Flexible energy storage devices for wearable bioelectronics

With the growing market of wearable devices for smart sensing and personalized healthcare applications,energy storage devices that ensure stable power supply and can be constructed in flexible platforms have attracted tremendous research interests.A variety of active materials and fabrication strategies of flexible energy storage devices have been intensively studied in recent years,especially for integrated self-powered systems and biosensing.A series of materials and applications for flexible energy storage devices have been studied in recent years.In this review,the commonly adopted fabrication methods of flexible energy storage devices are introduced.Besides,recent advances in integrating these energy devices into flexible self-powered systems are presented.Furthermore,the applications of flexible energy storage devices for biosensing are summarized.Finally,the prospects and challenges of the self-powered sensing system for wearable electronics are discussed.

The essential adaptors of innate immune signaling

Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors(PRRs)to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1,where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/AP-1 and the signal transducer and activator of tran-scription 6(STAT6)to trigger the expression of typeІinterferons and inflammatory cytokines or the assem-bly of inflammasomes.Most pleiotropic cytokines are secreted and bind to specific receptors,activating the signaling pathways including JAK-STAT for the prolif-eration,differentiation and functional capacity of im-mune cells.This review focuses on several critical adaptors in innate immune signaling cascades and recent progress in their molecular mechanisms.

Manganese salts function as potent adjuvants

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines.To date,only a few adjuvants have been approved for use in humans,among which aluminum-containing adjuvants are the only ones widely used.However,the medical need for potent and safe adjuvants is currently continuously increasing,especially those triggering cellular immune responses for cytotoxic T lymphocyte activation,which are urgently needed for the development of efficient virus and cancer vaccines.Manganese is an essential micronutrient required for diverse biological activities,but its functions in immunity remain undefined.We previously reported that Mn^(2+) is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn^(2+)alone directly activates cGAS independent of dsDNA,leading to an unconventional catalytic synthesis of 2′3′-cGAMP.Herein,we found that Mn^(2+) strongly promoted immune responses by facilitating antigen uptake,presentation,and germinal center formation via both cGAS-STING and NLRP3 activation.Accordingly,a colloidal manganese salt(Mn jelly,MnJ)was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses,inducing antibody production and CD4^(+)/CD8^(+)T-cell proliferation and activation by either intramuscular or intranasal immunization.When administered intranasally,MnJ also worked as a mucosal adjuvant,inducing high levels of secretory IgA.MnJ showed good adjuvant effects for all tested antigens,including T cell-dependent and T cell-independent antigens,such as bacterial capsular polysaccharides,thus indicating that it is a promising adjuvant candidate.

Caspases control antiviral innate immunity

Caspases are a family of cysteine proteases whose functions have been scrutinized intensively in recent years.Beyond their established roles in programmed cell death and inflammatory response,some caspases are also fundamental players in antiviral immunity by fine-tuning the levels of antiviral signaling adapters and cytokines,such as type I interferons,which serves as a major,sophisticated weapon against viruses.Viral infections can result in inflammasome activation and the initiation of cell death,including apoptosis and pyroptosis,and multiple caspases are significantly involved in these processes.This review will focus on the cutting-edge discoveries regarding the multifaceted roles of caspases in antiviral innate immunity.

Improved clinical outcomes of rhG-CSF-mobilized blood and marrow haploidentical transplantation compared to propensity score-matched rhG-CSF-primed peripheral blood stem cell haploidentical transplantation:a multicenter study

The effects of haploidentical rhG-CSF-mobilized blood and marrow transplantation(HBMT) on hematological malignances are well established. Previous prospective single-center studies have demonstrated better survival after HBMT versus haploidentical rhG-CSF-mobilized peripheral blood stem cell transplantation(HPBSCT) for acute leukemia(AL) not in remission(NR) or in more than the second complete remission(>CR2). To test the hypothesis that HBMT is still superior to HPBSCT for patients with AL, multiple myeloma(MM), or non-Hodgkin lymphoma(NHL) in CR1/CR2 and for patients with chronic myeloid leukemia in the first and second chronic phase lacking a matched donor, we designed a propensity score method-based multicenter study.Hematopoietic recovery, acute graft-versus-host disease(aGVHD), and chronic GVHD were comparable between the HBMT group(n=168) and the HPBSCT group(n=42). No significant differences were found in non-relapse mortality rate(20.17%±3.58%and 27.24%±7.16%, P=0.18) or relapse rate(19.96%±3.72% and 28.49%±8.25%, P=0.32) between the HBMT group and the HPBSCT group. HBMT recipients had better overall survival(65.0%±4.2% and 54.2%±8.3%, P=0.037) and disease-free survival(59.9%±4.6% and 44.3%±8.7%, P=0.051). Multivariate analysis showed that HPBSCT was associated with poorer DFS(HR(95%CI), 1.639(0.995–2.699), P=0.052). Our comparisons showed that HBMT was superior to HPBSCT as a post-remission treatment for patients lacking an identical donor.

STING-mediated DNA sensing in cancer immunotherapy

While STING(STimulator of INterferon Genes) has been shown to be essential for cytosolic DNA-triggered innate immune activation, accumulated evidence obtained from various studies suggested that an intrinsic relevance of STING-associated signaling in tumorigenesis can be observed. Also, several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for STING, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. However, cases have also been reported where the involvement of STING shows a protective role in tumor growth. Here we summarize recent findings that have pointed towards the STING pathway as an innate immune sensing mechanism driving type I interferon production in the tumor context. Better understanding of this pathway can guide further development of novel immunotherapeutic strategies in the treatment of cancer.

Manganese enhances the antitumor function of CD8^(+)T cells by inducing type I interferon production

The presence of cytosolic DNA at tumor sites and the activation of the cGAS-STING pathway have been implicated in the activation of antitumor immune responses.1,2,3 Manganese (Mn) is a necessary trace element for intracellular activities. It plays important roles in development, digestion, reproduction, antioxidant defense, energy production, immunity, and neuronal activity regulation.4 Mn was reported to enhance cGAS-STING activation through increased sensitivity to dsDNA during viral infections.5 However, it is unclear whether Mn can enhance antitumor immune functions. Here, we revealed that Mn2+ could inhibit the development of murine hepatocellular carcinoma (HCC) through immune modulations. It upregulated IFN-γ and TNF-α production in splenic and tumor-infiltrating CD8+ T cells. Moreover, Mn2+ significantly increased type I interferon (IFN) production and type I IFN-stimulated gene (ISG) expression in tumor-bearing mice. Further analysis revealed that myeloid cells could upregulate type I IFN production and increase costimulatory molecule expression upon Mn2+ stimulation. In vivo depletion of CD8+ T cells or treatment of IFNAR KO mice diminished the antitumor activity of Mn2+, suggesting that the antitumor function of Mn2+ is dependent on both CD8+ T cells and type I IFN signaling. Our results provide evidence to support Mn2+ as a novel agent that can be incorporated into cancer immunotherapy.

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection

The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved.Here,we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway.SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation.cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection.We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion.Furthermore,cytoplasmic chromatin-cGAS-STING pathway,but not MAVS-mediated viral RNA sensing pathway,contributes to interferon and pro-inflammatory gene expression upon cell fusion.Finally,we show that cGAS is required for host antiviral responses against SARS-CoV-2,and a STING-activating compound potently inhibits viral replication.Together,our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection,mediated by cytoplasmic chromatin from the infected cells.Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19.In addition,these findings extend our knowledge in host defense against viral infection by showing that host cells’self-nucleic acids can be employed as a“danger signal”to alarm the immune system.

