Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Molecular logic of cellular diversification in the mouse cerebral cortex.

The mammalian cerebral cortex has an unparalleled diversity of cell types, which are generated during development through a series of temporally orchestrated events that are under tight evolutionary constraint and are critical for proper cortical assembly and function1,2. However, the molecular logic that governs the establishment and organization of cortical cell types remains unknown, largely due to the large number of cell classes that undergo dynamic cell-state transitions over extended developmental timelines. Here we generate a comprehensive atlas of the developing mouse neocortex, using single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing. We sampled the neocortex every day throughout embryonic corticogenesis and at early postnatal ages, and complemented the sequencing data with a spatial transcriptomics time course. We computationally reconstruct developmental trajectories across the diversity of cortical cell classes, and infer their spatial organization and the gene regulatory programs that accompany their lineage bifurcation decisions and differentiation trajectories. Finally, we demonstrate how this developmental map pinpoints the origin of lineage-specific developmental abnormalities that are linked to aberrant corticogenesis in mutant mice. The data provide a global picture of the regulatory mechanisms that govern cellular diversification in the neocortex.

Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.

De novo heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are strongly associated with autism spectrum disorders; however, it is unclear how heterozygous mutations in this gene affect different cell types during human brain development and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics and spatial transcriptomics and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep-layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity.

A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics.

Mitochondrial inner NEET (MiNT) and the outer mitochondrial membrane (OMM) mitoNEET (mNT) proteins belong to the NEET protein family. This family plays a key role in mitochondrial labile iron and reactive oxygen species (ROS) homeostasis. NEET proteins contain labile [2Fe-2S] clusters which can be transferred to apo-acceptor proteins. In eukaryotes, the biogenesis of [2Fe-2S] clusters occurs within the mitochondria by the iron-sulfur cluster (ISC) system; the clusters are then transferred to [2Fe-2S] proteins within the mitochondria or exported to cytosolic proteins and the cytosolic iron-sulfur cluster assembly (CIA) system. The last step of export of the [2Fe-2S] is not yet fully characterized. Here we show that MiNT interacts with voltage-dependent anion channel 1 (VDAC1), a major OMM protein that connects the intermembrane space with the cytosol and participates in regulating the levels of different ions including mitochondrial labile iron (mLI). We further show that VDAC1 is mediating the interaction between MiNT and mNT, in which MiNT transfers its [2Fe-2S] clusters from inside the mitochondria to mNT that is facing the cytosol. This MiNT-VDAC1-mNT interaction is shown both experimentally and by computational calculations. Additionally, we show that modifying MiNT expression in breast cancer cells affects the dynamics of mitochondrial structure and morphology, mitochondrial function, and breast cancer tumor growth. Our findings reveal a pathway for the transfer of [2Fe-2S] clusters, which are assembled inside the mitochondria, to the cytosol.

Transient Dynamic Operation of G-Quadruplex-Gated Glucose Oxidase-Loaded ZIF-90 Metal-Organic Framework Nanoparticle Bioreactors.

Glucose oxidase-loaded ZIF-90 metal-organic framework nanoparticles conjugated to hemin-G-quadruplexes act as functional bioreactor hybrids operating transient dissipative biocatalytic cascaded transformations consisting of the glucose-driven H2O2-mediated oxidation of Amplex-Red to resorufin or the glucose-driven generation of chemiluminescence by the H2O2-mediated oxidation of luminol. One system involves the fueled activation of a reaction module leading to the temporal formation and depletion of the bioreactor conjugate operating the nickase-guided transient biocatalytic cascades. The second system demonstrates the fueled activation of a reaction module yielding a bioreactor conjugate operating the exonuclease III-dictated transient operation of the two biocatalytic cascades. The temporal operations of the bioreactor circuits are accompanied by kinetic models and computational simulations enabling us to predict the dynamic behavior of the systems subjected to different auxiliary conditions.

Reconfigurable Low-Voltage Hexagonal Boron Nitride Nonvolatile Switches for Millimeter-Wave Wireless Communications.

