Solanum tuberosum L.) is often affected by an unfavorable external environment in the process of cultivation. The MYB family is one of the largest and most important gene families, participating in the regulation of plant growth and development and response to abiotic stresses. Several MYB genes in potato that regulate anthocyanin synthesis and participate in abiotic stress responses have been identified. To identify all Solanum tuberosum L. MYB (StMYB) genes involved in hormone or stress responses to potentially regulate potato growth and development, we identified the MYB gene family at the genome-wide level. In this work, 158 StMYB genes were found in the potato genome. According to the amino acid sequence of the MYB domain and gene structure, the StMYB genes were divided into R2R3-MYB and R1R2R3-MYB families, and the R2R3-MYB family was divided into 20 subgroups (SGs). The expression of 21 StMYB genes from different SGs in roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression patterns of StMYB genes in potatoes treated with abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin acid 3 (GA3), NaCl, mannitol, and heat were also measured. We have identified several potential candidate genes that regulate the synthesis of potato flavonoids or participate in hormone or stress responses. This work provides a comprehensive understanding of the MYB family in potato and will lay a foundation for the future investigation of the potential functions of StMYB genes in the growth and development of potato.As an important nongrain crop, the growth and yield of potato ( The abiotic stresses that plants encounter in their growth process seriously affect their growth and productivity. At every moment of a plant’s life, thousands of genes are expressed in a coordinated manner to regulate its growth and development and help it resist adverse external environments. Identifying the key genes involved in plant responses to abiotic stress and exploring their molecular mechanisms can lay a foundation for the breeding of crops resistant to abiotic stress ,2. TransMYB genes and their functions, the R2R3-MYB family in Arabidopsis thaliana (L.) Heynh. is divided into 23 subgroups (SGs) [AtMYB11, AtMYB12, and AtMYB111 in SG 7 were found to be involved in the regulation of flavonoid biosynthesis in Arabidopsis thaliana (L.) Heynh. [AtMYB75, AtMYB90, AtMYB113, and AtMYB114 in SG 6 can regulate anthocyanin biosynthesis, while AtMYB123 in SG 5 can regulate proanthocyanidin synthesis in the seed coat of Arabidopsis thaliana (L.) Heynh. [The R2R3-MYB family is widely involved in various physiological activities of plants, such as responding to environmental factors and plant hormones, participating in the regulation of primary and secondary metabolism, regulating cell cycle and cell differentiation, and leaf morphogenesis ,16. Accops (SGs) . Each su) Heynh. . Members) Heynh. ,19.MYB genes involved in stress response have been identified in wheat, among which TaMYB1 can respond to abiotic stress and ABA treatment, TaMYB2A in transgenic Arabidopsis thaliana (L.) Heynh. showed a variety of abiotic stress tolerances, while TaMYB33 can reconstruct the osmotic balance of transgenic plants, thereby improving their salt tolerance and drought tolerance [MYB genes, an increasing number of MYB genes have been identified, and the MYB gene family has been identified from many dicotyledonous and monocotyledonous plants, including Arabidopsis thaliana (L.) Heynh. (197 members) [Cucumis sativus L. (55 members) [Pyrus bretschneideri Rehd. (184 members) [Beta vulgaris L. (70 members) [Gossypium hirsutum Linn. (524 members) [Oryza sativa L. (155 members) [Zea mays Linn. (158 members) [Studies have shown that R2R3-MYB family genes also play an important role in the plant responses to abiotic stress, besides participating in various physiological activities. Several olerance ,21,22. Omembers) , Cucumismembers) , Pyrus bmembers) , Beta vumembers) , Gossypimembers) , Oryza smembers) , and Zeamembers)  at the gMYB genes involved in stress response have been identified in potato. For example, StMYB1R-1 is involved in activating drought-related genes and improves potato drought tolerance by regulating water loss [IbMYB1 affects secondary metabolism, thereby improving potato tolerance to stress [MYB genes in potato development and stress response [MYB genes were identified from the potato genome by different identification methods, and genes related to growth, development, and stress response were excavated. Their motif composition, intron and exon distribution, and tandem duplication and segmental duplication events were comprehensively analyzed. Their evolutionary relationships with dicotyledonous Arabidopsis thaliana (L.) Heynh., Fagopyrum tataricum Gaertn., Manihot esculenta Crantz, Nicotiana attenuate, Solanum lycopersicum, Vitis vinifera L., and monocotyledonous Oryza sativa L. were compared. At the same time, we measured the expression levels of StMYB genes in roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers. More importantly, by determining the expression patterns of StMYB genes under ABA, IAA, GA3, NaCl, mannitol, and high temperature treatments, we identified some StMYB genes that may potentially play a vital role in potato growth and hormone stress resistance. This study can provide a meaningful reference for potato breeding improvement.In the potato cultivation process, abiotic stresses, including drought and high salt, often harm potato growth and lead to a decline in yield. Therefore, it is urgent to explore potato stress resistance genes for potato breeding and production. At present, some ter loss . In addio stress . Li et aresponse . In thisMYB genes from the potato genome and named them StMYB1 to StMYB158 according to their distribution on the chromosomes  Heynh. using Mega 7.0. Five of 128 MYB genes in Arabidopsis thaliana (L.) Heynh. belonged to the 3R-MYB subfamily, and the others belonged to the R2R3-MYB subfamily. The R2R3-MYB subfamily was further divided into S 1, S 2, S 3, S 4, S 5, S 6, S 7, S 9, S 10, S 11, S 12, S 13, S 14, S 15, S 17, S 18, S 19, S 20, S 21, S 22, S 23, S 24, and S 25. From the phylogenetic tree, we can see that three StMYB genes belonged to the 3R-MYB subfamily , while 155 R2R3-MYB subfamily genes belonged to S 1 (8 members), S 2 (6 members), S 3 (2 members), S 4 (8 members), S 6 (2 members), S 7 (6 members), S 9 (7 members), S 11 (4 members), S 13 (10 members), S 14 (24 members), S 15 (6 members), S 17 (7 members), S 18 (7 members), S 19 (1 member), S 20 (30 members), S 21 (4 members), S 22 (15 members), S 23 (2 members), S 24 (3 members), and S 25 (3 members) subgroups  phylogenetic tree with 158 StMYB proteins and 128 MYB proteins from ubgroups . There wStMYB genes, and the R2R3-MYB family genes were still divided into 20 subgroups , StMYB121 (7 introns), and StMYB146 (10 introns) from the 3R-MYB family and StMYB45 (5 introns), StMYB50 (9 introns), StMYB51 (7 introns), StMYB52 (10 introns), StMYB71 (7 introns), and StMYB72 (8 introns) in S 20. The other StMYB genes had 1 to 3 introns, and the number of introns of StMYB genes in the same subgroup was generally similar.The phylogenetic tree was constructed from the amino acid sequences of 158 ubgroups A. FigureBy detecting the motif composition of StMYB proteins characteristic regions, it was found that StMYB51, StMYB135, StMYB136, StMYB10, StMYB28, StMYB36, StMYB33, and StMYB32 only contain motif 1 C. ProteiStMYB genes included MeJA responsiveness elements, MYB-binding sites that were part of light responsiveness elements, ABA responsiveness elements, defense and stress responsiveness elements, low temperature responsiveness elements, gibberellin acid (GA) responsiveness elements, salicylic acid (SA) responsiveness elements, and auxin responsiveness elements  and chromosome 5 ; 4 tandem-duplicated gene pairs on chromosome 1 , chromosome 6 , chromosome 7 , and chromosome 10 ; 2 tandem-duplicated gene pairs on chromosome 2 , chromosome 9 , chromosome 11 , and chromosome 12 ; and only one tandem-duplicated gene pair on chromosome 4 (StMYB51 and StMYB52) and chromosome 8 (StMYB113 and StMYB114)  .StMYB genes, we found that some StMYB genes were produced by tandem duplication and segmental duplication, and these gene duplication events may be one of the drivers of the evolution of StMYB genes.In addition to tandem-duplicated gene pairs, 41 pairs of segmental-duplicated gene pairs were also found on potato chromosomes . All in MYB genes in potato, we constructed a phylogenetic tree including dicotyledonous potato, Arabidopsis thaliana (L.) Heynh., Solanum lycopersicum, Vitis vinifera L., Manihot esculenta Crantz, and monocotyledonous Oryza sativa L. to explore the evolutionary relationship of MYB genes in different plants  Heynh. and Manihot esculenta Crantz in S 12. In addition to these subgroups, other subgroups included MYB genes from six plants. Ten motifs were detected in all MYB protein sequences, and most MYB proteins contained motifs 1, 2, 4, and 5, while motifs 6 to 9 only existed in a few MYB proteins. MYB genes of the same subgroup, especially those with similar homology, have similar motif compositions and similar positions, which further supports the reliability of phylogenetic trees.After exploring the evolutionary relationship of t plants . As showMYB genes in potato and MYB genes in many plants, including dicotyledonous Arabidopsis thaliana (L.) Heynh., Fagopyrum tataricum Gaertn., Manihot esculenta Crantz, Nicotiana attenuate, Solanum lycopersicum, Vitis vinifera L., and monocotyledonous Oryza sativa L. , Manihot esculenta Crantz , Vitis vinifera L. , Fagopyrum tataricum Gaertn. , Arabidopsis thaliana (L.) Heynh. , Nicotiana attenuate , and Oryza sativa L.   . The resvolution .MYB genes in different subgroups may perform different functions during the growth and development of potato. To explore their specific functions, we selected a StMYB gene from each subgroup and determined their expression levels in roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers by quantitative real-time polymerase chain reaction (qRT-PCR)  A. With tin stems A.StMYB3 and StMYB44, as well as StMYB12 and StMYB133, were significantly positively correlated.We analyzed the correlation between the expression of these genes in different tissues. It can be seen from StMYB genes in ABA, IAA, GA3, high temperature (35 °C), drought, and NaCl were measured by qRT-PCR  Heynh. protoplasts. The CAMV35S driven eGFP was transferred into Arabidopsis thaliana (L.) Heynh. protoplasts as a control  were constructed in the CAMV35S promoter, and then transferred into the  control . It is f control . However control .MYB genes play key roles in plant growth and development and a large number of biological processes [MYB gene family has been identified in many plants at the whole-genome level, including Manihot esculenta Crantz (299 members) [Solanum lycopersicum (121 members) [Brassica napus L. (249 members) [Oryza sativa L. (155 members) [Arabidopsis thaliana (L.) Heynh. (197 members) [Manihot esculenta Crantz is 742 MB [Solanum lycopersicum genome size is 828.349 MB [Brassica napus L. genome size is 912.169 MB [Arabidopsis thaliana (L.) Heynh. genome size is 125 MB [MYB genes identified in these plants is different, and their genome size is also different. By comparing the genome size of these plants and the number of identified MYB genes, it is found that the number of MYB genes in each plant did not depend entirely on the genome size. For example, the genome size of Solanum lycopersicum was medium, but the number of MYB genes in Solanum lycopersicum was the lowest.The MYB gene family is one of the largest transcription factor families in plants . MYB genrocesses ,32,33,34members) , Solanummembers) , Brassicmembers) , Oryza smembers) , Arabidomembers) , soybeanmembers) , and so s 742 MB , the Sol8.349 MB , the Bra2.169 MB , the rics 125 MB , and thes 125 MB . The numStMYB genes and 31 pairs of segmental-duplicated StMYB genes from 230 StMYB genes [StMYB and 41 pairs of segmental-duplicated StMYB genes were identified from 158 StMYB