) in damages, depending on the baseline emissions scenario. Energy-based adaptation lowers business-as-usual emissions for 85% of countries, reducing the mitigation required to meet their unilateral Nationally Determined Contributions by 20% on average. These findings indicate that while business-as-usual adaptive energy use is unlikely to accelerate warming, it raises important implications for countries’ existing mitigation commitments.

Interactive symbolic regression with co-design mechanism through offline reinforcement learning

Structural basis for the activation of proteinase-activated receptors PAR1 and PAR2

Concerted catalysis of single atom and nanocluster enhances bio-ethanol activation and dehydrogenation

Abstract Single atom and nanocluster catalysts are extensively investigated in heterogeneous catalysis due to their high catalytic activity and atomic utilization, while their coexisting properties and potentially synergistic effect are yet to be clarified. Herein, we construct three systems of atomic-scale catalysts (xNi/Mo2TiAlC2, x = 0.5, 1, and 1.5) for bio-ethanol reforming, which correspond to single atoms, single atoms mixed with nanoclusters, and nanoclusters. The respective hydrogen utilization efficiency of mixed-form catalyst increases by 43.7% and 29.3% compared to single atom and nanocluster catalysts. Results demonstrate that the adjacent Ni single atom facilitates electron transfer from Mo2TiAlC2 to Ni-Mo interface and raises the d-band center, thus enhancing bio-ethanol adsorption and activation; while the existence of Ni nanoclusters contributes to lowering the energy barriers of CH3CHO* dehydrogenation. The catalytically active sites are Ni-Mo alloyed single atoms with adjacent Ni nanoclusters. This work provides new implications for highly activated catalytic site construction and advanced catalyst design.

scMultiMap: Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data

Gapless dispersive continuum in a modulated quantum kagome antiferromagnet

Correlated fermionic-bosonic insulating states in twisted hetero-trilayer semiconductors

CLAVATA signalling shapes barley inflorescence by controlling activity and determinacy of shoot meristem and rachilla

Abstract The large variety of inflorescence architectures evolved in grasses depends on shape, longevity and determinacy of meristems directing growth of the main and lateral axes. The CLAVATA pathway is known to regulate meristem size and inflorescence architecture in grasses. However, how individual meristem activities are determined and integrated to generate specific inflorescences is not yet understood. We found that activity of distinct meristems in the barley inflorescence is controlled by a signalling pathway comprising the receptor-like kinase Hordeum vulgare CLAVATA1 (HvCLV1) and the secreted CLAVATA3/EMBRYO-SURROUNDING REGION RELATED (CLE)-family peptide FON2-LIKE CLE PROTEIN1 (HvFCP1). HvFCP1 and HvCLV1 interact to promote spikelet formation, but restrict inflorescence meristem and rachilla proliferation. Hvfcp1 or Hvclv1 mutants generate additional rows of spikelets and supernumerary florets from extended rachilla activity. HvFCP1/HvCLV1 signalling coordinates meristem activity through regulation of trehalose-6-phosphate levels. Our discoveries outline a path to engineer inflorescence architecture via specific regulation of distinct meristem activities.

Ultrasensitive detection of clinical pathogens through a target-amplification-free collateral-cleavage-enhancing CRISPR-CasΦ tool

Abstract Clinical pathogen diagnostics detect targets by qPCR (but with low sensitivity) or blood culturing (but time-consuming). Here we leverage a dual-stem-loop DNA amplifier to enhance non-specific collateral enzymatic cleavage of an oligonucleotide linker between a fluophore and its quencher by CRISPR-CasΦ, achieving ultrasensitive target detection. Specifically, the target pathogens are lysed to release DNA, which binds its complementary gRNA in CRISPR-CasΦ to activate the collateral DNA-cleavage capability of CasΦ, enabling CasΦ to cleave the stem-loops in the amplifier. The cleavage product binds its complementary gRNA in another CRISPR-CasΦ to activate more CasΦ. The activated CasΦ collaterally cleaves the linker, releasing the fluophore to recover its fluorescent signal. The cycle of stem-loop-cleavage/CasΦ-activation/fluorescence-recovery amplifies the detection signal. Our target amplification-free collateral-cleavage-enhancing CRISPR-CasΦ method (TCC), with a detection limit of 0.11 copies/μL, demonstrates enhanced sensitivity compared to qPCR. It can detect pathogenic bacteria as low as 1.2 CFU/mL in serum within 40 min.

A molecular framework for the GS2-SUG1 module-mediated control of grain size and weight in rice

Junctional force patterning drives both positional order and planar polarity in the auditory epithelia

Different factors control long-term versus short-term outcomes for bacterial colonisation of a urinary catheter

Abstract Urinary catheters are used extensively in hospitals and long-term care and they are highly prone to infection. Understanding the pathways by which bacteria colonise a urinary catheter could guide strategies to mitigate infection, but quantitative models for this colonisation process are lacking. Here we present a mathematical model for bacterial colonisation of a urinary catheter that integrates population dynamics and fluid dynamics. The model describes bacteria migrating up the outside surface of the catheter, spreading into the bladder and being swept through the catheter lumen. Computer simulations of the model reveal that clinical outcomes for long-term versus short-term catheterisation are controlled by different factors: the rate of urine production by the kidneys as opposed to urethral length, catheter surface properties and bacterial motility. Our work may help explain variable susceptibility to catheter-associated urinary tract infection (CAUTI) among individuals and the mixed success of antimicrobial surface coatings. Our model suggests that for long-term catheterised patients, increasing fluid intake or reducing residual urine volume in the bladder may help prevent infection, while antimicrobial surface coatings are predicted to be effective only for short-term catheterised patients. Therefore, different catheter management strategies could be rationally targeted to long-term vs short-term catheterised patients.