Recently, nonvolatile resistive switching memory effects have been actively studied in two-dimensional (2D) transition metal dichalcogenides and boron nitrides to advance future memory and neuromorphic computing applications. Here, we report on radiofrequency (RF) switches utilizing hexagonal boron nitride (h-BN) memristors that afford operation in the millimeter-wave (mmWave) range. Notably, silver (Ag) electrodes to h-BN offer outstanding nonvolatile bipolar resistive switching characteristics with a high ON/OFF switching ratio of 1011 and low switching voltage below 0.34 V. In addition, the switch exhibits a low insertion loss of 0.50 dB and high isolation of 23 dB across the D-band spectrum (110 to 170 GHz). Furthermore, the S21 insertion loss can be tuned through five orders of current compliance magnitude, which increases the application prospects for atomic switches. These results can enable the switch to become a key component for future reconfigurable wireless and 6G communication systems.

NMR Shows Why a Small Chemical Change Almost Abolishes the Antimicrobial Activity of Glycocin F.

Glycocin F (GccF), a ribosomally synthesized, post-translationally modified peptide secreted by Lactobacillus plantarum KW30, rapidly inhibits the growth of susceptible bacteria at nanomolar concentrations. Previous studies have highlighted structural features important for its activity and have shown the absolute requirement for the Ser18 O-linked GlcNAc on the eight-residue loop linking the two short helices of the (C-X6-C)2 structure. Here, we show that an ostensibly very small chemical modification to Ser18, the substitution of the Cα proton with a methyl group, reduces the antimicrobial activity of GccF 1000-fold (IC50 1.5 µM cf. 1.5 nM). A comparison of the GccFα-methylSer18 NMR structure (PDB 8DFZ) with that of the native protein (PDB 2KUY) showed a marked difference in the orientation and mobility of the loop, as well as a markedly different positioning of the GlcNAc, suggesting that loop conformation, dynamics, and glycan presentation play an important role in the interaction of GccF with as yet unknown but essential physiological target molecules.

Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain.

Mutations in the Kelch-like 3 (KLHL3) gene are the most common cause of inherited pseudohypoaldosteronism type II (PHAII) featuring thiazide-sensitive hypertension and hyperkalemic metabolic acidosis. Although Klhl3R528H/+ knock-in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense KLHL3 mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed Klhl3 KI mice harboring a nonsense W523X mutation (corresponding to the human KLHL3 W470X mutation). Both heterozygous and homozygous Klhl3W523X/+ KI mice exhibited typical PHAII with low-renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of Klhl3 mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1/4-Spak/Osr1-N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p-)Spak, total Ncc, and p-Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk-mediated Ncc pathway. In vitro studies showed that the human KLHL3 W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense Klhl3W523X/+ mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK-mediated Na+ -Cl- co-transporter reiterated the in vivo pathogenic role of nonsense KLHL3 mutations in PHAII.

Thermococcus argininiproducens sp. nov., an arginine biosynthesis archaeal species isolated from the Central Indian Ocean ridge.

A strictly anaerobic hyperthermophilic archaeon, designated strain IOH2T, was isolated from a deep-sea hydrothermal vent (Onnuri vent field) area on the Central Indian Ocean Ridge. Strain IOH2T showed high 16S rRNA gene sequence similarity to Thermococcus sibiricus MM 739T (99.42 %), Thermococcus alcaliphilus DSM 10322T (99.28 %), Thermococcus aegaeus P5T (99.21 %), Thermococcus litoralis DSM 5473T (99.13 %), 'Thermococcus bergensis' T7324T (99.13 %), Thermococcus aggregans TYT (98.92 %) and Thermococcus prieurii Bio-pl-0405IT2T (98.01 %), with all other strains showing lower than 98 % similarity. The average nucleotide identity and in silico DNA-DNA hybridization values were highest between strain IOH2T and T. sibiricus MM 739T (79.33 and 15.00 %, respectively); these values are much lower than the species delineation cut-offs. Cells of strain IOH2T were coccoid, 1.0-1.2 µm in diameter and had no flagella. Growth ranges were 60-85 °C (optimum at 80 °C), pH 4.5-8.5 (optimum at pH 6.3) and 2.0-6.0 % (optimum at 4.0 %) NaCl. Growth of strain IOH2T was enhanced by starch, glucose, maltodextrin and pyruvate as a carbon source, and elemental sulphur as an electron acceptor. Through genome analysis of strain IOH2T, arginine biosynthesis related genes were predicted, and growth of strain IOH2T without arginine was confirmed. The genome of strain IOH2T was assembled as a circular chromosome of 1 946 249 bp and predicted 2096 genes. The DNA G+C content was 39.44 mol%. Based on the results of physiological and phylogenetic analyses, Thermococcus argininiproducens sp. nov. is proposed with type strain IOH2T (=MCCC 4K00089T=KCTC 25190T).

Cell diversity and network dynamics in photosensitive human brain organoids.

In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.

Clinical history of female-to-male transgender patients is needed to avoid misinterpretation of cervical Papanicolaou tests.

OBJECTIVE: Cervical cancer screening is as important in female-to-male transgender (FTMT) patients as it is in cisgender female patients. The aim of this study was to examine the impact of clinical information regarding gender identity and testosterone therapy on the cytological interpretations. METHODS: A list of FTMT patients and cisgender female patients who had received a cervical Papanicolaou (Pap) test for cancer screening was obtained. The cytological diagnoses, rendered at the time of collection, were recorded. A retrospective slide review with knowledge of the pertinent clinical information, including testosterone therapy status, was performed. The data sets were statistically compared. RESULTS: Of 122 cervical Pap tests in 111 FTMT individuals, 23 (19%) had surgical follow-ups; 73 (60%) had HPV testing, of which 12 (16%) were positive for high-risk strains; and 79 (65%) were known to be receiving testosterone. On the "original" review, 12 (9.8%) tests were diagnosed as unsatisfactory. Seventy-one (58%) Pap tests were initially diagnosed as negative for intraepithelial lesion or malignancy (NILM) without atrophy and 32 (26%) with atrophy. Seven (5.7%) of the tests were initially diagnosed as abnormal. On the "retrospective" review, the rate of unsatisfactory tests remained the same, and atrophy was observed in 76 (62%) tests. The number of abnormal tests was reduced to 4 (3.3%) after the retrospective review. Almost all comparative studies returned a P-value of ≤0.05. CONCLUSION: Our findings indicate that clinical information regarding whether a subject is transgender and/or is receiving testosterone therapy is crucial to avoiding Pap test overcalls.

Semi-Supervised Adversarial Auto-Encoder to Expedite Human Activity Recognition.

The study of human activity recognition concentrates on classifying human activities and the inference of human behavior using modern sensing technology. However, the issue of domain adaptation for inertial sensing-based human activity recognition (HAR) is still burdensome. The existing requirement of labeled training data for adapting such classifiers to every new person, device, or on-body location is a significant barrier to the widespread adoption of HAR-based applications, making this a challenge of high practical importance. We propose the semi-supervised HAR method to improve reconstruction and generation. It executes proper adaptation with unlabeled data without changes to a pre-trained HAR classifier. Our approach decouples VAE with adversarial learning to ensure robust classifier operation, without newly labeled training data, under changes to the individual activity and the on-body sensor position. Our proposed framework shows the empirical results using the publicly available benchmark dataset compared to state-of-art baselines, achieving competitive improvement for handling new and unlabeled activity. The result demonstrates SAA has achieved a 5% improvement in classification score compared to the existing HAR platform.

Flow-Based Fmoc-SPPS Preparation and SAR Study of Cathelicidin-PY Reveals Selective Antimicrobial Activity.

Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH2-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog Paa yunnanensis (PY) and reported to possess broad-spectrum antibacterial and antifungal properties, exhibiting low cytotoxic and low hemolytic activity. Herein, we detail the total synthesis of cathelicidin-PY using an entirely on-resin synthesis, including assembly of the linear sequence by rapid flow Fmoc-SPPS and iodine-mediated disulfide bridge formation. By optimising a synthetic strategy to prepare cathelicidin-PY, this strategy was subsequently adapted to prepare a bicyclic head-to-tail cyclised derivative of cathelicidin-PY. The structure-activity relationship (SAR) of cathelicidin-PY with respect to the N-terminally positioned disulfide was further probed by preparing an alanine-substituted linear analogue and a series of lactam-bridged peptidomimetics implementing side chain to side chain cyclisation. The analogues were investigated for antimicrobial activity, secondary structure by circular dichroism (CD), and stability in human serum. Surprisingly, the disulfide bridge emerged as non-essential to antimicrobial activity and secondary structure but was amenable to synthetic modification. Furthermore, the synthetic AMP and multiple analogues demonstrated selective activity towards Gram-negative pathogen E. coli in physiologically relevant concentrations of divalent cations.

A Prospective Analysis of the SVS WIfI Classification System to Stratify Immediate and 1-Year Patient Outcomes.

The purpose of this study was to prospectively enroll patients that presented to the emergency department with a lower extremity infection, stratify risk and record outcomes. Risk stratification was performed based on the Society of Vascular Surgery Wound, foot Infection, and Ischemia (WIfI) classification system. This study aimed to establish the efficacy and validity of this classification in predicting patient outcomes during immediate hospitalization and throughout a 1 year follow up. A total of 152 patients were enrolled in the study and of these, 116 met the inclusion criteria and had at least 1 year of follow up for analysis. Each patient was assigned a WIfI score based on wound, ischemia, and foot infection severity according to the classification guidelines. Patient demographics as well as all podiatric and vascular procedures were recorded. The major end points of the study were rates of proximal amputation, time to wound healing, surgical procedures, surgical dehiscence, readmission rates, and mortality. A difference in rates of healing (p = .04), surgical dehiscence (p < .01), and 1 year mortality (p = .01) with increasing WIfI stage as well as across the individual component scores was noted. This analysis further supports the application of the WIfI classification system early during patient care to stratify risk and identify the need for early intervention and a multispecialty team approach to potentially improve outcomes in the severe multicomorbid patient.

Treatment of Soft Tissue Defects after Minimally Invasive Plate Osteosynthesis in Fractures of the Distal Tibia: Clinical Results after Reverse Sural Artery Flap.

Introduction: Distal tibial fractures make up approximately 3% to 10% of all tibial fractures or about 1% of lower extremity fractures. MIPO is an appropriate procedure and method to achieve stable metal plate fixation and osseointegration by minimizing soft tissue damage and vascular integrity at the fracture site. MIPO to the medial tibia during distal tibial fractures induces skin irritation due to the thickness of the metal plate, which causes discomfort and pain on the medial side of the distal leg, and if severe, complications such as infection and skin defect may occur. The reverse sural flap is a well-researched approach for covering defects in the lower third of the leg, ankle, and foot. Materials and Methods: Among 151 patients with distal tibia fractures who underwent minimally invasive metal plate fixation, soft tissue was injured due to postoperative complications. We treated 13 cases with necrosis and exposed metal plates by retrograde nasogastric artery flap surgery. For these patients, we collected obligatory patient records, radiological data, and wound photographs of the treatment results and complications of reconstructive surgery. Results: In all the cases, flap survival was confirmed at the final outpatient follow-up. The exposed area of the metal plate was well coated, and there was no plate failure due to complete necrosis. Three out of four women complained of aesthetic dissatisfaction because the volume of the tunnel through which the skin mirror passed and the skin plate itself were thick. In two cases, defatting was performed to reduce the thickness of the plate while removing the metal plate. Conclusions: Metal plate exposure after distal tibial fractures have been treated with minimally invasive metal plate fusion and can be successfully treated with retrograde nasogastric artery flaps, and several surgical techniques are used during flap surgery.

DNA-Tetrahedra Corona-Modified Hydrogel Microcapsules: "Smart" ATP- or microRNA-Responsive Drug Carriers.

The assembly of adenosine triphosphate (ATP)-responsive and miRNA-responsive DNA tetrahedra-functionalized carboxymethyl cellulose hydrogel microcapsules is presented. The microcapsules are loaded with the doxorubicin-dextran drug or with CdSe/ZnS quantum dots as a drug model. Selective unlocking of the respective microcapsules and the release of the loads in the presence of ATP or miRNA-141 are demonstrated. Functionalization of the hydrogel microcapsules a with corona of DNA tetrahedra nanostructures yields microcarriers that revealed superior permeation into cells. This is demonstrated by the effective permeation of the DNA tetrahedra-functionalized microcapsules into MDA-MB-231 breast cancer cells, as compared to epithelial MCF-10A nonmalignant breast cells. The superior permeation of the tetrahedra-functionalized microcapsules into MDA-MB-231 breast cancer cells, as compared to analog control hydrogel microcapsules modified with a corona of nucleic acid duplexes. The effective permeation of the stimuli-responsive, drug-loaded, DNA tetrahedra-modified microcapsules yields drug carriers of superior and selective cytotoxicity toward cancer cells.

Genome-wide association study reveals ethnicity-specific SNPs associated with ankylosing spondylitis in the Taiwanese population.

BACKGROUND: Ankylosing spondylitis (AS) is an autoimmune disease affecting mainly spine and sacroiliac joints and adjacent soft tissues. Genome-wide association studies (GWASs) are used to evaluate genetic associations and to predict genetic risk factors that determine the biological basis of disease susceptibility. We aimed to explore the race-specific SNP susceptibility of AS in Taiwanese individuals and to investigate the association between HLA-B27 and AS susceptibility SNPs in Taiwan. METHODS: Genotyping data were collected from a medical center participating in the Taiwan Precision Medicine Initiative (TPMI) in the northern district of Taiwan. We designed a case-control study to identify AS susceptibility SNPs through GWAS. We searched the genome browser to find the corresponding susceptibility genes and used the GTEx database to confirm the regulation of gene expression. A polygenic risk score approach was also applied to evaluate the genetic variants in the prediction of developing AS. RESULTS: The results showed that the SNPs located on the sixth chromosome were related to higher susceptibility in the AS group. There was no overlap between our results and the susceptibility SNPs found in other races. The 12 tag SNPs located in the MHC region that were found through the linkage disequilibrium method had higher gene expression. Furthermore, Taiwanese people with HLA-B27 positivity had a higher proportion of minor alleles. This might be the reason that the AS prevalence is higher in Taiwan than in other countries. We developed AS polygenic risk score models with six different methods in which those with the top 10% polygenic risk had a fivefold increased risk of developing AS compared to the remaining group with low risk. CONCLUSION: A total of 147 SNPs in the Taiwanese population were found to be statistically significantly associated with AS on the sixth pair of chromosomes and did not overlap with previously published sites in the GWAS Catalog. Whether those genes mapped by AS-associated SNPs are involved in AS and what the pathogenic mechanism of the mapped genes is remain to be further studied.

Bioinspired Control of Calcium Phosphate Liesegang Patterns Using Anionic Polyelectrolytes.

The Liesegang phenomenon is a spontaneous pattern formation, which is a periodic distribution of the precipitate discovered in diffusion-limited systems. Over the past century, it has been experimentally attempted to control the periodicity of patterns and structures of precipitates by varying the concentration of the hydrogel or electrolytes, adding organic or inorganic impurities, and applying an electric or pH field. In this work, the periodic patterns of calcium phosphate were manipulated with an anionic macromolecular additive inspired by bone mineralization in which various noncollagenous proteins are involved in the formation of a polymer-induced liquid precursor. The periodic patterns were systematically controlled by adjusting the amount of poly(acrylic acid), and they were numerically simulated by adjusting the threshold concentration of nucleation. The change of the pattern is explained by improved stability and directional diffusion of the intermediate.

Ultrathin Nanostructured Films of Hyaluronic Acid and Functionalized ß-Cyclodextrin Polymer Suppress Bacterial Infection and Capsular Formation of Medical Silicone Implants.

A type of ultrathin films has been developed for suppressing capsule formation induced by medical silicone implants and hence reducing the inflammation response to such formation and the differentiation to myofibroblasts. The films were each fabricated from hyaluronic acid (HA) and modified ß-cyclodextrin (Mod-ß-CyD) polymer which was synthesized with a cyclodextrin with partially substituted quaternary amine. Ultrathin films comprising HA and Mod-ß-CyD or poly(allylamine hydrochloride) (PAH) were fabricated by using a layer-by-layer dipping method. The electrostatic interactions produced from the functional groups of Mod-ß-CyD and HA influenced the surface morphology, wettability, and bio-functional activity of the film. Notably, medical silicone implants coated with PAH/HA and Mod-ß-CyD multilayers under a low pH condition exhibited excellent biocompatibility and antibiofilm and anti-inflammation properties. Implantation of these nanoscale film-coated silicones showed a reduced capsular thickness as well as reduced TGFß-SMAD signaling, myofibroblast differentiation, biofilm formation, and inflammatory response levels. We expect our novel coating system to be considered a strong candidate for use in various medical implant applications in order to decrease implant-induced capsule formation.

Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics.

Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER-mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research.