Capillary electrophoresis mass spectrometry identifies new isomers of inositol pyrophosphates in mammalian tissues.

Technical challenges have to date prevented a complete profiling of the levels of myo-inositol phosphates (InsPs) and pyrophosphates (PP-InsPs) in mammalian tissues. Here, we have deployed capillary electrophoresis mass spectrometry to identify and record the levels of InsPs and PP-InsPs in several tissues obtained from wild type mice and a newly created PPIP5K2 knockout strain. We observe that the mouse colon harbours unusually high levels of InsPs and PP-InsPs. Additionally, the PP-InsP profile is considerably more complex than previously reported for animal cells: using chemically synthesized internal stable isotope references and high-resolution mass spectra, we characterize two new PP-InsP isomers as 4/6-PP-InsP5 and 2-PP-InsP5. The latter has not previously been described in nature. The analysis of feces and the commercial mouse diet suggests that the latter is one potential source of noncanonical isomers in the colon. However, we also identify both molecules in the heart, indicating unknown synthesis pathways in mammals. We also demonstrate that the CE-MS method is sensitive enough to measure PP-InsPs from patient samples such as colon biopsies and peripheral blood mononuclear cells (PBMCs). Strikingly, PBMCs also contain 4/6-PP-InsP5 and 2-PP-InsP5. In summary, our study substantially expands PP-InsP biology in mammals.

The role of meaning in life in psychological distress during the COVID-19 pandemic.

BACKGROUND/OBJECTIVE: Meaning in life may function as a protective factor in the context of potentially traumatic experiences, such as the COVID-19 pandemic. We investigated the associations between meaning and psychological distress (i.e., depression, anxiety, COVID-19-related PTSD) prospectively and cross-sectionally. We hypothesized that meaning inversely predicts peri-pandemic distress and that meaning moderates the association between being negatively affected by the pandemic and distress. We additionally explored cross-sectional associations between meaning subcomponents and distress and a meaning violations perspective. METHODS: Undergraduate students (N = 109) completed questionnaires before (October 2019 to March 2020; meaning, anxiety) and during the pandemic (April to June 2020; meaning, meaning subcomponents, depression, anxiety, PTSD). RESULTS: Correcting for family-wise errors, meaning prospectively predicted less depression and anxiety, but not PTSD. Correcting for family-wise errors, peri-pandemic meaning was consistently related with peri-pandemic distress. Meaning did not moderate the link between being affected by the pandemic and distress. The meaning subcomponent comprehension was most strongly related with distress and a meaning violations perspective was partly supported. CONCLUSION: Meaning emerged as a significant correlate of peri-pandemic distress. Current findings should be replicated longitudinally and experimentally to establish their robustness and to examine the causal influence of meaning on distress.

Social Anxiety and Empathy: A Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to clarify the association between social anxiety and affective (AE) and cognitive empathy (CE). METHODS: 1442 studies from PsycINFO, Medline, and EMBASE (inception-January 2020) were systematically reviewed. Included studies (N = 48) either predicted variance in empathy using social anxiety scores or compared empathy scores between socially anxious individuals and a control group. RESULTS: Social anxiety and AE were statistically significantly positively associated, k = 14, r = .103 (95%CI [.003, .203]), z = 2.03, p = .043. Sex (QM (2) = 18.79, p <  .0001), and type of measures (QM (1 = 7.34, p = .007) moderated the association. Correlations were significant for male samples (rmale = .316, (95%CI [.200, .432])) and studies using self-report measures (rself-report = .162 (95%CI [.070, .254])). Overall, social anxiety and CE were not significantly associated, k = 52, r =-.021 (95%CI [-.075, .034]), z= -0.74, p = .459. Sample type moderated the association (QM (1) = 5.03, p < .0001). For clinical samples the association was negative (rclinical= -.112, (95%CI [-.201, -.017]). CONCLUSION: There was evidence for a positive association between social anxiety and AE, but future studies are needed to verify the moderating roles of sex and type of measure. Besides, low CE might only hold for patients with SAD.

Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells.

Emerging data indicate that SARS-CoV-2-specific CD8+ T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals1-5. However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8+ T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8+ T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8+ T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8+ T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8+ T cells exhibited functional characteristics comparable to influenza-specific CD8+ T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8+ T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.

Shed it, and help-LAG3 cleavage drives conventional CD4+ T cells to overcome resistance to PD-1 immunotherapy.

LAG3 cleavage from conventional CD4+ T cells, but not CD8+ T cells, is required for effective PD-1 blockade.

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells.

B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner.