Opioid-induced fragile-like regulatory T cells contribute to withdrawal.

Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms.

The enormous repetitive Antarctic krill genome reveals environmental adaptations and population insights.

Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research.

A Milieu Molecule for TGF-ß Required for Microglia Function in the Nervous System.

Extracellular proTGF-ß is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-ß is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVß8-dependent TGF-ß activation. Lrrc33-/- mice lack CNS vascular abnormalities associated with deficiency in TGF-ß-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33-/- microglia in the same brain suggest that there is little spreading of TGF-ß activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-ß provide localized and selective activation of TGF-ß.

Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production.

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α. We also identified a requirement for cystathionine-γ-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.

2'-O-methylation at internal sites on mRNA promotes mRNA stability.

2'-O-methylation (Nm) is a prominent RNA modification well known in noncoding RNAs and more recently also found at many mRNA internal sites. However, their function and base-resolution stoichiometry remain underexplored. Here, we investigate the transcriptome-wide effect of internal site Nm on mRNA stability. Combining nanopore sequencing with our developed machine learning method, NanoNm, we identify thousands of Nm sites on mRNAs with a single-base resolution. We observe a positive effect of FBL-mediated Nm modification on mRNA stability and expression level. Elevated FBL expression in cancer cells is associated with increased expression levels for 2'-O-methylated mRNAs of cancer pathways, implying the role of FBL in post-transcriptional regulation. Lastly, we find that FBL-mediated 2'-O-methylation connects to widespread 3' UTR shortening, a mechanism that globally increases RNA stability. Collectively, we demonstrate that FBL-mediated Nm modifications at mRNA internal sites regulate gene expression by enhancing mRNA stability.

Endogenous hydrogen sulfide production is essential for dietary restriction benefits.

Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation. PAPERFLICK:

Negative mixing enthalpy solid solutions deliver high strength and ductility.

Body-centred cubic refractory multi-principal element alloys (MPEAs), with several refractory metal elements as constituents and featuring a yield strength greater than one gigapascal, are promising materials to meet the demands of aggressive structural applications1-6. Their low-to-no tensile ductility at room temperature, however, limits their processability and scaled-up application7-10. Here we present a HfNbTiVAl10 alloy that shows remarkable tensile ductility (roughly 20%) and ultrahigh yield strength (roughly 1,390 megapascals). Notably, these are among the best synergies compared with other related alloys. Such superb synergies derive from the addition of aluminium to the HfNbTiV alloy, resulting in a negative mixing enthalpy solid solution, which promotes strength and favours the formation of hierarchical chemical fluctuations (HCFs). The HCFs span many length scales, ranging from submicrometre to atomic scale, and create a high density of diffusive boundaries that act as effective barriers for dislocation motion. Consequently, versatile dislocation configurations are sequentially stimulated, enabling the alloy to accommodate plastic deformation while fostering substantial interactions that give rise to two unusual strain-hardening rate upturns. Thus, plastic instability is significantly delayed, which expands the plastic regime as ultralarge tensile ductility. This study provides valuable insights into achieving a synergistic combination of ultrahigh strength and large tensile ductility in MPEAs.

Targeted protein degradation reveals RNA Pol II heterogeneity and functional diversity.

RNA polymerase II (RNA Pol II) subunits are thought to be involved in various transcription-associated processes, but it is unclear whether they play different regulatory roles in modulating gene expression. Here, we performed nascent and mature transcript sequencing after the acute degradation of 12 mammalian RNA Pol II subunits and profiled their genomic binding sites and protein interactomes to dissect their molecular functions. We found that RNA Pol II subunits contribute differently to RNA Pol II cellular localization and transcription processes and preferentially regulate RNA processing (such as RNA splicing and 3' end maturation). Genes sensitive to the depletion of different RNA Pol II subunits tend to be involved in diverse biological functions and show different RNA half-lives. Sequences, associated protein factors, and RNA structures are correlated with RNA Pol II subunit-mediated differential gene expression. These findings collectively suggest that the heterogeneity of RNA Pol II and different genes appear to depend on some of the subunits.

Excitonic topological order in imbalanced electron-hole bilayers.

