Complex interactions between the immune system and tumor cells exist throughout the initiation and development of cancer. Although the immune system eliminates malignantly transformed cells in the early stage, surviving tumor cells evade host immune defense through various methods and even reprogram the anti-tumor immune response to a pro-tumor phenotype to obtain unlimited growth and metastasis. The high proliferation rate of tumor cells increases the demand for local nutrients and oxygen. Poorly organized vessels can barely satisfy this requirement, which results in an acidic, hypoxic, and glucose-deficient tumor microenvironment. As a result, lipids in the tumor microenvironment are activated and utilized as a primary source of energy and critical regulators in both tumor cells and related immune cells. However, the exact role of lipid metabolism reprogramming in tumor immune response remains unclear. A comprehensive understanding of lipid metabolism dysfunction in the tumor microenvironment and its dual effects on the immune response is critical for mapping the detailed landscape of tumor immunology and developing specific treatments for cancer patients. In this review, we have focused on the dysregulation of lipid metabolism in the tumor microenvironment and have discussed its contradictory roles in the tumor immune response. In addition, we have summarized the current therapeutic strategies targeting lipid metabolism in tumor immunotherapy. This review provides a comprehensive summary of lipid metabolism in the tumor immune response. Each of these has distinctive effects on tumor immunology [Discriminating between transformed cells and normal cells by recognizing unique antigens and combating malignant tumors with humoral and cell-mediated immune responses are critical functions of the immune system . Many int manner . CD4+ T munology . Tumor-imunology . MDSCs amunology , 10. Besmunology –13. Excemunology .Energy and metabolites are indespensible in cell survival. Malignant tumor cells require extensive energy and raw materials to support their uncontrolled proliferation and sustenance of daughter cells. Although angiogenesis in the TME is increased, it can barely meet the glucose and oxygen demands of the expansion and dissemination of cancer cells, consequently leading to a glucose-deficient and hypoxic microenvironment. This forces malignant tumor cells to adjust their metabolic profiles to sustain activated proliferation. In the 1920s, Otto Warburg et al. first proposed that tumor tissues metabolize approximately ten-fold more glucose to lactic acid than normal tissues in a given time regardless of the oxygen content in the TME, which is known as the Warburg effect . Since tIn this review, we have discussed the complex effects of lipid metabolism on the tumor-associated immune response from two perspectives. In addition, we have explored current strategies and molecular targets aimed at the lipid metabolism in the TME, while describing the limitations and future directions.Lipids are divided into three general categories based on their structure: (a) simple lipids containing long-chain FAs and their esterification products, such as triacylglycerol (TAG), (b) derived lipids like steroids, fat-soluble vitamins, and carotenoids, and (c) compound lipids containing various functional groups, such as phospholipids, glycolipids, and lipoproteins (LP).Exogenous FAs are mainly derived from TAGs, which are digested primarily in the upper jejunum by the catalytic activity of pancreatic lipase . These FIn cells, FAs primarily act as an energy source through fatty acid oxidation (FAO). Fatty acyl CoA synthetase (ACS) and carnitine palmitoyltransferase I CPT1) are critical enzymes in the generation of fatty acyl-CoA and fatty acylcarnitine . After s are critCholesterol is an indispensable component of lipid metabolism. Its absorption is accompanied by FAs through CD36 and Niemann–Pick C1 like 1, and then they are re-assembled into chylomicron . SimilarTo avoid the cytotoxicity of extensive accumulation of free intercellular cholesterol, acyl-coenzyme A-cholesterol acyltransferase (ACAT) transforms cholesterol into cholesterol ester (CE) and stores it in lipid droplets (LDs) . ACAT2 dLDs are important subcellular organelles that regulate cellular lipid metabolism by maintaining the balance of lipid storage and breakdown and protecting cells from potentially toxic lipids . LD contThese complex lipid components and underlying metabolic processes are abnormally regulated in the TME, and thus exert a significant impact on tumor immune responses.Nutrient limitation caused by an insufficient vascular exchange in the TME can result in intense competition between immune cells and rapidly proliferating cancer cells, which modifies anti-tumor immune defense . Immune + T cells are regarded as the most critical executors of adaptive anti-tumor immunity. Tumor-specific MHC-restricted CTLs can lyse neoplastic cells without influencing normal cells [+ T cells, facilitating their lipid metabolism and preserving effector functions [+ T cells improves their anti-tumor activity. Activation of PPAR-γ, a critical ligand-inducible nuclear receptor in lipid metabolism, facilitates differentiation of naïve T cells into effector T cells (Teffs) by upregulating FAO and inhibiting apoptosis of Teffs. In addition, it increases the abundance and activity of effector/memory CD8+ T cells in the drained lymph nodes and tumor sites [+ T cells remarkably impedes their proliferation and cytotoxicity, leading to functional exhaustion characterized by reduced interferon (IFN)-γ and high programmed cell death protein-1 (PD-1) expression [CD8al cells . As the unctions . Besidesor sites  , IFN-γ, and tumor necrosis factor (TNF)-α [+ Trm cells and reverse the apoptosis induced by cancer cell-caused lipid-deprivation [+ T cells strengthens their anti-tumor response, especially when combined with anti-PD-1 therapy. As a result, T cell-mediated anti-tumor immune response is at least partially enhanced by FA metabolism, which means that stimulating FA uptake and FAO in T cells could be a therapeutic method in malignant tumor treatment. Future clinical treatment of malignant tumors should combine therapy with the intervention of lipid metabolism in T cells.It has been reported that the application of anti-PD-1 antibody suppresses the FAO level of T cells and results in cell death due to their over-activation . These r T cells . In contpression . In addi (TNF)-α , 55  T cells, an effective option for relapsed or refractory malignant tumors . 4-1BB C+ T cells both in vitro and in vivo [+ T cell inhibition in chemo-immunotherapy [Cholesterol is another critical regulator of T cell-mediated anti-tumor immune response. Free cholesterol in T cell membranes is an important component of T cell receptors (TCRs) and T cell immunological synapses that directly regulate signaling pathways and effector functions  Fig. 2aa2a. Elev in vivo . Meanwhiotherapy , 61. Morotherapy . Thus, lotherapy   and apoptosis-related genes , that induce ROS-mediated macrophage apoptosis and reduce pro-tumor activity. High E-FABP-expressing macrophages have enhanced IFN-β production and recruit more tumoricidal immune cells, especially NK cells [In the TME, macrophages and DCs play roles in antigen presentation and display anti-tumor effects mainly through antibody-dependent cytotoxicity and soluble cytotoxicity factors. Obesity has been reported to accumulate pro-inflammatory macrophages with increased levels of reactive oxygen species (ROS) levels  Fig. 2bb2b. Howefed mice . In addifed mice . This giNK cells  , rather than the amount of lipid, is more critical for DCs to process antigens or release anti-tumor cytokines . DCs wit lesions . AlthougHighly proliferating tumor cells give rise to a glucose-deficient and lipid-enriched TME, which has been shown to facilitate their growth and dissemination and give rise to an immunosuppressive milieu. However, it needs to be mentioned that lipids can also function as indispensable fuels and metabolic components to facilitate the anti-tumor activity of immune cells. Current lipid metabolism-targeted therapies for malignant tumors are more devoted to simply impeding pan-lipid metabolism in the TME and achieve limited effects. As discussed above, specific activation of metabolic pathways in some immune cells could dramatically stimulate anti-tumor immune responses and facilitate anti-tumor therapy.Although the immune system is devoted to surveilling and eliminating transformed cells, some cunning tumor cells can disguise themselves, leading to immune evasion. To build a suitable environment for growth, tumor cells remodel surrounding stromal cells and reeducate immune cells from an anti-tumor phenotype to bystanders or even pro-tumor phenotypes . As mentRecent studies have reported that naïve T cells rely more on mitochondrial respiration and FAO to minimize the cell-damaging effects of toxic metabolites. However, to sustain the high proliferation rate and activities, Teffs are prone to utilize glycolysis and aerobic respiration to satisfy their need for ATP . This me+ T cells cannot catabolize accumulated intercellular very long chain FAs or store them in LDs, resulting in severe lipotoxicity and subsequent T cell exhaustion [+ T cells to sustain lipid homeostasis and compromises their anti-tumor ability. Accumulated FAs in Teffs cells enhance subsequent catabolism and FAO.Due to the lack of key enzymes, CD8haustion . Lipid-rhaustion  , and higher expression of cholesterol efflux enzymes (Abca and Abcg1). The addition of cholesterol-derived oxysterols inhibits IL-9 expression, induces apoptosis of Tc9 cells, and results in impaired anti-tumor activity [+ T cells  [Macrophages and MDSCs are both derived from the bone marrow and migrate to tumor tissues. As a result, these two cell subtypes exhibit similar characteristics of lipid metabolism. Although macrophages participate in various tumoricidal immune responses, tumor-associated macrophages (TAMs) are influenced by many factors in the TME, reprogrammed to the M2 phenotype, and exert pro-tumor effects. M1 is prone to utilize glycolysis, whereas M2 mainly depends on FAO. TAMs tend to uptake more lipids via CD36 from the TME to sustain their tumor-promoting ability . Moreovend Hadh) . These rSlc27a1/Fatp1, Slc27a6/Fatp6, Msr1, CD36, and ldlr) accounts for the metabolic reprogramming of tumor-infiltrating MDSCs [+ T cell-dependent tumor delay due to reduced ARG1 and iNOS [MDSCs in the TME exhibit potent and comprehensive immunosuppressive effects not only by promoting tumor cell growth but also by building a complicated network with other immune cells , 95. Uncng MDSCs . Unsaturng MDSCs . (α-) ling MDSCs  , LD formation and lipases (Lipe and Plin2), and lipid metabolism  in NK cells in high-fat diet mice, which displayed low cytotoxicity [Cd36, Fabp4, Fabp5, and Pparg, in mice with diffuse large B cell lymphoma, which was consistent with the marked increase in