Search Results (18)

Environmental contamination with xenobiotics affects organisms and the symbiotic relations between them. A convenient object to study relationships between parasites and their hosts is the host–parasite system “Tenebrio molitor Linnaeus, 1758 (Coleoptera, Tenebrionidae)—Gregarina polymorpha (Hammerschmidt, 1838) Stein, 1848 (Eugregarinorida, Gregarinidae)”. For this experiment, we took 390 T. molitor larvae and 24 organic compounds. Groups of mealworms, 15 in each, were subjected to those compounds for 10 days. Then, we recorded the vitality of both the larvae of T. molitor and G. polymorpha. To assess how G. polymorpha had affected the hosts’ wellbeing, we looked for changes in the larvae’s body mass and compared them to the number of gregarines in their intestines. The vitality of the larvae was inhibited by cyclopentanol and 2-naphthol. The intensity of gregarine invasion was reduced by diphenyl ether, benzyl alcohol, catechol, and 3-aminobenzoic acid. No effect on the number of gregarines was produced by 3,4,5-trihydroxybenzoic acid, cyclohexanemethanol, phenol, benzalkonium chloride, maleic anhydride, cyclohexanol, resorcin, benzoic acid, 2-methylfuran, terpinen-4-ol, 1-phenylethylamine, dibutyl phthalate, 3-furancarboxylic acid, 5-methyl furfural, 6-aminohexanoic acid, succinic anhydride, o-xylene, and benzaldehyde. In the infected T. molitor individuals, the mean number of G. polymorpha equaled 45 specimens per host. The groups of smaller mealworms had fewer gregarines. Positive correlation was seen between growth rates of T. molitor larvae and the intensity of invasion by gregarines. Full article

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient’s chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (⁶⁸Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC₅₀ value being about 867 nM. The biodistribution and PET/CT studies revealed that [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [⁶⁸Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression. Full article

Leucine residues are commonly found in the hydrophobic face of antimicrobial peptides (AMPs) and are crucial for membrane permeabilization, leading to the cell death of invading pathogens. Melittin, which contains four leucine residues, demonstrates broad-spectrum antimicrobial properties but also significant cytotoxicity against mammalian cells. To enhance the cell selectivity of melittin, this study synthesized five analogs by replacing leucine with its structural isomer, 6-aminohexanoic acid. Among these analogs, Mel-LX3 exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Importantly, Mel-LX3 displayed significantly reduced hemolytic and cytotoxic effects compared to melittin. Mechanistic studies, including membrane depolarization, SYTOX green uptake, FACScan analysis, and inner/outer membrane permeation assays, demonstrated that Mel-LX3 effectively permeabilized bacterial membranes similar to melittin. Notably, Mel-LX3 showed robust antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Furthermore, Mel-LX3 effectively inhibited biofilm formation and eradicated existing biofilms of MDRPA. With its improved selective antimicrobial and antibiofilm activities, Mel-LX3 emerges as a promising candidate for the development of novel antimicrobial agents. We propose that the substitution of leucine with 6-aminohexanoic acid in AMPs represents a significant strategy for combating resistant bacteria. Full article

The paucity of multi-component compounds containing the non-steroidal anti-inflammatory drug (NSAID) S-(+)-ibuprofen (S-IBU) in combination with other drugs prompted the present study, which describes 1:1 salts of this active pharmaceutical ingredient (API) with the two most widely used antifibrinolytic APIs, namely 6-aminohexanoic acid (aminocaproic acid, ACA) and tranexamic acid (TXA), which are zwitterions in the solid state. Since NSAIDs are known to cause adverse side effects such as gastrointestinal ulceration, the presence of ACA and TXA in the salts with S-(+)-ibuprofen might counter these effects via their ability to prevent excessive bleeding. The salts were prepared by both the liquid-assisted grinding method and co-precipitation and were characterized by X-ray powder diffraction and single-crystal X-ray diffraction, thermal analysis, Fourier transform infrared spectroscopy, and solubility measurements. The X-ray analyses revealed a high degree of isostructurality, both at the level of their respective asymmetric units and in their extended crystal structures, with charge-assisted hydrogen bonds of the type N-H⁺⋅⋅⋅O⁻ and O-H⁺⋅⋅⋅O⁻ featuring prominently. The thermal analysis indicated that both salts had significantly higher thermal stability than S-(+)-ibuprofen. Solubility measurements in a simulated biological medium showed insignificant changes in the solubility of S-(+)-ibuprofen when tested in the form of the salts (S-IBU)⁻(ACA)⁺ and (S-IBU)⁻(TXA)⁺. Full article

