Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.Fil: Russo, Ashley J.. UConn Health School of Medicine; Estados UnidosFil: Vasudevan, Swathy O.. UConn Health School of Medicine; Estados UnidosFil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kumari, Puja. UConn Health School of Medicine; Estados UnidosFil: Menoret, Antoine. UConn Health School of Medicine; Estados UnidosFil: Duduskar, Shivalee. Jena University Hospital; AlemaniaFil: Wang, Chengliang. UConn Health School of Medicine; Estados UnidosFil: Pérez Sáez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fettis, Margaret M.. University of Florida; Estados UnidosFil: Li, Chuan. UConn Health School of Medicine; Estados UnidosFil: Liu, Renjie. University of Florida; Estados UnidosFil: Wanchoo, Arun. University of Florida; Estados UnidosFil: Chandiran, Karthik. UConn Health School of Medicine; Estados UnidosFil: Ruan, Jianbin. UConn Health School of Medicine; Estados UnidosFil: Vanaja, Sivapriya Kailasan. UConn Health School of Medicine; Estados UnidosFil: Bauer, Michael. Jena University Hospital; AlemaniaFil: Sponholz, Christoph. Jena University Hospital; AlemaniaFil: Hudalla, Gregory A.. University of Florida; Estados UnidosFil: Vella, Anthony T.. UConn Health School of Medicine; Estados UnidosFil: Zhou, Beiyan. UConn Health School of Medicine; Estados UnidosFil: Deshmukh, Sachin D.. Jena University Hospital; AlemaniaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rathinam, Vijay A.. UConn Health School of Medicine; Estados Unido

T cell sensitivity to TGF-β is required for the effector function but not the generation of splenic CD8+ regulatory T cells induced via the injection of antigen into the anterior chamber

The introduction of antigen into the anterior chamber (AC) of the eye induces the production of antigen-specific splenic CD8+ regulatory T cells (AC-SPL cells) that suppress a delayed-type hypersensitivity (DTH) reaction in immunized mice. Because the generation of these regulatory T cells is also induced by exposure to transforming growth factor (TGF)-β and antigen or F4/80+ cells exposed to TGF-β and antigen in vitro, we investigated (i) whether these cells are produced in dominant negative receptor for transforming growth factor β receptor type II (dnTGFβRII) or Cbl-b−/− mice whose T cells are resistant to TGF-β, (ii) whether DTH is suppressed by wild type (WT) CD8+ AC-SPL cells in Cbl-b−/− and dnTGFβRII mice and (iii) the effect of antibodies to TGF-β on the suppression of DTH by CD8+ AC-SPL cells. DnTGFβRII immunized and Cbl-b−/− mice produced splenic CD8+ regulatory cells after the intracameral injection of antigen and immunization. The suppression of a DTH reaction by CD8+ AC-SPL cells in WT mice was blocked by the local inclusion of antibodies to TGF-β when WT splenic CD8+ AC-SPL cells were injected into the DTH reaction site. Moreover, the DTH reaction in immunized dnTGFβRII and Cbl-b−/− mice was not suppressed by the transfer of WT CD8+ AC-SPL cells to the site challenged with antigen. In aggregate, these observations suggest that T cell sensitivity to TGF-β is not an obligate requirement for the in vivo induction of CD8+ AC-SPL T cells but the suppression of an in vivo DTH reaction by CD8+ AC-SPL cells is dependent on TGF-β

The Saudi experiment with career guidance

Saudi Arabia has recently embarked on an ambitious experiment with career guidance. The country has identified that career guidance offers a range of potential cultural, educational and economic benefits. These include supporting the Saudisation of the workforce, the development of the vocational education system and the engagement of the Saudi ‘youth bulge’ in the labour market and wider society. However, the country has a weak tradition of career guidance and a need to develop new policies and systems rapidly. The Saudi Ministry of Labour has driven the development of the country’s new career guidance system and has sought to learn from global best practice. However, Saudi Arabia offers a very different context from those where career guidance has flourished. Particularly distinctive features of Saudi society include its limited civil society, the central role that religion plays, the place of women, the role of oil within the economy and the high level of migrant workers in the labour market. Taken together these issues offer challenges of culture, theory, policy and practice. Negotiating these challenges and building an organic body of theory and practice will be critical to the success or otherwise of the Saudi experiment with career guidance.N/

Honokiol Induces Calpain-Mediated Glucose-Regulated Protein-94 Cleavage and Apoptosis in Human Gastric Cancer Cells and Reduces Tumor Growth

Background. Honokiol, a small molecular weight natural product, has been shown to possess potent anti-neoplastic and anti-angiogenic properties. Its molecular mechanisms and the ability of anti-gastric cancer remain unknown. It has been shown that the anti-apoptotic function of the glucose-regulated proteins (GRPs) predicts that their induction in neoplastic cells can lead to cancer progression and drug resistance. We explored the effects of honokiol on the regulation of GRPs and apoptosis in human gastric cancer cells and tumor growth. Methodology and Principal Findings. Treatment of various human gastric cancer cells with honokiol led to the induction of GRP94 cleavage, but did not affect GRP78. Silencing of GRP94 by small interfering RNA (siRNA) could induce cell apoptosis. Treatment of cells with honokiol or chemotherapeutics agent etoposide enhanced the increase in apoptosis and GRP94 degradation. The calpain activity and calpain-II (m-calpain) protein (but not calpain-I (mu-calpain)) level could also be increased by honokiol. Honokiol-induced GRP94 down-regulation and apoptosis in gastric cancer cells could be reversed by siRNA targeting calpain-II and calpain inhibitors. Furthermore, the results of immunofluorescence staining and immunoprecipitation revealed a specific interaction of GRP94 with calpain-II in cells following honokiol treatment. We next observed that tumor GRP94 over-expression and tumor growth in BALB/c nude mice, which were inoculated with human gastric cancer cells MKN45, are markedly decreased by honokiol treatment. Conclusions and Significance. These results provide the first evidence that honokiol-induced calpain-II-mediated GRP94 cleavage causes human gastric cancer cell apoptosis. We further suggest that honokiol may be a possible therapeutic agent to improve clinical outcome of gastric cancer

µ-Calpain Conversion of Antiapoptotic Bfl-1 (BCL2A1) into a Prodeath Factor Reveals Two Distinct alpha-Helices Inducing Mitochondria-Mediated Apoptosis

Anti-apoptotic Bfl-1 and pro-apoptotic Bax, two members of the Bcl-2 family sharing a similar structural fold, are classically viewed as antagonist regulators of apoptosis. However, both proteins were reported to be death inducers following cleavage by the cysteine protease µ-calpain. Here we demonstrate that calpain-mediated cleavage of full-length Bfl-1 induces the release of C-terminal membrane active α-helices that are responsible for its conversion into a pro-apoptotic factor. A careful comparison of the different membrane-active regions present in the Bfl-1 truncated fragments with homologous domains of Bax show that helix α5, but not α6, of Bfl-1 induces cell death and cytochrome c release from purified mitochondria through a Bax/Bak-dependent mechanism. In contrast, both helices α5 and α6 of Bax permeabilize mitochondria regardless of the presence of Bax or Bak. Moreover, we provide evidence that the α9 helix of Bfl-1 promotes cytochrome c release and apoptosis through a unique membrane-destabilizing action whereas Bax-α9 does not display such activities. Hence, despite a common 3D-structure, C-terminal toxic domains present on Bfl-1 and Bax function in a dissimilar manner to permeabilize mitochondria and induce apoptosis. These findings provide insights for designing therapeutic approaches that could exploit the cleavage of endogenous Bcl-2 family proteins or the use of Bfl-1/Bax-derived peptides to promote tumor cell clearance

New species of Rockacestus (Cestoda, Phyllobothriidea) from skates of the genus Bathyraja (Rajiformes, Arhynchobatidae) in the Southwestern Atlantic Ocean with comments on the distribution of the genus

Three new species of Rockacestus Caira, Bueno & Jensen, 2021 were recovered from arhynchobatid skates taken between 37°S–55°S in the Magellanic Province, Southwestern Atlantic Ocean. Rockacestus blasi sp. nov. was found in Bathyraja macloviana (Norman, 1937), whereas Rockacestus magellanicus sp. nov., and Rockacestus ottavianoi sp. nov. were found in Bathyraja magellanica (Philippi, 1902). These species differ from their congeners in having a particular combination of anatomical features, including a moderate to highly folded bothridia, presence of a uteroduct, and a seminal receptacle. Cross-sections of mature proglottids were made for the first time in members of the genus. In addition, the microthrix pattern was described in detail, focusing on the distal bothridial surface, including the apical sucker and marginal loculi resulting in a common microthrix configuration with filitriches and small lanceolate, lingulate, and a particular kind of coniform spinitriches. The diagnosis of Rockacestus is revised to include several features exhibited by the new species. The distribution data of the species currently assigned to Rockacestus are compiled and updated. The finding of R. blasi sp. nov., R. magellanicus sp. nov., and R. ottavianoi sp. nov. not only increases the number of members of Rockacestus in the Magellanic Province in the Southwestern Atlantic from one to four but also expands our knowledge of phyllobothriideans and their association with the softnose skates of the genus Bathyraja Ishiyama, 1958 in the Southern Hemisphere