genes  Heynh., Manihot esculenta Crantz, Solanum lycopersicum, Vitis vinifera L., and Oryza sativa L. At the same time, we analyzed the motif compositions of MYB genes in these plants  Heynh., and regulate flavonoid biosynthesis in all tissues [StMYB6 also belonged to SG 7, which is a homologous gene of AtMYB11, AtMYB12, and AtMYB111. qRT-PCR showed that it was expressed in all tissues of potato, but the highest expression level was found in flowers . We obtained the hidden Markov model (HMM) profile of the MYB domain (PF00249) through the Pfam protein family database (http://pfam.sanger.ac.uk/). The specific identification method of MYB genes was as follows. We downloaded the amino acid sequences of all MYB genes in Arabidopsis thaliana (L.) Heynh. from the Arabidopsis Information Resource (TAIR) library. All MYB genes were identified from the potato genome using downloaded AtMYB gene sequences as target sequences. The conserved domains of the potato MYB genes identified above were analyzed, and the genes that did not contain the PF00249 conserved domain were removed. Then, the identified potato MYB genes were run against BLASTp at National Center for Biotechnology Information (NCBI) to determine whether they belonged to the MYB gene family. Finally, we identified 158 StMYB genes from the potato genome. Basic information about these genes, including PIs, MWs, and subcellular localization, was predicted through the ExPASy website (https://web.expasy.org/protparam/).We downloaded the potato genome sequence from the Potato Genome Sequencing Consortium  Heynh., Solanum lycopersicum, Vitis vinifera L., Manihot esculenta Crantz, and Oryza sativa L.) from the UniProt database (https://www.uniprot.org/) for constructing a multispecies maximum likelihood (ML) phylogenetic tree. Multiple amino acid sequences of MYB proteins from different plants were aligned using MUSCLE [Arabidopsis thaliana (L.) Heynh., Solanum lycopersicum, Vitis vinifera L., Manihot esculenta Crantz, and Oryza sativa L. was constructed with Mega 7.0 [Arabidopsis thaliana (L.) Heynh. was constructed by the same method mentioned above, and the MYB protein sequences of potato and Arabidopsis thaliana (L.) Heynh. were aligned using MUSCLE before constructing the phylogenetic tree. The DNA and cDNA sequences of MYB genes were compared by online Gene Structure Display Service (http://gsds.cbi.pku.edu.cn/) to predict the structure of introns and exons. The conserved motifs of MYB proteins were determined by the Multiple Em for Motif Elicitation (MEME) online program (http://meme-suite.org/tools/meme) (http://bioinformatics.psb.ugent.be/webtools/plantcare/html/?tdsourcetag=s_pcqq_aiomsg) was used to predict the cis-acting elements within 2000 bp upstream of all StMYB genes.We downloaded MYB protein sequences  . PlantCAStMYB gene localization information from circos and observed that all StMYB genes were located on different chromosomes of potato [StMYB gene duplication events were analyzed with a multiple collinear scanning toolkit (MCScanX) [StMYB genes and MYB genes from Solanum lycopersicum, Manihot esculenta Crantz, Vitis vinifera L., Fagopyrum tataricum Gaertn., Arabidopsis thaliana (L.) Heynh., Nicotiana attenuate, and Oryza sativa L. were determined using Dual Synteny Plotter software [We obtained f potato . StMYB gMCScanX) . The synsoftware .StMYB genes identified in the roots, stems, leaves, flowers, shoots, stolons, young tubers, and mature tubers were measured by qRT-PCR. Meanwhile, the expression levels of StMYB genes in potatoes treated with ABA, IAA, GA3, NaCl, mannitol, and heat were also measured. The qRT-PCR primers of the StMYB genes listed in https://www.ncbi.nlm.nih.gov/tools/primer-blast/). The qRT-PCR used elongation factor 1-α (ef1α) as internal reference gene [-△△CT method [Total RNA was extracted from the samples using the RNAout Kit , and cDNA was synthesized using the PrimeScript™ 1st Strand cDNA Synthesis Kit  according to the manufacturer’s instructions. The expression levels of nce gene . The corT method . Three bStMYB6 and StMYB19 were amplified by PCR and fused to the pCAMBIA2300-eGFP plant expression vector. Arabidopsis thaliana (L.) Heynh. protoplasts were prepared from leaves of Arabidopsis thaliana (L.) Heynh. eGFP, StMYB6-eGFP, and StMYB19-eGFP were transferred into Arabidopsis thaliana (L.) Heynh. protoplasts. After 12 h transformation, the eGFP fluorescence was observed under an Olympus confocal microscope.The coding regions of We processed and analyzed our experimental data with the Origin Pro 2018b , and we used the least significant difference (LSD) test to compare the data.


The 61,437 bp genome of Vid5 has a G–C content of 48.8% and contains 99 probable protein encoding genes and one gene for tRNASer. A comparative sequence analysis revealed that 46 out of 99 Vid5 open reading frames (ORFs) code for unique proteins that have no reliable identity to database entries. In total, 33 Vid5 ORFs were given a putative functional annotation, including those coding for the proteins responsible for virion morphogenesis, phage-host interactions, and DNA metabolism. In addition, a cluster of genes possibly involved in the biosynthesis of 7-deazaguanine derivatives was identified. Notably, one of these genes encodes a putative preQ0/preQ1 transporter, which has never been detected in bacteriophages to date. A proteomic analysis led to the experimental identification of 11 virion proteins, including nine that were predicted by bioinformatics approaches. Based on the phylogenetic analysis, Vid5 cannot be assigned to any genus currently recognized by ICTV, and may represent a new one within the family of Siphoviridae.A novel low Pantoea is a genus of highly diverse, yellow-pigmented, and rod-shaped Gram-negative bacteria of the family Enterobacteriaceae. Although members of this genus have been found to predominate in the phyllosphere of various plants, both as epiphytes and endophytes, Pantoea is being frequently isolated from many aquatic and terrestrial environments, and is also known to form host associations with insects, animals, and humans  and 9.01 ± 1.10 nm in width [n = 30]), with a single central tail fiber attached to a distal part of the tail. Notably, no side tail fibers were clearly visible using TEM.Bacteriophage Vid5, together with its host  of Vid5 A,B reveaPantoea agglomerans strain MMG, the remaining five Pantoea sp. Isolates, as well as all of the tested strains of Acinetobacter, Arthrobacter, Citrobacter, Enterobacter, Erwinia, Escherichia, Klebsiella, Salmonella, and Pseudomonas spp. were found to be resistant to Vid5.In total, 26 bacterial strains  were useIn order to determine the optimal conditions for phage propagation, the effect of temperature on the efficiency of plating (e.o.p.) was examined in the temperature range of 3–37 °C. The test revealed that Vid5 is a low-temperature virus—the phage forms plaques with a clear center surrounded by halo zone at 4–32 °C, and has an optimum temperature for plating about 22 °C . In addiPantoea spp. [Ser  observed for pp. [Ser . Notablypp. [Ser .Erwinia, Escherichia, Klebsiella, Pseudomonas, Salmonella, Pectobacterium, and Vibrio. Two Vid5 gene products showed similarity to proteins found in bacteria exclusively, as follows: hypothetical protein encoded by Vid5 ORF92 had the best match with hypothetical protein (WP_071680676.1) from Serratia, meanwhile the amino acid sequence of a putative PreQ0/PreQ1 transporter encoded by Vid5 ORF41 shared the highest identity with VUT family protein (WP_023656680.1) from Erwinia piriflorinigrans  to the database entries. In the case of Vid5 ORFs that encode proteins with matches to those in other sequenced genomes, the percentage of amino acid identity ranged from 28% to 77% and, in most cases (31 out of 53 Vid5 ORFs), from 43% to 58% . Among tinigrans .Siphoviridae, the Vid5 genome appears to have a modular organization, with genes for DNA packaging, structure/morphogenesis, host lysis, replication/regulation, and nucleotide metabolism clustered together . Three other Vid5 head-related proteins, readily identifiable by sequence homology, namely the portal protein gp03, the head-tail adaptor protein gp11, and the head completion protein gp12, show similarity to SPP1 gp6 , SPP1 gp15 , and gpFII from bacteriophage lambda , respectively. Based on the BLASTP analysis, the gene product of Vid5 ORF13 shares 39% amino acid sequence identity with the tail protein gp59 of Enterobacteria phage 9g , however, based on the HHsearch analysis against the ACLAME database conducted by VIRFAM, gp13 of Vid5 has been annotated as the neck protein .A bioinformatics analysis of the genome sequence of Vid5 allowed for the identification of twelve genes coding for proteins involved in virion structure and assembly . A BLASTEscherichia phage Seurat , has been annotated based on a VIRFAM analysis . As mentioned above, only one Vid5 tail fiber/spike is visible when using TEM. Nevertheless, two putative tail fiber proteins, DUF1983 domain-containing Phage-tail_3 superfamily (cl26145) protein gp22 and the minor tail protein gp25, have been identified by the bioinformatics approaches.Three gene products of Vid5 have been assigned as tail proteins. A BLASTP analysis allowed for the identification of the major tail protein encoded by ORF15, and the tape measure protein gp18, which belongs to the Tape_meas_lam_C superfamily (cl26614). The tail completion protein Vid5 gp14, which is homologous to the hypothetical protein CPT_Seurat11 from Salmonella podovirus P22 tail spike protein. Notably, the C terminus of Vid5 gp10 has no reliable homologues in databases.FASP followed by LC-MS/MS confirmed that all of the aforementioned structural proteins, except for gp12 (head completion protein) and gp14 (tail completion protein), are present in the virion of Vid5 . The fai−8), and is followed by ORF30-encoded DNA polymerase beta subunit, which shows the highest similarity to DNA polymerase III, beta subunit from Eubacterium rectale . A helicase of Vid5 (ORF45) contains a conserved SSL2 superfamily domain in its N terminus , whereas the DNA ligase of Vid5 (ORF50) possesses Adenylation_kDNA_ligase_like superfamily domain (cd07896) in its N terminus  and OBF_kDNA_ligase_like superfamily domain (cd08041) in the C terminus .The bioinformatics analysis revealed that the genes associated with Vid5 DNA packaging, replication, recombination, and repair included those coding for terminase small subunit and terminase large subunit , DNA polymerase B and DNA polymerase beta subunit , helicase (ORF45), putative exonuclease (ORF46), ATPase (ORF49), DNA ligase (ORF50), RNAse H (ORF51), nucleotide pyrophosphohydrolase (ORF53), putative endonuclease (ORF54), and primase (ORF61). Based on the results of the bioinformatics analysis, the TerS and TerL of Vid5 have been predicted to belong to the Terminase_2 (pfam03592) and to the Terminase_6 (pfam03237) superfamilies, respectively, and show detectable similarity to other phage-encoded TerS and TerL proteins, respectively. DNA polymerase B, encoded by the ORF29 of Vid5, has a DNA polymerase type-II B subfamily catalytic domain (cd05538) in the region between 373 and 549 amino acids ), Phage_holin_3_3 domain-containing holin (cl24062), and a putative phage lysis regulatory protein , encoded by ORF97, ORF98, and ORF99, respectively. In addition, a gene cluster encoding enzymes possibly involved in the biosynthesis of 7-deazaguanine derivatives has been detected. Notably, none of the predicted Vid5 proteins showed sequence homology with integration-related proteins, antibiotic resistance determinants, or virulence factors.Siphoviridae phage SPP1 neck. Notably, cluster five is composed strictly of siphophages, of which all but two, Streptomyces phages phi-C31 and phi-BT1, infect Proteobacteria [The VIRFAM analysis, a “head-neck-tail”-based classification method proposed by Lopes and coauthors , classifbacteria . Howeverbacteria  was carrNonagvirus genus , and those that represent the genus Seuratvirus . According to the 2017 ICTV taxonomy release , the genus Nonagvirus includes four Enterobacteria viruses, 9g [Seuratvirus. Last year, 14 novel phages potentially belonging to the genus Seuratvirus were described by Sazinas and coauthors [Escherichia phage slur01 [As seen in uses, 9g , JenK1, uses, 9g , whereasuses, 9g  and Cajaoauthors . Howevere slur01 , Greed [e slur01 , and vB_e slur01 , have beNonagvirus and Seuratvirus and phage Vid5, the genome sequences of nine Enterobacteria phages were compared to that of Vid5 using mVISTA. A comparative whole-genome sequence alignment revealed that the genome of Vid5 shared several regions of nucleotide sequence similarity with the genomes of all of the phages analyzed. In the case of Vid5, the aforementioned regions covered the virion morphogenesis as well as DNA metabolism and modification genes  to 34.23% (Vid5 vs. Seurat). Also, as seen in To obtain a more detailed picture of the phylogenetic relationships between the viruses classified within the genera on genes . NeverthSiphoviridae.According to the Bacterial and Archaeal Viruses Subcommittee (BAVS) of the ICTV, a genus is a cohesive group of viruses sharing a high degree (>50%) of nucleotide sequence similarity . Followique-tgt possibly involved in the biosynthesis of 7-deazaguanine derivatives. Based on a comparative sequence analysis, the gene cluster que-tgt of Vid5 is similar to that of Escherichia coli phage 9g, the prototype of the genus Nonagvirus (+) [+ is a complex pathway requiring the 7-cyano-7-deazaguanine intermediate (preQ0) [0, namely GTP cyclohydrolase I (folE), 6-carboxy-5,6,7,8-tetrahydropterin synthase (queD), and 7-carboxy-7-deazaguanine synthase (queE) , and has been suggested to catalyze the conversion of preQ0 to G+ [As mentioned previously, a bioinformatics analysis of Vid5 genome revealed the presence of the gene cluster nagvirus . In the irus (+) . Accordi (preQ0) . As obsee (queE) . Both phQ0 to G+ . FollowiAlthough further experiments are needed to confirm the aforementioned assumption, according to Tsai and colleagues, the presence of dG+ in the 9g genome renders the DNA resistant to many of the Type II REases . Based oPantoea phages currently available in Genbank. Both of these Pantoea phages, namely bacteriophages LIMElight and LIMEzero, are classified within the Autographivirinae subfamily of the Podoviridae. However, a number of broad-host range Erwinia or Serratia phages have been reported to be able to infect bacteria from the genus Pantoea [Myoviridae or Podoviridae. However, the genome sequences of only two of the aforementioned viruses, Erwinia phages PhiEaH1 and PhiEaH2, have been published to date, but there is no publicly available information on the host range of these bacteriophages. Therefore, it is unclear whether these phages are capable of infecting Pantoea. In addition, with the genome size of 61,437 bp, phage Vid5 rather differs from phages PhiEaH1 and PhiEaH2, which possess genomes of 218,339 bp and 243,050 bp, respectively. In contrast to PhiEaH1 and PhiEaH2, Erwinia phage KEY and Serratia phage phiOT8 have been shown to infect Pantoea sp., but no complete genome sequences of these phages have been published so far. Hence, based on the data presented in the literature to date, we state that bacteriophage Vid5 is the first Pantoea-infecting siphovirus with completely sequenced and publicly available genome.There are only two genome sequences of bacteriophages annotated as  Pantoea ,7,8,9,16 Pantoea , PhiEaH2 Pantoea , KEY [14Nonagvirus, and has been shown to modify its DNA with G+. As discussed in the previous section, bacteriophage Vid5 has homologues of archeosine biosynthesis genes as well, and the gene cluster responsible for this potential modification in Vid5 is rather similar in the overall structure and organization to that of 9g, suggesting that the DNA of Vid5 may also contain dG+. Moreover, the restriction digestion analysis suggests that the genomes of both Vid5 and 9g contain similar DNA modifications.A whole-genome sequence comparison using Megablast revealed that the Vid5 genome produces no significant matches to any GenBank entries. However, when compared using the BlastN algorithm, Vid5 shares 65% identity over 14% of its genome with that of Enterobacteria phage 9g. Bacteriophage 9g is a siphovirus of the genus 1), 7-cyano-7-deazaguanine (preQ0), 7-amido-7-deazaguanine (ADG), or 7-formamidino-7-deazaguanosine  into their DNA [folE, queD, queE, and queC) essential for the biosynthesis of preQ0, the precursor for all 7-deazapurines [Seuratvirus genus and have been suggested to modify their DNA with 7-deazapurines other than G+. As these phages contain no queA, queF, and queG homologs, they may be predicted to insert preQ0 or ADG into their DNA [7-deazaguanine derivatives have long been thought to exist exclusively in tRNA, however, recent studies indicate that certain phages may incorporate 7-aminomethyl-7-deazaguanine  transporter that is similar to the preQ0/preQ1 transporters from various bacteria, yet has no homologs in bacteriophages. The Vid5 preQ0/preQ1 transporter has been predicted to belong to the Vut_1 superfamily, which includes the COG1738 family proteins. Last year, the COG1738 family protein YhhQ from Escherichia coli was proved to be involved in the preQ0/preQ1 salvage [0/PreQ1 by bioinformatics approaches. Therefore, it may be hypothesized that, in the case of bacteriophage Vid5, the preQ0 precursor may be salvaged. According to the literature, preQ0 is available in natural environments as an intermediate of the Q or G+ pathways, as well as a secondary metabolite or secondary metabolite precursor [0 for the synthesis of G+.Bacteriophage Vid5 has no homologue to QueC, the 7-Cyano-7-deazaguanine synthase that catalyzes the formation of preQnd JG054 E. Notabl salvage . Notablyrecursor ,47. As sPantoea sp. infecting bacteriophage Vid5 is a low-temperature siphovirus possessing the archaeosine biosynthesis genes, including preQ0/preQ1, which has never been detected in bacteriophage genomes to date. In addition, our results indicate that Vid5 is substantially distinct from all of the previously described phages, and may be considered as a representative of a novel genus within the family Siphoviridae. Also, according to the literature, only a limited number of low-temperature enterobacteria phages have been described to date, and little is known about the molecular mechanisms underlying the cold-adaptation of bacterial viruses [In conclusion, we have shown that  viruses ,49,50, s


Solanum tuberosum LEA (StLEA) proteins belonging to nine groups. StLEA genes have few introns (≤2) and are distributed on all chromosomes, occurring as gene clusters on chromosomes 1, 2, and 10. All four StASR (StLEA7 group) genes were concentrated on chromosome 4, suggesting their evolutionary conservation on one chromosome. Expression profiles of StLEA genes, in different tissues and in response to hormone and stress treatments, indicated that 71 StLEA genes had differential expression levels, of which 68 StLEA genes were differentially expressed in response to hormones and stress exposure in the potato. Continuous high expression of StASR-2, StLEA3-3, StDHN-3, StLEA2-29, and StLEA2-14 in different tissues indicated their contribution to plant development processes. StLEA2-14, StLEA2-31, StLEA3-3, StASR-1, and StDHN-1 were upregulated by six abiotic stresses, showing their tolerance to a wide spectrum of environmental stresses. Expression analysis of 17 selected StLEA genes in response to drought, salt, heavy metal, heat, and cold treatments by quantitative real-time polymerase chain reaction indicated that StLEA proteins may be involved in distinct signalling pathways. Taken together, StLEA3, StDHN, and StASR subgroup genes may be excellent resources for potato defence against environmental stresses. These results provide valuable information and robust candidate genes for future functional analysis aimed at improving the stress tolerance of the potato.Late embryogenesis-abundant (LEA) proteins are a large and highly diverse family believed to function in normal plant growth and development, and in protecting cells from abiotic stress. This study presents a characterisation of 74  Late embryogenesis-abundant (LEA) proteins are a type of highly hydrophilic glycine-rich protein with antioxidant, metal ion binding, membrane and protein stabilisation, hydration buffering, and DNA and RNA interaction properties. They play an important role in protecting cells from abiotic stress, and in plant normal growth and development. More importantly, LEA expression is often induced by abiotic stresses such as cold, drought, or high salinity ,2,3. LEAOryza sativa [Hordeum vulgare [Arabidopsis thaliana [Prunus mume [Malus domestica [Populus trichocarpa [Solanum lycopersicum [Pinus tabuliformis [Dendrobium officinale [LEA genes play an important role in the response to abiotic stress. Indeed, overexpression of LEA genes enhances the abiotic tolerance of transgenic lines, such as the cold tolerance of transgenic Arabidopsis thaliana, and the drought- and salt-tolerance of transgenic rice and wheat. However, silencing of the LEA4 subgroup gene in A. thaliana results in sensitivity to water deficit, which may be related to the protective effect of LEA proteins on membrane systems and other biological macromolecules during water deficit [Pinus tabuliformis LEA (PtaLEA) in Escherichia coli can also improve cellular salt and heat tolerance [In higher plants, many members of the LEA family are present. According to the similarity of amino acid sequences and differences in conserved domains, they can be divided into eight subgroups . Recent studies have shown that abscisic stress ripening (ASR) is also an LEA protein, classified into the LEA7 group ,9. To daa sativa , Hordeum vulgare , Arabidothaliana , Prunus nus mume , Malus domestica , Populuspersicum , Pinus tficinale , indicat deficit ,17,18. TLEA4 group members [CuLEA5, a gene encoding an LEA5 subgroup that plays an important role in fruit ripening in Citrus unshiu, is also induced by ABA, cold, and drought stresses [E. coli and plants by increasing the thermal hysteresis value of solution systems to inhibit ice crystallisation [The expression of many LEA proteins is regulated by abscisic acid (ABA), a key hormone in dehydration. During the development of maize embryos, exogenous ABA can upregulate the expression of  members ,20. CuLEstresses ,22. In rstresses . DHN implisation ,24. ThesSolanum tuberosum L.) is the third largest food crop in the world [LEA family, and the results confirmed the ability of the five Solanum tuberosum LEA (StLEA) genes of the DHN subfamily to respond to salt and drought stress. With the updating of protein domain databases, such as the potato genome, Pfam, and the Conserved Domain Database (CDD), more members of the LEA family have been annotated successively. Due to the obvious functional differentiation among different protein subgroups, functional, evolutionary analyses, and analysis of the distribution of chromosomes of different LEA subgroups, are necessary to study their application to potato stress resistance. In this study, 74 members of the StLEA family were identified; their structure, evolutionary relationships, and chromosome locations were analysed, and their expression patterns in different tissues during development and stress tolerance were investigated to deepen understanding of the functions of the StLEA family and their applications in potato genetic improvement.The potato  using the keyword “late embryogenesis abundant“. The obtained amino acid sequences were aligned using CD-Search tool  in Conserved Domains database (CDD) (https://www.ncbi.nlm.nih.gov/cdd/), and repeated and non-LEA domain sequences were eliminated manually. The physical and chemical properties of StLEA amino acid sequences were analysed using the ProtParam online tool (https://web.expasy.org/protparam/).Using Pfam ID PF03760 (LEA-1), PF03168 (LEA-2), PF03242 (LEA-3), PF02987 (LEA-4), PF00477 (LEA-5), PF10714 (LEA-6), PF02496 , PF00257 (DHN), and PF04927 (SMP), the LEA amino acid sequence of the potato was searched and downloaded in the Solanum tuberosum v4.03 database