Nuclear localization of STING1 competes with canonical signaling to activate AHR for commensal and intestinal homeostasis.

Extensive studies demonstrate the importance of the STING1 (also known as STING) protein as a signaling hub that coordinates immune and autophagic responses to ectopic DNA in the cytoplasm. Here, we report a nuclear function of STING1 in driving the activation of the transcription factor aryl hydrocarbon receptor (AHR) to control gut microbiota composition and homeostasis. This function was independent of DNA sensing and autophagy and showed competitive inhibition with cytoplasmic cyclic guanosine monophosphate (GMP)-AMP synthase (CGAS)-STING1 signaling. Structurally, the cyclic dinucleotide binding domain of STING1 interacted with the AHR N-terminal domain. Proteomic analyses revealed that STING1-mediated transcriptional activation of AHR required additional nuclear partners, including positive and negative regulatory proteins. Although AHR ligands could rescue colitis pathology and dysbiosis in wild-type mice, this protection was abrogated by mutational inactivation of STING1. These findings establish a key framework for understanding the nuclear molecular crosstalk between the microbiota and the immune system.

Tuning the Chern number in quantum anomalous Hall insulators.

A quantum anomalous Hall (QAH) state is a two-dimensional topological insulating state that has a quantized Hall resistance of h/(Ce2) and vanishing longitudinal resistance under zero magnetic field (where h is the Planck constant, e is the elementary charge, and the Chern number C is an integer)1,2. The QAH effect has been realized in magnetic topological insulators3-9 and magic-angle twisted bilayer graphene10,11. However, the QAH effect at zero magnetic field has so far been realized only for C = 1. Here we realize a well quantized QAH effect with tunable Chern number (up to C = 5) in multilayer structures consisting of alternating magnetic and undoped topological insulator layers, fabricated using molecular beam epitaxy. The Chern number of these QAH insulators is determined by the number of undoped topological insulator layers in the multilayer structure. Moreover, we demonstrate that the Chern number of a given multilayer structure can be tuned by varying either the magnetic doping concentration in the magnetic topological insulator layers or the thickness of the interior magnetic topological insulator layer. We develop a theoretical model to explain our experimental observations and establish phase diagrams for QAH insulators with high, tunable Chern number. The realization of such insulators facilitates the application of dissipationless chiral edge currents in energy-efficient electronic devices, and opens up opportunities for developing multi-channel quantum computing and higher-capacity chiral circuit interconnects.

Electrical switching of the edge current chirality in quantum anomalous Hall insulators.

A quantum anomalous Hall (QAH) insulator is a topological phase in which the interior is insulating but electrical current flows along the edges of the sample in either a clockwise or counterclockwise direction, as dictated by the spontaneous magnetization orientation. Such a chiral edge current eliminates any backscattering, giving rise to quantized Hall resistance and zero longitudinal resistance. Here we fabricate mesoscopic QAH sandwich Hall bar devices and succeed in switching the edge current chirality through thermally assisted spin-orbit torque (SOT). The well-quantized QAH states before and after SOT switching with opposite edge current chiralities are demonstrated through four- and three-terminal measurements. We show that the SOT responsible for magnetization switching can be generated by both surface and bulk carriers. Our results further our understanding of the interplay between magnetism and topological states and usher in an easy and instantaneous method to manipulate the QAH state.

The Arabidopsis Rab protein RABC1 affects stomatal development by regulating lipid droplet dynamics.

