Observation and quantification of the pseudogap in unitary Fermi gases.

The microscopic origin of high-temperature superconductivity in cuprates remains unknown. It is widely believed that substantial progress could be achieved by better understanding of the pseudogap phase, a normal non-superconducting state of cuprates1,2. In particular, a central issue is whether the pseudogap could originate from strong pairing fluctuations3. Unitary Fermi gases4,5, in which the pseudogap-if it exists-necessarily arises from many-body pairing, offer ideal quantum simulators to address this question. Here we report the observation of a pair-fluctuation-driven pseudogap in homogeneous unitary Fermi gases of lithium-6 atoms, by precisely measuring the fermion spectral function through momentum-resolved microwave spectroscopy and without spurious effects from final-state interactions. The temperature dependence of the pairing gap, inverse pair lifetime and single-particle scattering rate are quantitatively determined by analysing the spectra. We find a large pseudogap above the superfluid transition temperature. The inverse pair lifetime exhibits a thermally activated exponential behaviour, uncovering the microscopic virtual pair breaking and recombination mechanism. The obtained large, temperature-independent single-particle scattering rate is comparable with that set by the Planckian limit6. Our findings quantitatively characterize the pseudogap in strongly interacting Fermi gases and they lend support for the role of preformed pairing as a precursor to superfluidity.

TOP2ß-Dependent Nuclear DNA Damage Shapes Extracellular Growth Factor Responses via Dynamic AKT Phosphorylation to Control Virus Latency.

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival, and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2ß-DNA cleavage complex (TOP2ßcc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA-repair pathways that remove TOP2ßcc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission.

The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells.

CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.

Porcine deltacoronavirus nucleocapsid protein antagonizes JAK-STAT signaling pathway by targeting STAT1 through KPNA2 degradation.

Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection.

Cutting Edge: Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages.

CXCR5 is a hallmark of T follicular helper (Tfh) cells. The mechanism of CXCR5 induction, however, is still incompletely understood. In this study, we report that in mice with the absence of transcription factor Bach2, the Th17-inducing cytokines IL-6 and TGF-ß together induced CXCR5 expression in vitro. Mechanistically, IL-6/STAT3 drove Cxcr5 promoter activity via the upstream site 1 regulatory element, whereas TGF-ß enhanced permissive histone modifications, and the STAT3 binding to the site 1 regulatory element was higher in the absence of Bach2. Subsequently, despite previous studies showing enhanced Th17 cell differentiation in the absence of Bach2 in vitro, we found that in vivo, the Bach2 deficiency led to an enhanced Tfh cell response at the expense of the Th17 cell response. These findings suggest that Bach2 helps integrate cytokine signals to arbitrate differentiation decisions between Tfh and Th17 lineages.

AnimalTFDB 4.0: a comprehensive animal transcription factor database updated with variation and expression annotations.

Transcription factors (TFs) are proteins that interact with specific DNA sequences to regulate gene expression and play crucial roles in all kinds of biological processes. To keep up with new data and provide a more comprehensive resource for TF research, we updated the Animal Transcription Factor Database (AnimalTFDB) to version 4.0 (http://bioinfo.life.hust.edu.cn/AnimalTFDB4/) with up-to-date data and functions. We refined the TF family rules and prediction pipeline to predict TFs in genome-wide protein sequences from Ensembl. As a result, we predicted 274 633 TF genes and 150 726 transcription cofactor genes in AnimalTFDB 4.0 in 183 animal genomes, which are 86 more species than AnimalTFDB 3.0. Besides double data volume, we also added the following new annotations and functions to the database: (i) variations (including mutations) on TF genes in various human cancers and other diseases; (ii) predicted post-translational modification sites (including phosphorylation, acetylation, methylation and ubiquitination sites) on TFs in 8 species; (iii) TF regulation in autophagy; (iv) comprehensive TF expression annotation for 38 species; (v) exact and batch search functions allow users to search AnimalTFDB flexibly. AnimalTFDB 4.0 is a useful resource for studying TF and transcription regulation, which contains comprehensive annotation and classification of TFs and transcription cofactors.

Long-distance transport of sucrose in source leaves promotes sink root growth by the EIN3-SUC2 module.

In most plants, sucrose, a major storage sugar, is transported into sink organs to support their growth. This key physiological process is dependent on the function of sucrose transporters. Sucrose export from source tissues is predominantly controlled through the activity of SUCROSE TRANSPORTER 2 (SUC2), required for the loading of sucrose into the phloem of Arabidopsis plants. However, how SUC2 activity is controlled to support root growth remains unclear. Glucose is perceived via the function of HEXOKINASE 1 (HXK1), the only known nuclear glucose sensor. HXK1 negatively regulates the stability of ETHYLENE-INSENSITIVE3 (EIN3), a key ethylene/glucose interaction component. Here we show that HXK1 functions upstream of EIN3 in the regulation of root sink growth mediated by glucose signaling. Furthermore, the transcription factor EIN3 directly inhibits SUC2 activity by binding to the SUC2 promoter, regulating glucose signaling linked to root sink growth. We demonstrate that these molecular components form a HXK1-EIN3-SUC2 module integral to the control of root sink growth. Also, we demonstrate that with increasing age, the HXK1-EIN3-SUC2 module promotes sucrose phloem loading in source tissues thereby elevating sucrose levels in sink roots. As a result, glucose signaling mediated-sink root growth is facilitated. Our findings thus establish a direct molecular link between the HXK1-EIN3-SUC2 module, the source-to sink transport of sucrose and root growth.

TcdB from Hypervirulent Clostridioides difficile Induces Neuronal Loss and Neurotransmitter Alterations in the Intrinsic Enteric Nervous System.

Clostridioides difficile infection (CDI) is a predominant cause of intestinal infections. The intrinsic enteric nervous system (ENS) occupies the intestinal tissue in large numbers and intricately regulates various aspects of intestinal function. Nonetheless, the specific effects of CDI on the intrinsic ENS remain underexplored. Herein, we employed the TcdB variant (TcdB2) derived from hypervirulent C. difficile to elucidate the impact of CDI on neurons located in colonic wall. We found that TcdB2 directly induced dose-dependent cytopathic effects on enteric neurons both in vitro and in adult mice colons. Notably, an increased expression of choline acetyltransferase (ChAT) and neural nitric oxide synthase (nNOS) in colonic neurons prior to the onset of cytopathic changes following treatment with TcdB2 were observed, both in vivo and in vitro. These findings suggest that during CDI, TcdB not only causes neuronal loss but also alters the composition of neurotransmitters in the ENS.

A Radical Approach for Asymmetric α-C-H Addition of N-Sulfonyl Benzylamines to Aldehydes.

Efficient synthesis of enantioenriched amines is of great importance due to their significant synthetic and biological applications. Photoredox-mediated asymmetric α-amino C(sp3)-H functionalization offers an atom-economical and sustainable approach to access chiral amines. However, the development of analogous reactions is in its early stages, generally affording chiral amines with a single stereocenter. Herein, we present a novel synergistic triple-catalysis approach for the asymmetric α-C-H addition of readily available N-sulfonyl amines to aldehydes under mild conditions. This method allows for the efficient synthesis of a diverse array of valuable ß-amino alcohols bearing vicinal stereocenters. Unlike previous reports, our protocol employs a radical approach using earth-abundant Cr catalysis. Quinuclidine plays a dual role by facilitating highly selective hydrogen-atom transfer to generate α-amino radicals and promoting the dissociation of the Cr-O bond, which is crucial for the overall catalytic cycle as evidenced by control, NMR, and DFT experiments. Preliminary mechanistic studies, including radical trapping, nonlinear effect, Stern-Volmer plot, kinetic isotope effect, and Hammett plot, offer valuable insights into the reaction pathway.

Identification of reliable QTLs and designed QTL breeding for grain shape and milling quality in the reciprocal introgression lines in rice.

Milling quality (MQ) and grain shape (GS) of rice (Oryza sativa L.) are correlated traits, both determine farmers' final profit. More than one population under multiple environments may provide valuable information for breeding selection on these MQ-GS correlations. However, suitable analytical methods for reciprocal introgression lines with linkage map for this kind of correlation remains unclear. In this study, our major tasks were (1) to provide a set of reciprocal introgression lines (composed of two BC2RIL populations) suitable for mapping by linkage mapping using markers/bins with physical positions; (2) to test the mapping effects of different methods by using MQ-GS correlation dissection as sample case; (3) to perform genetic and breeding simulation on pyramiding favorite alleles of QTLs for representative MQ-GS traits. Finally, with four analysis methods and data collected under five environments, we identified about 28.4 loci on average for MQ-GS traits. Notably, 52.3% of these loci were commonly detected by different methods and eight loci were novel. There were also nine regions harboring loci for different MQ-GS traits which may be underlying the MQ-GS correlations. Background independent (BI) loci were also found for each MQ and GS trait. All these information may provide useful resources for rice molecular breeding.

Effects of polyethylene, polylactic acid, and tire particles on the sediment microbiome and metabolome at high and low temperatures.

Global warming has led to a high incidence of extreme heat events, and the frequent occurrence of extreme heat events has had extensive and far-reaching impacts on wetland ecosystems. The widespread distribution of plastics in the environment, including polyethylene (PE), polylactic acid (PLA), and tire particles (TPs), has caused various environmental problems. Here, high-throughput sequencing techniques and metabolomics were used for the first time to investigate the effects of three popular microplastic types: PE, PLA, and TP, on the sediment microbiome and the metabolome at both temperatures. The microplastics were incorporated into the sediment at a concentration of 3% by weight of the dry sediment (wt/wt), to reflect environmentally relevant conditions. Sediment enzymatic activity and physicochemical properties were co-regulated by both temperatures and microplastics producing significant differences compared to controls. PE and PLA particles inhibited bacterial diversity at low temperatures and promoted bacterial diversity at high temperatures, and TP particles promoted both at both temperatures. For bacterial richness, only PLA showed inhibition at low temperature; all other treatments showed promotion. PE, PLA, and TP microplastics changed the community structure of sediment bacteria, forming two clusters at low and high temperatures. Furthermore, PE, PLA, and TP changed the sediment metabolic profiles, producing differential metabolites such as lipids and molecules, organic heterocyclic compounds, and organic acids and their derivatives, especially TP had the most significant effect. These findings contribute to a more comprehensive understanding of the potential impact of microplastic contamination.IMPORTANCEIn this study, we added 3% (wt/wt) microplastic particles, including polyethylene, polylactic acid, and tire particles, to natural sediments under simulated laboratory conditions. Subsequently, we simulated the sediment microbial and ecosystem responses under different temperature conditions by incubating them for 60 days at 15°C and 35°C, respectively. After synthesizing these results, our study strongly suggests that the presence of microplastics in sediment ecosystems and exposure under different temperature conditions may have profound effects on soil microbial communities, enzyme activities, and metabolite profiles. This is important for understanding the potential hazards of microplastic contamination on terrestrial ecosystems and for developing relevant environmental management strategies.

Long-lived nitric oxide molecular tagging velocimetry with 1 + 1 REMPI.

The successful demonstration of long-lived nitric oxide (NO) fluorescence for molecular tagging velocimetry (MTV) measurements is described in this Letter. Using 1 + 1 resonance-enhanced multiphoton ionization (REMPI) of NO at a wavelength near 226 nm, targeting the overlapping Q1(7) and Q21(7) lines of the A-X (0, 0) electronic system, the lifetime of the NO MTV signal was observed to be approximately 8.6 µs within a 100-Torr cell containing 2% NO in nitrogen. This is in stark contrast to the commonly reported single photon NO fluorescence, which has a much shorter calculated lifetime of approximately 43 ns at this pressure and NO volume fraction. While the shorter lifetime fluorescence can be useful for molecular tagging velocimetry with single laser excitation within very high-speed flows at some thermodynamic conditions, the longer lived fluorescence shows the potential for an order of magnitude more accurate and precise velocimetry, particularly within lower speed regions of hypersonic flow fields such as wakes and boundary layers. The physical mechanism responsible for the generation of this long-lived signal is detailed. Furthermore, the effectiveness of this technique is showcased in a high-speed jet flow, where it is employed for precise flow velocity measurements.

Enhanced intrinsic chiroptical response of resonant metallic metasurfaces.

The physics of resonant metasurfaces underpins many electromagnetic functionalities with enhanced performance by virtue of resonant excitations. Resonances originating from bound states in the continuum (BICs) were recently recognized in photonics for their superior optical properties, strong local field enhancement, and suppression of radiative losses. Very recently, a concept of intrinsically chiral dielectric BIC metasurfaces was proposed that combines strong narrowband resonant features with the polarization control of scattered light. Here, we design a resonant chiral metallic metasurface supporting a BIC resonance in the microwave wavelength range. In our structure, the metasurface units (meta-atoms) are characterized with rotational and mirror spatial symmetries. We numerically characterize metasurface mode properties in eigenmode calculations and scattering spectra for linearly polarized excitation under oblique incidence. Then, we investigate intrinsic chiroptical effects for transmission of normally propagating excitation beams by breaking the meta-atom in-plane mirror symmetries. We predict that the intrinsic circular dichroism in such structures may exceed 0.74.

