The heterojunction material completely inherits the special skeleton of the template material and optimizes the nano-scale morphology, and achieves the transformation from nanometer structure to quantum dots (QDs). The introduction of Cu ions not only tuned the band gap of the composites to promote the utilization of solar photons, more importantly, Fenton-like catalysis was combined into the degradation process. Compared with the experiments of organic dye degradation under different illumination conditions, the degradability of the CdS/Cu7S4 QDs is greatly superior to pure CdS. Therefore, the constructed CdS/Cu7S4 QDs further realized the optimization of degradation performance by the synergic effect of photo-catalysis and Fenton-like catalysis.CdS has attracted extensive attention in the photocatalytic degradation of wastewater due to its relatively narrow bandgap and various microstructures. Previous reports have focused on CdS coupled with other semiconductors to reduce the photocorrosion and improve the photocatalytic performance. Herein, a 3D hierarchical CdS/Cu CdS has attracted extensive attention in the photocatalytic degradation of wastewater due to its relatively narrow bandgap and various microstructures. Compared with traditional methods, the Fenton oxidation process is based on freshly generated hydroxyl radicals (OH˙) with a high oxidation potential (2.8 V) to completely break down organic macromolecules into small molecules  and have become one of the highly efficient candidates for degradation of dye wastewater, which relies heavily on the activity of Fenton catalysts.6,7 Nevertheless, the traditional Fe-based Fenton catalysts are harsh on the pH of the degradation system, easily oxidized and difficult to preserve.8,9 To push the complete treatment of dye wastewater, it is highly desirable to develop a Fenton-like catalyst with adequate activity and stability.6,10Industrial wastewater, especially dye wastewater containing refractory and virulent organic ingredients, is one of the main culprits of ecological environmental damage.11,12 So the development of a novel copper sulfide crystal with a three-dimensional hierarchical structure as a high efficiency Fenton-like catalyst is of great interest. In recent years, the micro/nano construction method is often used to construct inorganic compounds with a special structure and morphology for providing a large specific surface area and abundant active sites.13–15 For instance, solvothermal synthesis of 3D hierarchical CuS microspheres and CuS nanoparticles were prepared by in situ precipitation.16,17 Besides, the soft-template method is also a popular method used to regulate the morphology of copper sulfide. Different morphologies  of CuS nanostructures were synthesized by adjusting the amount of biomolecule assistance.18 And a CuS nanoplate was prepared in the presence of cation surfactant cetyltrimethylammonium bromide (CTAB).19 These reports have promoted the rapid development of morphology research of copper sulfide. There are several classical reports on regulation of morphology and structure of copper sulfide at the lattice level.20–23 These reports provide a good reference for morphological control. Recently, ion-exchange method is considered to be a general strategy for the preparation of materials with special structures and morphologies, which uses an existing crystal lattice as a template to enable the realization of morphological inheritance of parent materials and introduce abundant lattice defects resulting in the synergy and complementarity between different atoms. For example, lavender-like Ni3S2/Co9S8/NiSe nanoarrays synthesized by sequential partial ion exchange exhibited excellent rate performance as electrode materials for supercapacitors.20 The ions exchange between bromide or iodide ions and chloride ions on the QDs improve photoluminescence quantum yield.21 Therefore, it is of great significance to prepare copper sulfide with excellent morphology and excellent Fenton-like catalyst activity by ion exchange method by using the parent material with special structure and morphology.Copper sulfide is considered to be an ideal candidate for Fenton-like catalysis because of its multivalent state similar to Fe-based catalysts and high stability and low dependence on degradation system. The performance of the material is closely related to their structure and morphology.30–33 especially the CdS QDs owing to their unique optoelectronic properties including a high absorption coefficient, band gap tunability and potential multiple exciton generation.34,35 Micro-emulsion method and hot injection method as the common strategies for synthesizing CdS QDs have cumbersome process.26–29 The design of a mild and simple method to realize the transformation of CdS micro–nanometer structure to CdS QDs will open a shortcut for the preparation of CdS QDs. In previous reports,24,25 ion exchange method has been proved to be an ingenious strategy to realize the continuous transformation of material composition, which can also be used to replace most of cadmium ions in CdS micro–nanomaterials with multi-functional copper ions, leading to the preparation of CdS/CuxS QDs heterojunction material with the synergistic effect of photocatalyst and Fenton-like catalyst. These findings have been rarely reported.As a typical photocatalyst, the fabrication of CdS nanocrystals with various structures, including QDs, nanospheres, nanorods and nanoflowers has been extensively studied,via a simple solvent-thermal method with the assistance of CTAB. This special three-dimensional hierarchical structure endows the as-obtained CdS material with large specific surface area and luxuriant active sites, which can improve the internal performance effectively. Consequently, CdS/Cu7S4 nanocrystals were synthesized through the continuous copper-ion exchange using the 3D hierarchical lily-like CdS microflowers as template. As the proportion of copper ions to replace cadmium ions in the lattice increases, the controllable preparation of 3D hierarchical lily-like CdS/Cu7S4 QDs was also achieved. On the whole, CdS/Cu7S4 perfectly inherited the excellent morphology of the parent material. Moreover, many nanoholes and lattice defects are introduced into the target material along with ion exchange, which further increases the specific surface area and active sites of nanocrystals effectively. More importantly, the heterojunction materials of CdS/Cu7S4 QDs realize the synergistic effect of photocatalyst and Fenton-like catalyst. Then, CdS/Cu7S4 QDs was used to degrade the organic dyes such as methylene blue (MB) and rhodamine B (RB) assisted by hydrogen peroxide and illuminated by ultraviolet light. Compared with CdS nanocrystals, the 3D hierarchical lily-like CdS/Cu7S4 QDs show the higher degradation efficiency. This work provides a novel reference for the preparation of CdS QDs and multi-functional and efficient dye wastewater degradation catalyst.Herein, the 3D hierarchical lily-like CdS microflowers with several single ultrathin nanosheets as building block were successfully synthesized 3)2·4H2O, AR, 99%, Sinopharm Chemical Reagent Co., Ltd), copper nitrate trihydrate (Cu(NO3)2·3H2O, AR, 99%, Sinopharm Chemical Reagent Co., Ltd), thiourea , hexadecyltrimethylammonium bromide , ethylenediamine , ethylene glycol , ethanol  and distilled water.All chemical reagents in the present work were analytical grade and used without further purification. Cadmium nitrate tetrahydrate 2·3H2O were added into the above reaction solution. The mixture was transferred into a 30 mL Teflon-lined autoclave, stirred for 0.5 h, and then reacted for overnight at room temperature about 25 °C. Finally, the product was collected by centrifugation, washed with distilled water and ethanol for several times each, and then dried at 60 °C for 8 h.The hierarchical CdS/Cu2+ concentration on the morphology and component of the final products during ion exchange reaction process. A series of samples were prepared with different cation mole ratio. The molar ratio of CdS and Cu2+ was 1 : 0.05, 1 : 0.2, 1 : 0.5, 1 : 1 and 1 : 2, and the corresponding samples were labelled as CdS/Cu7S4-1, CdS/Cu7S4-2, CdS/Cu7S4-3, CdS/Cu7S4-4 and CdS/Cu7S4-5, respectively.In order to explore the influence of Cu−1, 30 mL), and the reaction was initiated by adding H2O2 (10 mL). The reaction was conducted under different illumination environment , and the whole reaction process was proceed at 30 °C under slowly stirring. Every 5 min of reaction time, about 3 mL of solution was collected from the dye solution. The mixture was centrifuged at 12 000 rpm for 2 min and the remaining solution was continuously used for analysis. The concentration of dye was determined by a UV-vis spectrophotometer. The mixed solution of RB@MB was degraded by the CdS, CdS/Cu7S4 catalysts in the same manner, the only difference was that the dyes solution consisted of MB  and RB .MB and RB are representative organic dyes used to evaluate the catalytic performance. Typically, the as-prepared dry sample as the catalyst (30 mg) was added to the single dye solution  and benzoquinone  were used in radical trapping experiment. 1 mM scavenger, 30 mg catalyst and 10 mL H2O2 were added into 30 mL of MB solution (30 ppm). The subsequent experiment operation was the same as the degradation experiment.In order to identify the major active radical in the degradation of MB solution, isopropyl alcohol , disodium ethylenediaminetetraacetate (Na−1 All XRD measurements were performed within 20° ≤ 2θ ≤ 80°. The X-ray photoelectron spectroscopy (XPS) of the as-prepared samples were analysed using a Kratos AXIS ULTRA X-ray photoelectron microscope with Al-Kα X-rays as the excitation source. The morphologies and sizes of the as-obtained samples were investigated with a scanning electron microscope  equipped with an energy-dispersive X-ray spectroscopy (EDS) system. The ultraviolet-visible (UV-vis) spectra were measured on a PerkinElmer Lambda 950 UV/VIS/NIR spectrometer in the 350 nm to 800 nm wavelength range. The photoluminescence spectra of the samples were measured by Hitachi U-4100 with an excitation wavelength of 450 nm. The photocurrent intensity was carried out on CHI 660E electrochemical workstation . The photocurrent measurements were carried out in 0.2 M of Na2SO4 solution using an Ag/AgCl as the reference electrode, a Pt wire as the counter electrode and ITO precoated photocatalyst (0.25 cm2). Xe lamp equipped with a 420 nm monochromator was used to provide the visible light irradiation. The Mott–Schottky measurements were carried out at 10 Hz and the three-electrode system was same as the photocurrent measurements. Nitrogen adsorption/desorption measurements were performed to investigate the surface characteristics on a Micromeritics ASAP2420 instrument. The specific surface area of the as-prepared samples were calculated by the Brunauer–Emmett–Teller (BET) method.Characterizations were carried out to fully realize the physical and chemical properties of the samples. X-ray diffraction (XRD) patterns were obtained with a Bruker D8 Advance X-ray powder diffractometer using Cu-Kα irradiation at a scan rate of 0.1° s2+ and S2− are distributed uniformly in CdS nanomaterials (as shown in d = 1.97 Å) and Cu ion (d Cu(i) = 1.54 Å, d Cu(ii) = 1.46 Å).3D hierarchical CdS nanomaterials were prepared by a modified one step solvothermal method. The high-magnification SEM images  reveal t5/2 and Cd 3d3/2, respectively with the binding energy located at 404.58 and 411.34 eV, which is similar to those reported in the literature.37,383/2 and S 2p1/2, respectively. The peaks in 39To further investigate the surface chemical states of CdS, the binding energies of elements were measured by X-ray photoelectron spectroscopy (XPS). As indicated in 2+ and S2− are combined rapidly and generated crystal nucleons in solution. The SEM image of CdS-1 shows that the collected precipitation is composed of some irregular particles. As the reaction proceed, some nanosheets gradually grow on these nanoparticles  and Cu7S4 (JCPDS no. 23-958), respectively , (3 7 2), (6 0 0), (8 0 4), (8 2 1), (20 0 1), (20 4 0), (0 16 0) and (8 8 6) planes of monoclinic phase, indicating that the phase is changed from hexagonal phase to monoclinic phase after the ion exchange reaction. According to the above analysis, the Cu7S4 phase is generated gradually as the copper ion doping. Additionally, the energy-dispersive X-ray (EDX) maps of CdS/Cu7S4-4  analysis. As indicated in 7S4-5 nanostructures. 