ZNF692 regulates nucleolar morphology by interacting with NPM1 and modifying its self-assembly properties.

The nucleolus, a membrane-less organelle, is responsible for ribosomal RNA transcription, ribosomal RNA processing, and ribosome assembly. Nucleolar size and number are indicative of a cell's protein synthesis rate and proliferative capacity, and abnormalities in the nucleolus have been linked to neurodegenerative diseases and cancer. In this study, we demonstrated that the nucleolar protein ZNF692 directly interacts with nucleophosmin 1 (NPM1). Knocking down ZNF692 resulted in the nucleolar redistribution of NPM1 in ring-like structures and reduced protein synthesis. Purified NPM1 forms spherical condensates in vitro but mixing it with ZNF692 produces irregular condensates more closely resembling living cell nucleoli. Our findings indicate that ZNF692, by interacting with NPM1, plays a critical role in regulating nucleolar architecture and function in living cells.

Membrane phospholipids activate the inflammatory response in macrophages by various mechanisms.

Exosomes, which are small membrane-encapsulated particles derived from all cell types, are emerging as important mechanisms for intercellular communication. In addition, exosomes are currently envisioned as potential carriers for the delivery of drugs to target tissues. The natural population of exosomes is very variable due to the limited amount of cargo components present in these small vesicles. Consequently, common components of exosomes may play a role in their function. We have proposed that membrane phospholipids could be a common denominator in the effect of exosomes on cellular functions. In this regard, we have previously shown that liposomes made of phosphatidylcholine (PC) or phosphatidylserine (PS) induced a robust alteration of macrophage (Mϕ) gene expression. We herewith report that these two phospholipids modulate gene expression in Mϕs by different mechanisms. PS alters cellular responses by the interaction with surface receptors, particularly CD36. In contrast, PC is captured by a receptor-independent process and likely triggers an activity within endocytic vesicles. Despite this difference in the capture mechanisms, both lipids mounted similar gene expression responses. This investigation suggests that multiple mechanisms mediated by membrane phospholipids could be participating in the alteration of cellular functions by exosomes.

Solving the conundrum of intra-specific variation in metabolic rate: A multidisciplinary conceptual and methodological toolkit: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species: New technical developments are opening the door to an understanding of why metabolic rate varies among individual animals of a species.

Researchers from diverse disciplines, including organismal and cellular physiology, sports science, human nutrition, evolution and ecology, have sought to understand the causes and consequences of the surprising variation in metabolic rate found among and within individual animals of the same species. Research in this area has been hampered by differences in approach, terminology and methodology, and the context in which measurements are made. Recent advances provide important opportunities to identify and address the key questions in the field. By bringing together researchers from different areas of biology and biomedicine, we describe and evaluate these developments and the insights they could yield, highlighting the need for more standardisation across disciplines. We conclude with a list of important questions that can now be addressed by developing a common conceptual and methodological toolkit for studies on metabolic variation in animals.

Multi-cell type gene coexpression network analysis reveals coordinated interferon response and cross-cell type correlations in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease disproportionately affecting women. A major obstacle in finding targeted therapies for SLE is its remarkable heterogeneity in clinical manifestations as well as in the involvement of distinct cell types. To identify cell-specific targets as well as cross-correlation relationships among expression programs of different cell types, we here analyze six major circulating immune cell types from SLE patient blood. Our results show that presence of an interferon response signature stratifies patients into two distinct groups (IFNneg vs. IFNpos). Comparing these two groups using differential gene expression and differential gene coexpression analysis, we prioritize a relatively small list of genes from classical monocytes including two known immune modulators: TNFSF13B/BAFF (target of belimumab, an approved therapeutic for SLE) and IL1RN (the basis of anakinra, a therapeutic for rheumatoid arthritis). We then develop a multi-cell type extension of the weighted gene coexpression network analysis (WGCNA) framework, termed mWGCNA. Applying mWGCNA to RNA-seq data from six sorted immune cell populations (15 SLE, 10 healthy donors), we identify a coexpression module with interferon-stimulated genes (ISGs) among all cell types and a cross-cell type correlation linking expression of specific T helper cell markers to B cell response as well as to TNFSF13B expression from myeloid cells, all of which in turn correlates with disease severity of IFNpos patients. Our results demonstrate the power of a hypothesis-free and data-driven approach to discover drug targets and to reveal novel cross-correlation across cell types in SLE with implications for other autoimmune diseases.

Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders.

Neuropathic lysosomal storage disorders (LSDs) present with activated pro-inflammatory microglia. However, anti-inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann-Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration-prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build-up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann-Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.

Arrhythmias induced by dextrose-insulin challenge test in nondiagnostic Brugada ECG patterns.

INTRODUCTION: Dynamic ECG changes in Brugada syndrome (BrS) are influenced by several factors, may not be apparent, and can be unmasked by a drug test. METHODS AND RESULTS: Four of six patients with nondiagnostic Brugada ECG index patterns underwent a dextrose-insulin challenge test that resulted in J-ST segment elevation and triggered arrhythmias. CONCLUSION: Insulin action may be due in part to an outward shift in the K+ current at the end of action potential phase 1 and the dispersion of repolarization, leading to local re-entry with arrhythmogenicity. This effect is likely a phenomenon-specific to BrS.

Rewiring Vascular Metabolism Prevents Sudden Death due to Aortic Ruptures-Brief Report.

BACKGROUND: The goal of this study was to determine whether boosting mitochondrial respiration prevents the development of fatal aortic ruptures triggered by atherosclerosis and hypertension. METHODS: Ang-II (angiotensin-II) was infused in ApoE (Apolipoprotein E)-deficient mice fed with a western diet to induce acute aortic aneurysms and lethal ruptures. RESULTS: We found decreased mitochondrial respiration and mitochondrial proteins in vascular smooth muscle cells from murine and human aortic aneurysms. Boosting NAD levels with nicotinamide riboside reduced the development of aortic aneurysms and sudden death by aortic ruptures. CONCLUSIONS: Targetable vascular metabolism is a new clinical strategy to prevent fatal aortic ruptures and sudden death in patients with aortic aneurysms.

Long-Term Exposure of the Red Cherry Shrimp Neocaridina davidi to Diclofenac: Impact on Survival, Growth, and Reproductive Potential.

The current study was aimed at studying the long-term effects of diclofenac on the freshwater shrimp Neocaridina davidi, concerning survival, somatic growth, and reproduction. In this study, both ovigerous females and males of this species were exposed for 63 d to 0 (control), 0.1, or 1 mg/L of diclofenac. At the highest concentration, significant mortality was detected, and the somatic growth of females was significantly decreased. The percentage of females with a second spawn, observable from day 45, significantly increased at 1 mg/L, while the time between spawns was significantly reduced at both concentrations assayed. However, the gonadal analysis made at the end of the assay in the surviving females showed a significantly lower proportion of advanced oocytes in females exposed to 1 mg/L, as compared to control. Concerning hatching, the percentage of ovigerous females that could have successful hatching was reduced at 1 mg/L of diclofenac, especially for the first spawn. For the second spawn, the low number of juveniles hatched from females exposed to 1 mg/L also showed a significantly higher incidence of morphological abnormalities, such as hydropsy and underdeveloped appendages. Taken together, these results showed that even when diclofenac was able to produce earlier spawns, the reproductive output of each spawn was reduced.

Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. METHODS: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration. RESULTS: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice. CONCLUSIONS: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Inhibition of Oocyte Maturation in the Estuarine Crab Neohelice Granulata, by the Effect of Anti-Inflammatory Drugs.

The drugs ibuprofen and diclofenac were assessed in vivo on adult females of the estuarine crab Neohelice granulata. In a first, preliminary assay comprising 60-d, a significant (p < 0.05) lower content of total vitellogenic proteins was detected in the ovary at 10 mg/L of each drug. In a second 90-d assay, comprising the exposure of crabs to 5 mg/L of each drug during the entire pre-reproductive period, a significant (p < 0.05) decrease in the proportion of vitellogenic oocytes was observed by effect of diclofenac. The same effect was also observed in a third assay only comprising the last month of the pre-reproductive period, at 5 mg/L of diclofenac, and also at a mixture of both drugs; besides, this mixture significantly (p < 0.05) increased the proportion of reabsorbed vitellogenic oocytes. The obtained results indicate that the effect of diclofenac is critical at the final stage of ovarian maturation, when the participation of prostaglandins is relevant.

In vitro Interference of a Glyphosate Commercial Formulation with the Stimulation of Ovarian Maturation by Progesterone, in the Estuarine Crab Neohelice granulata.

This study was aimed at evaluating the possible interference of formulated glyphosate to the endocrine control of ovarian growth exerted by progesterone, in the estuarine crab Neohelice granulata. The addition of Roundup Ultramax® (0.2 mg/L of glyphosate in the incubation medium) was able to potentiate the stimulating effect of progesterone on total vitellogenic protein (Vg) content of ovarian pieces from crabs. Moreover, the sole addition of mifepristone (antagonist of progesterone receptors) was able to produce a decrement of the Vg content, which was not reverted by the addition of Roundup. A similar result was confirmed by means of histological analysis, which showed that mifepristone, both alone and in combination with Roundup, inhibited ovarian maturation, while Roundup alone increased it, in terms of a higher proportion of vitellogenic oocytes. We conclude that Roundup could stimulate the progesterone secretion exerted by the ovary and/or could act as a partial agonist of this hormone in the same tissue.

Microglial phagocytosis in aging and Alzheimer's disease.

Microglia are the innate immune cells of the brain, which maintain homeostasis by constantly scanning and surveying the environment with their highly ramified processes. In order to exert this function, they need to phagocytose synapses as well as debris and dead cells, a process that is further amplified in pathological conditions. Importantly, it has been shown that microglia phagocytic capacity is altered in the course of neurodegenerative disease, for which aging is one of the highest risk factors. Thus, understanding how phagocytosis is impaired during aging is a priority for future research. Advances in this area are expected to significantly contribute to our understanding of normal cognition during aging, as well as changes that take place in age-associated neurodegenerative diseases. In this review, we will summarize the current knowledge on how phagocytosis is executed and affected by aging or in age-associated neurological disorders, such as Alzheimer's disease (AD). Furthermore, we will summarize both protective and deleterious consequences of altered phagocytosis in AD and where relevant in other neurodegenerative diseases.

Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial.

Background and objectives: Oxidative stress (OS) participates in the pathophysiology of septic shock, which leads to multiple organ failure (MOF), ischemia-reperfusion injury, and acute respiratory distress syndrome. Therefore, antioxidants have been proposed as therapy. Here, we evaluated the effect of antioxidant treatments in patients with septic shock with MOF and determined levels OS before and after treatment. This study was a randomized, controlled, triple-masked, and with parallel assignment clinical trial with a control group without treatment. Materials and Methods: It included 97 patients of either sex with septic shock. 5 treatments were used each in an independent group of 18 patients. Group 1 received vitamin C (Vit C), group 2 vitamin E (Vit E), group 3 n-acetylcysteine (NAC), group 4 melatonin (MT), and group 5 served as control. All antioxidants were administered orally or through a nasogastric tube for five days as an adjuvant to the standard therapy. Results: The results showed that all patients presented MOF due to sepsis upon admission and that the treatment decreased it (p = 0.007). The antioxidant treatment with NAC increased the total antioxidant capacity (p < 0.05). The patients that received Vit C had decreased levels of the nitrate and nitrite ratio (p < 0.01) and C-reactive protein levels (p = 0.04). Procalcitonin levels were reduced by Vit E (p = 0.04), NAC (p = 0.001), and MT (p = 0.04). Lipid-peroxidation was reduced in patients that received MT (p = 0.04). Conclusions: In conclusion, antioxidant therapy associated with standard therapy reduces MOF, OS, and inflammation in patients with septic shock.

What modulates animal longevity? Fast and slow aging in bivalves as a model for the study of lifespan.

Delineating the physiological and biochemical causes of aging process in the animal kingdom is a highly active area of research not only because of potential benefits for human health but also because aging process is related to life history strategies (growth and reproduction) and to responses of organisms to environmental conditions and stress. In this synthesis, we advocate studying bivalve species as models for revealing the determinants of species divergences in maximal longevity. This taxonomic group includes the longest living metazoan on earth (Arctica islandica), which insures the widest range of maximum life span when shorter living species are also included in the comparative model. This model can also be useful for uncovering factors modulating the pace of aging in given species by taking advantages of the wide disparity of lifespan among different populations of the same species. For example, maximal lifespan in different populations of A islandica range from approximately 36 years to over 500 years. In the last 15 years, research has revealed that either regulation or tolerance to oxidative stress is tightly correlated to longevity in this group which support further investigations on this taxon to unveil putative mechanistic links between Reactive Oxygen Species and aging process.

Metabolic remodelling associated with mtDNA: insights into the adaptive value of doubly uniparental inheritance of mitochondria.

Mitochondria produce energy through oxidative phosphorylation (OXPHOS), which depends on the expression of both nuclear and mitochondrial DNA (mtDNA). In metazoans, a striking exception from strictly maternal inheritance of mitochondria is doubly uniparental inheritance (DUI). This unique system involves the maintenance of two highly divergent mtDNAs (F- and M-type, 8-40% of nucleotide divergence) associated with gametes, and occasionally coexisting in somatic tissues. To address whether metabolic differences underlie this condition, we characterized the OXPHOS activity of oocytes, spermatozoa, and gills of different species through respirometry. DUI species express different gender-linked mitochondrial phenotypes in gametes and partly in somatic tissues. The M-phenotype is specific to sperm and entails (i) low coupled/uncoupled respiration rates, (ii) a limitation by the phosphorylation system, and (iii) a null excess capacity of the final oxidases, supporting a strong control over the upstream complexes. To our knowledge, this is the first example of a phenotype resulting from direct selection on sperm mitochondria. This metabolic remodelling suggests an adaptive value of mtDNA variations and we propose that bearing sex-linked mitochondria could assure the energetic requirements of different gametes, potentially linking male-energetic adaptation, mitotype preservation and inheritance, as well as resistance to both heteroplasmy and ageing.

Differences in scar lesion formation between radiofrequency and cryoballoon in atrial fibrillation ablation: a comparison study using ultra-high-density mapping.

AIMS: Atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) is usually associated to conduction gaps in pulmonary veins (PVs). Our objective was to characterize gaps in patients with recurrences after a first radiofrequency (RF) or cryoballoon (CB) PVI procedure, using a high-density mapping (HDM) system. METHODS AND RESULTS: Fifty patients with AF recurrence after a first PVI procedure (pre-RF 25 patients; pre-CB 25 patients) were included at two centres. Activation map (AM) and voltage map (VM) of the left atrium and PVs were built using the HDM Rhythmia® system. Superior PVs were reconnected more frequently in both groups. Right PVs were reconnected more frequently in pre-RF patients. Pre-RF patients had more reconnected veins than pre-CB patients (mean ± standard deviation: 3.00 ± 0.96 vs. 1.88 ± 1.13; P < 0.001) and more gaps (4.84 ± 2.06 vs. 2.16 ± 1.49; P < 0.001). Gaps in the VM were wider in pre-CB patients (16.5 ± 9.5 mm vs. 12.1 ± 4.8 mm; P = 0.006). There was a gap in 179 of the 800 PV segments analysed (22%); 52% were identified in both AM and VM maps; 39% only in the AM and 8% only in the VM. The highest sensitivity and specificity for gap detection was obtained with VM in pre-CB patients and with AM in pre-RF patients. CONCLUSION: In conclusion, HDM seems to be a useful and precise tool to detect conduction gaps after a first PVI procedure. The anatomical pattern and location of gaps depends on the technique used previously, usually being multiple, smaller, and better detected by AM after RF, and fewer, wider, and better detected by VM after CB.

Imbalances in the male reproductive function of the estuarine crab Neohelice granulata, caused by glyphosate.

The effect of glyphosate, both pure and formulated (Roundup Ultramax®), was evaluated on males of the estuarine crab Neohelice granulata, by means of both in vivo and in vitro assays. The in vivo assays comprised the exposure for 30 d to 1 mg/L of the herbicide, until finally assessing weight gain, levels of energy reserves, sperm number per spermatophore, proportion of abnormal spermatophores, and sperm viability. At the end of this assay, significant (p < 0.05) decrease in weight gain and muscle protein levels was detected by effect of both pure and formulated glyphosate. In spermatophores from the vas deferens, a significant (p < 0.05) decrease of the sperm count was observed by effect of Roundup, while a significant incidence (p < 0.05) of abnormal spermatophores was observed either with glyphosate or with Roundup treatment. No changes were seen in the spermatophore area or in vas deferens secretions. Since no sperm mortality was induced by the formulated herbicide, we propose a probable inhibiting effect on spermatogenesis might explain the observed sperm count decrease. In this sense, an in vitro assay was designed by incubating testes and vasa deferentia with Roundup, in order to corroborate the possible interference of glyphosate with the secretion of the androgenic gland hormone that controls the spermatogenesis, in the presence or absence of the androgenic gland. Although the herbicide per se was able to reduce the sperm count to some extent, the increase in the number of spermatozoa/spermatophore produced by the co-incubation with the androgenic gland was completely reverted by the addition of Roundup (1 mg/L of glyphosate a.e.), suggesting that an inhibition on the secretion and/or transduction of the androgenic gland hormone could be taking place.

Identification of pulmonary vein reconnection gaps with high-density mapping in redo atrial fibrillation ablation procedures.

Aims: Maps obtained by means of electroanatomic high-density mapping (HDM) systems have shown their use in the identification of conduction gaps in experimental atrial linear lesion models. The objective of this study was to assess the use of HDM in the recognition of reconnection gaps in pulmonary veins (PV) in redo atrial fibrillation (AF) ablation procedures. Methods and results: One hundred and eight patients were included in a non-randomized study that assessed the recognition of reconnection gaps in PV by means of HDM compared to a control group that received conventional non-fluoroscopic guidance with a circular multipolar catheter (CMC). Among the HDM group, adequate recognition of reconnection gaps was obtained in 60.99% of the reconnected PVs (86 of 141), a figure significantly higher than that achieved with analysis of CMC recorded signals (39.66%, 48 of 121; P = 0.001). The number of applications and total radiofrequency time were also significantly lower in the HDM group (12.46 ± 6.1 vs. 15.63 ± 7.7 and 7.61 ± 3 vs. 9.29 ± 5; P = 0.02, and P = 0.03, respectively). At the 6-month follow-up, no statistically significant differences were found in recurrence of AF or any other atrial tachycardia between the HDM group (8 patients, 14.8%) and the control group in (16 patients, 29.6%; P = 0.104). Conclusion: An analysis of the high-density activation maps allows greater precision in the identification of reconnection gaps in PV, which results in lower radiofrequency time for the new isolation.

Functionalization of stable fluorescent nanodiamonds towards reliable detection of biomarkers for Alzheimer's disease.

BACKGROUND: Stable and non-toxic fluorescent markers are gaining attention in molecular diagnostics as powerful tools for enabling long and reliable biological studies. Such markers should not only have a long half-life under several assay conditions showing no photo bleaching or blinking but also, they must allow for their conjugation or functionalization as a crucial step for numerous applications such as cellular tracking, biomarker detection and drug delivery. RESULTS: We report the functionalization of stable fluorescent markers based on nanodiamonds (NDs) with a bifunctional peptide. This peptide is made of a cell penetrating peptide and a six amino acids long ß-sheet breaker peptide that is able to recognize amyloid ß (Aß) aggregates, a biomarker for the Alzheimer disease. Our results indicate that functionalized NDs (fNDs) are not cytotoxic and can be internalized by the cells. The fNDs allow ultrasensitive detection (at picomolar concentrations of NDs) of in vitro amyloid fibrils and amyloid aggregates in AD mice brains. CONCLUSIONS: The fluorescence of functionalized NDs is more stable than that of fluorescent markers commonly used to stain Aß aggregates such as Thioflavin T. These results pave the way for performing ultrasensitive and reliable detection of Aß aggregates involved in the pathogenesis of the Alzheimer disease.