of Phytozome v12.1, and in the Spud DB database . The segmental duplicated and tandem repeated genes were determined by MEGA X [StLEA genes with a threshold similarity >75%, and analysis of their genomic locations and tandem duplications, were restricted to a distance range of 100 kb [y MEGA X . Clustalf 100 kb .StLEA gene coding sequence (CDS) to the genomic DNA sequences, and displayed using the Gene Structure Display Server (GSDS) 2.0 online software (http://gsds.cbi.pku.edu.cn/). The Multiple Expectation Maximisation for Motif elicitation (MEME) tool (http://meme-suite.org/index.html) was used to identify conserved domains and motifs of each subgroup of StLEA proteins.Gene structure was obtained through alignment of each Multiple sequence alignments of StLEA proteins were performed using ClustalW ALGN within MEGA X ; these w2 (FPKMTreatment/FPKMControl) and displayed according to colour; expression was transformed by square root and displayed according to column height.The RNA sequencing (RNA-Seq) data used for generating gene expression levels were downloaded from the Spud DB database. These data were sequenced from the heterozygous diploid (RH89-039-16 (RH)) and the doubled monoploid potato (Group Phureja clone DM1-3 (DM)). The sequenced tissues included leaves, stems, roots, stolons, young tubers, mature tubers, tuber sprouts, petiole, apices, and flowers, as well as those that received the following treatments: ABA, indole-3-acetic acid (IAA), gibberellin A3 (GA3), 6-benzylaminopurine (BAP), and abiotic stresses such as water stress, mannitol, NaCl, heat (35 °C), primary wounding, and secondary wounding . Gene ex−1 NaCl, 5 mmol L−1 ZnSO4, and 20% PEG6000 at 4 °C and 35 °C for 24 h. High expression level LEA genes, including StLEA1-3, StLEA2-1, StLEA2-14, StLEA2-17, StLEA2-21, StLEA2-25, StLEA2-31, StLEA2-40, StLEA3-3, StLEA6-1, StASR-1, StASR-2, StASR-3, StASR-4, StDHN-1, StDHN-2, and StDHN-3, were collected for quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and templated by cDNA of the aforementioned root and leaf samples. Three independent biological duplicates were performed in this study. All primer sequences used are listed in StLEA genes were analysed using the 2−ΔCt method [StEF1α [Hydroponic potato tissue cultured seedlings (tetraploid variety Cooperation-88) were transplanted to perlite medium. Plants were initially irrigated with Hoagland’s nutrient solution and cultured for 15 days. The medium was leached with one-quarter Hoagland’s solution three times. Then, the seedlings were each treated with 150 mmol Lt method  with the [StEF1α .StLEA genes were identified from the potato genome, based on keywords and a Pfam ID search of potato genome databases, identification of Arabidopsis LEA amino acid homologous sequence alignment, and a Pfam domain search of the CDD database. These 74 genes were divided into nine groups    based onStLEA-encoded amino acids ranged from 80–501; molecular weights ranged from 8.5 kDa (StDHN-4) to 53.3 kDa (StLEA4-2), with an average of 22.5 kDa. Only seven proteins had molecular weights >30 kDa . The pI values ranged from 4.47 (StSMP-1) to 10.42 (StLEA2-41), with an average of 8.33. Of all StLEA proteins, 73.0% had a pI > 7.0, with the LEA3 group having the largest pI (9.60) and th SMP group having the smallest pI (5.14). A grand average of hydropathicity (GRAVY) index analysis showed that most of the StLEA proteins were hydrophilic. Of these, 10 proteins with a GRAVY index >0 belonged to group LEA2. The most stable protein was StDNH-1, which had a stability index of 15.36, while LEA2-23 had the highest stability index (118.43).The physical and chemical parameters of most StLEA proteins in the same group were similar according to an analysis using the ProtParam online tool. The 74 A phylogenetic analysis  showed tStLEA gene contained few introns, and 39 contained no introns. Only six of the 35 intron-containing LEA proteins contained two introns. The StLEA6 group contained only one intron-free gene, while subgroups StLEA1, StLEA4, StASR, and StDHN contained one intron, which was located in the same clade in the phylogenetic tree .The tic tree A. SMP coon genes A. Two ofStLEA gene sequences, the MEME online tool was used to analyse the motif structure of each subgroup  of the StLEA genes had a low expression level in each tissue, and the FPKM value was <20. All members of the StLEA1 and StSMP subgroups had lower overall expression levels, except in individual tissues.Apart from  Spud DB . Among tStLEA genes in different tissues and organs were quite different ; however, six gene pairs had tandem duplicates or segmental duplications, including StASR-3/StASR-4, StLEA2-41/StLEA2-42, StLEA2-30/StLEA2-32, StLEA2-17/StLEA2-29, and StLEA2-25/StLEA2-37, which had similar expression patterns in different tissues. For example, StLEA2-17 and StLEA2-29 were expressed in various tissues without any apparent preference.Of the 17 sister gene pairs included in the phylogenetic tree , genes iStLEA genes were induced by ABA. Fourteen genes were highly upregulated by ABA treatment, with FPKM values >100. Specifically, the FPKM values of StLEA1-3, StASR-2, and StDHN-1 were >1000. After ABA treatment, StLEA1-3 and StDHN-1 expression was upregulated more than 5-fold, indicating the highest induction level. The induction of StLEA by IAA, GA3, and BAP treatment was not as obvious as that by ABA. The expression of 54 StLEA genes was significantly inhibited by BAP treatment. StDHN-1 was highly induced by GA3, and StLEA1-3 and StASR-2 were induced not only by ABA, but also by IAA and GA3, demonstrating that many StLEA genes are induced by multiple hormones. In addition, ABA, IAA, and GA3 induced the expression of 29 genes, including 1 StLEA1, StLEA4, StLEA5, and StLEA6 subgroup gene, 17 StLEA2 subgroup genes, 3 StLEA3 and StASR subgroup genes, and 2 StDHN subgroup genes. However, the upregulation and FPKM values in these subgroups were much lower than those of StLEA1-3 and StASR-2. Four members of the StASR subgroup were induced by ABA, IAA, and GA3, and inhibited by BAP.Some StLEA proteins can be induced by hormones B. IndeedStLEA genes in response to abiotic stresses, such as drought, high temperature, salt, and mechanical damage were obtained by analysing RNA-seq of data in the Spud DB database  ranged from 2.03–12.13-fold. StDHN-1 expression was upregulated by 12.13-fold and the FPKM value reached 8636.74 after exposure to drought stress. The induction of these genes by mannitol-induced drought stress was at a level similar to that induced by drought stress, but the expression level was significantly lower than that induced by drought stress. Among the 11 drought-induced genes, StLEA2-17 and StASR-3 expression was inhibited by mannitol, indicating that mannitol stress could not fully reflect the response of plants to drought. Salt and heat-induced StLEA gene expression was significantly lower than that induced by drought, but StLEA3-1–3, StDHN-1, StDHN-3, and StASR-4 expression was significantly induced by salt stress . Moreover, the expression of StLEA3-1–3 and StDHN-1 was also induced by heat. Few studies investigating the induction of StLEA by mechanical damage exist. The response of genes to mechanical damage could simulate the response to insect bites. Analysis of StLEA expression patterns by primary and secondary wounding treatments showed that mechanical damage induced upregulation of 44 StLEA genes, with that of StLEA3-3 and StDHN-3 being the most significant. After secondary wounding, the FPKM value of StLEA3-3 was >3000, with a 3.30-fold upregulation (log2FC). The expression and upregulation levels of StLEA2-14, StLEA2-17, StLEA2-29, StLEA3-2, and StASR-1 were also much higher than those of other StLEA genes. Based on the above results, the StLEA3, StDHN, and StASR subgroups would be excellent genetic resources to exploit in order to promote stress resistance in the potato.Thirty-four StLEA genes in abiotic stress, 17 candidate genes of six subgroups with high expression levels were selected, and their expression in potato roots and leaves after treatment with drought, salt, heavy metals, high temperature, and low temperature was analysed by qRT-PCR.To verify the potential role of StLEA genes was induced by different stress treatments  in roots was significantly higher than that in leaves, the expression of three genes  was similar in roots and leaves, and the other eight genes were more highly expressed in leaves. In response to low temperature, the expression of 15 StLEA genes was upregulated, excepting StLEA2–17 and StASR-4. However, compared with the response to drought, 13 of the 15 LEA genes were significantly upregulated in roots, especially StLEA2-1, StLEA2-21, StLEA3-3, and StDNH-1. The response pattern of LEA to NaCl stress was similar to that to drought stress. Apart from StLEA2-14, the expression of the remaining 16 StLEA genes in leaves and roots was upregulated to varying degrees, but the degree to which they were upregulated was significantly lower than relative to drought-induced expression. The extent to which 17 genes were induced by high temperature was also lower relative to induction by drought. However, the expression of 14 genes, excepting StLEA1-3, StLEA2-14, and StLEA2-40, was also upregulated. The mild upregulation by salt and high temperature stress may be related to insufficient treatment strength. Moreover, the induction of heavy metal stress by StLEA was not as obvious as that of the first four stresses. Apart from StLEA2-14, StLEA2-21, StLEA2-25, StLEA2-31, and StASR-4, the other 12 detected genes were downregulated or minimally different from control levels.The results of qRT-PCR showed that the expression of these eatments . Most siStLEA genes under different stresses measured by qRT-PCR analysis was similar to that shown by RNA-seq of data in the Spud DB database. However, some differences existed. For example, under drought stress, the expression of StLEA2-40, StLEA3-3, and StLEA6-1 of 17 selected StLEA genes in leaves of Cooperation-88 was contrary to that in leaves of RH, which may be related to the plant material and intensity of stress treatment. Most of the StLEA genes were induced by drought, low temperature, salt, and high temperature, and a few were induced by heavy metal exposure. The response of StLEA genes to abiotic stresses differed between leaves and roots.Overall, the expression pattern of most LEA gene plays an important role in the response to abiotic stress in O. sativa, A. thaliana, P. trichocarpa, and other plants [LEA family members, while more than 50 members of the LEA family have been identified in A. thaliana and P. trichocarpa [Brassica napus and upland cotton [LEA family were identified by genomic analysis, and were divided into nine subgroups. Their common characteristics include that they have small molecular weights, are rich in hydrophilic amino acids, and contain few introns [StLEA gene has more than two introns, similar to the trehalose-6-phosphate synthase gene family, which has also been shown to be a stress-response gene family [Potato production is threatened by a variety of environmental stresses due to global climate change, especially drought and high temperature, which is driving the need for a greater understanding of the genes in potatoes that are able to cope with these stresses . The LEAr plants ,4,10,12.r plants  identifichocarpa , and mord cotton ,38. In t introns . Indeed,e family . The smae family .Oryza, Arabidopsis, S. lycopersicum, and P. tabuliformis, [StASR family was concentrated on chromosome 4, and all of members were clustered in a small region  were highly expressed in various tissues (StLEA gene family. Moreover, LEA subgroups have evolved different adaptive effects against abiotic stresses, as reported in D. officinale, P. tabuliformis, and upland cotton [StLEA4, StLEA5, StLEA6, and StSMP subgroups to various stresses was not obvious. The StLEA3 and StDHN subgroups showed a high response to abiotic stress, with only StLEA1-3 being prominent in the LEA1 subgroup. The StLEA2 subgroup was diverse due to its large number of members. Indeed, StLEA2-14 and StLEA2-37 were induced by all stresses, while StLEA2-28 was inhibited by all stresses. Moreover, some genes were upregulated after various stresses, such as StLEA2-14, StLEA3-3, and StDHN-1 (LEA family. It has been reported that the expression of ASR is indeed induced by ABA and water stress (StASR group was regulated by ABA, and was also induced by IAA and GA3, but inhibited by BAP. It was additionally induced by various abiotic stresses, especially drought, high temperature, and mechanical damage (StASR-2 in various tissues indicates that ASR genes are also involved in growth and development. These results indicate that the ASR group is a valuable genetic resource in stress resistance research.Many studies have shown that sistance ,42. Acco tissues A, indicad cotton ,6. Accor StDHN-1 B, whose r stress B, and itl damage B. The hiStLEA subgroups were expressed in different tissues in response to these stresses, especially drought and low temperature, followed by salt and high temperature, and a few genes were induced by heavy metal stress (LEA1, LEA2, LEA4, and DHN groups were upregulated after drought and salt stress [LEA1, LEA2, LEA3 and DHN group genes strongly responded to osmotic stress, salt, and ABA exposure [LEA1 also increased drought resistance in rice [Brassica juncea, two DHN genes were induced by Zn/Cd, and overexpression increased heavy metal resistance in tobacco [LEA genes play important roles in plant resistance to various abiotic stresses. The expression patterns of 17 candidate genes in potatoes under drought, salt, high temperature, low temperature, and heavy metal stress were analysed by qRT-PCR. The majority of l stress . In the t stress , while iexposure ,45. In a tobacco . These rStLEA genes were identified in S. tuberosum and classified into nine groups. Chromosomal location and duplication analysis revealed that 74 StLEA genes were distributed in all S. tuberosum chromosomes with some gene clustering. All StLEA genes contained the LEA motif and had few introns. StLEA genes belonging to the same group exhibit similar gene structures. The knowledge garnered from this study may increase understanding of LEA genes in S. tuberosum in order to lay the foundation for further investigations of the functions of LEA proteins.In conclusion, a total of 74


Since 2014, nanoplatelet light-emitting diodes (NPL-LEDs) have been emerged as a new kind of LEDs. At first, NPL-LEDs are mainly realized by CdSe based NPLs. Since 2016, hybrid organic-inorganic perovskite NPLs are found to be effective to develop NPL-LEDs. In 2017, all-inorganic perovskite NPLs are also demonstrated for NPL-LEDs. Therefore, the development of NPL-LEDs is flourishing. In this review, the fundamental concepts of NPL-LEDs are first introduced, then the main approaches to realize NPL-LEDs are summarized and the recent progress of representative NPL-LEDs is highlighted, finally the challenges and opportunities for NPL-LEDs are presented. In 1987, organic light-emitting diodes (OLEDs) have been developed, which greatly inspires researchers to take their endeavors to explore new-generation displays and solid-state lighting technologies . In 1994Different from the semiconductor colloidal QD with a zero-dimensional (0D) structure or nanorod with a 1D structure, a semiconductor nanoplatelet (NPL) is 2D material via the management of the shape to tune the confinement of charges and as a result of its density of states ,15,16,17To engineer electronic structures as well as optical characteristics, a plenty of NPLs having heterostructures have been achieved, such as core/crown NPLs, core/shell NPLs and core/crown/shell NPLs, besides core-only structures with various tuned chemical composition and vertical thickness. Besides, NPLs exhibit a number of thickness-dependent optical properties, including ultrashort radiative fluorescence lifetime, giant oscillator strength transition and narrow emission. This is because only the vertical direction exists the tight quantum confinement ,33. Thus3  perovskite NPLs are found to be effective to develop NPL-LEDs since 2016 imidazol-2-yl) benzene /Ca (25 nm)/Al (100 nm), as shown in 2PbBr4 thin films into high-quality micrometer-sized single-crystal NPLs by the dimethylformamide solvent vapor annealing. As a result, an EQE of 0.04% is obtained. However, from the EL emission , a PE of 1.0 lm W−1 and EQE of 0.48% [3NH3PbBr3/bathocuproine /LiF (1 nm)/Al (150 nm), as shown in 3NH3PbBr3 (MAPbBr3) NPLs  have been produced, which is crucial to the LED. Besides, by using bipolar PVK:PBD in the emitting layer, charge balance has been optimized, which is also responsible for high performance. For example, without this bipolar host, the LED only exhibits EQE of 0.038% and luminance of 1113 cd m−2. Furthermore, their perovskite-NPLs materials is very stable. For instance, with humidity (~55%) for at least one week, the perovskites endow fabricating perovskite LEDs without using the inert-gas glovebox. To enhance the performance of hybrid perovskite NPL-LEDs, perovskites with high crystallinity as well as high PLQY are crucial ,125,126.of 0.48% . The dev3), formamidinium lead bromide (FAPbBr3) is another type of hybrid perovskite materials for LEDs. Similar to MAPbBr3, 2D FAPbBr3 NPLs can be very efficient emitters. Recently, with about 7–10 unit cells colloidal FAPbBr3 NPLs, Kumar et al. have reported a pure green LED [3 perovskites via the dielectric quantum well engineering. As a consequence, the PLQY as high as 92% for thin film. Then, by optimizing the device architecture , the champion structure of ITO/PEDOT:PSS/poly-TPD/PMMA:FAPbBr3/3TPYMB/LiF/Al is obtained, as displayed in −1. Besides, the FWHM of 22.8 nm and an EL peak located at 529 nm could be achieved, leading to a CIE 1931 coordinates of . Hence, their LED possesses a wide color gamut, which can cover 97% of the Rec. 2020 standard in the CIE 1931 color space. Compared with the LED without PMMA, the efficiency of LED using FAPbBr3-PMMA complex significantly improves (~3 times), which can be attributed to dielectric confinement effect and formation of a smoother emitting layer. In addition, the superior device performance can be attributed to the effective exciton recombination as well as the balanced charge, which can be explained as follows. First, the cascade carrier injection is achieved by the deep LUMO of 3TPYMB (3.3 eV) as well as shallow HOMO of poly-TPD (5.4 eV). Second, 3TPYMB and poly-TPD possess comparable carrier mobilities. Besides, the deep HOMO 3TPYMB (6.8 eV) together with the shallow LUMO of poly-TPD (2.0 eV) can form an effective carrier confinement. Aside from methylammonium lead bromide  show better thermal stabilities, which may overcome the notorious stability issue [3 NPLs showing the 1–5 unit cells thickness in 2015 [3 NPLs [For hybrid organic-inorganic perovskite materials, they have been well demonstrated to develop high-efficiency LEDs. However, this kind of material usually have a stability problem. As an alternative, all-inorganic perovskites CsPbXty issue ,130,131.ty issue ,135,136.ty issue , many mety issue ,139,140. in 2015 . Since t [3 NPLs ,144,145.2Br5 and 3D CsPbBr3 as the emitter to realize perovskite LEDs, exhibiting an EQE of 2.21%, a current efficiency of 8.98 cd A−1 and a maximum luminance of 3853 cd m−2 [3-CsPb2Br5 composite nanocrystals present a new route of perovskite material for light emission applications. Particularly, the parasite of secondary phase CsPb2Br5 nanoparticles on the cubic CsPbBr3 nanocrystals can (i) improve current efficiency by lowering diffusion length of excitons; (ii) reduce the trap density in the bandgap; (iii) enhance the ionic conductivity by lowering the barrier against the electronic and ionic transport; (iv) enhance emission lifetime by reducing non-radiative energy transfer to trap states by controlling trap density, which is a key to the high performance. However, detailed EL as well as optical properties for single-component CsPb2Br5 film was not reported [In 2016, Zhang et al. used the mixture of 2D CsPb3 cd m−2 . Hence, reported ,149,150.2Br5 films [2Br5 film has PLQY of ~35%, which is highly desired to develop NPL-LEDs. By using this CsPb2Br5 NPL, LEDs were fabricated with a structure of ITO (100 nm)/PEDOT:PSS (30 nm)/CsPb2Br5 (30 nm)/TPBi (40 nm)/LiF (0.8 nm)/Al (100 nm), as shown in −2, turn-on voltage of 3.8 V, EQE of 1.1%, as well as good stability. Furthermore, by exchanging halogen Br with I in CsPb2Br5, a red emission has been obtained by CsPb2I5. The CsPb2I5 films have an emission peak wavelength of 685 nm, an optical bandgap of 1.75 eV and a PLQY of ~15%. With a same device architecture except for the emitter, the red NPL-LED has the peak EQE of 0.14%.In 2017, Qin et al. studied the optical, structural as well as EL properties of pure CsPbr5 films . With th3, CsPbBr3 and CsPbI3 can furnish red green and blue color, respectively. However, when various nanocrystal CsPbX3 have been utilized together as emitters in LEDs, the fast anion exchange can occur [3 nanocrystals with precisely tunable thickness are promising to optoelectronic applications due to the merits, particularly for their quantum confinement effect [3 NPLs having precisely tunable dimensions could be achieved in a large scale via a simple one-pot method and could be utilized to be the emitting layer of blue LEDs [3 NPLs/TPBi/LiF/Al, as shown in 3 NPLs, their thickness can be precisely varied in a monolayer level by controlling the reaction kinetics. Besides, due to the high uniformity, no purification is required. In addition, through changing the reaction time, edge length could be adjusted broadly. As a result, the NPL-LED can exhibit an EQE of ~0.1% and a maximum luminance of 25 cd m−2. After this report, blue, green and red colors have been realized in all-inorganic perovskite NPL-LEDs. Finally, it is believed that the performance  of perovskite NPL-LEDs can be much higher via the enhancement of both NPL emitters and LED architectures.According to the EL emissions, CsPbClan occur ,152. As t effect ,154. Towlue LEDs . The devAs a new class of optoelectronic materials, NPLs exhibit a number of advantages, which is promising to establish high-performance LEDs. Over the past 4 years, the performance of NPL-LEDs has been step-by-step enhanced. Although NPL-LEDs still lag behind state-of-the-art QD-LEDs and OLEDs, currently, it is believed that NPL-LEDs can be comparable to their counterparts in the foreseeable future. Herein, the development of various NPL-LEDs has been presented. Particularly, we have highlighted recent development of CdSe based NPL-LEDs , hybrid perovskite NPL-LEDs and all-inorganic perovskite NPL-LEDs. The detailed performances of representative NPL-LEDs are shown in To achieve higher performance, there are still many challenges before NPL-LEDs can be as good as QD-LEDs and OLEDs, such as the efficiency and lifetime. In the case of efficiency, there is much room for EQE of NPL-LEDs to the theoretical limit of 20% (assuming the outcoupling factor is 0.2) . Accordi