Today, the high concentrations of copper found in water resources result in an urgent problem to solve since human health and aquatic ecosystems have been affected. Functionalized crosslinked polyketone resins (XLPK) have demonstrated high performance for the uptake of heavy metals in water solutions. In addition, its green chemical synthesis makes these resins very attractive as sorbents for metal ions contained in wastewater. XLPK are not soluble in aqueous media and do not require any catalyst, solvent, or harsh conditions to carry out the uptake process. In this paper, a series of functionalized XLPK with pending amino-derivatives namely; butylamine (BA), amino 2-propanol (A2P), 4-(aminomethyl) benzoic acid (HAMC), 6-aminohexanoic acid (PAMBA), and 1,2 diamino propane (DAP) directly attached to the pyrrole backbone of the polymers and crosslinked by di-amine derivatives was investigated using Density Functional Theory (DFT) calculations. Our computational analysis revealed that dipole-dipole interactions played a crucial role in enhancing the adsorption of Cu²⁺ ions onto XLPKs. The negatively charged ketone moieties and functional groups within XLPKs were identified as key adsorption sites for the selective binding of Cu²⁺ ions. Additionally, we found that XLPKs exhibited strong electrostatic interactions primarily through the –NH₂ and –C=O groups. Evaluation of the adsorption energies in XLPK-Cu(II) complexes showed that the DAP-Cu(II) complex exhibited the highest stability, attributed to strong Cu(II)-N binding facilitated by the amino moiety (–NH₂). The remaining XLPKs displayed binding modes involving oxygen atoms (Cu(II)-O) within the ketone moieties in the polymer backbone. Furthermore, the complexation and thermochemical analysis emphasized the role of the coordinator atom (N or O) and the coordinating environment, in which higher entropic effects involved in the adsorption of Cu²⁺ ions onto XLPKs describes a lower spontaneity of the adsorption process. The adsorption reactions were favored at lower temperatures and higher pressures. These findings provide valuable insights into the reactivity and adsorption mechanisms of functionalized and crosslinked polyketones for Cu²⁺ uptake, facilitating the design of high-performance polymeric resins for water treatment applications. Full article

Recent findings qualified aldehydes as potential biomarkers for disease diagnosis. One of the possibilities is to use electrochemical biosensors in point-of-care (PoC), but these need further development to overcome some limitations. Currently, the primary goal is to enhance their metrological parameters in terms of sensitivity and selectivity. Previous findings indicate that peptide OBPP4 (KLLFDSLTDLKKKMSEC-NH₂) is a promising candidate for further development of aldehyde-sensitive biosensors. To increase the affinity of a receptor layer to long-chain aldehydes, a structure stabilization of the peptide active site via the incorporation of different linkers was studied. Indeed, the incorporation of linkers improved sensitivity to and binding of aldehydes in comparison to that of the original peptide-based biosensor. The tendency to adopt disordered structures was diminished owing to the implementation of suitable linkers. Therefore, to improve the metrological characteristics of peptide-based piezoelectric biosensors, linkers were added at the C-terminus of OBPP4 peptide (KLLFDSLTDLKKKMSE-linker-C-NH₂). Those linkers consist of proteinogenic amino acids from group one: glycine, L-proline, L-serine, and non proteinogenic amino acids from group two: β-alanine, 4-aminobutyric acid, and 6-aminohexanoic acid. Linkers were evaluated with in silico studies, followed by experimental verification. All studied linkers enhanced the detection of aldehydes in the gas phase. The highest difference in frequency (60 Hz, nonanal) was observed between original peptide-based biosensors and ones based on peptides modified with the GSGSGS linker. It allowed evaluation of the limit of detection for nonanal at the level of 2 ppm, which is nine times lower than that of the original peptide. The highest sensitivity values were also obtained for the GSGSGS linker: 0.3312, 0.4281, and 0.4676 Hz/ppm for pentanal, octanal, and nonanal, respectively. An order of magnitude increase in sensitivity was observed for the six linkers used. Generally, the linker’s rigidity and the number of amino acid residues are much more essential for biosensors’ metrological characteristics than the amino acid sequence itself. It was found that the longer the linkers, the better the effect on docking efficiency. Full article

