The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.

Continuous symmetry breaking in a two-dimensional Rydberg array.

Spontaneous symmetry breaking underlies much of our classification of phases of matter and their associated transitions1-3. The nature of the underlying symmetry being broken determines many of the qualitative properties of the phase; this is illustrated by the case of discrete versus continuous symmetry breaking. Indeed, in contrast to the discrete case, the breaking of a continuous symmetry leads to the emergence of gapless Goldstone modes controlling, for instance, the thermodynamic stability of the ordered phase4,5. Here, we realize a two-dimensional dipolar XY model that shows a continuous spin-rotational symmetry using a programmable Rydberg quantum simulator. We demonstrate the adiabatic preparation of correlated low-temperature states of both the XY ferromagnet and the XY antiferromagnet. In the ferromagnetic case, we characterize the presence of a long-range XY order, a feature prohibited in the absence of long-range dipolar interaction. Our exploration of the many-body physics of XY interactions complements recent works using the Rydberg-blockade mechanism to realize Ising-type interactions showing discrete spin rotation symmetry6-9.

Scalable spin squeezing in a dipolar Rydberg atom array.

The standard quantum limit bounds the precision of measurements that can be achieved by ensembles of uncorrelated particles. Fundamentally, this limit arises from the non-commuting nature of quantum mechanics, leading to the presence of fluctuations often referred to as quantum projection noise. Quantum metrology relies on the use of non-classical states of many-body systems to enhance the precision of measurements beyond the standard quantum limit1,2. To do so, one can reshape the quantum projection noise-a strategy known as squeezing3,4. In the context of many-body spin systems, one typically uses all-to-all interactions (for example, the one-axis twisting model4) between the constituents to generate the structured entanglement characteristic of spin squeezing5. Here we explore the prediction, motivated by recent theoretical work6-10, that short-range interactions-and in particular, the two-dimensional dipolar XY model-can also enable the realization of scalable spin squeezing. Working with a dipolar Rydberg quantum simulator of up to N = 100 atoms, we demonstrate that quench dynamics from a polarized initial state lead to spin squeezing that improves with increasing system size up to a maximum of -3.5 ± 0.3 dB (before correcting for detection errors, or roughly -5 ± 0.3 dB after correction). Finally, we present two independent refinements: first, using a multistep spin-squeezing protocol allows us to further enhance the squeezing by roughly 1 dB, and second, leveraging Floquet engineering to realize Heisenberg interactions, we demonstrate the ability to extend the lifetime of the squeezed state by freezing its dynamics.

Landscape-scale benefits of protected areas for tropical biodiversity.

The United Nations recently agreed to major expansions of global protected areas (PAs) to slow biodiversity declines1. However, although reserves often reduce habitat loss, their efficacy at preserving animal diversity and their influence on biodiversity in surrounding unprotected areas remain unclear2-5. Unregulated hunting can empty PAs of large animals6, illegal tree felling can degrade habitat quality7, and parks can simply displace disturbances such as logging and hunting to unprotected areas of the landscape8 (a phenomenon called leakage). Alternatively, well-functioning PAs could enhance animal diversity within reserves as well as in nearby unprotected sites9 (an effect called spillover). Here we test whether PAs across mega-diverse Southeast Asia contribute to vertebrate conservation inside and outside their boundaries. Reserves increased all facets of bird diversity. Large reserves were also associated with substantially enhanced mammal diversity in the adjacent unprotected landscape. Rather than PAs generating leakage that deteriorated ecological conditions elsewhere, our results are consistent with PAs inducing spillover that benefits biodiversity in surrounding areas. These findings support the United Nations goal of achieving 30% PA coverage by 2030 by demonstrating that PAs are associated with higher vertebrate diversity both inside their boundaries and in the broader landscape.

Naa10p Inhibits Beige Adipocyte-Mediated Thermogenesis through N-α-acetylation of Pgc1α.

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.

The presence of broadly neutralizing anti-SARS-CoV-2 RBD antibodies elicited by primary series and booster dose of COVID-19 vaccine.

Antibody-mediated immunity plays a key role in protection against SARS-CoV-2. We characterized B-cell-derived anti-SARS-CoV-2 RBD antibody repertoires from vaccinated and infected individuals and elucidate the mechanism of action of broadly neutralizing antibodies and dissect antibodies at the epitope level. The breadth and clonality of anti-RBD B cell response varies among individuals. The majority of neutralizing antibody clones lose or exhibit reduced activities against Beta, Delta, and Omicron variants. Nevertheless, a portion of anti-RBD antibody clones that develops after a primary series or booster dose of COVID-19 vaccination exhibit broad neutralization against emerging Omicron BA.2, BA.4, BA.5, BQ.1.1, XBB.1.5 and XBB.1.16 variants. These broadly neutralizing antibodies share genetic features including a conserved usage of the IGHV3-53 and 3-9 genes and recognize three clustered epitopes of the RBD, including epitopes that partially overlap the classically defined set identified early in the pandemic. The Fab-RBD crystal and Fab-Spike complex structures corroborate the epitope grouping of antibodies and reveal the detailed binding mode of broadly neutralizing antibodies. Structure-guided mutagenesis improves binding and neutralization potency of antibody with Omicron variants via a single amino-substitution. Together, these results provide an immunological basis for partial protection against severe COVID-19 by the ancestral strain-based vaccine and indicate guidance for next generation monoclonal antibody development and vaccine design.

Multiomics analysis reveals the molecular mechanisms underlying virulence in Rhizoctonia and jasmonic acid-mediated resistance in Tartary buckwheat (Fagopyrum tataricum).

Rhizoctonia solani is a devastating soil-borne pathogen that seriously threatens the cultivation of economically important crops. Multiple strains with a very broad host range have been identified, but only 1 (AG1-IA, which causes rice sheath blight disease) has been examined in detail. Here, we analyzed AG4-HGI 3 originally isolated from Tartary buckwheat (Fagopyrum tataricum), but with a host range comparable to AG1-IA. Genome comparison reveals abundant pathogenicity genes in this strain. We used multiomic approaches to improve the efficiency of screening for disease resistance genes. Transcriptomes of the plant-fungi interaction identified differentially expressed genes associated with virulence in Rhizoctonia and resistance in Tartary buckwheat. Integration with jasmonate-mediated transcriptome and metabolome changes revealed a negative regulator of jasmonate signaling, cytochrome P450 (FtCYP94C1), as increasing disease resistance probably via accumulation of resistance-related flavonoids. The integration of resistance data for 320 Tartary buckwheat accessions identified a gene homolog to aspartic proteinase (FtASP), with peak expression following R. solani inoculation. FtASP exhibits no proteinase activity but functions as an antibacterial peptide that slows fungal growth. This work reveals a potential mechanism behind pathogen virulence and host resistance, which should accelerate the molecular breeding of resistant varieties in economically essential crops.

PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

New Guinea has the world's richest island flora.

New Guinea is the world's largest tropical island and has fascinated naturalists for centuries1,2. Home to some of the best-preserved ecosystems on the planet3 and to intact ecological gradients-from mangroves to tropical alpine grasslands-that are unmatched in the Asia-Pacific region4,5, it is a globally recognized centre of biological and cultural diversity6,7. So far, however, there has been no attempt to critically catalogue the entire vascular plant diversity of New Guinea. Here we present the first, to our knowledge, expert-verified checklist of the vascular plants of mainland New Guinea and surrounding islands. Our publicly available checklist includes 13,634 species (68% endemic), 1,742 genera and 264 families-suggesting that New Guinea is the most floristically diverse island in the world. Expert knowledge is essential for building checklists in the digital era: reliance on online taxonomic resources alone would have inflated species counts by 22%. Species discovery shows no sign of levelling off, and we discuss steps to accelerate botanical research in the 'Last Unknown'8.

Triggering photocatalytic performance of La2CoxMn2-xO6 via heat activation.

The La-based perovskite (LaBO3) exhibits excellent optical properties. However, its valence band (VB) potential is not sufficiently positive to reach the oxidation potential required for the cleavage of chemical bonds (such as benzylic C-H), limiting its application in photocatalysis. Herein, we report the unconventional effects of heat activation on the reduction of the dissociation energy of benzylic C-H and aqueous H-O, thereby triggering the photocatalytic activity of La2CoxMn2-xO6 perovskites. Additionally, we demonstrate that photocatalysis is the main contributor to substrate conversion in the selective oxidation of toluene and reduction of CO2. Particularly, La2Co1.5Mn0.5O6 shows excellent performance with a product yield of 550.00 mmol gcat-1 and a toluene conversion of 22,866.67 µmol gcat-1 h-1. To the best of our knowledge, this is the highest reported product yield for the selective oxidation of benzylic C-H bond of toluene. Our findings provide insight into the specific role of heat activation in photocatalysis, which is crucial for breaking and overcoming the VB barrier to realize challenging reactions.

