5' UTR m(6)A Promotes Cap-Independent Translation.

Protein translation typically begins with the recruitment of the 43S ribosomal complex to the 5' cap of mRNAs by a cap-binding complex. However, some transcripts are translated in a cap-independent manner through poorly understood mechanisms. Here, we show that mRNAs containing N(6)-methyladenosine (m(6)A) in their 5' UTR can be translated in a cap-independent manner. A single 5' UTR m(6)A directly binds eukaryotic initiation factor 3 (eIF3), which is sufficient to recruit the 43S complex to initiate translation in the absence of the cap-binding factor eIF4E. Inhibition of adenosine methylation selectively reduces translation of mRNAs containing 5'UTR m(6)A. Additionally, increased m(6)A levels in the Hsp70 mRNA regulate its cap-independent translation following heat shock. Notably, we find that diverse cellular stresses induce a transcriptome-wide redistribution of m(6)A, resulting in increased numbers of mRNAs with 5' UTR m(6)A. These data show that 5' UTR m(6)A bypasses 5' cap-binding proteins to promote translation under stresses.

Tobacco smoking and somatic mutations in human bronchial epithelium.

Tobacco smoking causes lung cancer1-3, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the genome of lung cancer cells are well-documented6-10, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

Social memory in female mice is rapidly modulated by 17ß-estradiol through ERK and Akt modulation of synapse formation.

Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17ß-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and coordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Mice performed a short-term social memory task or were used as task-naïve controls. ERK and PI3K pathway inhibitors were infused intradorsal hippocampally 5 min before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (bassoon puncta positive for GluA1) in task-performing mice but decreased synapse number in task-naïve mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naïve mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. While ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behavior and underscores the importance of estrogen signaling in the brain to social behavior.

m6A enhances the phase separation potential of mRNA.

N6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA1,2, with around 25% of mRNAs containing at least one m6A. Methylation of mRNA to form m6A is required for diverse cellular and physiological processes3. Although the presence of m6A in an mRNA can affect its fate in different ways, it is unclear how m6A directs this process and why the effects of m6A can vary in different cellular contexts. Here we show that the cytosolic m6A-binding proteins-YTHDF1, YTHDF2 and YTHDF3-undergo liquid-liquid phase separation in vitro and in cells. This phase separation is markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including a reduction in the stability and translation of mRNA. These studies reveal that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of m6A-modified mRNAs are governed by liquid-liquid phase separation principles.

Neuroligin-3 and neuroligin-4X form nanoscopic clusters and regulate growth cone organization and size.

The cell-adhesion proteins neuroligin-3 and neuroligin-4X (NLGN3/4X) have well described roles in synapse formation. NLGN3/4X are also expressed highly during neurodevelopment. However, the role these proteins play during this period is unknown. Here we show that NLGN3/4X localized to the leading edge of growth cones where it promoted neuritogenesis in immature human neurons. Super-resolution microscopy revealed that NLGN3/4X clustering induced growth cone enlargement and influenced actin filament organization. Critically, these morphological effects were not induced by autism spectrum disorder (ASD)-associated NLGN3/4X variants. Finally, actin regulators p21-activated kinase 1 and cofilin were found to be activated by NLGN3/4X and involved in mediating the effects of these adhesion proteins on actin filaments, growth cones and neuritogenesis. These data reveal a novel role for NLGN3 and NLGN4X in the development of neuronal architecture, which may be altered in the presence of ASD-associated variants.

Schizophrenia risk proteins ZNF804A and NT5C2 interact in cortical neurons.

The zinc finger protein 804A (ZNF804A) and the 5'-nucleotidase cytosolic II (NT5C2) genes are amongst the first schizophrenia susceptibility genes to have been identified in large-scale genome-wide association studies. ZNF804A has been implicated in the regulation of neuronal morphology and is required for activity-dependent changes to dendritic spines. Conversely, NT5C2 has been shown to regulate 5' adenosine monophosphate-activated protein kinase activity and has been implicated in protein synthesis in human neural progenitor cells. Schizophrenia risk genotype is associated with reduced levels of both NT5C2 and ZNF804A in the developing brain, and a yeast two-hybrid screening suggests that their encoded proteins physically interact. However, it remains unknown whether this interaction also occurs in cortical neurons and whether they could jointly regulate neuronal function. Here, we show that ZNF804A and NT5C2 colocalise and interact in HEK293T cells and that their rodent homologues, ZFP804A and NT5C2, colocalise and form a protein complex in cortical neurons. Knockdown of the Zfp804a or Nt5c2 genes resulted in a redistribution of both proteins, suggesting that both proteins influence the subcellular targeting of each other. The identified interaction between ZNF804A/ZFP804A and NT5C2 suggests a shared biological pathway pertinent to schizophrenia susceptibility within a neuronal cell type thought to be central to the neurobiology of the disorder, providing a better understanding of its genetic landscape.

Design and Advanced Manufacturing of NU-1000 Metal-Organic Frameworks with Future Perspectives for Environmental and Renewable Energy Applications.

Metal-organic frameworks (MOFs) represent a relatively new family of materials that attract lots of attention thanks to their unique features such as hierarchical porosity, active metal centers, versatility of linkers/metal nodes, and large surface area. Among the extended list of MOFs, Zr-based-MOFs demonstrate comparably superior chemical and thermal stabilities, making them ideal candidates for energy and environmental applications. As a Zr-MOF, NU-1000 is first synthesized at Northwestern University. A comprehensive review of various approaches to the synthesis of NU-1000 MOFs for obtaining unique surface properties (e.g., diverse surface morphologies, large surface area, and particular pore size distribution) and their applications in the catalysis (electro-, and photo-catalysis), CO2 reduction, batteries, hydrogen storage, gas storage/separation, and other environmental fields are presented. The review further outlines the current challenges in the development of NU-1000 MOFs and their derivatives in practical applications, revealing areas for future investigation.

Graphene-Based Metal-Organic Framework Hybrids for Applications in Catalysis, Environmental, and Energy Technologies.

Current energy and environmental challenges demand the development and design of multifunctional porous materials with tunable properties for catalysis, water purification, and energy conversion and storage. Because of their amenability to de novo reticular chemistry, metal-organic frameworks (MOFs) have become key materials in this area. However, their usefulness is often limited by low chemical stability, conductivity and inappropriate pore sizes. Conductive two-dimensional (2D) materials with robust structural skeletons and/or functionalized surfaces can form stabilizing interactions with MOF components, enabling the fabrication of MOF nanocomposites with tunable pore characteristics. Graphene and its functional derivatives are the largest class of 2D materials and possess remarkable compositional versatility, structural diversity, and controllable surface chemistry. Here, we critically review current knowledge concerning the growth, structure, and properties of graphene derivatives, MOFs, and their graphene@MOF composites as well as the associated structure-property-performance relationships. Synthetic strategies for preparing graphene@MOF composites and tuning their properties are also comprehensively reviewed together with their applications in gas storage/separation, water purification, catalysis (organo-, electro-, and photocatalysis), and electrochemical energy storage and conversion. Current challenges in the development of graphene@MOF hybrids and their practical applications are addressed, revealing areas for future investigation. We hope that this review will inspire further exploration of new graphene@MOF hybrids for energy, electronic, biomedical, and photocatalysis applications as well as studies on previously unreported properties of known hybrids to reveal potential "diamonds in the rough".

In vitro characterization on the role of APOE polymorphism in human hippocampal neurogenesis.

Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimer's disease progression. APOE polymorphism is the most common genetic risk factor for late-onset Alzheimer's disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time-dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell-like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear "maturation of functional neurons" phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in "metabolism and mitochondrial function." Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome-wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.

Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.

Ocular pterygium-digital keloid dysplasia (OPDKD) presents in childhood with ingrowth of vascularized connective tissue on the cornea leading to severely reduced vision. Later the patients develop keloids on digits but are otherwise healthy. The overgrowth in OPDKD affects body parts that typically have lower temperature than 37°C. We present evidence that OPDKD is associated with a temperature sensitive, activating substitution, p.(Asn666Tyr), in PDGFRB. Phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts at 37°C but were further greatly increased at the average corneal temperature of 32°C. This suggests that the substitution cause significant constitutive autoactivation mainly at lower temperature. In contrast, a different substitution in the same codon, p.(Asn666Ser), is associated with Penttinen type of premature aging syndrome. This devastating condition is characterized by widespread tissue degeneration, including pronounced chronic ulcers and osteolytic resorption in distal limbs. In Penttinen syndrome fibroblasts, equal and high levels of phosphorylated PDGFRB was present at both 32°C and 37°C. This indicates that this substitution causes severe constitutive autoactivation of PDGFRB regardless of temperature. In line with this, most downstream targets were not affected by lower temperature. However, STAT1, important for tissue wasting, did show further increased phosphorylation at 32°C. Temperature-dependent autoactivation offers an explanation to the strikingly different clinical outcomes of substitutions in the Asn666 codon of PDGFRB.

Water-Stable Fluorous Metal-Organic Frameworks with Open Metal Sites and Amine Groups for Efficient Urea Electrocatalytic Oxidation.

Urea oxidation reaction (UOR) is one of the promising alternative anodic reactions to water oxidation that has attracted extensive attention in green hydrogen production. The application of specifically designed electrocatalysts capable of declining energy consumption and environmental consequences is one of the major challenges in this field. Therefore, the goal is to achieve a resistant, low-cost, and environmentally friendly electrocatalyst. Herein, a water-stable fluorinated Cu(II) metalorganic framework (MOF) {[Cu2 (L)(H2 O)2 ]·(5DMF)(4H2 O)}n (Cu-FMOF-NH2 ; H4 L = 3,5-bis(2,4-dicarboxylic acid)-4-(trifluoromethyl)aniline) is developed utilizing an angular tetracarboxylic acid ligand that incorporates both trifluoromethyl (-CF3 ) and amine (-NH2 ) groups. The tailored structure of Cu-FMOF-NH2 where linkers are connected by fluoride bridges and surrounded by dicopper nodes reveals a 4,24T1 topology. When employed as electrocatalyst, Cu-FMOF-NH2 requires only 1.31 V versus reversible hydrogen electrode (RHE) to deliver 10 mA cm-2 current density in 1.0 m KOH with 0.33 m urea electrolyte and delivered an even higher current density (50 mA cm-2 ) at 1.47 V versus RHE. This performance is superior to several reported catalysts including commercial RuO2 catalyst with overpotential of 1.52 V versus RHE. This investigation opens new opportunities to develop and utilize pristine MOFs as a potential electrocatalyst for various catalytic reactions.

Reconfiguring the Electronic Structure of Heteroatom Doped Carbon Supported Bimetallic Oxide@Metal Sulfide Core-Shell Heterostructure via In Situ Nb Incorporation toward Extrinsic Pseudocapacitor.

High-energy-density battery-type materials have sparked considerable interest as supercapacitors electrode; however, their sluggish charge kinetics limits utilization of redox-active sites, resulting in poor electrochemical performance. Here, the unique core-shell architecture of metal organic framework derived N-S codoped carbon@Cox Sy micropetals decorated with Nb-incorporated cobalt molybdate nanosheets (Nb-CMO4 @Cx Sy NC) is demonstrated. Coordination bonding across interfaces and π-π stacking interactions between CMO4 @Cx Sy and N and, S-C can prevent volume expansion during cycling. Density functional theory analysis reveals that the excellent interlayer and the interparticle conductivity imparted by Nb doping in heteroatoms synergistically alter the electronic states and offer more accessible species, leading to increased electrical conductivity with lower band gaps. Consequently, the optimized electrode has a high specific capacity of 276.3 mAh g-1 at 1 A g-1 and retains 98.7% of its capacity after 10 000 charge-discharge cycles. A flexible quasi-solid-state SC with a layer-by-layer deposited reduced graphene oxide /Ti3 C2 TX anode achieves a specific energy of 75.5 Wh kg-1 (volumetric energy of 1.58 mWh cm-3 ) at a specific power of 1.875 kWh kg-1 with 96.2% capacity retention over 10 000 charge-discharge cycles.

Electronic Structure Engineered Heteroatom Doped All Transition Metal Sulfide Carbon Confined Heterostructure for Extrinsic Pseudocapacitor.

Ultra-high energy density battery-type materials are promising candidates for supercapacitors (SCs); however, slow ion kinetics and significant volume expansion remain major barriers to their practical applications. To address these issues, hierarchical lattice distorted α-/γ-MnS@Cox Sy core-shell heterostructure constrained in the sulphur (S), nitrogen (N) co-doped carbon (C) metal-organic frameworks (MOFs) derived nanosheets (α-/γ-MnS@Cox Sy @N, SC) have been developed. The coordination bonding among Cox Sy , and α-/γ-MnS nanoparticles at the interfaces and the π-π stacking interactions developed across α-/γ-MnS@Cox Sy and N, SC restrict volume expansion during cycling. Furthermore, the porous lattice distorted heteroatom-enriched nanosheets contain a sufficient number of active sites to allow for efficient electron transportation. Density functional theory (DFT) confirms the significant change in electronic states caused by heteroatom doping and the formation of core-shell structures, which provide more accessible species with excellent interlayer and interparticle conductivity, resulting in increased electrical conductivity. . The α-/γ-MnS@Cox Sy @N, SC electrode exhibits an excellent specific capacity of 277 mA hg-1 and cycling stability over 23 600 cycles. A quasi-solid-state flexible extrinsic pseudocapacitor (QFEPs) assembled using layer-by-layer deposited multi-walled carbon nanotube/Ti3 C2 TX nanocomposite negative electrode. QFEPs deliver specific energy of 64.8 Wh kg-1 (1.62 mWh cm-3 ) at a power of 933 W kg-1 and 92% capacitance retention over 5000 cycles.

Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells.

BACKGROUND: Prenatal exposure to elevated interleukin (IL)-6 levels is associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ), autism spectrum condition (ASC) and bipolar disorder (BD). Although rodent models provide causal evidence for this association, we lack a detailed understanding of the cellular and molecular mechanisms in human model systems. To close this gap, we characterized the response of human induced pluripotent stem cell (hiPSC-)derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture. RESULTS: We observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both protein and transcript levels due to the absence of IL6R expression and soluble (s)IL6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL6, JMJD3 and IL10 expression in MGL, confirming activation of canonical IL6Ra signaling. Bulk RNAseq identified 156 up-regulated genes (FDR < 0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an up-regulated gene set from human post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility, consistent with gene ontology pathways highlighted from the RNAseq data and replicating rodent model indications that IRF8 regulates microglial motility. Finally, IL-6 induces MGLs to secrete CCL1, CXCL1, MIP-1α/ß, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 after 3 h and 24 h. CONCLUSION: Our data provide evidence for cell specific effects of acute IL-6 exposure in a human model system, ultimately suggesting that microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms.

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Reversible methylation of m6Am in the 5' cap controls mRNA stability.

Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5' end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2'-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.

Inflammation and Fibrosis in Orbital Inflammatory Disease: A Histopathologic Analysis.

PURPOSE: The purpose of this study was to compare the histopathologic inflammation and fibrosis of orbital adipose tissue in orbital inflammatory disease (OID) specimens. METHODS: In this retrospective cohort study, inflammation, and fibrosis in orbital adipose tissue from patients with thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis, nonspecific orbital inflammation (NSOI), and healthy controls were scored by 2 masked ocular pathologists. Both categories were scored on a scale of 0 to 3 with scoring criteria based on the percentage of specimens containing inflammation or fibrosis, respectively. Tissue specimens were collected from oculoplastic surgeons at 8 international centers representing 4 countries. Seventy-four specimens were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 24 with NSOI, and 12 healthy controls. RESULTS: The mean inflammation and fibrosis scores for healthy controls were 0.0 and 1.1, respectively. Orbital inflammatory disease groups' inflammation (I) and fibrosis (F) scores, formatted [I, F] with respective p -values when compared to controls, were: TAO [0.2, 1.4] ( p = 1, 1), GPA [1.9, 2.6] ( p = 0.003, 0.009), sarcoidosis [2.4, 1.9] ( p = 0.001, 0.023), and NSOI [1.3, 1.8] ( p ≤ 0.001, 0.018). Sarcoidosis had the highest mean inflammation score. The pairwise analysis demonstrated that sarcoidosis had a significantly higher mean inflammation score than NSOI ( p = 0.036) and TAO ( p < 0.0001), but no difference when compared to GPA. GPA had the highest mean fibrosis score, with pairwise analysis demonstrating a significantly higher mean fibrosis score than TAO ( p = 0.048). CONCLUSIONS: Mean inflammation and fibrosis scores in TAO orbital adipose tissue samples did not differ from healthy controls. In contrast, the more "intense" inflammatory diseases such as GPA, sarcoidosis, and NSOI did demonstrate higher histopathologic inflammation and fibrosis. This has implications in prognosis, therapeutic selection, and response monitoring in orbital inflammatory disease.

Hierarchical porous metal-organic gels and derived materials: from fundamentals to potential applications.

Metal-organic gels (MOGs) emerged as a novel class of functional soft materials in which the scaffolding framework is fabricated by metal-ligand coordination in combination with other supramolecular interactions (for example, hydrogen bonding or π-π stacking). Through the combination of organic and inorganic (metal/metal-oxo clusters) building blocks, significant steps forward have been made in the development of new electrochemical sensors, superhydrophobic materials and ion storage devices, among others. These leaps forward are to some extend induced by the intrinsic hierarchical microporous/mesoporous pore structure of these metal-organic materials. Within this review we give an overview of recent developments of this growing field. First, we shed light onto the parallels to the well-established field of conventional gels and outline similarities and differences. Afterwards, we classify different types of MOGs according to their architectural/structural nature: (1) pristine MOGs, (2) hybrid MOGs, (3) crosslinking-based MOGs and (4) MOG-derived materials. Furthermore, we look at the different properties of MOGs and the requirements for the preparation of spatially patterned macro-structured MOGs by emerging additive manufacturing technologies. Moreover, different potential fields of application for MOGs and MOG derived materials are critically evaluated and potential improvements and pitfalls in comparison to traditional gel-based materials are given. Finally, a comprehensive outlook into future directions for the development of MOGs is provided.

Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells.

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/µl) or interleukin (IL)-1ß (10 ng/µl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1ß-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1ß impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1ß receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1ß than IFNγ; and c) the genes differentially regulated in SZ lines - in the face of a cytokine challenge - are primarily associated with mitochondrial, "loss-of-function", pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.

m(6)A RNA methylation promotes XIST-mediated transcriptional repression.

The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N6-methyladenosine (m6A) residues-a reversible base modification of unknown function in long non-coding RNAs. We show that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data reveal a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression.