Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation.

Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4+ T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4+ T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4+ T cells that potentiates aging-related autoimmunity.

Goliath induces inflammation in obese mice by linking fatty acid ß-oxidation to glycolysis.

Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity-associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4+ T cells from obese mice exhibit elevated basal levels of fatty acid ß-oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate-limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF-AT signaling, thereby promoting glycolysis and hyperactivation of CD4+ T cells in obesity. We also report the specific GOLIATH inhibitor DC-Gonib32, which blocks this FAO-glycolysis metabolic axis in CD4+ T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath-bridged FAO-glycolysis axis in mediating CD4+ T cell hyperactivation and thus inflammation in obese mice.

Trinitarian Design of Gradient Artificial Interphase Enables Colossal Granular Li Deposits for Stable Li-Metal Batteries.

The cycling lifespan of Li-metal batteries is compromised by the unstable solid electrolyte interphase (SEI) and the continuous Li dendrites, restricting their practical implementations. Given these challenges, establishing an artificial SEI holds promise. Herein, a trinitarian gradient interphase is innovatively designed through composite coatings of magnesium fluoride (MgF2), N-hexadecyltrimethylammonium chloride (CTAC), and polyvinylidene fluoride-hexafluoropropylene copolymer (PVDF-HFP) on Li-metal anode (LMA). Specifically, the MgF2/CTAC/PVDF-HFP SEI spontaneously forms a lithium fluoride (LiF)-rich PVDF-HFP-based SEI, along with lithium-magnesium (Li-Mg) alloy substrate as lithiophilic electronic conductor and positively charged CTAC during plating. Noticeably, the Li-Mg alloy homogenizes the distribution of electric field and reduce the internal resistance, while the electronically insulated LiF/PVDF-HFP composite SEI offers fast ion-conducting and mechanical flexibility, accommodating the volumetric expansion and ensuring stable Li-ion flux. Additionally, CTAC at the dendritic tip is pivotal for mitigating dendrites through its electrostatic shield mechanism. Innovatively, this trinitarian synergistic mechanism, which facilitates colossal granular Li deposits, constructs a dendrite-free LMA, leading to stable cycling performances in practical Li||LFP, popular Li||NCM811, and promising Li||S full cells. This work demonstrates the design of multifunctional composite SEI for comprehensive Li protection, thereby inspiring further advancements in artificial SEI engineering for alkali-metal batteries.

Damage-Tolerant and Self-Repairing Web-Like Borate Type Binder Enable Stable Operation of Efficient Si-Based Anodes.

Novel binder designs are shown to be fruitful in improving the electrochemical performance of silicon (Si)-based anodes. However, issues with mechanical damage from dramatic volume change and poor lithium-ion (Li+) diffusion kinetics in Si-based materials still need to be addressed. Herein, an aqueous self-repairing borate-type binder (SBG) with a web-like architecture and high ionic conductivity is designed for Si and SiO electrodes. The 3D web-like architecture of the SBG binder enables uniform stress distribution, while its self-repairing ability promotes effective stress dissipation and mechanical damage repair, thereby enhancing the damage tolerance of the electrode. The tetracoordinate boron ions ( - BO 4 - $ - {\mathrm{BO}}_4^ - $ ) in the SBG binder boosts the Li transportation kinetics of Si-based electrodes. Based on dynamic covalent and ionic conductive boronic ester bonds, the diverse requirements of the binder, including uniform stress distribution, self-repairing ability, and high ionic conductivity, can be met by simple components. Consequently, the proposed straightforward multifunction design strategy for binders based on dynamic boron chemistry provides valuable insights into fabricating high-performance Si-based anodes.

Peli1 impairs microglial Aß phagocytosis through promoting C/EBPß degradation.

Amyloid-ß (Aß) accumulation in the brain is a hallmark of Alzheimer's disease (AD) pathology. However, the molecular mechanism controlling microglial Aß phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aß was then impaired, and therefore Peli1 depletion suppressed the Aß deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)ß, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBPß and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBPß and the expression of CD36 and thus, promoted the phagocytic ability in microglial cells. Together, our findings established Peli1 as a critical regulator of microglial phagocytosis and highlighted the therapeutic potential by targeting Peli1 for the treatment of microglia-mediated neurological diseases.

Palladium-Catalyzed Enantioselective Thiocarbonylation of Styrenes.

A highly enantioselective thiocarbonylation of styrenes with CO and thiols has been achieved by Pd catalysis, providing highly enantioenriched thioesters in good to excellent yields. Key to the successful execution of this reaction is the use of a chiral sulfoxide-(P-dialkyl)-phosphine (SOP) ligands. This thiocarbonylation proceeds smoothly under mild reaction conditions (1 atm CO and 0 °C) and displays broad substrate scope. Also demonstrated is that this transformation can be conducted using surrogates of CO, greatly increasing the safety aspects of running the reaction. The generality and utility of the method is manifested by its application to the synthetic transformations of thioester products and the direct acylation of cysteine-containing dipeptides. A primary mechanism was investigated and a plausible catalytic cycle was proposed.

