Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt signaling  leads to a variety of human diseases, including cancers, neurodegenerative disorders, skin and bone diseases, and heart deficiencies. Therefore, Wnt/β-Catenin signal transduction is a potential clinical target for the treatment of not only human cancers but also some other human chronic diseases. Here, some recent results including those from my laboratory highlighting the role of Wnt/β-Catenin signal transduction in human cancers will be reviewed. After a brief overview on canonical Wnt signaling and introducing some critical β-Catenin/TCF-target genes, the interaction of canonical Wnt signaling with some common human cancers will be discussed. In the end, the different segments of the aforesaid signaling pathway, which have been considered as targets for clinical purposes, will be scrutinized.  The original model for Wnt signaling pathway had a central component called β-Catenin, the homolog of Armadillo protein in Drosophila. Today, this signaling pathway has been named “the canonical Wnt signaling” or “the Wnt/β-Catenin” pathway[5 ▶-7 ▶]. For years, it has been thought that Wnt signaling is only one pathway  can activate both types of Wnt pathways[13 ▶]. The specificity of the signals via Wnt proteins probably depends on many proteins, which regulate canonical and non-canonical Wnt signaling pathways, especially the regulators at upstream levels. Both heterotrimeric G-protein-coupled receptors and Frizzleds demonstrate a high level of structural similarities as they contain seven hydrophobic transmembrane domains[14 ▶]. There is sufficient evidence for the involvement of G-proteins in the regulation of both canonical and non-canonical Wnt pathways[15 ▶-22 ▶]. The regulatory role of heterotrimeric G-proteins can probably help us to find out more about the specificity of the signals through Wnt/Frizzled proteins. Also, this very important discovery that Frizzled proteins are not the only receptors for Wnt ligands adds another level of complexity to the Wnt-mediated signaling pathways. LRP5/6 and the receptor tyrosine kinases, ROR/RYK, are the known co-receptors for canonical and non-canonical Wnt pathways, respectively.The first indication of the interaction between Wnt signaling pathways and cancer was discovered in Harold Varmus’s laboratory where it was found that the retroviral integration-mediated activation of a gene called The current model for the canonical Wnt signaling. This behavior is due to the phosphorylation of β-Catenin by CK1 and GSK-3β at serine and threonine residues located within the amino terminal of the protein . This phosphorylation leads to According to the present model, in the absence of the Wnt ligands, a destruction protein complex, including APC, Axin, GSK-3β, CK1, and β-TrCP, maintains cellular β-Catenin protein at physiological levels[23 ▶]. Formation of signalosome results in a decrease in β-Catenin phosphorylation, followed by the cellular accumulation of this protein (ubiquitination and proteasome degradation of β-Catenin. Upon the interaction of the Wnt proteins to their receptors (Frizzled and LRP5/6), the destruction complex dissociates , and a new protein complex forms at the cell membrane , which contains some of the components of the destruction complex protein . A brief discussion of some Wnt/β-Catenin target genes[24 ▶]. WREs are the binding sites for the β-Catenin/TCF complex[24 ▶]. Activation of Wnt/β-Catenin signaling either increases or decreases the expression of some cellular genes. The number of genes regulated by the Wnt/β-Catenin signaling is probably cell context-dependent. In normal human cells, especially epithelial tissues, the activity of Wnt/β-Catenin signaling is extremely low (due to very low levels of cytoplasmic β-Catenin), and higher activation of this signaling pathway is limited to the situations like tissue regeneration and human malignancies.Wnt/β-Catenin target gene promoters contain WREs as a part of their regulatory sequencesCCND1. Cyclin D1 has been considered as R factor[27 ▶]. The cellular concentration of R factor should reach a certain level before the progression of cell cycle from G1 phase to S phase. Cyclin D1 mainly interacts with the G1-S transition protein kinases, CDK4 and CDK6. Activation of these two protein kinases is required to progress cell cycle toward the S phase. Deregulation of cell cycle is a feature of nearly all human cancers. Cancer cells use several mechanisms to deregulate the cell cycle. Increase in CCND1 gene expression and/or protein stabilization is among these mechanisms. The mitogenic signals via receptor tyrosine kinases together with PI3-kinase/AKT signaling are the most known pathways to enhance gene expression and protein stability of Cyclin D1[29 ▶]. In addition, the gene-encoding Cyclin D1 is a target of the Wnt/β-Catenin pathway. Therefore, cancer cells with upregulated Wnt/β-Catenin signaling are expected to have higher levels of Cyclin D1 protein and therefore higher cell proliferation rate.This gene encodes Cyclin D1, one of the critical components of the G1-S transition of cell cycle in all animal cellsc-MYC[30 ▶-33 ▶]. c-Myc can heterodimerize with other transcription factors like Max to increase the number of the target genes. It is estimated that c-Myc is involved in the expression of more than 15% of cellular genes supporting the role of this protein in many cellular functions[33 ▶]. c-Myc binds to the enhancer box sequences on DNA, and by recruiting important proteins like histone acetyltransferases, it regulates gene expression. c-Myc activates cell growth by upregulating the expression of ribosomal RNAs and proteins and also by decreasing the expression of the genes encoding pro-apoptotic Bcl-2 proteins. c-Myc is also required for cancer cell metabolism and stemness of cancer stem cells. Increase in c-Myc expression and activity has been observed in a wide range of human cancers[30 ▶-33 ▶]. In addition to the Wnt/β-Catenin pathway, some other mitogenic signals  can enhance the c-Myc expression. In normal cells, the mRNA and protein levels of c-Myc are low, and this is due to the fact that c-Myc mRNA and protein are unstable[30 ▶]. Since the overexpression of c-Myc in normal cells can lead to oncogenic shock and induce apoptosis, cancer cells should probably obtain new features to tolerate higher levels of c-Myc activation.This gene is one of the most potent cellular proto-oncogenes and encodes c-Myc protein. c-Myc is a transcription factor that binds to DNA (via helix-loop-helix and leucine zipper domains) and regulates the expression of the genes involved in many cellular functions, including cell proliferation and DNA replicationc-JUN[34 ▶]. c-Jun can heterodimerize with c-Fos to form a new transcription factor called AP1. The expression and function of c-Jun are dependent on several signaling pathways mediated by some growth factors, pre-inflammatory signals, oxidative stress, and ultraviolet radiation[35 ▶]. The promoter region of c-JUN is responsive to the combinatorial transcription factor, AP1, which can be considered as a positive feedback for c-Jun expression[35 ▶]. One of the target genes of c-Jun is CCND1, which encodes Cyclin-D1[34 ▶]. Since CCND1 is also a direct target of the Wnt/β-Catenin pathway, it can be concluded that Wnt/β-Catenin signaling has a powerful cell proliferation effect. A target gene that its expression is negatively affected by AP1 is TP53, the gene encoding the tumor suppressor, p53[36 ▶]. p53 is a known mediator of cell cycle arrest and apoptosis. Therefore, it appears that c-Jun not only induces cell proliferation but also can make cells resistant to cell cycle arrest and apoptosis by inhibiting the expression of p53. These features of c-Jun may have a significant role in tumor growth and tumor resistance to chemotherapy.The product of this gene is also a transcription factorMMP7[37 ▶]. However, deregulated expression and/or function of MMPs (including MMP7) can lead to angiogenesis, cancer invasion, and metastasis[37 ▶]. MMP7 is normally translated as a pro-enzyme (28 kDa), which is then processed to the active form of MMP7 (19 kDa). It has been demonstrated that the overexpression of MMP7 enhances cancer invasion and metastasis[37 ▶-39 ▶]. Immunohistochemistry experiments have also indicated that cancer cells compared to the corresponding normal cells may express higher levels of MMP7 protein[40 ▶].This gene encodes MMP7, which belongs to the family of matrix metalloproteinases and is involved in the degradation of the extracellular matrix. In normal situations, these proteins have an important role in embryogenesis, wound healing, and tissue regenerationVEGF[41 ▶]. Upregulation of this protein is very important for tumor growth and angiogenesis[42]. During animal development, VEGF stimulates embryonic vascular formation, and postnatally, this protein acts in neo-vascularization upon injuries or blockade of veins or capillaries. It has also been demonstrated that VEGF enhances vascular permeability[41 ▶]. The function of this protein in cancer growth has drawn attention since without this protein the tumors cannot grow beyond a certain size. It has been shown that about 50% of colorectal cancer tissues express higher levels of VEGF protein compared to the corresponding normal cells[43 ▶]. Moreover, the expression of VEGF in colorectal tumor indicates poor prognosis and poor response to the therapy[43 ▶]. VEGF receptor belongs to the family of receptor tyrosine kinases, which are known as potent transducers of mitogenic signals. One of the inducers of VEGF expression and release is hypoxia[42 ▶]. Hypoxia increases the expression of hypoxia-inducible factor, a transcription factor whose activity can lead to VEGF release and its binding to the receptor[42 ▶]. The above information reveals that VEGF expression by Wnt/β-Catenin signaling can have an important role in tumor growth, tumor angiogenesis, and tumor invasion. This gene encodes VEGF protein, which was originally identified as a hormone for growth and proliferation of endothelial cellsFGF18[44]. FGF18 is involved in animal development and tissue regeneration by regulating different cellular functions, including growth, proliferation, and survival[44 ▶]. When deregulated, FGF18 promotes cancer growth, angiogenesis, and metastasis[45 ▶]. The receptor for FGF18 is FGFR3, a member of the family of mitogenic receptor tyrosine kinases, which functions through Ras and Map kinases[44 ▶]. It is worth mentioning that FGF family of growth factors include at least 22 members (FGF1-FGF22), which some of them are preferentially expressed during embryonic development[46 ▶]. One of the known functions of FGF18 is growth and development of cartilage and bone during embryogenesis and post-embryonic development. In mice, overexpression of FGF18 leads to cartilage thickness[47 ▶]. FGF18 null mice die very early after birth, probably due to the deformation of the ribs[47 ▶]. Although FGF18 is a potent mitogen for osteoblasts and chondrocytes, this protein can also enhance the growth and proliferation of other cells, including neurons, intestine, and liver cells[46 ▶]. It has been reported that there is a positive association between FGF18 expression and development of some human cancers, including colon cancer[45 ▶]. Interestingly, it has been observed that in slow proliferating colon cancer cell lines (like Caco-2 and LT-97), addition of FGF18 to the cell culture can elevate cell proliferation[45 ▶].This gene encodes FGF18 protein, which is an important cellular mitogenic growth factorc-MET[48 ▶]. c-Met is a key player in animal development, and therefore, homozygous deletion of c-Met gene, similar to the gene encoding the c-Met ligand (HGF), is embryonically lethal in mice. HGF is mainly expressed by mesenchymal cells, while c-Met (HGFR) is normally expressed by epithelial cells, which signifies that epithelial cells expressing c-Met can respond to paracrine signals from mesenchymal cells expressing HGF[49 ▶]. As mentioned above, c-Met is a member of the RTK family, and therefore it can potentially be involved in several biological activities. It has been displayed that upon damage to tissues like liver, kidney, and heart, the expression of c-Met in these tissues increases, suggesting that this protein has a positive role in tissue repair. In addition to the known components of the RTK signaling, some other important signaling molecules such as the intracellular tyrosine kinase, Src, the regulatory subunit of PI3-Kiase (p85 protein), Phosphlipase Cβ, Ship1, and STAT3 can be activated by c-Met[48 ▶]. Also, the c-Met-mediated signaling can activate gene expression that some of the target genes encode matrix metalloproteinases[50 ▶]. Regarding the interaction with human cancers, c-Met has been considered a potent oncogene involved in cancer cell growth, invasion, and metastasis. Induction of EMT is one of the mechanisms of c-Met-mediated cancer cell invasion. Genetic mutations and chromosomal rearrangements can lead to the upregulation of c-Met in human cancers. The genes encoding c-Met and its ligand (HGF) are located on chromosome 7, and trisomy of this chromosome has been observed in most cases of capillary renal carcinoma[51 ▶]. In addition, duplication of c-MET gene has been reported in familial forms of renal carcinoma. Studies have also indicated that the expression of c-Met and its ligand is higher in colorectal cancer tissues than that of these proteins in the corresponding normal mucosa, and this increase is normally accompanied with cancer invasion, metastasis, and patient poor prognosis. In fact, c-Met has been considered as a potential clinical target for the treatment of colorectal cancer[52 ▶]. The product of this gene, c-Met, which has also been called “HGFR” is a receptor tyrosine kinaseTERTTERT is an important Wnt/β-Catenin target gene and encodes the enzyme Telomerase, a significant marker of proliferating cells, including stem cells[53 ▶]. Many non-proliferative somatic cells in adults do not express TERT and may remain Telomerase-negative until the end of their lifespan. Although Telomerase is primarily known as an enzyme adding telomere repeats to the chromosome ends during chromosome replication, further studies have shown that Telomerase is a multi-functional protein and positively regulates cell proliferation. Telomerase also supports chromosomal stability in cells having short telomeres. Many carcinomas do not express Telomerase at early stages, likely because these tumor cells need genomic instability to progress[55 ▶]. However, many of these cancers re-express Telomerase at late stages, the time when further chromosomal instability may lead to cancer cell death. Telomerase has been considered as a therapeutic target for the late stages of carcinogenesis or for the tumors originating from Telomerase-positive cells like leukemia and lymphoma[55 ▶].A conclusion on the expression of the discussed genes[56 ▶]. Activation of the canonical Wnt signaling (or the Wnt/β-Catenin pathway) occurs in more than 85% of colon cancer cases in which this signaling pathway is involved in tumor formation and progression[5 ▶-8 ▶]. The transcriptional activities of β-Catenin protein are a hallmark of deregulation of this signaling pathway in colon cancer and some other malignancies. We have learned that each one of the target genes (some of them mentioned above) may produce a multi-functional protein, which can greatly influence cellular activities, including growth, proliferation, survival, polarity, cytoskeleton organization, and movement. Therefore, we can easily conclude that the deregulation of the Wnt/β-Catenin signaling in cells  can potentially lead to the formation and progression of neoplastic cells. It is worth mentioning that the transcription of some of the target genes decreases upon the activation of the Wnt/β-Catenin signaling. A good example is CDH1, which encodes E-Cadherin, a true marker of epithelial cells. Decrease in E-Cadherin expression can induce EMT, which may activate a Wnt-independent β-Catenin signaling. Another mechanism to reduce the expression of CDH1 by Wnt/β-Catenin is the activation of a gene called SNAI1, encoding a transcription factor (Snail), which negatively regulates the transcription of CDH1.It definitely cannot be expected that β-Catenin has ability to regulate all its target genes in a specific colon cancer patient or in a cell line in which β-Catenin has been overexpressed. The correct number of genes, which are regulated by the Wnt/β-Catenin pathway, is most likely dependent on the cell contextβ-Catenin and human cancers and/or the induction of EMT. We and others have also suggested that the activation of some classes of heterotrimeric G-proteins  can cause cellular accumulation of β-Catenin and its transcriptional activities. An important question is whether the β-Catenin proteins activated by these signaling pathways functionally behave similarly, or there are different species of this protein that each tumor is dependent on one or two of them. It is also important to consider that some tumors may use two or more components of Wnt signaling pathway to perhaps amplify β-Catenin activation. An example is the colon cancer cell line, HCT-116, which carries both β-Catenin-activating gene mutations together with epigenetic silencing of the sFRP encoding gene. Based on the above information, it appears that β-Catenin deregulation occurs in many human cancers[5 ▶-9 ▶], and the examples below are just representatives of those tumors.Before discussing human cancers, which are dependent on β-Catenin deregulation, it is interesting to know that different tumors may use various mechanisms to upregulate β-Catenin signaling. We know that β-Catenin cellular accumulation and its transcriptional activities are not due to only activation of the canonical Wnt pathway. The mitogenic and surviving signals through RTKs and PI3-Kinas/AKT can also upregulate β-Catenin activity via phosphorylation (at serine 9) and inactivation of GSK-3βColon cancer[5 ▶-8 ▶]. All familial adenomatous polyposis patients and more than 85% of the sporadic cases of colon cancer carry genetic mutations in the APC gene, resulting in the complete or partial inactivation of the APC protein. During Wnt/β-Catenin signal transduction, APC protein functions as a regulator and a large scaffold protein to maintain β-Catenin protein levels at physiological concentrations. Upon the inactivation of APC in colon epithelial cells, β-Catenin accumulates in the cell. This cellular accumulation of β-Catenin may result in its nuclear translocation and transcriptional activity of this protein, which appears to be the main cause of colon cancer initiation. Interestingly, the remaining cases (nearly 15%) of colon cancer, which lack APC mutations, carry genetic or epigenetic changes in some other components of the Wnt/β-Catenin signaling pathway [60 ▶-63 ▶]. Even in hereditary non-polyposis colorectal cancer patients, which initially carry genetic mutations in the genes encoding the proteins of the mismatch DNA repair system, genetic mutations (point mutations) in the β-Catenin-encoding gene (CTNNB1) is very common at later stages[64 ▶]. β-Catenin mutations normally affect the N-terminal of the protein replacing the GSK-3β or Casein kinase phosphorylation sites[64 ▶]. As mentioned above, deregulation of the Wnt/β-Catenin pathway is an early event in colon cancer. Clinically, this is a very important issue because targeting the biological pathways involved in the initiation of tumorigenesis can potentially block tumor formation. Colon cancer is perhaps the best example of the interaction between Wnt/β-Catenin signaling and human cancers and has very well been investigated over the decadesMelanoma. Melanoma is a type of skin tumor that originates from the basal layer of the skin and from the pigment producing cells, melanocytes. Compared to other types of skin tumors, melanoma is a more malignant one. The interaction between this tumor and Wnt/β-Catenin signaling has been known for years. It has been reported that almost all forms of benign melanoma have nuclear β-Catenin. Therefore, the Wnt/β-Catenin pathway appears to support proliferation and escape from senescence of early melanoma tumor cells[65 ▶]. It has also been shown that the advanced melanoma cells lackβ-Catenin in the nucleus. These observations are very interesting as they suggest a very complex role of Wnt/β-Catenin pathway in this type of malignancy. Probably cancer stage and tumor microenvironment are important factors when studying the interaction between Wnt/β-Catenin signaling and melanoma tumorigenesis. As mentioned before, the signals through Wnt and Frizzled proteins have generally been divided into canonical (the Wnt/β-Catenin) and non-canonical pathways. Although the role of canonical Wnt signaling was originally highlighted in human cancers , more recent results indicate that the non-canonical Wnt pathways are also involved in human carcinogenesis[5 ▶-7 ▶]. Based on the current knowledge about human carcinomas , in the case of the tumors dependent on Wnt signaling, it appears that the canonical Wnt pathway supports early tumorigenesis, while the non-canonical Wnt pathways help tumor invasion and metastasis[5 ▶-7 ▶]. In melanoma, the genetic mutations of the components of the canonical Wnt pathway (including β-Catenin itself) are rare, but the non-canonical Wnt pathway (mediated by Wnt-5a) helps tumor metastasis[65 ▶]. The increased intracellular levels of β-Catenin during early stages of melanoma is likely due to the activation of other signaling pathways[65 ▶]. The experiments performed in mice have suggested that β-Catenin-mediated melanoma formation is dependent on the activation of the proto-oncogene, N-Ras[66 ▶]. It has been speculated that the downregulation of β-Catenin signaling, which occurs during melanoma aggression, is possibly due to the activation of non-canonical Wnt pathways[65 ▶-67 ▶]. One proposed mechanism is that interaction of Wnt-5a with Frizzled 2/5 and the coreceptor, ROR2 (a receptor tyrosine kinase) activates phosphatidylinositol signaling, which leads to the release of calcium from intracellular stores and activation of protein kinase C. The outcome of the released calcium could include the activation of calpain-mediated proteolysis of filamin, upregulation of the transcription factor, Snail, and upregulation of the cytoskeleton protein, Vimentin, which collectively enhance cell motility and transition of tumor cells to a mesenchymal phenotype. It has also been revealed that Wnt-5a activation leads to the proteolysis of β-Catenin via a mechanism that is independent of GSK-3β and is through the activation of the ubiquitin ligase, SIAH2[65 ▶]. These results all show that the downregulation of β-Catenin occurs during melanoma tumor invasion.Melanocytes developmentally originate from the migration of neural crest cells and the Wnt signaling plays an essential role in the determination of melanocyte cell fateHepatocellular carcinoma[69 ▶-73 ▶]. HCC (like many other carcinomas) is a multi-stage and complex disease that requires the accumulation of several genetic and epigenetic changes to develop. Deregulation of the canonical Wnt signaling (and therefore the upregulation of β-Catenin) in HCC is very common and occurs in nearly 95% of the cases. It appears that a relatively similar mechanism to what discussed for melanoma applies for HCC as well, that the canonical Wnt signaling (the Wnt/β-Catenin pathway) is involved in the initiation of hepatocellular tumorigenesis, while the non-canonical Wnt pathway helps tumor advancement and invasion[71 ▶]. Therefore, a combination of Wnt signaling pathways can support the proliferation, survival, migration, and invasiveness of hepatocytes[69 ▶-72 ▶]. The molecular events leading to the activation of β-Catenin in HCC include CTNNB1 and AXIN gene mutations, WNT3/FZD7 overexpression, and sFRP1/5 repression[71]. APC gene mutations in HCC are rare and include only 1% to 3% of cases[71 ▶]. It has been estimated that between 40% to 70% of HCC cases have nuclear β-Catenin accumulation. It is interesting to mention that β-Catenin gene (CTNNB1) mutations normally occur late in HCC tumorigenesis, but the cellular accumulation of β-Catenin is an early event[71 ▶]. This means that the early cellular accumulation of β-Catenin in HCC is probably not due to the mutations in the β-Catenin-encoding gene. The above information also suggests that the late β-Catenin mutations probably have an extra role in HCC tumorigenesis. A balanced β-Catenin signaling is important for liver tissue homeostasis, and therefore the deregulation of Wnt/β-Catenin pathway probably has an important role in the initiation of HCC[69 ▶-72 ▶]. However, studies in mice have shown that β-Catenin upregulation per se is not sufficient to initiate hepatoma, and other pathways like H-Ras signaling are also required for the initiation of the tumor[71 ▶]. Also, by using conditional knockout experiments, it has been reported that diethyl-nitrosamine-induced HCC in mice can be enhanced severalfold either in the absence of wild type β-Catenin or in the presence of a mutant β-Catenin. These results have made it difficult to conclude that Wnt/β-Catenin signaling is involved in the initiation of HCC tumorigenesis, but more recent results have indicated that both types of Wnt signaling pathway  help HCC aggressiveness and resistance to therapy and also provide an appropriate microenvironment to support tumor growth and survival.HCC is one of the leading cause of death from cancer in many populations, and studies have exhibited that the aberrant regulation of Wnt signaling  is involved in hepatocellular carcinogenesisPancreatic cancer[74 ▶-77 ▶]. The metastasis is relatively common and more than half of the patients have already distant metastases at the time of diagnosis[74]. Activating mutations in the KRAS gene have been detected in more than 95% of the cases. Also, inactivation of the tumor suppressors like p53, INK4a, and DPC4 is documented in pancreatic cancer progression and development[74 ▶]. In addition, deregulation of signaling pathways like those mediated by Hedgehog, Notch, and Wnt may occur in pancreatic cancer, which has an important role in the progression of the tumor[75 ▶]. Nuclear accumulation of β-Catenin has been detected in moderate to poorly differentiated PDAC, and it has been noted that nuclear β-Catenin accompanies with poor prognosis[74 ▶]. Meanwhile, the genetic mutations of downstream components of the canonical Wnt pathway are not very common in pancreatic cancer. This means that probably molecular changes affecting the upstream levels of Wnt signaling are acting in β-Catenin upregulation. In fact, overexpression of Wnts and Frizzled receptors has been reported in PDAC[75 ▶]. It has been shown that the upregulation of β-Catenin during mice development leads to pancreatoblastoma, while upregulation of this protein after birth results in PDAC. Interestingly, several β-Catenin target genes  have been linked to the tumorigenesis of PDAC. In this sense, the role of CYR61 has been highlighted in malignant potential of PDAC[74 ▶]. Higher expression of CYR61 has been detected in about 85% of PDAC cases, and expression of this gene has been associated with the later stages of the disease[74 ▶]. It has been suggested that CYR61 binds to LRP6 and activates Wnt/β-Catenin pathway using a positive feedback loop[74 ▶]. Although the role of non-canonical Wnt pathways in PDAC development is unclear, studies have revealed that Wnt-5a-mediated signaling is involved in the transformation of pancreatic cancer cells[74 ▶].PDAC is among the deadliest human cancers with an overall survival rate of about 8%Clinical targeting of the Wnt/β-Catenin signaling [78 ▶], there are still some unanswered questions about the regulation of this signaling pathway. Despite these limitations, several compounds have been introduced as candidates to downregulate Wnt/β-Catenin signaling in human cancers. Although none of these compounds has yet been approved for clinical use, some have produced promising results in pre-clinical studies. Some of these compounds and their specific targets have been briefly discussed below.Due to the interaction between Wnt/β-Catenin signaling and human carcinogenesis, this signaling pathway has been considered as a potential clinical target for the prevention and treatment of a large number of human cancers, especially those dependent on Wnt/β-Catenin signaling at early stages (like colon cancer). However, targeting such an important signaling pathway without clinical side effects seems to be difficult. This issue gets more serious when there are cross-talks between Wnt/β-Catenin signaling and other signaling pathways. After about 40 years of intensive research on Wnt signalingβ-Catenin/TCF[79 ▶-82 ▶].Perhaps the most specific segment of Wnt/β-Catenin signaling is the interaction of β-Catenin with TCF/Lef family members and the transcriptional activities of this protein complex. Although the genes regulated by the complex of β-Catenin/TCF may vary based on the cell-context, specific targeting of this protein complex appears to be promising. Currently, several compounds, including PKF115-584, CGP049090, iCRT3, iCRT5, iCRT14, PNU-74654, and BC21, against β-Catenin/TCF complex are under preclinical investigationsTankyrase 1/2. These compounds are, in fact, the inhibitors of the enzyme, Tankyrase. Tankyrase 1/2 is involved in ADP-ribosylation of Axin and therefore destabilizes this protein via inducing its ubiquitylation and degradation. As mentioned above, Axin, as a second scaffold protein (after APC), functions as a negative regulator of β-Catenin stability.Several compounds, like XAV939, IWR, and G007-LK, have been designed to upregulate Axin, an inherent component of the Wnt/β-Catenin signaling pathwayPorcupine[6 ▶]. Secretion of Wnt ligands is a very complex process, and for most Wnt proteins, glycosylation and lipid modification (acylation) are prerequisites for appropriate vesicular trafficking and secretion. Porcupine is a membrane protein with O-acyltransferase activity and is involved in palmitoylation (at a serine residue) and maturation of most Wnt proteins. It has been demonstrated that the palmitoylated serine is one of the interacting sites of the Wnt proteins to the extracellular cysteine-rich domain of Frizzled receptors. It has also been shown that in the absence of Porcupine, the Wnt proteins cannot be secreted and are trapped in endoplasmic reticulum[83 ▶]. Based on these data, it can be concluded that Porcupine is a potential clinical target although it seems likely that the blockade of Porcupine affects the secretion of many Wnt proteins and produces non-specific and unwanted results. The compounds IWP2, LGK974, and C59 are among the blockers of Porcupine.Appropriate synthesis and secretion of Wnt proteins have crucial roles in the activation of both canonical and non-canonical Wnt signaling pathwaysOther targets[82 ▶]. The compounds like FJ9, NSC668036, and 3289-8625 have been used for preclinical studies against DVL (the human homologue for Drosophila Dishevelled proteins) [82 ▶]. Based on the knowledge about the role of DVL proteins in regulating Wnt signaling, it is quite predictable that blocking these proteins may have a huge effect on the biological activities of many cells (including cancer cells). DVL is a critical protein involved in regulating both canonical and non-canonical Wnt signaling. DVL is, in fact, an upstream component of the Wnt pathways and has a very important role in specifying the signals through Wnt and Frizzled proteins[5 ▶-7 ▶]. These features of DVL proteins make them challenging targets as far as the cytotoxicity and drug side effects are concerned. A monoclonal antibody (OMP-18R5) has been generated that recognizes several Frizzled receptors and is currently in phase I clinical trial[84 ▶]. Application of specific monoclonal antibodies against oncogenic tyrosine kinase receptors has been proven to be successful, and some of such antibodies (like Herceptin against Her2/Neu) have been approved for clinical use. RTKs are more diverse than Frizzled proteins (58 vs. 10), and they have potential mitogenic activities. Also, overexpression of RTKs has been observed in several human cancers[85 ▶], while the expression levels of Frizzled proteins in human cancers have not been extensively studied. Since there are only 10 Frizzled proteins encoded by human genome and the involvement of these proteins in both canonical and non-canonical Wnt pathways, it can be concluded that each Frizzled protein may regulate several biological activities. Therefore, for clinical purposes, targeting a Frizzled receptor with monoclonal antibodies appears to be more challenging than that for receptor tyrosine kinases. It is worth mentioning that the above targets are not the only ones that have been considered for clinical investigations to modulate Wnt/β-Catenin signaling. The other targets include DVL, Wnts, and Frizzled proteinsConclusions and future directionsThere is no doubt that the canonical Wnt signaling (or the Wnt/β-Catenin pathway) is a potential clinical target for cancer therapy. However, an important question is which segment of this pathway should be targeted to produce better and more specific results. The final step of a signaling pathway appears to be the best choice, which for the canonical Wnt pathway includes the β-Catenin-mediated gene transcription. However, the transcriptional activities of β-Catenin should be cellular context-dependent, and the β-Catenin/TCF complex may not be the only factor in specifying the target genes. Definitely, further investigations on molecular details of β-Catenin transcriptional complexes are needed to address the above question.


Misolampus Latreille, 1807  encompass six species: M.gibbulus , M.goudotii Guérin-Méneville, 1834, M.lusitanicus Brême, 1842, M.ramburii Brême, 1842, M.scabricollis Graells, 1849, and M.subglaber Rosenhauer, 1856. Previously known distribution ranges of the species were delineated using many old records, the persistence of such populations being questionable under the current situation of global biodiversity loss. Additionally, the status of geographically isolated populations of the genus have been the subject of taxonomic controversy. An exhaustive bibliographical revision and field search was undertaken, and the Misolampus collection of the Museo Nacional de Ciencias Naturales (MNCN-CSIC) was revised. The aims are to (i) provide an updated geographic distribution range for the species of Misolampus; (ii) to determine the taxonomic status of controversial populations; (iii) to provide a catalogue for Misolampus; and (iv) to discuss the conservation status of these saproxylic beetles. As a result, a catalogue including synonymies and type localities, geographical records, diagnoses, and information on natural history for all species of Misolampus is presented. The results reveal that the distribution ranges of the species of Misolampus have not undergone a reduction in the last century, and indicate the presence of the genus in areas where it had never been recorded before. The morphological variability of M.goudotii drove the proposal of different taxa that are here formally synonymised as follows: M.goudotii Guérin-Méneville, 1834 = M.erichsoni Vauloger de Beaupré, 1900, syn. nov. = M.peyerimhoffi Antoine, 1926, syn. nov.Hunchback darkling beetles of the Ibero-Maghrebian genus  Species identification is an essential process for almost all biodiversity studies and can constitute a major constraint for conservation evaluation and legislation due to the inherent difficulty of identifying many of the groups, the long time needed for processing the samples, and the extensive taxonomic experience that this process requires . MeetingTenebrionidae is one of the most species-rich families of beetles, with approximately 20,000 species worldwide and many more taxa yet to be described , by monotypy], currently included within Cnodalonini Oken, 1843, in the subfamily Stenochiinae Kirby, 1837 , only retrieved a total of 49 records for Misolampus (once records for other genera were discarded), three of them identified at genus level, and at least one misidentified species; 14 of 49 had geographic coordinates data, eleven of which corresponded to a single locality. Excluding all additional specimens with imprecise locality data, fewer than 30 specimens remained available for scientific use.The genus gibbulus , M.gouder, 1856 , all of er, 1856 . Five of Islands . Reitter Islands , 1954, aMisolampus are relatively well known  in Madrid (Spain). Secondly, and as a result of the field data collection, we aimed to determine the taxonomic status of geographically isolated populations of the genus, including those that have been the subject of taxonomic controversy . Information on the location of previously known populations was obtained by undertaking an exhaustive bibliographic revision and by reviewing the Misolampus collection held at the MNCN .Field work to locate Misolampus . Of those, 355 specimens are preserved in ethanol, and 949 specimens dry-mounted . The list of examined specimens is included in the corresponding paragraph of the species catalogue. Collectors are specified when different from authors or members of the research team; collector name is indicated for old collections only when printed in the labels; “ex.” or “exx.” is used to abbreviate “specimen” or “specimens”.We studied 1304 specimens representing all known taxa of Unresolved taxonomic issues, such as the validity of subspecies within the North African taxon, the specific assignation of the populations from Algarve , and taxSDMs) to obtain the potential distribution of each species . We used Maximum entropy algorithm (MaxEnt)  value .Distribution maps based on current data represent the extent of occurrence of each species following a relaxed modification of IUCN criteria . We perf(MaxEnt) , 2011 an(MaxEnt) . The SDMC) value . All SDMTo obtain morphological data, dry-mounted specimens were examined under a stereomicroscopy. Specimen length was measured in dorsal view as the distance between the anterior margin of the pronotum and the elytral apex . The head was excluded from measurement since it is usually directed ventrally. Maximum width was measured as the distance between the outer edges of the elytra at approximately three-fourths of the elytral length, also in dorsal view. Photographs of live specimens were taken with a Nikon digital camera. Extended depth-of-focus images of dry-mounted specimens, were taken on a Leica M165C stereo-microscope, with a digital camera Leica DFC450, using the LAS X software from Leica Microsystems.Taxon classificationAnimaliaColeopteraTenebrionidaeDE0F63A3-C070-50F4-AB22-B336FBB55932Pimeliagibbula Herbst, 1799: 51. Terra typica: unknown: “Das vaterland ist mir unbekannt”.MisolampushoffmannsegiiM.hoffmansegii” and “M.hoffmanseggii”, respectively, M.hoffmanseggii”, and M.hoffmansseggii”. Synonymy with M.gibbulus proposed by  Latreille, 1807: 161. Terra typica: “e Lusitania allatus”. Misolampusgibbulus : 37°36'57.4"N, 08°27'57.3"W, 4-I-2013: 10 exx. – Evora: Evoramonte, 17-X-1992: 1 ex.; Monte São Bento, 353 m, 38°34'54.33"N, 7°56'12.10"W, 11-III-2010: 1 ex.; Valverde, 232 m, 38°31'39.8"N, 8°00'25.4"W, 4-X-2002: 1 ex.; – Faro: Alferce: 1 ex.; Alferce, V-1909 (Exp. del Museo): 2 exx.; carretera Monchique-Laranjeira [Gil Bordalo], 21-X-1992: 6 exx.; Foia, 742 m, 37°18'29.4"N, 08°35'56.2"W, 4-I-2013: 1 ex.; Monchique, 439 m, 37°21'40.3"N, 08°32'23.6"W, 4-I-2013: 8 exx.; San Marcos da Serra [São Marcos da Serra]: 2 exx.; San Marcos da Serra [São Marcos da Serra], V-1909 (exp. del Museo): 23 exx.; São Marcos da Serra, 140 m, 37°21'02.5"N, 08°22'48.4"W, 3-I-2013: 24 exx.; Sierra de Monchique, V-1909 (exp. del Museo): 1 ex.; Portalegre: Santo Antonio de Alcorrego, 150 m, 38°58'59.5"N, 7°56'54.1"W, 18-IV-2013: 6 exx. Spain – Andalucía: Córdoba: Córdoba (Col. del Sr. Pérez Arcas): 2 exx.; Córdoba: 2 exx.; Córdoba, IV-1901 : 4 exx.; Córdoba, VI-1909 (Exp. del Museo): 3 exx.; Manueles, 30SUH82, 7-V-1982 (M.A. Alonso Z. leg.): 1 ex.; Huelva: Barranco Riofrío [La Nava], 28-XII-1985: 1 ex.; Cala (C. Bolívar leg.): 15 exx.; Cortegana, Puerto del Corzo (hacia Gil Márquez), 664 m, 37°52'56.1"N, 06°50'42.3"W, 3-I-2013: 7 exx.; Patrás, 397 m, 37°48'04.4"N, 6°43'30.8"W, 1-V-2004: 3 exx.; Jaén: [3 km al SO de] Aldeaquemada, 25-IV-1992: 3 exx.; Lugar Nuevo, 24-X-1991: 2 exx.; Santa Elena, carretera hacia La Aliseda, 795 m, 38°20'53.1"N, 03°33'20.6"W, 28-XII-2010: 14 exx.; Santa Elena, 12-III-1901: 2 exx.; Santa Elena: 2 exx.; Sierra Morena: 1 ex.; Sevilla: Constantina: 1 ex.; – Castilla –La Mancha: Ciudad Real: Almadén (Belbeze leg.): 1 ex.; Navas de Estena: 1 ex.; Pueblo Nuevo del Bullaque, 7-XII-1992: 2 exx.; Puerto Madrona, 20-XI-1992: 8 exx.; Saceruela (Paz leg.): 1 ex.; Solana del Pino: Puerto Madrona, 38°25'07.3"N, 4°03'33.1"W, 06-III-2012: 1 ex.; Toledo: Santa Cruz del R. [Retamar] (Paz leg.) (Col. del Sr. Pérez Arcas): 1 ex.; – Castilla y León: Ávila: Candeleda, XI-1933: 1 ex.; 8 km NE Hoyo de Pinares, 40°31'40.6"N, 4°20'04.5"W, 1-IV-2013: 2 exx.; Mombeltrán – Navalperal [de Pinares]: 1 ex.; Extremadura: Badajoz: Aljucén (Pacheco leg.): 2 exx.; Cáceres: Alcuéscar: I-1894: 3 exx.; Belvís de Monroy, 373 m, 39°48'04.8"N, 5°37'01.1"W, 24-XII-2011: 6 exx.; Castillo de Trevejo, 714 m, 40°10'20.9"N, 6°46'48.9"W, 17-IV-2011: 1 ex.; Valdemorales, 420 m, 39°12'08.1"N, 06°03'57.8"W, 2-I-2012: 2 exx. Madrid: Brunete (Bolívar leg.): 2 exx.; Cadalso [de los Vidrios] (J. Ardois leg.): 120 exx.; Cadalso de los Vidrios, hacia Almorox, 12-IV-1992: 1 ex.; Cerro de San Pedro, 29-X-2004: 4 exx.; Collado Mediano (C. Bolívar leg.): 1 ex.; Collado Mediano: 13 exx.; Collado Mediano (G. Schramm leg.): 4 exx.; Collado Mediano (Moróder leg.): 5 exx.; Fresnedillas de la Oliva, 941 m, 40°29'38.57"N, 4°10'12.90"W, 14-III-2001: 14 exx.; Galapagar (Col. del Sr. Pérez Arcas) (Misolampusgibbulus Hbst.): 1 ex.; Manzanares [El Real], 30-III-1928: 1 ex.; Moralzarzal: Cerro del Telégrafo, 23-IV-2017: 1 ex.; Navas del Rey, 2-XII-1990: 2 exx.; Pelayos de la Presa, 799 m, 40°20'19.40"N, 4°21'34.84"W, 3-III-2001: 1 ex.; [3 km al S de] Quijorna, 5-II-1992: 1 ex.; Robledo de Chavela: 7 exx.; Santa María de la Alameda (estación), 1-IV-1991: 10 exx.; Sierra de Guadarrama (J. Lauffer leg.): 1 ex.; Torrelodones, 7-XI-1992: 4 exx.; Valdemaqueda, 40°30'30.0"N, 4°17'00.1"W, 1-IV-2013: 2 exx.; Valdemorillo, 12-IV-1992: 7 exx.; Villa del Prado (J. Ardois leg.): 105 exx.; Villa del Prado: 4 exx.; Villa del Prado, Encinar del Alberche, 742 m, 40°17'29.7"N, 04°21'11.9"W, 4-I-2009: 5 exx.; Villalba: 1 ex.Portugal – Beja: Beja: 1 ex.; Beja, V-1909 (exp. del Museo): 1 ex.; São Martinho das Amoreiras, 200 m, Misolampusgibbulus presents acutely protruding prothoracic anterior angles, strong pronotal punctation, deep, and densely covering most of its surface; elytra with well-marked deeply excavated striae, with large and deep punctation, and shiny interstriae intervals often with additional series of punctures 2). Its gM.gibbulus. In addition to previously published data, we add new records for the district of Évora and Portalegre in Portugal, and from the provinces of Ávila, Badajoz, and Toledo in Spain; together with numerous localities for some provinces represented by a few records, such as Cáceres, Ciudad Real, and Madrid. With the addition of these records, the distribution of M.gibbulus seems to be more or less continuous along the southern slopes of the Sistema Central: from Cáceres and Ávila to Madrid, along both slopes of Montes de Toledo and Sierra Morena, and in a more or less extended area in southern Portugal, from Évora to Serra de Monchique in the Algarve region. The Guadalquivir river basin seems to conform the southeastern distribution limit for the species  and broadleaved trees , and also dense shrublands of Cistus L. , Retama Raf. and Cytisus Desf. (“retamares”)  and montane agrosystems with olive and chestnuts trees (Oleaeuropaea L. and Castaneasativa Mill.)  