Recent progress on the activation of the cGAS–STING pathway and its regulation by biomolecular condensation

The cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthetase (cGAS)–stimulator of interferon genes(STING) pathway, comprising the DNA sensor cGAS, the second messenger cyclic GMP–AMP (cGAMP), and the endoplasmicreticulum (ER) adaptor protein STING, detects cytoplasmic double-stranded DNA (dsDNA) to trigger type I-interferon responses forhost defense against pathogens. Previous studies defined a model for the allosteric activation of cGAS by DNA-binding, but recentwork reveals other layers of mechanisms to regulate cGAS activation such as the phase condensation and metal ions, especially thediscovery of Mn^(2+) as a cGAS activator. Activation of the 23-cGAMP sensor STING requires translocating from the ER to the Golgiapparatus. The sulfated glycosaminoglycans at the Golgi are found to be the second STING ligand promoting STING oligomerizationand activation in addition to 23-cGAMP, while surpassed levels of 23-cGAMP induce ER-located STING to form a highly organizedER membranous condensate named STING phase-separator to restrain STING activation. Here, we summarize recent advances in theregulation of cGAS–STING activation and their implications in physiological or pathological conditions, particularly focusing on theemerging complexity of the regulation.

Apoptosis of carrot nuclei in in vitro system induced by cytochrome c

The apoptosis of carrot nuclei induced in cytosol of carrot cells by cytochrome c is reported. This kind of cell-free apoptosis system of plant, CS-100, is an efficient In vitro inducing system. Several typical characteristics of apoptosis including chromatin condensation, margina-tion and apoptotic bodies could be detected, and the degradation of genome in carrot nuclei

N4 DNA recognition by STAT6： structural and functional implications

On Nov. 1st 2016, a research paper titled Structural basis for DNA recognition by STAT6 was published online on PNAS （Li et al., 2016）, which revealed for the first time the mech- anism of signal transducer and activator of transcription 6 （STAT6） recognition by DNA with N4 site. The authors are from the Institute of Biophysics, Chinese Academy of Sciences （CAS）.

Differences in IFNβ secretion upon Rab1 inactivation in cells exposed to distinct innate immune stimuli

Type I interferons(IFNs)are secretory cytokines with protective roles against viral infection.Most studies have focused on the signaling pathways that regulate the transcriptional activation of type I IFNs;however,little is known about the secretory mechanism of these cytokines,except for information obtained from a few studies reporting the secretion polarity of IFNβin epithelial cells.1,2,3,4 Here,we investigate the role of Rab1,a small GTPase of the Rab family,in IFNβsecretion.We show that Rab1 inactivation blocked the secretion of IFNβfrom human embryonic kidney 293T(HEK293T)cells transfected with IFNβ-inducing molecules(TRIF,MAVS,and TBK1)but not from cells stimulated with RNA ligands(Sendai virus)(SeV)or polyinosinic:polycytidylic acid(poly(I:C)).Despite the differential effects of Rab1 inactivation and regardless of the triggering stimuli,IFNβsecretion was inhibited by brefeldin A(BFA),a fungal metabolite that inhibits ER-to-Golgi transport.In addition,a proportion of endogenous 3×Flag-tagged IFNβcolocalized with the cis-Golgi marker GM130 within SeV-infected cells.Our results indicate that IFNβsecretion generally requires the conventional ER-Golgi pathway while showing differential responses to Rab1 inactivation in cells exposed to distinct innate immune stimuli.

Identification of a DNase activated in Xenopus egg extracts undergoing apoptosis

A cell-free apoptosis system was established by adding dATP and cytochrome c to Xenopus laevis egg extracts S-150. Accompanied by an incubation process, an apoptosis-specific DNase was activated in egg extracts which depended on Mg 2+ and inhibited by Zn 2+. Two nucleases existing in egg extracts were revealed by in-gel nuclease assay. Further experiments showed that 27 ku nuclease which was different from other Ca 2+/Mg 2+-dependent nucleases was a possible candidate involved in apoptosis.