5/2 and Cd 3d3/2, respectively with the binding energy located at 405.20 eV and 411.95 eV. 3/2 and Cu 2p1/2, respectively, which proves the presence of Cu+ in the CdS/Cu7S4-5 nanostructures. And the two peaks located at 933.53 and 953.03 eV are assigned to Cu 2p3/2 and Cu 2p1/2, respectively, demonstrating the existence of Cu2+ in the CdS/Cu7S4-5 nanomaterials. 3/2 and S 2p1/2, respectively, indicating the existence of S2− coordinated with Cu+ and Cu2+ species in the CdS/Cu7S4-5 nanostructures. In addition, the binding energy concentrated in the range of 168–170 eV matches with S–O bond resulted from the oxidation effect.47,48In order to investigate the valence state and chemical composition, the CdS/Cu7S4 nanomaterials were obtained through UV-vis absorbance spectroscopy . Therefore, plugging R into the above function and the [F(R)hv]2vs. hv plot was obtained hv]2vs. hv plots, indicating that the direct band gap value of CdS was 2.44 eV, CdS/Cu7S4-1 was 2.41 eV, CdS/Cu7S4-2 was 2.37 eV, CdS/Cu7S4-3 was 2.32 eV, CdS/Cu7S4-4 was 2.12 eV and CdS/Cu7S4-5 was 1.61 eV, consistent with the absorption edge of the corresponding samples. The evaluated direct band gap value of CdS was very close to the reported.50,51 Contrast CdS and CdS/Cu7S4-5, the band gap value was tuned from about 2.44 eV to 1.61 eV and the narrow band gap is conducive to the generation of photogenerated electron–hole pairs, thus improving the photocatalytic performance.The diffuse reflectance spectra of the CdS and CdS/Cutroscopy . A sharpobtained . Bandgap2SO4 aqueous solution at pH 7.52,53 As shown in Fig. S6,versus a saturated calomel electrode (SCE) for CdS, CdS/Cu7S4-1, CdS/Cu7S4-2, CdS/Cu7S4-3, CdS/Cu7S4-4 and CdS/Cu7S4-5, respectively. The CB potentials vs. SCE were converted to the normal hydrogen electrode (NHE) scale by ENHE = ESCE + 0.197 eV at pH 7, and the converted values are −0.413, −0.393, −0.393, −0.363, −0.423 and −0.403 eV versus NHE for CdS, CdS/Cu7S4-1, CdS/Cu7S4-2, CdS/Cu7S4-3, CdS/Cu7S4-4 and CdS/Cu7S4-5, respectively. It is obvious that the band gap and potential of VB both change significantly upon Cu ion-exchange. Photoluminescence (PL) spectra were used to investigate the properties of the all samples at room temperature. As shown in Fig. S7,7S4-5 is significantly higher than other catalysts, indicating that higher separation efficiency of the photogenerated electron–hole pairs and lower recombination rate in the CdS/Cu7S4-5 photocatalyst under the visible-light illumination.To better understand the effect of Cu ion-exchange on the band structure of the as-prepared catalysts, the Mott–Schottky test was performed in 0.2 M Na7S4 microflowers with high specific surface area and adequate surface active sites were effectively used as the catalysts for the degradation of organic dye such as MB and RB molecules. As show in 7S4 was further explored. In an environment of complete darkness, the degradation of MB and RB mainly depends on the hydroxyl radical produced by hydrogen peroxide decomposition under the catalysis of copper ion, then these hydroxyl radicals would degrade the organic molecules into smaller molecules (H2O and CO2). The following are the relevant equations of the degradation reaction:The as-prepared 3D hierarchical lily-like CdS/Cu2+ react with H2O2 to promote the formation of hydroxyl radicals and the generated Cu+ are oxidized into Cu2+ by H2O2   of CdS and Cuon band) , then thradicals , these r and CO2 . In orde2O2 for the organic dye solutions without the assistance of the cocatalyst is very slow. With the deepening of the research, the ultraviolet light was introduced into the Fenton reaction and the oxidation performance of H2O2 was greatly improved. The degradation performance of as-prepared samples has been investigated by the UV-vis absorption spectra in 2O2 and exposing to UV light for different times. 7S4 synthesized through cation exchange method are shown in 7S4-1 is evidently reduced to about less than a quarter of the time which is needed by the pure CdS under the same conditions (as shown in 7S4 is evidently better than single photocatalytic of pure CdS catalyst.The degradation rate of H7S4 components, the degradation time is gradually shortened. And the as-synthesized CdS/Cu7S4 materials from CdS/Cu7S4-1 to CdS/Cu7S4-5, spend 65 min, 50 min, 45 min, 35 min and 20 min to degrade MB solution to nearly 100%, respectively. The good catalytic performance is attributed to the special 3D hierarchical lily-like microstructure, the band gap adjustment and the synergistic effect of CdS/Cu7S4 catalysts. In order to further demonstrate the significant impact of structure and component has significant impact on the catalytic performance, the Cu1.97S nanomaterials with different morphology synthesized by a conventional method are used to compare with the as-prepared CdS/Cu7S4-5 microflowers (as shown in Fig. S2a, b and S91.97S catalysts need 30 min to thoroughly degrade MB solution under the same conditions (as shown in Fig. S107S4-1, 63% for CdS/Cu7S4-2, 74% for CdS/Cu7S4-3, 76% for CdS/Cu7S4-4 and 98% for CdS/Cu7S4-5 after the degradation of MB for 20 min under the same condition. The SEM images of CdS/Cu7S4-5 after the violent degradation reaction (Fig. S11k is the first order rate constant, C0 is the original concentration of MB solution, and C is the MB or RB@MB solution concentration at the specific reaction time. The first order rate constant of CdS, CdS/Cu7S4-1, CdS/Cu7S4-2, CdS/Cu7S4-3, CdS/Cu7S4-4 and CdS/Cu7S4-5 for degradation of the MB solution (−1, 0.039 min−1, 0.058 min−1, 0.076 min−1, 0.086 min−1 and 0.168 min−1, respectively.Along with the increase of Cu Fig. S11 show thasolution  are calc7S4-1, 72.34% for CdS/Cu7S4-2, 72.77% for CdS/Cu7S4-3, 87.23% for CdS/Cu7S4-4 and 97.87% for CdS/Cu7S4-5 after the degradation of MB for 15 min under the same condition. The directly synthesized Cu1.97S catalysts need 25 min to thoroughly degrade RB@MB solution under the same conditions (as shown in Fig. S107S4-1, CdS/Cu7S4-2, CdS/Cu7S4-3, CdS/Cu7S4-4 and CdS/Cu7S4-5 for degradation of the mixed solution of RB@MB (−1, 0.058 min−1, 0.067 min−1, 0.076 min−1, 0.148 min−1 and 0.245 min−1, respectively. It is clearly seen that the degradation rate of CdS/Cu7S4-5 is higher than that of other samples.The excellent performance degradation of the as-prepared samples not only for single organic dye, but also for the mixture of different kinds of organic dyes. The degradation performance for the RB@MB mixed solution of as-prepared samples has been investigated by the UV-vis absorption spectra in of RB@MB  are calc7S4-5 as catalyst and without catalyst. These test data reveal that in the absence of catalyst, the degradation performance is poor because of the decomposition of H2O2 become very slowly. When the visible light is used as the light source instead of the ultraviolet light, the catalytic performance is slightly weakened because of the weakening of the light energy. Even in the dark environment, the degradation capability is still substantial due to the high Fenton-like catalytic activity of the CdS/Cu7S4-5. Therefore, the ion exchange reaction can be used to modify the properties of crystalline materials and the synergistic catalytic effect of the as-prepared CdS/Cu7S4 nanocrystals has great practical and potential value in industrial wastewater treatment.In addition, a series of contrast experiment is carried out in the case of a single variable. Fig. S12–S147S4 QDs heterojunction material, owning the dual functions of photocatalyst and Fenton-like catalyst. During morphology genetic, the smooth nanosheets were transformed into the nanosheets composed of many nano particles, further endowing CdS/Cu7S4 QDs material with the larger specific surface area and more active sites. In the organic dyes degradation process, the degradation time of CdS/Cu7S4 QDs is about ten times shorter than CdS and robustly proved that the ion-exchange method is a feasible way to optimize the properties of nanocrystals.In summary, ion exchange strategy was successfully popularized and applied to the construction of 3D hierarchical lily-like CdS/CuThere are no conflicts to declare.RA-009-C8RA09331H-s001