Brain Gene Regulatory Networks Coordinate Nest Construction in Birds.

Nest building is a vital behavior exhibited during breeding in birds, and is possibly induced by environmental and social cues. Although such behavioral plasticity has been hypothesized to be controlled by adult neuronal plasticity, empirical evidence, especially at the neurogenomic level, remains limited. Here, we aim to uncover the gene regulatory networks that govern avian nest construction and examine whether they are associated with circuit rewiring. We designed an experiment to dissect this complex behavior into components in response to pair bonding and nest material acquisition by manipulating the presence of mates and nest materials in 30 pairs of zebra finches. Whole-transcriptome analysis of 300 samples from five brain regions linked to avian nesting behaviors revealed nesting-associated gene expression enriched with neural rewiring functions, including neurogenesis and neuron projection. The enriched expression was observed in the motor/sensorimotor and social behavior networks of female finches, and in the dopaminergic reward system of males. Female birds exhibited predominant neurotranscriptomic changes to initiate the nesting stage, while males showed major changes after entering this stage, underscoring sex-specific roles in nesting behavior. Notably, major neurotranscriptomic changes occurred during pair bonding, with minor changes during nest material acquisition, emphasizing social interactions in nest construction. We also revealed gene expression associated with reproductive behaviors and tactile sensing for nesting behavior. This study presents novel neurogenomic evidence supporting the hypothesis of adult neural plasticity underlying avian nest-construction behavior. By uncovering the genetic toolkits involved, we offer novel insights into the evolution of animals' innate ability to construct nests.

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.

Endogenous mutant Huntingtin alters the corticogenesis via lowering Golgi recruiting ARF1 in cortical organoid.

Pathogenic mutant huntingtin (mHTT) infiltrates the adult Huntington's disease (HD) brain and impairs fetal corticogenesis. However, most HD animal models rarely recapitulate neuroanatomical alterations in adult HD and developing brains. Thus, the human cortical organoid (hCO) is an alternative approach to decode mHTT pathogenesis precisely during human corticogenesis. Here, we replicated the altered corticogenesis in the HD fetal brain using HD patient-derived hCOs. Our HD-hCOs had pathological phenotypes, including deficient junctional complexes in the neural tubes, delayed postmitotic neuronal maturation, dysregulated fate specification of cortical neuron subtypes, and abnormalities in early HD subcortical projections during corticogenesis, revealing a causal link between impaired progenitor cells and chaotic cortical neuronal layering in the HD brain. We identified novel long, oriented, and enriched polyQ assemblies of HTTs that hold large flat Golgi stacks and scaffold clathrin+ vesicles in the neural tubes of hCOs. Flat Golgi stacks conjugated polyQ assemblies by ADP-ribosylation factor 1 (ARF1). Inhibiting ARF1 activation with Brefeldin A (BFA) disassociated polyQ assemblies from Golgi. PolyQ assembles with mHTT scaffolded fewer ARF1 and formed shorter polyQ assembles with fewer and shorter Golgi and clathrin vesicles in neural tubes of HD-hCOs compared with those in hCOs. Inhibiting the activation of ARF1 by BFA in healthy hCOs replicated impaired junctional complexes in the neural tubes. Together, endogenous polyQ assemblies with mHTT reduced the Golgi recruiting ARF1 in the neuroepithelium, impaired the Golgi structure and activities, and altered the corticogenesis in HD-hCO.

MiRNA let-7d-5p Alleviates Inflammatory Responses by Targeting Map3k1 and Inactivating ERK/p38 MAPK Signaling in Microglia.

Alzheimer's disease (AD) is the most common form of dementia. Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of AD. In a large case-control study recruiting 208 patients with AD and 205 elderly control subjects, miRNA-let-7d-5p attracted our attention for its downregulated level in patients with AD. However, the biological functions of let-7d-5p in AD pathogenesis have not been investigated. This study emphasized the functions and mechanisms of let-7d-5p in the pathogenesis of AD. Mouse microglial BV2 cells treated with amyloid-ß (Aß)1-42 were used as in vitro AD inflammation models. We reported that let-7d-5p was downregulated in Aß1-42-stimulated BV2 cells, and upregulation of let-7d-5p promoted the transversion of microglial cells from Ml phenotype to M2 phenotype. Then, the binding relationship between let-7d-5p and Map3k1 was verified by luciferase reporter assays. Mechanistically, let-7d-5p could target Map3k1 3'UTR to inactivate ERK/p38 MAPK signaling. Therefore, it was suggested that let-7d-5p might be a novel modulator of microglial neuroinflammation and serve as a novel target for diagnosis and treatment of AD.

The Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting.

Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and embryonic stem cells. Mechanistically, Naa10p facilitates binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates, including the ICRs of the imprinted allele during S phase. Moreover, the lethal Ogden syndrome-associated mutation of human Naa10p disrupts its binding to the ICR of H19 and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated Ogden syndrome to defective DNA methylation and genomic imprinting.

Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization.

Hepatic insulin resistance is a hallmark feature of nonalcoholic fatty liver disease and type-2 diabetes and significantly contributes to systemic insulin resistance. Abnormal activation of nutrient and stress-sensing kinases leads to serine/threonine phosphorylation of insulin receptor substrate (IRS) and subsequent IRS proteasome degradation, which is a key underlying cause of hepatic insulin resistance. Recently, members of the cullin-RING E3 ligases (CRLs) have emerged as mediators of IRS protein turnover, but the pathophysiological roles and therapeutic implications of this cellular signaling regulation is largely unknown. CRLs are activated upon cullin neddylation, a process of covalent conjugation of a ubiquitin-like protein called Nedd8 to a cullin scaffold. Here, we report that pharmacological inhibition of cullin neddylation by MLN4924 (Pevonedistat) rapidly decreases hepatic glucose production and attenuates hyperglycemia in mice. Mechanistically, neddylation inhibition delays CRL-mediated IRS protein turnover to prolong insulin action in hepatocytes. In vitro knockdown of either cullin 1 or cullin 3, but not other cullin members, attenuates insulin-induced IRS protein degradation and enhances cellular insulin signaling activation. In contrast, in vivo knockdown of liver cullin 3, but not cullin 1, stabilizes hepatic IRS and decreases blood glucose, which recapitulates the effect of MLN4924 treatment. In summary, these findings suggest that pharmacological inhibition of cullin neddylation represents a therapeutic approach for improving hepatic insulin signaling and lowering blood glucose.

Hydrogen-bonded organic frameworks for membrane separation.

Hydrogen-bonded organic frameworks (HOFs) are a new class of crystalline porous materials that are formed through the interconnection of organic or metal-organic building units via intermolecular hydrogen bonds. The remarkable flexibility and reversibility of hydrogen bonds, coupled with the customizable nature of organic units, endow HOFs with mild synthesis conditions, high crystallinity, solvent processability, and facile self-healing and regeneration properties. Consequently, these features have garnered significant attention across various fields, particularly in the realm of membrane separation. Herein, we present an overview of the recent advances in HOF-based membranes, including their advanced fabrication strategies and fascinating applications in membrane separation. To attain the desired HOF-based membranes, careful consideration is dedicated to crucial factors such as pore size, stability, hydrophilicity/hydrophobicity, and surface charge of the HOFs. Additionally, diverse preparation methods for HOF-based membranes, including blending, in situ growth, solution-processing, and electrophoretic deposition, have been analyzed. Furthermore, applications of HOF-based membranes in gas separation, water treatment, fuel cells, and other emerging application areas are presented. Finally, the challenges and prospects of HOF-based membranes are critically pointed out.

Adaptive Gap-Tunable Surface-Enhanced Raman Spectroscopy.

Gap plasmon (GP) resonance in static surface-enhanced Raman spectroscopy (SERS) structures is generally too narrow and not tunable. Here, we present an adaptive gap-tunable SERS device to selectively enhance and modulate different vibrational modes via active flexible Au nanogaps, with adaptive optical control. The tunability of GP resonance is up to ∼1200 cm-1 by engineering gap width, facilitated by mechanical bending of a polyethylene terephthalate substrate. We confirm that the tuned GP resonance selectively enhances different Raman spectral regions of the molecules. Additionally, we dynamically control the SERS intensity through the wavefront shaping of excitation beams. Furthermore, we demonstrate simulation results, exhibiting the mechanical and optical properties of a one-dimensional flexible nanogap and their advantage in high-speed biomedical sensing. Our work provides a unique approach for observing and controlling the enhanced chemical responses with dynamic tunability.