This study proposes a revised interpretation of Foucault’s views on literature. It has been argued that the philosopher’s interest in literature was limited to the 1960s and of a mostly depoliticized ...nature. However, Foucault’s previously unpublished later works suggest a different reality, showing a sustained interest in literature and its politics. In the light of this new material, the book repositions Foucault's ideas within recent debates on the politics of literature.
Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafficking defects. There is a paucity of data describing the intracellular transport of IgG in the context of ...endosomal-lysosomal alterations linked to trisomy 21. In this study, we analyzed the intracellular traffic of IgG mediated by the human neonatal Fc receptor (FcRn) in fibroblast cell lines with trisomy 21. Intracellular IgG trafficking studies in live cells showed that fibroblasts with trisomy 21 exhibit higher proportion of IgG in lysosomes (~ 10% increase), decreased IgG content in intracellular vesicles (~ 9% decrease), and a trend towards decreased IgG recycling (~ 55% decrease) in comparison to diploid cells. Amyloid-beta precursor protein (APP) overexpression in diploid fibroblasts replicated the increase in IgG sorting to the degradative pathway observed in cells with trisomy 21. The impact of APP on the expression of FCGRT (alpha chain component of FcRn) was investigated by APP knock down and overexpression of the APP protein. APP knock down increased the expression of FCGRT mRNA by ~ 60% in both diploid and trisomic cells. Overexpression of APP in diploid fibroblasts and HepG2 cells resulted in a decrease in FCGRT and FcRn expression. Our results indicate that the intracellular traffic of IgG is altered in cells with trisomy 21. This study lays the foundation for future investigations into the role of FcRn in the context of DS.
The efficient and timely resolution of DNA recombination intermediates is essential for bipolar chromosome segregation. Here, we show that the specialized chromosome segregation patterns of meiosis ...and mitosis, which require the coordination of recombination with cell-cycle progression, are achieved by regulating the timing of activation of two crossover-promoting endonucleases. In yeast meiosis, Mus81-Mms4 and Yen1 are controlled by phosphorylation events that lead to their sequential activation. Mus81-Mms4 is hyperactivated by Cdc5-mediated phosphorylation in meiosis I, generating the crossovers necessary for chromosome segregation. Yen1 is also tightly regulated and is activated in meiosis II to resolve persistent Holliday junctions. In yeast and human mitotic cells, a similar regulatory network restrains these nuclease activities until mitosis, biasing the outcome of recombination toward noncrossover products while also ensuring the elimination of any persistent joint molecules. Mitotic regulation thereby facilitates chromosome segregation while limiting the potential for loss of heterozygosity and sister-chromatid exchanges.
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► Mus81-Mms4 and Yen1 endonucleases collaboratively resolve DNA joint molecules in meiosis ► Cdc5 activates Mus81-Mms4 during meiosis I through the phosphorylation of Mms4 ► Phosphorylation inhibits Yen1 until the onset of meiosis II ► Yen1/GEN1 and Mus81-Mms4/EME1 are specifically activated during M phase of mitosis
Endonucleases resolve DNA recombination intermediates at different stages to promote and prevent crossing over in meiosis and mitosis, respectively.
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused ...by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop ...between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis—licensed by unrestrained CDK1 activity during S phase—requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.
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•CDK1-dependent phosphorylation of SLX4 controls MUS81-SLX4 complex formation•CDK1 activation in S phase drives MUS81-SLX4-mediated chromosome pulverization•WEE1 inhibitors cause cell death partly by MUS81-SLX4-dependent chromosome breakage•DNA replication and WEE1 collaboratively suppress CDK1 activity during S phase
MUS81 nuclease resolves persistent replication intermediates at mitotic onset to safeguard chromosome segregation. Duda et al. uncover dynamic regulation of MUS81 function during the cell cycle to protect S-phase chromosomes from unscheduled breakage and pulverization. This regulation ensures that DNA replication and mitosis occur sequentially and in a mutually exclusive manner.
The careful orchestration of cellular events such as DNA replication, repair, and segregation is essential for equal distribution of the duplicated genome into two daughter cells. To ensure that ...persistent recombination intermediates are resolved prior to cell division, the Yen1 Holliday junction resolvase is activated at anaphase. Here, we show that the master cell-cycle regulators, cyclin-dependent kinase (Cdk) and Cdc14 phosphatase, control the actions of Yen1. During S phase, Cdk-mediated phosphorylation of Yen1 promotes its nuclear exclusion and inhibits catalytic activity by reducing the efficiency of DNA binding. Later in the cell cycle, at anaphase, Cdc14 drives Yen1 dephosphorylation, leading to its nuclear relocalization and enzymatic activation. Using a constitutively activated form of Yen1, we show that uncontrolled Yen1 activity is detrimental to the cell: spatial and temporal restriction of Yen1 protects against genotoxic stress and, by avoiding competition with the noncrossover-promoting repair pathways, prevents loss of heterozygosity.