The divergent roles of the CIPK-CBL interaction in plants include responding to environmental stresses , ion homeostasis , biotic stress, and plant development. Each member of this gene family produces distinct proteins that help plants adapt to diverse stresses or stimuli by interacting with calcium ion signals. CIPK consists of two structural domains—an N-terminal domain and a C-terminal domain—connected by a junction domain. The N-terminal domain, the site of phosphorylation, is also called the activation domain and kinase domain. The C-terminal, also known as the regulatory domain of CIPK, further comprises NAF/FISL and PPI. CBL comprises four EF domains and conserved PFPF motifs and is the site of binding with the NAF/FISL domain of CIPK to form a CBL-CIPK complex. In addition, we also performed a bibliometric analysis of the CIPK gene family of data extracted from the WoSCC. A total of 95 documents were retrieved, which had been published by 47 sources. The production over time was zigzagged. The top key terms were gene, CIPK, abiotic stress, and gene expression. Beijing Forestry University was the top affiliation, while The Plant Cell was the top source. The genomics and metabolomics of this gene family require more study.CIPKs are a subclass of serine/threonine (Ser/Thr) protein kinases. CBLs are ubiquitous Ca CBL  are ubiquitous Cay plants . Ca2+ plactivity . The varelopment . Each me2+ is less, the NAF domain is not bound to the PFPF domain due to the self-inhibitory property of FISL the domain, thus blocking the kinase activity . Several of these genes and their roles are described in A total of 26 CIPK genes from other plant species have also been reported and characterized in terms of function. For instance, OsCIPK23 overexpression improved rice drought tolerance by increasing the expression levels of drought-related genes , biotic stress, and plant development , ion homeostasis  pathway. High Na+ concentration activates the formation of CBL4/SOS3 and CIPK24/SOS2 complex due to increased concentration of Ca2+  negatively regulates H+-ATPase AHA2, as shown in +-ATPase AHA2, preventing it from interacting with the 14-3-3 protein in alkaline conditions  and NRT2.1 transporters. CIPK23 is a negative regulator of high-affinity response and acts in antagonism with CIPK8  and low-affinity (km = 0.9 µM)  stages. th CIPK8 . The CBLth CIPK8 .4+ are toxic for plant growth. The CBL1-CIPK23 complex helps maintain ammonium balance by phosphorylating and inactivating the threonine residue of cytosolic AMT1, thus preventing the entry of further ammonium ions (High levels of NHium ions  (Straub ium ions .+ transporter) and KUP4 (K+ regulator)  . Many esgulator) .via the production of ROS. Similarly, respiratory burst oxidase homolog (RBOH) is also involved in ROS production in plants. The CBL1/9-CIPK26 complex activates RBOH, which further triggers ROS production via the ABA pathway and leads to stomata closure  production . ROS are closure . Similar closure  , salt overly sensitive (SOS), and reactive oxygen species (ROS) pathways. AtCBL4/SOS3 was the first CBL protein identified in Arabidopsis and was shown to function specifically in the SOS pathway, interacting with AtCIPK24/SOS2 under salinity stress in roots  is a subscription platform available to institutions and offers access to numerous databases containing reference and citation data from conference proceedings, academic journals, and other publications in a variety of disciplines . WoS wasElsevier is among the top abstract and citation databases. Scopus was first introduced in 2004 and comprises almost 36,377 titles from approximately 11,678 publishers worldwide . Among tAlthough several bibliometric databases are available, each was created with a specific objective . Among bVOSviewer  is a program for creating and visualizing bibliometric networks. Different types of networks can be developed using VOSviewer. For instance, bibliographic coupling and co-authorship relationships can be shown as attractive networks . VOSviewAll of the primary bibliometric methods of analysis are included in the open-source, scientometric, and bibliometric research tool known as Bibliometrix developed by Aria and Cuccurullo . No codiGephi is another free program for bibliometric data visualization as massive network graphs . To speeCIPK gene family was performed. Data were extracted from the Web of Science Core Collection on August 26, 2022. We selected three editions of the core collection; namely, the “Science Citation Index Expanded (SCI-EXPANDED)-1999-present”, “Conference Proceedings Citation Index (AHCI)—2003-present”, and “Emerging Sources Citation Index  authors’ affiliations, 2) title terms, and 3) keywords. The top title terms were gene, cipk, family, and identification. The leading keywords were cipk, abiotic stress, gene expression, and salt stress. The top affiliation was Beijing Forestry University .Frontiers in Plant Science was the most common journal, with 10 publications. The current IF of the journal is 6.627 and is in category Q1. The most locally cited sources were also identified (Plant Cell was first with 486 citations, followed by Plant Physiology Journal, with 474 citations.The retrieved data was analyzed to find the most relevant sources . Frontieentified , among wArabidopsis were the leading terms (We used VOSviewer to map the co-authorship-to-author network . Similarng terms .We used VOSviewer to sketch the term co-occurrence map based on the text data. The terms were extracted from the titles and abstracts. A total of 2,856 terms were included. To draw the network map, we set the threshold criterion of minimum occurrence to 3 for key terms and applied “binary” counting. A total of 300 terms met this criterion. The mapped network is shown in 2+ signaling pathway and affect plant development, in addition to participating in biotic and abiotic stress responses. CIPKs have been identified and functionally characterized in many crops such as Arabidopsis, rice, maize, and canola (CIPK proteins play important roles in the Cad canola , but les


Covalent organic frameworks (COFs) are structurally tuneable, porous and crystalline polymers constructed through the covalent attachment of small organic building blocks as elementary units. Using the myriad of such building blocks, a broad spectrum of functionalities has been applied for COF syntheses for broad applications, including heterogeneous catalysis. Herein, we report the synthesis of a new family of porous and crystalline COFs using a novel acridine linker and benzene‐1,3,5‐tricarbaldehyde derivatives bearing a variable number of hydroxy groups. With the broad absorption in the visible light region, the COFs were applied as photocatalysts in metallaphotocatalytic C−N cross‐coupling. The fully β‐ketoenamine linked COF showed the highest activity, due to the increased charge separation upon irradiation. The COF showed good to excellent yields for several aryl bromides, good recyclability and even catalyzed the organic transformation in presence of green light as energy source. β‐ketoenamine‐linked COF showed the highest catalytic activity and was shown to be recyclable and even catalyzed the cross‐coupling efficiently under green light irradiation.A new family of porous crystalline COFs bearing acridine moieties was synthesized and applied as photocatalysts in metallaphotocatalytic C−N cross‐coupling. Among these materials the fully  The field of covalent organic frameworks (COFs)—crystalline and porous polymers that are solely consisting of organic building blocks reticulated via covalent bonds—has gained significant attention in the last decade.5, 6 A2 reduction dominate this application branch, and only few examples using COF photocatalysts in organic synthesis were reported.As an impact of these properties, COFs are promising candidates for heterogeneous photocatalysis using visible‐light due to the long‐range π‐conjugation. Water splitting and CON‐alkylation, decarboxylative conjugate addition or dehydrocarboxylation of carboxylic acids.[The acridine motif is commonly found in organic dyes and enables efficient intersystem crossing upon excitation. This results in long‐lived excited states that are crucial for efficient photocatalysis using low catalyst loadings.39, 40β‐ketoenamine structure and high charge separation under light irradiation are the key factors for high catalytic activity.Herein, we describe the synthesis of novel COFs bearing acridine moieties in reticulation with three different benzene‐1,3,5‐tricarbaldehyde derivatives with a variable number of hydroxy groups. The resulting materials were evaluated for their application as photocatalysts in metallaphotocatalytic C−N cross‐couplings. Our results indicate that not only a high surface area and crystallinity, but also a N‐(4‐nitrophenyl)aniline was obtained by a Buchwald–Hartwig amination.β‐ketoenamine to imine ratio in Tp‐Acr, DHTA‐Acr and HTA‐Acr COFs  in the reaction with 2‐hydroxybenzene‐1,3,5‐tricarbaldehyde , while the amount of 2,6‐diaminoacridine and acetic acid was kept constant (Section S3.2). All the precursor mixtures were heated for 72 h at 120 °C and the solid product washed with acetone, methanol (MeOH) and cyclohexane prior to Soxhlet extraction using MeOH to obtain the COFs as dark red solids.We began our investigations by synthesizing a C2‐linker bearing the acridine moiety  by a three step reaction, where 3‐nitro‐s Figure a. In theα radiation. All materials show the most intense reflections in the low angle region at 3.5 2θ degrees for Tp‐Acr as well as DHTA‐Acr, and 3.6 2θ degrees for HTA‐Acr  facet and confirm the crystalline π‐π stacked 2D structure for all three COFs. According to the geometry of the linkers, structural models with hcb topology were constructed for eclipsed (AA) and staggered (AB) stacking sequences . After geometrical optimization, the theoretical PXRD patterns of the structures were calculated and compared to the experimental diffraction pattern. All three COFs showed good agreement for the eclipsed stacking pattern, whereas the simulated staggered pattern did not fit with the measured diffractogram . Additionally, a full Pawley refinement was carried out to fit the final unit cell parameters, which led to acceptably low residual values and profile differences  analyses with a Cu Kr Figure e–g. Thesto the 00 facet an13C cross‐polarization magic angle spinning nuclear magnetic resonance (CP‐MAS NMR) analyses  are present (Section S5.1). From the CP‐MAS NMR and FTIR data, the structural integrity and formation of acridine COFs has been validated.All COFs were studied using s Figure a. The pr2 g−1, compared to 408 m2 g−1 for DHTA‐Acr COF and 127 m2 g−1 for the HTA‐Acr COF. This shows that the number of hydroxy groups in the aldehyde linker influences the final accessible surface area of the COFs. The additional keto‐/enol groups within the COF structure work as pore‐directing “anchors”, improving the stacking of the layers, which results in the increase of surface area.The permanent porosity of the acridine based COFs was confirmed using nitrogen sorption measurements at 77 K Figure b. The suJ‐aggregates”, was previously reported for porphyrin COFs.From the diffuse reflectance ultraviolet‐visible (UV/Vis) spectroscopy, it was confirmed that all acridine containing COFs show a very similar absorption behavior in the visible light region. In order to distinctly investigate the effect of the acridine moiety on the optical properties, an isoreticular COF with anthracene edges  was synthesized for comparison (Section S6).g=2.007, which can be attributed to unpaired electrons in the conduction band.g=2.007) COF shows a decreased efficiency in charge separation , highlighting the benefit of introducing the acridine moiety into the framework structure.The conduction band electrons of the acridine COF species were monitored by electron paramagnetic resonance (EPR) spectroscopy. To visualize the charge separation and transfer properties, EPR spectra of the COFs have been recorded in the dark and under photocatalytic reaction conditions. All three acridine based COFs show a singlet signal with Lorentzian line shape at 1) was obtained within 16 h when Tp‐Acr COF (2 mg mL−1), NiBr2 ⋅ 3H2O (5 mol%) and three equivalents of the amine coupling partner were used in DMAc . On the contrary, DHTA‐Acr and HTA‐Acr showed only minor product formation, while using Tp‐DAA 38 % of the coupling product was obtained (Entries 14 and 16). These results emphasize that embedding the acridine unit into a fully keto tautomerized COF resulted in a highly efficient photocatalyst both under blue and green light irradiation. With the optimized conditions using the most efficient COF (Tp‐Acr) as photocatalyst, the versatility of the semi‐heterogeneous catalytic system was evaluated . An aryl bromide with electron‐donating group (6) reacted with slightly less selectivity, which is in agreement with most dual nickel/photocatalytic C−N coupling protocols.