Glycolysis inhibition for synergistic phototherapy of triple-negative breast cancer.

Phototherapy is a local and precise therapeutic technique for tumor treatment. However, the therapeutic effects of photothermal and photodynamic therapies are inevitably encountered by hypoxia of the tumor microenvironment and heat shock protein induced by hyperthermia, respectively. Herein, we found that mannose, a glucose analog, could reverse tumor hypoxia by inhibiting glycolysis of cancer cells and suppressing the expression of heat shock protein through inhibiting cellular adenosine triphosphate (ATP) generation. Next, we used lipid nanoparticles simultaneously loaded with indocyanine green (ICG) and mannose molecules, named imLipo, for tumor therapy. Both in vitro and in vivo experiments evidenced that the imLipo nanoplatform has significant therapeutic efficacy through synergistic phototherapy under single near-infrared laser irradiation. This work shows that glycolysis inhibition can overcome the challenges of phototherapy. In addition, all three parts (mannose, ICG, and lipid) of imLipo are clinically approved and our designed nanoplatforms have great potential for future tumor treatment.

Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response.

TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with Trex1 deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in TREX1 deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in Trex1-/- mice are induced by multiple factors, particularly DNA damage. The cGAS-STING and DNA damage response pathways are required for maintaining TREX1 deletion-induced cellular senescence. Inhibition of the DNA damage response, such as with Checkpoint kinase 2 (CHK2) inhibitor, partially alleviated progression of type I interferonopathies and lupus-like features in the mice. These data provide insights into the initiation and development of type I interferonopathies and lupus-like diseases, and may help inform the development of targeted therapeutics.

Generalized Meta-FDMixup: Cross-Domain Few-Shot Learning Guided by Labeled Target Data.

The vanilla Few-shot Learning (FSL) learns to build a classifier for a new concept from one or very few target examples, with the general assumption that source and target classes are sampled from the same domain. Recently, the task of Cross-Domain Few-Shot Learning (CD-FSL) aims at tackling the FSL where there is a huge domain shift between the source and target datasets. Extensive efforts on CD-FSL have been made via either directly extending the meta-learning paradigm of vanilla FSL methods, or employing massive unlabeled target data to help learn models. In this paper, we notice that in the CD-FSL task, the few labeled target images have never been explicitly leveraged to inform the model in the training stage. However, such a labeled target example set is very important to bridge the huge domain gap. Critically, this paper advocates a more practical training scenario for CD-FSL. And our key insight is to utilize a few labeled target data to guide the learning of the CD-FSL model. Technically, we propose a novel Generalized Meta-learning based Feature-Disentangled Mixup network, namely GMeta-FDMixup. We make three key contributions of utilizing GMeta-FDMixup to address CD-FSL. Firstly, we present two mixup modules - mixup-P and mixup-M that help facilitate utilizing the unbalanced and disjoint source and target datasets. These two novel modules enable diverse image generation for training the model on the source domain. Secondly, to narrow the domain gap explicitly, we contribute a novel feature disentanglement module that learns to decouple the domain-irrelevant and domain-specific features. By stripping the domain-specific features, we alleviate the negative effects caused by the domain inductive bias. Finally, we repurpose a new contrastive learning module, dubbed ConL. ConL prevents the model from only capturing category-related features via introducing contrastive loss. Thus, the generalization ability on novel categories is improved. Extensive experimental results on two benchmarks show the superiority of our setting and the effectiveness of our method. Code and models will be released.

Cyclic dinucleotides mediate bacterial immunity by dinucleotide cyclase in Vibrio.

The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and synthesizes the second messenger, cGAMP, thus activating the adaptor protein stimulator of interferon genes (STING) and initiating the innate immune responses against microbial infections. cGAS-STING pathway has been crucially implicated in autoimmune diseases, cellular senescence, and cancer immunotherapy, while the cGAS-like receptors in bacteria can protect it against viral infections. Dinucleotide cyclase in Vibrio (DncV) is a dinucleotide cyclase originally identified in Vibrio cholerae. The synthesis of cyclic nucleotides by DncV, including c-di-GMP, c-di-AMP, and cGAMP mediates bacterial colonization, cell membrane formation, and virulence. DncV is a structural and functional homolog of the mammalian cytoplasmic DNA sensor, cGAS, implicating cGAS-STING signaling cascades may have originated in the bacterial immune system. Herein, we summarize the roles of DncV in bacterial immunity, which are expected to provide insights into the evolution of cGAS-STING signaling.

Polymer-integrated amnion scaffold significantly improves cleft palate repair.

Cleft palate is a common oral and craniomaxillofacial birth defect. As the ideal surgery time is shortly after birth, clinical treatments should result in minimal disruption of theskeleton to allow tissue growth in children. A tissue-engineered graft was created in this study for cleft palate repair by integrating poly(1,8-octamethylene-citrate) (POC) with a decellularized amnion membrane (DAM-POC) to incorporate the advantages of both the synthetic polymer and the native tissue. The success of POC incorporation was confirmed by laser-induced breakdown spectroscopy and fluorescence detection. The DAM-POC scaffold showed a certain level of structure collapse and lower stiffness but better resistance to enzyme digestion than the native amnion and DAM scaffold. The DAM-POC scaffold is cell compatible when seeded with mesenchymal stem cells, as evidenced by adequate cell viability and improved alkaline phosphatase (ALP) activity and calcium deposit. A large palate defect was first surgically created in a young rat model and then repaired with the DAM-POC scaffold. Eight weeks postsurgery, histological study and CT scans showed nearly complete healing of both soft and hard tissues. In conclusion, we developed a cell-free, resorbable graft by incorporating and integrating a synthetic polymer with a human DAM. When the DAM-POC scaffold was applied to repair a large palate defect in young rats, it showed adequate biocompatibility as evidenced by its effectiveness in guiding hard and soft tissue regeneration and minimum interference with natural growth and palate development of rats. STATEMENT OF SIGNIFICANCE: Proper restoration of severe cleft palate remains a major challenge because of insufficient autologous soft tissues to close the open wounds, thereby causing high tension at the surgical junction, secondary palatal fistulas, wound contraction, scar tissue formation, and facial growth disturbances. In this study, we have developed a tissue-engineered graft through incorporating and integrating a synthetic polymer with the human amnion membrane for cleft palate repair. The significance of this study lies in our ability to develop a cell-free, resorbable graft that can provide a less surgically invasive option to cover the open defect and support palate regeneration and tissue growth. This technique could potentially advance soft and hard tissue regeneration in children with birth craniomaxillofacial defects.