A natural gene drive system confers reproductive isolation in rice.

Hybrid sterility restricts the utilization of superior heterosis of indica-japonica inter-subspecific hybrids. In this study, we report the identification of RHS12, a major locus controlling male gamete sterility in indica-japonica hybrid rice. We show that RHS12 consists of two genes (iORF3/DUYAO and iORF4/JIEYAO) that confer preferential transmission of the RHS12-i type male gamete into the progeny, thereby forming a natural gene drive. DUYAO encodes a mitochondrion-targeted protein that interacts with OsCOX11 to trigger cytotoxicity and cell death, whereas JIEYAO encodes a protein that reroutes DUYAO to the autophagosome for degradation via direct physical interaction, thereby detoxifying DUYAO. Evolutionary trajectory analysis reveals that this system likely formed de novo in the AA genome Oryza clade and contributed to reproductive isolation (RI) between different lineages of rice. Our combined results provide mechanistic insights into the genetic basis of RI as well as insights for strategic designs of hybrid rice breeding.

The fractalkine/CX3CR1 system regulates ß cell function and insulin secretion.

Here, we demonstrate that the fractalkine (FKN)/CX3CR1 system represents a regulatory mechanism for pancreatic islet ß cell function and insulin secretion. CX3CR1 knockout (KO) mice exhibited a marked defect in glucose and GLP1-stimulated insulin secretion, and this defect was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca(2+) and potentiated insulin secretion in both mouse and human islets. The KO islets exhibited reduced expression of a set of genes necessary for the fully functional, differentiated ß cell state, whereas treatment of wild-type (WT) islets with FKN led to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and high-fat diet/obesity, suggesting that decreased FKN/CX3CR1 signaling could be a mechanism underlying ß cell dysfunction in type 2 diabetes.

Unconventional spectral signature of Tc in a pure d-wave superconductor.

In conventional superconductors, the phase transition into a zero-resistance and perfectly diamagnetic state is accompanied by a jump in the specific heat and the opening of a spectral gap1. In the high-transition-temperature (high-Tc) cuprates, although the transport, magnetic and thermodynamic signatures of Tc have been known since the 1980s2, the spectroscopic singularity associated with the transition remains unknown. Here we resolve this long-standing puzzle with a high-precision angle-resolved photoemission spectroscopy (ARPES) study on overdoped (Bi,Pb)2Sr2CaCu2O8+δ (Bi2212). We first probe the momentum-resolved electronic specific heat via spectroscopy and reproduce the specific heat peak at Tc, completing the missing link for a holistic description of superconductivity. Then, by studying the full momentum, energy and temperature evolution of the spectra, we reveal that this thermodynamic anomaly arises from the singular growth of in-gap spectral intensity across Tc. Furthermore, we observe that the temperature evolution of in-gap intensity is highly anisotropic in the momentum space, and the gap itself obeys both the d-wave functional form and particle-hole symmetry. These findings support the scenario that the superconducting transition is driven by phase fluctuations. They also serve as an anchor point for understanding the Fermi arc and pseudogap phenomena in underdoped cuprates.

Improved green and red GRAB sensors for monitoring spatiotemporal serotonin release in vivo.

The serotonergic system plays important roles in both physiological and pathological processes, and is a therapeutic target for many psychiatric disorders. Although several genetically encoded GFP-based serotonin (5-HT) sensors were recently developed, their sensitivities and spectral profiles are relatively limited. To overcome these limitations, we optimized green fluorescent G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensors and developed a red fluorescent GRAB5-HT sensor. These sensors exhibit excellent cell surface trafficking and high specificity, sensitivity and spatiotemporal resolution, making them suitable for monitoring 5-HT dynamics in vivo. Besides recording subcortical 5-HT release in freely moving mice, we observed both uniform and gradient 5-HT release in the mouse dorsal cortex with mesoscopic imaging. Finally, we performed dual-color imaging and observed seizure-induced waves of 5-HT release throughout the cortex following calcium and endocannabinoid waves. In summary, these 5-HT sensors can offer valuable insights regarding the serotonergic system in both health and disease.

Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

A high-dimensional omnibus test for set-based association analysis.

