Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks.

The protection of DNA replication forks under stress is essential for genome maintenance and cancer suppression. One mechanism of fork protection involves an elevation in intracellular Ca2+ ([Ca2+]i), which in turn activates CaMKK2 and AMPK to prevent uncontrolled fork processing by Exo1. How replication stress triggers [Ca2+]i elevation is unclear. Here, we report a role of cytosolic self-DNA (cytosDNA) and the ion channel TRPV2 in [Ca2+]i induction and fork protection. Replication stress leads to the generation of ssDNA and dsDNA species that, upon translocation into cytoplasm, trigger the activation of the sensor protein cGAS and the production of cGAMP. The subsequent binding of cGAMP to STING causes its dissociation from TRPV2, leading to TRPV2 derepression and Ca2+ release from the ER, which in turn activates the downstream signaling cascade to prevent fork degradation. This Ca2+-dependent genome protection pathway is also activated in response to replication stress caused by oncogene activation.

VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.

The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.

A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Acyl carrier protein OsMTACP2 confers rice cold tolerance at the booting stage.

Low temperatures occurring at the booting stage in rice (Oryza sativa L.) often result in yield loss by impeding male reproductive development. However, the underlying mechanisms by which rice responds to cold at this stage remain largely unknown. Here, we identified MITOCHONDRIAL ACYL CARRIER PROTEIN 2 (OsMTACP2), the encoded protein of which mediates lipid metabolism involved in the cold response at the booting stage. Loss of OsMTACP2 function compromised cold tolerance, hindering anther cuticle and pollen wall development, resulting in abnormal anther morphology, lower pollen fertility, and seed setting. OsMTACP2 was highly expressed in tapetal cells and microspores during anther development, with the encoded protein localizing to both mitochondria and the cytoplasm. Comparative transcriptomic analysis revealed differential expression of genes related to lipid metabolism between the wild type and the Osmtacp2-1 mutant in response to cold. Through a lipidomic analysis, we demonstrated that wax esters, which are the primary lipid components of the anther cuticle and pollen walls, function as cold-responsive lipids. Their levels increased dramatically in the wild type but not in Osmtacp2-1 when exposed to cold. Additionally, mutants of two cold-induced genes of wax ester biosynthesis, ECERIFERUM1 and WAX CRYSTAL-SPARSE LEAF2, showed decreased cold tolerance. These results suggest that OsMTACP2-mediated wax ester biosynthesis is essential for cold tolerance in rice at the booting stage.

C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor ß1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.

Misregulation of MYB16 expression causes stomatal cluster formation by disrupting polarity during asymmetric cell divisions.

Stomatal pores and the leaf cuticle regulate evaporation from the plant body and balance the tradeoff between photosynthesis and water loss. MYB16, encoding a transcription factor involved in cutin biosynthesis, is expressed in stomatal lineage ground cells, suggesting a link between cutin biosynthesis and stomatal development. Here, we show that the downregulation of MYB16 in meristemoids is directly mediated by the stomatal master transcription factor SPEECHLESS (SPCH) in Arabidopsis thaliana. The suppression of MYB16 before an asymmetric division is crucial for stomatal patterning, as its overexpression or ectopic expression in meristemoids increased stomatal density and resulted in the formation of stomatal clusters, as well as affecting the outer cell wall structure. Expressing a cutinase gene in plants ectopically expressing MYB16 reduced stomatal clustering, suggesting that cutin affects stomatal signaling or the polarity setup in asymmetrically dividing cells. The clustered stomatal phenotype was rescued by overexpressing EPIDERMAL PATTERNING FACTOR2, suggesting that stomatal signaling was still functional in these plants. Growing seedlings ectopically expressing MYB16 on high-percentage agar plates to modulate tensile strength rescued the polarity and stomatal cluster defects of these seedlings. Therefore, the inhibition of MYB16 expression by SPCH in the early stomatal lineage is required to correctly place the polarity protein needed for stomatal patterning during leaf morphogenesis.

Quantifying inactive lithium in lithium metal batteries.

Lithium metal anodes offer high theoretical capacities (3,860 milliampere-hours per gram)1, but rechargeable batteries built with such anodes suffer from dendrite growth and low Coulombic efficiency (the ratio of charge output to charge input), preventing their commercial adoption2,3. The formation of inactive ('dead') lithium- which consists of both (electro)chemically formed Li+ compounds in the solid electrolyte interphase and electrically isolated unreacted metallic Li0 (refs 4,5)-causes capacity loss and safety hazards. Quantitatively distinguishing between Li+ in components of the solid electrolyte interphase and unreacted metallic Li0 has not been possible, owing to the lack of effective diagnostic tools. Optical microscopy6, in situ environmental transmission electron microscopy7,8, X-ray microtomography9 and magnetic resonance imaging10 provide a morphological perspective with little chemical information. Nuclear magnetic resonance11, X-ray photoelectron spectroscopy12 and cryogenic transmission electron microscopy13,14 can distinguish between Li+ in the solid electrolyte interphase and metallic Li0, but their detection ranges are limited to surfaces or local regions. Here we establish the analytical method of titration gas chromatography to quantify the contribution of unreacted metallic Li0 to the total amount of inactive lithium. We identify the unreacted metallic Li0, not the (electro)chemically formed Li+ in the solid electrolyte interphase, as the dominant source of inactive lithium and capacity loss. By coupling the unreacted metallic Li0 content to observations of its local microstructure and nanostructure by cryogenic electron microscopy (both scanning and transmission), we also establish the formation mechanism of inactive lithium in different types of electrolytes and determine the underlying cause of low Coulombic efficiency in plating and stripping (the charge and discharge processes, respectively, in a full cell) of lithium metal anodes. We propose strategies for making lithium plating and stripping more efficient so that lithium metal anodes can be used for next-generation high-energy batteries.

Preservation of Topological Surface States in Millimeter-Scale Transferred Membranes.

Ultrathin topological insulator membranes are building blocks of exotic quantum matter. However, traditional epitaxy of these materials does not facilitate stacking in arbitrary orders, while mechanical exfoliation from bulk crystals is also challenging due to the non-negligible interlayer coupling therein. Here we liberate millimeter-scale films of the topological insulator Bi2Se3, grown by molecular beam epitaxy, down to 3 quintuple layers. We characterize the preservation of the topological surface states and quantum well states in transferred Bi2Se3 films using angle-resolved photoemission spectroscopy. Leveraging the photon-energy-dependent surface sensitivity, the photoemission spectra taken with 6 and 21.2 eV photons reveal a transfer-induced migration of the topological surface states from the top to the inner layers. By establishing clear electronic structures of the transferred films and unveiling the wave function relocation of the topological surface states, our work lays the physics foundation crucial for the future fabrication of artificially stacked topological materials with single-layer precision.

Plastid genome data provide new insights into the dynamic evolution of the tribe Ampelopsideae (Vitaceae).

BACKGROUND: Ampelopsideae J. Wen & Z.L. Nie is a small-sized tribe of Vitaceae Juss., including ca. 47 species from four genera showing a disjunct distribution worldwide across all the continents except Antarctica. There are numerous species from the tribe that are commonly used as medicinal plants with immune-modulating, antimicrobial, and anti-hypertensive properties. The tribe is usually recognized into three clades, i.e., Ampelopsis Michx., Nekemias Raf., and the Southern Hemisphere clade. However, the relationships of the three clades differ greatly between the nuclear and the plastid topologies. There has been limited exploration of the chloroplast phylogenetic relationships within Ampelopsideae, and studies on the chloroplast genome structure of this tribe are only available for a few individuals. In this study, we aimed to investigate the evolutionary characteristics of plastid genomes of the tribe, including their genome structure and evolutionary insights. RESULTS: We sequenced, assembled, and annotated plastid genomes of 36 species from the tribe and related taxa in the family. Three main clades were recognized within Ampelopsideae, corresponding to Ampelopsis, Nekemias, and the Southern Hemisphere lineage, respectively, and all with 100% bootstrap supports. The genome sequences and content of the tribe are highly conserved. However, comparative analyses suggested that the plastomes of Nekemias demonstrate a contraction in the large single copy region and an expansion in the inverted repeat region, and possess a high number of forward and palindromic repeat sequences distinct from both Ampelopsis and the Southern Hemisphere taxa. CONCLUSIONS: Our results highlighted plastome variations in genome length, expansion or contraction of the inverted repeat region, codon usage bias, and repeat sequences, are corresponding to the three lineages of the tribe, which probably faced with different environmental selection pressures and evolutionary history. This study provides valuable insights into understanding the evolutionary patterns of plastid genomes within the Ampelopsideae of Vitaceae.

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Cancer cell extravasation requires iplectin-mediated delivery of MT1-MMP at invadopodia.