neutral lipid levels. In vivo experiments also confirmed that a simulation of physiological conditions with a combination of FAs at lower concentrations resulted in significant reductions of IFN-γ and GzmB. One interesting phenomenon is that surgical treatment of tumor-bearing mice upregulates the lipid content of splenic NK cells with high CD36 and low GzmB expression [NK cells are rapid and potent responders in the anti-tumor immune response by producing cytotoxic granules, such as perforin and GzmB or inflammatory cytokines, such as IFN-γ and TNF to kill tumor cells directly . Many fatoxicity  -hydroxycholesterol, indicating that G-protein-coupled receptors mediate the migration of these cells toward LXR ligands and subsequent activation of CXCR2 signaling [Ns have also been found to participate in tumor-associated immune responses. Contrary to their normal abilities, such as engulfing bacteria, inducing tissue damage, and activating the immune system in infections, tumor-associated Ns are thought to participate in the pro-tumor immune response . It is wtastasis  , ATGL (SML1075), and MAGL (SML0872) in macrophages attenuates their immunosuppressive capacity . Therapirophages . In otherophages . Another[+ Teffs .All these studies present solid evidence that interference in the FA metabolism in tumor-associated immune cells could recuse the immunosuppressive effects that tumor cells exert on the immune system. Once released from the metabolic block, tumor-associated immune cells switch from pro-tumor phenotype to anti-tumor phenotype and exhibit enforced tumor-eliminating ability alone or in combination with other therapies.Except for FAs, cholesterol is also under investigation for tumor immunotherapy. LXRs are the primary sensors of dietary cholesterol and transcriptionally regulate cholesterol homeostasis by enhancing excretion and decreasing the resorption of cholesterol . LXR agoIn addition to their roles as an energy source or physical regulator, lipids can be remolded to effective transporters due to their physicochemical and biological properties. To date, lipid-based vesicles, including liposomes, solid lipid-based systems, lipid particles, nonionic surfactant vesicles, and micelles, have been developed as drug carriers to enhance drug delivery efficiency and have achieved promising outcomes in preclinical and clinical studies . LiposomAs a result, although FA and cholesterol metabolism are important in tumor-associated immune cells, the corresponding treatments remain scarce. Given that lipid metabolism has distinct effects on different tumor-associated immune cells and even has adverse effects in the same cell type due to the types of malignant tumors and lipids, these complex phenomena and mechanisms require novel therapeutic strategies that target lipid metabolism in tumor-associated immune cells. More specifically, targeting specific lipid subtypes, enzymes, and immune cells in different malignant tumors might be a promising direction for the development of lipid-associated anti-tumor drugs.+ T cells [+ Trm cells [Lipid metabolism reprogramming is now regarded as a critical characteristic of malignant tumors. In hypoxic, acidic, and nutrition-deficient TMEs, cancer and immune cells tend to rely on lipids for storage of energy, cellular building blocks for membrane formation, and sources of signaling molecules. As a result, abnormally regulated lipids in the TME can dramatically influence tumorigenesis, subsequent development, and metastasis. Meanwhile, tumor-associated immune cells residing in the TME are also affected by these ubiquitous lipid biomolecules. Tumor-infiltrating immune cells in the TME can be classified into anti-tumor and pro-tumor phenotypes based on their roles in tumor-associated immune responses. Within the TME, lipids work as a double-edged sword, which can support both anti-tumor immune response and pro-tumor immune response. For example, promoting FAO neutralizes the suppressive effects of PD-1 antibody in CD8 T cells  and enharm cells . Modificrm cells . Howeverrm cells  and supprm cells . These cIn conclusion, our review summarizes numerous studies concerning lipid metabolism and relevant signaling pathways within the TME, which exert diverse and deep influences on many types of malignant tumors. However, the specific mechanisms involved remain to be elucidated. Further basic research and drug development are needed to elucidate the role of lipids in tumor immunology and to optimize existing cancer treatments.


Plants in nature or crops in the field interact with a multitude of beneficial or parasitic organisms, including bacteria, fungi and viruses. Viruses are highly specialized to infect a limited range of host plants, leading in extreme cases to the full invasion of the host and a diseased phenotype. Resistance to viruses can be mediated by various passive or active mechanisms, including the RNA-silencing machinery and the innate immune system.RNA-silencing mechanisms may inhibit viral replication, while viral components can elicit the innate immune system. Viruses that successfully enter the plant cell can elicit pattern-triggered immunity (PTI), albeit by yet unknown mechanisms. As a counter defense, viruses suppress PTI. Furthermore, viral Avirulence proteins (Avr) may be detected by intracellular immune receptors (Resistance proteins) to elicit effector-triggered immunity (ETI). ETI often culminates in a localized programmed cell death reaction, the hypersensitive response (HR), and is accompanied by a potent systemic defense response. In a dichotomous view, RNA silencing and innate immunity are seen as two separate mechanisms of resistance. Here, we review the intricate connections and similarities between these two regulatory systems, which are collectively required to ensure plant fitness and resilience.The detailed understanding of immune regulation at the transcriptional level provides novel opportunities for enhancing plant resistance to viruses by RNA-based technologies. However, extensive use of RNA technologies requires a thorough understanding of the molecular mechanisms of RNA gene regulation. We describe the main examples of host RNA-mediated regulation of virus resistance. Plants encounter numerous microorganisms and other higher living organisms throughout their life span. Some are beneficial, and even symbiotic. Others are harmful and can cause disease and death of the host if a prompt defense reaction or immunity is not triggered. The resilience of plants to environmental conditions and changes depends on their ability to promote beneficial interactions and activate defenses, when necessary, in a robust and energy-efficient manner. Based on this, the numerous mechanisms of molecular signal perception which are similar, yet distinct in downstream responses, during interactions with symbionts and pathogens, therefore require a coordinated machinery of control .) passive resistance in which the host blocks or lacks a component required by the virus to complete its life cycle, (iii) pattern-triggered immunity (PTI), (iv) effector-triggered immunity (ETI), and (v) the RNA-silencing system. Several RNA-based regulatory mechanisms of genes involved in resistance to microbes have been identified so far . Ac. Ac18]. In view of the above considerations, PTI was only recently included into virus–host interaction models, whereas ETI has long been recognized as an efficient plant defense mechanism against viruses. ETI is considered as a second layer of the plant innate immune system: effector proteins, delivered into host cells by adapted plant pathogens to suppress PTI, can become recognized by intracellular immune receptors in resistant host isolates. Effector recognition and immune receptor activation induce the rapid and efficient ETI response . As an eR genes that mediate dominant resistance against viruses have been identified  and the corresponding, recognized component in the pathogen (encoded by the Avr gene). Thus, ETI-mediated virus resistance generally is dominant and monogenic. Intracellular immune receptors can either recognize non-self as direct binders, or modified self as guardian NLRs [Over the past decade, several iewed in ). Viral iewed in . Both th channel , 28. By  channel , 30. Dow channel –34. RNLsMILDEW 8 , 35. Whin plants –38. ETI ian NLRs , 40. In ian NLRs . ETI agaian NLRs . By subsIn this section we describe the main examples of host RNA-mediated regulation of virus resistance factors playing a role in PTI and ETI.Arabidopsis miR393 was the first miRNA implicated in bacterial PTI [miR393 gene is transcriptionally activated by flg22. High miR393 levels repress accumulation of the transcripts of the auxin receptor TRANSPORT INHIBITOR RESPONSE 1 (TIR1) and related AUXIN-SIGNALING F-BOX (AFB) proteins. This leads to reduced ubiquitination-mediated turnover of the auxin/indole-3-acetic acid (Aux/IAA) co-repressors, and thus suppression of auxin-responsive gene expression and PTI defenses. Indeed, bacterial growth was reduced in miR393 overexpressing Arabidopsis lines [MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread post-transcriptional gene repression. rial PTI . The miRis lines .Similarly, TIR1-mediated Aux/IAA turnover and auxin signalling were found to be significantly affected in rice during infection by rice black-streaked dwarf virus (RBSDV) . HoweverArabidopsis, antiviral DCLs, i.e. DCL4 and DCL2, act redundantly in antiviral immunity: DCL4 and DCL2 are both sufficient for blocking the virus from spreading in plant tissues. However, viral suppressors of RNA-silencing (VSRs) reveal non-redundant functions and sub-specialization among DCL2/4 by specific inhibition of DCL4 activity [AGO1-regulating miR168 ensures homeostasis of AGO1 [However, given that RNAi-mediated antiviral immunity acts as the major virus resistance mechanism in plants and exhibits PTI features , the maiactivity , 48. In activity . In the  of AGO1  Fig. 2)Arabidopsdcl2-deficient plants, whereas the 22-nt miR482 level is unaffected except in dcl1-deficient lines [DCL2 transcript isoforms are among the miR6026 target mRNAs. In Arabidopsis, the 22-nt miRNAs trigger secondary sRNA production using their mRNA targets as template [dcl2-deficient plants, the 22-nt viral sRNAs were less abundant than in wild-type.The basis for the DCL1-dependent negative regulation of DCL4 levels remains to be established. However, a novel regulatory mechanism of the antiviral DCL2 was recently revealed Fig. a. DCL2 pnt lines  Fig. 3)dcl2-defitemplate . Similartemplate . The antDCL2 mRNAs, slTM2 mRNA regulation is apparently not dependent on miR6026 targeting [slTM2 mRNA and could trigger secondary siRNA in the absence of miR6026.The RNA-silencing pathway further controls plant immune capacities via the ETI system. E.g., in tomato, levels of the NLR-type immune receptor slTM2, involved in antiviral ETI, are controlled by the 22-nt miR6026. Conversely to argeting . The autNLR genes needs to be tightly controlled, as NLRs can also