C. elegans embryos exhibit an invariant lineage comprised primarily of a stepwise binary diversification of anterior-posterior (A-P) blastomere identities. This binary cell fate specification requires input from both the Wnt and MAP kinase signaling pathways. The nuclear level of the TCF protein POP-1 is lowered in all posterior cells. We show here that the ␤-catenin SYS-1 also exhibits reiterated asymmetry throughout multiple A-P divisions and that this asymmetry is reciprocal to that of POP-1. Furthermore, we show that SYS-1 functions as a coactivator for POP-1, and that the SYS-1-to-POP-1 ratio appears critical for both the anterior and posterior cell fates. A high ratio drives posterior cell fates, whereas a low ratio drives anterior cell fates. We show that the SYS-1 and POP-1 asymmetries are regulated independently, each by a subset of genes in the Wnt/MAP kinase pathways. We propose that two genetic pathways, one increasing SYS-1 and the other decreasing POP-1 levels, robustly elevate the SYS-1-to-POP-1 ratio in the posterior cell, thereby driving A-P differential cell fates.KEY WORDS: C. elegans, TCF/POP-1, ␤-catenin/SYS-1, Cell fate specification Development 134, 2685Development 134, -2695Development 134, (2007 POP-1 (Kidd et al., 2005). Recently, SYS-1 has been implicated in endoderm precursor specification (Phillips et al., 2007). Whereas animals homozygous for a reduction-of-function mutation are sterile, sys-1(RNAi) resulted in a very low penetrance gutless phenotype.We show here that SYS-1 is a limiting coactivator for POP-1 in the activation of Wnt/MAPK-responsive genes in the E blastomere. SYS-1 exhibits a reiterated asymmetry that is reciprocal to the reiterated asymmetry of nuclear POP-1 through all A-P divisions examined. We show that the SYS-1-to-POP-1 ratio appears critical for both anterior and posterior cell fates at multiple divisions: a high ratio drives the posterior cell fate, whereas a low ratio drives the anterior cell fate. SYS-1 and POP-1 levels are regulated in opposite directions by two pathways known to regulate endoderm specification: SYS-1 levels are increased primarily by the MOM-2/MOM-5/APR-1 pathway, whereas nuclear POP-1 levels are decreased primarily by the MOM-4/LIT-1/WRM-1 pathway. Together, these two pathways efficiently increase the SYS-1-to-POP-1 ratio in the posterior cell, promoting asymmetric cell fates. MATERIALS AND METHODS StrainsN2 was used as the wild-type strain. Genetic markers:LGI, pop-1(zu189), dpy-5(e61), mom-5(or57), mom-4(ne19), sys-1(q544), fog-3(q520), teIs3 (P med-1 gfp::pop-1), hT1(I:V), szT1(I:X);LGII, rol-1(e91), mom-3(or78), mnC1; LGIII, unc-119(ed3), lit-1(t1512), lit-1(t1534), unc32(e189);LGIV, teIs46(P end-1 gfp::H2B); LGV, mom-2(or42), DnT1(IV;V), teIs18 (P sdz-23 gfp::H2B); LGX,. TX796 [teEx321(P med-1 gfp::sys-1)]. gfp::H2B)(V)]. TX691 [teIs46(P end-1 gfp::H2B)(IV)] (Shetty et al., 2005). TX932 [sys-1(q544)/fog-3(q470)(I); teIs3(P med-1 gfp::pop-1)(V)] (Miskowski et al., 2001). TX964 [teIs98(P pie-1 gfp::sys-1)]. JM139 [P pho-1 ...

Larvae of the polychaete worm Hydroides elegans settle and metamorphose in response to marine biofilms. Phylogenetic relationships among 4 marine-biofilm bacterial species identified by 16S rDNA sequences were not predictive of their inductive capacity. Two bacterial species separated by a genetic distance of 30% shared the greatest capacity for inducing metamorphosis in H. elegans. Two bacterial strains with only a 3% divergence in 16S rRNA gene sequences were very different; one strain induced metamorphosis strongly while the other one did not. The percent of larvae that metamorphosed correlated positively with bacterial density in either natural biofilms or biofilms composed of a single bacterial species. When results of tests across 4 bacterial species were compared, the most inductive bacterial species was effective in much lower biofilm densities than weakly or non-inductive bacteria. Evidence presented here indicates that the cue that triggers settlement and metamorphosis in larvae of H. elegans is not unique to a single bacterial taxon and is likely to be an insoluble, surface-bound material. KEY WORDS: Biofilm bacteria · Larval settlement · Metamorphosis · Hydroides elegansResale or republication not permitted without written consent of the publisher

Dihydroceramide desaturases are evolutionarily conserved enzymes that convert dihydroceramide (dhCer) to ceramide (Cer). While elevated Cer levels cause neurodegenerative diseases, the neuronal activity of its direct precursor, dhCer, remains unclear. We show that knockout of the fly dhCer desaturase gene, (), results in larval lethality with increased dhCer and decreased Cer levels. Light stimulation leads to ROS increase and apoptotic cell death in -KO photoreceptors, resulting in activity-dependent neurodegeneration. Lipid-containing Atg8/LC3-positive puncta accumulate in-KO photoreceptors, suggesting lipophagy activation. Further enhancing lipophagy reduces lipid droplet accumulation and rescues -KO defects, indicating that lipophagy plays a protective role. Reducing dhCer synthesis prevents photoreceptor degeneration and rescues-KO lethality, while supplementing downstream sphingolipids does not. These results pinpoint that dhCer accumulation is responsible for -KO defects. Human dhCer desaturase rescues-KO larval lethality, and rapamycin reverses defects caused by dhCer accumulation in human neuroblastoma cells, suggesting evolutionarily conserved functions. This study demonstrates a novel requirement for dhCer desaturase in neuronal maintenance and shows that lipophagy activation prevents activity-dependent degeneration caused by dhCer accumulation.

SUMMARYWnt target gene activation in C. elegans requires simultaneous elevation of -catenin/SYS-1 and reduction of TCF/POP-1 nuclear levels within the same signal-responsive cell. SYS-1 binds to the conserved N-terminal -catenin-binding domain (CBD) of POP-1 and functions as a transcriptional co-activator. Phosphorylation of POP-1 by LIT-1, the C. elegans Nemo-like kinase homolog, promotes POP-1 nuclear export and is the main mechanism by which POP-1 nuclear levels are lowered. We present a mechanism whereby SYS-1 and POP-1 nuclear levels are regulated in opposite directions, despite the fact that the two proteins physically interact. We show that the C terminus of POP-1 is essential for LIT-1 phosphorylation and is specifically bound by the diverged -catenin WRM-1. WRM-1 does not bind to the CBD of POP-1, nor does SYS-1 bind to the C-terminal domain. Furthermore, binding of WRM-1 to the POP-1 C terminus is mutually inhibitory with SYS-1 binding at the CBD. Computer modeling provides a structural explanation for the specificity in WRM-1 and SYS-1 binding to POP-1. Finally, WRM-1 exhibits two independent and distinct molecular functions that are novel for -catenins: WRM-1 serves both as the substrate-binding subunit and an obligate regulatory subunit for the LIT-1 kinase. Mutual inhibitory binding would result in two populations of POP-1: one bound by WRM-1 that is LIT-1 phosphorylated and exported from the nucleus, and another, bound by SYS-1, that remains in the nucleus and transcriptionally activates Wnt target genes. These studies could provide novel insights into cancers arising from aberrant Wnt activation.

Background: Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. Objective: Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. Methods: We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. Results: Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103–1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. Conclusion: Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.

BackgroundThis nationwide study was performed to evaluate the evolution of distributions of patients with COPD according to the 2011 and 2017 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines and to assess the concordance between the prescribed medications and the pharmacological management recommended by the two distinct classification systems in Taiwan.Subjects and methodsData were retrospectively retrieved from stable COPD patients in 11 participating hospitals across Taiwan. Patients were grouped according to GOLD 2011 and 2017 guidelines respectively. Definitions of undertreatment and overtreatment were based on the pharmacological recommendations in the individual guidelines.ResultsA total of 1,053 COPD patients were included. The percentages of patients in GOLD 2011 groups A, B, C and D were 18.4%, 40.6%, 6.7% and 34.2%, respectively. When reclassified according to the GOLD 2017, the percentages of group A and B increased to 23.3% and 63.2%, and groups C and D decreased to 1.9% and 11.6%, respectively. Up to 67% of patients in GOLD 2011 groups C and D were reclassified to GOLD 2017 groups A and B. The pharmacological concordance rate was 60.9% for GOLD 2011 and decreased to 44.9% for GOLD 2017. Overtreatment was found in 29.5% of patients according to GOLD 2011 and the rate increased to 46.1% when classified by the GOLD 2017. The major cause of overtreatment was unnecessary inhaled corticosteroids and the main cause of undertreatment was a lack of maintenance long-acting bronchodilators.ConclusionThe distribution of COPD patients in Taiwan was more uneven with the GOLD 2017 than with the GOLD 2011. A pharmacological discordance to the guidelines was identified. Updated guidelines with reclassification of COPD patients resulted in more discordance between prescribed medications and the guidelines. Physicians should make proper adjustments of the prescriptions according to the updated guidelines to ensure the mostly appropriate treatment for COPD patients.

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Efficient apoptotic corpse clearance is essential for metazoan development and adult tissue homeostasis. Several autophagy proteins have been previously shown to function in apoptotic cell clearance; however, it remains unknown whether autophagy genes are essential for efficient apoptotic corpse clearance in the developing embryo. Here we show that, in Caenorhabditis elegans embryos, loss-of-function mutations in several autophagy genes that act at distinct steps in the autophagy pathway resulted in increased numbers of cell corpses and delayed cell corpse clearance. Further analysis of embryos with a null mutation in bec- 1, the C. elegans ortholog of yeast VPS30/ATG6/mammalian beclin 1 (BECN1), revealed normal phosphatidylserine exposure on dying cells. Moreover, the corpse clearance defects of bec- 1(ok691) embryos were rescued by BEC-1 expression in engulfing cells, and bec- 1(ok691) enhanced corpse clearance defects in nematodes with simultaneous mutations in the engulfment genes, ced- 1, ced- 6 or ced- 12. Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal.