The ER-Golgi transport of influenza virus through NS1-Sec13 association during virus replication.

IMPORTANCE: Influenza A virus is a respiratory virus that can cause complications such as acute bronchitis and secondary bacterial pneumonia. Drug therapies and vaccines are available against influenza, albeit limited by drug resistance and the non-universal vaccine administration. Hence there is a need for host-targeted therapies against influenza to provide an effective alternative therapeutic target. Sec13 was identified as a novel host interactor of influenza. Endoplasmic reticulum-to-Golgi transport is an important pathway of influenza virus replication and viral export. Specifically, Sec13 has a functional role in influenza replication and virulence.

Macrophage IL-1ß contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment.

Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1ß production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1ß enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.

Annexin-A1 deficiency attenuates stress-induced tumor growth via fatty acid metabolism in mice: an Integrated multiple omics analysis on the stress- microbiome-metabolite-epigenetic-oncology (SMMEO) axis.

Background: High emotional or psychophysical stress levels have been correlated with an increased risk and progression of various diseases. How stress impacts the gut microbiota to influence metabolism and subsequent cancer progression is unclear. Methods: Feces and serum samples from BALB/c ANXA1+/+ and ANXA1-/- mice with or without chronic restraint stress were used for 16S rRNA gene sequencing and GC-MS metabolomics analysis to investigate the effect of stress on microbiome and metabolomics during stress and breast tumorigenesis. Breast tumors samples from stressed and non-stressed mice were used to perform Whole-Genome Bisulfite Sequencing (WGBS) and RNAseq analysis to construct the potential network from candidate hub genes. Finally, machine learning and integrated analysis were used to map the axis from chronic restraint stress to breast cancer development. Results: We report that chronic stress promotes breast tumor growth via a stress-microbiome-metabolite-epigenetic-oncology (SMMEO) axis. Chronic restraint stress in mice alters the microbiome composition and fatty acids metabolism and induces an epigenetic signature in tumors xenografted after stress. Subsequent machine learning and systemic modeling analyses identified a significant correlation among microbiome composition, metabolites, and differentially methylated regions in stressed tumors. Moreover, silencing Annexin-A1 inhibits the changes in the gut microbiome and fatty acid metabolism after stress as well as basal and stress-induced tumor growth. Conclusions: These data support a physiological axis linking the microbiome and metabolites to cancer epigenetics and inflammation. The identification of this axis could propel the next phase of experimental discovery in further understanding the underlying molecular mechanism of tumorigenesis caused by physiological stress.

"Where-There-Is-No-Psychiatrist Integrated Personal Therapy" among Community-Dwelling Older Adults: A Randomized Pilot Study.

In Singapore, many older adults suffer from subsyndromal depression and/or subsyndromal anxiety, which can negatively impact their physical and mental well-being if left untreated. Due to the general public's reluctance to seek psychological help and the low psychiatrist-to-population ratio in Singapore, this study aims to examine the preliminary efficacy, perceptions, and acceptability of a trained volunteer-led community-based intervention on community-dwelling older adults. Twenty-one participants (control: n = 11; intervention: n = 10) completed the randomized pilot study. A mixed-methods approach (questionnaires, semistructured interviews, examining blood samples, intervention fidelity) was adopted. No significant differences were found between the intervention and the control groups in depression, anxiety, life satisfaction, friendship, and quality of life. However, there was a positive change in quality-of-life scores from baseline to 6 months in the intervention group. The control group had significantly higher cortisol levels and lower annexin-A1 levels at 6 months, while the intervention group did not. Three themes emerged from the interviews: (1) impact of the intervention on older adults' well-being, (2) attitudes toward intervention, and (3) a way forward. However, intervention efficacy could not be established due to small sample size caused by the coronavirus pandemic. Future randomized controlled trials should evaluate volunteer-led, technology-based psychosocial interventions to support these older adults.

AIM2 inflammasome mediates apoptotic and pyroptotic death in the cerebellum following chronic hypoperfusion.

Vascular dementia (VaD) is the second most common form of dementia and is caused by vascular pathologies resulting in chronic cerebral hypoperfusion (CCH)- induced brain injury, and ultimately cognitive impairment and memory loss. Several lines of evidence have demonstrated chronic inflammation may be involved in VaD disease progression. It is now recognized that a major contributor to cerebral and systemic chronic inflammation involves the activation of innate immune molecular complexes termed inflammasomes. Whilst previous studies on animal models of VaD have focused on the cortex, hippocampus and striatum, few studies have investigated the effect of CCH on the cerebellum. Emerging studies have found new roles of the cerebellum in cognition, based on its structural interconnectivity with other brain regions and clinical relevance in neuropsychological deficits. In the present study, we conducted our investigation on the cerebellum using a CCH mouse model of VaD following bilateral common carotid artery stenosis (BCAS). This study is the first to characterize an increased expression of inflammasome receptors, adaptor and effector proteins, markers of inflammasome activation, proinflammatory cytokines, and apoptotic and pyroptotic cell death proteins in the cerebellum following CCH. Furthermore, in AIM2 knockout mice, we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis in the cerebellum following CCH. Collectively, our findings provide novel evidence that AIM2 inflammasome activation promotes apoptosis and pyroptosis in the cerebellum following chronic hypoperfusion in a mouse model of VaD.

AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia.

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1ß and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.