We discuss these roles for STAT3 and STAT5, and weigh the attractiveness of different modes of targeting each cancer therapy. Moreover, we discuss how anti-tumorigenic STATs, including STAT1 and STAT2, may be leveraged to suppress the pro-tumorigenic functions of STAT3/STAT5 signaling.Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell (CSC) properties, important determinants of metastatic potential and therapy failure. Moreover, STAT3 signaling within tumor-associated macrophages and neutrophils drives secretion of factors that facilitate metastasis and suppress immune cell function. Persistent STAT5 activation is responsible for cancer cell maintenance through suppression of apoptosis and tumor suppressor signaling. Furthermore, STAT5-mediated CD4+/CD25+ regulatory T cells (T Hereafter, when discussing the overlapping functions of STAT5A and STAT5B, we will refer to them as “STAT5”. STAT proteins transduce signals from the cell membrane to the nucleus, bypassing the need for second messengers ,38,39. SThe crucial role STATs play in these normal physiological processes was first demonstrated in STAT-deficient mouse models. The generation of tissue-specific STAT3 knockout models have identified STAT3 as a key component in a wide variety of processes, including, but not limited to: T-cell proliferation, suppression of apoptosis, epidermal regeneration during wound healing, macrophage and neutrophil anti-inflammatory responses, and mammary gland involution ,45,46. DAdvances in sequencing technologies have allowed scientists to investigate the frequency of mutations in the JAK/STAT signaling pathway, resulting in the identification of mutations that constitutively activate STAT3, STAT5, and JAK2. The majority of STAT mutations occur in the SH2 and C-terminal domains of STAT3 and STAT5B and associate with leukemias and lymphomas ,51. STATregs [A number of IL-6 family members have long been recognized for their involvement in the pathogenesis of aggressive cancers ,79,80,81regs ,91,92. Fregs ,94.Interestingly, IL-6 activation of STAT3 functions in a positive feed-forward loop to drive the secretion of new IL-6 into the TME, which then interacts with IL-6R/gp130 to further activate JAK/STAT signaling ,95. OSM IL-11 similarly engages in an autocrine feed-forward mechanism to drive persistent JAK2/STAT3 activation, which can promote resistance to platinum-based therapies . FurtherThe majority of cancers have constitutive activation of STAT3 ,131,132.While EMT is important in normal physiology to allow cells to migrate during development and wound healing, inappropriate EMT and the loss of cell-cell interactions contributes to aggressive cancer cell behaviors, including metastasis and resistance to therapy. In TNBC, the loss of E-cadherin or gain of Vimentin, N-Cadherin, or Snail expression, typically at the tumor’s edge, correlates with poor clinical outcome ,148,149.Likewise, the emergence of CSC properties, which are often defined experimentally as using tumorsphere- or tumor-initiating assays, frequently occur concomitantly with a mesenchymal phenotype ,162,163.HIGH CSC in both breast tumor explants and breast cancer cell lines [The importance of mesenchymal/CSC reprogramming in metastasis and therapy failure continues to emerge. For example, single-cell analysis identified a predominantly mesenchymal/CSC program in early-stage TNBC micro-metastases, in contrast to late-stage metastases . The finll lines . scRNA-sll lines . In mousll lines ,179. TheIndeed, STAT3 has also been implicated in acquired therapy resistance in many cancers including NSCLC, GBM, PDAC, melanoma, and breast cancer ,184,185.An important and rapidly emerging area of research is the impact of the immune microenvironment on metastasis and therapy failure. Beyond its impact on tumor cells, STAT3 has an important role in restricting immune cell functions and producing immunosuppressive factors. STAT3-induced cytokines are important mediators of the crosstalk between tumor cells, tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs), which are responsible for generating a pro-metastatic and pro-angiogenic TME . In the Importantly, because of their localization at the invasive edge of tumors, the contribution of M2-TAMs and N2-TANs to metastasis is increasingly being recognized. For example, TAMs have been demonstrated to form simultaneous physical contacts with tumor cells and endothelial cells that result in the formation of invadopodia, which assist cancer cells in transendothelial migration and escape into the circulatory system. These sites of cancer cell intravasation are called “tumor microenvironment of metastasis (TMEM)” and have been validated as prognostic markers of metastasis. Chemotherapy increases TMEM in breast cancer patients, thereby potentially facilitating metastasis ,210. STAFollowing the classical events of the metastatic cascade, after a tumor cell intravasates into circulation, it extravasates to establish secondary sites. An emerging concept in the metastatic cascade is the role of myeloid cells- such as basophils, neutrophils, eosinophils, monocytes, and macrophages- in the establishment of a pre-metastatic niche . AlthougAs previously mentioned, cells produce two different STAT5 proteins, STAT5A and STAT5B, which share greater than 90% sequence homology . HoweverGiven its role in lymphoid cell development and differentiation, it is not surprising that STAT5 activity contributes to hematologic malignancies. Deletion of STAT5 prevents transformation by the Abl oncogene, thereby preventing leukemia development . GeneticSTAT5 activation has also been implicated in the progression of solid tumor malignancies. Deletion of STAT5 in the mammary gland, hepatocytes, and prostate cells delays the development of mammary, liver, and prostate cancer ,231,232.An increasing number of reports demonstrate that STAT5 drives tumorigenesis and cancer progression through cooperation with other intracellular signaling cascades and activation of additional feed-forward loops. STAT5 activates transcription of AKT1 and PI3K, and, in turn, Akt1 phosphorylates STAT5 to induce cell survival ,241. FurSurprisingly, STAT5 in certain model systems has been demonstrated to function in a tumor suppressive manner. Human breast cancers infrequently (~7%) show signs of STAT5 activation (compared to 40% of STAT3 activation). This elevated STAT5 activity trends with more differentiated and lower grade tumors, suggesting that STAT5 does not induce the aggressive cancer cell program initiated by STAT3, at least in breast cancer . STAT5 eregs, a subset of T cells that contribute to tumor progression and metastasis [reg population that, in turn, significantly diminishes the function of cytotoxic and helper T cells [regs from the TME results in enhanced infiltration of mature CD4+ and CD8+ T cells into the tumor, leading to tumor rejection [reg expansion increases IL-10, IL-4, and IL-13, which skew TAMs to an M2 immunosuppressive phenotype. M2 macrophages are immunosuppressive because they release elevated levels of IL-10 and transforming growth factor-β (TGF-β) and restrict secretion of immune stimulatory cytokines via NF-kB repression [regs and M2 macrophage populations secrete VEGF-A, which, along with TGF-β, promotes angiogenesis [In addition to its impact on cancer cells, activated STAT5 dampens anti-tumor immune function. This immunosuppressive function is largely driven by CD4+/CD25+ Ttastasis  and corrtastasis ,252. Sus T cells ,254,255.ejection ,257. Furpression ,259. STAogenesis ,261.reg expansion through impediment of B cell development and maturation [regs result in a decrease in follicular helper T (Tfh) cell populations via Blimp-1, which severely hampers germinal center formation in lymph nodes [regs, relies on STAT5-mediated alteration in T-cell metabolism. Mature effector T cells preferentially undergo glycolysis and require a de novo fatty acid synthesis reliant on acetyl-coA carboxylase 1 whereas Tregs undergo lipid-oxidation and readily synthesize fatty acids because of a structural reconfiguration of mitochondrial cristae [reg-mediated immunosuppression [regs.Tumor clearance mechanisms are also suppressed by Tturation . STAT5-aph nodes . This re cristae ,265,266.pression ,268. Jusregs increases tumor immunity, provided STAT5 remains functional, the overall impact of suppressing STAT5 signaling in the remaining immune cells of the TME remains open to debate. Mouse models deficient in STAT5 have depleted CD8+ T cell, NK cell, and Treg populations, suggesting STAT5 plays an integral role in the proper development of multiple immune cell types [h1, Th2, Th9, ThGM, and Tregs, while inhibition of STAT5 is required for the generation of Th17 and Tfh cells [However, while the suppression of Tll types . STAT5 sfh cells ,271. Impfh cells ,272. Takfh cells ,272.Given the roles of STAT3 and STAT5 in tumor progression and immunosuppression discussed above , multiplOne of the first IL-6 monoclonal antibodies generated was Tocilizumab, which inhibits IL-6 signaling by preventing IL-6 binding to both the soluble and transmembrane forms of IL-6R ,279. PreOur lab has focused on OSM, given its potent activity at inducing numerous inflammatory cytokines that promote mesenchymal/CSC reprogramming in cancer cells and generate a pro-tumor immune microenvironment ,289,290.Another recent study investigating the effects of an anti-OSM antibody in a murine model of lupus nephritis demonstrated that OSM-driven EMT and extracellular matrix secretion, leading to renal fibrosis, could be suppressed, concomitant with the suppression of JAK/STAT3 activation . More reCurrently, JAK inhibitors are the most promising inhibitors of STAT-driven phenotypes. Commonly used JAK 1/2 inhibitor, Ruxolitinib, has been shown to robustly block both STAT3 and STAT5 activation. Yet, while JAK inhibitors can reduce STAT3 activation, there is conflicting data on the impact of JAK inhibitors. Some studies find that JAK inhibition suppresses tumor growth , while oThough STAT proteins are grouped together based on their structural similarities and common functions as transcription factors, individual STAT proteins can have diverse functions. We have focused extensively on STAT3 and STAT5 and their described roles in cancer progression, however this is not the universal effect among all STATs. For example, Interferon-β (IFNβ) induces the phosphorylation and activation of STAT1/2, which form a complex with IRF9 to create the transcription factor complex ISGF3. IFNβ/P-ISGF3 signaling induces interferon-stimulated genes (ISG), mesenchymal-epithelial transition (MET), and the differentiation of CSC into a less aggressive epithelial, non-CSC state with reduced migratory potential and reduced tumorsphere forming capabilities ,300,301.regs [In addition to the impact of IFNβ on cancer cells, increasing rationale supports developing methods for the delivery of P-ISGF3 activators  directly to the TME. First, favorable responses to frontline chemotherapy correlate with robust IFN signaling in both mouse and human studies ,303,304.regs ,306,307.regs ,309. Typregs . Fourth,regs . Thereforegs ,312,313.regs . The desregs .regs could also prove beneficial, but STAT5 is essential for many other immune cells as well. Thus, systemic suppression of STAT5 activity could undermine tumor immunity and promote tumor progression, as recently reported for STAT5 knock-out from NK cells [As discussed throughout this review, STAT3 and STAT5 have emerged as essential components involved in regulating tumor progression. Cytokines and cytokine receptors of the IL-6 family are some of the most widely recognized STAT activators and are abundantly expressed on cancer cells as well as tumor-infiltrating immune cells. The role of STAT3 in promoting molecular programs in cancer cells that induce tumor metastasis and therapy resistance mechanisms continue to emerge, as does the impact of STAT3 as a suppressor of immune cell function in the TME. These findings suggest that specifically suppressing STAT3 activation would be beneficial to patients. Targeting STAT5 in hematological malignancies is gaining traction, and the clinical successes of JAK and tyrosine kinase inhibitors in disrupting STAT3 and STAT5 activation, provide strong support for the development of direct STAT3 and STAT5 inhibitors, summarized in NK cells . However


Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow limitation. Early-onset COPD in non-smoker subjects is ≥60 years and in the elderly is often associated with different comorbidities. Cognitive impairment is one of the most common feature in patients with COPD, and is associated with COPD severity and comorbidities. Cognitive impairment in COPD enhances the assistance requirement in different aspects of daily living, treatment adherence, and effectual self-management.This review describes various bioactive compounds of natural marine sources that modulate different targets shared by both COPD and cognitive impairment and hypothesizes a possible link between these two syndromes. Chronic obstructive pulmonary disease (COPD) causes chronic airflow limitation, breathlessness, exercise intolerance, cough, difficulty with daily activities, infections, and (re)hospitalization . COPD phThe concept of MCI is evolving overtime, from the first definition of Reisberg and collaborators in the late 1980s ,12,13,14Actually determining the primary underlying etiology of MCI is still a challenge, and is strictly dependent to the patient’s history. Some neuroimaging, genetic, and neuropsychological assessment may be considered as suggested by NIA-AA see  8,14,15,20,21,22Currently, there are no accepted pharmacologic treatments for MCI approved by the FDA (U.S. Food and Drug Administration), the EMA (European Medicines Agency), or the Pharmaceuticals and Medical Devices Agency in Japan. None of the proposed interventions has indicated effectiveness and/or helpfulness in delaying the progression from MCI to AD dementia ,47,48,49Thus, on the light of the heterogeneity of MCI, further studies testing different compounds in all of its subtypes are necessary to draw clear conclusions.criteria, found that patients with moderate to severe COPD are at high risk for MCI. The association between COPD and MCI remains significant even after adjusting for cardiovascular comorbidities and other covariates . A recent systematic review and meta-analysis of observational studies, including 23,116 subjects with COPD with a mean age of 66.3 years, found that the prevalence of MCI is 25% [Starting in 2011, important studies ,50,51, uI is 25% . These fI is 25% . The preI is 25% . These dI is 25% . The perI is 25% ,56. MoreI is 25% . SecretoI is 25% . On the I is 25% .i. Abnormal microRNA pattern. MicroRNAs (miRNAs), a class of small non-coding RNAs, are involved in post-transcriptional gene repression. Alterations in miRNA abundance occurs in lung tissue, inflammatory cells, and freely circulating cells in blood, and are thought to function both as drivers and modifiers of disease [ disease ,62. In C disease . In MCI/ii. Activation of PI3K-mTOR signaling. PI3K-AKT-mammalian target of rapamycin (mTOR) pathway is critical for cellular senescence and aging. In parallel, mTOR is a negative regulator of autophagia. There is evidence for PI3K activation in the lungs and cells of COPD patients, as shown by increased expression of the downstream kinase phosphorylated Akt, which in turn activates mTOR [tes mTOR . mTOR hates mTOR .iii. Altered autophagy. Refers to a pathway of cellular self-digestion controlling the degradation of subcellular constituents, including misfolded proteins and damaged organelles. Increasing numbers of autophagic vacuoles are observed in COPD lung tissues under electron microscopy, whereas low vacuole formation is observed in control tissues. Autophagy and mitophagy play a complex role in the lungs, and its related phenomena can have both protective and injurious effects on the progression of COPD. Currently, there is no unifying explanation for the discrepancies between various studies [ studies . Althoug studies . A mutat studies .iv. Decreased anti-aging molecules. Many endogenous antiaging molecules counteract the mechanisms of senescence, and a reduction in their expression may accelerate the aging process [+-dependent deacetylases enzymes that play a role in resistance to stress, genomic stability, and energy metabolism. Defective sirtuins are proposed as a mechanism for accelerated lung aging in COPD. SIRT1, 120 kDa , levels are decreased in patients with COPD, as a result of oxidative stress [Klotho, is downregulated in COPD [Klotho is necessary for oligodendrocyte maturation and myelin integrity.The Klotho KL-VS variant is associated with an increase in the incidence of dementia in older men, in a dose-dependent fashion [ process . Sirtuine stress . SIRT1 d in COPD .There is fashion .v. Defective DNA damage repair. Effective repair of DNA damage is essential for the survival of cells, and most individual organisms and species. Ineffective repair can result in cell death, cancer, and neurological disease. COPD and AD are associated with excessive DNA damage [N-methyl-d-aspartate (NMDA) receptor [A damage ,70. SeveA damage . BRCA1 (A damage . BRCA1 creceptor .vi. Cellular senescence. Senescence is a state of irreversible cell cycle arrest. Senescent cells accumulate in the lung of COPD patients leading to persistent secretory phenotype (SASP) factors, and contributing to increased tissue dysfunction and COPD severity [severity . p16 andseverity .vii. Epigenetic changes. They include DNA methylation, covalent modifications of histone proteins and non-coding RNAs, and increases or decreases in gene transcription. In patients with COPD, there is emerging evidence showing aberrant expression of epigenetic marks, such as DNA methylation, histone modifications, and microRNAs in blood, sputum, and lung tissue [g tissue . AD entag tissue .viii. Immunosenescence. Immunosenescence affects both innate and adaptive immunity, leading to a loss of function, and is implicated in chronic inflammatory diseases. In COPD, there is reduced immunity, which results in a low-grade chronic inflammatory response. Cluster of differentiation 8 + 28 (CD8 + CD28) null cells from COPD patients have reduced histone deacetylase 2 (HDAC2) expression and are corticosteroid resistant [+, but not CD8+ cells lacking the important costimulatory receptor CD28 [esistant . Patienttor CD28 .ix. Mitochondrial dysfunction. The key function of mitochondria is to produce ATP through the coupling of oxidative phosphorylation with cellular respiration. Mitochondria play a crucial role in the maintenance of intracellular Ca2+ homeostasis, because they can take up substantial amounts of cytosolic Ca2+. COPD is linked to increased mitochondrial reactive oxygen species (ROS) production, decreased intracellular antioxidants, and reduced numbers of mitochondria. The mitochondrial stress markers Parkin and PTEN-induced protein kinase-1 (PINK1) are increased in COPD patients [2+ homeostasis, increased levels of ROS, lipid peroxidation and apoptosis, as well as hyperphosphorylation, aggregation, and damage of axonal transport leading to abnormal mitochondrial distribution. These pathological features impair mitochondrial dynamics by regulating mitochondrial fission/fusion proteins, causing mitochondrial dysfunction and neuronal damage [patients . Mitochol damage .x. Stem cell exhaustion. Airway basal progenitor cells are crucial for lung health and resilience because of their ability to repair injured airways. Basal progenitor count, self-renewal, and multipotentiality are all reduced. COPD progenitors produce an epithelium with increased basal and mucous cells and decreased ciliated cells, replicating the COPD phenotype [henotype .xi. Telomere shortening. Studies analyzing leukocyte telomere length (LTL) at the population level have provided ample evidence for the hypothesis that LTL shortening is associated with aging and with age-related chronic diseases , although some inconsistencies have been observed.The exact mechanisms leading to telomere shortening in association with COPD are not yet understood [derstood . Increasderstood . Intermederstood .It seems that the existing relationships between COPD and MCI are independent of the presence of comorbidities  ,51. COPDAll of these data are useful for finding new molecules able to act both in COPD and in MCI/AD.Today, ocean habitats are the newest frontier in drug medical research. Thus, starting in 1969, FDA/EMA approved eight drugs obtained by marine sources including important antineoplastic  and anti-pain (ziconotide) compounds . The actDrug activities and drug mechanisms of action are investigated on cellular and/or in mouse model systems. Every marine bioactive compound is studied in a single disease (COPD or MCI/AD) model ,93,94,9542H58O6 , phosphatidylinositol 3-kinase (PI3K)/Akt, and Smad2/Smad3 (Smad2/3) after Fx treatment, has been observed. Collagen contraction decreased significantly upon Fx treatment. Intraperitoneal injection of Fx in mice inhibits bleomicyn-induced lung fibrosis [Fucoxanthin (Fx) is a xanthophyll, with chemical formula C42H58O6 , isolatefibrosis . Fx attefibrosis .6H10O3S -1 signaling pathways [Austrasulfone, with chemical formula C6H10O3S , from thpathways .15H12O5  and PI3K/Akt signaling pathways in mouse BV2 microglial cells [TMC-256C1, with chemical formula C15H12O5 , isolateal cells .O-(Myristoyl) glycerol (MG), with chemical formula C17H34O4  cells through the activation of ERK, cAMP responsive element-binding protein (CREB) and PI3K signaling pathways [1-C17H34O4 , from thpathways .27H36O4 , with chemical formula C35H58O9 , a familysosomes .65H110N10O16 -dependent manner [Coibamide A, with chemical formula C10N10O16 , an antit manner .C36H44N4O  [Manzamine A, with chemical formula 36H44N4O , a β-carC25H40N2 , a penta 3 (LC3) .15H22O4  phosphorylation [Apo-9′-fucoxanthinone (ApoF9), with chemical formula C15H22O4 , from brrylation .Euphausia superb, is rich in polyunsaturated fatty acids, and two of the most important components are omega-3 fatty acids similar to those in fish oil (Alpha-linolenic acid (ALA) with chemical formula C18H30O2 (22H32O2 (20H30O2 (46H84NO8P (Antarctic krill oil (AKO), from C18H30O2 a, docosa and ph6H84NO8P . A proted-galactose on human neurons-hippocampal (HN-h) cells in a dose-dependent manner. This protein alleviates mitochondrial inactivation, decreasing mitochondrial membrane potential oxidative stress, and fusion/fission state at non-cytotoxic concentrations of d-galactose-treated HN-h cells. The induced recovery of metallathionein-3 (MT-3) decreases and inhibits β- and γ-secretase, as well as Aβ accumulation in HN-h cells caused by d-galactose induction [A 43 kD protein, isolated from atlantic oysters, attenuates neuronal cell death induced by 100 mM nduction .15H20O3 , after chronicintraperitoneal treatments, in preliminary behavioral test, points to a positive trend on learning and spatial memory of treated mice. Gracilins decrease Aβ42 and hyperphosphorylated levels, inhibit ERK and β-secretase enzyme1 (BACE1),and preserves neurons against oxidative damage [Gracilin(s), with chemical formula C15H20O3 , a famile damage ,95.The majority of new marine bioactive compounds are investigated in the field of neurodegeneration. COPD appears to be a neglected field of research. Nevertheless, according to the US Burden of Disease Collaborators, in 2016 COPD was the third cause of death in the United States, with an increasing trend in comparison with 2010 . In ItalThe first report of an association between COPD and AD is recordedin 1982 . Since t(i) a unique disease pathway or (ii) belonging to multiple disease pathways. In this scenario,precision pharmacology (PP), a new theoretical paradigm, has in mind to help in exploring andpredicting the whole effect of a given drug at the systems level  [(i) developing multi-target therapeutic approaches for multifactorial diseases, such as COPD and AD; and (ii) finding frameworks of therapeutic efficacy/adverse risks [Although, the present gold-standardrecommendations recognize comorbidities as important to COPD prognosis and severity, in general, they suggest that the presence of comorbidities should not alter COPD treatment, and “should be treated per usual standards regardless of the presence of COPD” . This ap levels) .The longse risks ,110.Bugulaneritina, is emblematic of marine bioactive compounds’ potential, since Bry-1 is exploited in, according to the classic concept, different non-correlated diseases, such as cancer, HIV, and neurodegenerative diseases [Marine bioactive compounds, by nature, are often structurally complex compounds with efficacy relying on multitarget intervention via their multiple active components. Thus, they can be examined for developing network-based multicomponent drugs. The example of bryostatin (Bry-1), a potent modulator of PKC, initially isolated from the extract of diseases .In A recent paper revised the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products . The autWe hereby suggest a screening of marine bioactive compounds having antioxidant, anti-inflammatory, anti-mitochondrial dysfunction, and anti-accelerated aging activity on COPD and MCI/AD models.


Staphylococcus aureus indicated that these compounds have a great potency to be developed into antimicrobial and anti-inflammatory drugs.Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 46 prototype compounds isolated from 33 marine and terrestrial actinomycetes and 17 structural derivatives. Combining with their antimicrobial mechanisms, structure-activity relationship analyses indicated that the terminal guanidine group and lactone ring of these compounds are vital for their antibacterial and antifungal activities. Further, based on their bioactivities and toxicity analyses, the discovery of guanidyl side-chain targeting to lipoteichoic acid of  Until 2013, the relative configurations of azalomycins F5a, F4a, and F3a as three representatives of these compounds, together with seven new analogs, were reported by Yuan et al. [5a could bind to the polar head of cell-membrane phospholipid and target to lipoteichoic acid (LTA) to kill methicillin-resistant Staphylococcus aureus (MRSA). Up to 2019, approximately 48 guanidine-containing polyhydroxyl macrolides have been isolated from 33 marine and terrestrial actinomycetes. Moreover, 15 structural derivatives were synthesized. These compounds have broad-spectrum antimicrobial activity  [Antimicrobial resistance has become a serious threat to human health and economic development . Many styceticus ,12,13,14yceticus ,16,17, ayceticus . Contempyceticus ,21,22,23n et al. ,25. Moren et al. ,27,28,29n et al.  reportedd fungi) ,32,33, ad fungi) , cytotoxd fungi) ,32, and d fungi) ,32, whil1–7, 8–43, 44–48) macrolides T [Streptomyces malaysiensis MJM1968 [Streptomyces olivaceus Tü 4018 [Streptomyces violaceoniger TÜ 905 [Streptomyces violaceusniger RS-22 [S rRNA gene sequences, were used) [S rRNA gene sequences were aligned against sequences of reference strains using the BLAST program (http://www.ncbi.nlm.nih.gov/). All the selected DNA multiple sequences were matched by means of software package Clustal_X 1.83 [Among 33 guanidine-containing polyhydroxyl macrolide-producing strains , sixteenHV17(2)T , Strepto MJM1968 , Strepto Tü 4018 , Streptor TÜ 905 , Streptoer RS-22 ,42. To ure used) . Brieflyl_X 1.83 , and evol_X 1.83 . Based ol_X 1.83 . From Fi8–10, 13–19) [27–33) [These molecules contain many chair centers (more than eighteen). As they have lager flexibility attributed to the larger ring and the longer side-chain, their single crystals were hardly obtained for determining the stereochemistry using an x-ray single diffraction method . Simulta, 13–19) ,25 and t [27–33) .49–63, Moreover, 15 derivatives 49–63,  were synAs the chemical structures of these compounds have many similar fragments and groups, many NMR signals are close to each other, and some even overlap. These will increase the difficulties of their structural elucidations, while some regularity spectroscopic characterizations could be summarized, which would be very conducive to the structural elucidations of these compounds.13C NMR spectra, and their chemical shifts decrease from approximately 158.7, 158.3 to 157.3 when the methyl number linking with guanidino nitrogen increases from 0, 1 to 2 [1H NMR spectra. Moreover, the stereochemistry of chain double bond is generally oriented in E-configuration. This is hardly established from the NMR spectrometric data due to overlapping signals; however, it can be confirmed by comparing the band at 969 cm−1 in the IR spectrum with the spectral data in the book [For the guanidyl side-chain, their guanidyl carbon signals at 157.3 to 158.3 ppm are easily observed from their , 1 to 2 ,22,25,53the book ,72.13C NMR spectra. As all these compounds share polyketide biosynthesis pathway [α, β, γ, and δ-unsaturated acid (or ester) group can be easily deduced from whether there are UV absorption maxima at 240 nm (lgε more than 4) and/or 269 nm (lgε more than 4) [d4, as the keto-enol tautomerization rapidly occurs [d6. Simultaneously, the two protons present multiple peaks in the 1H NMR spectrum as they quickly exchange with deuterium at the measurement conditions, especially at higher temperatures [For the lactone ring, many methyl and oxygenated methine signals can be observed from their  pathway ,9,10,53, than 4) . For they occurs ,53, whileratures .Guanidine-containing polyhydroxyl macrolides have been experimentally documented to possess broad-spectrum antibacterial and antifungal activities, and they can remarkably inhibit the growth of Gram-positive bacteria, yeast, and fungi  25,28,3,53,58,6428) and azalomycin F (8–10) could inhibit the type-I interleukin-1 receptor [Fusarium oxysporum, Fusarium moliniforme, Asparagus officinalis, Rhizoctonia solani, Colletotrichum gloeosporioides, and Alternaria mali [Azalomycin F has remarkable bioactivities against Gram-positive bacteria, yeast, fungi, and protozoa ,34,73,75receptor . Moreoveria mali ,36.1), azalomycin F (8–10), and scopafungin  could inhibit the secretion of gastric acid in the gastric parietal cells of rats by inhibiting H+/K+-ATPase with the IC50s of 15.7, 16.4, and 35.9 μg/mL, respectively. The inhibitory potency of copiamycin was found to be comparable to that of omeprazole and SCH-28080, both specific inhibitors of the gastric H+/K+-ATPase in vitro and in vivo [Hamagishi et al.  discover in vivo .28) was an inhibitor of mitochondrial oxidative phosphorylation and respiration, and mainly a decoupling agent for oxidative phosphorylation. Furthermore, Mogi et al. [In addition, Reusser  proposedi et al.  discover47) was identified as a selective inhibitor of Ras-responsive transcription. The expression of matrix metalloproteinases MMP-1 and MMP-9 in NIH3T3 cells line could be reduced by treatment with malolactomycin D at the translational and transcriptional levels, and this was achieved likely by inhibiting the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) [Using an NIH3T3 cell line, a screening system for Ras signal inhibitors was developed to search for anti-cancer agents by Futamura et al. . Malolacse (JNK) ,83. As Mse (JNK) ,85, maloS. aureus and C. albicans, MT2617-2B had a remarkable inhibitory activity against phospholipase C with the IC50 values against PLC-γ1 and PLC-β1 of 25 and 50 μg/mL, respectively.Ko et al.  isolated50) and maximal tolerable dose (MTD or LD0) of some guanidine-containing polyhydroxyl macrolides were determined. As shown in 50 or LD0 doses of each compound successively decreased from oral, subcutaneous, intraperitoneal to intravenous administrations. Moreover, Benziger and Edelson reported that azalomycin F administered intravaginally presented limited absorption [50 or LD0 of neocopiamycins A and B administered intraperitoneally were more than 1000 mg/kg, which indicated that they had low toxicity, while the LD50 or LD0 of neocopiamycins A and B administered intravenously were only more than 30 or 25 mg/kg. Moreover, these compounds, except for neocopiamycins A and B in To understand the safety of these compounds, the median lethal dose  and phosphatidylcholine [5a, the main component of azalomycin F, could lead to the leakage of cellular substances possibly by increasing permeability to kill S. aureus and confirmed that cell-membrane lipids, especially 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DPPG), might be important targets of azalomycin F5a against S. aureus after its relative configurations were assigned [5a, increasing the cell membrane permeability of S. aureus, was likely achieved by the synergy of its lactone ring binding to the polar head of phospholipid and its guanidyl side-chain targeting to lipoteichoic acid (LTA), and which had eventually led to the autolysis of S. aureus cells [S. aureus cell-membrane phospholipid, and PG was the largest one [S. aureus was resistant to daptomycin [5a had greater adhesive force to plasma membrane assembled by DPPG plus lysyl-DPPG than by DPPG, indicated that azalomycin F5a likely had greatly antagonistic activity to daptomycin-resistant S. aureus strains, and then proposed that these compounds had a great potency to be developed into new antimicrobial agents as LTA is also an important target for new antibiotics [As Sugawara reported , azalomylcholine , Yuan etlcholine  discoverassigned ,26. Furtus cells . The comgest one ,91. Simuptomycin . Therebyibiotics ,93.Although these compounds can change the cell membrane permeability of microbe and lead to the leakage of cellular substances, there are different mechanisms of them against bacteria and fungi as the components of their cell envelopes are different.C. albicans and the lysis of rabbit erythrocytes, and strongly inhibit amino acid incorporation into cellular protein and oxidative deamination of amino acid metabolism, but not decarboxylation and transamination. Simultaneously, it insignificantly inhibited the incorporation of phosphate into nucleic acids and the glycolytic pathway and did not exert any noticeable inhibition in cell-free protein-synthesizing systems of E. coli, rat liver, and C. albicans, and mitochondrial enzyme systems. Thereby, the cell surface was proposed as the primary site of azalomycin F acting on C. albicans [Saccharomyces cerevisiae [Sugawara  discoveralbicans . Moreovealbicans ,28,89. Frevisiae , and prorevisiae , dependirevisiae  inferredAs antimicrobial activity is one of the most important bioactivities of these compounds, most of them presented their minimum inhibitory concentration (MIC) against bacteria and fungi  when the(1) The atom number composed of the lactone ring is less important for their antimicrobial activities ,66,86 an(2) Antimicrobial activity is significantly affected by the guanidyl side-chain, especially by the terminal guanidine group, which is a key for their antibacterial and antifungal activities. The substitution of guanidino residue to urea will lead to the loss of antibacterial activity and significantly narrow the antifungal spectrum ,38,95, w17 hydroxyl will slightly reduce the antimicrobial activity, and sometimes this decrease can be counteracted by the increase of antimicrobial activity due to the removal of the malonyl group [(3) The hydrolysis of the lactone ring will lead to the loss of antimicrobial activity . The sixyl group ,58,70,71(4) There is no significant influence on the antimicrobial activity when hydrogenation, methyl removal, or/and methyl substitution occur to the double bond of the lactone ring. Similarly, methyl substitution of the double bond on the guanidyl side-chain is less important for the antimicrobial activity ,23,38,63(5) The introduction of malonyl moiety will reduce the antimicrobial activity ,70,71,975a could increase the cell membrane permeability of S. aureus and eventually lead to the autolysis of S. aureus cells, by the synergy of its lactone ring binding to the polar head of phospholipid and its guanidyl side-chain targeting to LTA, which is a vital anion component anchoring on the phospholipid bilayer of Gram-positive bacteria. This was in accordance with the above structure-activity relationship that the lactone ring and the terminal guanidyl side-chain were vital for the antimicrobial activity. As the carboxyl group of malonyl monoester can theoretically form an intramolecular hydrogen bond or ionic bond with the guanidyl of side-chain, the existence of malonyl will likely block the interaction between the guanidyl of side-chain and LTA. This was confirmed by their 3D molecular structures obtained by ChemBio3D Ultra 12.0 run with MM2 calculation (As we reported , azalomyculation  and by pculation , and cou+/K+-ATPase, mitochondrial oxidative phosphorylation, NADH dehydrogenase, and phospholipase C, while they also have a little toxicity. Structure-activity relationships indicate that both the terminal guanidine group and the lactone ring are the key for their antimicrobial activities. As LTA anchoring to the cell membrane is an important polymer for the resistance to cationic antibiotics, the autolysin regulation, and the cell division of Gram-positive bacteria, LTA synthase gradually becomes a proposed drug target for the development of antibiotics against drug-resistant Gram-positive bacteria [To date, a total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 48 prototype compounds isolated from 33 actinomycete strains and 15 structural derivatives. These compounds have various bioactivities, such as broad-spectrum antimicrobial activity, anti-trichomonas, anti-tumor, and inhibitory activities against Hbacteria ,100,101.