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•Yen1 undergoes a dual mode of regulation: activity and subcellular localization•Cdk phosphorylation inhibits Yen1 at S phase by reducing its DNA binding affinity•Yen1 activation at anaphase is driven by the Cdc14 phosphatase•Premature activation of Yen1 leads to loss of heterozygosity and genome instability
The complete elimination of DNA recombination intermediates is essential for chromosome segregation. Blanco et al. show that the master cell-cycle regulators Cdk and Cdc14 control both the localization and nuclease activation of the Holliday junction resolvase Yen1. Cdk/Cdc14 therefore control the final wave of joint molecule resolution at anaphase.
Este artículo propone un avance en la aplicación del concepto «transsecular», atendiendo a tres de sus rasgos (Bengert y otros, en prensa), a saber: la crítica de la temporalidad progresiva, la ...crítica de la secularidad como rasgo distintivo de la Modernidad y su hermenéutica sincrética, definida allí como hermenéutica de la hospitalidad. A partir de esta definición, el artículo propone pensar Las moradas de Teresa de Ávila, primero, en relación con la Apología de Sócrates de Platón, dada su coincidencia con el desarrollo parresiástico de sus discursos; y, por otra parte, en relación con el concepto de intelecto como habitus. Como consecuencia de esta lectura transsecular, concluimos que el texto teresiano nos propone un modo de lectura hospitalaria, abierta a todos, haciendo coincidir la lectura literal y la simbólica; y como resistencia, en tanto que la política del texto se enfrenta a la tradición del acceso de una élite a la verdad como enigma.
Though postpartum family planning helps women to achieve the recommended birth interval before next pregnancy, its utilization in Ethiopia is low. Understanding drivers and barriers is key to improve ...postpartum family planning uptake. The aim of this systematic review and meta-analysis is to analyze and summarize predictors of postpartum family planning uptake, during the first year after birth, in Ethiopia. We conducted a systematic review and meta-analysis of observational studies published in English before April 16, 2021. We searched electronic sources like PubMed, MEDLINE, CINHAL Embase, Google and supplemented it with manual search. Two reviewers appraised independently the studies using the Joanna Briggs Institute Quality Assessment Tool for the observational studies. Data synthesis and analysis were conducted using Review Manager Version 5.3. The Cochrane Q test statistic and I2 tests were used to assess the heterogeneity among the included studies. A random-effects and fixed effect model were used to calculate pooled Odds Ratio and its 95% CI. A total of 22 studies were included in the review. Better educational status of womenOR = 2.60; 95% CI: 2.15, 3.14, women's marital status OR = 4.70; 95% CI: 1.51, 14.60, resumption of sexual intercourse OR = 6.22; 95% CI: 3.01, 12.86, menses return OR = 3.72; 95% CI: 1.98, 6.99, PPFP discussion with partner OR = 2.53; 95% CI: 2.00, 3.20, women's previous PPFP information OR = 4.93; 95% CI: 2.26, 10.76, PPFP counseling during ANC OR = 3.95; 95% CI: 2.50, 6.23, having PNC OR = 4.22; 95% CI: 2.80, 6.34, having experience of modern contraceptive use OR = 2.90; 95% CI: 1.62, 5.19, facility birth OR = 6.70; 95% CI: 3.15, 14.25, and longer interval after last delivery OR = 0.37; 95% CI: 0.32, 0.43 were significantly associated with modern contraceptive uptake during postpartum period. Our systematic review identified modifiable factors and estimated their association with PPFP uptake. Since most of these factors are related to reproductive health characteristics and MNCH services, integrating PPFP into MNCH services particularly at primary health care unit may improve contraceptive uptake during postpartum period. Systematic review registration: PROSPERO: 2020: CRD42020159470.
This collected volume explores Foucault's literary thought, in light of the recent publication of unpublished works from his first period (1960s–1970s). It aims at establishing an archeology of the ...texts that Foucault devotes to literary theory and to clearly literary concepts such as fiction, outside (Blanchot) or transgression (Bataille), in order to relate them to key concepts of the second Foucault (parresia, self-care, veridiction).
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