Set-based association analysis is a valuable tool in studying the etiology of complex diseases in genome-wide association studies, as it allows for the joint testing of variants in a region or group. Two common types of single nucleotide polymorphism (SNP)-disease functional models are recognized when evaluating the joint function of a set of SNP: the cumulative weak signal model, in which multiple functional variants with small effects contribute to disease risk, and the dominating strong signal model, in which a few functional variants with large effects contribute to disease risk. However, existing methods have two main limitations that reduce their power. Firstly, they typically only consider one disease-SNP association model, which can result in significant power loss if the model is misspecified. Secondly, they do not account for the high-dimensional nature of SNPs, leading to low power or high false positives. In this study, we propose a solution to these challenges by using a high-dimensional inference procedure that involves simultaneously fitting many SNPs in a regression model. We also propose an omnibus testing procedure that employs a robust and powerful P-value combination method to enhance the power of SNP-set association. Our results from extensive simulation studies and a real data analysis demonstrate that our set-based high-dimensional inference strategy is both flexible and computationally efficient and can substantially improve the power of SNP-set association analysis. Application to a real dataset further demonstrates the utility of the testing strategy.

The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4⁺ T cells.

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.

The transcriptional hub SHORT INTERNODES1 integrates hormone signals to orchestrate rice growth and development.

Plants have evolved sophisticated mechanisms to coordinate their growth and stress responses via integrating various phytohormone signaling pathways. However, the precise molecular mechanisms orchestrating integration of the phytohormone signaling pathways remain largely obscure. In this study, we found that the rice (Oryza sativa) short internodes1 (shi1) mutant exhibits typical auxin-deficient root development and gravitropic response, brassinosteroid (BR)-deficient plant architecture and grain size as well as enhanced abscisic acid (ABA)-mediated drought tolerance. Additionally, we found that the shi1 mutant is also hyposensitive to auxin and BR treatment but hypersensitive to ABA. Further, we showed that OsSHI1 promotes the biosynthesis of auxin and BR by activating the expression of OsYUCCAs and D11, meanwhile dampens ABA signaling by inducing the expression of OsNAC2, which encodes a repressor of ABA signaling. Furthermore, we demonstrated that 3 classes of transcription factors, AUXIN RESPONSE FACTOR 19 (OsARF19), LEAF AND TILLER ANGLE INCREASED CONTROLLER (LIC), and OsZIP26 and OsZIP86, directly bind to the promoter of OsSHI1 and regulate its expression in response to auxin, BR, and ABA, respectively. Collectively, our results unravel an OsSHI1-centered transcriptional regulatory hub that orchestrates the integration and self-feedback regulation of multiple phytohormone signaling pathways to coordinate plant growth and stress adaptation.

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

A universal approach to dual-metal-atom catalytic sites confined in carbon dots for various target reactions.

Here, a molecular-design and carbon dot-confinement coupling strategy through the pyrolysis of bimetallic complex of diethylenetriamine pentaacetic acid under low-temperature is proposed as a universal approach to dual-metal-atom sites in carbon dots (DMASs-CDs). CDs as the "carbon islands" could block the migration of DMASs across "islands" to achieve dynamic stability. More than twenty DMASs-CDs with specific compositions of DMASs (pairwise combinations among Fe, Co, Ni, Mn, Zn, Cu, and Mo) have been synthesized successfully. Thereafter, high intrinsic activity is observed for the probe reaction of urea oxidation on NiMn-CDs. In situ and ex situ spectroscopic characterization and first-principle calculations unveil that the synergistic effect in NiMn-DMASs could stretch the urea molecule and weaken the N-H bond, endowing NiMn-CDs with a low energy barrier for urea dehydrogenation. Moreover, DMASs-CDs for various target electrochemical reactions, including but not limited to urea oxidation, are realized by optimizing the specific DMAS combination in CDs.

Whole-brain mapping of histaminergic projections in mouse brain.

Histamine is a conserved neuromodulator in mammalian brains and critically involved in many physiological functions. Understanding the precise structure of the histaminergic network is the cornerstone in elucidating its function. Herein, using histidine decarboxylase (HDC)-CreERT2 mice and genetic labeling strategies, we reconstructed a whole-brain three dimensional (3D) structure of histaminergic neurons and their outputs at 0.32 × 0.32 × 2 µm3 pixel resolution with a cutting-edge fluorescence microoptical sectioning tomography system. We quantified the fluorescence density of all brain areas and found that histaminergic fiber density varied significantly among brain regions. The density of histaminergic fiber was positively correlated with the amount of histamine release induced by optogenetic stimulation or physiological aversive stimulation. Lastly, we reconstructed a fine morphological structure of 60 histaminergic neurons via sparse labeling and uncovered the largely heterogeneous projection pattern of individual histaminergic neurons. Collectively, this study reveals an unprecedented whole-brain quantitative analysis of histaminergic projections at the mesoscopic level, providing a foundation for future functional histaminergic study.

Efficacy and Safety of Catheter-Based Radiofrequency Renal Denervation in Chinese Patients With Uncontrolled Hypertension: The Randomized, Sham-Controlled, Multi-Center Iberis-HTN Trial.

BACKGROUND: Renal denervation (RDN) can lower blood pressure (BP) in patients with hypertension in both the presence and absence of medication. This is the first sham-controlled trial investigating the safety and efficacy of RDN in China. METHODS: This prospective, multicenter, randomized, patient- and outcome-assessor-blinded, sham-controlled trial investigated radiofrequency RDN in patients with hypertension on standardized triple antihypertensive therapy. Eligible patients were randomized 1:1 to undergo RDN using a multi-electrode radiofrequency catheter (Iberis; AngioCare, Shanghai, China) or a sham procedure. The primary efficacy outcome was the between-group difference in baseline-adjusted change in mean 24-hour ambulatory systolic BP from randomization to 6 months. RESULTS: Of 217 randomized patients (mean age, 45.3±10.2 years; 21% female), 107 were randomized to RDN and 110 were randomized to sham control. At 6 months, there was a greater reduction in 24-hour systolic BP in the RDN (-13.0±12.1 mm Hg) compared with the sham control group (-3.0±13.0 mm Hg; baseline-adjusted between-group difference, -9.4 mm Hg [95% CI, -12.8 to -5.9]; P<0.001). Compared with sham, 24-hour diastolic BP was lowered by -5.0 mm Hg ([95% CI, -7.5 to -2.4]; P<0.001) 6 months after RDN, and office systolic and diastolic BP was lowered by -6.4 mm Hg ([95% CI, -10.5 to -2.3]; P=0.003) and -5.1 mm Hg ([95% CI, -8.2 to -2.0]; P=0.001), respectively. One patient in the RDN group experienced an access site complication (hematoma), which resolved without sequelae. No other major device- or procedure-related safety events occurred through follow-up. CONCLUSIONS: In this trial of Chinese patients with uncontrolled hypertension on a standardized triple pharmacotherapy, RDN was safe and reduced ambulatory and office BP at 6 months compared with sham. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02901704.

E3 ligase DECREASED GRAIN SIZE 1 promotes degradation of a G-protein subunit and positively regulates grain size in rice.

Grain size is one of the most important traits determining crop yield. However, the mechanism controlling grain size remains unclear. Here, we confirmed the E3 ligase activity of DECREASED GRAIN SIZE 1 (DGS1) in positive regulation of grain size in rice (Oryza sativa) suggested in a previous study. Rice G-protein subunit gamma 2 (RGG2), which negatively regulates grain size, was identified as an interacting protein of DGS1. Biochemical analysis suggested that DGS1 specifically interacts with canonical Gγ subunits (rice G-protein subunit gamma 1 [RGG1] and rice G-protein subunit gamma 2 [RGG2]) rather than non-canonical Gγ subunits (DENSE AND ERECT PANICLE 1 [DEP1], rice G-protein gamma subunit type C 2 [GCC2], GRAIN SIZE 3 [GS3]). We also identified the necessary domains for interaction between DGS1 and RGG2. As an E3 ligase, DGS1 ubiquitinated and degraded RGG2 via a proteasome pathway in several experiments. DGS1 also ubiquitinated RGG2 by its K140, K145, and S147 residues. Thus, this work identified a substrate of the E3 ligase DGS1 and elucidated the post-transcriptional regulatory mechanism of the G-protein signaling pathway in the control of grain size.

Advanced Techniques for Detecting Protein Misfolding and Aggregation in Cellular Environments.

Protein misfolding and aggregation, a key contributor to the progression of numerous neurodegenerative diseases, results in functional deficiencies and the creation of harmful intermediates. Detailed visualization of this misfolding process is of paramount importance for improving our understanding of disease mechanisms and for the development of potential therapeutic strategies. While in vitro studies using purified proteins have been instrumental in delivering significant insights into protein misfolding, the behavior of these proteins in the complex milieu of living cells often diverges significantly from such simplified environments. Biomedical imaging performed in cell provides cellular-level information with high physiological and pathological relevance, often surpassing the depth of information attainable through in vitro methods. This review highlights a variety of methodologies used to scrutinize protein misfolding within biological systems. This includes optical-based methods, strategies leaning on mass spectrometry, in-cell nuclear magnetic resonance, and cryo-electron microscopy. Recent advancements in these techniques have notably deepened our understanding of protein misfolding processes and the features of the resulting misfolded species within living cells. The progression in these fields promises to catalyze further breakthroughs in our comprehension of neurodegenerative disease mechanisms and potential therapeutic interventions.

Modulation of receptor-like transmembrane kinase 1 nuclear localization by DA1 peptidases in Arabidopsis.

The cleavage of intracellular domains of receptor-like kinases (RLKs) has an important functional role in the transduction of signals from the cell surface to the nucleus in many organisms. However, the peptidases that catalyze protein cleavage during signal transduction remain poorly understood despite their crucial roles in diverse signaling processes. Here, we report in the flowering plant Arabidopsis thaliana that members of the DA1 family of ubiquitin-regulated Zn metallopeptidases cleave the cytoplasmic kinase domain of transmembrane kinase 1 (TMK1), releasing it for nuclear localization where it represses auxin-responsive cell growth during apical hook formation by phosphorylation and stabilization of the transcriptional repressors IAA32 and IAA34. Mutations in DA1 family members exhibited reduced apical hook formation, and DA1 family-mediated cleavage of TMK1 was promoted by auxin treatment. Expression of the DA1 family-generated intracellular kinase domain of TMK1 by an auxin-responsive promoter fully restored apical hook formation in a tmk1 mutant, establishing the function of DA1 family peptidase activities in TMK1-mediated differential cell growth and apical hook formation. DA1 family peptidase activity therefore modulates TMK1 kinase activity between a membrane location where it stimulates acid cell growth and initiates an auxin-dependent kinase cascade controlling cell proliferation in lateral roots and a nuclear localization where it represses auxin-mediated gene expression and growth.

Biomimetic Lung-Targeting Nanoparticles with Antioxidative and Nrf2 Activating Properties for Treating Ischemia/Reperfusion-Induced Acute Lung Injury.

Ischemia/reperfusion (IR)-induced acute lung injury (ALI) has a high mortality rate. Reactive oxygen species (ROS) play a crucial role in causing cellular damage and death in IR-induced ALI. In this work, we developed a biomimetic lung-targeting nanoparticle (PC@MB) as an antioxidative lung protector for treating IR-induced ALI. PC@MBs showed excellent ROS scavenging and Nrf2 activation properties, along with a lung-targeting function through autologous cell membrane coating. The PC@MBs exhibited an impressive antioxidative and pulmonary protective role via redox homeostasis recovery through Nrf2 and heme oxygenase-1 activation. PC@MBs could maintain cell viability by effectively scavenging the intracellular ROS and restoring the redox equilibrium in the lesion. In the IR mouse model, the PC@MBs preferentially accumulated in the lung and distinctly repaired the pneumonic damage. Our strategy has the potential to offer a promising therapeutic paradigm for treating IR-induced ALI through the incorporation of different therapeutic mechanisms.

Design of Antiferromagnetic Second-Order Band Topology with Rotation Topological Invariants in Two Dimensions.

The existence of fractionally quantized topological corner charge serves as a key indicator for two-dimensional (2D) second-order topological insulators (SOTIs), yet it has not been experimentally observed in realistic materials. Here, based on effective model analysis and symmetry arguments, we propose a strategy for achieving SOTI phases with in-gap corner states in 2D systems with antiferromagnetic (AFM) order. We discover that the band topology originates from the interplay between intrinsic spin-orbital coupling and interlayer AFM exchange interactions. Using first-principles calculations, we show that the 2D AFM SOTI phase can be realized in (MnBi2Te4)(Bi2Te3)m films. Moreover, we demonstrate that the SOTI states are linked to rotation topological invariants under 3-fold rotation symmetry C3, resulting in fractionally quantized corner charge, i.e., n3|e| (mod e). Due to the great achievements in (MnBi2Te4)(Bi2Te3)m systems, our results providing reliable material candidates for experimentally accessible AFM SOTIs should draw intense attention.