[3–5), ester (2), trifluoromethyl‐ (1) as well as a bulky aliphatic residue (6) were tolerated in the dual catalytic amination. Substrates with an electron withdrawing meta‐substituent (4) or ortho‐substituent (5) did also yield the desired products in similar selectivity, although with lower efficiency than the para‐substituted analogue (3).Control studies using the linker 2,6‐diaminoacridine (Acr) or a model compound  as photocatalyst showed no formation of the product (Entries 7 and 8), emphasizing that only after incorporation into the COF backbone, the repeating units build up their photocatalytic properties through conjugation. In case of omitting a photocatalyst, still minor product formation (18 %) was detected (Entry 7). This can be explained by photoexcitation and productive catalysis of nickel‐amine complexes by the small portion of UV‐light in the emission of the used light source .rotocols.57, 581 was observed. We hypothesized that the loss in catalytic activity can be attributed to a collapse of the pores of the COF due to removal of DMAc. Performing a solvent exchange with MeOH and hexane prior to drying improved the recyclability significantly  after the first and fifth cycle. Ni 2p core‐level spectra  of the recycled material confirmed the presence of nickel(II) species with a doublet at 856 eV and 874 eV after the catalysis. Although the crystallinity of the COF is lost due to the intense light irradiation, N 1s XPS core‐level spectra show that both the aminic and pyridinic nitrogen species from the COF backbone remain unchanged during the catalysis . The structural integrity of the COF after the cross‐coupling reaction was further confirmed by IR spectroscopy . From additional TEM analyses it is clear that the morphology of the materials stays intact throughout the catalysis .β‐ketoenamine tautomerized COF, Tp‐Acr, showed a high catalytic activity both under blue and green light radiation for several aryl bromides, which is attributed to higher charge carrier separation efficiency as well as surface area. In addition, it was demonstrated that the COF could be recycled with a small drop in catalytic activity. To the best of our knowledge, this is the first example of a heterogenization of acridine photocatalysts via formation of crystalline organic frameworks.In summary, we report the first successful preparation of crystalline and porous acridine‐based COFs by following an acid‐catalyzed Schiff base synthesis route using three different 1,3,5‐triformylbenzene based linkers. The acridine‐based conjugated COFs show light absorption over a broad range of the visible light spectrum. Owing to these properties, the acridine‐based COFs were applied for the first time in semi‐heterogeneous metallaphotocatalytic C−N cross‐couplings. Among the novel COFs, the fully The authors declare no conflicts.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


Surgical scene understanding is a key barrier for situation-aware robotic surgeries and the associated surgical training. With the presence of domain shifts and the inclusion of new instruments and tissues, learning domain generalization (DG) plays a pivotal role in expanding instrument–tissue interaction detection to new domains in robotic surgery. Mimicking the ability of humans to incrementally learn new skills without forgetting their old skills in a similar domain, we employ incremental DG on scene graphs to predict instrument–tissue interaction during robot-assisted surgery. To achieve incremental DG, incorporate incremental learning (IL) to accommodate new instruments and knowledge-distillation-based student–teacher learning to tackle domain shifts in the new domain. Additionally, we designed an enhanced curriculum by smoothing (E-CBS) based on Laplacian of Gaussian (LoG) and Gaussian kernels, and integrated it with the feature extraction network (FEN) and graph network to improve the instrument–tissue interaction performance. Furthermore, the FEN’s and graph network’s logits are normalized by temperature normalization (T-Norm), and its effect in model calibration was studied. Quantitative and qualitative analysis proved that our incrementally-domain generalized interaction detection model was able to adapt to the target domain  while retaining its performance in the source domain (nephrectomy surgery). Additionally, the graph model enhanced by E-CBS and T-Norm outperformed other state-of-the-art models, and the incremental DG technique performed better than the naive domain adaption and DG technique. Surgical scene understanding paves the way for embedding situational awareness into robotic systems assisting surgeons in minimally invasive surgery. The current systems’ inability to understand the surgical scene renders it difficult to address the key limitations of minimally invasive surgery—lack of haptic sense, situation responsiveness, and lack of a standard surgeon evaluation matrix ,2,3,4,5.The different numbers of inputs and outputs in each scene, domain shifts, continued inclusion of novel instruments and tissues in the new surgical procedures, and scarce data availability make the interaction detection model domain-specific and less effective for general minimally invasive surgery. A naive solution would be to train a model specific to each surgical procedure. However, common surgical tools used in various surgeries may play different roles based on the surgery. With the lack of massive procedure-specific datasets, it is better to create a domain-generalized model encoded with the universal purpose of each tool that can output its interaction with the tissue based on the surgical scene. To address this, with the assumption of no novel instrument or interaction in the new domain, the old network could be domain adapted by further training only on the new domain dataset. Alternatively, the network could be retrained on both the old and new domain datasets by scarifying the training time. While both methods could serve as an interim solution, the continued emergence of novel instruments and new surgical procedures makes these solutions inefficient eventually. Therefore, there is a dire need for a method to domain-generalize the surgical scene understanding model to include new domain shifts, instruments, and tissues from new surgical procedures without the need to retrain the model from scratch.–Incremental DG: Integrating (i) a graph network with knowledge distillation and (ii) FEN with IL, to domain generalize the instrument–tissue interaction detection model. The proposed model was first trained for nephrectomy surgery and then incrementally domain generalized to transoral robotic surgery.–Enhancing a graph model for surgical scene understanding: The graph network and FEN were enhanced by T-Norm and our proposed E-CBS. The E-CBS introduced (i) 2D convolution layers with its kernel (3 × 3) weights based on LoG and Gaussian to enhance the FEN and (ii) a 1D convolution layer with kernel (1 × 3) weights based on LoG to enhance the graph model. T-Norm normalizes the network logits during training and inferences to improve model reliability.–Quantitatively and qualitatively, we proved that (i) our model enhanced by E-CBS and T-Norm outperformed other state-of-the-art models, and (ii) our knowledge-distillation-based incremental DG performed better than the naive domain adaption and DG technique.Humans with a specific set of skills often display the ability to incrementally learn a new skill for a similar domain with ease, without unlearning the previous skills. For instance, cricket players can quickly learn and adapt to playing baseball without scarifying their skills in cricket. Furthermore, to maintain and improve their skills in both domains, they can train at regular intervals in both domains instead of re-learning those skills from scratch. Mimicking this, we propose an incremental domain generalization technique, where a graph model initially trained for instrument–tissue interaction detection in nephrectomy surgical scenes is incrementally domain generalized to detect interactions in transoral robotic surgical scenes. Firstly, inspired by the use of visual, semantic, and word2vec features in a graph network for the task of human–object interaction detection, we employed the visual-semantic graph attention network (VS-GAT)  model tosurgical scene understanding, we employed a graph network inspired from VS-GAT [incremental DG in surgical scene understanding, a two-tier approach was adopted: (a) As the graph network relies heavily on its embedded features, the FEN was extended to the target domain using IL [To perform m VS-GAT  that usem VS-GAT  as the Fusing IL  to caterusing IL , we thenFeature extraction network (FEN): ResNet18 [Graph network: The surgical scene understanding task is theorized as ResNet18  is initiword2vec  is emploures Fsp . Upon agx, y), the pixel locations in the kernel, the weights of the LoG kernel are calculated based on:CBS  proposesFEN: E-CBS is employed in the FEN using both the LoG and Gaussian kernels. In ResNet18 [Graph network: E-CBS is employed using a LoG-kernel-based 1D convolution layer at the visual graph ))3)) duriFEN: Initially, the FEN was trained to classify 9 classes (1 tissue and 8 instruments) found in the source domain. We then implemented IL [Graph network: To achieve DG, two key problems, (i) new instruments and (ii) domain shift, must be addressed. As each scene frame is considered as a sparse graph n) of the source domain dataset based on ented IL  to extenks in IL . The soun) source and target domain.(a) Incremental DG in surgical scene understanding: Instrument Segmentation Challenge 2018 [nge 2018  consists(b) FEN: Both source and target domains were exploited to train the FEN to classify tissues and instruments. Tissues (kidney/tissue) and 10 instruments  were cropped from the datasets and resized to 224 × 224 pixels. In total, the training set consisted of 7019 images and the test set consisted of 1460 images.(c) E-CBS: Cifar10 [ Cifar10  was empl Cifar10  comprise(a) Graph network: The graph network was trained on each domain using a constant learning rate = n = 143 was used to sample frames from the source domain. For the final balanced fine-tuning phase during DG, learning rate = (b) FEN: All variants of FENs, with and without label-smoothing [moothing , with an(c) E-CBS: Three variants, (i) the CBS [ the CBS , (ii) th the CBS . Each va Cifar10  dataset,https://github.com/lalithjets/Domain-Generalization-for-Surgical-Scene-Graph, accessed on 12 April 2022) in this work was implemented using the PyTorch framework on three GPUs (1× Nvidia GTX 1080 Ti and 2× Nvidia GTX Titan X).All code  in n samples from both domains. It is observed that our proposed incremental DG technique improved the model’s performance in both the source domain and target domain, extending the model to the target domain while retaining its performance in the source domain. Secondly, the performance of our model trained using our proposed knowledge distillation-based incremental DG technique is also compared against our model trained using the naive domain adaption and DG techniques . Under nThirdly, an ablation study of our model trained using unsupervised DG (trained only on source domain) technique and using our incremental DG technique, with and without label-smoothing , with anFourthly, an ablation study was conducted on the FEN with and without IL , E-CBS, Finally, an ablation study is reported in Mimicking a human-like incremental learning regime, we proposed an incremental domain generalization technique to generalize an instrument–tissue interaction detection graph model to a target domain without sacrificing its performance on the source domain. This is achieved by incorporating an enhanced graph network with a teacher–student model-based knowledge distillation to handle domain shifts and an enhanced feature extractor network with incremental learning to include novel instruments. Furthermore, we introduced an E-CBS that uses (i) 2D convolution layers based on the Laplace of a Gaussian kernel and a Gaussian kernel to enhance the performance of feature extractor, and (ii) a 1D convolution layer based on the Laplace of a Gaussian kernel to enhance the graph network. We also employ temperature normalization to both the feature extraction and graph network’s output logits during training and inference to improve model calibration. Incrementally, domain-generalized graph models can expand surgical scene understanding across various surgical procedures with novel instruments and domain shifts. Our proposed model was able to detect interaction with an inference time of