Fig. . The spes L’Hér. , as wellll.) see .Misolampusgibbulus is commonly found under bark or within decomposing dead logs and stumps of pines (mainly of Pinuspinea L. and Pinussylvestris L.), including reforested areas , where they appear to be particularly common. It is also found in dead or old trunks of perennial or deciduous oaks , under the dry layers that cover roots and thick stems of Cistusladanifer L. and Cistuslaurifolius L., and at the base of brooms, mainly Cytisusscoparius (L.) Link and Retamasphaerocarpa (L.) Boiss. Occasionally found under loose bark or at the base, among decaying wood of standing Eucalyptus trees, and also in rotten Eucalyptus stumps , northern Extremadura (Cáceres), Montes de Toledo (Toledo)  (pers. obs.). Adults can be found across most of the year (do) Fig. , and southe year  but accoTaxon classificationAnimaliaColeopteraTenebrionidaeGuérin-Méneville, 1834AF57D823-BE12-5C5D-B5EF-0C611A597DA3MisolampusgoudotiiMisolampusnigrita Dejean”, and M.moraguesi”. Guérin-Méneville, 1834: 28. Terra typica: “trouvée à Tanger... ...à trois lieues de Tanger, sur les bords d’une rivière, dans le tronc d’un olivier.” Vauloger de Beaupré , ReitterMisolampusgoudotii Erichson in Wagner, 1841: 184 non . Terra tMisolampuserichsoni Vauloger de Beaupré, 1900: 674 syn. nov. Terra typica: “Algérie: O., Oran...; Daya...; Tlemcen...; Mascara..., Ammi Moussa; A.: Blidah...; La Chiffa...; Margueritte...; forêt de Boghar...; mont Ouarsenis...; forêts de la Grande-Kabylie...”.Misolampuspeyerimhoffi Antoine, 1926: 257 syn. nov. Terra typica: “Grand Atlas, région du Glaoui: plateau des Aït Rba...”.31°28'34.6"N, 7°26'06.5"W, 11-III-2013: 4 exx. – Meknès – Tafilalet: Ain Leuh, 17-V-1925: 1 ex.; Azrou, 1900 m (Alluaud 79) (Misolampusgoudoti var. laevior Alluaud): 1 ex.; Azrou, 19-V-1925: 1 ex.; Dj. [Yebel] Hebri, 20-V-1925: 1 ex.; Timadit [Timahdite], 21-V-1923: 1 ex. – Tanger – Tétouan: Rif: Beni Siyyel: Bab Ruadi: VI-1932 (C. Bolívar leg.): 6 exx.; Tanger, 1897: 3 exx.; Tanger  : 36 exx., plus 3 exx. only square-labelled; 2 km al O de Bab Berret, 1318 m, 35°00'02.57"N, 4°55'31.91"W, 12-VI-2011: 3 exx.; Crtra. Zinat-Mulay Abdeselam, P-4702, Beni Aros, Yebala, 513 m, 35°22'04"N, 5°32'17"W, 29-IV-2016: 5 exx.; Yebel Bou-Hachem, Beni Aros, Yebala, 1160 m, 35°15'31"N, 5°30'49"W, 12-V-2012: 6 exx.; Crtra. Mulay Abdeselam-Al Hamra, P-4704, Beni Aros, 985 m, 35°15'50"N, 5°25'36"W, 28-XI-2019: 2 exx.; Larache: Yebala: Beni Arós: Yebel Bou-Hachem, 35°15'31"N, 5°30'49"W, 9-VI-2012: 2 exx.; Pinsapar del Talassemtane, 1900 m, 35°08'36.7"N, 5°08'13.0"W, 11-VI-2011: 2 exx.; Bab Taza: Talassemtane, 1401 m, 35°06'10.9"N, 5°08'21.3"W, 27-VII-2013: 1 ex.; Bab Taza: Talassemtane: Plaza de España, 1667 m, 35°09'03.7"N, 5°08'28.6"W, 27-VII-2013: 1 ex.; Casa Forestal, Yebel Lekraa, P.N. Talasemtane, Chefchaouen, 35°07'56"N, 5°08'11"W, 1695 m, 7-VI-2008: 3 exx.; Yebel Talassemtane-vertiente sur, P.N. Talasemtane, Chefchaouen, 35°07'53"N, 5°08'01"W, 1650 m, 11-IV-2011: 4 exx.; P.N. Yebel Tazaot, Pinsapar, P.N. Talasemtane, Chefchaouen, 35°15'N, 5°07'W, 1670 m, 7-V-2011: 2 exx.; Pista hacia Casa Forestal, Yebel Lekraa, P.N. Talasemtane, Chefchaouen, 35°07'45"N, 5°08'09"W, 1700 m, 28-VII-2011: 1 ex.; E. de Yebel Talaousisse, P.N. Talasemtane, Chefchaouen, 35°07'33"N, 5°04'03"W, 1350 m, 1-XII-2018: 2 exx.; Pista hacia Haout Taznout, P.N. Talasemtane, Chefchaouen, 35°08'20"N, 5°07'24"W, 1712 m, 27-IV-2019: 2 exx.; Yebel Tizirhen, Bab Berred, Rif Central, 1585 m, 35°00'54"N, 4°54'57"W, 27-IV-2017: 3 exx.; Yebel Tizirhen, Bab Berred, Rif Central, 1570 m, 35°00'47"N, 4°54'03"W, 28-IV-2018: 1 ex.; Pista de Bab El Kar, Montañas de Fifi, Rif, 1512 m, 34°59'13"N, 5°11'20"W, 2-VI-2019: 2 exx. – Taza – Al Hoceima – Taounate: Iguermalen [Targuist]: Beni Mesdui, VI-1932 : 6 exx.; Rif: Beni Seddat: Imosiner: VI-1930 (exp. C. Bolívar leg.): 3 exx.; Rif: Beni Seddat: Tizi Taka, VI-1932 (C. Bolívar leg.): 4 exx.; Rif: Beni Seddat: Tizi Taka, VI-1932 (Exp. C. Bolívar leg.): 1 ex.; Rif: Iguermalen (Targuist), VI-1930 (exp. C. Bolívar leg.): 4 exx.; Rif: Ketama, Bab Chiquer, VI-1932 (C. Bolívar leg.): 8 exx.; Rif: Ketama, Bab Chiquer, VI-1932 : 2 exx.; Rif: Ketama: Tainza, VI-1930 (exp. C. Bolívar leg): 3 exx.; Rif: Ketama: Tidiguin [Tidghine], VI-1930 (exp. C. Bolívar leg.): 1 ex.; Rif: Ketama: Zoco Telata, VI-1932 : 7 exx.; Lurdeka [?]: 1 ex.; Yebel Tidighin, Azila, Rif central, 1705 m, 34°51'14"N, 4°32'19"W, 29-XI-2019: 1 ex; Carretera P-5420, P.N. Tazzeka, Medio Atlas nororiental, 1000 m, 34°03'N, 4°15'W, 25-XI-2004 (F.J. Martínez leg.): 2 exx. – Souss-Massa-Drâa: Yebel Tual, 28-VII-1934: 1 ex.; Ifni: Yebel Tamarrut [25 km SE Ifni], I-1935 : 1 ex.; Sidi Ifni: Akarkor, Jbel Toual, 627 m, 29°13'48.9"N, 10°00'44.1"W, 21-I-2020: 4 exx. Spain – Islas Baleares: Mallorca (Mas de Xaxars leg.) (Misolampuserichsoni): 2 exx.; Escorca, 26-III-1985, 1 ex.; Escorca, Coll de Femenia, 545 m, 39°51'33.68"N, 2°54'19.27"W, 25-III-2012: 10 exx.; Menorca (Cardona leg.): 2 exx. plus 6 exx. without data; 2 exx.; Menorca: 2 exx.; Algaiarens, 14 m, 40°02'28.3"N, 03°55'28.4"W, 27-IV-2006: 2 exx.Algeria: “Argelia” (Dufour leg.): 1 ex. Morocco – Marrakech-Tensift-Al Hauz: Toufliht, 1483 m, Misolampus by the following traits: fore angles of the prothorax not protruding, almost rounded, forming an obtuse angle at apex; lateral surface of pronotum shallowly rugose, with the rugosity progressively erased towards the dorsal areas that appear smoother, propleural punctation fine and often erased; elytra with longitudinal series of small elongated tubercles, more apparent on the sides of the posterior half of the elytra  and from the Moroccan regions of Meknès-Tafilalet, Souss-Massa-Drâa, Tanger-Tétouan, and Taza-Al Hoceima-Taounate. Recent data are available from all four regions, with a large number of localities from the Rif, and less numerous in the Middle and High Atlas. Among these records, we emphasise the re-discovery of the population from the province of Sidi Ifni, in January-2020, 85 years after its original finding, by F. Martínez de la Escalera in 1934 and 1935 . The latMisolampusgoudotii is widely distributed over northwestern Africa, though restricted to mountain ranges and adjacent areas: Rif, Middle Atlas, western High Atlas, Beni Snassen mountains, southwestern foothills of the Anti-Atlas (Morocco) and Tellian Atlas (Algerie)  Mast., Abiesmaroccana Trab., Cedrusatlantica (Endl.) Manetti ex Carrière, Juniperusphoenicea L., Juniperusthurifera L., Pinusnigra J.F. Arnold, Pinushalepensis Mill., P.pinaster] and broadleaved  (see Arganiaspinosa (L.) Skeels, with sparse cactiform and arbustive Euphorbia L.  Fig. . Altitudie) Fig. , 2019b. perhumid , and occehr] see . It alsoehr] see . The popehr] see . The vegorbia L. , and larill Fig. .M.goudotii is often encountered under bark, inside fallen logs or stumps, and at the base of dead old oaks , arbutus trees (Arbutusunedo L.), wild olive trees (O.europaeavar.sylvestris), pines , firs (Abiesmaroccana), and cedars (Cedrusatlantica), as already reported partially by Vauloger de Beaupré . In the Middle and High Atlas, it is usually found under bark and inside large decaying logs of Q.ilex (P.nigra and C.atlantica. Tetraclinisarticulata) in the Korifla Valley (northwestern Morocco). Sidi Ifni specimens were found within crevices in old dead logs of Arganiaspinosa, almost buried on the ground of a steep slope  as described by Q.ilex, under bark or under stones and leaf litter (P.pinea) and old oaks (Q.ilex)  Fig. .M.goudotii together with Helopsinsignismaroccanus   under bark of dead trees of Q.suber, A.maroccana and C.atlantica in the Rif Mountains. P.halepensis) in active colonies of ants of the genus Messor Forel, 1890 and of the species Monomoriumbicolor Emery, 1877 : 1 ex.Portugal – Porto: Fervença – Eido, 585 m, Total length 7.5–8.0 mm, one of the smaller species within the genus . PronotuEndemism of northern Portugal and northwestern Spain  Fig. 6)6). PubliThe material we studied includes recent representation from the provinces of León and Ourense in Spain, and from the Porto district in Portugal. To date, the species is only known from ten localities Fig. . The potMisolampuslusitanicus is a medium altitude species , typical of mountainous reliefs of northwestern Iberian Peninsula . Geological substrates in its geographic range are mainly granite, gneiss and, to a lesser extent, quartzite, which form acid soils , hazel (Corylusavellana L.), birch (Betulapubescens ssp. celtiberica Rothm. & Vasc.), chestnut trees (Castaneasativa), and yews (Taxusbaccata L.), but also heathlands and rocky open areas covered by broom shrubs   see   see .P.pinaster, and also in chestnut groves (C.sativa). It has not been recorded in sympatry with any other species of Misolampus, but it has been found in company of Coelometopusclypeatus    . AccordiTaxon classificationAnimaliaColeopteraTenebrionidaeBrême, 18428DD087C6-088C-5B33-B1CE-C0C0E1F7FC35Misolampusramburii Brême, 1842: 82. Terra typica: “De l’Espagne meridionale”. Some authors wrote the species name with a single final -i .36°59'25"N, 02°20'13"W, 30-XII-2003 (P. Barranco leg.): 1 ex.; Sierra de Gádor, 892 m, 36°55'32.18"N, 2°35'57.07"W, 27-III-2012: 3 exx.; Granada: Jayena, 30-VII-1920: 4 exx.; Puerto de la Mora, 1294 m, 37°15'19.71"N, 3°29'01.80"W, 26-III-2012: 2 exx.; Pista La Alcaicería-El Robledal (encinar), Sierra Tejeda, 1020 m, 36°57'07"N, 4°00'56"W, 5-I-2005: 1 ex.; Málaga: Málaga (Aragoncillo leg.) (Col. del Sr. Pérez Arcas): 1 exx.; Arroyo Güi, Torrox, 155 m, 36°46'36"N, 3°59'29"W, 23-XII-2000: 4 exx.; Lagos, Velez-Málaga, 102 m, 36°45'00"N, 4°00'28"W, 15-IV-2006: 2 exx.; Área El Pinarillo, Nerja, Sierra de Almijara, 485 m, 36°47'53"N, 3°50'55"W, 3-I-2003: 6 exx.; Área El Pinarillo, Nerja, Sierra de Almijara, 471 m, 36°47'52"N, 3°50'58"W, 4-I-2012: 3 exx.; Cerro El Cañuelo, Acantilados de Maro-Cerro Gordo, Nerja, 130 m, 36°44'57"N, 3°47'12"W, 29-XII-2007: 1 ex.; Carril Cuevas de Nerja-El Pinarillo, Sierra de Almijara, 340 m, 36°46'58"N, 3°50'24"W, 30-III-2018: 2 exx.; Alrededores Cuevas de Nerja, Maro, Nerja, 171 m, 36°45'46"N, 3°50'43"W, 2-XI-2018: 1 ex. – Murcia: Sierra Espuña: VIII-1943 (G. Menor leg.): 1 exx.Spain – Andalucía: Almería: Fondón: 2 exx.; Sierra Bacares: 1900 : 3 exx.; Sierra Alhamilla, Almería, 1240 m, Misolampusramburii is characterised by its shiny appearance and by presenting the anterior angles of prothorax slightly protruding forward. Pronotal punctation deep and dense, not as strong as in M.gibbulus, without granular areas. Elytra with shallow striae formed by series of punctures in longitudinal series, sometimes almost absent , and in Malllorca to the southwestern foothills of the Sierra de Tramuntana, including Palma Bay  .Endemism of southeastern Spain and Mallorca in the Balearic Islands Fig. . RecordsBay Fig. . The recGranada) , found iMaterials studied by us include specimens from all previously reported areas except Mallorca (not searched for). Records are recent for all localities except for those from the Murcia region (Sierra Espuña). The potential distribution map Fig.  shows thMisolampusramburii is a low-medium mountain species, even sub-coastal, with an altitudinal range between 14 and 1673 m a.s.l. ; in Mallorca it is also found at low altitude, 14–398 m a.s.l. Lithological substrates of its area of occupancy are very diverse, due to the high geostructural complexity of the Betic Mountain ranges, but are mainly dolomites, limestones, slates, phyllites, mycaschists, and, very locally, plutonic rocks , oaks , wild olive trees (Oleaeuropaeavar.sylvestris), and carob trees (Ceratoniasiliqua L.), but also in shrub-lands of Quercuscoccifera L., Genistaumbellata (L’Hér.) Dum. Cours., Rosmarinusofficinalis L., Pistacialentiscus L., Pistaciatherebinthus L., Buxusbalearica Lam., Maytenuseuropaeus (Boiss.) Rivas Mart., R.sphaerocarpa, and Cistus and Lavandula L. species, among other typical shrubs (Prunusdulcis (Mill.) D.A. Webb) with scattered oaks (Q.ilex) (pers. obs.)  