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During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development. Caspase independent alternative cell death (ACD) pathways exist, but have been largely investigated under non-physiological conditions. Here, the authors show that Drosophila primordial germ cells normally elicit DNase II-dependent DNA damage, triggering a parthanatos-like ACD pathway.

Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila , we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane. LC3-associated phagocytosis cascade of events, including recruitment of a Rubicon-based class III PI(3)K complex to the flagellum vesicular sheaths, its activation, and consequent recruitment of Atg8/LC3, are all required for paternal mitochondrial elimination. Finally, lysosomes fuse with strings of large vesicles derived from the flagellum vesicular sheaths and contain degrading fragments of the paternal mitochondrial derivative. Given reports showing that in some mammals, the paternal mitochondria are also decorated with Atg8/LC3 and surrounded by multivesicular bodies upon fertilization, our findings suggest that a similar pathway also mediates paternal mitochondrial elimination in other flagellated sperm-producing organisms. Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination remain unclear. Here, the authors show that Drosophila eggs rapidly degrade paternal mitochondria after fertilization by triggering an innate immunity pathway commonly employed against invading microbes.

Indolo[2,1-b]quinazolin-6,12-dione (tryptanthrin) derivatives present important types of nitrogen-containing heterocyclic compounds which are useful intermediate products in organic synthesis and have potential pharmaceutical applications. The new ethyl 5-oxo-5-(((12-oxoindolo[2,1-b]quinazolin-6(12H)-ylidene)amino)oxy)pentanoate (Compound 2) was synthesized. Compound 2 is the first example of a tryptanthrin derivative containing a dicarboxylic acid residue in the side chain. The Z,E-isomerism of Compound 2 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, Compound 2 is potentially highly bioavailable and has the prospective to be used as the main component for the development of anti-inflammatory drugs.

In Xenopus, specification of the three germ layers is one of the earliest developmental decisions occurring prior to gastrulation. The maternally-expressed vegetally-localized transcription factor VegT has a central role in cell autonomous specification of endoderm and in the generation of mesoderm-inducing signals. Yet, marginally-expressed transcription factors that cooperate with mesoderm-inducing signals are less investigated. Here we report that the transcription factors MEF2A and MEF2D are expressed in the animal hemisphere before mid-blastula transition. At the initiation of zygotic transcription, expression of MEF2D expands into the marginal region that gives rise to mesoderm. Knockdown of MEF2D delayed gastrulation movements, prevented embryo elongation at the subsequent tailbud stage and caused severe defects in axial tissues. At the molecular level, MEF2D knockdown reduced the expression of genes involved in mesoderm formation and patterning. We also report that MEF2D functions with FGF signaling in a positive feedback loop; each augments the expression of the other in the marginal region and both are necessary for mesodermal gene expression. One target of MEF2D is the Nodal-related 1 gene (Xnr1) that mediates some of MEF2D mesodermal activities. Chromatin immunoprecipitation analysis revealed that MEF2D associates with transcriptional regulatory sequences of the Xnr1 gene. Several MEF2 binding sites within the proximal promoter region of Xnr1 were identified by their in vitro association with MEF2D protein. The same promoter region was necessary but not sufficient to mediate MEF2D activity in a reporter gene assay. In sum, our results indicate that the MEF2D protein is a key transcription factor in the marginal zone acting in a positive feedback loop with FGF signaling that promotes mesoderm specification at late blastula stages.

Indolo[2,1-b]quinazolin-6,12-dione (tryptanthrin) derivatives present important types of nitrogen-containing heterocyclic compounds which are useful intermediate products in organic synthesis and have potential pharmaceutical applications. The new ethyl 5-oxo-5-(((12-oxoindolo[2,1-b]quinazolin-6(12H)-ylidene)amino)oxy)pentanoate (Compound 2) was synthesized. Compound 2 is the first example of a tryptanthrin derivative containing a dicarboxylic acid residue in the side chain. The Z,E-isomerism of Compound 2 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, Compound 2 is potentially highly bioavailable and has the prospective to be used as the main component for the development of anti-inflammatory drugs.

Background The research of cytokine-induced thyropathies in the midst of continuing COVID-19 pandemic is a very important and urgent problem. This work is based on the hypothesis that the hyperactivation of the immune system during COVID-19 is accompanied by a massive production of proinflammatory cytokines, and this could lead to thyroid gland disruption. Aim The primary endpoint is to assess the relationship between the levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3f), and free thyroxine (T4f) with the inflammatory process markers. The secondary endpoint is the identification of an association between TSH, T3f, T4f values, and patient survival. Materials and Methods This retrospective, single-center study included 122 patients hospitalized at the National Endocrinology Research Centre with a clinical and laboratory analysis of COVID-19 and bilateral polysegmental viral pneumonia. To assess the functional status of the thyroid gland all patients underwent observation of the TSH, T3f, T4f, AT-TPO, and AT-recTSH. Additionally, the markers of the inflammatory process were assessed in all patients, including: interleukin-6 (IL-6). Results Five patients (4%) were found with subclinical thyrotoxicosis. Serum TSH values were inversely correlated with IL-6 (r: -0.221; p = 0.024). Analysis of the level of hospital mortality, stratified by TSH, revealed statistically significantly lower TSH values in the group of deceased patients (p = 0.012). The median TSH in surviving patients was 1.34 [0.85; 1.80], for the deceased 0.44 [0.29; 0.99]. Based on the hypothesis that the immunosuppressive effect of genetically engineered biological therapy may have a protective role against thyroid damage in the development of cytokine storm, a comparative analysis of TSH values in two groups of patients with cytokine storm was performed (p=0.080). Conclusion Our research shows that the trigger of thyropathies in coronavirus infection is most likely thyroid tissue damage by the proinflammatory cytokines. In addition to the pathophysiological aspects of thyrotoxicosis, this study shows some specific clinical aspects regarding the clinical relevance in patients with thyrotoxicosis and COVID-19, namely, the high hospital mortality rate. The results obtained indicate a high risk of developing cytokine-induced thyropathies in patients with COVID-19. In support of the hypothesis of thyroid tissue damage being caused by pro-inflammatory cytokines, the differences in detected TSH values rose to the level of a statistical trend in 2 groups of patients with cytokine storm (i.e., patients who received tocilizumab therapy, and patients who received symptomatic therapy). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.