Correlation and frustration play essential roles in physics, giving rise to novel quantum phases1-6. A typical frustrated system is correlated bosons on moat bands, which could host topological orders with long-range quantum entanglement4. However, the realization of moat-band physics is still challenging. Here, we explore moat-band phenomena in shallowly inverted InAs/GaSb quantum wells, where we observe an unconventional time-reversal-symmetry breaking excitonic ground state under imbalanced electron and hole densities. We find that a large bulk gap exists, encompassing a broad range of density imbalances at zero magnetic field (B), accompanied by edge channels that resemble helical transport. Under an increasing perpendicular B, the bulk gap persists, and an anomalous plateau of Hall signals appears, which demonstrates an evolution from helical-like to chiral-like edge transport with a Hall conductance approximately equal to e2/h at 35 tesla, where e is the elementary charge and h is Planck's constant. Theoretically, we show that strong frustration from density imbalance leads to a moat band for excitons, resulting in a time-reversal-symmetry breaking excitonic topological order, which explains all our experimental observations. Our work opens up a new direction for research on topological and correlated bosonic systems in solid states beyond the framework of symmetry-protected topological phases, including but not limited to the bosonic fractional quantum Hall effect.

Ultrafast tunable lasers using lithium niobate integrated photonics.

Early works1 and recent advances in thin-film lithium niobate (LiNbO3) on insulator have enabled low-loss photonic integrated circuits2,3, modulators with improved half-wave voltage4,5, electro-optic frequency combs6 and on-chip electro-optic devices, with applications ranging from microwave photonics to microwave-to-optical quantum interfaces7. Although recent advances have demonstrated tunable integrated lasers based on LiNbO3 (refs. 8,9), the full potential of this platform to demonstrate frequency-agile, narrow-linewidth integrated lasers has not been achieved. Here we report such a laser with a fast tuning rate based on a hybrid silicon nitride (Si3N4)-LiNbO3 photonic platform and demonstrate its use for coherent laser ranging. Our platform is based on heterogeneous integration of ultralow-loss Si3N4 photonic integrated circuits with thin-film LiNbO3 through direct bonding at the wafer level, in contrast to previously demonstrated chiplet-level integration10, featuring low propagation loss of 8.5 decibels per metre, enabling narrow-linewidth lasing (intrinsic linewidth of 3 kilohertz) by self-injection locking to a laser diode. The hybrid mode of the resonator allows electro-optic laser frequency tuning at a speed of 12 × 1015 hertz per second with high linearity and low hysteresis while retaining the narrow linewidth. Using a hybrid integrated laser, we perform a proof-of-concept coherent optical ranging (FMCW LiDAR) experiment. Endowing Si3N4 photonic integrated circuits with LiNbO3 creates a platform that combines the individual advantages of thin-film LiNbO3 with those of Si3N4, which show precise lithographic control, mature manufacturing and ultralow loss11,12.

Oriented nucleation in formamidinium perovskite for photovoltaics.

The black phase of formamidinium lead iodide (FAPbI3) perovskite shows huge promise as an efficient photovoltaic, but it is not favoured energetically at room temperature, meaning that the undesirable yellow phases are always present alongside it during crystallization1-4. This problem has made it difficult to formulate the fast crystallization process of perovskite and develop guidelines governing the formation of black-phase FAPbI3 (refs. 5,6). Here we use in situ monitoring of the perovskite crystallization process to report an oriented nucleation mechanism that can help to avoid the presence of undesirable phases and improve the performance of photovoltaic devices in different film-processing scenarios. The resulting device has a demonstrated power-conversion efficiency of 25.4% (certified 25.0%) and the module, which has an area of 27.83 cm2, has achieved an impressive certified aperture efficiency of 21.4%.

A photonic integrated continuous-travelling-wave parametric amplifier.

The ability to amplify optical signals is of pivotal importance across science and technology typically using rare-earth-doped fibres or gain media based on III-V semiconductors. A different physical process to amplify optical signals is to use the Kerr nonlinearity of optical fibres through parametric interactions1,2. Pioneering work demonstrated continuous-wave net-gain travelling-wave parametric amplification in fibres3, enabling, for example, phase-sensitive (that is, noiseless) amplification4, link span increase5, signal regeneration and nonlinear phase noise mitigation6. Despite great progress7-15, all photonic integrated circuit-based demonstrations of net parametric gain have necessitated pulsed lasers, limiting their practical use. Until now, only bulk micromachined periodically poled lithium niobate (PPLN) waveguide chips have achieved continuous-wave gain16,17, yet their integration with silicon-wafer-based photonic circuits has not been shown. Here we demonstrate a photonic-integrated-circuit-based travelling-wave optical parametric amplifier with net signal gain in the continuous-wave regime. Using ultralow-loss, dispersion-engineered, metre-long, Si3N4 photonic integrated circuits18 on a silicon chip of dimensions 5 × 5 mm2, we achieve a continuous parametric gain of 12 dB that exceeds both the on-chip optical propagation loss and fibre-chip-fibre coupling losses in the telecommunication C band. Our work demonstrates the potential of photonic-integrated-circuit-based parametric amplifiers that have lithographically controlled gain spectrum, compact footprint, resilience to optical feedback and quantum-limited performance, and can operate in the wavelength ranges from visible to mid-infrared and outside conventional rare-earth amplification bands.