Fig. .P.halepensis, P.pinaster and P.nigra), and oaks (Q.ilex), or under stones in forests and shrub-lands. Occasionally found under the lose bark of standing live isolated Eucalyptus trees. In the island of Mallorca, it has been found in oak forests (Q.ilex), under bark or under stones and leaf litter : 1 ex. – Portalegre: Monte Palheiros, 632 m, 39°20'03.91"N, 7°25'38.63"W, 10-III-2012: 12 exx.; Ribeira de Nisa, [4 km al NE de Nisa], 23-X-1990: 1 ex. Spain – Andalucía: Huelva: Andalucía: Huelva: Cortegana, 706 m, 37°53'55.6"N, 06°50'16.3"W, 3-I-2013: 2 exx.; Cortegana: Puerto del Corzo (hacia Gil Márquez), 664 m, 37°52'56.1"N, 06°50'42.3"W, 3-I-2013: 9 exx. – Castilla – La Mancha: Ciudad Real: Fuencaliente (Sierra Morena) (J. Cabré leg.): 1 ex.; Navas de Estena: 2 exx.; Puebla de Don Rodrigo: El Vivero, 39°02'29.2"N, 4°33'40.9"W, 5-III-2012: 1 ex.; Saceruela: 1 ex., plus 1 without label; Guadalajara: 3 km al O de La Mierla, 1023 m, 40°56'27.6"N, 3°16'13.4"W, 26-X-2013: 12 exx.; Alpedrete de la Sierra, hacia el Atazar, 17-IV-1992: 3 exx.; Retiendas: Embalse del Vado, 931 m, 41°00'09.8"N, 3°17'41.6"W, 26-X-2013: 2 exx.; Umbralejo, 1256 m, 41°07'33.2"N, 3°10'39.4"W, 26-X-2013: 18 exx.; Toledo: Belvís de la Jara (N502 km 153), 584 m, 39°43'59.3"N, 4°58'14.6"W, 1-XI-2008: 1 ex.; Las Honfrías, Robledo del Mazo, 39°35'48"N, 04°53'15"W, 9-II-2011: 1 ex.; Navamorcuende: Sierra de San Vicente: El Piélago, 1154 m, 40°08'34.4"N, 4°44'09.2"W, 27-XII-2011: 3 exx.; Sierra de San Vicente: El Piélago, 1224 m, 40°08'03.91"N, 4°43'48.79"W, 13-V-2012: 1 ex. – Castilla y León: Ávila: Chamartín de la Sierra: Castro de la Mesa de Miranda, 40°43'24.7"N, 4°56'57.6"W, 10-II-2013: 1 ex.; [Navarredonda de] Gredos: 1 ex.; [Navarredonda de] Gredos (J. Ardois leg.): 10 exx.; Arenas [de San Pedro] (J. Ardois leg.): 1 ex.; Ávila (197) (Pérez leg.): 1 ex.; Casillas, 1158 m, 40°19'25.6"N, 4°35'14.0"W, 16-XI-2012: 1 ex.; Casillas: 4 exx.; Las Navas [del Marqués]: [Sierra de] Guadarrama (G. Schramm leg.): 75 exx.; 5 km S Navas del Marqués, 40°33'24.4"N, 4°19'32.5"W, 1-IV-2013: 1 ex.; Mombeltrán – Navalperal: 2 exx.; Navalperal [de Tormes], VII-1904 : 1 ex.; Navamorcuende (Ardois leg.): 1 ex.; Navas del Marqués: Carretera de Valdemaqueda, 1021 m, 0°32'14.3"N, 4°20'26.5"W, 20-III-2010: 1 ex.; Peguerinos: Valle de Enmedio, 1-VII-1992: 2 exx.; Puerto de Casillas, 1590 m, 40°20'37.1"N, 4°35'06.7"W, 15-V-2011: 1 ex.; Sierra de Gredos: 2 exx.; Valle de Iruelas, 10-V-1919 (J. Abajo leg.): 8 exx.; Valle de Iruelas, V-1920: 7 exx.; Villarejo [del Valle]): 1 ex. plus 1 without label; Burgos: Quemada, 848 m, 41°43'20.4"N, 3°33'00.3"W, 9-V-2013: 4 exx.; Salamanca: 1 km al N del Puerto de Perales, 884 m, 40°15'18.3"N, 6°41'22.2"W, 16-IV-2011: 2 exx.; Navasfrías, 959 m, 40°17'03.1"N, 6°49'49.1"W, 23-XII-2011: 9 exx.; Peña de Francia: 1 ex.; Puerto de Perales, 917 m, 40°14'46.2"N, 6°41'20.5"W, 22-XII-2011: 3 exx.; Serradilla del Llano, 13-X-1992: 2 exx.; Segovia: Balsaín (C. Bolívar leg.): 1 ex.; Balsaín (J. Abajo leg.): 1 ex.; Balsaín (J. Ardois leg.): 15 exx.; Collado Ventoso, 1964 m, 40°47'13.2"N, 4°02'32.8"W, 11-VIII-2013: 3 exx.; El Espinar: 1 exx.; Puerto de Los Cotos – Dos Hermanas, 40°49'27.1"N, 3°57'51.4"W, 19-XI-2012: 1 ex.; Puerto de Los Cotos – Dos Hermanas, 1900 m, 2-IX-1991: 2 exx.; Puerto de Navacerrada, 40°47'11"N, 4°01'05"W, 13-V-2012: 1 ex.; Puerto de Navacerrada, 40°47'17.83"N, 4°00'36.27"W, 30-V-2012: 1 ex.; Zamora: Santa Ana, 872 m, 41°42'17.66"N, 6°24'22.65"W, 25-IV-2012: 11 exx. – Extremadura: Cáceres: Alcuéscar, I-1894: 2 exx.; Carretera Villamiel – San Martín de Trevejo, 868 m, 40°11'43.8"N, 6°47'30.3"W, 23-XII-2011: 6 exx.; Casares de Las Hurdes: Puerto de Robledo, 1074 m, 40°27'07.06"N, 6°17'48.82"W, 17-IV-2012: 4 exx.; Hurdes: 1 exx.; Madrigal [de la Vera]: 1 exx.; Madrigal [de la Vera] (J. Ardois leg.): 21 exx.; Pico Villuercas, 1394 m, 39°28'19.72"N, 5°23'54.70"W, 12-V-2012: 7 exx. – Madrid: Dehesa de Braojos, 1400 m, 41°03'27.4"N, 3°38'51.1"W, 12-X-2013: 1 ex.; Cadalso [de los Vidrios] (J. Ardois leg.): 3 exx.; Cercedilla, 1460 m, VII-1945 (L. Esteban leg.): 1 ex.; Cercedilla, 1500 m, VIII-1935 (J. Hernández leg.): 4 exx.; Cercedilla, [Sierra de] Guadarrama (G. Schramm leg.): 11 exx.; Cercedilla, [Sierra de] Guadarrama (E. Zarco leg.): 2 exx.; Cercedilla (Lauffer leg.): 1 exx.; Cercedilla (Moróder leg.): 10 exx.; Cercedilla (Exp. del Museo): 20 exx.; Cercedilla (C. Bolívar leg.): 23 exx.; Cercedilla, 25-VII-1926: 1 ex.; Cercedilla (J. Ardois): 5 exx.; Cercedilla (Museo): 5 exx.; Cercedilla: 6 exx.; Cercedilla: El Ventorrillo, 1480 m: VIII-1960 (J. Abajo leg.): 2 exx.; Cercedilla: El Ventorrillo, 1478 m, 40°45'17.3"N, 4°01'21.6"W, 11-VI-2013: 11 exx.; Cercedilla: Estación Alpina, 1460 m (J. Abajo leg.): 1 ex.; Cercedilla: Estación Alpina, 1500 m: 2 exx.; Cercedilla: Estación Alpina, XII-1941 (E. Zarco leg.): 1 ex.; El Escorial (J. Dusmet leg.): 1 ex.; El Escorial (Misolampusscabricollis Graells): 1 ex. plus 1 without label; El Escorial, 10-V-1926: 3 exx.; El Escorial, 10-VI-1927: 2 exx.; El Escorial, 20-V-1925: 2 exx.; El Escorial, 22-V-1953 (W. Steiner leg.) (T-29) : 4 exx.; El Escorial (C. Bolívar leg.): 4 exx.; El Escorial: 4 exx.; El Escorial (Lauffer leg.): 5 exx.; El Escorial: Cuelgamuros, 1337 m, 40°38'53.8"N, 4°09'19.8"W, 10-VI-2013: 9 exx.; El Escorial: Puerto [de Malagón]: 1 ex.; El Paular (Exp. del Museo): 11 exx.; Garganta de Los Montes, 1346 m, 40°54'46.9"N, 3°40'05.5"W, 26-V-2013: 2 exx.; Lozoyuela, 1288 m, 40°55'31.4"N, 3°39'44.9"W, 26-V-2013: 5 exx.; Manzanares [El Real], 30-III-1928: 1 exx.; Manzanares El Real, 1156 m, 40°45'28.1"N, 3°54'56.0"W, 28-II-2012: 3 exx.; Pelayos de la Presa, 799 m, 40°20'19.40"N, 4°21'34.84"W, 3-III-2001: 1 ex.; Puerto de Cotos, 12-VIII-1925: 1 ex.; Puerto de La Hiruela, 1354 m, 41°03'42.5"N, 3°28'36.8"W, 6-IV-2011: 1 ex.; Puerto de La Puebla, 1633 m, 41°02'27.7"N, 3°28'48.9"W, 27-IV-2011: 3 exx.; Puerto de Navacerrada, 18-VIII-1923): 1 ex.; Puerto de Navacerrada (E. Zarco leg.): 2 exx.; San Lorenzo del Escorial, 40°35'58"N, 4°09'42"W, 14-III-2015 : 2 exx.; Santa María de la Alameda (estación), 1-IV-1991: 1 ex.; Santa María de la Alameda, 1437 m, 40°36'11.11"N, 4°15'18.93"W, 30-V-2012: 1 ex.; Sierra de Guadarrama (Lauffer leg.): 2 exx.; Tablada, 12-V-1957 (J. Álvarez leg.): 1 ex.; Valdemanco, 1090 m, 40°51'10.5"N, 3°38'48.5"W, 8-V-2013: 1 ex.Portugal – Guarda: 2 km al O de Vale de Estrela, 977 m, Total length 11–13 mm . PronotuM.scabricollis from Sierra Espuña , with an apparently isolated population in the western extreme of Sierra Morena  separated ca. 240 km from the eastern population of this same mountain system . Lithological materials of its area of occupancy are siliceous and very diverse, mainly granites, schists, gneisses, quartzites, and plutonic rocks , oaks  and chestnut trees (Castaneasativa), as well as substitution shrubs, mainly of Cistus, Cytisus, Ulex L. and Genista L.  are also frequently used by this species. Misolampusscabricollis can also be found in areas reforested with pines, and under stones, small pieces of wood, or inside tight clusters of branches, in shrub areas dominated by Cytisusscoparius, C.oromediterraneus, and less frequently by Cistusladanifer , northern Extremadura (Cáceres), Montes de Toledo (Toledo) and southern slopes of the Sistema Central  . It is often found in company of Coelometopusclypeatus in old chestnut trunks.do) Fig. , howeverTaxon classificationAnimaliaColeopteraTenebrionidaeRosenhauer, 18565BA4FFAA-A497-54A9-AFFD-0FED30083839Misolampussubglaber Rosenhauer, 1856: 204. Terra typica: “in der Sierra de Ronda”.38°00'23.6"N, 2°28'28.2"W, 10-IV-2011: 2 exx.; Valdeiglesias, 975 m, 36°56'49.3"N, 4°04'29.6"W, 24-X-2019: 3 exx.; Jaén: 3 km SO Aldeaquemada, 38°23'53.7"N, 3°24'00.5"W, 7-III-2012: 5 exx.; [3 km al SO de] Aldeaquemada, 26-IV-1992: 2 exx.; Cazorla: 7 exx.; Vadillo de Castril, Sierra de Cazorla, 995 m, 37°55'14"N, 2°55'50"W, 8-V-2008 (D. Ruiz leg.): 1 ex.; Santa Elena, carretera hacia La Aliseda, 768 m, 38°20'18.0"N, 3°32'56.8"W, 11-IV-2011: 3 exx.; Santa Elena, carretera hacia La Aliseda, 795 m, 38°20'53.1"N, 03°33'20.6"W, 28-XII-2010: 1 ex.; Santiago de la Espada (J. Martínez): 1 ex.; Segura [de la Sierra]: 1 ex.; Sierra Morena (Laguna leg.): 1 ex.; Málaga: 3 km al E de Jubrique, 786 m, 36°33'37.5"N, 5°10'40.9"W, 14-IV-2013: 6 exx.; Nerja: 1 ex.; El Colmenar, Gaucín, P.N. Los Alcornocales, 255 m, 36°32'29"N, 5°23'22"W, 17-II-2018 (S. Yubero leg.): 3 exx.; Carril Llanada de Sedella-Bco. de Valdeinfierno, Sierras de Tejeda y Almijara, 1495 m, 36°53'15"N, 3°56'40"W, 4-I-2017: 2 exx. – Castilla – La Mancha: Albacete: Agramón: 2 exx., plus 1 without label; Alcaraz: 3 exx.; Calar del Mundo, V-1904 (G. Schramm leg.): 1 ex.; Cañadillas, 15-VI-1938: 1 ex.; Cañadillas, 16-VI-1938: 1 ex.; Cañadillas, 17-VII-1938: 1 ex.; Los Collados, 20-II-1938: 1 ex.; Molinicos: 1 ex., plus 4 exx. without labels; Riópar, 25-VII-1926: 1 ex.; San Juan de Alcaraz [Fábricas de Riópar] (Paz leg.): 1 ex.; Ciudad Real: Solana del Pino: Puerto Madrona, 38°25'07.3"N, 4°03'33.1"W, 06-III-2012: 3 exx.; Cuenca: Puerto de Cabrejas, 1167 m, 40°04'17.9"N, 2°18'39.5"W, 10-XI-2012: 1 ex. – Murcia: Jumilla: 3 exx.Spain – Andalucía: Córdoba: Córdoba: 1 ex.; Granada: Güejar Sierra: 1 ex.; La Sagra : 4 exx.; Puebla de Don Fadrique : 5 exx.; Puebla de Don Fadrique: Nablanca, 1517 m, Total length 10–12 mm . SpeciesM.erichsoni, 2014b; Endemism of southeastern Spain  Fig. 1212. PubliM.subglaber is located in the Betic Mountain range , eastern and central Sierra Morena mountain range, and two apparently isolated populations in the Southern Iberian mountain range . There is a gap of records in the arid regions of the southeastern end of Spain, throughout the provinces of Almería and southern Murcia, including the eastern half of Sierra