The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function.

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function

The Effects of Seed Size on Hybrids Formed between Oilseed Rape (Brassica napus) and Wild Brown Mustard (B. juncea)

Background : Seed size has significant implications in ecology, because of its effects on plant fitness. The hybrid seeds that result from crosses between crops and their wild relatives are often small, and the consequences of this have been poorly investigated. Here we report on plant performance of hybrid and its parental transgenic oilseed rape (Brassica napus) and wild B. juncea, all grown from seeds sorted into three seed-size categories.[br/] Methodology/Principal Findings : Three seed-size categories were sorted by seed diameter for transgenic B. napus, wild B. juncea and their transgenic and non-transgenic hybrids. The seeds were sown in a field at various plant densities. Globally, small-seeded plants had delayed flowering, lower biomass, fewer flowers and seeds, and a lower thousand-seed weight. The seed-size effect varied among plant types but was not affected by plant density. There was no negative effect of seed size in hybrids, but it was correlated with reduced growth for both parents.[br/] Conclusions : Our results imply that the risk of further gene flow would probably not be mitigated by the small size of transgenic hybrid seeds. No fitness cost was detected to be associated with the Bt-transgene in this study

COVID-19 In Children Across Three Asian Cosmopolitan Regions

As another wave of COVID-19 outbreak has approached in July 2020, a larger scale COVID-19 pediatric Asian cohort summarizing the clinical observations is warranted. Children confirmed with COVID-19 infection from the Republic of Korea, the Hong Kong Special Administrative Region (HKSAR) and Wuhan, China, during their first waves of local outbreaks were included. Their clinical characteristics and the temporal sequences of the first waves of local paediatric outbreaks were compared. Four hundred and twenty three children with COVID-19 were analyzed. Wuhan had the earliest peak, followed by Korea and HKSAR. Compared with Korea and Wuhan, patients in HKSAR were significantly older (mean age: 12.9 vs. 10.8 vs. 6.6 years, p < 0.001, respectively) and had more imported cases (87.5% vs. 16.5% vs. 0%, p < 0.001, respectively). The imported cases were also older (13.4 vs. 7.6 years, p < 0.001). More cases in HKSAR were asymptomatic compared to Korea and Wuhan (45.5% vs. 22.0% vs. 20.9%, p < 0.001, respectively), and significantly more patients from Wuhan developed fever (40.6% vs. 29.7% vs. 21.6%, p=0.003, respectively). There were significantly less imported cases than domestic cases developing fever after adjusting for age and region of origin (p = 0.046). 5.4% to 10.8% of patients reported anosmia and ageusia. None developed pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PMIS-TS). In general, adolescents were more likely to be asymptomatic and less likely to develop fever, but required longer hospital stays. In conclusion, majority patients in this pediatric Asian cohort had a mild disease. None developed PIMS-TS. Their clinical characteristics were influenced by travel history and age

Moral judgments, gender, and antisocial preferences : an experimental study

Peer reviewedPostprin

The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus demonstrating that the NAD(+) glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms

CD38 promotes pristane-induced chronic inflammation and increases susceptibility to experimental lupus by an apoptosis-driven and TRPM2-dependent mechanism

In this study, we investigated the role of CD38 in a pristane-induced murine model of lupus. CD38-deficient (Cd38-/-) but not ART2-deficient (Art2-/-) mice developed less severe lupus compared to wild type (WT) mice, and their protective phenotype consisted of (i) decreased IFN-I-stimulated gene expression, (ii) decreased numbers of peritoneal CCR2hiLy6Chi inflammatory monocytes, TNF-α-producing Ly6G+ neutrophils and Ly6Clo monocytes/macrophages, (iii) decreased production of anti-single-stranded DNA and anti-nRNP autoantibodies, and (iv) ameliorated glomerulonephritis. Cd38-/- pristane-elicited peritoneal exudate cells had defective CCL2 and TNF-α secretion following TLR7 stimulation. However, Tnf-α and Cxcl12 gene expression in Cd38-/- bone marrow (BM) cells was intact, suggesting a CD38-independent TLR7/TNF-α/CXCL12 axis in the BM. Chemotactic responses of Cd38-/- Ly6Chi monocytes and Ly6G+ neutrophils were not impaired. However, Cd38-/- Ly6Chi monocytes and Ly6Clo monocytes/macrophages had defective apoptosis-mediated cell death. Importantly, mice lacking the cation channel TRPM2 (Trpm2-/-) exhibited very similar protection, with decreased numbers of PECs, and apoptotic Ly6Chi monocytes and Ly6Clo monocytes/macrophages compared to WT mice. These findings reveal a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via an apoptosis-driven mechanism. Furthermore, given the implications of CD38 in the activation of TRPM2, our data suggest that CD38 modulation of pristane-induced apoptosis is TRPM2-dependent.We would like to thank Dr. Yasuo Mori for providing the Tr pm 2−/− mice, Clara Sánchez for animal husbandry at the IPBLN-CSIC Animal Facility, and Thomas S. Simpler and Uma Mudunuru for animal husbandry at the University of Alabama at Birmingham (UAB). We would also like to thank Laura Montosa from the Centro de Instrumentación Cientifica (CIC) at the Universidad de Granada (UGR) for technical support with microscopy, as well as Mohamed Tassi and Ana Santos at CIC, UGR, and Sandra García-Jiménez, Victoria Romero-del-Amo, Gemma Palencia-López, and Samuel Ruiz-Santiago at Campus Formación Granada for tissue preparations, H&E staining, and other staining procedures. Work performed in the Sancho lab was supported in part by the European Commission in collaboration with the following Funding Agencies: (i) Junta de Andalucía (J.A.), Consejería Innovación Ciencia y Empresa y Consejería Educación y Ciencia, Project: PC08-CTS-04046 to J.S. and M.Z., and (ii) Ministerio de Economía y Competitividad (MINECO), Projects: SAF-2011-27261 to J.S. and M.Z. and SAF2014-55088-R to R.M. Work performed in the Lund lab was supported by funds provided by UAB.S