A multidimensional coding architecture of the vagal interoceptive system.

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

Stability-limiting heterointerfaces of perovskite photovoltaics.

Optoelectronic devices consist of heterointerfaces formed between dissimilar semiconducting materials. The relative energy-level alignment between contacting semiconductors determinately affects the heterointerface charge injection and extraction dynamics. For perovskite solar cells (PSCs), the heterointerface between the top perovskite surface and a charge-transporting material is often treated for defect passivation1-4 to improve the PSC stability and performance. However, such surface treatments can also affect the heterointerface energetics1. Here we show that surface treatments may induce a negative work function shift (that is, more n-type), which activates halide migration to aggravate PSC instability. Therefore, despite the beneficial effects of surface passivation, this detrimental side effect limits the maximum stability improvement attainable for PSCs treated in this way. This trade-off between the beneficial and detrimental effects should guide further work on improving PSC stability via surface treatments.

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

The F-box protein RhSAF destabilizes the gibberellic acid receptor RhGID1 to mediate ethylene-induced petal senescence in rose.

Roses are among the most popular ornamental plants cultivated worldwide for their great economic, symbolic, and cultural importance. Nevertheless, rapid petal senescence markedly reduces rose (Rosa hybrida) flower quality and value. Petal senescence is a developmental process tightly regulated by various phytohormones. Ethylene accelerates petal senescence, while gibberellic acid (GA) delays this process. However, the molecular mechanisms underlying the crosstalk between these phytohormones in the regulation of petal senescence remain largely unclear. Here, we identified SENESCENCE-ASSOCIATED F-BOX (RhSAF), an ethylene-induced F-box protein gene encoding a recognition subunit of the SCF-type E3 ligase. We demonstrated that RhSAF promotes degradation of the GA receptor GIBBERELLIN INSENSITIVE DWARF1 (RhGID1) to accelerate petal senescence. Silencing RhSAF expression delays petal senescence, while suppressing RhGID1 expression accelerates petal senescence. RhSAF physically interacts with RhGID1s and targets them for ubiquitin/26S proteasome-mediated degradation. Accordingly, ethylene-induced RhGID1C degradation and RhDELLA3 accumulation are compromised in RhSAF-RNAi lines. Our results demonstrate that ethylene antagonizes GA activity through RhGID1 degradation mediated by the E3 ligase RhSAF. These findings enhance our understanding of the phytohormone crosstalk regulating petal senescence and provide insights for improving flower longevity.

Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Wnt signaling regulates acetylcholine receptor translocation and synaptic plasticity in the adult nervous system.

The adult nervous system is plastic, allowing us to learn, remember, and forget. Experience-dependent plasticity occurs at synapses--the specialized points of contact between neurons where signaling occurs. However, the mechanisms that regulate the strength of synaptic signaling are not well understood. Here, we define a Wnt-signaling pathway that modifies synaptic strength in the adult nervous system by regulating the translocation of one class of acetylcholine receptors (AChRs) to synapses. In Caenorhabditis elegans, we show that mutations in CWN-2 (Wnt ligand), LIN-17 (Frizzled), CAM-1 (Ror receptor tyrosine kinase), or the downstream effector DSH-1 (disheveled) result in similar subsynaptic accumulations of ACR-16/α7 AChRs, a consequent reduction in synaptic current, and predictable behavioral defects. Photoconversion experiments revealed defective translocation of ACR-16/α7 to synapses in Wnt-signaling mutants. Using optogenetic nerve stimulation, we demonstrate activity-dependent synaptic plasticity and its dependence on ACR-16/α7 translocation mediated by Wnt signaling via LIN-17/CAM-1 heteromeric receptors.