In this work, a new Ch2 strain was isolated from soils polluted by agrochemical production wastes. This strain has a unique ability to utilize toxic synthetic compounds such as epsilon-caprolactam (CAP) as a sole carbon and energy source and the herbicide glyphosate (GP) as a sole source of phosphorus. Analysis of the nucleotide sequence of the 16S rRNA gene of Ch2 revealed that the strain belongs to the species Pseudomonas putida. This strain grew in the mineral medium containing CAP in a concentration range of 0.5 to 5.0 g/L and utilized 6-aminohexanoic acid and adipic acid, which are the intermediate products of CAP catabolism. The ability of strain Ch2 to degrade CAP is determined by a conjugative megaplasmid that is 550 kb in size. When strain Ch2 is cultured in a mineral medium containing GP (500 mg/L), more intensive utilization of the herbicide occurs in the phase of active growth. In the phase of declining growth, there is an accumulation of aminomethylphosphonic acid, which indicates that the C-N bond is the first site cleaved during GP degradation (glyphosate oxidoreductase pathway). Culture growth in the presence of GP during the early step of its degradation is accompanied by unique substrate-dependent changes in the cytoplasm, including the formation of vesicles of cytoplasmic membrane consisting of specific electron-dense content. There is a debate about whether these membrane formations are analogous to metabolosomes, where the primary degradation of the herbicide can take place. The studied strain is notable for its ability to produce polyhydroxyalkanoates (PHAs) when grown in mineral medium containing GP. At the beginning of the stationary growth phase, it was shown that, the amount and size of PHA inclusions in the cells drastically increased; they filled almost the entire volume of cell cytoplasm. The obtained results show that the strain P. putida Ch2 can be successfully used for the PHAs’ production. Moreover, the ability of P. putida Ch2 to degrade CAP and GP determines the prospects of its application for the biological cleanup of CAP production wastes and in situ bioremediation of soil polluted with GP. Full article

epsilon-Caprolactam (Caprolactam, CAP), a monomer of the synthetic non-degradable polymer nylon-6, is the major wastewater component in the production of caprolactam and nylon-6. Biological treatment of CAP, using microbes could be a potent alternative to the current waste utilization techniques. This work focuses on the characterization and potential use of caprolactam-degrading bacterial strain BS3 isolated from soils polluted by CAP production wastes. The strain was identified as Brevibacterium epidermidis based on the studies of its morphological, physiological, and biochemical properties and 16S rRNA gene sequence analysis. This study is the first to report the ability of Brevibacterium to utilize CAP. Strain BS3 is an alcalo- and halotolerant organism, that grows within a broad range of CAP concentrations, from 0.5 up to 22.0 g/L, optimally at 1.0–2.0 g/L. A caprolactam biodegradation experiment using gas chromatography showed BS3 to degrade 1.0 g/L CAP over 160 h. In contrast to earlier characterized narrow-specific CAP-degrading bacteria, strain BS3 is also capable of utilizing linear nylon oligomers (oligomers of 6-aminohexanoic acid), CAP polymerization by-products, as sole sources of carbon and energy. The broad range of utilized toxic pollutants, the tolerance for high CAP concentrations, as well as the physiological properties of B. epidermidis BS3, determine the prospects of its use for the biological cleanup of CAP and nylon-6 production wastes that contain CAP, 6-aminohexanoic acid, and low molecular weight oligomer fractions. Full article