Nevada and Sierra de Filabres. The record from Cartagena, Murcia . According to these data, , Murcia , require, Murcia . The pot, Murcia .Misolampussubglaber behaves as a low-medium altitude montane element, distributed within an altitudinal range of 56 to 1662 m a.s.l. (with 61% of its records above 800 m). Geological substrates along its distribution area are diverse, both acid and basic, including mainly sandstones, limestones, dolomites, slates, gneisses, schists and mycaschists  and pines , all of them usually with diverse undergrowth   (Adult specimens of ea) Fig. , inside Q.pyrenaica, Q.canariensis, Q.faginea, Q.suber, Q.ilex and P.pinaster and Ibañez Orrico (2002) on rotten logs of P.halepensis . According to M.subglaber is a typical saproxylic species.M.subglaber  and from Ifni  . M.g.erichsoni should be included in the synonymy of M.goudotii, while North African  Morocco , M.eric Morocco   Fig.  at the Mllection . Antoinellection , 1954a, Characters initially used for separation of the North African taxa were: pronotal punctation, shape of the anterior margin of the pronotum, shape and sculpture of the propleurae, and width of the second interstria on the elytra . A closeMisolampus, and therefore we consider necessary to synonymise all three subspecies , retaining thus a single North African species: M.goudotii Guérin-Méneville, 1834. The morphological similarity between the Balearic specimens and the Eastern Moroccan and Algerian ones drove Morphological similarity between specimens located in geographically isolated areas, separated by hundreds of kilometres, reflects that the morphological diversity documented across populations, lies within the phenotypic variability of a single evolutionary entity, rather than being a consequence of ancient isolation processes . AlternaMisolampus from southern Portugal (Serra de Monchique). Specimens from that region often present not strongly marked elytral striae, and relatively smooth thoracic impressions  have smoother pronotal sculpture, and less marked, almost absent elytral striae , even with cases of microsympatric distribution. These levels of sympatry among ecologically similar, phylogenetically closely related taxa are not common because of demographic processes such as competitive exclusion  for all the Iberian species combined , suggests that further populations could be discovered with more intensive sampling, at least in the southern parts of the Sistema Ibérico. Similarly, our records of M.scabricollis from the provinces of Burgos and Guadalajara are relatively close to the Sistema Ibérico mountains, where the species could be present, but still undetected. Similar cases of long undetected presence of arthropod species in the Sistema Ibérico have been recently published , which could ensure to some extent the long-term persistence of these saproxylic beetles, if combined with the implementation of adequate agroforestry practices, consistent with the general strategies of saproxylic arthropods conservation from the Mediterranean forests ecosystems (However, our comparison of historical data with recent records to assess the current population trends of the species of osystems .Misolampus, disjunct distribution records such as Ifni for M.goudotii (Fig. M.subglaber (Fig. Considering the habitat specificity of tii Fig. , or Cuenber Fig. , can invber Fig. , but alsber Fig. . Distingber Fig. .


The results of this study confirm the possibility of the directional regulation of operational properties of epoxy composites by the use of small additives of hexagonal boron nitride (h-BN), providing the creation of epoxy composites with high performance properties. The effectiveness of h-BN surface modification by γ-aminopropyltriethoxysilane and the formation of strong chemical bonds at the polymer matrix/filler interface has been proved, which ensures an increase in physico-mechanical characteristics of epoxy composites: bending stress increases by 142% and bending modulus increases by 52%, strength increases by 53% and tensile elastic modulus increases by 37%, toughness increases by 400% and Brinell hardness increases by 96%, compared with an unfilled plasticized epoxy composite. The use of nanocomposites is determined by their unique properties, which are due to the huge specific surface and high surface energy of nanoparticles. Nanometer particles, unlike micro- and larger inclusions, are not stress concentrators, which contributes to a significant increase in the mechanical properties of nanocomposites7.Research in the field of polymer modification with functional additives is widely used to create polymer materials with a given set of consumer characteristics. So, to give polymer composite materials and products made from them enhanced functional characteristics, various modifying additives are used, for example, graphite, CNTs, TEG, graphene or metal oxides9.However, the addition of nanomaterials into epoxy compositions only slightly increases the strength of composites and in some cases even decreases it. This is due to small adhesion between nanomaterials and the polymer matrix and to the fact that it is often energetically more profitable for nanomaterials to agglomerate with each other. As a result, to improve adhesion interaction with the polymer matrix and to improve dispersion (reduce agglomeration) hardening nanomaterials are modified in various ways: by plasma treatment, by acid treatment, amines, etc.7. The addition of 0.1 mass % fluorinated CNTs improves physical and mechanical properties: 50% increase in strength and 74% increase in modulus of elasticity during tension, 60% increase in strength and 66% increase in modulus of elasticity during bending, and besides, abrasive wear decreases by 33%.A promising method of surface modification of nanomaterials is direct fluorination, i.e. the effect of fluorine gas mixtures at temperatures from room temperature to 400–500 °C. Fluorination also leads to improved solubility of nanomaterials in various solvents. The effect of CNTs modified by direct fluorination on the properties of epoxy composites was shown in6, aminopropyltrimethoxysilane was incorporated as an interfacial modifier on the surface of graphene (Gr) nanoplatelets. The addition of functionalized Gr enhanced the tensile strength and strain to failure only at low contents . Besides, this decreased the coefficient of friction and wear rate by approximately 40% and 68%, respectively. Enhanced tensile, compressive, and wear properties in the functionalized Gr–epoxy samples were observed compared to those in the Gr–epoxy samples.In this research16 proposed a technology for combining an epoxy oligomer with a nanoscale filler, which consists in joint grinding using microwave-assisted ball milling. Such modification ensures the chemical interaction of the epoxy oligomer with a titanium hydride, proved by IR spectroscopy, which could not be obtained by conventional grinding using a ball mill. The proposed technology leads to improved compatibility of TiH2 nanoparticles with the epoxy oligomer, their uniform distribution in the composition, which provides an increase in the physicomechanical characteristics of polymer composite materials.The authors17, zinc borate nanoparticles coated with a silicon oxide were obtained to create fire-resistant composites. It was found out that zinc borate nanoparticles modified with a silicon oxide are more uniformly distributed in the epoxy resin compared to the unmodified additive.In17.The incorporation of nanomodifiers into the epoxy composition leads to a change in its structure to a greater or lesser extent compared to the unfilled cured epoxy binder. Besides, the matrix affects the nature of the distribution of nanoparticles by volume, which is especially important in cases when it comes to the separation of the nanomodifier. The matrix determines the size and the shape of the resulting nanoparticles. Their interaction with epoxy resin forms interphase layers. Undoubtedly, all these factors affect the properties of epoxy nanocompositesThe various nanosystems will produce different effect in the same polymer matrix due to the diversity in reactivity, compatibility, and dispersion stability.Currently, there is still a lack of understanding on the suitability of functionalization of h-BN in the epoxy matrix with different composition. Issues related to the influence of aminofunctionalized h-BN on the structure formation processes, on the structure and operational characteristics of polymer composite materials are still not completely studied, which predetermines the goal of the study of the given work.The aim of this work is to increase physicochemical and mechanical properties of epoxy composites using nanodispersed particles of hexagonal boron nitride functionalized with aminosilane.-20 (GOST 10587-93), because it has low viscosity, a narrow limit of the epoxy groups content, stability of physico-chemical properties, epoxy equivalent—195–216 g/mol, epoxy groups content 20.0–22.5%, manufactured by CHIMEX Limited (Russia). As a hardener of an epoxy oligomer, an amine type hardener was used—polyethylene polyamine (PEPA) (TS 6-02-594-85) manufactured by CHIMEX Limited (Russia), capable of forming a three-dimensional network structure without heating, molecular mass—230–250 g/mol, amine number—1,250 mg KOH/g19.The compositions were developed on the basis of epoxy resin EDThe tri-2-chloroethyl ether of orthophosphoric acid (TCEP) with purity of 95–99% which is an orthophosphoric acid and ethylene chlorohydrin ester, manufactured by Xuancheng City Trooyawn Refined Chemical Industry Co., Ltd (China) was used to plasticize epoxy composites.18.The choice of TCEP is due to the presence of combustion inhibitors—phosphorus (10.8%) and chlorine (36.9%). During thermal decomposition of the composite, the presence of phosphorus provides an increase in the yield of carbonized structures, which are a physical barrier for the inter-diffusion of the oxidant and combustible gases to the combustion zone. Chlorine, being formed during the pyrolysis of the compositions, gets into the gas phase and dilutes the combustible gases, reducing the concentration limit of ignition, which, in general, reduces the flammability of epoxy composite20.Hexagonal boron nitride (h-BN) manufactured by Nanoamor, Inc. (USA) which resembles graphite in its structure was used as a nanostructural additive. The main difference between the crystal structure of h-BN and graphite is the position of planes with strong interatomic bonds relative to each other. If in graphite every second atomic layer is shifted relative to other layers by a constant value, then in h-BN the hexagons formed by three boron atoms and three nitrogen atoms are directly under each other. Moreover, each boron atom in one atomic layer has a nitrogen atom in the other layer as its nearest neighbor2O—APTES (95–5) solution with ultrasonic homogenizer for 10 min. The suspension was kept under reflux at 80 °C under constant low-speed stirring at 100 rpm for 12 h. The pH of the mixture was adjusted to 5. We selected an acidic media (CH3COOH) in order to increase the level of silanol formation and to decrease self-condensation reactions between the hydrolyzed silanol groups. To remove the remaining silane compound around the h-BN particles the resulting suspension was centrifuged and washed twice with H2O. Then, the product was dried (80 °C for 5 h) in the laboratory oven.To impart hydrophilicity to the surface of h-BN and to make possible its sizing, h-BN was annealed at 1,100 °C for 1 h. The surface of h-BN was functionalized with a γ-aminopropyltriethoxysilane (APTES) coupling agent, manufactured by the Penta-91 company (Russia). For this purpose, 0.5 g of h-BN was dispersed in 100 ml of the H22. In plasticized epoxy composition h-BN was added as a modifying agent (0.01–1.0 parts by weight). To increase the uniformity of distribution and hinder the aggregation of h-BN particles, as well as the activation of its surface and binder, ultrasonic treatment of the composition was used. The parameters of the ultrasound exposure: frequency—22 ± 2 kHz, power—400 W, duration—60 min23. The mixture was degassed at 25 ± 5 °C for 30 min under vacuum before curing.The ratio of epoxy oligomer, plasticizer and hardener was previously determined experimentally: 100 parts by mass of ED-20, 40 parts by mass of TCEP and 15 parts by mass of PEPA19.The preparation method of the composition: addition of TCEP to epoxy oligomer → mechanical stirring of the composition (ED-20 + TCEP) for 15 min → addition of h-BN to the epoxy composition (ED-20 + TCEP) → mechanical stirring of the composition for 15 min → further dispersion by sonication for 1 h  → addition of the curing agent PEPA to the mixture at 25 ± 5 °C → degasification to remove air bubbles at 25 ± 5 °C for 30 min under vacuum before curing → pouring into a mould and curing at 25 ± 5 °C for 24 h → heat treatment of the epoxy composite at 100 ± 5 °C for 2 h; 120 ± 5 °C for 2 h18; determination of the curing kinetics of the epoxy composition was carried out according to the method described in24; the specific surface area of the samples was determined by means of the Quantachrome Nova 2200 specific surface area and porosity analyzer using the initial portion of the isotherm of physical nitrogen sorption (99.999%). The studied samples were placed in a cell preliminarily calibrated with respect to internal volume at a temperature of liquid nitrogen (about 78 K), which was degassed in vacuum to a constant mass at a given temperature (150 °C) for 3 h. After that, the cell was installed in the device and the isotherm of nitrogen adsorption was measured in the pressure range 0.03–0.3 P/Po. The specific surface of the test sample was calculated by the BET method with the Quantachrome Nova 2200 software.The research was carried out using the following methods: determination of bending stress and flexural modulus [ISO 178: 2010]; determination of strength and modulus of tensile elasticity [ISO 527-2: 2012]; determination of compressive strength [ISO 604: 2002]; determination of impact strength [ISO 179-1: 2010]; determination of Brinell hardness [ISO 2039-1: 2001]; determination of heat resistance according to Vicat [ISO 306: 2004]; change in mass, rate of change in mass and magnitude of thermal effects during the heating of the samples was studied using the method of thermogravimetric analysis with the help of a derivator of the “Paulik—Paulik—Erdei” system of the MOM brand Q-1500D under the experimental conditions: weight—100 mg, medium—air, heating interval—up to 800 °C, heating rate—10 °C/min, relative error does not exceed 1%; the study of the surface morphology of the samples was carried out using a Tescan VEGA 3 SBH scanning electron microscope; determination of thermal conductivity and thermal resistance was carried out using the ITP-MG4 "100" instrument [ISO 22007-2: 2015]; FT-IR spectroscopy of TEG particles was carried out using the Shimadzu IRTracer-100; X-ray phase analysis was performed using ARL X’TRA X-ray diffractometerThe surface morphology of the dispersed h-BN powder was analyzed by scanning electron microscopy, Fig. The fractional composition of pristine h-BN is characterized by the unimodal distribution of particles and is represented by particles from 1 to 100 μm, with a predominant number of particles with sizes of 40 μm, Fig. 2/g.The specific surface area of h-BN particles, determined by using the specific surface area and porosity analyzer (Quantachrome Nova 2200) and the low-temperature nitrogen adsorption method, is 20.3 m22, consisting of 100 parts by weight of epoxy resin brand ED-20, 40 parts by weight of TCEP and 15 parts by weight of a PEPA hardener.As a polymer matrix we used a previously developed composition22. In addition, the presence of a chemical interaction of TCEP with an epoxy oligomer during curing was previously proved22.TCEP performs the functions of both a plasticizer and a flame retardant. In this case, bending stress increases by 32% and toughness is 2.6 times higher, the flammability index–oxygen index (CI) increases from 19 to 27% by volume, which ensures the transition of the material to the class of hardly flammableIn plasticized epoxy composition h-BN was added as a modifying agent (0.01–1.0 parts by weight).The conducted research has shown that the most rational content of h-BN as a structuring additive, providing maximum values of physical and mechanical properties is 0.05 parts by mass, Figs. To ensure the chemical interaction of the mineral filler with the polymer matrix and to increase physicomechanical characteristics of epoxy composites based on them, the h-BN surface was treated with the APTES sizing additive.To impart hydrophilicity to the surface of h-BN and to make possibie its sizing, h-BN was annealed at 1,100 °C for 1 h. In this case, the main goal of pretreatment of boron nitride powder is to create a sufficient amount of hydroxogroups on its surface, which, when further treated with a silane modifier, will lead to the deposition and fixing of the modifier molecule on the h-BN surface.−1 range, which is characteristic of the OH group. Besides, a broad line with a maximum of about 1,300–1,350 cm−1 also increases, which also indicates the formation of bonds B-OH.Hydroxyl surface group formation was verified using FT-IR spectroscopy, Fig. 3 phase, as well as some other lines of lower intensity characteristic of this phase20.The results of the X-ray phase analysis, Fig. Thus, on the base of all the data obtained, it can be concluded that annealing the initial h-BN powder at 1,100 °C for 1 h leads to the formation of a hydroxide phase, presumably on the fine faces of h-BN flakes, in the amount sufficient for the subsequent treatment. This is a simple and rather effective method of hydrophilization of the surface of hexagonal boron nitride.–1), which is involved in the formation of the APTES layer, disappears almost completely. After APTES treatment, the peak separation in the range of plane stretching vibrations of the B–N bond  can also be noted in the spectrum of the sample. The peak separation in this area may indicate an increase in the ordering of the h-BN structure as a result of the material surface treatment. One can also see a broad maximum of about 1,100 cm–1, which indicates the presence of Si–O bonds in the sample.The formation of strong bonds between h-BN and APTES was proved by IR Fourier spectroscopy, Fig. The chemical interaction of the APTES functional groupsand the epoxy oligomer was also proved by IR Fourier spectroscopy, Fig. −1) is observed, Fig. APTES contains an amine group that can interact with the epoxy ring of the resin when added into the composite. After mixing APTES and ED-20, in the absence of PEPA, a significant decrease in the intensity of the absorption peak corresponding to the epoxy ring , which is evident in a decrease in the wetting angle from 27° to 22°, their specific surface area increasing from 20.3 to 35.2 mThe organization of the chemical interaction at the h-BN/polymer matrix interface, by treating the h-BN APTES surface, results in an increase in the physicomechanical properties of epoxy composites: bending stress increases by 142% and bending modulus increases by 52%, strength increases by 53% and thetensile elastic modulus increases by 37%, impact strength increases by 400% and Brinell hardness increases by 96%, in comparison with plasticized epoxy composite that does not contain h-BN, Fig. 24.When assessing the effect of the modifying additive on network polymers, it is necessary to take into account that the curing process takes place in the presence of a developed surface of the solid material (h-BN), which can influence the kinetic characteristics of the polymerization reaction during curing, as well as the formation of the material phase structure. The role of the adsorption interaction of the components of the oligomeric composition with the solid surface of the h-BN is also great23.The study of the curing kinetics of epoxy compositions, Fig. Using the method of thermogravimetric analysis, it was stated that the addition of pristine h-BN and h-BN after APTES treatment does not reduce the heat resistance of epoxy composites based on them, while the Vicat heat resistance increases from 100 to 114–170 °C, Table 25.An important characteristic of materials used in electronic equipment is thermal conductivity. Unmodified epoxy composites have a low thermal conductivity (0.1 W/m K), therefore, when locally heated, they work as thermal insulation, which can lead to overheating and thermal decomposition of the compositeThe addition of even small additives of h-BN into the epoxy composition increases the thermal conductivity coefficient by 52–217%, while a decrease in thermal resistance is noted, Table As a result of the research, the possibility of the directional regulation of operational properties of epoxy composites using small h-BN additives which provide the creation of epoxy composites with high performance properties has been proved. The effectiveness of the surface modification of h-BN by γ-aminopropyltriethoxysilane and the formation of strong chemical bonds at the polymer matrix/filler interface have been proved, which ensured an increase in the physico-mechanical characteristics of epoxy composites.It has been confirmed that h-BN particles after APTES treatment are better wetted by the epoxy composition (ED-20 + TCEP).The study of the curing kinetics of epoxy compositions containing pristine h-BN and h-BN after APTES treatment show that they have a different effect on the structure formation of the epoxy composite.The introduction of even small h-BN additives into the epoxy composition increases the thermal conductivity coefficient by 52–217%, while a decrease in thermal resistance is noted.Thus, the developed materials can be used for sealing electronic products, for the impregnation and filling of units in aircraft, ship and automotive industries.