Neurodegenerative diseases have acquired the status of one of the leading causes of death in developed countries, which requires creating new model systems capable of accurately reproducing the mechanisms underlying these pathologies. Here we analyzed modern model systems and their contribution to the solution of unexplored manifestations of neuropathological processes. Each model has unique properties that make it the optimal tool for modeling certain aspects of neurodegenerative disorders. We concluded that to optimize research, it is necessary to combine models into complexes that include organisms and artificial systems of different organizational levels. Such complexes can be organized in two ways. The first method can be described as “step by step”, where each model for studying a certain characteristic is a separate step that allows using the information obtained in the modeling process for the gradual study of increasingly complex processes in subsequent models. The second way is a ‘network’ approach. Studies are carried out with several types of models simultaneously, and experiments with each specific type are adjusted in conformity with the data obtained from other models. In our opinion, the ‘network‘ approach to combining individual model systems seems more promising for fundamental biology as well as diagnostics and therapy. Aging and the loss of ability to maintain normal processes of cell death and the utilization of abnormal proteins associated with aging. The most characteristic cases are taupathies (Alzheimer’s disease) and synucleinopathy (Parkinson’s disease);Mutations, most often expansion of trinucleotide repeats ;Inflammatory processes in the nervous system;The effect of adverse environmental factors.Neurodegenerative diseases, once rare in developed countries, are becoming a major public health threat and a leading cause of death in parallel with an increase in life expectancy. These diseases are quite diverse in their pathophysiology—with some causing memory and cognitive impairments and others affecting a person’s ability to move, speak and even, breathe. Effective methods of treating neurodegenerative diseases are extremely necessary, but modern medicine still does not have such methods. Targeted treatment methods can appear only after an in-depth study of the causes and mechanisms of each disease. All diseases of this type have several common features, such as prolonged development (years or decades), mass death of neurons and neuroglia, and the formation and spread of protein aggregates with an abnormal tertiary structure. Among the main reasons for their development are:Affecting mainly the elderly, neurodegenerative diseases increase the number of disabled people, which creates an additional burden on families, the economy and social services. In addition, in recent years cases of neurodegenerative diseases are becoming increasingly frequent in younger people; the development of Huntington’s disease was reported in 9-year-old patients ,2. MoreoNeurodegenerative diseases can have both a hereditary nature or develop sporadically. The development of the neurodegenerative process is based on disorders in the structure and function of certain proteins. Abnormal aggregation and the toxic effect of these proteins on cells lead to the occurrence of diseases. Neurodegenerative pathologies include tauopathies (Parkinson’s disease), amyloidosis (Alzheimer’s disease), α-synucleinopathies (Levi’s bodies in Parkinson’s disease), TDP-43 (TAR DNA-binding protein 43) and SOD1 (superoxide dismutase 1) proteinopathy , prionopathy and others. A separate group consists of polyglutamine diseases resulting from a congenital mutation—triplet expansion of CAG (polyglutamine—polyQ) in certain genes. Huntington’s disease is an example of such a neurodegenerative disease [The study of the neurodegenerative disease models and the modification and rethinking of old models along with the creation of fundamentally new systems are important for several reasons. The first reason is that our knowledge of neurodegenerative diseases is expanding rapidly, and old models are no longer adequate. The second reason is that drugs and treatments that were projected to be effective during development and testing in cell cultures have shown their failure in clinical trials. These facts indicate the insufficiency of the existing model systems . FinallyOne way to learn about how a disease works to destroy the normal functions of an organism is to develop a model system that recapitulates the hallmark characteristics of the disease.The main requirement for a neurodegenerative disease model is the ability to reproduce characteristic pathological processes resulting from specific molecular and cellular disorders. The importance of this requirement is due to the fact that most modern methods of treatment do not address the basic mechanisms of neurodegenerative diseases, but only relieve symptoms ,7. In adNumerous studies have shown that neurodegenerative diseases can have a variety of mechanisms of occurrence ,9,10,11.As has already been mentioned, to obtain the most accurate results, a model of a neurodegenerative disease should approximate the ‘original’ organism from the point of view of metabolic disorders as well. The model should not only reproduce the symptoms of the disease but also copy the pathological process at the molecular level and the signaling cascade (or proteinopathy) that is disturbed in a specific disease. It has been proved that models of hereditary forms of neurodegenerative diseases, even in the case of incomplete compliance with phenocopic changes occurring under the influence of unfavorable environmental factors, make it possible to fully reproduce the molecular mechanisms underlying the disease . This apThe approach to the treatment of any neurodegenerative disease involves three stages: diagnosis, actual treatment and further evaluation of its effectiveness. Each of these stages is important and can become an object of modeling. The time frame is no less important since the development of neurodegenerative pathologies can last for years and even decades. Thus, the development of Alzheimer’s disease takes an average of three years and Creutzfeldt-Jakob disease—within nine to ten years ,18. The This requirement applies to animal models of neurodegenerative diseases, more precisely, to models based on vertebrates, since only they have a sufficiently developed nervous system and complex types of behavior comparable to the higher nervous activity of man.The described complex types of behavior are associated with the fact that the nervous system is never in a stable state, as it is constantly rebuilt and modified. The formation of reflex arcs and the memorization of information and learning require the restructuring of neural connections, the decay of old ones and the formation of new ones. Moreover, the nervous system is rebuilt in the process of body growth and maturation. One should not forget that the nervous system is not protected from damage, and inflammation and regeneration processes take place in it. The processes of neuroplasticity are especially strongly activated after craniocerebral injuries and stroke. In general, neuroplasticity processes can be divided into two types: regeneration (the formation of new cells or new synaptic contacts) and functional restructuring (occurs without changing the number of cells) . These pProkaryotic organisms are routinely used in modern biology and biotechnology to produce substances with set properties (mainly proteins), including mutant proteins characteristic of certain neuropathology (act as protein factories). Thus, researchers have the opportunity to study the proteins involved in neurodegeneration without using human material to identify their structure, aggregation mechanisms, etc.Today prokaryotes are increasingly used to create models of the ‘microbiome-brain-gut’ system in neurodegeneration studies . These mThe gut microbiome, together with the immune, endocrine and all three sections of the autonomic nervous system  forms a complex that allows bacteria to influence the central nervous system . The metIn earlier works, the main research tool in this area was model animals with impaired microflora. Now models of the intestinal microbiome in vitro allow us to more accurately analyze the composition of the microflora of the gastrointestinal tract.SHIME—The Simulator of the Human Intestinal Microbial Ecosystem. The system is a complex consisting of bioreactors connected in series with peristaltic pumps. In each bioreactor conditions specific to a particular section of the digestive system are created . The reactors correspond to the following sections of the gastrointestinal tract: stomach, small intestine, ascending colon, transverse colon, and descending colon ;SIMGI—SIMulator of GastroIntestinal tract. This system is similar to SHIME in many ways, but there are some differences. This model is not only fully automated but also controlled by a computer. Moreover, the gastric compartment has a peristaltic mixing system ;Organ-On-A-Chip Systems. These include microfluidic systems, which are ultra-compact (within fractions of a millimeter) bioreactors containing organotypic cell cultures capable of reproducing the pathophysiological processes in miniature. In the case of modeling the ‘microbiome-brain-gut’ axis, the role of these systems is to reproduce the processes of the transfer of bacterial neurotoxins through various microanatomical barriers, including the blood-brain barrier ;Several in vitro microbiome systems have been described, among which three main types can be distinguished:The main sphere of application of transgenic bacterial models of neurodegenerative diseases is the synthesis of pathological proteins and the subsequent study of how they fold, interact and aggregate dynamically .E. coli, being one of the most thoroughly studied prokaryotic organisms, turned out to be not the most convenient model organism for use as a ‘protein factory’. The reasons are the need for the constant application of antibiotics to maintain the culture, low transformation efficiency associated with the loss of plasmids, as well as problems at the stage of formation of the final product such as the violation of the formation of secondary and tertiary structures, protein aggregation and the absence of the necessary post-translational modifications. Therefore, the search for optimal cell factories should be carried out among bacterial species adapted to more diverse and extreme conditions [nditions .Prions are a key factor that brings together a variety of disorders of the nervous system, from Creutzfeldt-Jakob disease to amyotrophic lateral sclerosis. They are a group of a wide variety of protein molecules that have an abnormal tertiary structure that can transfer their structure to homologous proteins, as well as form insoluble aggregates that gradually accumulate and are the main cause of the detrimental effect of prions on the nervous system . Such a Bacterial cells can be used as ‘protein factories’ that synthesize prions specific to humans or other mammalian organisms. For instance, a recombinant mouse prion protein (recMoPrP) produced in transgenic E. coli has been used to study polymerization and amyloid fibril formation. Further, fibrils consisting of recMoPrP (89–230) were administered intracerebral to experimental mice. The mice developed neurological dysfunction on the 380th to 660th day after the administration . This stSaccharomyces cerevisiae as a model organism lies in the fact that many of the biochemical and signaling pathways present in the human cell are highly conserved and perform similar functions in yeast cells. Evolutionary conservatism underlies the main method of working with yeast models. After a gene is found in the human genome that can be associated with a particular pathology, a line of yeast is created, in the genome of which there are mutations in a homologous sequence. If the homologous gene is absent in S. cerevisiae, then the corresponding defective gene is introduced into the genome of the model. In both cases, if the defective gene is responsible for the development of pathologies , then the corresponding phenotype develops in yeast cells [The value of the yeast st cells .Yeast models, due to their simplicity, are not suitable for reproducing the complex symptoms of neuropathology such as behavioral disorders or changes in the structure of brain tissue. Therefore, the main symptoms modeled in yeast are the accumulation of abnormal proteins, as well as the disruption of the normal course of cell death and autophagy.The functioning of all intracellular mechanisms aimed at combating proteins with an abnormal tertiary structure is ensured by the functioning of the chaperone and ubiquitin-proteasome systems of the cell . Thus, yMolecular chaperones can be called the first line of defense against neurodegenerative diseases. They eliminate misfolded proteins, preventing their aggregation and the formation of amyloid structures ,34,35. AProteasomes cleave misfolded and mutated proteins into short peptide fragments. The active 26S proteasome is formed from a 20S subunit (core) and several 19S (regulatory) subunits. Experiments with yeast models have shown that the 20S subunit is inhibited by three-dimensional structures resulting from the oligomerization of proteins that are specific for neurodegenerative diseases such as Alzheimer’s (β-amyloid), Parkinson’s (α-synuclein) and Huntington’s disease (HTT protein) .S. cerevisiae [Autophagy is an intracellular process necessary to maintain cell homeostasis. During autophagy, unnecessary and damaged cellular organelles and proteins are utilized. Autophagy is a critical process in a multicellular organism during embryogenesis, and in aging, and also plays a role in the development of diseases, including heart failure , myopathrevisiae . Yeast mrevisiae . Studiesrevisiae ).S. cerevisiae proceeds synchronously in a homogeneous culture and depends on the amount of nutrients in the medium, which makes it easy to control it in experiments [Autophagy in yeast is known in sufficient detail at the molecular level. In addition, the autophagic process in eriments . Thanks Models of neurodegenerative diseases based on multicellular animals have several specific properties that are not available for unicellular systems. The most significant is the ability to simulate the systemic processes of the human body: the functioning of intercellular signaling pathways, the restoration of the nervous system after cell death and the distribution of proteins with an abnormal tertiary structure inside the body ,48,49.The loss of the ability of cells and tissues to maintain normal cell death processes;Disorders in the utilization of misfolded and aggregated proteins that are toxic;The accumulation of cellular debris due to disorders of the autophagolysosomal apparatus;The uncontrolled course of inflammatory processes, mainly in the CNS.One of the most important fields of application for animal models of neurodegenerative diseases is aging. Aging is a universal process in which the normal functions of cells in multicellular organisms are disrupted; there is also a loss of the tissues’ ability to renew and maintain a functional state. Aging is characterized by a number of pathological processes caused by:What does the toxic activity of abnormal protein aggregates look like at the molecular level?Is there a relationship between aggregation and toxicity?Do protein aggregates observed in neurodegenerative diseases have any common properties, including pathological ones?Why are these diseases associated with aging?What causes the development of pathologies associated with a particular cell type ?The aggregation of abnormal proteins is considered one of the main causes of the development of neurodegenerative diseases associated with aging. The main questions which are yet to be answered by researchers of each specific disease are as follows:The role of multicellular models is to approximate molecular biology data from single-cell models to fundamental processes such as growth, morphogenesis, aging, stress adaptation, synaptic network formation, and neurodegenerative processes. Models of neurodegenerative diseases based on invertebrates have several characteristic features, which could provide answers to the above questions, the most significant of which are the following:(A) Presence of specialized cells and tissues. Unlike previous types of models, in a multicellular organism, several types of cells that perform different functions are combined into a system where they have a direct or indirect effect on each other. An example is the interaction of neuroglia with neurons, which is one of the key aspects of the accumulation and distribution of amyloids in the nervous system .(B) Evolutionary relationship. Despite the fact that the external differences between humans and Drosophila seem colossal, at the molecular level there are significant similarities and conservatism, especially in the mechanisms of morphogenesis, autophagy, and cell death. An example is the signaling cascades including Wnt proteins. Wnt proteins are a family of secreted glycoproteins responsible for patterning embryonic development, gastrulation, formation of synaptic connections, axonal remodeling, regulation of cell proliferation, stem cell development, and many other processes. Wnt protein binds to the frizzled receptor (Fz), which has seven transmembrane domains and is topologically similar to G-protein coupled receptors, which leads to the separation of the GSK3, Axin, and APC protein complexes. In turn, this prevents the phosphorylation of β-catenin. This protein, in its unphosphorylated form, enters the nucleus and binds there to transcription factors .Dr. melanogaster has shown that these ions affect the canonical (β-catenin-dependent) Wnt pathway [An example of a direct application of evolutionary conservatism in the field of neurodegenerative disease models is the neuroprotective effect of lithium ions. From ancient times to the present day they have been used to treat nervous disorders ,54,55. R pathway . Transge pathway ,58,59. S(C) The presence of nervous activity and behavior. Behavioral changes, especially in basic responses such as foraging and spatial orientation, are among the most easily recorded signs. Since the main goal of research in neurodegenerative diseases is the restoration of normal intellectual and social functions in patients, behavioral changes in animal models are still of great value to researchers, because due to the relative evolutionary conservatism of many molecular and signaling pathways, they allow for the establishment of parallels between the behavior of experimental animals, including invertebrates, and humans suffering from neurodegeneration .(D) Autophagy. Invertebrates are also a classic model for studying autophagy processes in neurodegeneration and are often used to study several signaling pathways and molecular cascades.Caenorhabditis elegans is a quite convenient model for the study of cell death. The advantage of this model is the constancy of the cellular composition. Adult hermaphroditic individuals have 959 somatic nuclei, and the number of nerve cells is 302 [The nematode s is 302 . All thes is 302 . This alC. elegans as a connectome model lies not only in the small number of cells and its determinism but also in the permeability of the worm body to light, which makes it possible to conduct studies with fluorescent proteins included in nerve cells [C. elegans a popular model for studying various neurodegenerative diseases.The advantage of using ve cells . For exave cells ,65. ApprThe use of mammals as model organisms is due to their physiological, anatomical and genetic similarity to humans. For centuries mammals have acted as a ‘visual aid’, a source of knowledge about the structure of the human body—the data obtained during the autopsy of animal corpses have served to create an increasingly detailed diagram of the human body structure since ancient times. Moreover, although even then the researchers realized that human and animal organisms are not absolutely identical, the fact that there is a significant similarity between humans and other mammalian species was undeniable.The necessity to study the molecular mechanisms and mechanisms of initiation of proteinopathy. The neurodegenerative process can be considered in its entirety, considering the influence of all organs and systems of the body, even if phenotypically the degeneration is not fully manifested;The relative ease of maintaining the model system;The presence of age-related changes as a natural process inherent in the body of an animal. Aging, being a systemic process of reducing the body’s ability to maintain its functional state, is the main risk factor for a number of diseases, including neurodegenerative ones;Highly organized immune system;Presence of complex neural activity and behavior .Today animal models, including neurodegenerative diseases, while still playing an important role in the study of human diseases, are experiencing serious competition from alternative systems, especially in vitro culture models. The reason is the difficulty of reproducing the symptoms of neurodegenerative disorders in the animal body. One of the main approaches in the degenerations study is the search for a new gene  responsible for the development of pathology, as well as proteins and protein complexes that can become disease markers. The data obtained form the basis of a model organism and act as a kind of guideline in its creation. The problem is that neurodegenerative processes in many cases occur sporadically without affecting the hereditary apparatus of the cell. In Alzheimer’s disease more than 90% of cases occur sporadically, and the exact cause of their development is unknown (it is assumed that in this case the main role is played by epigenetic mechanisms) . In addiFor gerontological research, various animal models of mammals have been used for a long time and have shown success ,68.Chronic oxidative stress is associated with damage to mitochondria and it is one of the causes of neurodegenerative disorder development . EvidencThe role of mitochondria and mitochondrial proteins in the development of neurodegenerative diseases is best studied for Parkinson’s disease. In most cases this disease is idiopathic, but there are rare hereditary forms, some of which are monogenic ,71. ObseDr. melanogaster or C. elegans: alopecia, cardiomyopathy, osteoporosis, anemia, sarcopenia and kyphosis [Mice have proved to be convenient animal models for the investigation of mitochondria and oxidative stress involvement in neurodegenerative processes due to the high degree of similarity with humans at the anatomical and molecular levels. At 25 weeks of age, test mice show symptoms of neurodegenerative disorders that simply could not be modeled in kyphosis .Autoimmune reactions are the risk factors for the development of neurodegenerative processes. Adaptive immune response cells, especially Th cells, play an important role in the pathogenesis of multiple sclerosis . ExperimThe ability to study complex behavioral reactions resulting from disorders of the structure and functions of the nervous system is a unique feature of animal models of neurodegenerative disorders. Experiments on mice have shown that an increased level of pro-inflammatory cytokines corresponds to a state similar to depression . MutatioOrganoids are called cultural model systems derived from stem cells and have a spatial structure that ensures their correspondence with human organs. In other words, the goal of creating organoid models is to reproduce a small copy of an organ under controlled in vitro conditions.Approaches based on the use of animal models have made it possible to reveal the basic principles of the development of many pathologies. However, the results obtained when working with such model systems could not be directly extrapolated to the human body. There are a number of mechanisms that are specific to the human body that cannot be modeled in other animals. The most striking example is brain development. The human brain is a structure unique in its complexity, variability and functional plasticity. The processes of memory formation, conditioned reflexes and, ultimately, higher nervous activity, which underlies the evolutionary success of man as a biological species, are provided by constant changes in the structure of the brain, restructuring of synaptic connections, removal of old and the creation of new nerve circuits. At the same time, many mechanisms of the functional reorganization of the brain  are unique to humans and cannot be modeled even in anthropoid primates. Differences already exist at the level of gene expression patterns. Thus, researchers from the Cold Spring Harbor Laboratory  analyzedAll types of models that have been discussed so far do not include human cells and tissues; therefore, they do not allow the direct ‘transfer’ of the obtained data to the human body. Even the smallest genetic and molecular differences could affect the signaling cascade leading to the accumulation of toxic proteins or, conversely, reduce the effectiveness of the drug that suppresses this process.Thus, the emergence of three-dimensional cultures of human cells, based on stem cells obtained from various organs, has become an important step in overcoming these limitations.Organoid models open prospects not only for creating systems for searching for the neurodegenerative processes mechanisms and testing drugs, but also for modeling processes associated with direct damage to brain tissues , and, possibly, treatment of brain-damaged areas with using organoid transplants grown on the basis of stem cells taken from a patient.The impossibility of reliable reproduction of inflammatory and degenerative processes associated with brain injuries in animal models, especially in rodents. In addition to differences between humans and model animals at the molecular level, interspecies differences in brain structure are a significant factor, such as different ratios of gray and white matter, the density of neurons in the cortex, and a number of other structural differences . SimulatThe ability to fully trace the cell path, from pluripotent stem cells to nerve and glial cells, so that changes in the architecture of the nervous tissue could be observed in real-time. In most methods of working with animal models, only a certain time ‘slice’ of structures is considered, corresponding to their state at a certain point in time;Creation within the model of niches with a unique microenvironment. The cell cultures used to model the long-term effects of brain injury prior to the introduction of organoid models into practice had a quite simple structure. For the most part, these are single-layer or multilayer structures containing one or more cell types . OrganoiDespite significant progress in the prevention of mechanical brain damage in terms of ensuring transport and industrial safety, disorders of nervous activity caused by the consequences of traumatic brain injuries still pose a serious threat to human health. The key to effectively eliminating the consequences of traumatic brain injury is to treat them as a chronic process with a wide range of pathophysiological disorders, one of which is an increased risk of neurodegenerative diseases. The use of organelles to establish the relationship between trauma and neurodegeneration, as well as to deeply study the degenerative processes caused by damage to the brain tissue at the molecular, cellular and tissue levels, is justified for several reasons:Organoid models are actively used to study the influence of the microenvironment on the emergence and development of brain tumors ,84. OrgaOne of the microenvironmental factors that are common for both brain tumorigenesis and neurodegenerative diseases is local inflammation. The key component of these reactions is RAGE receptors (Receptor for Advanced Glycation end products). In addition to that, these receptors play an important role in the development of diabetes, as well as heart and kidney failure . AdvanceIt is highly important to note that organoid models are suitable not only for modeling the consequences of traumatic brain injuries but also for their elimination . ParticuThe results of the data analysis on neurodegenerative disease models suggest that all types of models have characteristic properties that make them optimal tools for studying one or another aspect of neurodegenerative diseases. Bacterial and yeast models have shown themselves to be universal and unpretentious ‘protein factories’, suitable not only for studying evolutionarily conservative molecular mechanisms but also for the synthesis of transgenic proteins responsible for the onset and course of degenerative processes in the human body. The advantages of animal models (both invertebrates and vertebrates) lie, first of all, in the ability to show the effect of neurodegenerations on the body as a complex system with many aspects, including complex behavior. Organoid models are the most promising type. Their main advantage is the ability to trace the development of degenerations as sequential, chronic processes. Besides, organoid models have demonstrated their applicability not only as models but also as potential sources of transplants for the treatment of neurodegenerative diseases and conditions leading to them.At present, there is no universal model that can reflect all aspects of such a complex process as neurodegeneration. Therefore, it is advisable to use a complex consisting of models of different origins, simultaneously exploring not only processes at the molecular and cellular levels, but also the influence of environmental factors, such as the composition of the microbiome, stress and intellectual load. This complex can be organized in two forms .The first form appears as a kind of ‘step-by-step’, where each model is a separate step, allowing one to use information from the previous step to gradually study more and more complex processes. Thus, transgenic bacterial models would serve to produce a protein of interest, yeast to study the dynamics of abnormal proteins, invertebrates to monitor processes such as cell death and neuroplasticity, mammals to cognitive impairment, and in vitro systems to test drugs and treatments.The second approach, based on the “network” organization of a complex of model systems, is, in our opinion, more preferable. With the “network” approach, work is carried out simultaneously with several types of models, and work with each specific type is adjusted in accordance with data obtained from other parallel models (both more highly organized and less organized). An example is the creation of an in vitro continuous culture system that includes both human cells and microorganisms, the composition of which is adjusted in accordance with data on motor disorders that develop during life in mice with impaired intestinal microflora. A detailed analysis of the literature data presented in this review allows us to state that the ‘network’ approach to the combination of individual model systems seems to be more promising and fruitful both from the point of view of fundamental biology and diagnostics and therapy .Thus, a remarkable example of the application of the ‘network’ approach to models’ organization is described in detail by Ambrosini et al. . The autSummarizing the data above, we can conclude that the future of neurodegenerative disease research belongs to the ‘network’ models. The ‘network’ organized complex models are the most promising both for the fundamental investigation of the whole complex of causes leading to neurodegenerative disease development and for progress in the creation and development of approaches to their prevention and treatment.


Covalent organic frameworks are porous crystals of polymers with two categories based on their covalent linkages: layered structures with two dimensions and networks with three-dimensional structures. Three-dimensional covalent organic frameworks are porous, have large surface areas, and have highly ordered structures. Since covalent bonds are responsible for the formation of three-dimensional covalent organic frameworks, their synthesis has been a challenge and different structures are generated during the synthesis. Moreover, initially, their topologies have been limited to dia, ctn, and bor which are formed by the condensation of triangular or linear units with tetrahedral units. There are very few building units available for their synthesis. Finally, the future perspective of 3D COFs has been designated for the future development of three-dimensional covalent organic frameworks. Covalent organic frameworks (COFs), a branch of a crystalline framework with pores, are synthesised by combining directional organic fragments covalently to form reticular polymers. They are polymers having specific morphologies and geometrical conformations ,2,3. TheThe principle of polymer growth is controlled by a topology diagram that is different from the principle used for polymers such as cross-linked polymers, linear polymers, biopolymers, and hyperbranched polymers; thus, highly ordered structures can be predesigned at the primary stage ,5,6. TheSince the propelling force for the synthesis of 3D COFs is the formation of covalent bonds, it poses a difficulty for their synthesis . In contThe functional and structural diversity has been explored for different rigid building blocks to predict their geometry based on the restricted rotation of the building blocks. A process of reversible dynamic equilibrium is feasible because of the restricted rotation . There hThere are multiple reviews on porous COFs , enginee(1)The desired framework of the topology is selected and the framework is divided by slicing the edges into vertices;(2)The geometry, accurate angles, and vertices are analysed depending on the number of points required for extension;(3)Identification of molecular equivalents of vertices is conducted by selecting huge polyaromatic molecules as building blocks as an accurate geometry can be predicted with the rigid linkers;(4)The building blocks are connected through covalent linkages to create COFs by modulating the reaction kinetics and reversibility at a microscopic scale between the building units;(5)The reticulated structure should be analytically confirmed. The accurate architecture of the vertices should be clear since topologies depend on the type of connectivity.A particular net or topology of a COF can be aimed at using reticular chemistry. Building blocks of the desired geometry are selected and condensed to place them in a particular framework . There aThe 3D COFs are targeted by using two different tactics: (a) the topology is allowed to form by assembling supramolecules through a controlled alignment of the building units and (b) the application of polyhedral organic units, mainly organic cages, as building blocks . In the The flexibility in the conformation of the organic bonds is responsible for dictating the orientation of the building blocks . Since ttert-butyloxycarbonyl (Boc) group was used as the starting component. Deprotection of amine was conducted in situ in the presence of trifluoroacetic acid; this process boosted the crystallization of COFs by decreasing the reaction rate of the condensation reaction. The formation of insoluble amorphous intermediates was eradicated, and a woven 3D COF (3D COF-woven) was formed. The protected amine was allowed to form a Schiff base diiminopyridine (DIP) by reacting with Co(BF4)2·6H2O at ambient temperature. The formation of molecular threads is propelled by the metal complex for complete crystallization  condensation reaction of imines. The fluorescent property of the crystal was attributed to the isolated imine-functionalised pyrene moieties present in the 3D architecture. The presence of 20 ppm picric acid quenched its fluorescence properties.A pyrene-based 3D COF (3D-Py-COF) was synthesised to have a pts topology of two-fold points which can interpenetrate . The cryd) moiety by a [4 + 4] condensation reaction benzene (TFMB) having a C-O single bond by using the method of continuous rotation electron diffraction (cRED) with a pts topology and six-fold interpenetration . The skeImine linkers were used for joining a linear unit, pyromellitic dianhydride (PMDA), and two different tetrahedral units, tetra(4-aminophenyl)methane (TAPM) and 1,3,5,7-tetraaminoadamantane (TAA) to form two 3D polyimide (PI)-based COFs (3D COF-PI-1 and 3D COF-PI-2) with a dia topology having four-fold interpenetrated nets . The tetd-symmetric adamantane knot to fabricate 3D COF-DL229 with dia topology ) was selected, and the tetrakis(4-formylphenyl)-methane (TFPM) acted as the tetrahedral building blocks. The ionic liquid reacted with three different molecules to furnish three different ionic liquid-based-COFs: 4,4′-diaminobiphenyl (DABP), p-phenylenediamine (PDA), and 4,4″-diamino-p-terphenyl (DATP). The 3D-IL-COF with 4,4″-diamino-p-terphenyl (DATP) showed 11-fold interpenetrated dia nets, while that with 4,4′-diaminobiphenyl (DABP) showed nine-fold interpenetrated dia nets. Alternately, p-phenylenediamine (PDA) synthesised a 3D-IL-COF with showed five-fold interpenetrated dia nets. All three 3D-IL-COFs showed good uptake of carbon dioxide from a mixture containing nitrogen and methane. The enhancement in the absorption of the gas selectively is attributed to the presence of ionic liquid in the pores of the crystals. The pores in ionic liquids retain carbon dioxide while methane and nitrogen filter out through the pores.An ionothermal synthesis of 3D COFs using ionic liquids (3D-IL-COFs) at room temperature and pressure within a short synthesis time (3 min) was reported. The crystals possess a topology of diamondoid (dia) nets  as shown3NH3PbI3 layers for enhancing the performance of perovskite solar cells.Spirobifluorene was used as the core building block for fabricating conjugated SP-3D-COFs with imine linkers . Spirobi2N] (1-butyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide) at ambient temperature. The crystal possessed dia nets with a two-fold interpenetrated topology and is chemically and thermally stable. The crystal selectively absorbs carbon dioxide over nitrogen due to its porosity and narrow distribution of pore size. The skeleton was stable in the acidic solution but unstable in the alkaline solution as the reactions forming C=N gets reversed under alkaline conditions. Additionally, the crystal structure could not sustain very high alkaline and acidic conditions. The crystal was thermally stable even at 450 °C due to the existence of the conjugated and linear azine linker  were incorporated which exhibited good catalytic properties as antioxidants . The SalIn another report, two 3D salen-based COFs were fabricated by the reaction between methane or silane derivatives of tetra-salicylaldehydes with ethanediamine to form a 7-fold interpenetrated dia topology . These sSpirobifluorene with a tertragonal-disphenoid structure was used as a 3D building block to design 3D COFs (3D COF-SP) . The COF3D COFs having a cubic carbon nitride (ctn) net topology (3D-COF-FPBA and 3D-COF-FFPBA) were designed having two linking bonds, namely imine and boroxine with a huge capacity for storing carbon dioxide, methane, and hydrogen  as shownA building unit with a bulky phenyl moiety, 1,2,4,5-tetrakis(4-formylphenyl)-3,6-diphenylbenzene (TPB-Ph) was condensed with tetra(p-aminophenyl)-methane (TAPM) to undergo [4 + 4] condensation to obtain a thermally stable 3D COF (3D COF-TPB-Ph) with an ljh topology . Introdu3] and hydroxyl groups was conducted to obtain an anionic tetrahedral structure, tetrakis(spiroborate) [+, piperazine, and dimethylamine) were examined for forming three different COFs  with rra topology with high porosity as shown in The 3D CD-COFs were fabricated using cyclodextrin as flexible building entities to obtain channels comprising dynamic functional groups . Cyclodeoborate) . Thus, coborate) . Differe2 due to the presence of protonated piperazine around the pores that enhances the attraction for CO2 molecules through resilient quadrupole moments.The nodes in the net are occupied by building blocks, where four γ-cyclodextrin units combine with one boron atom while eight boron atoms combine into a single γ-cyclodextrin moiety. The presence of channels for trapping electrolytes and an anionic skeleton makes CD-COF-Li a promising Li-ion conductor in the solid state. An enhancement in temperature decreases the resistance of the material. The cell fabricated of this COF exhibited good cyclic stability since the polarization effect is diminished due to the reduction of the concentration gradients of anions by the porous anionic geometry. This also minimizes the formation of Li dendrites. Among the three different COFs, CD-COF-PPZ showed the highest absorption capacity of COIn one study, a 3D anionic COF-containing Si (3D Si-COF-5) was synthesised having an srs topology as shown in However, the preparation of the crystal was challenging as simple condensing of tetramethoxysilane (TMOS) or silica gel and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) failed to generate the crystal. The rate of the reaction can be modulated by controlling the amount of water, nucleation, growth, and solubility of linkers in the reaction system. Thus, the source of silicon was controlled in situ to propel the crystallization of 3D SiCOFs. Methyltrimethoxysilane was disproportionated in the presence of nucleophiles  to form tetramethoxysilane and tetramethylsilane in situ.The different COFs based on topology and pores size were summarized in According to computational investigations, the self-complementary π-electronic force increases the overall crystal stacking energy while minimizing the unit cell size, which improves the porosity of COFs .−1 at 298 K) of carbon dioxide was confirmed by pyridyl-based 3D COFs [Pengxin and co-workers  revealed 3D COFs . The retAdditionally, the uptake was further enriched in the presence of moisture . 1,2,4,5A good uptake of carbon dioxide was observed for an azine-based 3D COF due to the presence of abundant nitrogen atoms within the pores of the crystal . Thus, LWe have summarized our review with a growth mechanism and topologies of 3D COFs using tritopic building blocks and tetrahedrals units. Additionally, there is heavy demand for new topologies. The determination of 3D COF structures is a challenge due to the difficulty of obtaining a single crystal of large size. The 3D COFs are obtained as polycrystalline materials. Hence, techniques are essential for obtaining a large single crystal for the synthesised 3D COFs. The lack of additional propelling forces, such as π–π stacking, hinders the formation of crystals and initiates the formation of amorphous frameworks.The majority of the reported 3D COFs have interpenetrated structures with srs, pts, and dia topologies. An increase in the interpenetration number decreases the pore volume, specific surface area, and pore size of 3D COFs. Interconnected 3D channels are present in less or non-interpenetrated frameworks. High-interpenetrated channels contain interconnected 1D channels. The optimization of monomers and conditions for synthesis can modulate interpenetration. There requires a study for searching suitable monomers for specific topologies to reduce interpenetration. The development of more stable COFs is compulsory.The 3D COFs have potential applications based on their remarkable properties: high surface areas, interpenetrated channels, pore environment that can be manipulated, good chemical stability, and abundant active sites which are accessible. Numerous 3D COFs with different functional groups have been synthesised. However, the synthesis of 3D COFs is difficult. The funtionalisation and crystallization of 3D COFs require further research. Different synthetic methods of 3D COFs have been reported: ionothermal, solvothermal, microwave-assisted, and amorphous transformation methods.Hence, work is required for the development of facile synthetic methods  for 3D COFs which are not possible to obtain through conventional methods.