BACKGROUND: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear. METHODS: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo. RESULTS: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed iplectin (i = invadopodial). iPlectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed iplectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency. CONCLUSIONS: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and iplectin. CLINICAL TRIAL REGISTRATION NUMBER: NCT04608357.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

A Strategy for Enhancing Perpendicular Magnetic Anisotropy in Yttrium Iron Garnet Films.

In future information storage and processing, magnonics is one of the most promising candidates to replace traditional microelectronics. Yttrium iron garnet (YIG) films with perpendicular magnetic anisotropy (PMA) have aroused widespread interest in magnonics. Obtaining strong PMA in a thick YIG film with a small lattice mismatch (η) has been fascinating but challenging. Here, a novel strategy is proposed to reduce the required minimum strain value for producing PMA and increase the maximum thickness for maintaining PMA in YIG films by slight oxygen deficiency. Strong PMA is achieved in the YIG film with an η of only 0.4% and a film thickness up to 60 nm, representing the strongest PMA for such a small η reported so far. Combining transmission electron microscopy analyses, magnetic measurements, and a theoretical model, it is demonstrated that the enhancement of PMA physically originates from the reduction of saturation magnetization and the increase of magnetostriction coefficient induced by oxygen deficiency. The Gilbert damping values of the 60-nm-thick YIG films with PMA are on the order of 10-4. This strategy improves the flexibility for the practical applications of YIG-based magnonic devices and provides promising insights for the theoretical understanding and the experimental enhancement of PMA in garnet films.

E3 ubiquitin ligase TaSDIR1-4A activates membrane-bound transcription factor TaWRKY29 to positively regulate drought resistance.

Drought is a deleterious abiotic stress factor that constrains crop growth and development. Post-translational modification of proteins mediated by the ubiquitin-proteasome system is an effective strategy for directing plant responses to stress, but the regulatory mechanisms in wheat remain unclear. In this study, we showed that TaSDIR1-4A is a positive modulator of the drought response. Overexpression of TaSDIR1-4A increased the hypersensitivity of stomata, root length and endogenous abscisic acid (ABA) content under drought conditions. TaSDIR1-4A encodes a C3H2C3-type RING finger protein with E3 ligase activity. Amino acid mutation in its conserved domain led to loss of activity and altered the subcellular localization. The membrane-bound transcription factor TaWRKY29 was identified by yeast two-hybrid screening, and it was confirmed as interacting with TaSDIR1-4A both in vivo and in vitro. TaSDIR1-4A mediated the polyubiquitination and proteolysis of the C-terminal amino acid of TaWRKY29, and its translocation from the plasma membrane to the nucleus. Activated TaWRKY29 bound to the TaABI5 promoter to stimulate its expression, thereby positively regulating the ABA signalling pathway and drought response. Our findings demonstrate the positive role of TaSDIR1-4A in drought tolerance and provide new insights into the involvement of UPS in the wheat stress response.

Long-Term Survival and Recurrence Patterns in Locally Advanced Esophageal Squamous Cell Carcinoma Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy Followed by Surgery.

BACKGROUND: The higher pathologic complete response (pCR) after neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC) has not translated into significant gains in overall survival. Data on the long-term survival of patients who obtained a pCR after neoadjuvant chemotherapy are scarce. Therefore, this study aimed to evaluate the long-term prognosis and recurrence patterns in these patients. METHODS: The study enrolled patients with locally advanced ESCC after neoadjuvant chemotherapy followed by surgery in the authors' hospital between January 2007 and December 2020. The factors predictive of pCR were analyzed. Furthermore, propensity score-matching was performed for those who did and those who did not have a pCR using 1:5 ratio for a long-term survival analysis. Finally, the survival and recurrence patterns of patients obtaining pCR after neoadjuvant chemotherapy were analyzed. RESULTS: A pCR was achieved for 61 (8.70%) of the 701 patients in the study. Univariate analysis showed that the patients without alcohol drinking had a higher possibility of obtaining a pCR, although multivariate analysis failed to confirm the difference as significant. After propensity score-matching, the 5-year overall survival was 84.50% for the patients who had a pCR and 52.90% for those who did not (p < 0.001). Among the 61 patients with a pCR, 9 patients (14.80%) experienced recurrence, including 6 patients with locoregional recurrence and 3 patients with distant metastasis. CONCLUSION: Advanced ESCC patients with pCR after neoadjuvant chemotherapy had a favorable prognosis, yet some still experienced recurrence, particularly locoregional recurrence. Therefore, for this group of patients, regular follow-up evaluation also is needed.