Ubiquitylation activates a peptidase that promotes cleavage and destabilization of its activating E3 ligases and diverse growth regulatory proteins to limit cell proliferation in Arabidopsis.

The characteristic shapes and sizes of organs are established by cell proliferation patterns and final cell sizes, but the underlying molecular mechanisms coordinating these are poorly understood. Here we characterize a ubiquitin-activated peptidase called DA1 that limits the duration of cell proliferation during organ growth in Arabidopsis thaliana The peptidase is activated by two RING E3 ligases, Big Brother (BB) and DA2, which are subsequently cleaved by the activated peptidase and destabilized. In the case of BB, cleavage leads to destabilization by the RING E3 ligase PROTEOLYSIS 1 (PRT1) of the N-end rule pathway. DA1 peptidase activity also cleaves the deubiquitylase UBP15, which promotes cell proliferation, and the transcription factors TEOSINTE BRANCED 1/CYCLOIDEA/PCF 15 (TCP15) and TCP22, which promote cell proliferation and repress endoreduplication. We propose that DA1 peptidase activity regulates the duration of cell proliferation and the transition to endoreduplication and differentiation during organ formation in plants by coordinating the destabilization of regulatory proteins.

Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF-ß1/Smad2/3 signalling in post-infarction mice.

Histone deacetylase 6 (HDAC6) belongs to the class IIb group of the histone deacetylase family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of HDAC6 in cardiac remodelling post-infarction. Experimental myocardial infarction (MI) was created in HDAC6-deficient (HDAC6-/-) mice and wild-type (HADC6+/+) by left coronary artery ligation. At days 0 and 14 post-MI, we evaluated cardiac function, morphology and molecular endpoints of repair and remodelling. At day 14 after surgery, the ischemic myocardium had increased levels of HADC6 gene and protein of post-MI mice compared to the non-ischemic myocardium of control mice. As compared with HDAC6-/--MI mice, HADC6 deletion markedly improved infarct size and cardiac fibrosis as well as impaired left ventricular ejection fraction and left ventricular fraction shortening. At the molecular levels, HDAC6-/- resulted in a significant reduction in the levels of the transforming growth factor-beta 1 (TGF-ß1), phosphor-Smad-2/3, collagen I and collagen III proteins and/or in the ischemic cardiac tissues. All of these beneficial effects were reproduced by a pharmacological inhibition of HADC6 in vivo. In vitro, hypoxic stress increased the expressions of HADC6 and collagen I and III gene; these alterations were significantly prevented by the HADC6 silencing and TubA loading. These findings indicated that HADC6 deficiency resists ischemic injury by a reduction of TGF-ß1/Smad2/3 signalling activation, leading to decreased extracellular matrix production, which reduces cardiac fibrosis and dysfunction, providing a potential molecular target in the treatment of patients with MI.

Construction and validation of a SASP-related prognostic signature in patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a common and highly aggressive haematological malignancy in adults. Senescence-associated secretory phenotype (SASP) plays important roles in tumorigenesis and progression of tumour. However, the prognostic value of SASP in patients with AML has not been clarified. The present study aims to explore the prognostic value of SASP and develop a prognostic risk signature for AML. The RNA-sequencing data was collected from the TCGA, GTEx and TARGET databases. Subsequently, differentially expressed gene analysis, univariate Cox regression and LASSO regression were applied to identified prognostic SASP-related genes and construct a prognostic risk-scoring model. The risk score of each patient were calculated and patients were divided into high- or low-risk groups by the median risk score. This novel prognostic signature included 11 genes: G6PD, CDK4, RPS6KA1, UBC, H2BC12, KIR2DL4, HSF1, IFIT3, PIM1, RUNX3 and TRIM21. The patients with AML in the high-risk group had shorter OS, demonstrating that the risk score acted as a prognostic predictor, which was validated in the TAGET-AML dataset. Univariate and multivariate analysis revealed the risk score was an independent prognostic factor in patients with AML. Furthermore, the present study revealed that the risk score was associated with immune landscape, immune checkpoint gene expression and chemotherapeutic efficacy. In the present study, we constructed and validated a unique SASP-related prognostic model to assess therapeutic effect and prognosis in patients with AML, which might contribute to understanding the role of SASP in AML and guiding the treatment for AML.