Cancer cells secrete matrix metalloproteinases to remodel the extracellular matrix, which enables them to overcome tissue barriers and form metastases. The membrane-bound matrix metalloproteinase MT1-MMP (MMP14) is internalized by endocytosis and recycled in endosomal compartments. It is largely unknown how endosomal sorting and recycling of MT1-MMP are controlled. Here, we show that the endosomal protein WDFY2 controls the recycling of MT1-MMP. WDFY2 localizes to endosomal tubules by binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns3P). We identify the v-SNARE VAMP3 as an interaction partner of WDFY2. WDFY2 knockout causes a strong redistribution of VAMP3 into small vesicles near the plasma membrane. This is accompanied by increased, VAMP3-dependent secretion of MT1-MMP, enhanced degradation of extracellular matrix, and increased cell invasion. WDFY2 is frequently lost in metastatic cancers, most predominantly in ovarian and prostate cancer. We propose that WDFY2 acts as a tumor suppressor by serving as a gatekeeper for VAMP3 recycling.

A GGGGCC hexanucleotide repeat expansion in intron 1 of chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to the neuropathological features of c9FTD/ALS. Among the five DPRs, arginine-rich poly-PR are reported to be the most toxic. Here, we generate a transgenic mouse line that expresses poly-PR (GFP-PR28) specifically in neurons. GFP-PR28 homozygous mice show decreased survival time, while the heterozygous mice show motor imbalance, decreased brain weight, loss of Purkinje cells and lower motor neurons, and inflammation in the cerebellum and spinal cord. Transcriptional analysis shows that in the cerebellum, GFP-PR28 heterozygous mice show differential expression of genes related to synaptic transmission. Our findings show that GFP-PR28 transgenic mice partly model neuropathological features of c9FTD/ALS, and show a role for poly-PR in neurodegeneration.

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.

Plant survival necessitates constant monitoring of fluctuating light and balancing growth demands with adaptive responses, tasks mediated via interconnected sensing and signaling networks. Photoreceptor phytochrome B (phyB) and plastidial retrograde signaling metabolite methylerythritol cyclodiphosphate (MEcPP) are evolutionarily conserved sensing and signaling components eliciting responses through unknown connection(s). Here, via a suppressor screen, we identify two phyB mutant alleles that revert the dwarf and high salicylic acid phenotypes of the high MEcPP containing mutant ceh1. Biochemical analyses show high phyB protein levels in MEcPP-accumulating plants resulting from reduced expression of phyB antagonists and decreased auxin levels. We show that auxin treatment negatively regulates phyB abundance. Additional studies identify CAMTA3, a MEcPP-activated calcium-dependent transcriptional regulator, as critical for maintaining phyB abundance. These studies provide insights into biological organization fundamentals whereby a signal from a single plastidial metabolite is transduced into an ensemble of regulatory networks controlling the abundance of phyB, positioning plastids at the information apex directing adaptive responses.

Sterols and hopanoids are chemically and structurally related lipids mostly found in eukaryotic and bacterial cell membranes. Few bacterial species have been reported to produce sterols and this anomaly had originally been ascribed to lateral gene transfer (LGT) from eukaryotes. In addition, the functions of sterols in these bacteria are unknown and the functional overlap between sterols and hopanoids is still unclear. Gemmata obscuriglobus is a bacterium from the Planctomycetes phylum that synthesizes sterols, in contrast to its hopanoid-producing relatives. Here we show that sterols are essential for growth of G. obscuriglobus, and that sterol depletion leads to aberrant membrane structures and defects in budding cell division. This report of sterol essentiality in a prokaryotic species advances our understanding of sterol distribution and function, and provides a foundation to pursue fundamental questions in evolutionary cell biology.

Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show that protein disorder is abundant in protein/RNA granules and lysine is enriched in disordered regions of proteins in P-bodies compared to the entire human disordered proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates that are more dynamic and differ at the molecular level from arginine/RNA-coacervates. Consistent with the ability of lysine to drive phase separation, lysine-rich variants of the Alzheimer's disease-linked protein tau undergo coacervation with RNA in vitro and bind to stress granules in cells. Acetylation of lysine reverses liquid-liquid phase separation and reduces colocalization of tau with stress granules. Our study establishes lysine as an important regulator of cellular condensation.

Genomic DNA in eukaryotes is organized into chromatin through association with core histones to form nucleosomes, each distinguished by their DNA sequences and histone variants. Here, we used a single-chain antibody fragment (scFv) derived from the anti-nucleosome antibody mAb PL2-6 to stabilize human CENP-A nucleosome containing a native α-satellite DNA and solved its structure by the cryo-electron microscopy (cryo-EM) to 2.6 Å resolution. In comparison, the corresponding cryo-EM structure of the free CENP-A nucleosome could only reach 3.4 Å resolution. We find that scFv binds to a conserved acidic patch on the histone H2A-H2B dimer without perturbing the nucleosome structure. Our results provide an atomic resolution cryo-EM structure of a nucleosome and insight into the structure and function of the CENP-A nucleosome. The scFv approach is applicable to the structural determination of other native-like nucleosomes with distinct DNA sequences.

Solid polymer electrolyte electrochemical energy conversion devices that operate under highly alkaline conditions afford faster reaction kinetics and the deployment of inexpensive electrocatalysts compared with their acidic counterparts. The hydroxide anion exchange polymer is a key component of any solid polymer electrolyte device that operates under alkaline conditions. However, durable hydroxide-conducting polymer electrolytes in highly caustic media have proved elusive, because polymers bearing cations are inherently unstable under highly caustic conditions. Here we report a systematic investigation of novel arylimidazolium and bis-arylimidazolium compounds that lead to the rationale design of robust, sterically protected poly(arylimidazolium) hydroxide anion exchange polymers that possess a combination of high ion-exchange capacity and exceptional stability.

Ca2+ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca2+ diffusion and by nanocourse-specific Ca2+-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca2+ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca2+ flux through RyR2/3 clusters selects for rapid propagation of Ca2+ signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca2+ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.

Cardioprotection by salvage of the infarct-affected myocardium is an unmet yet highly desired therapeutic goal. To develop new dedicated therapies, experimental myocardial ischemia/reperfusion (I/R) injury would require methods to simultaneously characterize extent and localization of the damage and the ensuing inflammatory responses in whole hearts over time. Here we present a three-dimensional (3D), simultaneous quantitative investigation of key I/R injury-components by combining bleaching-augmented solvent-based non-toxic clearing (BALANCE) using ethyl cinnamate (ECi) with light sheet fluorescence microscopy. This allows structural analyses of fluorescence-labeled I/R hearts with exceptional detail. We discover and 3D-quantify distinguishable acute and late vascular I/R damage zones. These contain highly localized and spatially structured neutrophil infiltrates that are modulated upon cardiac healing. Our model demonstrates that these characteristic I/R injury patterns can detect the extent of damage even days after the ischemic index event hence allowing the investigation of long-term recovery and remodeling processes.

Psychological sciences have identified a wealth of cognitive processes and behavioral phenomena, yet struggle to produce cumulative knowledge. Progress is hamstrung by siloed scientific traditions and a focus on explanation over prediction, two issues that are particularly damaging for the study of multifaceted constructs like self-regulation. Here, we derive a psychological ontology from a study of individual differences across a broad range of behavioral tasks, self-report surveys, and self-reported real-world outcomes associated with self-regulation. Though both tasks and surveys putatively measure self-regulation, they show little empirical relationship. Within tasks and surveys, however, the ontology identifies reliable individual traits and reveals opportunities for theoretic synthesis. We then evaluate predictive power of the psychological measurements and find that while surveys modestly and heterogeneously predict real-world outcomes, tasks largely do not. We conclude that self-regulation lacks coherence as a construct, and that data-driven ontologies lay the groundwork for a cumulative psychological science.

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.

Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease.

Complex conformational dynamics are essential for function of the dimeric molecular chaperone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimerization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90.

Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

Formic acid (or formate) is suggested to be one of the most economically viable products from electrochemical carbon dioxide reduction. However, its commercial viability hinges on the development of highly active and selective electrocatalysts. Here we report that structural defects have a profound positive impact on the electrocatalytic performance of bismuth. Bismuth oxide double-walled nanotubes with fragmented surface are prepared as a template, and are cathodically converted to defective bismuth nanotubes. This converted electrocatalyst enables carbon dioxide reduction to formate with excellent activity, selectivity and stability. Most significantly, its current density reaches ~288 mA cm-2 at -0.61 V versus reversible hydrogen electrode within a flow cell reactor under ambient conditions. Using density functional theory calculations, the excellent activity and selectivity are rationalized as the outcome of abundant defective bismuth sites that stabilize the *OCHO intermediate. Furthermore, this electrocatalyst is coupled with silicon photocathodes and achieves high-performance photoelectrochemical carbon dioxide reduction.

The realisation of photonic devices for different energy ranges demands materials with different bandgaps, sometimes even within the same device. The optimal solution in terms of integration, device performance and device economics would be a simple material system with widely tunable bandgap and compatible with the mainstream silicon technology. Here, we show that gallium arsenide nanowires grown epitaxially on silicon substrates exhibit a sizeable reduction of their bandgap by up to 40% when overgrown with lattice-mismatched indium gallium arsenide or indium aluminium arsenide shells. Specifically, we demonstrate that the gallium arsenide core sustains unusually large tensile strain with hydrostatic character and its magnitude can be engineered via the composition and the thickness of the shell. The resulted bandgap reduction renders gallium arsenide nanowires suitable for photonic devices across the near-infrared range, including telecom photonics at 1.3 and potentially 1.55 μm, with the additional possibility of monolithic integration in silicon-CMOS chips.

Continuity, robustness, and regeneration of cell lineages relies on stem cell pools that are established during development. For the mammalian spermatogenic lineage, a foundational spermatogonial stem cell (SSC) pool arises from prospermatogonial precursors during neonatal life via mechanisms that remain undefined. Here, we mapped the kinetics of this process in vivo using a multi-transgenic reporter mouse model, in silico with single-cell RNA sequencing, and functionally with transplantation analyses to define the SSC trajectory from prospermatogonia. Outcomes revealed that a heterogeneous prospermatogonial population undergoes dynamic changes during late fetal and neonatal development. Differential transcriptome profiles predicted divergent developmental trajectories from fetal prospermatogonia to descendant postnatal spermatogonia. Furthermore, transplantation analyses demonstrated that a defined subset of fetal prospermatogonia is fated to function as SSCs. Collectively, these findings suggest that SSC fate is preprogrammed within a subset of fetal prospermatogonia prior to building of the foundational pool during early neonatal development.

Materials combining optical transparency and mechanical strength are highly demanded for electronic displays, structural windows and in the arts, but the oxide-based glasses currently used in most of these applications suffer from brittle fracture and low crack tolerance. We report a simple approach to fabricate bulk transparent materials with a nacre-like architecture that can effectively arrest the propagation of cracks during fracture. Mechanical characterization shows that our glass-based composites exceed up to a factor of 3 the fracture toughness of common glasses, while keeping flexural strengths comparable to transparent polymers, silica- and soda-lime glasses. Due to the presence of stiff reinforcing platelets, the hardness of the obtained composites is an order of magnitude higher than that of transparent polymers. By implementing biological design principles into glass-based materials at the microscale, our approach opens a promising new avenue for the manufacturing of structural materials combining antagonistic functional properties.

Here we report the results of multiple analytical techniques on sub-mm particulate material derived from Unit 1 of the Fukushima Daiichi Nuclear Power Plant to provide a better understanding of the events that occurred and the environmental legacy. Through combined x-ray fluorescence and absorption contrast micro-focused x-ray tomography, entrapped U particulate are observed to exist around the exterior circumference of the highly porous Si-based particle. Further synchrotron radiation analysis of a number of these entrapped particles shows them to exist as UO2-identical to reactor fuel, with confirmation of their nuclear origin shown via mass spectrometry analysis. While unlikely to represent an environmental or health hazard, such assertions would likely change should break-up of the Si-containing bulk particle occur. However, more important to the long-term decommissioning of the reactors at the FDNPP (and environmental clean-upon), is the knowledge that core integrity of reactor Unit 1 was compromised with nuclear material existing outside of the reactors primary containment.