Theory of the Spectral Function of Fermi Polarons at Finite Temperature.

We develop a general theory of Fermi polarons at nonzero temperature, including particle-hole excitations of the Fermi sea shakeup to arbitrarily high orders. The exact set of equations of the spectral function is derived by using both Chevy ansatz and diagrammatic approach, and their equivalence is clarified to hold in free space only, with an unregularized infinitesimal interaction strength. The correction to the polaron spectral function arising from two-particle-hole excitations is explicitly examined for an exemplary case of Fermi polarons in one-dimensional optical lattices. We find quantitative improvements at low temperatures with the inclusion of two-particle-hole excitations, in both polaron energies and decay rates. Our exact theory of Fermi polarons with arbitrary orders of particle-hole excitations might be used to better understand the intriguing polaron dynamical responses in two or three dimensions, whether in free space or within lattices.

Magnetic Resonance Imaging-Based Classification Systems for Informing Better Outcomes of Adenomyosis After Ultrasound-Guided High-Intensity Focused Ultrasound Ablating Surgery.

BACKGROUND: A referenced MRI-based classification associated with focused ultrasound ablation surgery (FUAS) outcomes is lacking in adenomyosis. PURPOSE: To identify an MRI-based classification system for informing the FUAS outcomes. STUDY TYPE: Retrospective. POPULATION: Patients with FUAS for adenomyosis, were divided into a training set (N = 643; 355 with post-FUAS gonadotropin-releasing hormone/levonorgestrel, 288 without post-FUAS therapy) and an external validation set (N = 135; all without post-FUAS therapy). FIELD STRENGTH/SEQUENCE: 1.5 T, turbo spin-echo T2-weighted imaging and single-shot echo-planar diffusion-weighted imaging sequences. ASSESSMENT: Five MRI-based adenomyosis classifications: classification 1 (C1) (diffuse, focal, and mild), C2 (intrinsic, extrinsic, intramural, and indeterminate), C3 (internal, adenomyomas, and external), C4 (six subtypes on areas [internal or external] and volumes [<1/3 or ≥2/3]), and C5 (internal [asymmetric or symmetric], external, intramural, full thickness [asymmetric or symmetric]) for FUAS outcomes (symptom relief and recurrence). STATISTICAL TESTS: The optimal classification was significantly associated with the most subtypes of FUAS outcomes. Relating to the timing of recurrence was measured using Cox regression analysis and median recurrence time was estimated by a Kaplan-Meier curve. A P value <0.05 was considered statistically significant. RESULTS: Dysmenorrhea relief and recurrence were only associated with C2 in training patients undergoing FUAS alone. Compared with other subtypes, the extrinsic subtype of C2 was significantly associated with dysmenorrhea recurrence in the FUAS group. Besides, the median dysmenorrhea recurrence time of extrinsic subtype was significantly shorter than that of other subtypes (42.0 months vs. 50.3 months). In the validation cohort, C2 was confirmed as the optimal system and its extrinsic subtype was confirmed to have a significantly shorter dysmenorrhea recurrence time than other subtypes. DATA CONCLUSION: Classification 2 can inform dysmenorrhea relief and recurrence in patients with adenomyosis undergoing FAUS only. Itsextrinsic subtype was associated with an earlier onset of dysmenorrhea recurrence after treatment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors.

Growing evidence suggests that neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown underlies the development of psychiatric disorders, such as major depressive disorder (MDD). Tight junction (TJ) proteins are critical modulators of homeostasis and BBB integrity. TJ protein Claudin-5 is the most dominant BBB component and is downregulated in numerous depression models; however, the underlying mechanisms remain elusive. Here, we demonstrate a molecular basis of BBB breakdown that links stress and depression. We implemented an animal model of depression, chronic unpredictable mild stress (CUMS) in male C57BL/6 mice, and showed that hippocampal BBB breakdown was closely associated with stress vulnerability. Concomitantly, we found that dysregulated Cldn5 level coupled with repression of the histone methylation signature at its promoter contributed to stress-induced BBB dysfunction and depression. Moreover, histone methyltransferase enhancer of zeste homolog 2 (EZH2) knockdown improved Cldn5 expression and alleviated depression-like behaviors by suppressing the tri-methylation of lysine 27 on histone 3 (H3K27me3) in chronically stressed mice. Furthermore, the stress-induced excessive transfer of peripheral cytokine tumor necrosis factor-α (TNF-α) into the hippocampus was prevented by Claudin-5 overexpression and EZH2 knockdown. Interestingly, antidepressant treatment could inhibit H3K27me3 deposition at the Cldn5 promoter, reversing the loss of the encoded protein and BBB damage. Considered together, these findings reveal the importance of the hippocampal EZH2-Claudin-5 axis in regulating neurovascular function and MDD development, providing potential therapeutic targets for this psychiatric illness.