trigger autoimmunity in the absence of pathogen infection and inhibit plant growth; referred to as the “growth-defense trade-off” [NLR genes, thus preventing autoimmunity, and opening the "gates" to establish symbiosis [NLR immune receptor gene family via the production of phased secondary siRNAs [NLR alleles [NLR transcripts causes mRNA decay and RDR6-dependent production of phased secondary siRNAs in register with the cleavage site, which can regulate further transcripts upon incorporation into the RNA-induced silencing complex (RISC) [NLR-derived secondary siRNA was shown to act in trans and target mRNAs of additional defense-related proteins. Further, secondary siRNAs acting in cis fuel the cascade mechanism and boost the down-regulation of NLR genes. Viruses or bacteria can suppress sRNA-mediated NLR regulation by preventing miRNA incorporation into RISCs. As a result, a pathogen-induced expression of NLRs occurs and broad-spectrum defense mechanisms are activated [Expression of ade-off” –60. Therymbiosis . miRNAs y siRNAs –66. In ty siRNAs   . At leasctivated , 69.NLR gene expression is further emphasized by characterization of miR1885 in Brassica rapa [NLR gene. miR1885 expression is specifically induced upon TuMV infection, and regulates expression of highly sequence-related TNL genes [BraTIR1 [BraTIR1 is entailed by repression of the photosynthesis-related gene BraCP24, which subsequently accelerates floral transition [The requirement for dynamic regulation of ica rapa . Here, mNL genes . However[BraTIR1 . In the ansition . This soArabidopsis, BIR1 gene expression is activated in a partly salicylic acid-dependent manner, and is an important regulator of antiviral defenses [BIR1 mRNA were found to be produced during TRV infection and are involved in BIR1 homeostasis [BIR1 regulation in the TRV-Arabidopsis system extend observations from cucumber mosaic virus (CMV) and TuMV-infected Arabidopsis and CaMV-infected Brassicaeae.BAK1-INTERACTING RECEPTOR-LIKE KINASE 1 (BIR1) was identified as a negative regulator of plant immunity and cell death in a systematic reverse genetic screen, and shown to interact with the PRR co-receptor BAK1 . Howeverdefenses . Intereseostasis  , there were reactive oxygen species (ROS) scavenging factors such as Catalase 3 (Cat3), which could represent an element of parallelism with canonical PTI [In the case of canonical PTI and PAMP perception, PRRs initiate signalling pathways leading to ROS production. Recent investigations (highlighted in ) have reical PTI . ROS patical PTI . It therical PTI . In the Triticum aestivum thioredoxin-like gene (TaAAED1) encodes a negative regulator of ROS production in the chloroplast. Wheat yellow mosaic virus-derived dsRNAs are perceived and processed by DCL4 to produce 21-nt vsiRNAs. Upon incorporation into the RISC, the vsiRNAs suppress the expression of TaAAED1 in a dose-dependent  and sequence-specific manner. Therefore, chloroplast-generated ROS are known to induce retrograde signalling (from the chloroplast to the nucleus), leading to the modulation of the expression of pathogenesis-related genes that are involved in the defense response to viruses [In rice infected with RSV, miR528 is suppressed at both the transcriptional and post-transcriptional levels. Furthermore, RSV induces the accumulation of the non-catalytic AGO18. AGO18 sequesters miR528 away from AGO1 to block the formation of an effective RISC. These events induce the accumulation of the miR528 target, L-ascorbate oxidase, thereby regulating cellular redox status and priming ROS-mediated resistance against RSV infection . Based o viruses .All together, these studies demonstrate that plant viruses are causal agents of ROS induction in infected plants; however, the function of ROS in plant-virus interactions remains unclear, because despite the intuitive idea that ROS are plant defence tools, in many cases intracellular bursts of ROS have been associated with increased viral fitness.Recent discoveries emphasize consistent parallels and connections between canonical plant immunity mechanisms  and the RNA-silencing pathway in orchestrating resistance to viruses and microbes. Especially the PTI system has been previously well-studied for its role and molecular functions in plant–microbe interactions, which may help to decipher its role in virus resistance in future. A most relevant finding is that DCLs may be the main actors, able to perceive viral PAMPs (VAMPs), in analogy to PRRs, and trigger resistance. These findings are extendable to mammalian cells where RNA detection mechanisms are well-established . Recent


To the Editor—We read with interest the article by Wong et al describing the impact of infection control measures introduced during the COVID-19 pandemic on nosocomial transmission of influenza and respiratory syncytial virus (RSV). Although the authors experienced zero nosocomial transmission of enveloped respiratory viral infections (RVIs), nonenveloped RVIs, such as adenoviruses, may pose greater challenges in infection prevention. Indeed, given the relative hardiness of the nonenveloped adenoviruses, evidence of contamination with adenoviruses has been reported in healthcare environments as well as on the outer surface of medical masks used by healthcare workers (HCWs). Given the potential of adenoviruses to persist on inanimate surfaces and retain infectivity and the limited effectiveness of alcohol-based hand disinfection in eliminating this viral pathogen, adenovirus outbreaks can occur even in the setting of good hand hygiene compliance. Although adenoviruses generally cause self-limiting disease in immunocompetent hosts, infections in vulnerable populations, such as transplant recipients and neonates, can be potentially devastating. Therefore, we sought to determine whether infection prevention measures introduced during the COVID-19 pandemic could potentially influence transmission of adenoviral infections. Before the pandemic, patients were predominantly nursed in multi-bedded open-plan wards. During the pandemic, patients with respiratory symptoms were segregated in dedicated wards with reduced bed density, and HCWs used disposable gloves, gowns, eye protection, and N95 respirators until COVID-19 was excluded. The combined infection prevention bundle successfully prevented patient–HCW transmission of SARS-CoV-2 and reduced healthcare-associated influenza transmission, but the impact on transmission of adenoviral infections was not specifically assessed. Our institution provides neonatal services, as well as an active bone-marrow and solid-organ transplant program. During the pandemic, our institution continued to function and accept patients as usual. Over a 9-month study period during the COVID-19 pandemic from February to October 2020, all symptomatic inpatients were tested for SARS-CoV-2; adenovirus was also tested as 1 of the 16 common circulating RVIs on our institution’s multiplex PCR panel. Adenoviral infections were categorized as healthcare associated if the RVI was identified beyond the maximum incubation period (14 days) from admission. Comparisons of adenoviral infection rates  during the pandemic period were made with the corresponding period before the pandemic (January 2015–January 2020) using the incidence rate ratio (IRR) method. Our institution’s institutional review board approved this study with a waiver of informed consent.In Singapore, a Southeast Asian city-state, various infection prevention measures were implemented across all public hospitals soon after the first reported case of COVID-19 at the end of January 2020. At our institution, the largest acute- and tertiary-care hospital in Singapore, an integrated strategy was introduced from February 2020 to mitigate healthcare-associated transmission of SARS-CoV-2.This strategy focused on universal masking for all HCWs, adherence to basic infection prevention measures including hand hygiene, and improved segregation of patients with respiratory symptoms.P < .05). The sole case of potential healthcare-associated infection during the pandemic occurred in a returning COVID-19–positive traveler, who was isolated in a negative-pressure airborne-infection isolation room (AIIR) in our institution’s isolation ward for 21 days . He was retested for RVIs due to new-onset respiratory symptoms. Although respiratory specimens at admission were negative for adenovirus, repeated specimens at day 21 were positive. All HCWs used disposable gloves, gowns, eye protection, and N95 respirators, changed at each patient encounter. Hand hygiene compliance remained at 100% and compliance with personal protective equipment use was maintained at ≥90%. The patient was confined to the same AIIR throughout, and our isolation ward had a strict no-visitor policy, although one-way transfer of personal items into the AIIR was allowed to mitigate the psychological effects of prolonged isolation. Though a fomite source is possible, it could not be conclusively proven. The mortality rate among all patients with adenoviral infections was 5.53% (42 deaths among 759 cases) . From March to October 2020, there were zero cases of healthcare-associated adenoviral infections over a sustained 8-month period, an observation unprecedented in the preceding 5 years of surveillance .Before the pandemic, the incidence of healthcare-associated adenoviral infections was 0.40 cases per 10,000 patient days . After the implementation of the integrated infection prevention bundle in February 2020, the incidence of healthcare-associated adenoviral infections fell to 0.03 cases per 10,000 patient days , a statistically significant decrease . Only after the imposition of a national “lockdown” period from April 7 through June 1, 2020, was there a significant decrease in the incidence of community-acquired adenoviral infections among admissions: the pandemic period  versus the prepandemic period from June through October 2015–2019  . This finding contrasts with observations made for enveloped RVIs, in which the introduction of community-wide public health measures, such as social distancing and the universal use of face coverings, was associated with a significant decrease in influenza-incidence in the general population.This significant decrease in healthcare-associated transmission of adenoviral infections occurred despite increased driving pressure from admissions with community-acquired adenoviral infections in the initial pandemic phase Fig. a. DuringThe key finding of this study is that infection prevention precautions have been effective in reducing healthcare-associated transmission of adenoviral infections during the COVID-19 pandemic, despite the increased rate of community-acquired adenoviral infections in the corresponding period. However, the sole case of healthcare-associated transmission of adenoviral infection in a COVID-19–positive individual, despite full isolation precautions, demonstrates the significant infection prevention challenges posed by this hardy nonenveloped viral pathogen.


The WNT (Wingless/Integrated) signaling pathway is implicated in various stages of glioblastoma, which is an aggressive brain tumor for which therapeutic options are limited. WNT has been recognized as a hallmark of therapeutic challenge due to its context-dependent role and critical function in healthy tissue homeostasis. In this review, we deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance. We also provide an analysis of the WNT pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation.  WNT (Wingless/Integrated) signaling regulates key cellular events during the development of the central nervous system. Particularly, it regulates self-renewal, differentiation, migration and signaling of neural stem cells in the fetal ventricular zone, the postnatal subventricular zone and the hippocampus ,2. It haWNT signaling operates through a group of signal transduction pathways that pass signals from outside of the cell through cell surface receptors into the cytoplasm and then into the nucleus . Three W2+-dependent transcription factor that is down stream of this pathway, is highly expressed in GBM where it regulates invasion [The non-canonical planar cell polarity pathway is initiated by the binding of WNT proteins to FZD; the signal is then transduced to DVL, which subsequently activates the GTPases Rho and Rac. Rac then activates c-Jun N-terminal kinase-dependent transcription and Rho activates Yes-associated protein/Transcriptional Co-activator with PDZ-biding Motif-dependent transcription . Since tinvasion .Recent efforts have been spent on targeting the β-catenin/TCF4 complex, i.e., the catenin responsive transcription (CRT), with an expectation to inhibit its downstream signaling. The CRT complex interacts with several gene regulators through a conserved mechanism, thus raising questions about the specificity of this approach. One recent study reports the discovery of inhibitor iCRT-3, which targets the CRT complex . While tGlioblastoma multiforme (GBM) is recognized as the most aggressive primary malignant brain tumor with a median survival of only 12–18 months upon diagnosis . The staGBM tumors display a high degree of complexity in terms of heterogeneity and cellular stratification—this indicates genomic and molecular diversity profiles of tumors ,27,28. PDespite accounting for less than 1% of cells within any given GBM tumor, cancer stem cells known as glioma stem cells (GSCs) have been associated with the origin and recurrence of GBM . These tThe WNT pathway, along with Notch, Hedgehog, RAS/RAF/MAPK and PI3K/Akt/MTOR, constitute the main signaling transduction pathways that confer stemness in GBM . NSC devWNT5A, a non-canonical WNT molecule, increases neural differentiation and is expressed during NSC proliferation ,55. ShRNThe canonical WNT pathway and the non-canonical (β-catenin-independent) WNT pathways are involved in promoting components of the epithelial-to-mesenchymal transition (EMT), a complex process that describes a pattern of phenotypic changes observed during embryonic development and regeneration. The EMT program, which has a role in metastasis, is hardly ever fully executed in solid tumor cells. Executing the endpoint of the transition would presumably result in differentiation, which generally follows the EMT events that occur during embryogenesis, and therefore a reduction in adaptive potential ,40. EMT-2+ and planar cell polarity pathways [2+ pathway [As previously stated, the non-canonical signaling predominantly activates the WNT/Capathways ,68. Thespathways ,69. The pathways . The uti pathway . In a st pathway .The capacity for aberrant WNT signaling to initiate and maintain stem-like characteristics in a subset of GBM tumor cells implicates this system in the onset, progression and recurrence of GBM, although the extent to which it is involved in each stage is highly variable among patients and within tumors. Although tumorigenic cells from GBM tissue will be enriched with WNT-dependent GSCs, subpopulations of GSC that are not functionally reliant on WNT signaling have been observed in GBM samples. Nevertheless, WNT-dependent GSCs are a pharmacologically relevant subpopulation of cells, as they are more associated with an aggressive phenotype . WNT sigThe importance of viewing the WNT system as a highly conserved means of cellular communication cannot be understated. The implications of an aberrant communication system extend at the very least to non-tumor cells in the tumor microenvironment, which is a crucial factor in cancer progression. Exposing microglial cells, which are common in the tumor microenvironment, to GBM-conditioned medium results in an increase in WNT3A expression and cell viability . GBM-der+ GSCs [WNT signaling has a role in many of the most pernicious characteristics of GBM, including resistance to therapeutics. Similar to GBM onset and progression, the inevitable recurrence after stand-of-care treatment is thought to be primarily mediated by GSCs. Cancer Stem cells CSCs, as well as normal stem cells, naturally possess an increased capacity for DNA repair and predisposes them to preferentially survive therapeutics that target DNA . Another+ GSCs . The WNTThe methylation status of O6-methylguanine-DNA methyltransferase (MGMT) is perhaps the most important epigenetic marker in the context of GBM treatment options. One of the predominant TMZ-induced DNA adducts, O6-methylguanine, is repaired by this mismatch repair protein ,89. TOPFAutophagy can operate as a pro-survival mechanism that assists in the TMZ resistance of GBM cell lines . ATG9B, WNT pathway proteins have been considered an attractive and validated cancer target for its critical roles in tumorigenesis and cancer progression as described above. Over the past decade, much effort has been made to develop WNT pathway inhibitors, some of which have been tested in clinical studies ,96. HoweVantictumab is a human IgG2 monoclonal antibody that binds Frizzled (FZD) receptors 1, 2, 5, 7 and 8 in the WNT signaling pathway and thereby prevents the activation of canonical WNT signaling . This anIpafricept is a recombinant fusion protein comprising the FZD8 cysteine-rich domain (CRD) fused to the human Fc domain . This fuThe radioimmunoconjugate drug, 90Y-OTSA101, comprises a humanized monoclonal FZD10 antibody OTSA101 labelled with 90Y . RadioacPORCN is a membrane-bound O-acyltransferase (MBOAT) involved in the posttranslational modification of WNT ligands, which is an important step for WNT ligand secretion. Therefore, the development of small molecule inhibitors that block PORCN have gained increasing attention. WNT974 (LGK974) is a first-in-class PORCN inhibitor that was shown to be potent and efficacious in multiple tumor models . In an oETC-159 is an orally administered and potent porcupine inhibitor that has shown preclinical efficacy in combinations with phosphoinositide 3-kinase (PI-3K) inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors ,111. ETCFLT3-mutant AML [PRI-724 is a first-in-class inhibitor of the interaction between β-catenin and its coactivator CBP. PRI-724 potently disrupts β-catenin interaction with CBP, thereby inhibiting acute myeloid leukemia (AML) cells and synergizing with FLT3 inhibition in tant AML . It alsotant AML ,118. A rtant AML . In a phtant AML ,121. Thetant AML , may mittant AML , will fuIn addition to the canonical WNT pathway targets, non-canonical WNT pathways are emerging as a new cancer target. One of the β-catenin-independent WNT pathway targets is a co-receptor for WNT ligands, ROR1 . ROR1, aCirmtuzumab is a humanized monoclonal antibody that targets ROR1. Treatment with Cirmtuzumab and ibrutinib was shown to be highly effective in clearing leukemia cells in vivo . Moreoven = 7/15) of patients with mantle cell lymphoma (MCL) and 80% (n = 4/5) of patients with diffuse large B-cell lymphoma.VLS-101 is an antibody-drug conjugate (ADC) for suppressing ROR1-positive cancers. VLS-101 comprises UC-961 (Cirmtuzumab), which is a maleimidocaproyl-valine-citrulline-para-aminobenzoate (mc-vc-PAB) linker, and the anti-microtubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 dramatically decreased tumor burden in all Richter syndrome-colonized tissues and significantly prolonged survival in mouse models . RecentlAnother ADC for ROR1 is NBE-002; NBE-002 has recently entered clinical trials to evaluate its safety and efficacy in patients with triple negative breast cancer and other solid tumors. NBE-002 uses a novel anthracycline payload which has been shown to induce a long-lasting anti-tumor immunity in preclinical models of solid tumors. Interestingly, the first chimeric antigen receptor (CAR) T-cell therapeutic for ROR1 developed by BMS/Celgene has entered a clinical trial . AdditioFor successful WNT pathway drug development, strategies to reduce normal cell toxicity and selectively kill cancer cells are necessary. Additionally, overcoming the unique challenges of targeting the CNS will require novel improvements to drug modalities and precise clinical trial design. As genomics, epigenomics, proteomics and related fields evolve, new drug targets derived from the discovery of unique molecular characteristics of WNT signaling in GBM will supply researchers with more options for treating this devasting condition. Testing new targets to identify untapped opportunities for WNT pathway therapies may help mitigate the negative impacts on tissue homeostasis and regeneration. Previous WNT pathway inhibitors have largely relied on antibodies and small molecules. Given the recent clinical data on ROR1-ADC, new modalities, such as ADC, CAR-T, CAR-NK and proteolysis targeting chimera (PROTAC), provide promising approaches that will either provide better patient outcomes or at least produce valuable data that will ultimately guide researchers to improved treatment solutions.


Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (


In-person learning benefits children and communities  and 700 staff members attended elementary school in person. During this period, COVID-19 incidence  in Cobb County, Georgia, increased almost 300%, from 152 to 577 cases.Reverse transcription–polymerase chain reaction (RT-PCR) testingDuring the investigation period, nine clusters of COVID-19 cases were identified, involving 13 educators and 32 students at six of the eight investigated elementary schools . The medPublic health investigators identified several COVID-19 mitigation challenges. Although plastic dividers were placed on desks between students, students sat <3 ft apart. Physical distancing of >6 ft was not possible because of the high number of in-person students and classroom layouts. In seven clusters , transmission among educators and students might have occurred during small group instruction sessions in which educators worked in close proximity to students. The school district mandated in-classroom mask use except while eating, and both reported and observed compliance during site visits was high. However, information obtained during interviews indicated that specific instances involving lack of or inadequate mask use by students likely contributed to spread in five clusters . Students ate lunch in their classrooms, which might have facilitated spread. Opportunities to decrease nonessential in-person interactions among staff members during lesson planning and lunches were noted.These findings suggest that educators can play an important role in in-school transmission and that in-school transmission can occur when physical distancing and mask compliance are not optimal. Previous investigations in other U.S. school districts found that low transmission rates in schools can be maintained in the setting of high community incidence  of school-associated cases.Educators might play a central role in in-school transmission networks. Preventing SARS-CoV-2 infections through multifaceted school mitigation measures and COVID-19 vaccination of educators is a critical component of preventing in-school transmission.


This article provides supplementary tables and figures to the research article: Frequency, Impact and Predictors of Access Complications with Plug-Based Large-Bore Arteriotomy Closure - A patient level meta-analysis  These supplementary data provide detailed insight into the type and management of MANTA related access complications across various large-bore catheter-based interventions and also in a more homogenous population of patients undergoing TAVR using contemporary valves.•The patients in this dataset reflect the largest study population undergoing arteriotomy closure with the MANTA VCD by operators at various levels of experience. It can be valuable to further build on research regarding large-bore arteriotomy management which ultimately benefits patients undergoing large-caliber catheter-based interventions.•The data described should help understand the mechanisms of MANTA related access complications in patients undergoing various catheter-based interventions such as TAVR, which can be useful to optimize risk stratification, pre-procedural planning, vascular management and future iterations in (plug-based) closure technologies.1, the data are summarized for the subgroup of TAVR procedures in which the Sapien S3 / Ultra or Evolut Pro-valve was used . The frequency of major / minor access complications was 10% in the TAVR-group and none of the access complications in TAVR were associated with life-threatening bleeding or death. The main article demonstrated that the frequency of access complications in Roll-in cases (first or second time operator use of MANTA) was similar as compared to non-Roll-in cases (third time or more operator experience with MANTA). p = 0.015). Fig. 2. It was found that the valve-platform exhibiting the smallest device profile (Evolut R) was associated with access complications in 7.1% while other (larger profile) valve-platforms were associated with complication rates between 8.3 and 13.1%.This dataset provides relevant details on the frequency, impact and predictors of MANTA related access complications. Data are presented in Tables and Figures. Table 322), excessive femoral calcium or severe peripheral vascular disease, marked tortuosity of the iliofemoral tract and puncture site other than the common femoral artery. Of note, in SAFE MANTA poor left ventricular function and severe renal dysfunction were also exclusion criteria. In all patients, major and minor access complications were defined according to the updated Valve Academic Research Consortium 2 criteria p<0.05 was considered to indicate significance. Statistical analyses were performed using Statistical Package for the Social Sciences version 25 As mentioned above, this patient-level meta-analysis pooled data from two medical device approval studies and one post-approval registry to assess the frequency, impact and predictors of MANTA related access complications after large-bore catheter-based cardiovascular interventions. Procedures were performed by 71 operators at 28 sites between 2015 and 2019. Informed consent was obtained from all patients that were enrolled with the use of a prespecified patient information form. The herein reported data were derived from the SAFE-MANTA study (protocol identifier: PSD-109), CE-Mark study (protocol identifier: PSD-051) and MARVEL registry (protocol identifier: PSD-212), and study protocols were approved by the Ethics Committees of each participating center.Rutger-Jan Nuis: Conceptualization, Methodology, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft; David Wood: Conceptualization, Writing - Review & Editing; Herbert Kroon: Writing - Review & Editing; Maarten van Wiechen: Writing - Review & Editing; Darra Bigelow: Writing - Review & Editing; Chris Buller: Writing - Review & Editing; Joost Daemen: Writing - Review & Editing; Peter de Jaegere: Writing - Review & Editing; Zvonimir Krajcer: Writing - Review & Editing; John Webb: Writing - Review & Editing; Nicolas Van Mieghem: Conceptualization, Methodology, Writing - Review & Editing.Dr. Van Mieghem reports receiving grant support from Teleflex. The other authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article.


Subarachnoid hemorrhage (SAH) is a common complication of cerebral vasculardisease. Hydrogen has been reported to alleviate early brain injury (EBI)through oxidative stress injury, reactive oxygen species (ROS), andautophagy. Autophagy is a programmed cell death mechanism that plays a vitalrole in neuronal cell death after SAH. However, the precise role ofautophagy in hydrogen-mediated neuroprotection following SAH has not beenconfirmed.In the present study, the objective was to investigate the neuroprotectiveeffects and potential molecular mechanisms of hydrogen-rich saline inSAH-induced EBI by regulating neural autophagy in the C57BL/6 mice model.Mortality, neurological score, brain water content, ROS, malondialdehyde(MDA), and neuronal death were evaluated.The results show that hydrogen-rich saline treatment markedly increased thesurvival rate and neurological score, increased neuron survival,downregulated the autophagy protein expression of Beclin-1 and LC3, andendoplasmic reticulum (ER) stress. That indicates that hydrogen-richsaline-mediated inhibition of autophagy and ER stress ameliorate neuronaldeath after SAH. The neuroprotective capacity of hydrogen-rich saline ispartly dependent on the ROS/Nrf2/heme oxygenase-1 (HO-1) signalingpathway.The results of this study demonstrate that hydrogen-rich saline improvesneurological outcomes in mice and reduces neuronal death by protectingagainst neural autophagy and ER stress. An occurrence of 6.2-10 per 100,000 hasbeen recorded in Western countries--Under various physiological and pathological settings, autophagy is the primarycellular lysosomal degradation process for degrading and recycling intracellularproteins and organelles--,Recently, hydrogen gas or hydrogen-rich saline have been commonly recognized fortheir ability to defend against a variety of diseases, includingischemia-reperfusion damage, stroke, spontaneous subarachnoid hemorrhage (SAH), andneurodegenerative diseases, by controlling oxidative stress, inflammatory response,and neuronal apoptosisThe study protocol was approved by the Quzhou Affiliated Hospital of Wenzhou MedicalUniversity Research Ethics Committee (WYLL-2020-11). All animal experimentsperformed for this study complied with the National Institutes of Health guidelinesfor the handling of laboratory animals and were approved by the Ethics Committee ofthe Wenzhou Medical University. All experiments were conducted on healthy adult maleC57BL/6J mice .Twenty-four mice were set in each group. The mice were housed in animal carefacilities with a 12 h light/dark cycle and had free access to food and water.,The endovascular perforation method was used to construct the SAH model based ona protocol that was previously described,2 wasdissolved in normal saline for 2 hours under high pressure with 0.4 MPa, and thephysiological concentration was kept at 1.73 mL hydrogen per 100 mL saline. Hydrogen-rich saline was stored at 4°C in analuminum bag with no dead volume under atmospheric pressure. Hydrogen-richsaline was freshly prepared every week to ensure a constant concentration. Thecontent of hydrogen in saline was evaluated and detected by gas chromatography,as a previous study reportedAfter the SAH model was established successfully, animals were given dailyintraperitoneal injections of either hydrogen-rich (5 mL/kg)  orplain (control) saline for 72 hours. The preparation of hydrogen-rich wasaccording to the previous studyThe severity of early brain injury was evaluated by neurological function at 48hours after SAH using a previously described neurological grading systemMortality was documented 48 hours after SAH. SAH grade was given according to apreviously described grading systemgrade 0: no subarachnoid blood;grade 1: minimal subarachnoid blood;grade 2: moderate blood clot with appreciable arteries;grade 3: blood clot obliterating all arteries within the segment.The grade ranges from 0 to 18. Mice with SAH grading scores of less than 7, whichhad no prominent brain injury, were excluded from the study.-The severity of brain edema was evaluated by brain water content, which wasdetermined by the standard wet-dry method as in previous studiesEvans blue extravasation was performed as previously describedThe non-fluorescent diacetylated 2′,7′-dichlorofluorescein (DCF-DA) probe, which becomes highly fluorescentupon oxidation, was used to evaluate intracellular ROS production according tothe manufacturer’s instructionsMalondialdehyde (MDA) levels were detected by lipid peroxidation assay kit , according to themanufacturer’s instructionsA terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay wasconducted to assess neuronal death in the brain cortex according to the previousstudyWestern blot analysis was performed as indicated previouslyThe membranes were then incubated with the following primary antibodies overnightat 4°C:rabbit anti-β-actin ;rabbit CHOP ;rabbit anti-cleaved-caspase-12 ;rabbit anti-GRP78 ;rabbit anti-Beclin-1 ;rabbit anti-Nrf2 ;rabbit anti-HO-1 ;rabbit anti-LC-3B .After washing the membranes with TBST three times, HRP-conjugated goatanti-rabbit IgG or goat anti-mouse IgG secondary antibodies  wereapplied, and the membranes were incubated in the secondary antibodies at roomtemperature for 1.5 h. The protein bands were detected using a Bio-Rad imagingsystem  and quantified with ImageJ.All experiments were repeated more than three times, and the data are expressedas the means and scanning electron microscope (SEM). Statistical Package for theSocial Sciences 14.0  and GraphPad Prism 6 were used for the statisticalanalyses. Student’s t-test was used when two groups were compared, and one-wayanalysis of variance (ANOVA) followed by Bonferroni’s post-hoc test was used forthe comparison of two independent variables. For non-normally distributed dataand/or non-homogeneous variance, Kruskal-Wallis test was used followed by Dunn’spost-hoc test. For all the statistical analyses, data were consideredsignificant at p < 0.05.To clarify the neuroprotection of hydrogen-rich saline, the endovascularperforation method was used to construct the SAH model in vivo. The effect ofhydrogen-rich saline treatment on the neurological damage parameters wasevaluated, including mortality rates and SAH grades. As shown in To clarify the neuroprotection of hydrogen-rich saline after SAH, modifiedneurological severity scores were used to evaluate neurological deficits, andbrain water content by the wet-dry and Evans blue extravasation method at 48 hafter SAH to evaluate brain damage.The results showed that SAH increased the brain water content significantlyp<0.05, , and BBBTo clarify whether autophagy plays an important role in SAH and hydrogen-richsaline can regulate autophagy, the expression levels of autophagy-relatedprotein by western blotting were also detected . The resTo investigate the effect of hydrogen-rich saline on ER stress after SAH, the ERstress core markers were GRP78, CHOP, and caspase-12. We detected the expressionof ER stress-associated proteins by Western blot . The resRapamycin was a specific activator for autophagyAdditionally, the TUNEL assay also showed that rapamycin could also significantlyincrease the neuron apoptosis in the injured hippocampus, compared with the SAH+ hydrogen-rich saline group .The autAutophagy through ROS/Nrf2/HO-1 signaling pathway after hydrogen-rich treatmentwas explored. It was detected the ROS levels by DCF-DA probe, and the degree ofmembrane lipid peroxidation was evaluated by MDA. The results showed that ROSand MDA levels were significantly increased after SAH, while they decreasedafter hydrogen-rich treatment .The proHere, the therapeutic potential of hydrogen-rich saline for alleviating early braininjury in a mouse in the SAH model was evaluated. The present study demonstratesthat hydrogen-rich saline was a neuroprotective agent that can attenuate EBIfollowing SAH. It was found that hydrogen-rich saline can improve neurologicaldysfunction after SAH; hydrogen-rich saline can alleviate brain damage in a mouseSAH model; hydrogen-rich saline can relieve ER stress after SAH; hydrogen-richsaline can prevent autophagy after ER stress and alleviate neuronal death; and theanti-ER stress and anti-autophagy roles of hydrogen-rich saline may be related tothe ROS/Nrf2/HO-1 pathway .-2 is safe for patients andanimalsHydrogen gas or hydrogen-rich saline can easily penetrate the BBB by gaseousdiffusion, which is widely accepted to exert protective effects in many CNSdiseases, including ischemia stroke, intracranial hemorrhage, TBI, andneurodegenerative diseases2 can markedlyimprove the survival rate and cognitive dysfunction, decrease inflammatory responseand oxidative stress, and increase activities of antioxidant enzymes in serum andhippocampus in a mouse model of sepsis. In the ICH model, it was also found thathydrogen plays a neuroprotective effect against EBI after ICH, alleviating brainedema and neurologic deficits through regulating oxidative stress,neuroinflammation, and apoptosisLiu2 inhalationadministration can alleviate brain damage and improve early neurological outcomes,the mechanisms also through antioxidant, antiapoptotic, and anti-inflammatoryresponses via MAPK/HO-1/PGC-1a pathwayIn the hypoxic-ischemic brain injury neonatal rats’ model, HZhuang reported that hydrogen can alleviate brain injury via decreasing oxidativestress injury and brain edema in experimental SAH rabbits-Autophagy regulates the turnover of cellular constituents to ensure the removal andrecycling of toxins and was very important in cell homeostasis. The role ofautophagy has been confirmed in many CNS diseases, including acute brain injury2 can alleviatevital organ damage, inhibited lipopolysaccharide (LPS) and ATP caused by NLRP3inflammasome pathway activation, and improve mitochondrial dysfunction viaregulating autophagy. Recent studies also indicated that hydrogen-rich saline orhydrogen gas can decrease cell death via regulating autophagy-Therefore, autophagy plays a very important role in neuronal injury and repair afterSAH. In the myocardial ischemia/reperfusion (I/R) in vitro and in vivo model,hydrogen-rich saline can improve the inflammatory response and apoptosis viaPINK1/Parkin mediated autophagyThe molecular mechanism of autophagy and ER stress is complicated, and the exactmechanisms of the neuroprotective effects of hydrogen-rich saline therapy remainunclear. Nrf2 was a very important transcriptional regulation factor that canregulate the expression of more than 250 genes and is marked by its binding site,antioxidant response element, most genes can regulate oxidative stress and cellapoptosis, necroptosis, autophagy, and ferroptosis2) gas inhalation can improve the survival rates, reduce the lungedema and the lung injury score, and ameliorate the injuries caused by oxidativestress and inflammation in the septic mice model. Knockout Nrf2 would reverse orweaken the protection of H2 gas on lung damage, and also depends on theHO-1 and high-mobility group box 1 (HMGB1).Yu2 attenuates endothelial injury and inflammation, increased the HO-1expression and in-vitro and in-vivo activity, and knockout Nrf2 or HO-1 inhibitionreversed the protection of H2, the process depending on the activity ofNrf2/HO-1 signaling pathway. Yu2 can improve survival in septic mice, and decrease escape latencyand platform crossing times, the brain water content, and extravascular dextran,while reversed in the Nrf2 knockout mice. WangAdditionally, ChenThe present study provided evidence that autophagy, which is mediated by theROS/Nrf2/HO-1, is an important cellular regulatory mechanism and contributes to EBIafter SAH. In this study, for the first time, it was reported that hydrogen-richsaline induced regulation of autophagy and ER stress, and also a new idea wasprovided to explore the biological effects and underlying mechanisms of thehydrogen-rich saline.


Age is the single major risk factor for human cancer, but naturally occurring cancers are rarely studied in aging models. Like humans, mice spontaneously develop cancer with age, and standard laboratory strains are predisposed for B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells acquire somatic mutations in tumor suppressors and oncogenes  and undergo monoclonal expansions, with some clones representing 86% of splenic B cells. Clonal B cells had hypermethylated promoters and globally silenced expression, suggesting a role of DNA methylation in clonal selection of premalignant B cells. B-cell size, spleen weight, and a novel population of B cells, which we named Myc+ cells, emerged as convenient markers of malignancy. High-throughput analyses of clonal B cells and the use of genetic mouse models revealed that c-Myc drives B-cell size increase and clonal expansion with age. Phoshoproteome and co-culture experiments revealed that c-Myc is activated by signals from the aging microenvironment. Moreover, single-cell RNA-seq suggested that clonal B cells originate from age-associated B cells, further underlying the importance of aging environment in cancer transformation. Longitudinal analyses demonstrated a negative impact of premalignant B cells on mouse lifespan and linked it to age-related myeloid bias. Together, our study revealed cell-autonomous changes that cooperate with the aging microenvironment to give rise to preneoplastic B cells. This stidy established a novel model to study how aging predisposes cells to cancer transformation.


Antioxidant ingredients are known to contribute to the beneficial effects of natural products in health promotion as well as disease prevention by reducing oxidative stress, caused by reactive oxygen or nitrogen species, in biological systems . VariousRibes dicanthum exerted a neuroprotective action through BDNF/TrkB pathway in glutamate-stimulated HT22 cells, and prevented against scopolamine-induced amnesia [Enteromorpha prolifera, a green algae [Ishie okamurae, belonging to a brown algae, expressed a neuroprotective action by regulating the MAPKs/Nrf-2/HO-1 pathway [Euonymus alatus alleviated the scopolamine-induced memory deficit through BDNF-mediated activation of Nrf2 signaling [Platycodon grandiflorum root protected against Aβ-induced cognitive dysfunction and pathology in female models of Alzheimer’s disease [Prunus avium L.) containing cyanidine-3-O-rutinoside as a major anthocyanin, where the antioxidant capacity was positively correlated with total anthocyanin index, demonstrated an antioxidant/neuroprotective action through downregulation of oxidative stress and upregulation of BDNF in neuronlike SH-Sy5Y cells [First, this issue provides a new insight into the biological action of herbal extracts containing antioxidants. The polyphenol-rich extract of  amnesia . A similen algae . Additio pathway . Likewisignaling . Further disease . Besides5Y cells . Taken tRibes dicanthum exerted anti-inflammatory action through the upregulation of Nrf2/HO-1 and the downregulation of NF-kB signaling in LPS-stimulated RAW 264.7 cells [Azolla pinnate extract containing polyphenols, demonstrated anti-inflammatory and antiapoptotic action, contributing to the curative action against lead-induced hepatotoxicity [Scutellaria baicalensis extract and Magnolia officinalis extract, designed for pharmacological advantage, exerted greater anti-inflammatory action than each single extract via the Nrf2/HO-1 and NF-kB signaling pathway [Lycium barbarum leaf containing polyphenols, which strengthened a tight junction integrity and reduced NO production, suppressed ER stress and LPS-induced inflammation via the IRE1 alpha and XBP1 pathway in Caco-2 cells as well as in inflamed intestine of mice [Panax Ginseng) extract containing Rb1, Rg3 and Rk1 was observed to express antioxidant and anti-inflammatory action in an IRE1 alpha-dependent and XBP1-independent manner in the ER stress pathway [Cephalaria gigantea and Cephalaria uralensis, containing 5-O-caffeoylquinic acid, isoorinetin and swertiajaponin, expressed potential action as an antiacne agent by showing anti-inflammatory action and antibacterial activity against S aureus, S epidermidis and P aces [Yak-Kong), fermented by lactic acid bacteria, and expressed an anti-aging effect by markedly reversing sUV-induced matrix metalloproteinase-1 in human keratinocytes [Vitis vinifera L. leaf were suggested to protect against various oxidative stress-induced disorders [Abeliophyllum distichum extract was proposed to be an effective antioxidant as a functional supplement [Separately, the extract of .7 cells . Similartoxicity . In addi pathway . It is n of mice . Similar pathway . Besidesd P aces , and theinocytes . Thus, aisorders . In an iisorders . In addipplement .2O2-induced oxidative damage in MDCK cells, suggesting a potential application of the modified antioxidants in functional supplements [Next, the formulation of antioxidants, such as antioxidant conjugates or fatty acyl hybrid of antioxidants, may contribute to the increase in the bioactivity or bioavailability in vivo system. Gallic acid conjugates were evaluated for the increase in antioxidant action; gallic acid–laminarin conjugate, more potent as than laminarin or carboxylated laminarin, protected against Hplements . In a seplements .Nigella sativa, is known to have various bioactivities. In particular, the potential role of thymoquinone or Nigella sativa extract as an adjuvant in periodontal therapy was proposed [Lastly, the review on specified antioxidants may expand the knowledge about the practical applications of antioxidants. Thymoquinone, a chief active constituent of proposed . Nonetheproposed . It is oHere, the pharmacological action of antioxidants from natural sources or extracts containing antioxidant constituents was reviewed, with the mode of action being highlighted. However, the toxicological aspects of the antioxidant compounds and the extracts containing antioxidants need further studies for their practical application. Additionally, the stability of the antioxidants or the extract preparation must be guaranteed for their convenient use and economic benefit.


CACNA1C is strongly associated with multiple neuropsychiatric dysfunctions. In a recent series of studies, we applied a genomically informed approach and contributed extensively to the behavioral characterization of a genetic rat model haploinsufficient for the cross-disorder risk gene Cacna1c. Because deficits in processing social signals are associated with reduced social functioning as commonly seen in neuropsychiatric disorders, we focused on socio-affective communication through 22-kHz and 50-kHz ultrasonic vocalizations (USV). Specifically, we applied a reciprocal approach for studying socio-affective communication in sender and receiver by including rough-and-tumble play and playback of 22-kHz and 50-kHz USV. Here, we review the findings obtained in this recent series of studies and link them to the key features of 50-kHz USV emission during rough-and-tumble play and social approach behavior evoked by playback of 22-kHz and 50-kHz USV. We conclude that Cacna1c haploinsufficiency in rats leads to robust deficits in socio-affective communication through 22-kHz and 50-kHz USV and associated alterations in social behavior, such as rough-and-tumble play behavior. The top-ranked cross-disorder risk gene  CACNA1C is strongly associated with multiple neuropsychiatric dysfunctions. This includes affective disorders, namely depression [CACNA1C encodes the pore-forming α1C subunit of the voltage-gated L-type calcium channel (LTCC) Cav1.2. Characterized by a broad tissue expression profile with high expression levels in the central nervous system, Cav1.2 accounts for the majority of all LTCCs in the brain. It is strongly involved in the regulation of depolarization-dependent calcium influx into the cell, triggering intracellular signaling cascades including major pathways involved in neuronal plasticity processes [The top-ranked cross-disorder risk gene pression , as wellpression  and schipression . CACNA1Crocesses .CACNA1C are amongst the best replicated and most robust genetic findings from genome-wide association studies (GWAS) in psychiatry [CACNA1C SNPs associated with neuropsychiatric dysfunctions are not fully understood. Often, such SNPs are intronic and it is widely believed that they exert their effects through altering CACNA1C gene expression. Albeit not consistently, a substantial number of studies reported such SNPs to result in decreased expression levels [CACNA1C dosage and how reductions in CACNA1C gene expression alter behavioral phenotypes with relevance to neuropsychiatric dysfunctions is therefore needed.Single-nucleotide polymorphisms (SNPs) within ychiatry . Up to nn levels ,10,11,12n levels  and schiCacna1c [CACNA1C SNPs and is commonly seen in neuropsychiatric disorders in humans [CACNA1C SNPs were associated with reduced socio-affective information processing capacities. This was reflected in altered facial emotion recognition and social outgroup processing [CACNA1C SNP risk carriers [In a recent series of studies, we applied a genomically informed approach and contributed extensively to the behavioral characterization of a genetic rat model haploinsufficient for the cross-disorder risk gene Cacna1c ,17,18,19Cacna1c ,21,22,23Cacna1c  and femaCacna1c . In a sin humans ,17,18,19ocessing ,25,26. Vcarriers . Wild rats live in large social colonies with overlapping generations, often in underground burrow systems with shared tunnels and chambers. Such colonies are typically structured into subgroups, with prominent near-linear dominance hierarchies, particularly in males. In line with the complexity of their social environment, the social life of rats is characterized by a broad variety of social behaviors . In adult rats, the social repertoire includes reproductive behaviors, with both sexes being highly promiscuous. In fact, there is little evidence for mate choice and stable pair bonds. Strong bonds, however, are formed between mother and their infants. Maternal caregiving behavior ranges from nursing to licking and grooming. Another important feature of the social repertoire displayed by adult rats are agonistic behaviors, usually directed against intruders from outside the colony. Males were found to be less socially tolerant than females, with males but not females patrolling and defending territory boarders. In females, aggressive behavior was found to be low except during lactation. Other prominent aspects of the social life of rats are huddling and social grooming . In juvenile rats, a very prominent component of their social repertoire is play fighting, also called rough-and-tumble play . As the While it is notoriously difficult to observe rats in the wild due to the fact that they are nocturnal and have a sub-terrestrial lifestyle, available evidence suggests that laboratory rats display the full behavioral repertoire of wild rats, albeit wild rats were reported to be more aggressive and less playful . MoreoveThe rich social repertoire of rats includes the emission of vocal signals, so called ultrasonic vocalizations (USV) ,41. As oJuvenile rats emit 50-kHz USV in anticipation and during rough-and-tumble play . AnticipDuring rough-and-tumble play, the highest numbers of 50-kHz USV occur during actual play phases as opposed to non-playful social interactions . MoreoveSynchronized recordings with high temporal resolution further allowed insights into how 50-kHz USV are integrated into the rough-and-tumble play repertoire . The synIn line with the more prominent rough-and-tumble play behavior in males , emissioThe high prevalence of 50-kHz USV in anticipation and during rough-and-tumble play and their fine temporal integration into the rough-and-tumble play repertoire suggest that 50-kHz USV promote and maintain playful social interactions by functioning as play signals and/or social contact calls. This view is supported by deafening experiments and devocalization studies. For instance, pinning was found to be diminished in deafened rats, while play initiation through dorsal contacts remained unchanged . MoreoveIn dyads with one devocalized and one intact rat, the effects were milder but alterations in specific components of the rough-and-tumble play repertoire, such as defensive responses, were repeatedly observed ,62. MoreThere is compelling evidence indicating that the emission of 50-kHz USV during rough-and-tumble play is under genetic control. A prominent role of genetic factors is highlighted by three independent selective breeding studies targeting distinct behavioral domains. In a first selective breeding study, rats were selected depending on their tendencies to emit low versus high rates of 50-kHz USV in response to rough-and-tumble play mimicked by a human experimenter through tickling ,65. WithA second selective breeding study assessed 50-kHz USV emission during rough-and-tumble play in rats selected for low versus high levels of separation-induced 40-kHz USV as pups . It was In fact, in a third selective breeding study, rats were selected for low versus high anxiety-related behavior on the elevated plus maze and through this means it was confirmed that 50-kHz USV emission is strongly affected by trait anxiety . Rats seBesides genetic factors, the environment has a strong impact on the emission of 50-kHz USV. For instance, play deprivation for about three weeks through individual housing was found to enhance 50-kHz USV emission during rough-and-tumble play, while aversive stimuli, such as bright white light reduced 50-kHz USV emission . Other sVarious psychoactive agents affect the emission of 50-kHz USV during rough-and-tumble play. This includes morphine , amphetaA prominent role in modulating the emission of 50-kHz USV is played by the endogenous vasopressin system. While the intracerebroventricular administration of synthetic vasopressin had no effect, blocking the central vasopressin system through injections of a vasopressin 1a receptor antagonist into the brain led to a reduction in rough-and-tumble play and 50-kHz USV . Other sThere is also a significant number of studies assessing the long-term effects of various early life stressors on 50-kHz USV emission during rough-and-tumble play. Such studies focused, for instance, on the effects of prenatal exposure to ethanol ,81 and vTo study the socio-affective communicative functions of the different types of USV in rats, we developed a playback paradigm . ThroughImportantly, strong social approach behavior is evoked exclusively in response to the playback of natural 50-kHz USV. Firstly, natural 22-kHz USV lead to behavioral inhibition in line with an alarming function , irrespeSocial approach behavior evoked by playback of 50-kHz USV is most prominent in juvenile rats and weaker in adult rats . In adulLong-term social isolation for four weeks, however, exerted an inhibitory effect and blocked social approach behavior in response to 50-kHz USV playback in juvenile but not adult rats, suggesting that social experiences during the rough-and-tumble play period are important for rats to develop their social behavioral repertoire . CorroboAnother important feature of the social approach response is the habituation phenomenon. Strong social approach behavior is typically only seen during the first exposure to playback of 50-kHz USV . Even afAt the neurobiological level, the social approach response is associated with increased neuronal activity in the nucleus accumbens, a key brain area involved in reward processing . AnotherThe social approach response evoked by playback of 50-kHz USV can be modulated pharmacologically. In line with the observation that increased dopamine release is associated with particularly strong social approach behavior , amphetaShank3 deficient rat model for autism [SHANK3 mutations lead to Phelan-McDermid syndrome and are one of the most penetrant causes of autism [Shank3 deficient rats displayed deficits and engaged less in social sniffing and allogrooming behaviors. While social approach behavior in response to 50-kHz USV playback was evident in male but not female Shank3 deficient rats, male Shank3 deficient rats did not display search behavior after the playback presentation ended [Ube3a3 deficient rats [Ube3a3 deficient rats, the response to 50-kHz USV playback was clearly reduced, as reflected in a less prominent increase in locomotor activity, lower levels of social approach behavior during 50-kHz USV playback, and lack of search behavior after the playback presentation ended. In humans, UBE3A deletions cause Angelman syndrome characterized by severe developmental delay and intellectual disability, most notably lack of language acquisition [Finally, we applied the 50-kHz USV playback paradigm repeatedly in rat models for neuropsychiatric dysfunctions, most notably rat models for neurodevelopmental disorders, such as autism. In a first study, we studied social behavior and ultrasonic communication in a r autism . In humaf autism . During on ended . More prent rats . In Ube3uisition . Finallyuisition . SpecifiCacna1c. Because deficits in processing social signals are associated with reduced social functioning as commonly seen in neuropsychiatric disorders, we focused on socio-affective communication through 22-kHz and 50-kHz USV. In our studies, we compared constitutive heterozygous +/−Cacna1c rats to wildtype +/+Cacna1c littermate controls [As part of a translational effort to better understand major genetic risk factors for neuropsychiatric dysfunctions , we applcontrols ,17,18,19In our first study, we focused on juvenile male rats . We appl+/−Cacna1c rats and +/+Cacna1c littermate controls. Rough-and-tumble play was not affected by Cacna1c haploinsufficiency in juvenile male rats. Specifically, the total time spent playing did not differ between genotypes. Moreover, the occurrence of specific components of the rough-and-tumble play repertoire, such as pinning, wrestling, and chasing, was not affected. Firstly, we compared rough-and-tumble play and concomitant 50-kHz USV emission between Cacna1c haploinsufficiency in juvenile male rats  expression in the prefrontal cortex [At the neurobiological level, we obtained evidence for function  by showi neurons . Howeverrichment . We alsol cortex . Likewisere seen . In anotte gyrus . Cacna1cl cortex .+/−Cacna1c rats, neurobiological mechanisms implicated in learning and memory were studied by focusing on the dorsal hippocampus [Cacna1c haploinsufficiency and that the induction of long-term potentiation through theta-burst pairing is impaired in +/−Cacna1c rats. It was further found that spine calcium signaling is impaired during postsynaptic spike bursts in CA1 pyramidal neurons form +/−Cacna1c rats. Moreover, phase-amplitude coupling during exploration of a novel environment was reduced in +/−Cacna1c rats in the absence of behavioral differences in the novelty response. Genotypes did not differ in a familiar environment. In the most recent study on impaired latent inhibition during contextual fear conditioning in pocampus . Specifi+/−Cacna1c rats and +/+Cacna1c littermate controls [+/−Cacna1c rats, without genotype effects on total ERK and CREB levels. It was thus suggested that impaired ERK- and CREB-mediated synapse-to-nucleus signaling in +/−Cacna1c rats might contribute to hippocampal dysfunctions, eventually translating into impairments in learning and memory. This view is supported by the observation that activation of ERK signaling through the BDNF mimetic TrkB/TrkC neurotrophin receptor co-activator LM22B-10 restored pERK and pCREB levels and led to a reversal of the long-term potentiation deficit in +/−Cacna1c rats. Most importantly, intra-hippocampal administration of LM22B-10 treatment also reversed the impairment in latent inhibition during contextual fear conditioning in +/−Cacna1c rats. A similar effect was seen following an intra-peritoneal injection of LM22B-10. Together, this suggests that impaired ERK signaling-mediated excitation-transcription coupling underlies the learning and memory deficits seen in +/−Cacna1c rats.Similar to previous studies ,111, hipcontrols . HoweverCacna1c haploinsufficiency in rats leads to robust deficits in socio-affective communication through 22-kHz and 50-kHz USV and associated alterations in social behavior, such as rough-and-tumble play behavior (Shank3 deficient rat model for autism. However, no neurobiological correlate has been identified yet. Comparatively mild effects of Cacna1c haploinsufficiency on learning and memory were reported. Such deficits were linked to impaired ERK signaling.We conclude that behavior . These dCacna1c haploinsufficiency on sender and receiver affect other social behaviors, such as cooperative actions [+/−Cacna1c rats occurs specifically in a social context or whether this is also seen in response to non-social stimuli. Because CACNA1C SNPs are strongly associated with affective disorders, namely depression [+/−Cacna1c rats. Amphetamine is known to be a very potent elicitor of 50-kHz USV in rats [+/−Cacna1c rats, it would be interesting to test whether impaired ERK signaling is associated with the deficits in socio-affective communication through 22-kHz and 50-kHz USV and whether associated alterations in social behavior can be similarly rescued by a BDNF mimetic, such as LM22B-10.Because socio-affective communication through 22-kHz and 50-kHz USV is involved in the regulation of many social behaviors, it would be interesting to see whether the effects of  actions , mutual  actions , general actions , and emp actions . For ins actions . Related in rats . Finally


Profound restrictions were placed on previously free-living older adults due to mandatory stay-at-home orders for Covid-19. Recognizing the potential for worsening health and heightened risk of Covid-19 complications with older age and obesity, we conducted a survey to assess the impact of stay-at-home requirements on diet, health/social behaviors, and food security in 58 older adults  who had participated in past obesity-reduction trials. A 71-item questionnaire was administered by phone and included demographics, health, lifestyle and dietary habits, food attitudes, and food security questions. Results showed indicators of heightened health risk, including health care appointments either delayed/cancelled (69%) and self-reported weight gain (62%). Of those with weight gain, 22% reported a gain of >10 pounds (33% gained 5-10 pounds and 7% < 5 pounds). Increased food intake was reported by 67% and 45% felt their eating patterns were less healthy due to increased snacking (71%) and consumption of sweets (41%). Food access and isolation were also an issue, as 51% were concerned about leaving the house for food and 81% reported eating alone. While some positive behaviors were reported , the majority of findings indicated increased risk of obesity and its complications. The findings emphasize the need for effective lifestyle interventions that can be delivered remotely to high-risk older adults; this would benefit those presently self-restricted for Covid-19 concerns as well as other isolated older adults who need better access to individualized interventions.