Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder

Caspase-8 is best known for its cell death function via death receptors. Recent evidence indicates that caspase-8 also has nonapoptotic functions. Caspase-8 deficiency is associated with pathologies that are unexpected for a proapoptotic molecule, such as abrogation of activation-induced lymphocyte proliferation, perturbed immune homeostasis, and immunodeficiency. In this study, we report the long-term physiological consequences of T cell–specific deletion of caspase-8 (tcasp8−/−). We show that tcasp8−/− mice develop an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and accumulation of T cell infiltrates in the lungs, liver, and kidneys. Peripheral casp8−/− T cells manifest activation marker up-regulation and are proliferating in the absence of any infection or stimulation. We also provide evidence suggesting that this immune disorder is different from the autoimmune lymphoproliferative syndrome. Interestingly, the condition described in tcasp8−/− mice manifests features consistent with the disorder described in humans with Caspase-8 deficiency. These findings suggest that tcasp8−/− mice may serve as an animal model to evaluate Caspase-8–deficient patient prognosis and therapy. Overall, our study uncovers novel in vivo functions for caspase-8 in immune regulation

I wish I had (not) taken a gap-year? The psychological and attainment outcomes of different post-school pathways

Existing gap-year research indicates a number of benefits of a gap-year at the end of school and before university enrollment. Lifespan theory of control, however, suggests that direct goal investment, rather than delay, at developmental transitions is associated with more adaptive outcomes. Comparing these perspectives, we undertake two studies: one in Finland (N = 384, waves = 3) and one in Australia (N = 2259, waves = 5) both with an initial time wave in the last year of high-school. We explore the effects of a gap-year on both psychological and attainment outcomes using an extensive propensity score matching technique. The Finnish study found no difference in growth in goal commitment, effort, expectations of attainment and strain, or in actual university enrollment in those planning to enter university directly versus those who plan to take a gap-year after matching. The Australian study found no difference in growth in outlooks for the future and career prospects, and life satisfaction between gap-year youth and direct university entrants. However, the study did find that gap-year students were more likely to drop out of a university degree. Implication for theory and practice are discussed

Critica ed anacritica di Gv. 18. 31 b. I poteri del Gran Sinedrio ai tempi della procuratoria romana in Giudea

Fin dall’alba primissima della sua storia plurimillenaria, Israele si è presentato sotto la triplice interdipendente connotazione di una religione rivelata, di un popolo nazionalmente qualificato e di uno Stato sovrano, che, per trascorrere di tempi e succedersi di eventi, resteranno anche in epoca romana, in atto o in potenza, in toto o singolarmente, le sue immutabili costanti. E fu contro l’una o l’altra di esse che, a seconda delle congiunture, i romani (e prima e dopo gli altri dominatori), allorquando se ne proposero la difficile amministrazione, diressero i loro intendimenti: ora verso la mitigazione delle strutture statali nell’ambito del territorio che le era proprio, ora col minarne il carattere nazionale di popolo sovrano (accanendosi in epoca tarda anche contro il suo carattere confessionale).Lo studio pone l’attenzione sul difficile intreccio di poteri e sui prevedibili conflitti gestiti in Israele durante la prima procuratoria, che nonostante i moti di liberazione maturati ossessivamente nelle sue diverse sfere sociali, attese sempre ad una coscienza nuova, la quale, riscoprendo e riattualizzando in termini culturali e politici quella triplice e originaria essenza, alimentò i diritti del luogo, seppure nella fisiologica attenuazione imposta ad un popolo conquistato.In tal senso l’ebraismo, compresso nella sua originaria concezione e nelle sue componenti, nazionale e statale, andò senz’altro scolorendosi, pur non essendogli negata una certa parità civile e di certo religiosa, tale da dare legalità alle sue istanze, fino al punto di autorizzare la morte immediata per qualsiasi uomo, fosse anch’esso un romano, che avesse profanato il recinto sacro del tempio.In una tale proiezione non trova conforto l’idea di un popolo largamente indipendente e con possibilità di giurisdizione capitale. Una precisa comparazione, anche sulla base di una diversa e nuova metodologia (il Concilio Ecumenico Vaticano II si è pronunciato in merito ai Vangeli definendoli una sintesi della tradizione apostolica adattati alle necessità delle chiese per le quali sono scritti e nello stile proprio della proclamazione (DV 19) mentre la lettera apostolica di Giovanni Paolo II, Tertio millennio adveniente. Preparazione del Giubileo dell’anno 2000, afferma che gli scritti del N. T., “Pur essendo documenti di fede non sono meno attendibili nell’insieme dei loro riferimenti, anche come testimonianze storiche”) tra i passi cristiani e quelli più salienti, in materia, della tradizione rabbinica, ha verificato che le autorità ebraiche, primo tra tutti il Gran Sinedrio di Gerusalemme, non conservavano più poteri di giurisdizione capitale.Sostenere il contrario sulla base di fonti lette forzatamente è un’aridità concettuale di teorie facinorose (l’exequatur o delibatio da parte del Praefectus Iudaeae), le quali, se riflettendo sul passato si potevano ancora sostenere, non trovano più giustificazione nella prospettiva della più recente esegesi biblica. In tal senso il vangelo di Giovanni nell’escludere senza rimedio la prerogativa degli ebrei di pronunciare sentenze di morte, di fronte alla domanda del Governatore romano (niente affatto interessato alla questione), riporta in 18. 31b l’eco lapidaria della risposta giudaica: “a noi non è permesso di mettere a morte nessuno”

Caspase-8 Inactivation in T Cells Increases Necroptosis and Suppresses Autoimmunity in Bim−/−Bim^{−/−} Mice

Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of $Bim^{−/−}$ mice restrained their autoimmunity and extended their life span. We show that, similar to $caspase-8^{−/−}$ T cells, $Bim^{−/−}$ T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of $Bim^{−/−}$ T cells and restrains autoimmunity in $Bim^{−/−}$ mice

PTEN controls glandular morphogenesis through a juxtamembrane β-Arrestin1/ARHGAP21 scaffolding complex

PTEN controls three-dimensional (3D) glandular morphogenesis by coupling juxtamembrane signalling to mitotic spindle machinery. While molecular mechanisms remain unclear, PTEN interacts through its C2 membrane-binding domain with the scaffold protein β-Arrestin1. Because β-Arrestin1 binds and suppresses the Cdc42 GTPase-activating protein ARHGAP21, we hypothesize that PTEN controls Cdc42-dependent morphogenic processes through a β-Arrestin1-ARHGAP21 complex. Here we show that PTEN knockdown (KD) impairs β-Arrestin1 membrane localization, β-Arrestin1-ARHGAP21 interactions, Cdc42 activation, mitotic spindle orientation and 3D glandular morphogenesis. Effects of PTEN-deficiency were phenocopied by β-Arrestin1 KD or inhibition of β-Arrestin1-ARHGAP21 interactions. Conversely, silencing of ARHGAP21 enhanced Cdc42 activation and rescued aberrant morphogenic processes of PTEN-deficient cultures. Expression of the PTEN C2 domain mimicked effects of full-length PTEN but a membrane-binding defective mutant of the C2 domain abrogated these properties. Our results show that PTEN controls multicellular assembly through a membrane-associated regulatory protein complex composed of β-Arrestin1, ARHGAP21 and Cdc42

Mechanisms of necroptosis in T cells

In caspase 8-deficient mouse T cells, necroptosis occurs via a Ripk3- and Ripk1-dependent pathway independent of autophagy and programmed necrosis

MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD