Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.

Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards "energy metabolism" as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Feeding patterns of Atlantic salmon (Salmo salar) parr are better explained by local drivers than by macroecological drivers.

We modeled feeding of the Atlantic salmon (Salmo salar) parr to understand the role of global (cross-continental) and regional (river) spatial scales for delineating feeding patterns. The diet composition differed between Eurasia and North America populations. Geographic location (latitude and elevation) had an influence for the most common prey (Ephemeroptera, Diptera and Plecoptera). The random factors (sampling location and river) had a strong explanatory power in our models, suggesting that local drivers may override the effects of large-scale drivers.

Formative Research to Design and Evaluate Caring Text Messages for American Indian and Alaska Native Youth, College Students, and Veterans.

Purpose. Caring Text Messages (CTM) is an evidence-based intervention, developed by the Northwest Portland Area Indian Health Board, modeled after the Caring Contacts (CC) intervention. CC has been shown to prevent suicide deaths, attempts, ideation, and hospitalizations in a variety of settings. Method. Three sets of CTM were developed by American Indian and Alaska Native (AI/AN) teens, college students, and veterans (tailored for each audience), which were reviewed by psychologists familiar with the intervention. To enroll in the service, participants texted a keyword to a text message short code and received two text messages per week with hopeful and encouraging messages. A robust multimedia social marketing campaign was designed to promote the service for each audience. Results. By September 2023, 387 participants enrolled in the Youth CTM intervention, 141 enrolled in the College CTM, and 31 enrolled in the Veterans CTM. Post surveys show elevated levels of user satisfaction. Conclusions. CTM can be tailored to reach populations at higher risk of suicide, including AI/AN youth, college students, and veterans, and connect them to culturally responsive peer and crisis support services. Continued monitoring and evaluation can guide next steps for marketing and outreach and will be useful to determine its impact on those who enroll.

TPPU_DSF: A Web Application to Calculate Thermodynamic Parameters Using DSF Data.

Here we present TPPU_DSF (https://maciasnmr.net/tppu_dsf/). This is a free and open-source web application that opens, converts, fits, and calculates the thermodynamic parameters of protein unfolding from standard differential scanning fluorimetry (DSF) data in an automated manner. The software has several applications. In the context of screening compound libraries for protein binders, obtaining thermodynamic parameters provides a more robust approach to detecting hits than the changes in the melting temperature (Tm) alone, thereby helping to increase the number of positive hits in screening campaigns. Moreover, changes in ΔGuo indicate protein response to binding at lower compound concentrations than those in the Tm, thereby reducing the costs associated with the amounts of protein and compounds required for the assays. Also, by adding thermodynamic information to the Tm comparison, the software can contribute to the optimization of protein constructs and buffer conditions, a common practice before structural and functional projects.

Mind4Health: decolonizing gatekeeper trainings using a culturally relevant text message intervention.

Background: When a person dies by suicide, it takes a reverberating emotional, physical, and economic toll on families and communities. The widespread use of social media among youth and adolescents, disclosures of emotional distress, suicidal ideation, intent to self-harm, and other mental health crises posted on these platforms have increased. One solution to address the need for responsive suicide prevention and mental health services is to implement a culturally-tailored gatekeeper training. The Northwest Portland Area Indian Health Board (NPAIHB) developed Mind4Health, an online gatekeeper training (90 min) and text message intervention for caring adults of American Indian/Alaska Native (AI/AN) youth. Methods: The Mind4Health intervention was a multi-phase, single-arm, pre-and post-test study of users enrolled in the intervention that is available via text message (SMS) or via a 90 min online, self-paced training. We produced four datasets in this study: Mobile Commons, pre-survey data, post-survey data, and Healthy Native Youth website's Google Analytics. The analysis included data cleaning, basic frequency counts, percentages, and descriptive statistics. Qualitative data were analyzed using thematic content analysis methods and hand-coding techniques with two independent coders. Results: From 2022 to 2024, 280 people enrolled in the Mind4Health SMS training, and 250 completed the 8-week intervention. Many messages in the sequence were multi-part text messages and over 21,500 messages were sent out during the timeframe. Of the 280 subscribers, 52 participated in the pre-survey. Pre-survey data show that 94% of participants were female, and nearly one-fourth lived in Washington state, 92% of participants in the pre-survey were very to moderately comfortable talking with youth about mental health (n = 48). Most participants interact with youth in grades K-12. Post-survey data demonstrate changes in knowledge, beliefs, comfort talking about mental health, and self-efficacy among participants. Mind4Health improved participant's skills to have mental health conversations with youth and refer youth to resources in their community.

IFN-γ stimulates Paneth cell secretion through necroptosis mTORC1 dependent.

Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut.

Significance of utilizing in silico structural analysis and phenotypic data to characterize phenylalanine hydroxylase variants: A PAH landscape.

Phenylketonuria (PKU) is a genetic disorder caused by variations in the phenylalanine hydroxylase (PAH) gene. Among the 3369 reported PAH variants, 33.7% are missense alterations. Unfortunately, 30% of these missense variants are classified as variants of unknown significance (VUS), posing challenges for genetic risk assessment. In our study, we focused on analyzing 836 missense PAH variants following the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines specified by ClinGen PAH Variant Curation Expert Panel (VCEP) criteria. We utilized and compared variant annotator tools like Franklin and Varsome, conducted 3D structural analysis of PAH, and examined active and regulatory site hotspots. In addition, we assessed potential splicing effect of apparent missense variants. By evaluating phenotype data from 22962 PKU patients, our aim was to reassess the pathogenicity of missense variants. Our comprehensive approach successfully reclassified 309 VUSs out of 836 missense variants as likely pathogenic or pathogenic (37%), upgraded 370 likely pathogenic variants to pathogenic, and reclassified one previously considered likely benign variant as likely pathogenic. Phenotypic information was available for 636 missense variants, with 441 undergoing 3D structural analysis and active site hotspot identification for 180 variants. After our analysis, only 6% of missense variants were classified as VUSs, and three of them (c.23A>C/p.Asn8Thr, c.59_60delinsCC/p.Gln20Pro, and c.278A >T/p.Asn93Ile) may be influenced by abnormal splicing. Moreover, a pathogenic variant (c.168G>T/p.Glu56Asp) was identified to have a risk exceeding 98% for modifications of the consensus splice site, with high scores indicating a donor loss of 0.94. The integration of ACMG/AMP guidelines with in silico structural analysis and phenotypic data significantly reduced the number of missense VUSs, providing a strong basis for genetic counseling and emphasizing the importance of metabolic phenotype information in variant curation. This study also sheds light on the current landscape of PAH variants.

Dopamine synthesis and transport: current and novel therapeutics for parkinsonisms.

Parkinsonism is the primary type of movement disorder in adults, encompassing a set of clinical symptoms, including rigidity, tremors, dystonia, bradykinesia, and postural instability. These symptoms are primarily caused by a deficiency in dopamine (DA), an essential neurotransmitter in the brain. Currently, the DA precursor levodopa (synthetic L-DOPA) is the standard medication to treat DA deficiency, but it only addresses symptoms rather than provides a cure. In this review, we provide an overview of disorders associated with DA dysregulation and deficiency, particularly Parkinson's disease and rare inherited disorders leading predominantly to dystonia and/or parkinsonism, even in childhood. Although levodopa is relatively effective for the management of motor dysfunctions, it is less effective for severe forms of parkinsonism and is also associated with side effects and a loss of efficacy over time. We present ongoing efforts to reinforce the effect of levodopa and to develop innovative therapies that target the underlying pathogenic mechanisms affecting DA synthesis and transport, increasing neurotransmission through disease-modifying approaches, such as cell-based therapies, nucleic acid- and protein-based biologics, and small molecules.

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

Advances in chitosan and chitosan derivatives for biomedical applications in tissue engineering: An updated review.

In recent years, chitosan (CS) has received much attention as a functional biopolymer for various applications, especially in the biomedical field. It is a natural polysaccharide created by the chemical deacetylation of chitin (CT) that is nontoxic, biocompatible, and biodegradable. This natural polymer is difficult to process; however, chemical modification of the CS backbone allows improved use of functional derivatives. CS and its derivatives are used to prepare hydrogels, membranes, scaffolds, fibers, foams, and sponges, primarily for regenerative medicine. Tissue engineering (TE), currently one of the fastest-growing fields in the life sciences, primarily aims to restore or replace lost or damaged organs and tissues using supports that, combined with cells and biomolecules, generate new tissue. In this sense, the growing interest in the application of biomaterials based on CS and some of its derivatives is justifiable. This review aims to summarize the most important recent advances in developing biomaterials based on CS and its derivatives and to study their synthesis, characterization, and applications in the biomedical field, especially in the TE area.

Mouse models for inherited monoamine neurotransmitter disorders.

Several mouse models have been developed to study human defects of primary and secondary inherited monoamine neurotransmitter disorders (iMND). As the field continues to expand, current defects in corresponding mouse models include enzymes and a molecular co-chaperone involved in monoamine synthesis and metabolism (PAH, TH, PITX3, AADC, DBH, MAOA, DNAJC6), tetrahydrobiopterin (BH4) cofactor synthesis and recycling (adGTPCH1/DRD, arGTPCH1, PTPS, SR, DHPR), and vitamin B6 cofactor deficiency (ALDH7A1), as well as defective monoamine neurotransmitter packaging (VMAT1, VMAT2) and reuptake (DAT). No mouse models are available for human DNAJC12 co-chaperone and PNPO-B6 deficiencies, disorders associated with recessive variants that result in decreased stability and function of the aromatic amino acid hydroxylases and decreased neurotransmitter synthesis, respectively. More than one mutant mouse is available for some of these defects, which is invaluable as different variant-specific (knock-in) models may provide more insights into underlying mechanisms of disorders, while complete gene inactivation (knock-out) models often have limitations in terms of recapitulating complex human diseases. While these mouse models have common phenotypic traits also observed in patients, reflecting the defective homeostasis of the monoamine neurotransmitter pathways, they also present with disease-specific manifestations with toxic accumulation or deficiency of specific metabolites related to the specific gene affected. This review provides an overview of the currently available models and may give directions toward selecting existing models or generating new ones to investigate novel pathogenic mechanisms and precision therapies.

Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model.

Proteostatic regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the TH gene are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH4) on the stability of TH in isolated protein and in DAn- differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH4 a knock-in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH4 significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH4 on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH4 as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.

One ring closer to a closure: the crystal structure of the ES3 hydroxymethylbilane synthase intermediate.

Hydroxymethylbilane synthase (HMBS), involved in haem biosynthesis, catalyses the head-to-tail coupling of four porphobilinogens (PBGs) via a dipyrromethane (DPM) cofactor. DPM is composed of two PBGs, and a hexapyrrole is built before the tetrapyrrolic 1-hydroxymethylbilane product is released. During this elongation, stable enzyme (E) intermediates are formed from the holoenzyme, with additional PBG substrates (S): ES, ES2 , ES3 and ES4 . Native PAGE and mass spectrometry of the acute intermittent porphyria (AIP)-associated HMBS variant p.Arg167Gln demonstrated an increased amount of ES3 . Kinetic parameters indicated catalytic dysfunction, however, the product release was not entirely prevented. Isolation and crystal structure analysis of the ES3 intermediate (PDB: 8PND) showed that a pentapyrrole was fully retained within the active site, revealing that polypyrrole elongation proceeds within the active site via a third interaction site, intermediate pyrrole site 3 (IPS3). The AIP-associated HMBS variant p.Arg195Cys, located on the opposite side to p.Arg167Gln in the active site, accumulated the ES4 intermediate in the presence of excess PBG, implying that product hydrolysis was obstructed. Arg167 is thus involved in all elongation steps and is a determinant for the rate of enzyme catalysis, whereas Arg195 is important for releasing the product. Moreover, by substituting residues in the vicinity of IPS3, our results indicate that a fully retained hexapyrrole could be hydrolysed in a novel site in proximity of the IPS3.

Phytochemical characterization and antifungal potential of leaf extracts of Mosiera bullata.

The investigation of natural alternatives to conventional fungicides is of imminent need. Mosiera bullata (Britton & P. Wilson) Bisse is a Cuban endemic plant species belonging to the Myrtaceae family. The objective of the present study was to perform a bioassay-guided fractionation to explore the potential of extracts and fractions from M. bullata leaves against a panel of fungal plant pathogens. The M. bullata total extract was confirmed to have good antifungal activity against R. oryzae (IC50 = 4.86 µg/mL) and moderate activity against F. oxysporum (IC50 = 352.40 µg/mL) and F. solani (IC50 = 427.38 µg/mL) and fungicidal effect against R. oryzae. Five compounds belonging to the class of phloroglucinol dimers were tentatively characterized by UHPLC-HRMS and reported for the first time in M. bullata and the genus Mosiera. These results suggest the potential of M. bullata total extract as a natural antifungal product for the control of diseases in agriculture.

Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review.

Potassium channels (K+-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K+-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K+-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K+-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K+-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K+-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K+-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.

Inhibition of VMAT2 by ß2-adrenergic agonists, antagonists, and the atypical antipsychotic ziprasidone.

Vesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington's chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably ß2-adrenergic agonists salmeterol, vilanterol and formoterol, ß2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.

Comparison Between the Wavefront-Optimized and Custom-Q Aspheric Ablation Profiles in Myopic Eyes With Two Different Q-targets: A Contralateral Eye Study.

PURPOSE: To compare two aspheric ablation profiles in myopic refractive surgery using different asphericity targets. METHODS: Patients underwent laser in situ keratomileusis (LASIK) with the WaveLight EX500 laser platform (Alcon, WaveLight Laser Technologie). Asymmetric surgery was performed, programming the wavefront-optimized (WFO) ablation profile in one eye and the custom-Q (CQ) profile in the contralateral eye. The patients were divided into two groups following a systematic randomization method. The Q-target programmed for the preoperative Q group was equal to the preoperative asphericity of the CQ profile, and for the -0.6 Q-target group, the Q-target was set to -0.6. RESULTS: The study included 100 patients (200 eyes). Both groups had comparable safety and efficacy indexes greater than 1. A similar oblate shift in postoperative asphericity was seen in both groups regardless of the ablation profile and programmed Q-target. Asphericity was 0.33 ± 0.34 and 0.35 ± 0.29 (P = .18) in the preoperative Q group and 0.26 ± 0.28 and 0.26 ± 0.27 (P = .89) in the -0.6 Q-target group for WFO and CQ, respectively. A lower spherical aberration was found with CQ compared to WFO when the Q-target was set to -0.6: 0.211 ± 0.121 versus 0.144 ± 0.114 (P < .01). However, no statistically significant differences were found when the preoperative Q-target was used. CONCLUSIONS: WFO and CQ treatments are similar in terms of refractive and visual outcomes. CQ offers greater control over the increase in positive spherical aberration after myopic refractive surgery, but it does not represent an advantage over WFO in the oblate shift in postoperative asphericity regardless of the Q-target programmed. [J Refract Surg. 2022;38(11):698-707.].

Acute lymphoblastic leukemia-secreted miRNAs induce a proinflammatory microenvironment and promote the activation of hematopoietic progenitors.

Leukemogenesis is proposed to result from the continuous interplay between inducive bone marrow (BM) microenvironments and malignant precursor cells. Recent findings point toward an abnormal production of proinflammatory mediators within the BM from acute lymphoblastic leukemia (ALL) patients, although the mechanism underlying this phenomenon is uncertain. Here, we have identified 3 miRNAs, miR-146a-5p, miR-181b-5p, and miR-199b-3p, as potential candidates for TLR8 ligation, which are overexpressed in ALL and show agonist functional binding. When purified from ALL exosomes, they demonstrated their capacity of inducing cytokine production by both, hematopoietic and stromal BM cells. Of note, the exposure of BM cells from ALL patients to the proinflammatory milieu resulting from these miRNAs agonist activity revealed the proliferation of normal progenitors, while poor effects were recorded in the leukemic counterpart. The unconventional roles of the tumor-secreted miRNAs as TLR8 agonist ligands may provide a novel mechanism contributing a tumor-microenvironment feedback loop by switching on proinflammatory pathways that further activate normal hematopoietic precursors and support ALL progression. Secreted B-ALL TLR8-agonist miRNAs are involved in the promotion of proinflammatory microenvironments that target normal hematopoietic cells. B-lineage ALL cells secrete exosomes containing miRNAs endowed with the ability of functionally binding TLR8 in hematopoietic and BM mesenchymal stromal cells. Upon TLR8 signaling, the activation of the NF-kB pathway induces secretion of proinflammatory cytokines that, in turn, promotes cell proliferation in early hematopoietic cell populations, driving a tumor-microenvironment-hematopoietic activation feedback loop that may reduce the normal hematopoietic stem and progenitor cell compartment and facilitate cancer progression.

High-affinity anti-Arc nanobodies provide tools for structural and functional studies.

Activity-regulated cytoskeleton-associated protein (Arc) is a multidomain protein of retroviral origin with a vital role in the regulation of synaptic plasticity and memory formation in mammals. However, the mechanistic and structural basis of Arc function is poorly understood. Arc has an N-terminal domain (NTD) involved in membrane binding and a C-terminal domain (CTD) that binds postsynaptic protein ligands. In addition, the NTD and CTD both function in Arc oligomerisation, including assembly of retrovirus-like capsids involved in intercellular signalling. To obtain new tools for studies on Arc structure and function, we produced and characterised six high-affinity anti-Arc nanobodies (Nb). The CTD of rat and human Arc were both crystallised in ternary complexes with two Nbs. One Nb bound deep into the stargazin-binding pocket of Arc CTD and suggested competitive binding with Arc ligand peptides. The crystallisation of the human Arc CTD in two different conformations, accompanied by SAXS data and molecular dynamics simulations, paints a dynamic picture of the mammalian Arc CTD. The collapsed conformation closely resembles Drosophila Arc in capsids, suggesting that we have trapped a capsid-like conformation of the human Arc CTD. Our data obtained with the help of anti-Arc Nbs suggest that structural dynamics of the CTD and dimerisation of the NTD may promote the formation of capsids. Taken together, the recombinant high-affinity anti-Arc Nbs are versatile tools that can be further developed for studying mammalian Arc structure and function, as well as mechanisms of Arc capsid formation, both in vitro and in vivo. For example, the Nbs could serve as a genetically encoded tools for inhibition of endogenous Arc interactions in the study of neuronal function and plasticity.