Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also ...directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1−/− mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1−/− progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1−/− neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1−/−Ripk3−/−, Ripk1−/−Mlkl−/−, and Ripk1−/−Myd88−/− mice prevented neonatal lethality, but only Ripk1−/−Ripk3−/−Casp8−/− mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.
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•RIPK1 delivers a TNF-dependent survival signal to HSC entering the bone marrow•RIPK1 can inhibit RIPK3/MLKL necroptosis•RIPK3/MLKL-dependent necroptosis causes IL-33 release in Ripk1−/− mice•Lethal, necroptosis-induced, systemic inflammation in Ripk1−/− mice is Myd88 dependent
Ripk1 deficiency induces RIPK3/MLKL-dependent necroptosis, triggers IL-33 release, and causes Myd88-dependent systemic inflammation and perinatal death. These phenotypes could be rescued by deletion of Ripk3 and Casp8, revealing a key function for RIPK1 in inhibiting necroptosis and limiting inflammation.
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids
. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ...ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols
. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions
, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death
. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines
, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q
(CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.
Second-generation sequencing technologies produce high coverage of the genome by short reads at a low cost, which has prompted development of new assembly methods. In particular, multiple algorithms ...based on de Bruijn graphs have been shown to be effective for the assembly problem. In this article, we describe a new hybrid approach that has the computational efficiency of de Bruijn graph methods and the flexibility of overlap-based assembly strategies, and which allows variable read lengths while tolerating a significant level of sequencing error. Our method transforms large numbers of paired-end reads into a much smaller number of longer 'super-reads'. The use of super-reads allows us to assemble combinations of Illumina reads of differing lengths together with longer reads from 454 and Sanger sequencing technologies, making it one of the few assemblers capable of handling such mixtures. We call our system the Maryland Super-Read Celera Assembler (abbreviated MaSuRCA and pronounced 'mazurka').
We evaluate the performance of MaSuRCA against two of the most widely used assemblers for Illumina data, Allpaths-LG and SOAPdenovo2, on two datasets from organisms for which high-quality assemblies are available: the bacterium Rhodobacter sphaeroides and chromosome 16 of the mouse genome. We show that MaSuRCA performs on par or better than Allpaths-LG and significantly better than SOAPdenovo on these data, when evaluated against the finished sequence. We then show that MaSuRCA can significantly improve its assemblies when the original data are augmented with long reads.
MaSuRCA is available as open-source code at ftp://ftp.genome.umd.edu/pub/MaSuRCA/. Previous (pre-publication) releases have been publicly available for over a year.
alekseyz@ipst.umd.edu.
Supplementary data are available at Bioinformatics online.
The COVID-19 pandemic continues to wreak havoc across the globe. According to the Centers for Disease Control and Prevention, limiting face-to-face interaction is the best strategy for reducing the ...spread of COVID-19. We investigate the impact of social distancing on social connection and well-being, while also considering the moderating influence of smartphone use. In a survey of 400 students, the study presented herein finds that smartphone use attenuates the negative impact of social distancing on social connection and well-being. Contrary to popular sentiments regarding the influence of smartphone use on well-being, increased smartphone use during the pandemic may foster social connection and well-being. Overall, the research presented provides evidence that the perceived loss of social connection with others is not a de facto outcome of social distancing. The study's findings have important implications for public policymakers, government officials, and others, including consumer researchers. These implications include stressing the important role technology can play in staying socially connected during the current pandemic and the importance of reframing "social distancing" as "physical distancing with social connectedness".
•We investigate synchronization of dynamics on the human connectome.•We analyze a phase oscillator brain network model with hierarchical timescales.•We find a counterintuitive effect where the ...addition of disorder (noise) yields a more ordered (synchronized) state.•The connectome is particularly conducive to generating noise-enhanced synchronization versus other randomized networks.•The effect replicates on other human connectome data.
Synchronization is a collective mechanism by which oscillatory networks achieve their functions. Factors driving synchronization include the network’s topological and dynamical properties. However, how these factors drive the emergence of synchronization in the presence of potentially disruptive external inputs like stochastic perturbations is not well understood, particularly for real-world systems such as the human brain. Here, we aim to systematically address this problem using a large-scale model of the human brain network (i.e., the human connectome). The results show that the model can produce complex synchronization patterns transitioning between incoherent and coherent states. When nodes in the network are coupled at some critical strength, a counterintuitive phenomenon emerges where the addition of noise increases the synchronization of global and local dynamics, with structural hub nodes benefiting the most. This stochastic synchronization effect is found to be driven by the intrinsic hierarchy of neural timescales of the brain and the heterogeneous complex topology of the connectome. Moreover, the effect coincides with clustering of node phases and node frequencies and strengthening of the functional connectivity of some of the connectome’s subnetworks. Overall, the work provides broad theoretical insights into the emergence and mechanisms of stochastic synchronization, highlighting its putative contribution in achieving network integration underpinning brain function.
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary ...substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into nontoxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer ...treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Using a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.
The human need to belong is an innate drive that dictates much of our behavior. Informed by The Belongingness Hypothesis and Information Foraging Theory, the present study examines the relationship ...between FoMO and well-being. Study 1 (107 college students) investigates the relationship between FoMO, social media intensity and social connection. Results find that FoMO is positively associated with social media intensity, but negatively associated with social connection. The mediation tests, interestingly, reveal more positive results regarding FoMO. Specifically, FoMO has a positive indirect effect on social connection through social media intensity, suggesting that FoMO may, in some cases, be a good thing leading to enhanced social connection. Study 2 (458 college students) finds that FoMO impacts subjective well-being both directly (negatively) and indirectly (positively) through its impact on social media intensity and social connection. Results of the two studies reveal a nuanced model of FoMO and its relationships with social media intensity, connection, and well-being. FoMO can have a positive impact on well-being if it leads to social media use that fosters social connection. Study limitations and future research directions are discussed.
Traveling patterns of neuronal activity-brain waves-have been observed across a breadth of neuronal recordings, states of awareness, and species, but their emergence in the human brain lacks a firm ...understanding. Here we analyze the complex nonlinear dynamics that emerge from modeling large-scale spontaneous neural activity on a whole-brain network derived from human tractography. We find a rich array of three-dimensional wave patterns, including traveling waves, spiral waves, sources, and sinks. These patterns are metastable, such that multiple spatiotemporal wave patterns are visited in sequence. Transitions between states correspond to reconfigurations of underlying phase flows, characterized by nonlinear instabilities. These metastable dynamics accord with empirical data from multiple imaging modalities, including electrical waves in cortical tissue, sequential spatiotemporal patterns in resting-state MEG data, and large-scale waves in human electrocorticography. By moving the study of functional networks from a spatially static to an inherently dynamic (wave-like) frame, our work unifies apparently diverse phenomena across functional neuroimaging modalities and makes specific predictions for further experimentation.
Densely seeded probabilistic tractography yields weighted networks that are nearly fully connected, hence containing many spurious fibers. It is thus necessary to prune spurious connections from ...probabilistically-derived networks to obtain a more reliable overall estimate of the connectivity. A standard method is to threshold by weight, keeping only the strongest edges. Here, by measuring the consistency of edge weights across subjects, we propose a new thresholding method that aims to reduce the rate of false-positives in group-averaged connectivity matrices. Close inspection of the relationship between consistency, weight, and distance suggests that the most consistent edges are in fact those that are strong for their length, rather than simply strong overall. Hence retaining the most consistent edges preserves more long-distance connections than traditional weight-based thresholding, which penalizes long connections for being weak regardless of anatomy. By comparing our thresholded networks to mouse and macaque tracer data, we also show that consistency-based thresholding exhibits the species-invariant exponential decay of connection weights with distance, while weight-based thresholding does not. We also show that consistency-based thresholding can be used to identify highly consistent and highly inconsistent subnetworks across subjects, enabling more nuanced analyses of group-level connectivity than just the mean connectivity.
•Thresholding is a common method for pruning networks.•We developed a novel method for thresholding networks by intersubject consistency.•Consistent edges tend to be those that are strong for their length, rather than strong overall.•Our method replicates in an independent dataset.•Consistent edges have similar distance dependence to mouse and macaque tracer data.
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