Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity.

The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8+ T cells exhibited impaired effector and stem cell-like properties compared with female CD8+ T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8+ T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8+ T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8+ T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8+ T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.

MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche.

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.

Nek7 Protects Telomeres from Oxidative DNA Damage by Phosphorylation and Stabilization of TRF1.

Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage. Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex. Our data reveal a mechanism of efficient protection of telomeres from damage through Nek7-dependent stabilization of TRF1.

Refraction/reflection reversal in two-dimensional acoustic metagratingsa).

Unlike acoustic metasurfaces that rely solely on phase gradients, acoustic metagratings (AMs) operate based on both phase gradients and grating diffraction, thus further extending the generalized Snell's law (GSL). In particular, AMs can achieve reversal of refraction and reflection based on the parity of the number of wave propagations inside the AMs. So far, discussions of this GSL extension have largely been applied to one-dimensional periodic AMs, while the designs of two-dimensional (2D) periodic AMs and their performance in three-dimensional (3D) space have been quite limited. Here, we study the GSL extension in 3D space and experimentally demonstrate a series of functional 2D periodic AMs. The designed AMs can achieve sound refraction/reflection under any incidence angle in 3D space, without restrictions to certain critical ranges; adjusting incident angles only enables the reversal of refraction and reflection. Additionally, we demonstrate two types of dual-layer sound lenses based on two AMs, whose reversal of refraction and reflection can be realized by simply attaching or separating the two AMs. Our work paves the way to complex 3D wavefront manipulation of AMs, which may find potential use in practical acoustic devices.

Nordalbergin Synergizes with Novel ß-Lactam Antibiotics against MRSA Infection.

The synergetic strategy has created tremendous advantages in drug-resistance bacterial infection treatment, whereas challenges related to novel compound discovery and identifying drug-binding targets still remain. The mechanisms of antimicrobial resistance involving ß-lactamase catalysis and the degradation of ß-lactam antibiotics are being revealed, with relevant therapies promising to improve the efficacy of existing major classes of antibiotics in the foreseeable future. In this study, it is demonstrated that nordalbergin, a coumarin isolated from the wood bark of Dalbergia sissoo, efficiently potentiated the activities of ß-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) by suppressing ß-lactamase performance and improving the bacterial biofilm susceptibility to antibiotics. Nordalbergin was found to destabilize the cell membrane and promote its permeabilization. Moreover, nordalbergin efficiently improved the therapeutic efficacy of amoxicillin against MRSA pneumonia in mice, as supported by the lower bacterial load, attenuated pathological damage, and decreased inflammation level. These results demonstrate that nordalbergin might be a promising synergist of amoxicillin against MRSA infections. This study provided a new approach for developing potentiators for ß-lactam antibiotics against MRSA infections.

Isorhamnetin as a novel inhibitor of pneumolysin against Streptococcus pneumoniae infection in vivo/in vitro.

The increasing incidence of Streptococcus pneumoniae (S. pneumoniae) infection severely threatened the global public heath, causing a significant fatality in immunocompromised hosts. Notably, pneumolysin (PLY) as a pore-forming cytolysin plays a crucial role in the pathogenesis of pneumococcal pneumonia and lung injury. In this study, a natural flavonoid isorhamnetin was identified as a PLY inhibition to suppress PLY-induced hemolysis by engaging the predicted residues and attenuate cytolysin PLY-mediated A549 cells injury. Underlying mechanisms revealed that PLY inhibitor isorhamnetin further contributed to decrease the formation of bacterial biofilms without affecting the expression of PLY. In vivo S. pneumoniae infection confirmed that the pathological injury of lung tissue evoked by S. pneumoniae was ameliorated by isorhamnetin treatment. Collectively, these results presented that isorhamnetin could inhibit the biological activity of PLY, thus reducing the pathogenicity of S. pneumoniae. In summary, our study laid a foundation for the feasible anti-virulence strategy targeting PLY, and provided a promising PLY inhibitor for the treatment of S. pneumoniae infection.

Spinful Topological Phases in Acoustic Crystals with Projective PT Symmetry.

For the classification of topological phases of matter, an important consideration is whether a system is spinless or spinful, as these two classes have distinct symmetry algebra that gives rise to fundamentally different topological phases. However, only recently has it been realized theoretically that in the presence of gauge symmetry, the algebraic structure of symmetries can be projectively represented, which possibly enables the switch between spinless and spinful topological phases. Here, we report the experimental demonstration of this idea by realizing spinful topological phases in "spinless" acoustic crystals with projective space-time inversion symmetry. In particular, we realize a one-dimensional topologically gapped phase characterized by a 2Z winding number, which features double-degenerate bands in the entire Brillouin zone and two pairs of degenerate topological boundary modes. Our Letter thus overcomes a fundamental constraint on topological phases by spin classes.

Dietary ingredient change induces a transient MyD88-dependent mucosal enteric glial cell response and promotes obesity.

OBJECTIVE: Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. METHODS: Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. RESULTS: A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. CONCLUSIONS: Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity.

3ß-Hydroxy-12-oleanen-27-oic Acid Exerts an Antiproliferative Effect on Human Colon Carcinoma HCT116 Cells via Targeting FDFT1.

3ß-hydroxy-12-oleanen-27-oic acid (ATA), a cytotoxic oleanane triterpenoid with C14-COOH isolated from the rhizome of Astilbe chinensis, has been previously proven to possess antitumor activity and may be a promising antitumor agent. However, its molecular mechanisms of antitumor action were still unclear. This study explored the underlying mechanisms of cytotoxicity and potential target of ATA against human colorectal cancer HCT116 cells via integrative analysis of transcriptomics and network pharmacology in combination with in vitro and in vivo experimental validations. ATA significantly inhibited the proliferation of HCT116 cells in a concentration- and time-dependent manner and induced the cell cycle arrest at the G0/G1 phase, apoptosis, autophagy, and ferroptosis. Transcriptomic analysis manifested that ATA regulated mRNA expression of the genes related to cell proliferation, cell cycle, and cell death in HCT116 cells. The integrated analysis of transcriptomics, network pharmacology, and molecular docking revealed that ATA exerted cytotoxic activity via interactions with FDFT1, PPARA, and PPARG. Furthermore, FDFT1 was verified to be an upstream key target mediating the antiproliferative effect of ATA against HCT116 cells. Of note, ATA remarkably suppressed the growth of HCT116 xenografts in nude mice and displayed an apparent attenuation of FDFT1 in tumor tissues accompanied by the alteration of the biomarkers of autophagy, cell cycle, apoptosis, and ferroptosis. These results demonstrate that ATA exerted in vitro and in vivo antiproliferative effects against HCT116 cells through inducing cell apoptosis, autophagy, and ferroptosis via targeting FDFT1.

Observation of Dirac Hierarchy in Three-Dimensional Acoustic Topological Insulators.

Dirac cones (DCs) play a pivotal role in various unique phenomena ranging from massless electrons in graphene to robust surface states in topological insulators (TIs). Recent studies have theoretically revealed a full Dirac hierarchy comprising an eightfold bulk DC, a fourfold surface DC, and a twofold hinge DC, associated with a hierarchy of topological phases including first-order to third-order three-dimensional (3D) topological insulators, using the same 3D base lattice. Here, we report the first experimental observation of the Dirac hierarchy in 3D acoustic TIs. Using acoustic measurements, we unambiguously reveal that lifting of multifold DCs in each hierarchy can induce two-dimensional topological surface states with a fourfold DC in a first-order 3D TI, one-dimensional topological hinge states with a twofold DC in a second-order 3D TI, and zero-dimensional topological corner states in a third-order 3D TI. Our Letter not only expands the fundamental research scope of Dirac physics, but also opens up a new route for multidimensional robust wave manipulation.

Observation of Dislocation-Induced Topological Modes in a Three-Dimensional Acoustic Topological Insulator.

The interplay between real-space topological lattice defects and the reciprocal-space topology of energy bands can give rise to novel phenomena, such as one-dimensional topological modes bound to screw dislocations in three-dimensional topological insulators. We obtain direct experimental observations of dislocation-induced helical modes in an acoustic analog of a weak three-dimensional topological insulator. The spatial distribution of the helical modes is found through spin-resolved field mapping, and verified numerically by tight-binding and finite-element calculations. These one-dimensional helical channels can serve as robust waveguides in three-dimensional media. Our experiment paves the way to studying novel physical modes and functionalities enabled by topological lattice defects in three-dimensional classical topological materials.

The intestinal microbial metabolite desaminotyrosine is an anti-inflammatory molecule that modulates local and systemic immune homeostasis.

It is considered that intestinal barrier dysfunction and systemic endotoxemia drive obesity and its related complications. However, what causes barrier dysfunction remains to be elucidated. Here, we showed that the gut microbiota from high-fat diet (HFD)-fed mice had impaired ability to degrade dietary flavonoids, and in correspondence, the microbial-derived flavonoid metabolite desaminotyrosine (DAT) was reduced. Supplementation of DAT in the drinking water was able to counter the HFD-induced body fat mass accumulation and body weight increment. This is correlated with the role of DAT in maintaining mucosal immune homeostasis to protect barrier integrity. DAT could attenuate dextran sodium sulfate (DSS)-induced mucosal inflammation in a type I interferon signal-dependent manner. Furthermore, intraperitoneal injection of DAT-protected mice from bacterial endotoxin-induced septic shock. Together, we identified DAT as a gut microbiota-derived anti-inflammatory metabolite that functions to modulate local and systemic immune homeostasis. Our data support the notion of dysbiosis being an important driving force of mucosal barrier dysfunction and systemic metabolic complications.

Commensal Bacteria Impact a Protozoan's Integration into the Murine Gut Microbiota in a Dietary Nutrient-Dependent Manner.

Our current understanding of the host-microbiota interaction in the gut is dominated by studies focused primarily on prokaryotic bacterial communities. However, there is an underappreciated symbiotic eukaryotic protistic community that is an integral part of mammalian microbiota. How commensal protozoan bacteria might interact to form a stable microbial community remains poorly understood. Here, we describe a murine protistic commensal, phylogenetically assigned as Tritrichomonas musculis, whose colonization in the gut resulted in a reduction of gut bacterial abundance and diversity in wild-type C57BL/6 mice. Meanwhile, dietary nutrient and commensal bacteria also influenced the protozoan's intestinal colonization and stability. While mice fed a normal chow diet had abundant T. musculis organisms, switching to a Western-type high-fat diet led to the diminishment of the protozoan from the gut. Supplementation of inulin as a dietary fiber to the high-fat diet partially restored the protozoan's colonization. In addition, a cocktail of broad-spectrum antibiotics rendered permissive engraftment of T. musculis even under a high-fat, low-fiber diet. Furthermore, oral administration of Bifidobacterium spp. together with dietary supplementation of inulin in the high-fat diet impacted the protozoan's intestinal engraftment in a bifidobacterial species-dependent manner. Overall, our study described an example of dietary-nutrient-dependent murine commensal protozoan-bacterium cross talk as an important modulator of the host intestinal microbiome.IMPORTANCE Like commensal bacteria, commensal protozoa are an integral part of the vertebrate intestinal microbiome. How protozoa integrate into a commensal bacterium-enriched ecosystem remains poorly studied. Here, using the murine commensal Tritrichomonas musculis as a proof of concept, we studied potential factors involved in shaping the intestinal protozoal-bacterial community. Understanding the rules by which microbes form a multispecies community is crucial to prevent or correct microbial community dysfunctions in order to promote the host's health or to treat diseases.

Topological Anderson Insulator in Disordered Photonic Crystals.

Recent studies have revealed the counterintuitive possibility that increasing disorder can turn a topologically trivial insulator into a nontrivial insulator, called a topological Anderson insulator (TAI). Here, we propose and experimentally demonstrate a photonic TAI in a two-dimensional disordered gyromagnetic photonic crystal in the microwave regime. We directly observe the disorder-induced topological phase transition from a trivial insulator to a TAI with robust chiral edge states. We also demonstrate topological heterostructures that host edge states at interfaces between domains with different disorder parameters.

LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

The physiologic signals that regulate beige adipogenesis remain incompletely understood, especially those that limit browning and prevent overexpenditure of energy. In this study, the TNF family member cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT), also known as TNF super family protein 14 (TNFSF14), can inhibit adipose precursor differentiation into beige adipocytes. In acute cold stress, LIGHT deficiency in mice accelerated browning in the subcutaneous white adipose tissue (scWAT). Further experiments showed that LIGHT interacting with lymphotoxin-ß receptor (LTßR) on adipose precursors blocked beige fat biogenesis. LTßR signals attenuated the JNK pathway, which contributed to their antibeiging effect. Blocking JNK activation using a small molecular inhibitor prevented cold-induced scWAT beiging. Furthermore, LIGHT/LTßR signals acted as an attenuator of white adipogenesis. LIGHT deficiency in mice promoted obesity during high-fat diet feeding. These findings identify the LIGHT axis as a regulator of adipose tissue homeostasis and suggest that LIGHT signaling functions as a mechanism to divert energy in favor of immune activation.-Kou, Y., Liu, Q., Liu, W., Sun, H., Liang, M., Kong, F., Zhang, B., Wei, Y., Liu, Z., Wang, Y. LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

Intestinal Epithelial Cell-Derived LKB1 Suppresses Colitogenic Microbiota.

Dysregulation of the immune barrier function of the intestinal epithelium can often result in dysbiosis. In this study we report a novel role of intestinal epithelial cell (IEC)-derived liver kinase B1 (LKB1) in suppressing colitogenic microbiota. IEC-specific deletion of LKB1 (LKB1ΔIEC) resulted in an increased susceptibility to dextran sodium sulfate (DSS)-induced colitis and a definitive shift in the composition of the microbial population in the mouse intestine. Importantly, transfer of the microbiota from LKB1ΔIEC mice was sufficient to confer increased susceptibility to DSS-induced colitis in wild-type recipient mice. Collectively, the data indicate that LKB1 deficiency in intestinal epithelial cells nurtures the outgrowth of colitogenic bacteria in the commensal community. In addition, LKB1 deficiency in the intestinal epithelium reduced the production of IL-18 and antimicrobial peptides in the colon. Administration of exogenous IL-18 restored the expression of antimicrobial peptides, corrected the outgrowth of several bacterial genera, and rescued the LKB1ΔIEC mice from increased sensitivity to DSS challenge. Taken together, our study reveals an important function of LKB1 in IECs for suppressing colitogenic microbiota by IL-18 expression.

Quick and improved immune responses to inactivated H9N2 avian influenza vaccine by purified active fraction of Albizia julibrissin saponins.

BACKGROUND: H9N2 Low pathogenic avian influenza virus (LPAIV) raises public health concerns and its eradication in poultry becomes even more important in preventing influenza. AJSAF is a purified active saponin fraction from the stem bark of Albizzia julibrissin. In this study, AJSAF was evaluated for the adjuvant potentials on immune responses to inactivated H9N2 avian influenza virus vaccine (IH9V) in mice and chicken in comparison with commercially oil-adjuvant. RESULTS: AJSAF significantly induced faster and higher H9 subtype avian influenza virus antigen (H9-Ag)-specific IgG, IgG1, IgG2a and IgG2b antibody titers in mice and haemagglutination inhibition (HI) and IgY antibody levels in chicken immunized with IH9V. AJSAF also markedly promoted Con A-, LPS- and H9-Ag-stimulated splenocyte proliferation and natural killer cell activity. Furthermore, AJSAF significantly induced the production of both Th1 (IL-2 and IFN-γ) and Th2 (IL-10) cytokines, and up-regulated the mRNA expression levels of Th1 and Th2 cytokines and transcription factors in splenocytes from the IH9V-immunized mice. Although oil-formulated inactivated H9N2 avian influenza vaccine (CH9V) also elicited higher H9-Ag-specific IgG and IgG1 in mice and HI antibody titer in chicken, this robust humoral response was later produced. Moreover, serum IgG2a and IgG2b antibody titers in CH9V-immunized mice were significantly lower than those of IH9V alone group. CONCLUSIONS: AJSAF could improve antigen-specific humoral and cellular immune responses, and simultaneously trigger a Th1/Th2 response to IH9V. AJSAF might be a safe and efficacious adjuvant candidate for H9N2 avian influenza vaccine.

Kaempferol-3-O-glucorhamnoside inhibits inflammatory responses via MAPK and NF-κB pathways in vitro and in vivo.

Klebsiella pneumoniae causes severe infections including pneumonia and sepsis and treatments are complicated by increased levels of antibiotic resistance. We have identified a flavonoid kaempferol-3-O-glucorhamnoside derived from the plant Thesium chinense Turcz that possessed potent anti-inflammatory effects in K. pneumoniae infected mice. Administration of kaempferol-3-O-glucorhamnoside before bacterial challenge effectively suppressed expression of the major inflammatory cytokines TNF-α, IL-6, IL-1ß and PGE2 and ameliorated lung edema. In addition, administration of this compound to cultured RAW macrophages or Balb/c mice resulted in the suppression of NFκB and MAP kinase phosphorylation indicating an inhibitory effect on inflammation in vitro and in vivo. Kaempferol-3-O-glucorhamnoside also decreased ROS levels and overall oxidative stress in lungs and in cultured cells generated by K. pneumoniae exposure. Taken together, kaempferol-3-O-glucorhamnoside is a potent anti-inflammatory in vitro and in vivo and is a promising therapeutic agent for treating K. pneumoniae infections in the clinic.

Evaluation and characteristics of immunological adjuvant activity of purified fraction of Albizia julibrissin saponins.

PURPOSE: The purified fraction of Albizia julibrissin saponins (AJSAF) was evaluated and characterized for the adjuvant activity on porcine reproductive and respiratory syndrome virus (PRRSV) vaccine. METHODS: The effects of AJSAF on serum PRRSV N protein-specific antibody titers, splenocyte proliferation, natural killer (NK) cell activity, mRNA expression of cytokines and transcription factors, secretion of cytokines, T cells response in splenocytes, as well as delayed type hypersensitivity (DTH) in the mice immunized PRRSV vaccine were determined by ELISA, MTT assay, flow cytometry and quantitative real-time PCR (qRT-PCR). RESULTS: AJSAF not only significantly enhanced the serum PRRSV N protein-specific IgG, IgG1, IgG2a and IgG2b antibody titers in the mice immunized with PRRSV CH-1R modified live vaccine (CH-1R MLV), inactivated vaccine (CH-1R IAV), and highly pathogenic JXA1-R modified live vaccine (JXA1-R MLV), but promoted the concanavalin A (Con A)-, lipopolysaccharide (LPS)- and PRRSV N protein-stimulated splenocyte proliferation, the activities of NK cells and delayed type hypersensitivity (DTH) in the mice immunized CH-1R MLV. AJSAF also remarkably induced the production of both Th1 (IFN-γ) and Th2 (IL-10) cytokines, and up-regulated the mRNA expression levels of Th1 cytokines (IFN-γ and IL-2) and transcription factors (T-bet and STAT4) as well as Th2 cytokines (IL-4 and IL-10) and transcription factors (GATA-3 and STAT6) in splenocytes from the CH-1R MLV-immunized mice. Furthermore, AJSAF markedly increased the frequencies of PRRSV N protein-specific Th1 (INF-γ+ and IL-2+) and Th2 (IL-4+ and IL-10+) CD4 T cells as well as Tc1 (INF-γ+ and IL-2+) and Tc2 (IL-4+ and IL-10+) CD8 T cells in splenocytes from the CH-1R MLV-immunized mice. CONCLUSIONS: Our results demonstrated that AJSAF had a potential to enhance and improve immune responses and elicit both Th1/Th2 and Tc1/Tc2 response to PRRSV vaccine, and that AJSAF would be a promising adjuvant candidate for PRRSV vaccine.