The Impact of Adjuvant Chemotherapy on the Long-Term Prognosis of Breast Malignant Phyllodes Tumors: A Propensity Score-Matched Study.

BACKGROUND: Malignant phyllodes tumors (MPTs) are rare breast tumors with high risks of local recurrence and distant metastasis. Surgical intervention is the primary treatment, but the effectiveness of adjuvant therapies is uncertain. This study was designed to analyze the prognostic risk factors associated with MPTs and evaluate the efficacy of postoperative adjuvant chemotherapy. PATIENTS AND METHODS: Patients who were first diagnosed with MPT without distant metastasis and received R0 resection surgery between 1999 and 2023 were included in the present study and stratified into 2 groups: chemotherapy and nonchemotherapy groups. Propensity score matching (PSM) was used to balance baseline characteristics between groups. Kaplan-Meier curves were used to estimate local recurrence-free survival (LRFS) and overall survival (OS). Cox proportional hazards analyses (univariate and multivariate) were conducted to identify prognostic risk factors. RESULTS: We conducted a study involving 145 patients, 31 of whom underwent a total of 12 different chemotherapy regimens following initial surgical resection. Most patients received chemotherapy regimens primarily consisting of anthracyclines, including anthracycline + ifosfamide (AI) or anthracycline + cyclophosphamide/docetaxel (AC-T) regimens. After a median follow-up of 54.5 months, 37 (25.5%) patients experienced local recurrence and 24 (16.6%) experienced distant metastasis. No significant difference was detected in the rates of local recurrence or distant metastasis between the 2 groups. Axillary lymph node positivity was the only risk factor for LRFS, whereas older age, larger tumors, axillary lymph node positivity, local recurrence, and distant metastasis were significantly associated with worse OS. Chemotherapy did not emerge as a protective factor for LRFS (P=.501) or OS (P=.854). After PSM, patients in the chemotherapy group did not exhibit better 5-year LRFS (P=.934) or 5-year OS (P=.328). CONCLUSIONS: According to our retrospective evaluation, postoperative adjuvant chemotherapy was not associated with improved survival in patients with MPTs without distant metastasis.

Single-cell transcriptomics identifies Gadd45b as a regulator of herpesvirus-reactivating neurons.

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for dissecting the complexity of normal and diseased tissues, enabling characterization of cell diversity and heterogeneous phenotypic states in unprecedented detail. However, this technology has been underutilized for exploring the interactions between the host cell and viral pathogens in latently infected cells. Herein, we use scRNA-seq and single-molecule sensitivity fluorescent in situ hybridization (smFISH) technologies to investigate host single-cell transcriptome changes upon the reactivation of a human neurotropic virus, herpes simplex virus-1 (HSV-1). We identify the stress sensor growth arrest and DNA damage-inducible 45 beta (Gadd45b) as a critical antiviral host factor that regulates HSV-1 reactivation events in a subpopulation of latently infected primary neurons. We show that distinct subcellular localization of Gadd45b correlates with the viral late gene expression program, as well as the expression of the viral transcription factor, ICP4. We propose that a hallmark of a "successful" or "aborted" HSV-1 reactivation state in primary neurons is determined by a unique subcellular localization signature of the stress sensor Gadd45b.