A new corrosion inhibitor called ATP-6-AHA was elaborated, and its inhibition action on S235 low carbon steel in 3.5% sodium chloride (NaCl) was investigated using gravimetry, potentiodynamic polarization (PP), and electrochemical impedance spectroscopy (EIS). The release of ecofriendly 6-aminohexanoic acid (6-AHA) from its established aluminum tri-polyphosphate intercalate (ATP-6-AHA) is investigated using electrochemical and surface characterization techniques such as X-ray diffraction (XRD) and X-ray fluorescence (XRF). The results revealed that ATP-6-AHA is a good inhibitor, with an inhibition efficiency of approximately 70%. The efficiency is related to the passivation of a steel surface by a phosphate protective layer due to the synergistic effect of 6-AHA, as confirmed by a steel surface analysis conducted using X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). This study suggests that the intercalation of 6-AHA as a sustainable organic molecule within the interlayer spaces of aluminum tri-polyphosphate can well serve as a good flaky inhibitor for protecting S235 low-carbon steel from corrosion in 3.5% NaCl. Full article

6-aminohexanoic acid is an ω-amino acid with a hydrophobic, flexible structure. Although the ω-amino acid in question is mainly used clinically as an antifibrinolytic drug, other applications are also interesting and important. This synthetic lysine derivative, without an α-amino group, plays a significant role in chemical synthesis of modified peptides and in the polyamide synthetic fibers (nylon) industry. It is also often used as a linker in various biologically active structures. This review concentrates on the role of 6-aminohexanoic acid in the structure of various molecules. Full article

Background: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. Methods: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl₆ mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1β and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. Results: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1β, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. Conclusions: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment. Full article

[^99mTc]Tc-HYNIC-TOC is the most widely used ^99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. ^99mTc-labeled SST antagonists are lacking in clinical practice. Surprisingly, when [^99mTc]Tc-HYNIC was conjugated to the SST2 antagonist SS01, SST2 imaging was not feasible. This was not the case when [^99mTc]Tc-N4 was conjugated to SS01. Here, we assessed the introduction of different spacers (X: β-Ala, Ahx, Aun and PEG₄) among HYNIC and SS01 with the aim of restoring the affinity of HYNIC conjugates. In addition, we used the alternative antagonist JR11 for determining the suitability of HYNIC with ^99mTc-labeled SST2 antagonists. We performed a head-to-head comparison of the N4 conjugates of SS01 and JR11. [^99mTc]Tc-HYNIC-TOC was used as a reference, and HEK-SST2 cells were used for in vitro and in vivo evaluation. EDDA was used as a co-ligand for all [^99mTc]Tc-HYNIC conjugates. The introduction of Ahx restored, to a great extent, the SST2-mediated cellular uptake of the [^99mTc]Tc-HYNIC-X conjugates (X: spacer), albeit lower than the corresponding [^99mTc]Tc-N4-conjugates. SPECT/CT images showed that all ^99mTc-labeled conjugates accumulated in the tumor and kidneys with [^99mTc]Tc-HYNIC-PEG₄-SS01, [^99mTc]Tc-N4-SS01 and [^99mTc]Tc-N4-JR11 having notably higher kidney uptake. Biodistribution studies showed similar or better tumor-to-non-tumor ratios for the [^99mTc]Tc-HYNIC-Ahx conjugates, compared to the [^99mTc]Tc-N4 counterparts. The [^99mTc]Tc-HYNIC-Ahx conjugates of SS01 and JR11 were comparable to [^99mTc]Tc-HYNIC-TOC as imaging agents. HYNIC is a suitable chelator for the development of ^99mTc-labeled SST2 antagonists when a spacer of appropriate length, such as Ahx, is used. Full article