Lipid droplets (LDs) are evolutionarily conserved organelles that serve as hubs of cellular lipid and energy metabolism in virtually all organisms. Mobilization of LDs is important in light-induced stomatal opening. However, whether and how LDs are involved in stomatal development remains unknown. We show here that Arabidopsis thaliana LIPID DROPLETS AND STOMATA 1 (LDS1)/RABC1 (At1g43890) encodes a member of the Rab GTPase family that is involved in regulating LD dynamics and stomatal morphogenesis. The expression of RABC1 is coordinated with the different phases of stomatal development. RABC1 targets to the surface of LDs in response to oleic acid application in a RABC1GEF1-dependent manner. RABC1 physically interacts with SEIPIN2/3, two orthologues of mammalian seipin, which function in the formation of LDs. Disruption of RABC1, RABC1GEF1, or SEIPIN2/3 resulted in aberrantly large LDs, severe defects in guard cell vacuole morphology, and stomatal function. In conclusion, these findings reveal an aspect of LD function and uncover a role for lipid metabolism in stomatal development in plants.

Engineering Plateau Phase Transition in Quantum Anomalous Hall Multilayers.

The plateau phase transition in quantum anomalous Hall (QAH) insulators corresponds to a quantum state wherein a single magnetic domain gives way to multiple domains and then reconverges back to a single magnetic domain. The layer structure of the sample provides an external knob for adjusting the Chern number C of the QAH insulators. Here, we employ molecular beam epitaxy to grow magnetic topological insulator multilayers and realize the magnetic field-driven plateau phase transition between two QAH states with odd Chern number change ΔC. We find that critical exponents extracted for the plateau phase transitions with ΔC = 1 and ΔC = 3 in QAH insulators are nearly identical. We construct a four-layer Chalker-Coddington network model to understand the consistent critical exponents for the plateau phase transitions with ΔC = 1 and ΔC = 3. This work will motivate further investigations into the critical behaviors of plateau phase transitions with different ΔC in QAH insulators.

Two adjacent NAC transcription factors regulate fruit maturity date and flavor in peach.

Although maturity date (MD) is an essential factor affecting fresh fruit marketing and has a pleiotropic effect on fruit taste qualities, the underlying mechanisms remain largely unclear. In this study, we functionally characterized two adjacent NAM-ATAF1/2-CUC2 (NAC) transcription factors (TFs), PpNAC1 and PpNAC5, both of which were associated with fruit MD in peach. PpNAC1 and PpNAC5 were found capable of activating transcription of genes associated with cell elongation, cell wall degradation and ethylene biosynthesis, suggesting their regulatory roles in fruit enlargement and ripening. Furthermore, PpNAC1 and PpNAC5 had pleiotropic effects on fruit taste due to their ability to activate transcription of genes for sugar accumulation and organic acid degradation. Interestingly, both PpNAC1 and PpNAC5 orthologues were found in fruit-producing angiosperms and adjacently arranged in all 91 tested dicots but absent in fruitless gymnosperms, suggesting their important roles in fruit development. Our results provide insight into the regulatory roles of NAC TFs in MD and fruit taste.

Environmental Doping-Induced Degradation of the Quantum Anomalous Hall Insulators.

The quantum anomalous Hall (QAH) insulator carries dissipation-free chiral edge current and thus provides a unique opportunity to develop energy-efficient transformative information technology. Despite promising advances, the QAH insulator has thus far eluded any practical applications. In addition to its low working temperature, the QAH state in magnetically doped topological insulators usually deteriorates with time in ambient conditions. In this work, we store three QAH devices with similar initial properties in different environments. The QAH device without a protection layer in air shows clear degradation and becomes hole-doped. The QAH device kept in an argon glovebox without a protection layer shows no measurable degradation after 560 h, and the device protected by a 3 nm AlOx protection layer in air shows minimal degradation with stable QAH properties. Our work shows a route to preserve the dissipation-free chiral edge state in QAH devices for potential applications in quantum information technology.

Crossover from Ising- to Rashba-type superconductivity in epitaxial Bi2Se3/monolayer NbSe2 heterostructures.