Obstructive Sleep Apnea Plasma-Derived Exosomes Mediate Cognitive Impairment Through Hippocampal Neuronal Cell Pyroptosis.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with impaired cognitive function. Exosomes are secreted by most cells and play a role in OSA-associated cognitive impairment (CI). The aim of this study was to investigate whether OSA plasma-derived exosomes cause CI through hippocampal neuronal cell pyroptosis, and to identify exosomal miRNAs in OSA plasma-derived. MATERIALS AND METHODS: Plasma-derived exosomes were isolated from patients with severe OSA and healthy comparisons. Daytime sleepiness and cognitive function were assessed using the Epworth Sleepiness Scale (ESS) and the Beijing version of the Montreal Cognitive Assessment Scale (MoCA). Exosomes were coincubated with mouse hippocampal neurons (HT22) cells to evaluate the effect of exosomes on pyroptosis and inflammation of HT22 cells. Meanwhile, exosomes were injected into C57BL/6 male mice via caudal vein, and then morris water maze was used to evaluate the spatial learning and memory ability of the mice, so as to observe the effects of exosomes on the cognitive function of the mice. Western blot and qRT-PCR were used to detect the expressions of Gasdermin D (GSDMD) and Caspase-1 to evaluate the pyroptosis level. The expression of IL-1ß, IL-6, IL-18 and TNF-α was detected by qRT-PCR to assess the level of inflammation. Correlations of GSDMD and Caspase-1 expression with clinical parameters were evaluated using Spearman's rank correlation analysis. In addition, plasma exosome miRNAs profile was identified, followed by Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. RESULTS: Compared to healthy comparisons, body mass index (BMI), apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and ESS scores were increased in patients with severe OSA, while lowest oxygen saturation during sleep (LSaO2), mean oxygen saturation during sleep (MSaO2) and MoCA scores were decreased. Compared to the PBS group (NC) and the healthy comparison plasma-derived exosomes (NC-EXOS), the levels of GSDMD and Caspase-1 and IL-1ß, IL-6, IL-18 and TNF-α were increased significantly in the severe OSA plasma-derived exosomes (OSA-EXOS) coincubated with HT22 cells. Compared to the NC and NC-EXOS groups, the learning and memory ability of mice injected with OSA-EXOS was decreased, and the expression of GSDMD and Caspase-1 in hippocampus were significantly increased, along with the levels of IL-1ß, IL-6, IL-18 and TNF-α. Spearman correlation analysis found that clinical AHI in HCs and severe OSA patients was positively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups, while negatively correlated with clinical MoCA. At the same time, clinical MoCA in HCs and severe OSA patients was negatively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups. A unique exosomal miRNAs profile was identified in OSA-EXOS group compared to the NC-EXOS group, in which 28 miRNAs were regulated and several KEGG and GO pathways were identified. CONCLUSIONS: The results of this study show a hypothesis that plasma-derived exosomes from severe OSA patients promote pyroptosis and increased expression of inflammatory factors in vivo and in vitro, and lead to impaired cognitive function in mice, suggesting that OSA-EXOS can mediate CI through pyroptosis of hippocampal neurons. In addition, exosome cargo from OSA-EXOS showed a unique miRNAs profile compared to NC-EXOS, suggesting that plasma exosome associated miRNAs may reflect the differential profile of OSA related diseases, such as CI.

Group A Streptococcal meningitis in children: a short case series and systematic review.

BACKGROUND: Group A streptococcal(GAS) meningitis is a severe disease with a high case fatality rate. In the era of increasing GAS meningitis, our understanding about this disease is limited. PURPOSE: To gain a better understanding about GAS meningitis. METHODS: Five new cases with GAS meningitis were reported. GAS meningitis related literatures were searched for systematic review in PUBMED and EMBASE. Case reports and case series on paediatric cases were included. Information on demographics, risk factors, symptoms, treatments, outcomes, and emm types of GAS was summarized. RESULTS: Totally 263 cases were included. Among 100 individuals, 9.9% (8/81) had prior varicella, 11.1% (9/81) had anatomical factors, and 53.2% (42/79) had extracranial infections. Soft tissue infections were common among infants (10/29, 34.5%), while ear/sinus infections were more prevalent in children ≥ 3 years (21/42, 50.0%). The overall case fatality rate (CFR) was 16.2% (12/74). High risk of death was found in patients with shock or systemic complications, young children(< 3 years) and cases related to hematogenic spread. The predominate cause of death was shock(6/8). Among the 163 patients included in case series studies, ear/sinus infections ranged from 21.4 to 62.5%, while STSS/shock ranged from 12.5 to 35.7%, and the CFR ranged from 5.9 to 42.9%. CONCLUSIONS: A history of varicella, soft tissue infections, parameningeal infections and CSF leaks are important clinical clues to GAS in children with meningitis. Young children and hematogenic spread related cases need to be closely monitored for shock due to the high risk of death.