Fungi fibrinolytic compound 1 (FGFC1) is a rare marine-derived compound that can enhance fibrinolysis both in vitro and in vivo. The fibrinolytic activity characterization of FGFC1 mediated by plasminogen (Glu-/Lys-) and a single-chain urokinase-type plasminogen activator (pro-uPA) was further evaluated. The binding sites and mode of binding between FGFC1 and plasminogen were investigated by means of a combination of in vitro experiments and molecular docking. A 2.2-fold enhancement of fibrinolytic activity was achieved at 0.096 mM FGFC1, whereas the inhibition of fibrinolytic activity occurred when the FGFC1 concentration was above 0.24 mM. The inhibition of fibrinolytic activity of FGFC1 by 6-aminohexanoic acid (EACA) and tranexamic acid (TXA) together with the docking results revealed that the lysine-binding sites (LBSs) play a crucial role in the process of FGFC1 binding to plasminogen. The action mechanism of FGFC1 binding to plasminogen was inferred, and FGFC1 was able to induce plasminogen to exhibit an open conformation by binding through the LBSs. The molecular docking results showed that docking of ligands (EACA, FGFC1) with receptors (KR1–KR5) mainly occurred through hydrophilic and hydrophobic interactions. In addition, the binding affinity values of EACA to KR1–KR5 were −5.2, −4.3, −3.7, −4.5, and −4.3 kcal/moL, respectively, and those of FGFC1 to KR1–KR5 were −7.4, −9.0, −6.3, −8.3, and −6.7 kcal/moL, respectively. The findings demonstrate that both EACA and FGFC1 bound to KR1–KR5 with moderately high affinity. This study could provide a theoretical basis for the clinical pharmacology of FGFC1 and establish a foundation for practical applications of FGFC1. Full article

Microplastics (MPs) quantification in benthic marine sediments is typically performed by time-consuming and moderately accurate mechanical separation and microscopy detection. In this paper, we describe the results of our innovative Polymer Identification and Specific Analysis (PISA) of microplastic total mass, previously tested on either less complex sandy beach sediment or less demanding (because of the high MPs content) wastewater treatment plant sludges, applied to the analysis of benthic sediments from a sublittoral area north-west of Leghorn (Tuscany, Italy). Samples were collected from two shallow sites characterized by coarse debris in a mixed seabed of Posidonia oceanica, and by a very fine silty-organogenic sediment, respectively. After sieving at <2 mm the sediment was sequentially extracted with selective organic solvents and the two polymer classes polystyrene (PS) and polyolefins (PE and PP) were quantified by pyrolysis-gas chromatography-mass spectrometry (Pyr-GC/MS). A contamination in the 8–65 ppm range by PS could be accurately detected. Acid hydrolysis on the extracted residue to achieve total depolymerization of all natural and synthetic polyamides, tagging of all aminated species in the hydrolysate with a fluorophore, and reversed-phase high performance liquid chromatography (HPLC) (RP-HPLC) analysis, allowed the quantification within the 137–1523 ppm range of the individual mass of contaminating nylon 6 and nylon 6,6, based on the detected amounts of the respective monomeric amines 6-aminohexanoic acid (AHA) and hexamethylenediamine (HMDA). Finally, alkaline hydrolysis of the residue from acid hydrolysis followed by RP-HPLC analysis of the purified hydrolysate showed contamination by polyethylene terephthalate (PET) in the 12.1–2.7 ppm range, based on the content of its comonomer, terephthalic acid. Full article

Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The ¹¹¹In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled ¹¹¹In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of ¹¹¹In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. ¹¹¹In-DOTA-hUII or ¹¹¹In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with ¹¹¹Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools. Full article