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model.

Parkinson's disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.

Mapping the Behavioral Signatures of Shank3b Mice in Both Sexes.

Autism spectrum disorders (ASD) are characterized by social and repetitive abnormalities. Although the ASD mouse model with Shank3b mutations is widely used in ASD research, the behavioral phenotype of this model has not been fully elucidated. Here, a 3D-motion capture system and linear discriminant analysis were used to comprehensively record and analyze the behavioral patterns of male and female Shank3b mutant mice. It was found that both sexes replicated the core and accompanied symptoms of ASD, with significant sex differences. Further, Shank3b heterozygous knockout mice exhibited distinct autistic behaviors, that were significantly different from those those observed in the wild type and homozygous knockout groups. Our findings provide evidence for the inclusion of both sexes and experimental approaches to efficiently characterize heterozygous transgenic models, which are more clinically relevant in autistic studies.

Design, Synthesis, and Acaricidal/Insecticidal Activities of New Phenylpyrazole Derivatives Comprising an Imide Moiety.

Using nicofluprole as the lead compound, we designed and synthesized a series of new phenylpyrazole analogues through substituting the methyl group on the nitrogen atom of the amide with an acyl group. Bioassay results showed that compounds A12-A17 with a 1-cyanocyclopropimide group exhibited outstanding insecticidal activity. The LC50 values for compounds A12-A17 against Tetranychus cinnabarinus ranged from 0.58 to 0.91 mg/L. Compound A15 showed an LC50 value of 0.29 and 3.10 mg/L against Plutella xylostella and Myzus persicae, respectively. Molecular docking indicated the potential binding interactions of compound A15 with a gamma-aminobutyric acid receptor. Additionally, density functional theory calculations implied that the 1-cyanocyclopropimide structure might be essential for its biological activity. Phenylpyrazole derivatives, containing a 1-cyanocyclopropimide fragment, have the potential for further development as potential insecticides.

Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and cervical cancer recurrence.

Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8+ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)+ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2+ tumor cells are induced to produce transforming growth factor ß to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8+ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2+ tumor cells driving CD8+ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8+ T cell senescence for chemoradiotherapy recurrence.

Lifespan changes in cannabinoid 1 receptor mRNA expression in the female C57BL/6J mouse brain.

Many brain functions that underlie behavior, cognition, and emotions vary with age, as does susceptibility to neuropsychological disorders. The expression of specific genes that are involved in these functions, such as the genes encoding for oxytocin, its receptors, and apolipoprotein D, varies with age across different brain regions. The cannabinoid 1 receptor (CB1 R) is one of the most widely spread G-protein coupled receptors in the central nervous system and is increasingly recognized for its important contribution to various brain functions. Although changes in CB1 R expression with age have been reported in the male mouse brain, they have not been well investigated in the female brain. Here, we used fluorescence in situ hybridization to target CB1 R mRNA in the whole brains of female C57BL/6J mice aged 4, 6, 12, 52 (12 months) and 86 weeks (20 months), and quantified CB1 R-positive cells in 36 brain regions across the whole brain. The results showed that CB1 R-positive cells number changed with age. Specifically, CB1 R expression increased with age in some subregions of the cortex, decreased with age in the lateral septal area, and reached its lowest level at 52 weeks in the thalamus, hypothalamus, and hindbrain subregions. Cluster analysis revealed that some brain regions shared similar temporal characteristics in CB1 R-positive cell number across the lifespan. Our results provide evidence that investigation of the neural basis of age-related characteristics of female brain functions is not only warranted but required.

The subthalamic corticotropin-releasing hormone neurons mediate adaptive REM-sleep responses to threat.

When an animal faces a threatening situation while asleep, rapid arousal is the essential prerequisite for an adequate response. Here, we find that predator stimuli induce immediate arousal from REM sleep compared with NREM sleep. Using in vivo neural activity recording and cell-type-specific manipulations, we identify neurons in the medial subthalamic nucleus (mSTN) expressing corticotropin-releasing hormone (CRH) that mediate arousal and defensive responses to acute predator threats received through multiple sensory modalities across REM sleep and wakefulness. We observe involvement of the same neurons in the normal regulation of REM sleep and the adaptive increase in REM sleep induced by sustained predator stress. Projections to the lateral globus pallidus (LGP) are the effector pathway for the threat-coping responses and REM-sleep expression. Together, our findings suggest adaptive REM-sleep responses could be protective against threats and uncover a critical component of the neural circuitry at their basis.

Halogenated salt assisted Cu-catalyzed asymmetric 1,4-borylstannation of 1,3-enynes: enantioselective synthesis of allenylstannes.

An enantioselective 1,4-borylstannation of 1,3-enynes employed a chiral sulfoxide phosphine (SOP)/Cu complex as a catalyst, and the desired products, chiral allenylstannes, were first synthesized by asymmetric catalysis with satisfactory yields and enantioselectivies. In this protocol, a catalytic amount of additive, a halogenated salt, plays a crucial role in the success. Control experiments and theoretical studies disclosed that the four-membered ring transmetallation transition states which were stabilized by a halide anion are the key to yields and stereochemical outcomes.

[Safety of promestriene capsule used in postmenopausal atrophic vaginitis].

OBJECTIVE: To investigate the safety and efficacy of promestriene capsule used in the treatment of postmenopausal atrophic vaginitis. METHODS: Fifty-three women at age of 45 - 75 years (more than one year history of menopause) diagnosed with postmenopausal atrophic vaginitis were enrolled in self-control study. They all had typicalsymptoms of postmenopausal vaginitis. Promestriene was given by continuous therapy for 20 days, then maintenance therapy for for 8 weeks (1 pill two times per week used). The level of follicle stimulation hormone (FSH) and estradiol (E(2)) in serum was and thickness of endometrium were detected before and after treatment. The routine biochemical test was used as index to monitoring the safety. The vaginal mature index (VMI), the atrophic vaginitis evaluating score and vaginal healthy evaluating score were evaluated for therapeutic effect. In the mean time, adverse effect was recorded. RESULTS: (1) SAFETY: during promestriene treatment, no case with adverse effect was observed. Before treatment, the mean level of FSH and E(2) was (71 +/- 3) U/L and (41 +/- 18) pmol/L, the mean thickness of endometrium was (2.4 +/- 0.9) mm. After treatment, the mean level of FSH and E(2) was (67 +/- 22) U/L and (43 +/- 37) pmol/L, the mean thickness of endometrium was (2.5 +/- 1.3) mm. No significant difference was observed (P > 0.05). (2) Therapeutic effect: VMI were 42 +/- 15 before and 54 +/- 8 after treatment. The atrophic vaginitis evaluating score were 3.4 +/- 1.7 before and 1.5 +/- 1.4 after treatment. Vaginal healthy evaluating score were 7.8 +/- 2.4 before and 12.0 +/- 2.4 after treatment. They all showed significant difference (P < 0.01). (3) Adverse effect: six cases with vaginal bleeding, 3 cases with breast nodules and 1 case with cervical polyp was observed, however, it was uncertain whether those events were associated with promestriene use. CONCLUSION: The premestriene capsule was safe and effective in the treatment of postmenopausal atrophic vaginitis.

[Epidemiological study of high risk human papillomavirus infection in 25 to 54 years old married women in Beijing.].

OBJECTIVE: To investigate high risk human papillomavirus (HR-HPV) prevalence among married women in Beijing and to study the high risk factors. METHODS: During March 2007 to September 2008, a total of 6185 married women sampled from 137 communities in 12 districts were screened by HR-HPV DNA test and cytological test. The interview was carried out with unified questionnaires. The database was set up and twice entered in EpiData 3.0. After checked up, the data were analyzed in SPSS 15.0. RESULTS: (1) The HR-HPV infection rate was 9.89%. The HR-HPV infection rate of the city zone, the suburb and the exurb were 9.34%, 10.51% and 9.51% (P > 0.05). The HR-HPV infection rate of the native and the outlander were 9.53%, 11.30% (P < 0.05). (2) The age distribution of HR-HPV infection was that the rate was around 10% among 25 to 44 age groups, which was the highest (11.21%) in 30 to 34 age group; then the rate was descended as the age raising, the rate of 50 to 54 age group was the lowest (7.78%). (3) Multiple logistic regression showed that the related risk factors of HR-HPV infection mainly included 1000 RMB and above of family income per person per month, possessing more than 1 sexual partner of her husband, outlander and high levels of education. (4) The prevalence of cervical intraepithelial neoplasia (CIN) in HR-HPV positive group was significantly higher than that in HR-HPV negative group (29.76% vs 3.32%, P < 0.01). CONCLUSIONS: (1) The HR-HPV infection rate among aged 25 to 54 years was 9.9% and there was no significant difference in area distribution. (2) The high risk population which should strengthen screening was the married bearing-age women with high level of family income, outlander, high levels of education and her husband possessing more than 1 sexual partner. (3) HR-HPV infection is the main risk factor for CIN and cervical cancer, while does not provide a causal relationship with them. The high risk population should be checked regularly to understand the development of HR-HPV infection and CIN incidence.

Cu-Catalyzed SN2' Substitution of Propargylic Phosphates with Vinylarene-Derived Chiral Nucleophiles: Synthesis of Chiral Allenes.

A new Cu-catalyzed enantioselective three-component (i.e., styrenes, B2pin2, and propargylic phosphates) allenylation via an SN2' substitution of propargylic electrophiles with vinylarene-derived chiral nucleophiles is presented. This method provides an efficient and enantioselective approach to access a range of optically pure di-(1,1-), tri-, and tetra-substituted allenes with α-central chirality and axial chirality in excellent chemo-, regio-, diastereo-, and enantioselectivities.