Phylogenomics and divergence pattern of Polygonatum (Asparagaceae: Polygonateae) in the north temperate region.

Polygonatum is the largest genus of tribe Polygonateae (Asparagaceae) and is widely distributed in the temperate Northern Hemisphere, especially well diversified in southwestern China to northeastern Asia. Phylogenetic relationships of many species are still controversial. Hence it is necessary to clarify their phylogenetic relationships and infer possible reticulate relationships for the genus. In this study, genome-wide data of 43 species from Polygonatum and its closely related taxa were obtained by Hyb-Seq sequencing. The phylogenetic trees constructed from genome-wide nuclear and chloroplast sequences strongly supported the monophyly of Polygonatum with division into three major clades. A high level of incongruence was detected between nuclear and chloroplast trees as well as among gene trees within the genus, but all occurred within each major clade. However, introgression tests and reticulate evolution analyses revealed low level of gene flow and weak introgression events in the genus, suggesting hybridization and introgression were not dominant during the evolutionary diversification of Polygonatum in the Northern Hemisphere. This study provides important insights into reconstructing evolutionary relationships and speciation pattern of taxa from the north temperate flora.

Failure mechanisms of a silicon-based CMOS image sensor irradiated by a 1550†nm nanosecond laser.

Cameras, LiDAR, and radars are indispensable for accurate perception of the surrounding environment and autonomous driving. Failure mechanisms of silicon-based CMOS image sensor (CIS) irradiated by 1550 nm nanosecond laser were investigated systematically in this paper. The damages of CIS were divided into point damage, line damage, and cross damage according to different damage performances. The damage thresholds under different irradiation conditions (different repetition rates, pulse widths, and irradiation times) were explored. Large repetition rates and long irradiation times would induce more heat accumulation, more temperature increase, and a low point damage threshold. The damage threshold for a pulse with a narrow pulse width is lower than that for a pulse with a long pulse width. The damaged CIS was analyzed further by focused ion beam (FIB) and scanning electron microscope (SEM). The damage location in the internal CIS structure was analyzed and the overall failure process was summarized. The results we get could enrich the database of laser damage mechanisms and laser damage thresholds of CIS, which will provide meaningful guidance for the camera design technology and anti-laser reinforcement technology of optoelectronic devices.

Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species-mediated activation of placental GCN2/eIF2α pathway.

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA). Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown-rump length, and increased the incidence of FGR in a dose-dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down-regulating the protein but not the mRNA level of placental 11ß-Hydroxysteroid dehydrogenase-2 (11ß-HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA-induced down-regulation of 11ß-HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA-induced placental barrier dysfunction by inhibiting activation of GCN2/eIF2α pathway and subsequent down-regulation of 11ß-HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA-induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS-mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding the mechanism of cholestasis-induced placental dysfunction and subsequent FGR.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Volumetric growth rate of incidentally found meningiomas on immunotherapy.

PURPOSE: The expression of PD-L1 in high-grade meningiomas made it a potential target for immunotherapy research in refractory cases. Several prospective studies in this field are still on going. We sought to retrospectively investigate the effects of check-point inhibitors (CI) on meningiomas that had been naïve to either surgical or radiation approaches by following incidental meningiomas found during treatment with CI for various primary metastatic cancers. METHODS: We used the NYU Perlmutter Cancer Center Data Hub to find patients treated by CI for various cancers, who also had serial computerized-tomography (CT) or magnetic-resonance imaging (MRI) reports of intracranial meningiomas. Meningioma volumetric measurements were compared between the beginning and end of the CI treatment period. Patients treated with chemotherapy during this period were excluded. RESULTS: Twenty-five patients were included in our study, of which 14 (56%) were on CI for melanoma, 5 (20%) for non-small-cell lung cancer and others. CI therapies included nivolumab (n = 15, 60%), ipilimumab (n = 11, 44%) and pembrolizumab (n = 9, %36), while 9 (36%) were on ipilimumab/nivolumab combination. We did not find any significant difference between tumor volumes before and after treatment with CI (1.31 ± 0.46 vs. 1.34 ± 0.46, p=0.8, respectively). Among patients beyond 1 year of follow-up (n = 13), annual growth was 0.011 ± 0.011 cm3/year. Five patients showed minor volume reduction of 0.12 ± 0.10 cm3 (21 ± 6% from baseline). We did not find significant predictors of tumor volume reduction. CONCLUSION: Check-point inhibitors may impact the natural history of meningiomas. Additional research is needed to define potential clinical indications and treatment goals.