A topological insulator (TI) interfaced with an s-wave superconductor has been predicted to host topological superconductivity. Although the growth of epitaxial TI films on s-wave superconductors has been achieved by molecular-beam epitaxy, it remains an outstanding challenge for synthesizing atomically thin TI/superconductor heterostructures, which are critical for engineering the topological superconducting phase. Here we used molecular-beam epitaxy to grow Bi2Se3 films with a controlled thickness on monolayer NbSe2 and performed in situ angle-resolved photoemission spectroscopy and ex situ magnetotransport measurements on these heterostructures. We found that the emergence of Rashba-type bulk quantum-well bands and spin-non-degenerate surface states coincides with a marked suppression of the in-plane upper critical magnetic field of the superconductivity in Bi2Se3/monolayer NbSe2 heterostructures. This is a signature of a crossover from Ising- to Rashba-type superconducting pairings, induced by altering the Bi2Se3 film thickness. Our work opens a route for exploring a robust topological superconducting phase in TI/Ising superconductor heterostructures.

Confinement-Induced Chiral Edge Channel Interaction in Quantum Anomalous Hall Insulators.

In quantum anomalous Hall (QAH) insulators, the interior is insulating but electrons can travel with zero resistance along one-dimensional (1D) conducting paths known as chiral edge channels (CECs). These CECs have been predicted to be confined to the 1D edges and exponentially decay in the two-dimensional (2D) bulk. In this Letter, we present the results of a systematic study of QAH devices fashioned in a Hall bar geometry of different widths under gate voltages. At the charge neutral point, the QAH effect persists in a Hall bar device with a width of only ∼72 nm, implying the intrinsic decaying length of CECs is less than ∼36 nm. In the electron-doped regime, we find that the Hall resistance deviates quickly from the quantized value when the sample width is less than 1 µm. Our theoretical calculations suggest that the wave function of CEC first decays exponentially and then shows a long tail due to disorder-induced bulk states. Therefore, the deviation from the quantized Hall resistance in narrow QAH samples originates from the interaction between two opposite CECs mediated by disorder-induced bulk states in QAH insulators, consistent with our experimental observations.

Vaspin alleviates the lncRNA LEF1-AS1-induced osteogenic differentiation of vascular smooth muscle cells via the Hippo/YAP signaling pathway.

Vascular calcification (VC) is closely related to higher cardiovascular mortality and morbidity, and vascular smooth muscle cell (VSMC) switching to osteogenic-like cells is crucial for VC. LncRNA LEF1-AS1 promotes atherosclerosis and dental pulp stem cells calcification, while its role in VC remains unknown. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine regulating bone metabolism. However, the relationship between vaspin and VC is still unclear. We aimed to explore the role of LEF1-AS1 on VSMC osteogenic transition, whether vaspin inhibited LEF1-AS1-mediated osteogenic differentiation of VSMCs, and the responsible mechanism. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis indicated that LEF1-AS1 overexpression significantly upregulated osteogenic marker Runt-related transcription factor-2 (RUNX2) level and downregulated VSMC contractile marker α-smooth muscle actin (α-SMA) level. Alizarin red staining, alkaline phosphatase (ALP) staining, ALP activity assay, and calcium content assay also suggested that LEF1-AS1 overexpression promoted calcium deposition in VSMCs. However, vaspin treatment abolished this phenomenon. Mechanistically, LEF1-AS1 markedly decreased phosphorylated YAP level, while vaspin reversed LEF1-AS1-induced phosphorylated YAP decline. Our results revealed that LEF1-AS1 accelerated the osteogenic differentiation of VSMCs by regulating the Hippo/YAP pathway, while vaspin eliminated the LEF1-AS1-meditated VSMCs osteogenic phenotype switch.

Pervasive and essential roles of the Top3-Rmi1 decatenase orchestrate recombination and facilitate chromosome segregation in meiosis.

The Bloom's helicase ortholog, Sgs1, plays central roles to coordinate the formation and resolution of joint molecule intermediates (JMs) during meiotic recombination in budding yeast. Sgs1 can associate with type-I topoisomerase Top3 and its accessory factor Rmi1 to form a conserved complex best known for its unique ability to decatenate double-Holliday junctions. Contrary to expectations, we show that the strand-passage activity of Top3-Rmi1 is required for all known functions of Sgs1 in meiotic recombination, including channeling JMs into physiological crossover and noncrossover pathways, and suppression of non-allelic recombination. We infer that Sgs1 always functions in the context of the Sgs1-Top3-Rmi1 complex to regulate meiotic recombination. In addition, we reveal a distinct late role for Top3-Rmi1 in resolving recombination-dependent chromosome entanglements to allow segregation at anaphase. Surprisingly, Sgs1 does not share this essential role of Top3-Rmi1. These data reveal an essential and pervasive role for the Top3-Rmi1 decatenase during meiosis.

The dualistic model of passion and the service quality of five-star hotel employees during the COVID-19 pandemic.

Given the generally stressful job demands of the hospitality industry during the COVID-19 pandemic, understanding the work passion and emotions of hotel employees is particularly important. Based on the conservation of resources theory and the job demands-resources model, this study develops a multiple mediation model to investigate how frontline hotel employees with different types of work passion choose emotional labor strategies under the effects of the COVID-19 pandemic and the impact of different choices on their service quality. A two-stage survey using data from 206 frontline employees of five-star hotels in China explored how work passion influences emotional labor and thereby affects emotional expression as well as service quality. The results showed emotional labor partially mediates the relationship between work passion and emotional expression, which in turn mediates the relationship between emotional labor and service quality during the COVID-19 pandemic. The theoretical and practical implications of this study are discussed.

Zero Magnetic Field Plateau Phase Transition in Higher Chern Number Quantum Anomalous Hall Insulators.

The plateau-to-plateau transition in quantum Hall effect under high magnetic fields is a celebrated quantum phase transition between two topological states. It can be achieved by either sweeping the magnetic field or tuning the carrier density. The recent realization of the quantum anomalous Hall (QAH) insulators with tunable Chern numbers introduces the channel degree of freedom to the dissipation-free chiral edge transport and makes the study of the quantum phase transition between two topological states under zero magnetic field possible. Here, we synthesized the magnetic topological insulator (TI)/TI pentalayer heterostructures with different Cr doping concentrations in the middle magnetic TI layers using molecular beam epitaxy. By performing transport measurements, we found a potential plateau phase transition between C=1 and C=2 QAH states under zero magnetic field. In tuning the transition, the Hall resistance monotonically decreases from h/e^{2} to h/2e^{2}, concurrently, the longitudinal resistance exhibits a maximum at the critical point. Our results show that the ratio between the Hall resistance and the longitudinal resistance is greater than 1 at the critical point, which indicates that the original chiral edge channel from the C=1 QAH state coexists with the dissipative bulk conduction channels. Subsequently, these bulk conduction channels appear to self-organize and form the second chiral edge channel in completing the plateau phase transition. Our study will motivate further investigations of this novel Chern number change-induced quantum phase transition and advance the development of the QAH chiral edge current-based electronic and spintronic devices.

Outcomes of allogeneic hematopoietic stem cell transplantation for primary hemophagocytic lymphohistiocytosis in adults.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative approach for primary hemophagocytic lymphohistiocytosis (pHLH), but data on adult patients are scarce. Here we present an 8-year experience on HSCT for adult pHLH to reveal the benefits and risks in this population. A total of 29 adult pHLH patients entered this study, at a median follow-up of 29 months (3-112 months), the 5-year probability of survival was 60%. Six patients rejected HSCT, of whom 1 alive in complete response (CR). In 23 patients who underwent HSCT, 5-year survival post-HSCT overall was 73%, and in haploidentical HSCT (haplo-HSCT) cases, 71%. Patients who achieved CR at HSCT had a better outcome than those of partial response (92% vs. 47%, p = 0.013). Neither the use of HLA mismatched donor (75% vs. 72%, p = 0.996) nor the use of donor with monoallelic mutation (74% vs. 71%, p = 0.901) affected the prognosis. Hemophagocytic lymphohistiocytosis status of CR at HSCT was a positive prognostic factor. We concluded that HSCT is a promising method to cure adult-onset pHLH. Achieving CR before HSCT contributes to better outcome. Haplo-HSCT is safe and effective for adult pHLH patients, donors with monoallelic mutations in pHLH related genes but normal cytotoxic functions are reliable.

Efficacy and steroid-sparing effect of tacrolimus in patients with autoimmune cytopenia.

The aim of this study was to evaluate the efficacy, safety, and steroid-sparing effect of tacrolimus in patients with autoimmune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES). Patients in the tacrolimus group were treated with tacrolimus in combination with steroids, and the control group received only steroids. Of the 318 patients finally enrolled, 87 (27.4%) were males, with a median age of 45 (14-90) years. The tacrolimus group comprised 144 patients, including 120 ITP, 19 AIHA, and 5 ES patients, and the control group comprised 174 patients, including 141 ITP, 25 AIHA, and 8 ES patients. The optimal ORR of the tacrolimus group was comparable to that of the control group, and the optimal CRR was higher (p < 0.05). Patients receiving tacrolimus had a decreased relapse rate and prolonged relapse-free survival (p < 0.05) compared with the controls for both the whole cohort and the ITP and AIHA subgroups. Compared with the control group, the tacrolimus group had a lower cumulative steroid dosage and earlier discontinuation of steroids (p < 0.05), which resulted in a decreased incidence of steroid-related adverse events (p < 0.05) although the total side effects were similar between the two groups. Similar drug expenses were observed between the tacrolimus and control groups at the 18-month follow-up. In conclusion, the early addition of tacrolimus had a similar ORR, better CRR, lower relapse rate, and prolonged relapse-free survival compared to steroids alone, with reduced steroid-related adverse events.

Dose of deferasirox correlates with its effects, which differ between low-risk myelodysplastic syndrome and aplastic anaemia.

WHAT IS KNOWN AND OBJECTIVE: Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anaemia (AA) often need transfusions, which may accelerate iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relationships of deferasirox (DFX) in patients with low-risk MDS and AA who were refractory to regular treatment in a real-world setting. METHODS: Patient data were recorded, and dose-effect relationships of DFX were calculated after the first 6 months. Total annual exposure to DFX was calculated after 12 months and expressed as the accumulated exposure time at a dosage of 20 mg/kg/day. RESULTS AND DISCUSSION: Sixty-one patients with low-risk MDS and 51 with AA were enrolled. The minimum dosage of DFX needed for a significant serum ferritin (SF) decrease was 20 mg/kg/day at 6 months, and the minimum accumulation of DFX had to reach 9 months at 20 mg/kg/day by 12 months for patients with low-risk MDS. For patients with AA, the minimum dosage was 10 mg/kg/day at 6 months, and the minimum accumulation had to reach 3 months at 20 mg/kg/day by 12 months. With the same exposure, significant improvements in haematological parameters were also observed in AA. Lower liver enzymes compared with baseline were observed. Gastrointestinal disorders and elevated serum creatinine were the most common side effects. Higher exposure to DFX correlated with longer overall survival (OS). WHAT IS NEW AND CONCLUSION: A significant decrease in SF and an improvement in haematologic parameters, organ function and even OS can be achieved if the accumulated DFX dose reaches a certain level. Patients with low-risk MDS need a higher dose than those with AA.

BIG Modulates Stem Cell Niche and Meristem Development via SCR/SHR Pathway in Arabidopsis Roots.

BIG, a regulator of polar auxin transport, is necessary to regulate the growth and development of Arabidopsis. Although mutations in the BIG gene cause severe root developmental defects, the exact mechanism remains unclear. Here, we report that disruption of the BIG gene resulted in decreased quiescent center (QC) activity and columella cell numbers, which was accompanied by the downregulation of WUSCHEL-RELATED HOMEOBOX5 (WOX5) gene expression. BIG affected auxin distribution by regulating the expression of PIN-FORMED proteins (PINs), but the root morphological defects of big mutants could not be rescued solely by increasing auxin transport. Although the loss of BIG gene function resulted in decreased expression of the PLT1 and PLT2 genes, genetic interaction assays indicate that this is not the main reason for the root morphological defects of big mutants. Furthermore, genetic interaction assays suggest that BIG affects the stem cell niche (SCN) activity through the SCRSCARECROW (SCR)/SHORT ROOT (SHR) pathway and BIG disruption reduces the expression of SCR and SHR genes. In conclusion, our findings reveal that the BIG gene maintains root meristem activity and SCN integrity mainly through the SCR/SHR pathway.

STING1 in sepsis: Mechanisms, functions, and implications.

Sepsis is a life-threatening clinical syndrome and one of the most challenging health problems in the world. Pathologically, sepsis and septic shock are caused by a dysregulated host immune response to infection, which can eventually lead to multiple organ failure and even death. As an adaptor transporter between the endoplasmic reticulum and Golgi apparatus, stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173) has been found to play a vital role at the intersection of innate immunity, inflammation, autophagy, and cell death in response to invading microbial pathogens or endogenous host damage. There is ample evidence that impaired STING1, through its immune and non-immune functions, is involved in the pathological process of sepsis. In this review, we discuss the regulation and function of the STING1 pathway in sepsis and highlight it as a suitable drug target for the treatment of lethal infection.

The MADS-box gene PpPI is a key regulator of the double-flower trait in peach.

Double flower is an invaluable trait in ornamental peach, but the mechanism underlying its development remains largely unknown. Here, we report the roles of ABCE model genes in double flower development in peach. A total of nine ABCE regulatory genes, including eight MADS-box genes and one AP2/EREBP gene, were identified in the peach genome. Subcellular localization assay showed that all the ABCE proteins were localized in the nucleus. Four genes, PpAP1, PpAP3, PpSEP3, and PpPI, showed a difference in expression levels between single and double flowers. Ectopic overexpression of PpPI increased petal number in Arabidopsis, while transgenic lines overexpressing PpAP3 or PpSEP3 were morphologically similar to wild-type. Ectopic overexpression of PpAP1 resulted in a significant decrease in the number of basal leaves and caused early flowering. These results suggest that PpPI is likely crucial for double flower development in peach. In addition, double flowers have petaloid sepals and stamens, and single flower could occasionally change to be double flower by converting stamens to petals in peach, suggesting that the double-flower trait is likely to have evolved from an ancestral single-flower structure. Our results provide new insights into mechanisms underlying the double-flower trait in peach.

Methotrexate Therapy Promotes Cell Coverage and Stability in in-Stent Neointima.

PURPOSE: Anti-proliferative drugs released from drug-eluting stents delay cell coverage and vascular healing, which increases the risk of late stent thrombosis. We assessed the potential effects of systemic methotrexate (MTX) on cell coverage, vascular healing and inflammation activation in vivo and in vitro. METHODS: We applied MTX in the right common carotid artery in a rabbit stenting model to determine the impact on cell coverage and inflammation activation using a serial optical coherence tomography (OCT) analysis and elucidated the molecular mechanism of MTX in human umbilical vein endothelial cells (HUVECs). RESULTS: Low-dose MTX promoted the development of cell coverage and vascular healing, which was associated with fewer uncovered struts (%) and cross-sections with any uncovered struts (%) at 4 weeks of stenting. The MTX group also exhibited lower rates of heterogeneity, microvessels and per-strut low-signal-intensity layers, indicating neointimal instability at 12 weeks of stenting. In vitro, low-dose MTX strongly inhibited HUVEC apoptosis, promoted proliferation and inhibited inflammatory activation by targeting the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. CONCLUSION: Low-dose MTX may be a key means of promoting early cell coverage via the inhibition of the inflammatory response and stability of neointima by targeting inflammatory pathways after stent implantation.